Esther Landhuis

Four years after new infant feeding guidelines were issued to prevent allergies to peanut and other foods, 70% of surveyed parents and caregivers in the United States said they had never heard about the new recommendation.

Food allergies in developed countries have doubled in each of the last decades and now affect 7.6% of U.S. children. About 1 in 50 are allergic to peanut. Data from the 2015 LEAP study and other research has convincingly shown that early, sustained feeding of peanuts, eggs, and other allergens can prevent babies from developing allergies to these foods.

Based on those findings, the National Institute of Allergy and Infectious Diseases (NIAID) updated its feeding guidelines in 2017, urging parents to introduce these foods to babies around 4-6 months of age rather than wait until 1-3 years of age, as previously recommended. The American Academy of Pediatrics approved those guidelines too, and in 2019 changed its own feeding recommendations.

To assess awareness of this new guidance and to what extent these recommendations are being translated into clinical practice, researchers surveyed a demographically representative U.S. sample of 3,062 parents and caregivers with children between 7 months and 3½ years old. The survey was conducted in English and Spanish over the web or by phone.

More than one-third reported that their child’s primary care physician never discussed when to start feeding peanut-containing foods. And among those whose doctors did offer guidance, fewer than 1 in 4 specifically recommended introducing peanut by 6 months of age.

These data show that “despite strong evidence that early introduction of peanut within the first year of life can prevent the development of peanut allergy, this evidence is simply not making its way to parents of infants,” said Christopher Warren, PhD, assistant professor of preventive medicine at the Northwestern University Feinberg School of Medicine, Chicago. Dr. Warren led the study and presented the findings on a poster at this year’s American College of Allergy, Asthma & Immunology annual meeting in New Orleans.

In addition to caregivers, the Northwestern team surveyed U.S. allergists and pediatricians about the new feeding guidelines. Uptake was fairly good among allergists, with 65% reporting full implementation. On the other hand, while most pediatricians seemed familiar with the 2017 recommendations, fewer than one-third said they were following them.

“What’s unique about this challenge is that it’s not just a guideline change – it’s a guideline reversal,” said Wendy Sue Swanson, MD, chief medical officer for SpoonfulONE, a company that makes mix-ins and other products for multi-allergen feeding. After telling families for years to avoid these allergens in early life because food allergies were rising, “it’s harder advice to say, actually, we were wrong. Not only should you not wait, you should get peanut in while your baby’s immune system has this critical moment to learn and develop, and you should keep getting it in,” Dr. Swanson said in an interview.

Making matters worse, pediatricians are time pressed. Typically, at 4- to 6-month-old well-check visits, “they’re talking about sleep and development and feeding and milestones,” said Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern Feinberg, who led the allergist and pediatrician analyses.

Another challenge: Guidelines differ depending on the child’s level of food allergy risk, so it’s hard to explain them clearly and quickly. Babies at highest risk – as judged by having severe eczema, egg allergy, or both – should get peanut IgE blood testing and, if negative, begin regular consumption of peanut by 4-6 months. Intermediate-risk babies who have mild-to-moderate eczema are recommended to start peanut-containing foods by 6 months. And for low-risk babies with no eczema or known food allergies, the guidance is simply to introduce peanut-containing foods “in accordance with family preferences and cultural practices.”

As for pediatricians who say it’s hard to distinguish mild-to-moderate from severe eczema, “any eczema puts you at some risk,” Dr. Gupta told this news organization. “If they’ve required steroid creams to clear up their skin, or if you look at their skin, and you think it’s severe, don’t hesitate. Go ahead and draw the IgE and send them to an allergist.”

Australia, which has the highest rate of confirmed food allergy, has had more success implementing early feeding guidelines, said Dr. Swanson. Unlike the United States’ tiered approach, she said, they “had a national guideline that very crisply, years ago, told parents what to do.” Australia also has nurse educators that follow up with new moms to make sure they understand and follow the recommendations.

Dr. Gupta receives research support from the National Institutes of Health, Food Allergy Research and Education, the Melchiorre Family Foundation, the Sunshine Charitable Foundation, the Walder Foundation, the UnitedHealth Group, Thermo Fisher Scientific, and Genentech. She serves as a medical consultant/advisor for Genentech, Novartis, and Food Allergy Research and Education. Dr. Swanson serves as chief medical officer for SpoonfulONE.

A version of this article first appeared on Medscape.com.

Four years after new infant feeding guidelines were issued to prevent allergies to peanut and other foods, 70% of surveyed parents and caregivers in the United States said they had never heard about the new recommendation.

Food allergies in developed countries have doubled in each of the last decades and now affect 7.6% of U.S. children. About 1 in 50 are allergic to peanut. Data from the 2015 LEAP study and other research has convincingly shown that early, sustained feeding of peanuts, eggs, and other allergens can prevent babies from developing allergies to these foods.

Based on those findings, the National Institute of Allergy and Infectious Diseases (NIAID) updated its feeding guidelines in 2017, urging parents to introduce these foods to babies around 4-6 months of age rather than wait until 1-3 years of age, as previously recommended. The American Academy of Pediatrics approved those guidelines too, and in 2019 changed its own feeding recommendations.

To assess awareness of this new guidance and to what extent these recommendations are being translated into clinical practice, researchers surveyed a demographically representative U.S. sample of 3,062 parents and caregivers with children between 7 months and 3½ years old. The survey was conducted in English and Spanish over the web or by phone.

More than one-third reported that their child’s primary care physician never discussed when to start feeding peanut-containing foods. And among those whose doctors did offer guidance, fewer than 1 in 4 specifically recommended introducing peanut by 6 months of age.

These data show that “despite strong evidence that early introduction of peanut within the first year of life can prevent the development of peanut allergy, this evidence is simply not making its way to parents of infants,” said Christopher Warren, PhD, assistant professor of preventive medicine at the Northwestern University Feinberg School of Medicine, Chicago. Dr. Warren led the study and presented the findings on a poster at this year’s American College of Allergy, Asthma & Immunology annual meeting in New Orleans.

In addition to caregivers, the Northwestern team surveyed U.S. allergists and pediatricians about the new feeding guidelines. Uptake was fairly good among allergists, with 65% reporting full implementation. On the other hand, while most pediatricians seemed familiar with the 2017 recommendations, fewer than one-third said they were following them.

“What’s unique about this challenge is that it’s not just a guideline change – it’s a guideline reversal,” said Wendy Sue Swanson, MD, chief medical officer for SpoonfulONE, a company that makes mix-ins and other products for multi-allergen feeding. After telling families for years to avoid these allergens in early life because food allergies were rising, “it’s harder advice to say, actually, we were wrong. Not only should you not wait, you should get peanut in while your baby’s immune system has this critical moment to learn and develop, and you should keep getting it in,” Dr. Swanson said in an interview.

Making matters worse, pediatricians are time pressed. Typically, at 4- to 6-month-old well-check visits, “they’re talking about sleep and development and feeding and milestones,” said Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern Feinberg, who led the allergist and pediatrician analyses.

Another challenge: Guidelines differ depending on the child’s level of food allergy risk, so it’s hard to explain them clearly and quickly. Babies at highest risk – as judged by having severe eczema, egg allergy, or both – should get peanut IgE blood testing and, if negative, begin regular consumption of peanut by 4-6 months. Intermediate-risk babies who have mild-to-moderate eczema are recommended to start peanut-containing foods by 6 months. And for low-risk babies with no eczema or known food allergies, the guidance is simply to introduce peanut-containing foods “in accordance with family preferences and cultural practices.”

As for pediatricians who say it’s hard to distinguish mild-to-moderate from severe eczema, “any eczema puts you at some risk,” Dr. Gupta told this news organization. “If they’ve required steroid creams to clear up their skin, or if you look at their skin, and you think it’s severe, don’t hesitate. Go ahead and draw the IgE and send them to an allergist.”

Australia, which has the highest rate of confirmed food allergy, has had more success implementing early feeding guidelines, said Dr. Swanson. Unlike the United States’ tiered approach, she said, they “had a national guideline that very crisply, years ago, told parents what to do.” Australia also has nurse educators that follow up with new moms to make sure they understand and follow the recommendations.

Dr. Gupta receives research support from the National Institutes of Health, Food Allergy Research and Education, the Melchiorre Family Foundation, the Sunshine Charitable Foundation, the Walder Foundation, the UnitedHealth Group, Thermo Fisher Scientific, and Genentech. She serves as a medical consultant/advisor for Genentech, Novartis, and Food Allergy Research and Education. Dr. Swanson serves as chief medical officer for SpoonfulONE.

A version of this article first appeared on Medscape.com.

Four years after new infant feeding guidelines were issued to prevent allergies to peanut and other foods, 70% of surveyed parents and caregivers in the United States said they had never heard about the new recommendation.

Food allergies in developed countries have doubled in each of the last decades and now affect 7.6% of U.S. children. About 1 in 50 are allergic to peanut. Data from the 2015 LEAP study and other research has convincingly shown that early, sustained feeding of peanuts, eggs, and other allergens can prevent babies from developing allergies to these foods.

Based on those findings, the National Institute of Allergy and Infectious Diseases (NIAID) updated its feeding guidelines in 2017, urging parents to introduce these foods to babies around 4-6 months of age rather than wait until 1-3 years of age, as previously recommended. The American Academy of Pediatrics approved those guidelines too, and in 2019 changed its own feeding recommendations.

To assess awareness of this new guidance and to what extent these recommendations are being translated into clinical practice, researchers surveyed a demographically representative U.S. sample of 3,062 parents and caregivers with children between 7 months and 3½ years old. The survey was conducted in English and Spanish over the web or by phone.

More than one-third reported that their child’s primary care physician never discussed when to start feeding peanut-containing foods. And among those whose doctors did offer guidance, fewer than 1 in 4 specifically recommended introducing peanut by 6 months of age.

These data show that “despite strong evidence that early introduction of peanut within the first year of life can prevent the development of peanut allergy, this evidence is simply not making its way to parents of infants,” said Christopher Warren, PhD, assistant professor of preventive medicine at the Northwestern University Feinberg School of Medicine, Chicago. Dr. Warren led the study and presented the findings on a poster at this year’s American College of Allergy, Asthma & Immunology annual meeting in New Orleans.

In addition to caregivers, the Northwestern team surveyed U.S. allergists and pediatricians about the new feeding guidelines. Uptake was fairly good among allergists, with 65% reporting full implementation. On the other hand, while most pediatricians seemed familiar with the 2017 recommendations, fewer than one-third said they were following them.

“What’s unique about this challenge is that it’s not just a guideline change – it’s a guideline reversal,” said Wendy Sue Swanson, MD, chief medical officer for SpoonfulONE, a company that makes mix-ins and other products for multi-allergen feeding. After telling families for years to avoid these allergens in early life because food allergies were rising, “it’s harder advice to say, actually, we were wrong. Not only should you not wait, you should get peanut in while your baby’s immune system has this critical moment to learn and develop, and you should keep getting it in,” Dr. Swanson said in an interview.

Making matters worse, pediatricians are time pressed. Typically, at 4- to 6-month-old well-check visits, “they’re talking about sleep and development and feeding and milestones,” said Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern Feinberg, who led the allergist and pediatrician analyses.

Another challenge: Guidelines differ depending on the child’s level of food allergy risk, so it’s hard to explain them clearly and quickly. Babies at highest risk – as judged by having severe eczema, egg allergy, or both – should get peanut IgE blood testing and, if negative, begin regular consumption of peanut by 4-6 months. Intermediate-risk babies who have mild-to-moderate eczema are recommended to start peanut-containing foods by 6 months. And for low-risk babies with no eczema or known food allergies, the guidance is simply to introduce peanut-containing foods “in accordance with family preferences and cultural practices.”

As for pediatricians who say it’s hard to distinguish mild-to-moderate from severe eczema, “any eczema puts you at some risk,” Dr. Gupta told this news organization. “If they’ve required steroid creams to clear up their skin, or if you look at their skin, and you think it’s severe, don’t hesitate. Go ahead and draw the IgE and send them to an allergist.”

Australia, which has the highest rate of confirmed food allergy, has had more success implementing early feeding guidelines, said Dr. Swanson. Unlike the United States’ tiered approach, she said, they “had a national guideline that very crisply, years ago, told parents what to do.” Australia also has nurse educators that follow up with new moms to make sure they understand and follow the recommendations.

Dr. Gupta receives research support from the National Institutes of Health, Food Allergy Research and Education, the Melchiorre Family Foundation, the Sunshine Charitable Foundation, the Walder Foundation, the UnitedHealth Group, Thermo Fisher Scientific, and Genentech. She serves as a medical consultant/advisor for Genentech, Novartis, and Food Allergy Research and Education. Dr. Swanson serves as chief medical officer for SpoonfulONE.

A version of this article first appeared on Medscape.com.

The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.

HconQ/ThinkStock

Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.

“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.

The findings were published online Oct. 27 in The Lancet Global Health.
 

Alternative mechanisms

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.

Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.

Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.

Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.

For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.

Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.

In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
 

Additional analysis requested

As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).

Among these three quarters of patients who took at least 80% of their doses, benefits were better.

Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.

Based on accumulating data, Dr. Reiersen said, some experts are recommending fluvoxamine for COVID-19 patients at high risk for morbidity and mortality from complications of the infection.

However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.

Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.

Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.

To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
 

‘A $10 medicine’

Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”

By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.

Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.

In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.

ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.

Unanswered safety, efficacy questions

In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.

However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.

The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.

“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.

In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.

Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.

“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.

Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.

HconQ/ThinkStock

Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.

“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.

The findings were published online Oct. 27 in The Lancet Global Health.
 

Alternative mechanisms

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.

Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.

Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.

Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.

For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.

Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.

In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
 

Additional analysis requested

As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).

Among these three quarters of patients who took at least 80% of their doses, benefits were better.

Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.

Based on accumulating data, Dr. Reiersen said, some experts are recommending fluvoxamine for COVID-19 patients at high risk for morbidity and mortality from complications of the infection.

However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.

Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.

Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.

To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
 

‘A $10 medicine’

Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”

By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.

Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.

In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.

ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.

Unanswered safety, efficacy questions

In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.

However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.

The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.

“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.

In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.

Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.

“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.

Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

The antidepressant fluvoxamine (Luvox) may prevent hospitalization and death in outpatients with COVID-19, new research suggests.

HconQ/ThinkStock

Results from the placebo-controlled, multisite, phase 3 TOGETHER trial showed that in COVID-19 outpatients at high risk for complications, hospitalizations were cut by 66% and deaths were reduced by 91% in those who tolerated fluvoxamine.

“Our trial has found that fluvoxamine, an inexpensive existing drug, reduces the need for advanced disease care in this high-risk population,” wrote the investigators, led by Gilmar Reis, MD, PhD, research division, Cardresearch, Belo Horizonte, Brazil.

The findings were published online Oct. 27 in The Lancet Global Health.
 

Alternative mechanisms

Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is an antidepressant commonly prescribed for obsessive-compulsive disorder.

Besides its known effects on serotonin, the drug acts in other molecular pathways to dampen the production of inflammatory cytokines. Those alternative mechanisms are the ones believed to help patients with COVID-19, said coinvestigator Angela Reiersen, MD, child psychiatrist at Washington University, St. Louis.

Based on cell culture and mouse studies showing effects of the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, Dr. Reiersen came up with the idea of testing if fluvoxamine could keep COVID-19 from progressing in newly infected patients.

Dr. Reiersen and psychiatrist Eric Lenze, MD, also from Washington University, led the phase 2 trial that initially suggested fluvoxamine’s promise as an outpatient medication. They are coinvestigators on the new phase 3 adaptive platform trial called TOGETHER, which was conducted by an international team of investigators in Brazil, Canada, and the United States.

For this latest study, researchers at McMaster University, Hamilton, Ont., partnered with the research clinic Cardresearch in Brazil to recruit unvaccinated, high-risk adults within 7 days of developing flu-like symptoms from COVID-19. They analyzed 1,497 newly symptomatic COVID-19 patients at 11 clinical sites in Brazil.

Patients entered the trial between January and August 2021 and were assigned to receive 100 mg fluvoxamine or placebo pills twice a day for 10 days. Investigators monitored participants through 28 days post treatment, noting whether complications developed requiring hospitalization or more than 6 hours of emergency care.

In the placebo group, 119 of 756 patients (15.7%) worsened to this extent. In comparison, 79 of 741 (10.7%) fluvoxamine-treated patients met these primary criteria. This represented a 32% reduction in hospitalizations and emergency visits.
 

Additional analysis requested

As Lancet Global Health reviewed these findings from the submitted manuscript, journal reviewers requested an additional “pre-protocol analysis” that was not specified in the trial’s original protocol. The request was to examine the subgroup of patients with good adherence (74% of treated group, 82% of placebo group).

Among these three quarters of patients who took at least 80% of their doses, benefits were better.

Fluvoxamine cut serious complications in this group by 66% and reduced mortality by 91%. In the placebo group, 12 people died compared with one who received the study drug.

Based on accumulating data, Dr. Reiersen said, some experts are recommending fluvoxamine for COVID-19 patients at high risk for morbidity and mortality from complications of the infection.

However, clinicians should note that the drug can cause side effects such as nausea, dizziness, and insomnia, she added. In addition, because it prevents the body from metabolizing caffeine, patients should limit their daily intake to half of a small cup of coffee or one can of soda or one tea while taking the drug.

Previous research has shown that fluvoxamine affects the metabolism of some drugs, such as theophylline, clozapine, olanzapine, and tizanidine.

Despite huge challenges with studying generic drugs as early COVID-19 treatment, the TOGETHER trial shows it is possible to produce quality evidence during a pandemic on a shoestring budget, noted co-principal investigator Edward Mills, PhD, professor in the department of health research methods, evidence, and impact at McMaster University.

To screen more than 12,000 patients and enroll 4,000 to test nine interventions, “our total budget was less than $8 million,” Dr. Mills said. The trial was funded by Fast Grants and the Rainwater Charitable Foundation.
 

‘A $10 medicine’

Commenting on the findings, David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota in Minneapolis, noted fluvoxamine is “a $10 medicine that’s available and has a very good safety record.”

By comparison, a 5-day course of Merck’s antiviral molnupiravir, another oral drug that the company says can cut hospitalizations in COVID-19 outpatients, costs $700. However, the data have not been peer reviewed – and molnupiravir is not currently available and has unknown long-term safety implications, Dr. Boulware said.

Pharmaceutical companies typically spend tens of thousands of dollars on a trial evaluating a single drug, he noted.

In addition, the National Institutes of Health’s ACTIV-6 study, a nationwide trial on the effect of fluvoxamine and other repurposed generic drugs on thousands of COVID-19 outpatients, is a $110 million effort, according to Dr. Boulware, who cochairs its steering committee.

ACTIV-6 is currently enrolling outpatients with COVID-19 to test a lower dose of fluvoxamine, at 50 mg twice daily instead of the 100-mg dose used in the TOGETHER trial, as well as ivermectin and inhaled fluticasone. The COVID-OUT trial is also recruiting newly diagnosed COVID-19 patients to test various combinations of fluvoxamine, ivermectin, and the diabetes drug metformin.

Unanswered safety, efficacy questions

In an accompanying editorial in The Lancet Global Health, Otavio Berwanger, MD, cardiologist and clinical trialist, Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil, commends the investigators for rapidly generating evidence during the COVID-19 pandemic.

However, despite the important findings, “some questions related to efficacy and safety of fluvoxamine for patients with COVID-19 remain open,” Dr. Berwanger wrote.

The effects of the drug on reducing both mortality and hospitalizations also “still need addressing,” he noted.

“In addition, it remains to be established whether fluvoxamine has an additive effect to other therapies such as monoclonal antibodies and budesonide, and what is the optimal fluvoxamine therapeutic scheme,” wrote Dr. Berwanger.

In an interview, he noted that 74% of the Brazil population have currently received at least one dose of a COVID-19 vaccine and 52% have received two doses. In addition, deaths have gone down from 4,000 per day during the March-April second wave to about 400 per day. “That is still unfortunate and far from ideal,” he said. In total, they have had about 600,000 deaths because of COVID-19.

Asked whether public health authorities are now recommending fluvoxamine as an early treatment for COVID-19 based on the TOGETHER trial data, Dr. Berwanger answered, “Not yet.

“I believe medical and scientific societies will need to critically appraise the manuscript in order to inform their decisions and recommendations. This interesting trial adds another important piece of information in this regard,” he said.

Dr. Reiersen and Dr. Lenze are inventors on a patent application related to methods for treating COVID-19, which was filed by Washington University. Dr. Mills reports no relevant financial relationships, as does Dr. Boulware – except that the TOGETHER trial funders are also funding the University of Minnesota COVID-OUT trial. Dr. Berwanger reports having received research grants outside of the submitted work that were paid to his institution by AstraZeneca, Bayer, Amgen, Servier, Novartis, Pfizer, and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

A handful of studies have suggested that for newly infected COVID-19 patients, risk for serious illness may be reduced with a short course of fluvoxamine (Luvox), a decades-old pill typically prescribed for depression or obsessive-compulsive disorder (OCD). But those were small studies involving just a few hundred people.

This week, researchers reported promising data from a large, randomized phase 3 trial that enrolled COVID-19 patients from 11 sites in Brazil. In this study, in which 1,472 people were assigned to receive either a 10-day course of fluvoxamine or placebo pills, the antidepressant cut emergency department and hospital admissions by 29%.

Findings from the new study, which have not yet been peer reviewed, were published August 23 in MedRxiv.

Around the globe, particularly in countries without access to vaccines, “treatment options that are cheap and available and supported by good-quality evidence are the only hope we’ve got to reduce mortality within high-risk populations,” said Edward Mills, PhD, professor in the department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont.

The new findings came from TOGETHER, a large platform trial coordinated by Dr. Mills and colleagues to evaluate the use of fluvoxamine and other repurposed drug candidates for symptomatic, high-risk, adult outpatients with confirmed cases of COVID-19.

The trial’s adaptive format allows multiple agents to be added and tested alongside placebo in a single master protocol – similar to the United Kingdom’s Recovery trial, which found that the common steroid dexamethasone could reduce deaths among hospitalized COVID-19 patients.

In platform trials, treatment arms can be dropped for futility, as was the case with hydroxychloroquine and lopinavir-ritonavir, neither of which did better than placebo at preventing hospitalization in an earlier TOGETHER trial analysis.
 

Study details

In the newly reported analysis, patients were randomly assigned to receive fluvoxamine or placebo between January and August 2021. Participants took fluvoxamine 100 mg twice daily for 10 days. By comparison, the U.S. Food and Drug Administration recommends a maximum daily dose of 300 mg of fluvoxamine for patients with OCD; full psychiatric benefits occur after 6 weeks.

For the primary outcome, the investigators assessed whether the conditions of patients with COVID worsened over a 28-day period so as to require either hospitalization or observation in the emergency department for more than 6 hours. In the placebo group, 108 of 733 patients’ conditions deteriorated to this extent (14.7%); by contrast, only 77 of 739 patients in the fluvoxamine group (10.4%) met these primary criteria – a relative risk reduction of 29%.

The treatment effect was greater (34%) in the per protocol analysis of participants who completed their course of pills.

The investigators also collected data on vital signs, including temperature and oxygen saturation, as well as adverse events reported at clinic visits or through video conferencing, phone calls, or social media applications. Side effects were mild, most commonly nausea and fatigue, and did not differ significantly between active treatment and control groups, Dr. Mills said in an interview.

Amid scores of studies evaluating repurposed drugs for COVID-19, the data on fluvoxamine are “looking much more favorable than anyone could have guessed – at least anyone in infectious disease,” said Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

The new TOGETHER trial results augment supportive data published in JAMA last November from a phase 2 randomized trial that was small but “very well done,” Dr. Sax told this news organization.

Those results got a boost from a subsequent study of 65 racetrack workers who chose to take fluvoxamine during a COVID-19 outbreak in the San Francisco Bay area. Forty-eight persons opted against taking the drug. In this small, nonrandomized study, “the people who chose to be treated with fluvoxamine were sicker [at baseline] than the people who didn’t go on it, and yet the [treated group] ended up better,” said Dr. Sax, who discussed accumulating data on the use of fluvoxamine for COVID-19 in a recent New England Journal of Medicine blog post.
 

Anti-inflammatory effect?

After reviewing the new findings, Frank Domino, MD, professor of family medicine and community health at the University of Massachusetts, Worcester, said he would encourage patients with high-risk COVID-19 to consider taking fluvoxamine to lower their risk of being hospitalized. “But I would make it clear this was not a ‘cure,’ “ he said, “and we are unsure how it helps.”

At this point, U.S. treatment guidelines do not recommend fluvoxamine as the standard of care for nonhospitalized COVID-19 patients, but the National Institutes of Health is “very aware of the data,” Dr. Sax told this news organization.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) – a class of drugs that includes the more commonly prescribed antidepressant fluoxetine (Prozac). If prescribed off-label to COVID-19 patients, fluvoxamine should not be used within 2 weeks of starting treatment with other SSRI or monoamine oxidase inhibitor antidepressants and should be used with caution with other QT-interval prolonging medications, Dr. Sax said.

In addition, fluvoxamine can enhance the effect of antiplatelet and anticoagulant drugs, potentially triggering bleeding.

On the basis of in vitro and mouse studies of fluvoxamine, “we think it has an anti-inflammatory effect,” said child psychiatrist Angela Reiersen, MD, of Washington University, St. Louis, who came up with the idea for testing fluvoxamine in last year’s phase 2 trial and coauthored a recent article describing the drug’s potential mechanisms of action in COVID-19.

She and other researchers believe fluvoxamine’s anti-inflammatory effects derive from the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, which regulates cellular responses to stress and infection.

Fluvoxamine also inhibits the activation of platelets. “In COVID-19, there does seem to be a problem with hyperactivation of platelets and excessive blood clots forming, so it is possible this could be another mechanism where it might be helping,” Dr. Reiersen said.

If sigma-1 activation turns out to be the main mechanism underlying fluvoxamine’s benefits in COVID-19, other sigma-1 agonists, such as fluoxetine, may also help. In a retrospective analysis of thousands of adults hospitalized for COVID-19 in France early in the pandemic, those who were taking antidepressants had a 44% lower risk for intubation or death.

And in a study under review, researchers at Stanford (Calif.) University and the University of California, San Francisco, analyzed electronic health records to explore a potential link between fluoxetine use and COVID outcomes among more than 80,000 patients from over 80 institutions across the United States. Other research suggests that antipsychotics could also have protective effects for patients with COVID-19.
 

Long COVID, long-term challenges

On the basis of its potential mechanisms of action, fluvoxamine may be able to prevent or treat long COVID, Dr. Reiersen said. That possibility will be assessed among other secondary endpoints in two ongoing studies of repurposed drugs: the NIH’s ACTIV-6, and the University of Minnesota’s COVID-OUT, an at-home trial of ivermectin, metformin, and fluvoxamine.

Dr. Reiersen and Washington University colleagues are also analyzing longer-term outcomes of participants in their own phase 3 trial of fluvoxamine (Stop COVID 2), which was discontinued when enrollment slowed to a trickle during the U.S. vaccine rollout. Logistical hurdles and scant funding have greatly hampered efforts to test the use of off-patent drugs for COVID-19 outpatients during the pandemic.

U.S. efforts face other obstacles as well. Elsewhere in the world – including Brazil, where the TOGETHER trial was run – vaccines are scarce, and there are no monoclonal antibodies.

“People have a great sense of community duty, and they’re participating in the trials,” Dr. Mills said. “You’re in a much more political environment in the U.S. on these outpatient trials.”

The TOGETHER trial was funded by Fast Grants and the Rainwater Foundation. Dr. Reiersen is an inventor on a patent application related to methods of treating COVID-19, which was filed by Washington University, St. Louis. Dr. Mills, Dr. Domino, and Dr. Sax report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A handful of studies have suggested that for newly infected COVID-19 patients, risk for serious illness may be reduced with a short course of fluvoxamine (Luvox), a decades-old pill typically prescribed for depression or obsessive-compulsive disorder (OCD). But those were small studies involving just a few hundred people.

This week, researchers reported promising data from a large, randomized phase 3 trial that enrolled COVID-19 patients from 11 sites in Brazil. In this study, in which 1,472 people were assigned to receive either a 10-day course of fluvoxamine or placebo pills, the antidepressant cut emergency department and hospital admissions by 29%.

Findings from the new study, which have not yet been peer reviewed, were published August 23 in MedRxiv.

Around the globe, particularly in countries without access to vaccines, “treatment options that are cheap and available and supported by good-quality evidence are the only hope we’ve got to reduce mortality within high-risk populations,” said Edward Mills, PhD, professor in the department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont.

The new findings came from TOGETHER, a large platform trial coordinated by Dr. Mills and colleagues to evaluate the use of fluvoxamine and other repurposed drug candidates for symptomatic, high-risk, adult outpatients with confirmed cases of COVID-19.

The trial’s adaptive format allows multiple agents to be added and tested alongside placebo in a single master protocol – similar to the United Kingdom’s Recovery trial, which found that the common steroid dexamethasone could reduce deaths among hospitalized COVID-19 patients.

In platform trials, treatment arms can be dropped for futility, as was the case with hydroxychloroquine and lopinavir-ritonavir, neither of which did better than placebo at preventing hospitalization in an earlier TOGETHER trial analysis.
 

Study details

In the newly reported analysis, patients were randomly assigned to receive fluvoxamine or placebo between January and August 2021. Participants took fluvoxamine 100 mg twice daily for 10 days. By comparison, the U.S. Food and Drug Administration recommends a maximum daily dose of 300 mg of fluvoxamine for patients with OCD; full psychiatric benefits occur after 6 weeks.

For the primary outcome, the investigators assessed whether the conditions of patients with COVID worsened over a 28-day period so as to require either hospitalization or observation in the emergency department for more than 6 hours. In the placebo group, 108 of 733 patients’ conditions deteriorated to this extent (14.7%); by contrast, only 77 of 739 patients in the fluvoxamine group (10.4%) met these primary criteria – a relative risk reduction of 29%.

The treatment effect was greater (34%) in the per protocol analysis of participants who completed their course of pills.

The investigators also collected data on vital signs, including temperature and oxygen saturation, as well as adverse events reported at clinic visits or through video conferencing, phone calls, or social media applications. Side effects were mild, most commonly nausea and fatigue, and did not differ significantly between active treatment and control groups, Dr. Mills said in an interview.

Amid scores of studies evaluating repurposed drugs for COVID-19, the data on fluvoxamine are “looking much more favorable than anyone could have guessed – at least anyone in infectious disease,” said Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

The new TOGETHER trial results augment supportive data published in JAMA last November from a phase 2 randomized trial that was small but “very well done,” Dr. Sax told this news organization.

Those results got a boost from a subsequent study of 65 racetrack workers who chose to take fluvoxamine during a COVID-19 outbreak in the San Francisco Bay area. Forty-eight persons opted against taking the drug. In this small, nonrandomized study, “the people who chose to be treated with fluvoxamine were sicker [at baseline] than the people who didn’t go on it, and yet the [treated group] ended up better,” said Dr. Sax, who discussed accumulating data on the use of fluvoxamine for COVID-19 in a recent New England Journal of Medicine blog post.
 

Anti-inflammatory effect?

After reviewing the new findings, Frank Domino, MD, professor of family medicine and community health at the University of Massachusetts, Worcester, said he would encourage patients with high-risk COVID-19 to consider taking fluvoxamine to lower their risk of being hospitalized. “But I would make it clear this was not a ‘cure,’ “ he said, “and we are unsure how it helps.”

At this point, U.S. treatment guidelines do not recommend fluvoxamine as the standard of care for nonhospitalized COVID-19 patients, but the National Institutes of Health is “very aware of the data,” Dr. Sax told this news organization.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) – a class of drugs that includes the more commonly prescribed antidepressant fluoxetine (Prozac). If prescribed off-label to COVID-19 patients, fluvoxamine should not be used within 2 weeks of starting treatment with other SSRI or monoamine oxidase inhibitor antidepressants and should be used with caution with other QT-interval prolonging medications, Dr. Sax said.

In addition, fluvoxamine can enhance the effect of antiplatelet and anticoagulant drugs, potentially triggering bleeding.

On the basis of in vitro and mouse studies of fluvoxamine, “we think it has an anti-inflammatory effect,” said child psychiatrist Angela Reiersen, MD, of Washington University, St. Louis, who came up with the idea for testing fluvoxamine in last year’s phase 2 trial and coauthored a recent article describing the drug’s potential mechanisms of action in COVID-19.

She and other researchers believe fluvoxamine’s anti-inflammatory effects derive from the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, which regulates cellular responses to stress and infection.

Fluvoxamine also inhibits the activation of platelets. “In COVID-19, there does seem to be a problem with hyperactivation of platelets and excessive blood clots forming, so it is possible this could be another mechanism where it might be helping,” Dr. Reiersen said.

If sigma-1 activation turns out to be the main mechanism underlying fluvoxamine’s benefits in COVID-19, other sigma-1 agonists, such as fluoxetine, may also help. In a retrospective analysis of thousands of adults hospitalized for COVID-19 in France early in the pandemic, those who were taking antidepressants had a 44% lower risk for intubation or death.

And in a study under review, researchers at Stanford (Calif.) University and the University of California, San Francisco, analyzed electronic health records to explore a potential link between fluoxetine use and COVID outcomes among more than 80,000 patients from over 80 institutions across the United States. Other research suggests that antipsychotics could also have protective effects for patients with COVID-19.
 

Long COVID, long-term challenges

On the basis of its potential mechanisms of action, fluvoxamine may be able to prevent or treat long COVID, Dr. Reiersen said. That possibility will be assessed among other secondary endpoints in two ongoing studies of repurposed drugs: the NIH’s ACTIV-6, and the University of Minnesota’s COVID-OUT, an at-home trial of ivermectin, metformin, and fluvoxamine.

Dr. Reiersen and Washington University colleagues are also analyzing longer-term outcomes of participants in their own phase 3 trial of fluvoxamine (Stop COVID 2), which was discontinued when enrollment slowed to a trickle during the U.S. vaccine rollout. Logistical hurdles and scant funding have greatly hampered efforts to test the use of off-patent drugs for COVID-19 outpatients during the pandemic.

U.S. efforts face other obstacles as well. Elsewhere in the world – including Brazil, where the TOGETHER trial was run – vaccines are scarce, and there are no monoclonal antibodies.

“People have a great sense of community duty, and they’re participating in the trials,” Dr. Mills said. “You’re in a much more political environment in the U.S. on these outpatient trials.”

The TOGETHER trial was funded by Fast Grants and the Rainwater Foundation. Dr. Reiersen is an inventor on a patent application related to methods of treating COVID-19, which was filed by Washington University, St. Louis. Dr. Mills, Dr. Domino, and Dr. Sax report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A handful of studies have suggested that for newly infected COVID-19 patients, risk for serious illness may be reduced with a short course of fluvoxamine (Luvox), a decades-old pill typically prescribed for depression or obsessive-compulsive disorder (OCD). But those were small studies involving just a few hundred people.

This week, researchers reported promising data from a large, randomized phase 3 trial that enrolled COVID-19 patients from 11 sites in Brazil. In this study, in which 1,472 people were assigned to receive either a 10-day course of fluvoxamine or placebo pills, the antidepressant cut emergency department and hospital admissions by 29%.

Findings from the new study, which have not yet been peer reviewed, were published August 23 in MedRxiv.

Around the globe, particularly in countries without access to vaccines, “treatment options that are cheap and available and supported by good-quality evidence are the only hope we’ve got to reduce mortality within high-risk populations,” said Edward Mills, PhD, professor in the department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont.

The new findings came from TOGETHER, a large platform trial coordinated by Dr. Mills and colleagues to evaluate the use of fluvoxamine and other repurposed drug candidates for symptomatic, high-risk, adult outpatients with confirmed cases of COVID-19.

The trial’s adaptive format allows multiple agents to be added and tested alongside placebo in a single master protocol – similar to the United Kingdom’s Recovery trial, which found that the common steroid dexamethasone could reduce deaths among hospitalized COVID-19 patients.

In platform trials, treatment arms can be dropped for futility, as was the case with hydroxychloroquine and lopinavir-ritonavir, neither of which did better than placebo at preventing hospitalization in an earlier TOGETHER trial analysis.
 

Study details

In the newly reported analysis, patients were randomly assigned to receive fluvoxamine or placebo between January and August 2021. Participants took fluvoxamine 100 mg twice daily for 10 days. By comparison, the U.S. Food and Drug Administration recommends a maximum daily dose of 300 mg of fluvoxamine for patients with OCD; full psychiatric benefits occur after 6 weeks.

For the primary outcome, the investigators assessed whether the conditions of patients with COVID worsened over a 28-day period so as to require either hospitalization or observation in the emergency department for more than 6 hours. In the placebo group, 108 of 733 patients’ conditions deteriorated to this extent (14.7%); by contrast, only 77 of 739 patients in the fluvoxamine group (10.4%) met these primary criteria – a relative risk reduction of 29%.

The treatment effect was greater (34%) in the per protocol analysis of participants who completed their course of pills.

The investigators also collected data on vital signs, including temperature and oxygen saturation, as well as adverse events reported at clinic visits or through video conferencing, phone calls, or social media applications. Side effects were mild, most commonly nausea and fatigue, and did not differ significantly between active treatment and control groups, Dr. Mills said in an interview.

Amid scores of studies evaluating repurposed drugs for COVID-19, the data on fluvoxamine are “looking much more favorable than anyone could have guessed – at least anyone in infectious disease,” said Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

The new TOGETHER trial results augment supportive data published in JAMA last November from a phase 2 randomized trial that was small but “very well done,” Dr. Sax told this news organization.

Those results got a boost from a subsequent study of 65 racetrack workers who chose to take fluvoxamine during a COVID-19 outbreak in the San Francisco Bay area. Forty-eight persons opted against taking the drug. In this small, nonrandomized study, “the people who chose to be treated with fluvoxamine were sicker [at baseline] than the people who didn’t go on it, and yet the [treated group] ended up better,” said Dr. Sax, who discussed accumulating data on the use of fluvoxamine for COVID-19 in a recent New England Journal of Medicine blog post.
 

Anti-inflammatory effect?

After reviewing the new findings, Frank Domino, MD, professor of family medicine and community health at the University of Massachusetts, Worcester, said he would encourage patients with high-risk COVID-19 to consider taking fluvoxamine to lower their risk of being hospitalized. “But I would make it clear this was not a ‘cure,’ “ he said, “and we are unsure how it helps.”

At this point, U.S. treatment guidelines do not recommend fluvoxamine as the standard of care for nonhospitalized COVID-19 patients, but the National Institutes of Health is “very aware of the data,” Dr. Sax told this news organization.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) – a class of drugs that includes the more commonly prescribed antidepressant fluoxetine (Prozac). If prescribed off-label to COVID-19 patients, fluvoxamine should not be used within 2 weeks of starting treatment with other SSRI or monoamine oxidase inhibitor antidepressants and should be used with caution with other QT-interval prolonging medications, Dr. Sax said.

In addition, fluvoxamine can enhance the effect of antiplatelet and anticoagulant drugs, potentially triggering bleeding.

On the basis of in vitro and mouse studies of fluvoxamine, “we think it has an anti-inflammatory effect,” said child psychiatrist Angela Reiersen, MD, of Washington University, St. Louis, who came up with the idea for testing fluvoxamine in last year’s phase 2 trial and coauthored a recent article describing the drug’s potential mechanisms of action in COVID-19.

She and other researchers believe fluvoxamine’s anti-inflammatory effects derive from the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, which regulates cellular responses to stress and infection.

Fluvoxamine also inhibits the activation of platelets. “In COVID-19, there does seem to be a problem with hyperactivation of platelets and excessive blood clots forming, so it is possible this could be another mechanism where it might be helping,” Dr. Reiersen said.

If sigma-1 activation turns out to be the main mechanism underlying fluvoxamine’s benefits in COVID-19, other sigma-1 agonists, such as fluoxetine, may also help. In a retrospective analysis of thousands of adults hospitalized for COVID-19 in France early in the pandemic, those who were taking antidepressants had a 44% lower risk for intubation or death.

And in a study under review, researchers at Stanford (Calif.) University and the University of California, San Francisco, analyzed electronic health records to explore a potential link between fluoxetine use and COVID outcomes among more than 80,000 patients from over 80 institutions across the United States. Other research suggests that antipsychotics could also have protective effects for patients with COVID-19.
 

Long COVID, long-term challenges

On the basis of its potential mechanisms of action, fluvoxamine may be able to prevent or treat long COVID, Dr. Reiersen said. That possibility will be assessed among other secondary endpoints in two ongoing studies of repurposed drugs: the NIH’s ACTIV-6, and the University of Minnesota’s COVID-OUT, an at-home trial of ivermectin, metformin, and fluvoxamine.

Dr. Reiersen and Washington University colleagues are also analyzing longer-term outcomes of participants in their own phase 3 trial of fluvoxamine (Stop COVID 2), which was discontinued when enrollment slowed to a trickle during the U.S. vaccine rollout. Logistical hurdles and scant funding have greatly hampered efforts to test the use of off-patent drugs for COVID-19 outpatients during the pandemic.

U.S. efforts face other obstacles as well. Elsewhere in the world – including Brazil, where the TOGETHER trial was run – vaccines are scarce, and there are no monoclonal antibodies.

“People have a great sense of community duty, and they’re participating in the trials,” Dr. Mills said. “You’re in a much more political environment in the U.S. on these outpatient trials.”

The TOGETHER trial was funded by Fast Grants and the Rainwater Foundation. Dr. Reiersen is an inventor on a patent application related to methods of treating COVID-19, which was filed by Washington University, St. Louis. Dr. Mills, Dr. Domino, and Dr. Sax report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network; Food Allergy Research and Education, and the Wallace Research Foundation. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network; Food Allergy Research and Education, and the Wallace Research Foundation. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network; Food Allergy Research and Education, and the Wallace Research Foundation. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Sublingual immunotherapy (SLIT) emerged over a century ago as a gentler alternative to allergy shots. It uses the same antigens found in allergy shots, delivering them through tablets or drops under the tongue rather than by injecting them into the skin.

Yet injection immunotherapy has been the mainstay of allergy treatment in the United States. Allergy shots are “the bread and butter, keeping the lights on at allergy practices,” said allergist Sakina Bajowala, MD, of Kaneland Allergy and Asthma Center, in the Chicago area. So even “when environmental SLIT showed quite clearly that it had efficacy, people were so slow to adapt.”

SLIT – a daily treatment that builds protection from allergens gradually over years with few side effects – is popular around the globe, particularly for environmental allergies. But only a handful of clinics offer food SLIT. Even though recent trials in peanut-allergic children show that SLIT is far safer than oral immunotherapy and about as effective as the Food and Drug Administration–approved peanut-allergy product and has lasting benefits for toddlers, many allergists lack experience with customized immunotherapies and hesitate to offer an unregulated treatment for which the evidence base is still emerging.
 

Why hasn’t food allergy SLIT caught on?

One issue is that there is scant evidence from randomized, controlled trials. The treatments that clinics offer often hinge on insurance coverage, and increasingly, insurers only cover FDA-approved products. FDA approval requires thousands of patients being enrolled in long, expensive studies to prove the treatment’s merit. In a similar vein, doctors are trained to question methods that lack a strong publication base, for good reason.

Yet SLIT caught the attention of pioneering physicians who were intrigued by this “low-and-slow” immune-modifying approach, despite limited published evidence, and they sought real-world experience.

The late physician David Morris, MD, came across SLIT in the 1960s while searching for alternative ways to help mold-allergic farmers who were suffering terrible side effects from allergy shots. Dr. Morris attended conferences, learned more about sublingual techniques, got board certified in allergy, and opened Allergy Associates of La Crosse (Wis.), in 1970 to offer SLIT as a treatment for food and environmental allergies.

Dr. Morris and colleagues developed a protocol to create custom SLIT drops tailored to individual patients’ clinical histories and allergy test results. The method has been used to treat more than 200,000 patients. It has been used by allergist Nikhila Schroeder, MD, MEng, who learned SLIT methods while treating nearly 1,000 patients at Allergy Associates. In 2018, she opened her own direct-care SLIT practice, Allergenuity Health, in the Charlotte metropolitan area of North Carolina (see part 2 of this series).

Dr. Bajowala’s clinic offers SLIT in addition to oral immunotherapy (OIT). She was encouraged by the recent toddler SLIT data but wondered whether it would translate to a real-world setting. According to her calculations, the published protocol – according to which participants receive up to 4 mg/d over 6 months and continue receiving a daily maintenance dose of 4 mg for 3 years – would cost $10,000 per patient.

With this dosing regimen, the intervention is unaffordable, Dr. Bajowala said. And “there’s no way to make it cheaper because that’s the raw materials cost. It does not include labor or bottles or profit at all. That’s just $10,000 in peanut extract.”

Owing to cost, Dr. Bajowala’s clinic generally uses SLIT as a bridge to OIT. Her food allergy patients receive up to 1 mg/d and remain at that dose for a month or so before transitioning to OIT, “for which the supplies are orders of magnitude cheaper,” she said.

Dr. Schroeder said there is evidence for efficacy at microgram and even nanogram dosing – much lower than used in the recent food SLIT trials. Maintenance doses range from 50 ng/d to 25 mcg/d for environmental SLIT and 4-37 mcg/d for food SLIT, she said. The La Crosse method uses even lower dose ranges.

However, dosing information is not readily available, Dr. Schroeder noted. She has spent years scrutinizing articles and compiling information from allergen extract suppliers – all the while treating hundreds of SLIT patients. “I have had to expend a lot of time and effort,” said Dr. Schroeder. “It’s really hard to explain quickly.”

In the published literature, SLIT dosing recommendations vary widely. According to a 2007 analysis, environmental allergy symptoms improved with doses over a 1,000-fold range. What’s more, success did not scale with increased dosing and seemed to depend more on frequency and duration of treatment.

There are fewer studies regarding food SLIT. The most promising data come from recent trials of peanut-allergic children led by Edwin Kim, MD, director of the UNC Food Allergy Initiative, University of North Carolina at Chapel Hill. Still, “I am nervous to tell people to go do this based on 150 kids at one site,” Dr. Kim said. “We need to have a gigantic study across multiple sites that actually confirms what we have found in our single center.”

Because there are few published trials of food SLIT, confusion about which doses are optimal, how early to start, and how long the benefits last will be a barrier for many clinicians, said Douglas Mack, MD, FRCPC, assistant clinical professor in pediatrics at McMaster University, Hamilton, Ont.

Much could be learned from Allergy Associates of La Crosse, Allergenuity Health, and other clinics with SLIT experience involving thousands of patients. But that real-world data are messy and difficult to publish. Plus, it is hard for private allergists to find time to review charts, analyze data, and draft papers alongside seeing patients and running a clinic – especially without students and interns, who typically assist with academic research, Dr. Schroeder said.

Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern University, Chicago, and colleagues worked with a La Crosse team 6 or 7 years ago to try to analyze and publish SLIT outcomes for 121 peanut-allergic children who were treated for food and environmental allergies at the Wisconsin clinic. The researchers had hoped to publish an article describing caregiver-reported and clinical outcomes.

Among 73 caregivers who responded to a survey, more than half reported improved eczema, asthma, and environmental allergy symptoms, and virtually all families said SLIT calmed anxieties and minimized fear of allergic reactions. However, the clinical outcomes – skinprick test results, immune changes, and oral food challenges – were not as robust. And the data were incomplete. Some patients had traveled to La Crosse for SLIT drops but underwent skin and blood testing with their local allergist. Compiling records is “so much harder when you’re not doing a prospective clinical trial,” Dr. Gupta said.

The caregiver-reported outcomes were presented as a poster at the 2015 annual meeting of the American College of Allergy, Asthma, and Immunology and the 2016 annual meeting of the Pediatric Academic Society, said Jeff Kessler, MBA, FACHE, who is practice executive at La Crosse. However, with only self-reported data and no convincing lab metrics, the findings were never submitted for publication.

Others are eager to see clearer proof that SLIT works at doses lower than those published in the most recent trials. “If we can get efficacy with lower doses, that means we can increase accessibility, because we can lower the cost,” Dr. Bajowala said.

Robert Wood, MD, professor of pediatrics and director of pediatric allergy and immunology at Johns Hopkins University, Baltimore, has a pending grant proposal for a multifood trial of SLIT. “It’s a big missing piece,” he said.

Dr. Mack said that in Canada there was “almost an instant change in group think” when the Canadian Society of Allergy and Clinical Immunology published guidelines in support of OIT. With the new guidelines, “people are less concerned about liability. Once they start getting into OIT, I think you’re going to see SLIT coming right along for the ride.”

The shift will be slower in the United States, which has 20 times as many practicing allergists as Canada. Nevertheless, “I totally think SLIT has a place at the table,” Dr. Mack said. “I hope we start to see more high-quality data and people start to use it and experiment with it a bit and see how it works.”

A version of this article first appeared on Medscape.com. This is part three of a three-part series. Part one is here. Part two is here.

Sublingual immunotherapy (SLIT) emerged over a century ago as a gentler alternative to allergy shots. It uses the same antigens found in allergy shots, delivering them through tablets or drops under the tongue rather than by injecting them into the skin.

Yet injection immunotherapy has been the mainstay of allergy treatment in the United States. Allergy shots are “the bread and butter, keeping the lights on at allergy practices,” said allergist Sakina Bajowala, MD, of Kaneland Allergy and Asthma Center, in the Chicago area. So even “when environmental SLIT showed quite clearly that it had efficacy, people were so slow to adapt.”

SLIT – a daily treatment that builds protection from allergens gradually over years with few side effects – is popular around the globe, particularly for environmental allergies. But only a handful of clinics offer food SLIT. Even though recent trials in peanut-allergic children show that SLIT is far safer than oral immunotherapy and about as effective as the Food and Drug Administration–approved peanut-allergy product and has lasting benefits for toddlers, many allergists lack experience with customized immunotherapies and hesitate to offer an unregulated treatment for which the evidence base is still emerging.
 

Why hasn’t food allergy SLIT caught on?

One issue is that there is scant evidence from randomized, controlled trials. The treatments that clinics offer often hinge on insurance coverage, and increasingly, insurers only cover FDA-approved products. FDA approval requires thousands of patients being enrolled in long, expensive studies to prove the treatment’s merit. In a similar vein, doctors are trained to question methods that lack a strong publication base, for good reason.

Yet SLIT caught the attention of pioneering physicians who were intrigued by this “low-and-slow” immune-modifying approach, despite limited published evidence, and they sought real-world experience.

The late physician David Morris, MD, came across SLIT in the 1960s while searching for alternative ways to help mold-allergic farmers who were suffering terrible side effects from allergy shots. Dr. Morris attended conferences, learned more about sublingual techniques, got board certified in allergy, and opened Allergy Associates of La Crosse (Wis.), in 1970 to offer SLIT as a treatment for food and environmental allergies.

Dr. Morris and colleagues developed a protocol to create custom SLIT drops tailored to individual patients’ clinical histories and allergy test results. The method has been used to treat more than 200,000 patients. It has been used by allergist Nikhila Schroeder, MD, MEng, who learned SLIT methods while treating nearly 1,000 patients at Allergy Associates. In 2018, she opened her own direct-care SLIT practice, Allergenuity Health, in the Charlotte metropolitan area of North Carolina (see part 2 of this series).

Dr. Bajowala’s clinic offers SLIT in addition to oral immunotherapy (OIT). She was encouraged by the recent toddler SLIT data but wondered whether it would translate to a real-world setting. According to her calculations, the published protocol – according to which participants receive up to 4 mg/d over 6 months and continue receiving a daily maintenance dose of 4 mg for 3 years – would cost $10,000 per patient.

With this dosing regimen, the intervention is unaffordable, Dr. Bajowala said. And “there’s no way to make it cheaper because that’s the raw materials cost. It does not include labor or bottles or profit at all. That’s just $10,000 in peanut extract.”

Owing to cost, Dr. Bajowala’s clinic generally uses SLIT as a bridge to OIT. Her food allergy patients receive up to 1 mg/d and remain at that dose for a month or so before transitioning to OIT, “for which the supplies are orders of magnitude cheaper,” she said.

Dr. Schroeder said there is evidence for efficacy at microgram and even nanogram dosing – much lower than used in the recent food SLIT trials. Maintenance doses range from 50 ng/d to 25 mcg/d for environmental SLIT and 4-37 mcg/d for food SLIT, she said. The La Crosse method uses even lower dose ranges.

However, dosing information is not readily available, Dr. Schroeder noted. She has spent years scrutinizing articles and compiling information from allergen extract suppliers – all the while treating hundreds of SLIT patients. “I have had to expend a lot of time and effort,” said Dr. Schroeder. “It’s really hard to explain quickly.”

In the published literature, SLIT dosing recommendations vary widely. According to a 2007 analysis, environmental allergy symptoms improved with doses over a 1,000-fold range. What’s more, success did not scale with increased dosing and seemed to depend more on frequency and duration of treatment.

There are fewer studies regarding food SLIT. The most promising data come from recent trials of peanut-allergic children led by Edwin Kim, MD, director of the UNC Food Allergy Initiative, University of North Carolina at Chapel Hill. Still, “I am nervous to tell people to go do this based on 150 kids at one site,” Dr. Kim said. “We need to have a gigantic study across multiple sites that actually confirms what we have found in our single center.”

Because there are few published trials of food SLIT, confusion about which doses are optimal, how early to start, and how long the benefits last will be a barrier for many clinicians, said Douglas Mack, MD, FRCPC, assistant clinical professor in pediatrics at McMaster University, Hamilton, Ont.

Much could be learned from Allergy Associates of La Crosse, Allergenuity Health, and other clinics with SLIT experience involving thousands of patients. But that real-world data are messy and difficult to publish. Plus, it is hard for private allergists to find time to review charts, analyze data, and draft papers alongside seeing patients and running a clinic – especially without students and interns, who typically assist with academic research, Dr. Schroeder said.

Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern University, Chicago, and colleagues worked with a La Crosse team 6 or 7 years ago to try to analyze and publish SLIT outcomes for 121 peanut-allergic children who were treated for food and environmental allergies at the Wisconsin clinic. The researchers had hoped to publish an article describing caregiver-reported and clinical outcomes.

Among 73 caregivers who responded to a survey, more than half reported improved eczema, asthma, and environmental allergy symptoms, and virtually all families said SLIT calmed anxieties and minimized fear of allergic reactions. However, the clinical outcomes – skinprick test results, immune changes, and oral food challenges – were not as robust. And the data were incomplete. Some patients had traveled to La Crosse for SLIT drops but underwent skin and blood testing with their local allergist. Compiling records is “so much harder when you’re not doing a prospective clinical trial,” Dr. Gupta said.

The caregiver-reported outcomes were presented as a poster at the 2015 annual meeting of the American College of Allergy, Asthma, and Immunology and the 2016 annual meeting of the Pediatric Academic Society, said Jeff Kessler, MBA, FACHE, who is practice executive at La Crosse. However, with only self-reported data and no convincing lab metrics, the findings were never submitted for publication.

Others are eager to see clearer proof that SLIT works at doses lower than those published in the most recent trials. “If we can get efficacy with lower doses, that means we can increase accessibility, because we can lower the cost,” Dr. Bajowala said.

Robert Wood, MD, professor of pediatrics and director of pediatric allergy and immunology at Johns Hopkins University, Baltimore, has a pending grant proposal for a multifood trial of SLIT. “It’s a big missing piece,” he said.

Dr. Mack said that in Canada there was “almost an instant change in group think” when the Canadian Society of Allergy and Clinical Immunology published guidelines in support of OIT. With the new guidelines, “people are less concerned about liability. Once they start getting into OIT, I think you’re going to see SLIT coming right along for the ride.”

The shift will be slower in the United States, which has 20 times as many practicing allergists as Canada. Nevertheless, “I totally think SLIT has a place at the table,” Dr. Mack said. “I hope we start to see more high-quality data and people start to use it and experiment with it a bit and see how it works.”

A version of this article first appeared on Medscape.com. This is part three of a three-part series. Part one is here. Part two is here.

Sublingual immunotherapy (SLIT) emerged over a century ago as a gentler alternative to allergy shots. It uses the same antigens found in allergy shots, delivering them through tablets or drops under the tongue rather than by injecting them into the skin.

Yet injection immunotherapy has been the mainstay of allergy treatment in the United States. Allergy shots are “the bread and butter, keeping the lights on at allergy practices,” said allergist Sakina Bajowala, MD, of Kaneland Allergy and Asthma Center, in the Chicago area. So even “when environmental SLIT showed quite clearly that it had efficacy, people were so slow to adapt.”

SLIT – a daily treatment that builds protection from allergens gradually over years with few side effects – is popular around the globe, particularly for environmental allergies. But only a handful of clinics offer food SLIT. Even though recent trials in peanut-allergic children show that SLIT is far safer than oral immunotherapy and about as effective as the Food and Drug Administration–approved peanut-allergy product and has lasting benefits for toddlers, many allergists lack experience with customized immunotherapies and hesitate to offer an unregulated treatment for which the evidence base is still emerging.
 

Why hasn’t food allergy SLIT caught on?

One issue is that there is scant evidence from randomized, controlled trials. The treatments that clinics offer often hinge on insurance coverage, and increasingly, insurers only cover FDA-approved products. FDA approval requires thousands of patients being enrolled in long, expensive studies to prove the treatment’s merit. In a similar vein, doctors are trained to question methods that lack a strong publication base, for good reason.

Yet SLIT caught the attention of pioneering physicians who were intrigued by this “low-and-slow” immune-modifying approach, despite limited published evidence, and they sought real-world experience.

The late physician David Morris, MD, came across SLIT in the 1960s while searching for alternative ways to help mold-allergic farmers who were suffering terrible side effects from allergy shots. Dr. Morris attended conferences, learned more about sublingual techniques, got board certified in allergy, and opened Allergy Associates of La Crosse (Wis.), in 1970 to offer SLIT as a treatment for food and environmental allergies.

Dr. Morris and colleagues developed a protocol to create custom SLIT drops tailored to individual patients’ clinical histories and allergy test results. The method has been used to treat more than 200,000 patients. It has been used by allergist Nikhila Schroeder, MD, MEng, who learned SLIT methods while treating nearly 1,000 patients at Allergy Associates. In 2018, she opened her own direct-care SLIT practice, Allergenuity Health, in the Charlotte metropolitan area of North Carolina (see part 2 of this series).

Dr. Bajowala’s clinic offers SLIT in addition to oral immunotherapy (OIT). She was encouraged by the recent toddler SLIT data but wondered whether it would translate to a real-world setting. According to her calculations, the published protocol – according to which participants receive up to 4 mg/d over 6 months and continue receiving a daily maintenance dose of 4 mg for 3 years – would cost $10,000 per patient.

With this dosing regimen, the intervention is unaffordable, Dr. Bajowala said. And “there’s no way to make it cheaper because that’s the raw materials cost. It does not include labor or bottles or profit at all. That’s just $10,000 in peanut extract.”

Owing to cost, Dr. Bajowala’s clinic generally uses SLIT as a bridge to OIT. Her food allergy patients receive up to 1 mg/d and remain at that dose for a month or so before transitioning to OIT, “for which the supplies are orders of magnitude cheaper,” she said.

Dr. Schroeder said there is evidence for efficacy at microgram and even nanogram dosing – much lower than used in the recent food SLIT trials. Maintenance doses range from 50 ng/d to 25 mcg/d for environmental SLIT and 4-37 mcg/d for food SLIT, she said. The La Crosse method uses even lower dose ranges.

However, dosing information is not readily available, Dr. Schroeder noted. She has spent years scrutinizing articles and compiling information from allergen extract suppliers – all the while treating hundreds of SLIT patients. “I have had to expend a lot of time and effort,” said Dr. Schroeder. “It’s really hard to explain quickly.”

In the published literature, SLIT dosing recommendations vary widely. According to a 2007 analysis, environmental allergy symptoms improved with doses over a 1,000-fold range. What’s more, success did not scale with increased dosing and seemed to depend more on frequency and duration of treatment.

There are fewer studies regarding food SLIT. The most promising data come from recent trials of peanut-allergic children led by Edwin Kim, MD, director of the UNC Food Allergy Initiative, University of North Carolina at Chapel Hill. Still, “I am nervous to tell people to go do this based on 150 kids at one site,” Dr. Kim said. “We need to have a gigantic study across multiple sites that actually confirms what we have found in our single center.”

Because there are few published trials of food SLIT, confusion about which doses are optimal, how early to start, and how long the benefits last will be a barrier for many clinicians, said Douglas Mack, MD, FRCPC, assistant clinical professor in pediatrics at McMaster University, Hamilton, Ont.

Much could be learned from Allergy Associates of La Crosse, Allergenuity Health, and other clinics with SLIT experience involving thousands of patients. But that real-world data are messy and difficult to publish. Plus, it is hard for private allergists to find time to review charts, analyze data, and draft papers alongside seeing patients and running a clinic – especially without students and interns, who typically assist with academic research, Dr. Schroeder said.

Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern University, Chicago, and colleagues worked with a La Crosse team 6 or 7 years ago to try to analyze and publish SLIT outcomes for 121 peanut-allergic children who were treated for food and environmental allergies at the Wisconsin clinic. The researchers had hoped to publish an article describing caregiver-reported and clinical outcomes.

Among 73 caregivers who responded to a survey, more than half reported improved eczema, asthma, and environmental allergy symptoms, and virtually all families said SLIT calmed anxieties and minimized fear of allergic reactions. However, the clinical outcomes – skinprick test results, immune changes, and oral food challenges – were not as robust. And the data were incomplete. Some patients had traveled to La Crosse for SLIT drops but underwent skin and blood testing with their local allergist. Compiling records is “so much harder when you’re not doing a prospective clinical trial,” Dr. Gupta said.

The caregiver-reported outcomes were presented as a poster at the 2015 annual meeting of the American College of Allergy, Asthma, and Immunology and the 2016 annual meeting of the Pediatric Academic Society, said Jeff Kessler, MBA, FACHE, who is practice executive at La Crosse. However, with only self-reported data and no convincing lab metrics, the findings were never submitted for publication.

Others are eager to see clearer proof that SLIT works at doses lower than those published in the most recent trials. “If we can get efficacy with lower doses, that means we can increase accessibility, because we can lower the cost,” Dr. Bajowala said.

Robert Wood, MD, professor of pediatrics and director of pediatric allergy and immunology at Johns Hopkins University, Baltimore, has a pending grant proposal for a multifood trial of SLIT. “It’s a big missing piece,” he said.

Dr. Mack said that in Canada there was “almost an instant change in group think” when the Canadian Society of Allergy and Clinical Immunology published guidelines in support of OIT. With the new guidelines, “people are less concerned about liability. Once they start getting into OIT, I think you’re going to see SLIT coming right along for the ride.”

The shift will be slower in the United States, which has 20 times as many practicing allergists as Canada. Nevertheless, “I totally think SLIT has a place at the table,” Dr. Mack said. “I hope we start to see more high-quality data and people start to use it and experiment with it a bit and see how it works.”

A version of this article first appeared on Medscape.com. This is part three of a three-part series. Part one is here. Part two is here.

With degrees in electrical engineering and computer science from the Massachusetts Institute of Technology, Nikhila Schroeder, MD, MEng, brings a problem-solving mindset to medicine.

Being a doctor means having to “figure out all aspects of [a patient’s] situation and do my best to come up with an answer,” said Dr. Schroeder, who founded Allergenuity Health, a solo allergy practice in Huntersville, N.C., with her husband James, who serves as practice executive. It’s “being a medical detective for your patient.”

Yet, during her training, Dr. Schroeder found that market-driven health care makes it hard to practice medicine with a patient’s best interest foremost. Procedures for diagnosing and treating disease cater to insurance companies’ reimbursement policies. “You wind up having to tailor your care to whatever insurance will cover,” she said.

Insurers, in turn, look for evidence from large, peer-reviewed studies to prove that a treatment works. Many physicians hesitate to offer therapies that aren’t covered by insurance, for both liability and financial reasons. So treatment tends to be limited to those options that were rigorously vetted in long, costly, multisite trials that are difficult to conduct without a corporate sponsor.

This is why there is still only one licensed treatment for people with food allergies – a set of standardized peanut powder capsules (Palforzia) that was approved by the Food and Drug Administration in early 2020 for peanut-allergic children aged 4-17 years. A small but growing number of allergists offer unapproved oral immunotherapy (OIT) using commercial food products to treat allergies to peanuts and other foods.

Even fewer allergists treat food allergy patients with another immune-modifying treatment, sublingual immunotherapy (SLIT), which delivers allergens through liquid drops held for several minutes under the tongue. Since 2018, Allergenuity Health, which offers SLIT to treat food and environmental allergies, has provided care to more than 400 patients. More than a third have come from out of state.

The clinic uses a direct-care approach. Rather than taking insurance, the clinic offers a monthly billing program that includes tests, SLIT bottles, and access to Dr. Schroeder via phone, email, or text. “I’m only contracted with the patient, and my only focus is the patient,” Dr. Schroeder said in an interview.
 

Unforgettable day

Allergy was not on Dr. Schroeder’s radar in medical school. She wanted to be a surgeon. But she loved working with children, so she did a pediatrics residency at the University of Virginia Children’s Hospital in Charlottesville. There Dr. Schroeder started seeing kids with eczema and allergies. While covering a friend’s clinic shift in 2010, she was thrust into an emergency. A family who didn’t speak English had just brought in their screaming 6-month-old baby, red and puffy with hives. “We didn’t know what was going on with this child,” Dr. Schroeder said. “Somehow I was elected to go in there.”

All of a sudden, things got quiet. Yet the baby was still screaming, mouth wide open. Dr. Schroeder had learned about anaphylaxis but had never witnessed it – until that day. The baby›s airways swelled so much that the crying became hoarse and soft. After working with a nurse to administer epinephrine, Dr. Schroeder saw something equally unforgettable: The baby’s heart rate soared, but within minutes the hives and swelling subsided and smiles returned. “It was incredible how quickly things changed,” Dr. Schroeder said. The baby had a reaction to rice, an uncommon allergen.

Dr. Schroeder stayed at UVA 2 more years to complete an allergy and immunology fellowship. She learned to diagnose food allergies but became frustrated having to tell patients they had little recourse but to avoid the food and to check in every year or 2. “I was, like, aren’t we specialists? Shouldn’t we have a little more expertise and maybe see if there are ways we could change this?” Dr. Schroeder said.

During those years, allergy shots were the only form of immunotherapy being taught to fellows. At clinic, Dr. Schroeder served as backup to the nurses when someone reacted to shots. She was troubled that some patients needed epinephrine to stop asthma attacks caused by injections they had received as treatment. The idea of injecting substances under the skin seemed akin to vaccination – where “you want to aggravate the immune system, you want it to get revved up, you want to build it up to fight,” she said. “But that’s not what you want for allergy. You want to tone it down. It didn’t really, to be honest, make a lot of sense to me.”

Dr. Schroeder started digging and asking questions. How does the immune system decide what is safe? Which cells and molecules communicate these decisions? She thought about babies and how they “learn” by putting stuff into their mouths. “If we don’t tolerate most of what we take in there, we wouldn’t survive,” Dr. Schroeder said. “It makes a lot of sense that a lot of tolerance begins with cells of the mouth.”

Dr. Schroeder discussed these concepts with her attendings. “They were all, like, no, there’s really no good evidence for that,” she said. But at some point, someone mentioned sublingual immunotherapy, and Schroeder came across Allergy Associates of La Crosse (Wis.).

The clinic’s late founder, David Morris, MD, learned about SLIT in the 1960s as an alternative option for farmers who suffered terrible side effects from injection immunotherapy they received to treat their mold allergies. Dr. Morris attended conferences, learned more about sublingual techniques – at times seeking advice from European allergists who offered SLIT – and became board certified in allergy before opening the La Crosse clinic in 1970. According to the clinic, more than 200,000 patients with environmental and food allergies have been treated with its SLIT protocol.

Dr. Schroeder was shocked to discover that this clinic had existed for 40 years, yet “I, as an allergist, had heard nothing about them,” she said.

Toward the end of her fellowship, OIT was becoming more well known. But she felt its risks were often downplayed. After years of talking with food allergy patients, Schroeder realized that most didn’t actually care about eating peanut butter sandwiches or sesame or walnuts. “Often I would hear, through tears: ‘I just want my child to be able to sit with their friends at lunch, to not be put at this other table, to not feel so isolated,’ ” she said. What mattered most to many families was gaining enough protection to not feel anxious about participating in social activities involving food.

Dr. Schroeder had a growing sense that SLIT – given its ease, safety, and sensible route of allergen delivery – seemed more useful. She wanted to learn more.

Her mentors urged her to stay in academia instead. “They were, like, you have a good academic reputation. You’re a solid thinker. You’re great at what you do. Do the traditional stuff,” Dr. Schroeder said.

Despite these admonitions, Dr. Schroeder left academia and took a job at La Crosse after completing her allergy fellowship. Determined to see whether SLIT could be effective, “I decided in the end, you know what, I have to go do this,” she said. “I need to know, and the only way I’m going to know is to do it, because no one was giving me good information.”

Before treating anyone with SLIT, Dr. Schroeder tried it herself – as a La Crosse patient. Growing up with severe eczema, eye swelling, and chronic nasal congestion leading to sinus infections, “I myself was a severely allergic person,” she said. Within several months, Dr. Schroeder saw dramatic improvement in her symptoms – “a night and day difference.” She experienced some mouth tingling, one of SLIT’s most common side effects, but found it “very tolerable, very mild.”

Allergenuity Health doesn’t aim to promote SLIT as the best treatment, said Dr. Schroeder, who has helped some families use avoidance or OIT as a better option. “An initial evaluation is always about proper diagnosis and education about all the treatment options available. Really, the point is education – be a detective for them and figure out what’s going on, be honest about what we know and what we don’t know, and give them the tools to figure out how to proceed.”

A version of this article first appeared on Medscape.com. This is part two of a three-part series. Part one is here. Part three is here.

With degrees in electrical engineering and computer science from the Massachusetts Institute of Technology, Nikhila Schroeder, MD, MEng, brings a problem-solving mindset to medicine.

Being a doctor means having to “figure out all aspects of [a patient’s] situation and do my best to come up with an answer,” said Dr. Schroeder, who founded Allergenuity Health, a solo allergy practice in Huntersville, N.C., with her husband James, who serves as practice executive. It’s “being a medical detective for your patient.”

Yet, during her training, Dr. Schroeder found that market-driven health care makes it hard to practice medicine with a patient’s best interest foremost. Procedures for diagnosing and treating disease cater to insurance companies’ reimbursement policies. “You wind up having to tailor your care to whatever insurance will cover,” she said.

Insurers, in turn, look for evidence from large, peer-reviewed studies to prove that a treatment works. Many physicians hesitate to offer therapies that aren’t covered by insurance, for both liability and financial reasons. So treatment tends to be limited to those options that were rigorously vetted in long, costly, multisite trials that are difficult to conduct without a corporate sponsor.

This is why there is still only one licensed treatment for people with food allergies – a set of standardized peanut powder capsules (Palforzia) that was approved by the Food and Drug Administration in early 2020 for peanut-allergic children aged 4-17 years. A small but growing number of allergists offer unapproved oral immunotherapy (OIT) using commercial food products to treat allergies to peanuts and other foods.

Even fewer allergists treat food allergy patients with another immune-modifying treatment, sublingual immunotherapy (SLIT), which delivers allergens through liquid drops held for several minutes under the tongue. Since 2018, Allergenuity Health, which offers SLIT to treat food and environmental allergies, has provided care to more than 400 patients. More than a third have come from out of state.

The clinic uses a direct-care approach. Rather than taking insurance, the clinic offers a monthly billing program that includes tests, SLIT bottles, and access to Dr. Schroeder via phone, email, or text. “I’m only contracted with the patient, and my only focus is the patient,” Dr. Schroeder said in an interview.
 

Unforgettable day

Allergy was not on Dr. Schroeder’s radar in medical school. She wanted to be a surgeon. But she loved working with children, so she did a pediatrics residency at the University of Virginia Children’s Hospital in Charlottesville. There Dr. Schroeder started seeing kids with eczema and allergies. While covering a friend’s clinic shift in 2010, she was thrust into an emergency. A family who didn’t speak English had just brought in their screaming 6-month-old baby, red and puffy with hives. “We didn’t know what was going on with this child,” Dr. Schroeder said. “Somehow I was elected to go in there.”

All of a sudden, things got quiet. Yet the baby was still screaming, mouth wide open. Dr. Schroeder had learned about anaphylaxis but had never witnessed it – until that day. The baby›s airways swelled so much that the crying became hoarse and soft. After working with a nurse to administer epinephrine, Dr. Schroeder saw something equally unforgettable: The baby’s heart rate soared, but within minutes the hives and swelling subsided and smiles returned. “It was incredible how quickly things changed,” Dr. Schroeder said. The baby had a reaction to rice, an uncommon allergen.

Dr. Schroeder stayed at UVA 2 more years to complete an allergy and immunology fellowship. She learned to diagnose food allergies but became frustrated having to tell patients they had little recourse but to avoid the food and to check in every year or 2. “I was, like, aren’t we specialists? Shouldn’t we have a little more expertise and maybe see if there are ways we could change this?” Dr. Schroeder said.

During those years, allergy shots were the only form of immunotherapy being taught to fellows. At clinic, Dr. Schroeder served as backup to the nurses when someone reacted to shots. She was troubled that some patients needed epinephrine to stop asthma attacks caused by injections they had received as treatment. The idea of injecting substances under the skin seemed akin to vaccination – where “you want to aggravate the immune system, you want it to get revved up, you want to build it up to fight,” she said. “But that’s not what you want for allergy. You want to tone it down. It didn’t really, to be honest, make a lot of sense to me.”

Dr. Schroeder started digging and asking questions. How does the immune system decide what is safe? Which cells and molecules communicate these decisions? She thought about babies and how they “learn” by putting stuff into their mouths. “If we don’t tolerate most of what we take in there, we wouldn’t survive,” Dr. Schroeder said. “It makes a lot of sense that a lot of tolerance begins with cells of the mouth.”

Dr. Schroeder discussed these concepts with her attendings. “They were all, like, no, there’s really no good evidence for that,” she said. But at some point, someone mentioned sublingual immunotherapy, and Schroeder came across Allergy Associates of La Crosse (Wis.).

The clinic’s late founder, David Morris, MD, learned about SLIT in the 1960s as an alternative option for farmers who suffered terrible side effects from injection immunotherapy they received to treat their mold allergies. Dr. Morris attended conferences, learned more about sublingual techniques – at times seeking advice from European allergists who offered SLIT – and became board certified in allergy before opening the La Crosse clinic in 1970. According to the clinic, more than 200,000 patients with environmental and food allergies have been treated with its SLIT protocol.

Dr. Schroeder was shocked to discover that this clinic had existed for 40 years, yet “I, as an allergist, had heard nothing about them,” she said.

Toward the end of her fellowship, OIT was becoming more well known. But she felt its risks were often downplayed. After years of talking with food allergy patients, Schroeder realized that most didn’t actually care about eating peanut butter sandwiches or sesame or walnuts. “Often I would hear, through tears: ‘I just want my child to be able to sit with their friends at lunch, to not be put at this other table, to not feel so isolated,’ ” she said. What mattered most to many families was gaining enough protection to not feel anxious about participating in social activities involving food.

Dr. Schroeder had a growing sense that SLIT – given its ease, safety, and sensible route of allergen delivery – seemed more useful. She wanted to learn more.

Her mentors urged her to stay in academia instead. “They were, like, you have a good academic reputation. You’re a solid thinker. You’re great at what you do. Do the traditional stuff,” Dr. Schroeder said.

Despite these admonitions, Dr. Schroeder left academia and took a job at La Crosse after completing her allergy fellowship. Determined to see whether SLIT could be effective, “I decided in the end, you know what, I have to go do this,” she said. “I need to know, and the only way I’m going to know is to do it, because no one was giving me good information.”

Before treating anyone with SLIT, Dr. Schroeder tried it herself – as a La Crosse patient. Growing up with severe eczema, eye swelling, and chronic nasal congestion leading to sinus infections, “I myself was a severely allergic person,” she said. Within several months, Dr. Schroeder saw dramatic improvement in her symptoms – “a night and day difference.” She experienced some mouth tingling, one of SLIT’s most common side effects, but found it “very tolerable, very mild.”

Allergenuity Health doesn’t aim to promote SLIT as the best treatment, said Dr. Schroeder, who has helped some families use avoidance or OIT as a better option. “An initial evaluation is always about proper diagnosis and education about all the treatment options available. Really, the point is education – be a detective for them and figure out what’s going on, be honest about what we know and what we don’t know, and give them the tools to figure out how to proceed.”

A version of this article first appeared on Medscape.com. This is part two of a three-part series. Part one is here. Part three is here.

With degrees in electrical engineering and computer science from the Massachusetts Institute of Technology, Nikhila Schroeder, MD, MEng, brings a problem-solving mindset to medicine.

Being a doctor means having to “figure out all aspects of [a patient’s] situation and do my best to come up with an answer,” said Dr. Schroeder, who founded Allergenuity Health, a solo allergy practice in Huntersville, N.C., with her husband James, who serves as practice executive. It’s “being a medical detective for your patient.”

Yet, during her training, Dr. Schroeder found that market-driven health care makes it hard to practice medicine with a patient’s best interest foremost. Procedures for diagnosing and treating disease cater to insurance companies’ reimbursement policies. “You wind up having to tailor your care to whatever insurance will cover,” she said.

Insurers, in turn, look for evidence from large, peer-reviewed studies to prove that a treatment works. Many physicians hesitate to offer therapies that aren’t covered by insurance, for both liability and financial reasons. So treatment tends to be limited to those options that were rigorously vetted in long, costly, multisite trials that are difficult to conduct without a corporate sponsor.

This is why there is still only one licensed treatment for people with food allergies – a set of standardized peanut powder capsules (Palforzia) that was approved by the Food and Drug Administration in early 2020 for peanut-allergic children aged 4-17 years. A small but growing number of allergists offer unapproved oral immunotherapy (OIT) using commercial food products to treat allergies to peanuts and other foods.

Even fewer allergists treat food allergy patients with another immune-modifying treatment, sublingual immunotherapy (SLIT), which delivers allergens through liquid drops held for several minutes under the tongue. Since 2018, Allergenuity Health, which offers SLIT to treat food and environmental allergies, has provided care to more than 400 patients. More than a third have come from out of state.

The clinic uses a direct-care approach. Rather than taking insurance, the clinic offers a monthly billing program that includes tests, SLIT bottles, and access to Dr. Schroeder via phone, email, or text. “I’m only contracted with the patient, and my only focus is the patient,” Dr. Schroeder said in an interview.
 

Unforgettable day

Allergy was not on Dr. Schroeder’s radar in medical school. She wanted to be a surgeon. But she loved working with children, so she did a pediatrics residency at the University of Virginia Children’s Hospital in Charlottesville. There Dr. Schroeder started seeing kids with eczema and allergies. While covering a friend’s clinic shift in 2010, she was thrust into an emergency. A family who didn’t speak English had just brought in their screaming 6-month-old baby, red and puffy with hives. “We didn’t know what was going on with this child,” Dr. Schroeder said. “Somehow I was elected to go in there.”

All of a sudden, things got quiet. Yet the baby was still screaming, mouth wide open. Dr. Schroeder had learned about anaphylaxis but had never witnessed it – until that day. The baby›s airways swelled so much that the crying became hoarse and soft. After working with a nurse to administer epinephrine, Dr. Schroeder saw something equally unforgettable: The baby’s heart rate soared, but within minutes the hives and swelling subsided and smiles returned. “It was incredible how quickly things changed,” Dr. Schroeder said. The baby had a reaction to rice, an uncommon allergen.

Dr. Schroeder stayed at UVA 2 more years to complete an allergy and immunology fellowship. She learned to diagnose food allergies but became frustrated having to tell patients they had little recourse but to avoid the food and to check in every year or 2. “I was, like, aren’t we specialists? Shouldn’t we have a little more expertise and maybe see if there are ways we could change this?” Dr. Schroeder said.

During those years, allergy shots were the only form of immunotherapy being taught to fellows. At clinic, Dr. Schroeder served as backup to the nurses when someone reacted to shots. She was troubled that some patients needed epinephrine to stop asthma attacks caused by injections they had received as treatment. The idea of injecting substances under the skin seemed akin to vaccination – where “you want to aggravate the immune system, you want it to get revved up, you want to build it up to fight,” she said. “But that’s not what you want for allergy. You want to tone it down. It didn’t really, to be honest, make a lot of sense to me.”

Dr. Schroeder started digging and asking questions. How does the immune system decide what is safe? Which cells and molecules communicate these decisions? She thought about babies and how they “learn” by putting stuff into their mouths. “If we don’t tolerate most of what we take in there, we wouldn’t survive,” Dr. Schroeder said. “It makes a lot of sense that a lot of tolerance begins with cells of the mouth.”

Dr. Schroeder discussed these concepts with her attendings. “They were all, like, no, there’s really no good evidence for that,” she said. But at some point, someone mentioned sublingual immunotherapy, and Schroeder came across Allergy Associates of La Crosse (Wis.).

The clinic’s late founder, David Morris, MD, learned about SLIT in the 1960s as an alternative option for farmers who suffered terrible side effects from injection immunotherapy they received to treat their mold allergies. Dr. Morris attended conferences, learned more about sublingual techniques – at times seeking advice from European allergists who offered SLIT – and became board certified in allergy before opening the La Crosse clinic in 1970. According to the clinic, more than 200,000 patients with environmental and food allergies have been treated with its SLIT protocol.

Dr. Schroeder was shocked to discover that this clinic had existed for 40 years, yet “I, as an allergist, had heard nothing about them,” she said.

Toward the end of her fellowship, OIT was becoming more well known. But she felt its risks were often downplayed. After years of talking with food allergy patients, Schroeder realized that most didn’t actually care about eating peanut butter sandwiches or sesame or walnuts. “Often I would hear, through tears: ‘I just want my child to be able to sit with their friends at lunch, to not be put at this other table, to not feel so isolated,’ ” she said. What mattered most to many families was gaining enough protection to not feel anxious about participating in social activities involving food.

Dr. Schroeder had a growing sense that SLIT – given its ease, safety, and sensible route of allergen delivery – seemed more useful. She wanted to learn more.

Her mentors urged her to stay in academia instead. “They were, like, you have a good academic reputation. You’re a solid thinker. You’re great at what you do. Do the traditional stuff,” Dr. Schroeder said.

Despite these admonitions, Dr. Schroeder left academia and took a job at La Crosse after completing her allergy fellowship. Determined to see whether SLIT could be effective, “I decided in the end, you know what, I have to go do this,” she said. “I need to know, and the only way I’m going to know is to do it, because no one was giving me good information.”

Before treating anyone with SLIT, Dr. Schroeder tried it herself – as a La Crosse patient. Growing up with severe eczema, eye swelling, and chronic nasal congestion leading to sinus infections, “I myself was a severely allergic person,” she said. Within several months, Dr. Schroeder saw dramatic improvement in her symptoms – “a night and day difference.” She experienced some mouth tingling, one of SLIT’s most common side effects, but found it “very tolerable, very mild.”

Allergenuity Health doesn’t aim to promote SLIT as the best treatment, said Dr. Schroeder, who has helped some families use avoidance or OIT as a better option. “An initial evaluation is always about proper diagnosis and education about all the treatment options available. Really, the point is education – be a detective for them and figure out what’s going on, be honest about what we know and what we don’t know, and give them the tools to figure out how to proceed.”

A version of this article first appeared on Medscape.com. This is part two of a three-part series. Part one is here. Part three is here.

For the 32 million people in the United States with food allergies, those who seek relief beyond constant vigilance and EpiPens face a confusing treatment landscape. In January 2020, the Food and Drug Administration approved an oral immunotherapy product (Palforzia) for peanut-allergic children. Yet the product’s ill-timed release during a pandemic and its black-box warning about the risk for anaphylaxis has slowed uptake.

A small number of allergists offer home-grown oral immunotherapy (OIT), which builds protection by exposing patients to increasing daily doses of commercial food products over months. However, as with Palforzia, allergic reactions are common during treatment, and the hard-earned protection can fade if not maintained with regular dosing.

An alternate approach, sublingual immunotherapy (SLIT), delivers food proteins through liquid drops held in the mouth – a site rich in tolerance-inducing immune cells. In a 2019 study of peanut-allergic children aged 1-11 years, SLIT offered a level of protection on par with Palforzia while causing considerably fewer adverse events. And at the 2021 annual meeting of the American Academy of Allergy, Asthma and Immunology, researchers reported that SLIT produced stronger, more durable benefits in toddlers aged 1-4.

Sublingual immunotherapy is “a bunch of drops you put under your tongue, you hold it for a couple minutes, and then you’re done for the day,” said Edwin Kim, MD, director of the UNC Food Allergy Initiative, University of North Carolina at Chapel Hill, who led the two recent studies. For protecting against accidental ingestions, SLIT “is pushing pretty close to what OIT is able to provide but seemingly with a superior ease of administration and safety profile.”

Many parents don’t necessarily want their allergic kids to be able to eat a peanut butter sandwich – but do want them to be able to safely sit at the same lunch table and attend birthday parties with other kids. SLIT achieves this level of protection about as well as OIT, with fewer side effects.

Still, because of concerns about the treatment’s cost, unclear dosing regimens, and lack of FDA approval, very few U.S. allergists – likely less than 5% – offer sublingual immunotherapy to treat food allergies, making SLIT even less available than OIT.
 

Concerns about SLIT

One possible reason: Success is slower and less visible for SLIT. When patients undergo OIT, they build up to dosing with the actual food. “To a family who has a concern about their kid reacting, they can see them eating chunks of peanut in our office. That is really encouraging,” said Douglas Mack, MD, FRCPC, an allergist with Halton Pediatric Allergy and assistant clinical professor of pediatrics at McMaster University, Hamilton, Ont.

On the other hand, ingestion isn’t the focus for SLIT, so progress is harder to measure using metrics in published trials. After holding SLIT drops under the tongue, some patients spit them out. If they swallow the dose, it’s a vanishingly small amount. Immune changes that reflect increasing tolerance, such as a decrease in IgE antibodies, tend to be more gradual with SLIT than with OIT. And because SLIT is only offered in private clinics, such tests are not conducted as regularly as they would be for published trials.

But there may be a bigger factor: Some think earlier trials comparing the two immunotherapy regimens gave SLIT a bad rap. For example, in studies of milk- and peanut-allergic children conducted in 2011 and 2014, investigators concluded that SLIT was safer and that OIT appeared to be more effective. However, those trials compared SLIT with OIT using a much higher dose (2,000 mg) than is used in the licensed product (300 mg).

Over the years, endpoints for food allergy treatment trials have shifted from enabling patients to eat a full serving of their allergen to merely raising their threshold to guard against accidental exposures. So in those earlier articles, “we would probably write the discussion section differently now,” said Corinne Keet, MD, PhD, first author on the 2011 milk study and an associate professor of pediatrics at Johns Hopkins University, Baltimore.

Indeed, “when you compare [SLIT] to Palforzia or other studies of low-dose OIT (300 mg/d), they look equal in terms of their efficacy,” said senior author Robert Wood, MD, professor of pediatrics and director of pediatric allergy and immunology at Johns Hopkins. Yet, “I’m afraid we had a major [negative] impact on pharma’s interest in pursuing SLIT.”

Without corporate funding, it’s nearly impossible to conduct the large, multisite trials required for FDA approval of a treatment. And without approved products, many allergists are reluctant to offer the therapy, Dr. Wood said. It “makes your life a lot more complicated to be dabbling in things that are not approved,” he noted.

But at least one company is giving it a go. Applying the SLIT principle of delivering food allergens to tolerance-promoting immune cells in the mouth, New York–based Intrommune Therapeutics recently started enrolling peanut-allergic adults for a phase 1 trial of its experimental toothpaste.

Interest in food-allergy SLIT seems to be growing. “I definitely think that it could be an option for the future,” said Jaclyn Bjelac, MD, associate director of the Food Allergy Center of Excellence at the Cleveland Clinic. “Up until a few months ago, it really wasn’t on our radar.”

On conversations with Dr. Kim, philanthropists and drug developers said they found the recent data on SLIT promising, yet pointed out that food SLIT protocols and products are already in the public domain – they are described in published research using allergen extracts that are on the market. They “can’t see a commercial path forward,” Dr. Kim said in an interview. “And that’s kind of where many of my conversations end.”

Although there are no licensed SLIT products for food allergies, between 2014 and 2017, the FDA approved four sublingual immunotherapy tablets to treat environmental allergies – Stallergenes-Greer’s Oralair and ALK’s Grastek for grass pollens, ALK’s Odactra for dust mites, and ALK’s Ragwitek for short ragweed.

SLIT tablets work as well as allergy shots (subcutaneous immunotherapy) for controlling environmental allergy symptoms, they have a better safety profile, according to AAAAI guidelines, and they can be self-administered at home, which has made them a popular option globally. “Our European colleagues have used sublingual immunotherapy much more frequently than, for example, in the U.S.,” said Kari Nadeau, MD, PhD, director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford (Calif.) University.

Use of SLIT is also increasing in the United States, especially as FDA-approved products become available. In a 2019 survey, the percentage of U.S. allergists who said they were offering sublingual treatment for environmental allergies increased from 5.9% in 2007 to 73.5% in 2019. However, only 11.2% reported extensive SLIT use; the remainder reported some (50.5%) or little (38.3%) use.

As noted above, considerably fewer U.S. allergists use SLIT to treat food allergies. Similarly, a 2021 survey of allergists in Canada found that only 7% offered food sublingual immunotherapy; more than half reported offering OIT.

One practice, Allergy Associates of La Crosse (Wis.), has offered SLIT drops for food and environmental allergies for decades. Since the clinic opened in 1970, more than 200,000 people have been treated with its protocol. Every patient receives customized sublingual drops – “exactly what they’re allergic to, exactly how allergic they are, and then we build from there,” said Jeff Kessler, MBA, FACHE, practice executive at Allergy Associates of La Crosse. “Quite frankly, it’s the way immunotherapy should be done.

A version of this article first appeared on Medscape.com. This is part one of a three-part series. Part two is here. Part three is here.

For the 32 million people in the United States with food allergies, those who seek relief beyond constant vigilance and EpiPens face a confusing treatment landscape. In January 2020, the Food and Drug Administration approved an oral immunotherapy product (Palforzia) for peanut-allergic children. Yet the product’s ill-timed release during a pandemic and its black-box warning about the risk for anaphylaxis has slowed uptake.

A small number of allergists offer home-grown oral immunotherapy (OIT), which builds protection by exposing patients to increasing daily doses of commercial food products over months. However, as with Palforzia, allergic reactions are common during treatment, and the hard-earned protection can fade if not maintained with regular dosing.

An alternate approach, sublingual immunotherapy (SLIT), delivers food proteins through liquid drops held in the mouth – a site rich in tolerance-inducing immune cells. In a 2019 study of peanut-allergic children aged 1-11 years, SLIT offered a level of protection on par with Palforzia while causing considerably fewer adverse events. And at the 2021 annual meeting of the American Academy of Allergy, Asthma and Immunology, researchers reported that SLIT produced stronger, more durable benefits in toddlers aged 1-4.

Sublingual immunotherapy is “a bunch of drops you put under your tongue, you hold it for a couple minutes, and then you’re done for the day,” said Edwin Kim, MD, director of the UNC Food Allergy Initiative, University of North Carolina at Chapel Hill, who led the two recent studies. For protecting against accidental ingestions, SLIT “is pushing pretty close to what OIT is able to provide but seemingly with a superior ease of administration and safety profile.”

Many parents don’t necessarily want their allergic kids to be able to eat a peanut butter sandwich – but do want them to be able to safely sit at the same lunch table and attend birthday parties with other kids. SLIT achieves this level of protection about as well as OIT, with fewer side effects.

Still, because of concerns about the treatment’s cost, unclear dosing regimens, and lack of FDA approval, very few U.S. allergists – likely less than 5% – offer sublingual immunotherapy to treat food allergies, making SLIT even less available than OIT.
 

Concerns about SLIT

One possible reason: Success is slower and less visible for SLIT. When patients undergo OIT, they build up to dosing with the actual food. “To a family who has a concern about their kid reacting, they can see them eating chunks of peanut in our office. That is really encouraging,” said Douglas Mack, MD, FRCPC, an allergist with Halton Pediatric Allergy and assistant clinical professor of pediatrics at McMaster University, Hamilton, Ont.

On the other hand, ingestion isn’t the focus for SLIT, so progress is harder to measure using metrics in published trials. After holding SLIT drops under the tongue, some patients spit them out. If they swallow the dose, it’s a vanishingly small amount. Immune changes that reflect increasing tolerance, such as a decrease in IgE antibodies, tend to be more gradual with SLIT than with OIT. And because SLIT is only offered in private clinics, such tests are not conducted as regularly as they would be for published trials.

But there may be a bigger factor: Some think earlier trials comparing the two immunotherapy regimens gave SLIT a bad rap. For example, in studies of milk- and peanut-allergic children conducted in 2011 and 2014, investigators concluded that SLIT was safer and that OIT appeared to be more effective. However, those trials compared SLIT with OIT using a much higher dose (2,000 mg) than is used in the licensed product (300 mg).

Over the years, endpoints for food allergy treatment trials have shifted from enabling patients to eat a full serving of their allergen to merely raising their threshold to guard against accidental exposures. So in those earlier articles, “we would probably write the discussion section differently now,” said Corinne Keet, MD, PhD, first author on the 2011 milk study and an associate professor of pediatrics at Johns Hopkins University, Baltimore.

Indeed, “when you compare [SLIT] to Palforzia or other studies of low-dose OIT (300 mg/d), they look equal in terms of their efficacy,” said senior author Robert Wood, MD, professor of pediatrics and director of pediatric allergy and immunology at Johns Hopkins. Yet, “I’m afraid we had a major [negative] impact on pharma’s interest in pursuing SLIT.”

Without corporate funding, it’s nearly impossible to conduct the large, multisite trials required for FDA approval of a treatment. And without approved products, many allergists are reluctant to offer the therapy, Dr. Wood said. It “makes your life a lot more complicated to be dabbling in things that are not approved,” he noted.

But at least one company is giving it a go. Applying the SLIT principle of delivering food allergens to tolerance-promoting immune cells in the mouth, New York–based Intrommune Therapeutics recently started enrolling peanut-allergic adults for a phase 1 trial of its experimental toothpaste.

Interest in food-allergy SLIT seems to be growing. “I definitely think that it could be an option for the future,” said Jaclyn Bjelac, MD, associate director of the Food Allergy Center of Excellence at the Cleveland Clinic. “Up until a few months ago, it really wasn’t on our radar.”

On conversations with Dr. Kim, philanthropists and drug developers said they found the recent data on SLIT promising, yet pointed out that food SLIT protocols and products are already in the public domain – they are described in published research using allergen extracts that are on the market. They “can’t see a commercial path forward,” Dr. Kim said in an interview. “And that’s kind of where many of my conversations end.”

Although there are no licensed SLIT products for food allergies, between 2014 and 2017, the FDA approved four sublingual immunotherapy tablets to treat environmental allergies – Stallergenes-Greer’s Oralair and ALK’s Grastek for grass pollens, ALK’s Odactra for dust mites, and ALK’s Ragwitek for short ragweed.

SLIT tablets work as well as allergy shots (subcutaneous immunotherapy) for controlling environmental allergy symptoms, they have a better safety profile, according to AAAAI guidelines, and they can be self-administered at home, which has made them a popular option globally. “Our European colleagues have used sublingual immunotherapy much more frequently than, for example, in the U.S.,” said Kari Nadeau, MD, PhD, director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford (Calif.) University.

Use of SLIT is also increasing in the United States, especially as FDA-approved products become available. In a 2019 survey, the percentage of U.S. allergists who said they were offering sublingual treatment for environmental allergies increased from 5.9% in 2007 to 73.5% in 2019. However, only 11.2% reported extensive SLIT use; the remainder reported some (50.5%) or little (38.3%) use.

As noted above, considerably fewer U.S. allergists use SLIT to treat food allergies. Similarly, a 2021 survey of allergists in Canada found that only 7% offered food sublingual immunotherapy; more than half reported offering OIT.

One practice, Allergy Associates of La Crosse (Wis.), has offered SLIT drops for food and environmental allergies for decades. Since the clinic opened in 1970, more than 200,000 people have been treated with its protocol. Every patient receives customized sublingual drops – “exactly what they’re allergic to, exactly how allergic they are, and then we build from there,” said Jeff Kessler, MBA, FACHE, practice executive at Allergy Associates of La Crosse. “Quite frankly, it’s the way immunotherapy should be done.

A version of this article first appeared on Medscape.com. This is part one of a three-part series. Part two is here. Part three is here.

For the 32 million people in the United States with food allergies, those who seek relief beyond constant vigilance and EpiPens face a confusing treatment landscape. In January 2020, the Food and Drug Administration approved an oral immunotherapy product (Palforzia) for peanut-allergic children. Yet the product’s ill-timed release during a pandemic and its black-box warning about the risk for anaphylaxis has slowed uptake.

A small number of allergists offer home-grown oral immunotherapy (OIT), which builds protection by exposing patients to increasing daily doses of commercial food products over months. However, as with Palforzia, allergic reactions are common during treatment, and the hard-earned protection can fade if not maintained with regular dosing.

An alternate approach, sublingual immunotherapy (SLIT), delivers food proteins through liquid drops held in the mouth – a site rich in tolerance-inducing immune cells. In a 2019 study of peanut-allergic children aged 1-11 years, SLIT offered a level of protection on par with Palforzia while causing considerably fewer adverse events. And at the 2021 annual meeting of the American Academy of Allergy, Asthma and Immunology, researchers reported that SLIT produced stronger, more durable benefits in toddlers aged 1-4.

Sublingual immunotherapy is “a bunch of drops you put under your tongue, you hold it for a couple minutes, and then you’re done for the day,” said Edwin Kim, MD, director of the UNC Food Allergy Initiative, University of North Carolina at Chapel Hill, who led the two recent studies. For protecting against accidental ingestions, SLIT “is pushing pretty close to what OIT is able to provide but seemingly with a superior ease of administration and safety profile.”

Many parents don’t necessarily want their allergic kids to be able to eat a peanut butter sandwich – but do want them to be able to safely sit at the same lunch table and attend birthday parties with other kids. SLIT achieves this level of protection about as well as OIT, with fewer side effects.

Still, because of concerns about the treatment’s cost, unclear dosing regimens, and lack of FDA approval, very few U.S. allergists – likely less than 5% – offer sublingual immunotherapy to treat food allergies, making SLIT even less available than OIT.
 

Concerns about SLIT

One possible reason: Success is slower and less visible for SLIT. When patients undergo OIT, they build up to dosing with the actual food. “To a family who has a concern about their kid reacting, they can see them eating chunks of peanut in our office. That is really encouraging,” said Douglas Mack, MD, FRCPC, an allergist with Halton Pediatric Allergy and assistant clinical professor of pediatrics at McMaster University, Hamilton, Ont.

On the other hand, ingestion isn’t the focus for SLIT, so progress is harder to measure using metrics in published trials. After holding SLIT drops under the tongue, some patients spit them out. If they swallow the dose, it’s a vanishingly small amount. Immune changes that reflect increasing tolerance, such as a decrease in IgE antibodies, tend to be more gradual with SLIT than with OIT. And because SLIT is only offered in private clinics, such tests are not conducted as regularly as they would be for published trials.

But there may be a bigger factor: Some think earlier trials comparing the two immunotherapy regimens gave SLIT a bad rap. For example, in studies of milk- and peanut-allergic children conducted in 2011 and 2014, investigators concluded that SLIT was safer and that OIT appeared to be more effective. However, those trials compared SLIT with OIT using a much higher dose (2,000 mg) than is used in the licensed product (300 mg).

Over the years, endpoints for food allergy treatment trials have shifted from enabling patients to eat a full serving of their allergen to merely raising their threshold to guard against accidental exposures. So in those earlier articles, “we would probably write the discussion section differently now,” said Corinne Keet, MD, PhD, first author on the 2011 milk study and an associate professor of pediatrics at Johns Hopkins University, Baltimore.

Indeed, “when you compare [SLIT] to Palforzia or other studies of low-dose OIT (300 mg/d), they look equal in terms of their efficacy,” said senior author Robert Wood, MD, professor of pediatrics and director of pediatric allergy and immunology at Johns Hopkins. Yet, “I’m afraid we had a major [negative] impact on pharma’s interest in pursuing SLIT.”

Without corporate funding, it’s nearly impossible to conduct the large, multisite trials required for FDA approval of a treatment. And without approved products, many allergists are reluctant to offer the therapy, Dr. Wood said. It “makes your life a lot more complicated to be dabbling in things that are not approved,” he noted.

But at least one company is giving it a go. Applying the SLIT principle of delivering food allergens to tolerance-promoting immune cells in the mouth, New York–based Intrommune Therapeutics recently started enrolling peanut-allergic adults for a phase 1 trial of its experimental toothpaste.

Interest in food-allergy SLIT seems to be growing. “I definitely think that it could be an option for the future,” said Jaclyn Bjelac, MD, associate director of the Food Allergy Center of Excellence at the Cleveland Clinic. “Up until a few months ago, it really wasn’t on our radar.”

On conversations with Dr. Kim, philanthropists and drug developers said they found the recent data on SLIT promising, yet pointed out that food SLIT protocols and products are already in the public domain – they are described in published research using allergen extracts that are on the market. They “can’t see a commercial path forward,” Dr. Kim said in an interview. “And that’s kind of where many of my conversations end.”

Although there are no licensed SLIT products for food allergies, between 2014 and 2017, the FDA approved four sublingual immunotherapy tablets to treat environmental allergies – Stallergenes-Greer’s Oralair and ALK’s Grastek for grass pollens, ALK’s Odactra for dust mites, and ALK’s Ragwitek for short ragweed.

SLIT tablets work as well as allergy shots (subcutaneous immunotherapy) for controlling environmental allergy symptoms, they have a better safety profile, according to AAAAI guidelines, and they can be self-administered at home, which has made them a popular option globally. “Our European colleagues have used sublingual immunotherapy much more frequently than, for example, in the U.S.,” said Kari Nadeau, MD, PhD, director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford (Calif.) University.

Use of SLIT is also increasing in the United States, especially as FDA-approved products become available. In a 2019 survey, the percentage of U.S. allergists who said they were offering sublingual treatment for environmental allergies increased from 5.9% in 2007 to 73.5% in 2019. However, only 11.2% reported extensive SLIT use; the remainder reported some (50.5%) or little (38.3%) use.

As noted above, considerably fewer U.S. allergists use SLIT to treat food allergies. Similarly, a 2021 survey of allergists in Canada found that only 7% offered food sublingual immunotherapy; more than half reported offering OIT.

One practice, Allergy Associates of La Crosse (Wis.), has offered SLIT drops for food and environmental allergies for decades. Since the clinic opened in 1970, more than 200,000 people have been treated with its protocol. Every patient receives customized sublingual drops – “exactly what they’re allergic to, exactly how allergic they are, and then we build from there,” said Jeff Kessler, MBA, FACHE, practice executive at Allergy Associates of La Crosse. “Quite frankly, it’s the way immunotherapy should be done.

A version of this article first appeared on Medscape.com. This is part one of a three-part series. Part two is here. Part three is here.