IBD & Intestinal Disorders

Inflammatory bowel disease (IBD) increases the risk and severity of Clostridium difficile infection (CDI) while CDI tends to complicate and worsen the clinical course of IBD, experts note in a clinical practice update.

Thus, it is crucial that clinicians pursue stool testing for toxigenic C. difficile infection whenever a patient with IBD presents with a colitis flare, regardless of the recent antibiotic history, wrote Sahil Khanna, MBBS, of the Mayo Clinic, Rochester, Minn., and his associates (Clin Gastroenterol Hepatol. 2016 Feb. doi: 10.1016/j.cgh.2016.10.024). Clinicians should also test for recurrent CDI if symptoms of colitis persist or return after antibiotic therapy for CDI, they emphasized.

Inflammatory bowel disease (IBD) increases the risk and severity of Clostridium difficile infection (CDI) while CDI tends to complicate and worsen the clinical course of IBD, experts note in a clinical practice update.

Thus, it is crucial that clinicians pursue stool testing for toxigenic C. difficile infection whenever a patient with IBD presents with a colitis flare, regardless of the recent antibiotic history, wrote Sahil Khanna, MBBS, of the Mayo Clinic, Rochester, Minn., and his associates (Clin Gastroenterol Hepatol. 2016 Feb. doi: 10.1016/j.cgh.2016.10.024). Clinicians should also test for recurrent CDI if symptoms of colitis persist or return after antibiotic therapy for CDI, they emphasized.

Inflammatory bowel disease (IBD) increases the risk and severity of Clostridium difficile infection (CDI) while CDI tends to complicate and worsen the clinical course of IBD, experts note in a clinical practice update.

Thus, it is crucial that clinicians pursue stool testing for toxigenic C. difficile infection whenever a patient with IBD presents with a colitis flare, regardless of the recent antibiotic history, wrote Sahil Khanna, MBBS, of the Mayo Clinic, Rochester, Minn., and his associates (Clin Gastroenterol Hepatol. 2016 Feb. doi: 10.1016/j.cgh.2016.10.024). Clinicians should also test for recurrent CDI if symptoms of colitis persist or return after antibiotic therapy for CDI, they emphasized.

Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.

The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).

Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.

Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.

Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.

Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.

Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.

Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.

“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.

The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.

Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.

The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).

Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.

Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.

Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.

Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.

Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.

Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.

“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.

The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.

Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.

The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).

Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.

Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.

Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.

Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.

Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.

Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.

“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.

The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

*This article was updated 1/31/2017.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

*This article was updated 1/31/2017.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

*This article was updated 1/31/2017.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

Adding bezlotoxumab to standard antibiotic treatment of primary or recurrent Clostridium difficile infection reduces recurrences by 38% (10 percentage points), according to a report published in the New England Journal of Medicine.

As many as 35% of patients who complete initial antibiotic treatment have at least one recurrence of C. difficile infection, and the rate of repeat recurrence rate jumps to 60% after the initial recurrence. Researchers performed two parallel international phase III trials to assess the efficacy and safety of bezlotoxumab, alone or in combination with actoxumab, for preventing such recurrences. Both monoclonal antibodies work by binding to and neutralizing C. difficile toxins; bezlotoxumab targets toxin B and actoxumab targets toxin A, said Mark H. Wilcox, MD, of the division of microbiology, Leeds (England) General Infirmary, and his associates.

cjc2nd/Wikimedia Commons/CC ASA-3.0

Adding bezlotoxumab to standard antibiotic treatment of primary or recurrent Clostridium difficile infection reduces recurrences by 38% (10 percentage points), according to a report published in the New England Journal of Medicine.

As many as 35% of patients who complete initial antibiotic treatment have at least one recurrence of C. difficile infection, and the rate of repeat recurrence rate jumps to 60% after the initial recurrence. Researchers performed two parallel international phase III trials to assess the efficacy and safety of bezlotoxumab, alone or in combination with actoxumab, for preventing such recurrences. Both monoclonal antibodies work by binding to and neutralizing C. difficile toxins; bezlotoxumab targets toxin B and actoxumab targets toxin A, said Mark H. Wilcox, MD, of the division of microbiology, Leeds (England) General Infirmary, and his associates.

cjc2nd/Wikimedia Commons/CC ASA-3.0

Adding bezlotoxumab to standard antibiotic treatment of primary or recurrent Clostridium difficile infection reduces recurrences by 38% (10 percentage points), according to a report published in the New England Journal of Medicine.

As many as 35% of patients who complete initial antibiotic treatment have at least one recurrence of C. difficile infection, and the rate of repeat recurrence rate jumps to 60% after the initial recurrence. Researchers performed two parallel international phase III trials to assess the efficacy and safety of bezlotoxumab, alone or in combination with actoxumab, for preventing such recurrences. Both monoclonal antibodies work by binding to and neutralizing C. difficile toxins; bezlotoxumab targets toxin B and actoxumab targets toxin A, said Mark H. Wilcox, MD, of the division of microbiology, Leeds (England) General Infirmary, and his associates.

cjc2nd/Wikimedia Commons/CC ASA-3.0

In another sign that immune-suppressing drugs may cause skin cancer, a new Irish study links immunomodulator use in younger patients with inflammatory bowel disease (IBD) to higher rates of nonmelanoma skin cancer (NMSC).

The 19-year study lacks information about medication doses or duration, and it doesn’t confirm a cause-and-effect link. Still, researchers recommend that all patients with IBD be urged to comply with skin cancer prevention guidelines.

As the study notes, previous research has linked immunosuppression – such as that in transplant patients and those with AIDS and lymphoma – to higher rates of NMSC.

Studies have also linked IBD to higher rates of NMSC even before the age of 50, possibly as the result of immune system dysfunction and exposure to immunomodulators, especially thiopurines. The risk of tumor necrosis factor–alpha (TNF-alpha) inhibitors, the study says, is less clear.

To better understand the risk of immunomodulators, researchers led by Julianne Clowry, MBBCh, of St Vincent’s University Hospital in Dublin tracked 2,053 IBD patients at a tertiary adult hospital from 1994 to 2013.

The median age at IBD diagnosis was 31 with a median of 19.6 years of illness, and the patients had both Crohn’s disease (41%) and ulcerative colitis (59%). Fifty-seven percent of patients had taken immunomodulating medication, although the database used didn’t disclose details about dose or duration, and 43% had not.

The study findings appeared Jan. 3 in the Journal of the European Academy of Dermatology and Venereology (doi: 10.1111/jdv.14105).

NMSC was diagnosed in 1.7% of the entire cohort, 1.4% of patients who’d taken immunosuppressants, and 1.9% of those who had not.

Older ages may explain the higher rate in those who didn’t take the medications. The researchers found that the standardized incidence ratio for the patients who took immunomodulators overall was 1.76 [confidence interval, 1.0-2.7], compared with a matched general population cohort, while the ratio was not considered significant among the nonimmunosuppressed [1.07; CI, 0.6-1.6].

The study links use of thiopurines alone and use of both thiopurines and TNF-alpha inhibitors to higher rates of NMSC [odds ratio, 5.26; 95% CI, 2.15-12.93; P less than .001, and OR: 6.45; 95% CI, 2.69-15.95; P less than .001, respectively].

The researchers note that 82% of those who had taken a TNF-alpha inhibitor also took a thiopurine at some point.

The study says the “relatively high” standardized incident ratios are worrisome amid more use of dual immunomodulators and higher IBD rates in kids and younger adults. But the medications are “vital,” the study says, and the researchers suggest “targeted dermatology referrals for IBD patients, particularly those exposed to dual immunomodulatory therapy from an early age.”

The study authors disclose no source of funding and report no relevant disclosures.

In another sign that immune-suppressing drugs may cause skin cancer, a new Irish study links immunomodulator use in younger patients with inflammatory bowel disease (IBD) to higher rates of nonmelanoma skin cancer (NMSC).

The 19-year study lacks information about medication doses or duration, and it doesn’t confirm a cause-and-effect link. Still, researchers recommend that all patients with IBD be urged to comply with skin cancer prevention guidelines.

As the study notes, previous research has linked immunosuppression – such as that in transplant patients and those with AIDS and lymphoma – to higher rates of NMSC.

Studies have also linked IBD to higher rates of NMSC even before the age of 50, possibly as the result of immune system dysfunction and exposure to immunomodulators, especially thiopurines. The risk of tumor necrosis factor–alpha (TNF-alpha) inhibitors, the study says, is less clear.

To better understand the risk of immunomodulators, researchers led by Julianne Clowry, MBBCh, of St Vincent’s University Hospital in Dublin tracked 2,053 IBD patients at a tertiary adult hospital from 1994 to 2013.

The median age at IBD diagnosis was 31 with a median of 19.6 years of illness, and the patients had both Crohn’s disease (41%) and ulcerative colitis (59%). Fifty-seven percent of patients had taken immunomodulating medication, although the database used didn’t disclose details about dose or duration, and 43% had not.

The study findings appeared Jan. 3 in the Journal of the European Academy of Dermatology and Venereology (doi: 10.1111/jdv.14105).

NMSC was diagnosed in 1.7% of the entire cohort, 1.4% of patients who’d taken immunosuppressants, and 1.9% of those who had not.

Older ages may explain the higher rate in those who didn’t take the medications. The researchers found that the standardized incidence ratio for the patients who took immunomodulators overall was 1.76 [confidence interval, 1.0-2.7], compared with a matched general population cohort, while the ratio was not considered significant among the nonimmunosuppressed [1.07; CI, 0.6-1.6].

The study links use of thiopurines alone and use of both thiopurines and TNF-alpha inhibitors to higher rates of NMSC [odds ratio, 5.26; 95% CI, 2.15-12.93; P less than .001, and OR: 6.45; 95% CI, 2.69-15.95; P less than .001, respectively].

The researchers note that 82% of those who had taken a TNF-alpha inhibitor also took a thiopurine at some point.

The study says the “relatively high” standardized incident ratios are worrisome amid more use of dual immunomodulators and higher IBD rates in kids and younger adults. But the medications are “vital,” the study says, and the researchers suggest “targeted dermatology referrals for IBD patients, particularly those exposed to dual immunomodulatory therapy from an early age.”

The study authors disclose no source of funding and report no relevant disclosures.

In another sign that immune-suppressing drugs may cause skin cancer, a new Irish study links immunomodulator use in younger patients with inflammatory bowel disease (IBD) to higher rates of nonmelanoma skin cancer (NMSC).

The 19-year study lacks information about medication doses or duration, and it doesn’t confirm a cause-and-effect link. Still, researchers recommend that all patients with IBD be urged to comply with skin cancer prevention guidelines.

As the study notes, previous research has linked immunosuppression – such as that in transplant patients and those with AIDS and lymphoma – to higher rates of NMSC.

Studies have also linked IBD to higher rates of NMSC even before the age of 50, possibly as the result of immune system dysfunction and exposure to immunomodulators, especially thiopurines. The risk of tumor necrosis factor–alpha (TNF-alpha) inhibitors, the study says, is less clear.

To better understand the risk of immunomodulators, researchers led by Julianne Clowry, MBBCh, of St Vincent’s University Hospital in Dublin tracked 2,053 IBD patients at a tertiary adult hospital from 1994 to 2013.

The median age at IBD diagnosis was 31 with a median of 19.6 years of illness, and the patients had both Crohn’s disease (41%) and ulcerative colitis (59%). Fifty-seven percent of patients had taken immunomodulating medication, although the database used didn’t disclose details about dose or duration, and 43% had not.

The study findings appeared Jan. 3 in the Journal of the European Academy of Dermatology and Venereology (doi: 10.1111/jdv.14105).

NMSC was diagnosed in 1.7% of the entire cohort, 1.4% of patients who’d taken immunosuppressants, and 1.9% of those who had not.

Older ages may explain the higher rate in those who didn’t take the medications. The researchers found that the standardized incidence ratio for the patients who took immunomodulators overall was 1.76 [confidence interval, 1.0-2.7], compared with a matched general population cohort, while the ratio was not considered significant among the nonimmunosuppressed [1.07; CI, 0.6-1.6].

The study links use of thiopurines alone and use of both thiopurines and TNF-alpha inhibitors to higher rates of NMSC [odds ratio, 5.26; 95% CI, 2.15-12.93; P less than .001, and OR: 6.45; 95% CI, 2.69-15.95; P less than .001, respectively].

The researchers note that 82% of those who had taken a TNF-alpha inhibitor also took a thiopurine at some point.

The study says the “relatively high” standardized incident ratios are worrisome amid more use of dual immunomodulators and higher IBD rates in kids and younger adults. But the medications are “vital,” the study says, and the researchers suggest “targeted dermatology referrals for IBD patients, particularly those exposed to dual immunomodulatory therapy from an early age.”

The study authors disclose no source of funding and report no relevant disclosures.

Trulance, a once-daily oral medication for chronic idiopathic constipation, has been approved by the Food and Drug Administration for adult patients as of Jan. 19.

Manufactured by Synergy Pharmaceuticals, Trulance (plecanatide) stimulates intestinal fluid secretion in the upper GI tract. Its efficacy and safety were determined to be sufficient in two 12-week placebo-controlled trials (NCT01982240 and NCT02122471). Participants taking Trulance were more likely than were those taking placebo to have improved bowel function and stool.

dwatson@frontlinemedcom.com

Trulance, a once-daily oral medication for chronic idiopathic constipation, has been approved by the Food and Drug Administration for adult patients as of Jan. 19.

Manufactured by Synergy Pharmaceuticals, Trulance (plecanatide) stimulates intestinal fluid secretion in the upper GI tract. Its efficacy and safety were determined to be sufficient in two 12-week placebo-controlled trials (NCT01982240 and NCT02122471). Participants taking Trulance were more likely than were those taking placebo to have improved bowel function and stool.

dwatson@frontlinemedcom.com

Trulance, a once-daily oral medication for chronic idiopathic constipation, has been approved by the Food and Drug Administration for adult patients as of Jan. 19.

Manufactured by Synergy Pharmaceuticals, Trulance (plecanatide) stimulates intestinal fluid secretion in the upper GI tract. Its efficacy and safety were determined to be sufficient in two 12-week placebo-controlled trials (NCT01982240 and NCT02122471). Participants taking Trulance were more likely than were those taking placebo to have improved bowel function and stool.

dwatson@frontlinemedcom.com

Two recent reports that provide opposing evidence about the potential for inflammatory bowel disease patients to develop articular manifestations after starting vedolizumab raise questions for future studies to answer in regard to a plausible mechanism for the adverse event and its relative importance.

The two reports, one a case series of 5 patients with inflammatory bowel disease (IBD) who developed articular manifestations after beginning vedolizumab (Entyvio) and the other a prospective cohort study of 53 patients with IBD who started vedolizumab without any subsequent cases of induction or flare of arthritis and/or sacroiliitis, came to somewhat different conclusions about the beneficial or paradoxical effects of vedolizumab’s blockade of the alpha4beta7 receptor on articular manifestations of IBD.

The five-patient cases series reported by Gaëlle Varkas, MD, a doctoral student at the University of Ghent, Belgium, and her colleagues consisted of five IBD patients, aged 26-50 years, who developed either new onset or an exacerbation of sacroiliitis or arthritis soon after starting vedolizumab. All but one of the patients was female (Ann Rheum Dis. 2016 Nov 29. doi: 10.1136/annrheumdis-2016-210233). In these patients, the investigators said, vedolizumab did not “seem to show any efficacy in and might even induce arthritis and/or sacroiliitis.”

The first was a 50-year-old woman who had progressive back pain with MRI-confirmed bilateral sacroiliitis about 2 months after beginning vedolizumab. The second patient, a 28-year-old woman with no previous history of spondyloarthropathy, had lower limb pain, a painful left shoulder, and arthritis of one wrist. Ultrasound examination confirmed intercarpal effusions and synovial hyperproliferation.

The third patient was 30 years old and male. He had both ankylosing spondylitis and Crohn’s disease, and experienced arthralgias, elevated C-reactive protein, and MRI-confirmed axial skeletal inflammation 4 weeks after starting vedolizumab.

The fourth patient was a 47-year-old woman with no previous history of spondyloarthropathy who developed MRI-confirmed sacroiliitis after beginning vedolizumab. The fifth patient, a 26-year-old woman, developed polyarticular joint pain after starting vedolizumab. Examination of this patient showed synovitis and enthesitis of multiple joints of the appendicular skeleton.

In discussion, Dr. Varkas and her colleagues noted that “one of the many hypotheses is that integrins and adhesion molecules play a role in the interception of recirculating activated lymphocytes between the gut and the synovial membrane due to the inhibition of the alpha4beta7 integrin homing at the level of the gut.” However, the investigators also acknowledged that other hypotheses may also account for their findings. “Alternatively, in the presence of vedolizumab, cellular recruitment may be mediated by yet to be determined adhesion molecules. This recirculation theory might explain the short mean interval of 64 days between vedolizumab initiation and the expression of symptoms.”

Another group, publishing its prospective cohort study in a letter, had different findings (Ann Rheum Dis. 2017 Jan 17. doi: 10.1136/annrheumdis-2016-211011).

“Although the hypotheses proposed by the authors to explain such events sounds reasonable,” wrote Ambrogio Orlando, MD, and his coauthors, their experience of the effect of vedolizumab on spondyloarthritis differed.

In the report on 53 patients who began treatment with vedolizumab at Villa Sofia-Cervello Hospital, Palermo, Italy, where Dr. Orlando and his associates work, almost all (96%) had been steroid dependent and 81% had been treated with at least one tumor necrosis factor inhibitor. About two-thirds had completed the induction phase of vedolizumab treatment during follow-up, which lasted a mean of 2.6 months. Of the 14 patients (26%) who had active IBD-associated spondyloarthropathy when starting vedolizumab, 6 (46.2%) saw “a sharp clinical benefit after the initiation of vedolizumab,” wrote Dr. Orlando and his colleagues. Five of these six patients experienced clinical remission of gut symptoms by 12 weeks of therapy.

Dr. Orlando and his colleagues wrote that “our preliminary prospective data indicate a potential benefit of vedolizumab on IBD-associated spondyloarthropathy.”

Looking for mechanistic reasons for this apparent benefit, Dr. Orlando and his collaborators wrote that “the previous demonstration of alpha4beta7 in the joint and the recent evidence of the upregulation of mucosal vascular address in cell adhesion molecule (MadCAM-1) in the high endothelial venules of bone marrow in patients with active axial SpA seem to strengthen the hypothesis of a beneficial rather than a paradoxical effect of alpha4beta7 blockade on articular manifestations of IBD.”

Two authors of the case series reported relationships with multiple pharmaceutical companies, as did Dr. Orlando and two other authors of the letter describing the prospective study.

koakes@frontlinemedcom.com

On Twitter @karioakes

Two recent reports that provide opposing evidence about the potential for inflammatory bowel disease patients to develop articular manifestations after starting vedolizumab raise questions for future studies to answer in regard to a plausible mechanism for the adverse event and its relative importance.

The two reports, one a case series of 5 patients with inflammatory bowel disease (IBD) who developed articular manifestations after beginning vedolizumab (Entyvio) and the other a prospective cohort study of 53 patients with IBD who started vedolizumab without any subsequent cases of induction or flare of arthritis and/or sacroiliitis, came to somewhat different conclusions about the beneficial or paradoxical effects of vedolizumab’s blockade of the alpha4beta7 receptor on articular manifestations of IBD.

The five-patient cases series reported by Gaëlle Varkas, MD, a doctoral student at the University of Ghent, Belgium, and her colleagues consisted of five IBD patients, aged 26-50 years, who developed either new onset or an exacerbation of sacroiliitis or arthritis soon after starting vedolizumab. All but one of the patients was female (Ann Rheum Dis. 2016 Nov 29. doi: 10.1136/annrheumdis-2016-210233). In these patients, the investigators said, vedolizumab did not “seem to show any efficacy in and might even induce arthritis and/or sacroiliitis.”

The first was a 50-year-old woman who had progressive back pain with MRI-confirmed bilateral sacroiliitis about 2 months after beginning vedolizumab. The second patient, a 28-year-old woman with no previous history of spondyloarthropathy, had lower limb pain, a painful left shoulder, and arthritis of one wrist. Ultrasound examination confirmed intercarpal effusions and synovial hyperproliferation.

The third patient was 30 years old and male. He had both ankylosing spondylitis and Crohn’s disease, and experienced arthralgias, elevated C-reactive protein, and MRI-confirmed axial skeletal inflammation 4 weeks after starting vedolizumab.

The fourth patient was a 47-year-old woman with no previous history of spondyloarthropathy who developed MRI-confirmed sacroiliitis after beginning vedolizumab. The fifth patient, a 26-year-old woman, developed polyarticular joint pain after starting vedolizumab. Examination of this patient showed synovitis and enthesitis of multiple joints of the appendicular skeleton.

In discussion, Dr. Varkas and her colleagues noted that “one of the many hypotheses is that integrins and adhesion molecules play a role in the interception of recirculating activated lymphocytes between the gut and the synovial membrane due to the inhibition of the alpha4beta7 integrin homing at the level of the gut.” However, the investigators also acknowledged that other hypotheses may also account for their findings. “Alternatively, in the presence of vedolizumab, cellular recruitment may be mediated by yet to be determined adhesion molecules. This recirculation theory might explain the short mean interval of 64 days between vedolizumab initiation and the expression of symptoms.”

Another group, publishing its prospective cohort study in a letter, had different findings (Ann Rheum Dis. 2017 Jan 17. doi: 10.1136/annrheumdis-2016-211011).

“Although the hypotheses proposed by the authors to explain such events sounds reasonable,” wrote Ambrogio Orlando, MD, and his coauthors, their experience of the effect of vedolizumab on spondyloarthritis differed.

In the report on 53 patients who began treatment with vedolizumab at Villa Sofia-Cervello Hospital, Palermo, Italy, where Dr. Orlando and his associates work, almost all (96%) had been steroid dependent and 81% had been treated with at least one tumor necrosis factor inhibitor. About two-thirds had completed the induction phase of vedolizumab treatment during follow-up, which lasted a mean of 2.6 months. Of the 14 patients (26%) who had active IBD-associated spondyloarthropathy when starting vedolizumab, 6 (46.2%) saw “a sharp clinical benefit after the initiation of vedolizumab,” wrote Dr. Orlando and his colleagues. Five of these six patients experienced clinical remission of gut symptoms by 12 weeks of therapy.

Dr. Orlando and his colleagues wrote that “our preliminary prospective data indicate a potential benefit of vedolizumab on IBD-associated spondyloarthropathy.”

Looking for mechanistic reasons for this apparent benefit, Dr. Orlando and his collaborators wrote that “the previous demonstration of alpha4beta7 in the joint and the recent evidence of the upregulation of mucosal vascular address in cell adhesion molecule (MadCAM-1) in the high endothelial venules of bone marrow in patients with active axial SpA seem to strengthen the hypothesis of a beneficial rather than a paradoxical effect of alpha4beta7 blockade on articular manifestations of IBD.”

Two authors of the case series reported relationships with multiple pharmaceutical companies, as did Dr. Orlando and two other authors of the letter describing the prospective study.

koakes@frontlinemedcom.com

On Twitter @karioakes

Two recent reports that provide opposing evidence about the potential for inflammatory bowel disease patients to develop articular manifestations after starting vedolizumab raise questions for future studies to answer in regard to a plausible mechanism for the adverse event and its relative importance.

The two reports, one a case series of 5 patients with inflammatory bowel disease (IBD) who developed articular manifestations after beginning vedolizumab (Entyvio) and the other a prospective cohort study of 53 patients with IBD who started vedolizumab without any subsequent cases of induction or flare of arthritis and/or sacroiliitis, came to somewhat different conclusions about the beneficial or paradoxical effects of vedolizumab’s blockade of the alpha4beta7 receptor on articular manifestations of IBD.

The five-patient cases series reported by Gaëlle Varkas, MD, a doctoral student at the University of Ghent, Belgium, and her colleagues consisted of five IBD patients, aged 26-50 years, who developed either new onset or an exacerbation of sacroiliitis or arthritis soon after starting vedolizumab. All but one of the patients was female (Ann Rheum Dis. 2016 Nov 29. doi: 10.1136/annrheumdis-2016-210233). In these patients, the investigators said, vedolizumab did not “seem to show any efficacy in and might even induce arthritis and/or sacroiliitis.”

The first was a 50-year-old woman who had progressive back pain with MRI-confirmed bilateral sacroiliitis about 2 months after beginning vedolizumab. The second patient, a 28-year-old woman with no previous history of spondyloarthropathy, had lower limb pain, a painful left shoulder, and arthritis of one wrist. Ultrasound examination confirmed intercarpal effusions and synovial hyperproliferation.

The third patient was 30 years old and male. He had both ankylosing spondylitis and Crohn’s disease, and experienced arthralgias, elevated C-reactive protein, and MRI-confirmed axial skeletal inflammation 4 weeks after starting vedolizumab.

The fourth patient was a 47-year-old woman with no previous history of spondyloarthropathy who developed MRI-confirmed sacroiliitis after beginning vedolizumab. The fifth patient, a 26-year-old woman, developed polyarticular joint pain after starting vedolizumab. Examination of this patient showed synovitis and enthesitis of multiple joints of the appendicular skeleton.

In discussion, Dr. Varkas and her colleagues noted that “one of the many hypotheses is that integrins and adhesion molecules play a role in the interception of recirculating activated lymphocytes between the gut and the synovial membrane due to the inhibition of the alpha4beta7 integrin homing at the level of the gut.” However, the investigators also acknowledged that other hypotheses may also account for their findings. “Alternatively, in the presence of vedolizumab, cellular recruitment may be mediated by yet to be determined adhesion molecules. This recirculation theory might explain the short mean interval of 64 days between vedolizumab initiation and the expression of symptoms.”

Another group, publishing its prospective cohort study in a letter, had different findings (Ann Rheum Dis. 2017 Jan 17. doi: 10.1136/annrheumdis-2016-211011).

“Although the hypotheses proposed by the authors to explain such events sounds reasonable,” wrote Ambrogio Orlando, MD, and his coauthors, their experience of the effect of vedolizumab on spondyloarthritis differed.

In the report on 53 patients who began treatment with vedolizumab at Villa Sofia-Cervello Hospital, Palermo, Italy, where Dr. Orlando and his associates work, almost all (96%) had been steroid dependent and 81% had been treated with at least one tumor necrosis factor inhibitor. About two-thirds had completed the induction phase of vedolizumab treatment during follow-up, which lasted a mean of 2.6 months. Of the 14 patients (26%) who had active IBD-associated spondyloarthropathy when starting vedolizumab, 6 (46.2%) saw “a sharp clinical benefit after the initiation of vedolizumab,” wrote Dr. Orlando and his colleagues. Five of these six patients experienced clinical remission of gut symptoms by 12 weeks of therapy.

Dr. Orlando and his colleagues wrote that “our preliminary prospective data indicate a potential benefit of vedolizumab on IBD-associated spondyloarthropathy.”

Looking for mechanistic reasons for this apparent benefit, Dr. Orlando and his collaborators wrote that “the previous demonstration of alpha4beta7 in the joint and the recent evidence of the upregulation of mucosal vascular address in cell adhesion molecule (MadCAM-1) in the high endothelial venules of bone marrow in patients with active axial SpA seem to strengthen the hypothesis of a beneficial rather than a paradoxical effect of alpha4beta7 blockade on articular manifestations of IBD.”

Two authors of the case series reported relationships with multiple pharmaceutical companies, as did Dr. Orlando and two other authors of the letter describing the prospective study.

koakes@frontlinemedcom.com

On Twitter @karioakes

Adults with self-reported lactose intolerance were shown to have significant improvement in their clinical outcomes, including abdominal pain, after consuming an oral, liquid supplement intended to increase lactose-fermenting gut bacteria, M. Andrea Azcarate-Peril, PhD, assistant professor of medicine at the University of North Carolina, Chapel Hill, and her colleagues have shown in a small phase IIa study (Proc Nat Acad Sci. doi: 10.1073/pnas.1606722113).

In a placebo-controlled, double-blind trial, randomly assigned in a 2:1 ratio and conducted at two U.S. sites, highly purified (more than 95%) short-chain galactooligosaccharide (GOS) was given to 42 adults with a self-reported history of lactose intolerance, confirmed by a hydrogen breath test administered after a 25-g lactose challenge. The 20 controls were given a corn syrup mixture formulated according to the same sweetness and consistency as the test drug. Each study arm was started on its regimen at 1.5 g daily, with incremental increases in dose every 5 days until reaching 15 g. Beginning with their first dose at day 1, through day 35, all participants avoided consumption of dairy foods. Stool samples were collected from both groups at days 0 and 36. After day 36, all participants were asked to resume eating dairy foods. At day 66, stool samples were once again collected. Changes in the microbiome at all endpoints were measured by testing the stools via polymerase chain reaction.

Heiko119/Thinkstock

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

Adults with self-reported lactose intolerance were shown to have significant improvement in their clinical outcomes, including abdominal pain, after consuming an oral, liquid supplement intended to increase lactose-fermenting gut bacteria, M. Andrea Azcarate-Peril, PhD, assistant professor of medicine at the University of North Carolina, Chapel Hill, and her colleagues have shown in a small phase IIa study (Proc Nat Acad Sci. doi: 10.1073/pnas.1606722113).

In a placebo-controlled, double-blind trial, randomly assigned in a 2:1 ratio and conducted at two U.S. sites, highly purified (more than 95%) short-chain galactooligosaccharide (GOS) was given to 42 adults with a self-reported history of lactose intolerance, confirmed by a hydrogen breath test administered after a 25-g lactose challenge. The 20 controls were given a corn syrup mixture formulated according to the same sweetness and consistency as the test drug. Each study arm was started on its regimen at 1.5 g daily, with incremental increases in dose every 5 days until reaching 15 g. Beginning with their first dose at day 1, through day 35, all participants avoided consumption of dairy foods. Stool samples were collected from both groups at days 0 and 36. After day 36, all participants were asked to resume eating dairy foods. At day 66, stool samples were once again collected. Changes in the microbiome at all endpoints were measured by testing the stools via polymerase chain reaction.

Heiko119/Thinkstock

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

Adults with self-reported lactose intolerance were shown to have significant improvement in their clinical outcomes, including abdominal pain, after consuming an oral, liquid supplement intended to increase lactose-fermenting gut bacteria, M. Andrea Azcarate-Peril, PhD, assistant professor of medicine at the University of North Carolina, Chapel Hill, and her colleagues have shown in a small phase IIa study (Proc Nat Acad Sci. doi: 10.1073/pnas.1606722113).

In a placebo-controlled, double-blind trial, randomly assigned in a 2:1 ratio and conducted at two U.S. sites, highly purified (more than 95%) short-chain galactooligosaccharide (GOS) was given to 42 adults with a self-reported history of lactose intolerance, confirmed by a hydrogen breath test administered after a 25-g lactose challenge. The 20 controls were given a corn syrup mixture formulated according to the same sweetness and consistency as the test drug. Each study arm was started on its regimen at 1.5 g daily, with incremental increases in dose every 5 days until reaching 15 g. Beginning with their first dose at day 1, through day 35, all participants avoided consumption of dairy foods. Stool samples were collected from both groups at days 0 and 36. After day 36, all participants were asked to resume eating dairy foods. At day 66, stool samples were once again collected. Changes in the microbiome at all endpoints were measured by testing the stools via polymerase chain reaction.

Heiko119/Thinkstock

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

Men who consume higher quantities of red meat are at an increased risk of developing diverticulitis, especially if they’re eating unprocessed red meat, according to a new study published in Gut.

“In our prior analysis from a large prospective cohort study, the Health Professionals Follow-Up Study (HPFS), we found that red meat intake, independent of fiber, may be associated with a composite outcome of symptomatic diverticular disease, which included 385 incident cases over 4 years of follow-up,” wrote the authors, led by Andrew T. Chan, MD, of Massachusetts General Hospital, Boston. Dr. Chan added that “in the present study, we updated this analysis, which allowed us to prospectively examine the association between consumption of meat (total red meat, red unprocessed meat, red processed meat, poultry, and fish) with risk of incident diverticulitis in 764 cases over 26 years of follow-up.”

Dr. Chan and his coinvestigators conducted a prospective cohort study using subjects from the ongoing HPFS. Men who already had a diagnosis of diverticulitis, associated complications, inflammatory bowel disease, or a GI-related cancer at baseline were excluded from this analysis, leaving 46,461 eligible subjects. Of those, 764 developed diverticulitis.

copyright Fuse/Thinkstock

dchitnis@frontlinemedcom.com

Men who consume higher quantities of red meat are at an increased risk of developing diverticulitis, especially if they’re eating unprocessed red meat, according to a new study published in Gut.

“In our prior analysis from a large prospective cohort study, the Health Professionals Follow-Up Study (HPFS), we found that red meat intake, independent of fiber, may be associated with a composite outcome of symptomatic diverticular disease, which included 385 incident cases over 4 years of follow-up,” wrote the authors, led by Andrew T. Chan, MD, of Massachusetts General Hospital, Boston. Dr. Chan added that “in the present study, we updated this analysis, which allowed us to prospectively examine the association between consumption of meat (total red meat, red unprocessed meat, red processed meat, poultry, and fish) with risk of incident diverticulitis in 764 cases over 26 years of follow-up.”

Dr. Chan and his coinvestigators conducted a prospective cohort study using subjects from the ongoing HPFS. Men who already had a diagnosis of diverticulitis, associated complications, inflammatory bowel disease, or a GI-related cancer at baseline were excluded from this analysis, leaving 46,461 eligible subjects. Of those, 764 developed diverticulitis.

copyright Fuse/Thinkstock

dchitnis@frontlinemedcom.com

Men who consume higher quantities of red meat are at an increased risk of developing diverticulitis, especially if they’re eating unprocessed red meat, according to a new study published in Gut.

“In our prior analysis from a large prospective cohort study, the Health Professionals Follow-Up Study (HPFS), we found that red meat intake, independent of fiber, may be associated with a composite outcome of symptomatic diverticular disease, which included 385 incident cases over 4 years of follow-up,” wrote the authors, led by Andrew T. Chan, MD, of Massachusetts General Hospital, Boston. Dr. Chan added that “in the present study, we updated this analysis, which allowed us to prospectively examine the association between consumption of meat (total red meat, red unprocessed meat, red processed meat, poultry, and fish) with risk of incident diverticulitis in 764 cases over 26 years of follow-up.”

Dr. Chan and his coinvestigators conducted a prospective cohort study using subjects from the ongoing HPFS. Men who already had a diagnosis of diverticulitis, associated complications, inflammatory bowel disease, or a GI-related cancer at baseline were excluded from this analysis, leaving 46,461 eligible subjects. Of those, 764 developed diverticulitis.

copyright Fuse/Thinkstock

dchitnis@frontlinemedcom.com

Payment for the infliximab biosimilar drug Inflectra will now be covered by Medicare, the drug’s manufacturer, Pfizer, said in an announcement.

The Centers for Medicare & Medicaid Services (CMS) included Inflectra (infliximab-dyyb) in its January 2017 Average Sales Price pricing file, which went into effect Jan. 1, 2017. Pfizer said that Inflectra is priced at a 15% discount to the current wholesale acquisition cost for the infliximab originator Remicade, but this price does not include discounts to payers, providers, distributors, and other purchasing organizations.

For the first quarter of 2017, the payment limit set by the CMS for Inflectra is $100.306 per 10-mg unit and $82.218 for Remicade.

Various national and regional wholesalers across the country began receiving shipments of Inflectra in November 2016, according to Pfizer.

In conjunction with the availability of Inflectra, Pfizer announced its enCompass program, “a comprehensive reimbursement service and patient support program offering coding and reimbursement support for providers, copay assistance to eligible patients who have commercial insurance that covers Inflectra, and financial assistance for eligible uninsured and underinsured patients.”

The FDA approved Inflectra in April 2016 for all of the same indications as Remicade: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, plaque psoriasis, and ulcerative colitis.

jevans@frontlinmedcom.com

Payment for the infliximab biosimilar drug Inflectra will now be covered by Medicare, the drug’s manufacturer, Pfizer, said in an announcement.

The Centers for Medicare & Medicaid Services (CMS) included Inflectra (infliximab-dyyb) in its January 2017 Average Sales Price pricing file, which went into effect Jan. 1, 2017. Pfizer said that Inflectra is priced at a 15% discount to the current wholesale acquisition cost for the infliximab originator Remicade, but this price does not include discounts to payers, providers, distributors, and other purchasing organizations.

For the first quarter of 2017, the payment limit set by the CMS for Inflectra is $100.306 per 10-mg unit and $82.218 for Remicade.

Various national and regional wholesalers across the country began receiving shipments of Inflectra in November 2016, according to Pfizer.

In conjunction with the availability of Inflectra, Pfizer announced its enCompass program, “a comprehensive reimbursement service and patient support program offering coding and reimbursement support for providers, copay assistance to eligible patients who have commercial insurance that covers Inflectra, and financial assistance for eligible uninsured and underinsured patients.”

The FDA approved Inflectra in April 2016 for all of the same indications as Remicade: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, plaque psoriasis, and ulcerative colitis.

jevans@frontlinmedcom.com

Payment for the infliximab biosimilar drug Inflectra will now be covered by Medicare, the drug’s manufacturer, Pfizer, said in an announcement.

The Centers for Medicare & Medicaid Services (CMS) included Inflectra (infliximab-dyyb) in its January 2017 Average Sales Price pricing file, which went into effect Jan. 1, 2017. Pfizer said that Inflectra is priced at a 15% discount to the current wholesale acquisition cost for the infliximab originator Remicade, but this price does not include discounts to payers, providers, distributors, and other purchasing organizations.

For the first quarter of 2017, the payment limit set by the CMS for Inflectra is $100.306 per 10-mg unit and $82.218 for Remicade.

Various national and regional wholesalers across the country began receiving shipments of Inflectra in November 2016, according to Pfizer.

In conjunction with the availability of Inflectra, Pfizer announced its enCompass program, “a comprehensive reimbursement service and patient support program offering coding and reimbursement support for providers, copay assistance to eligible patients who have commercial insurance that covers Inflectra, and financial assistance for eligible uninsured and underinsured patients.”

The FDA approved Inflectra in April 2016 for all of the same indications as Remicade: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, plaque psoriasis, and ulcerative colitis.

jevans@frontlinmedcom.com