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A Food and Drug Administration advisory panel has endorsed a pancreatic islet cell transplant therapy for the treatment of people with type 1 diabetes that can’t be managed with current therapies.
On April 15, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 12 to 4 in favor of approval of donislecel (Lantidra). There was one abstention. The panel regarded the drug as having “an overall favorable benefit-risk profile for some patients with type 1 diabetes.” The product consists of purified allogeneic pancreatic islets of Langerhans derived from cadaveric donors and is infused into the portal vein of the liver.
Benefits of the treatment include the potential for insulin independence and elimination of severe hypoglycemia. Risks are those associated with the surgical procedure and with long-term immunosuppression.
The therapy is manufactured by CellTrans. According to Jose Oberholzer, MD, the founder of CellTrans, the proposed indication is for adults with “brittle” type 1 diabetes who meet the American Diabetes Association’s (ADA) criteria for whole-organ pancreas-alone transplant (i.e., transplant of pancreas but not kidney).
The ADA criteria include the following: frequent, severe hypoglycemia, hyperglycemia, and/or ketoacidosis that requires medical attention; clinical or emotional problems regarding the use of exogenous insulin; and consistent failure of insulin-based management to prevent acute diabetes complications.
Success in two-thirds of patients in small studies
Dr. Oberholzer presented data from two single-arm open-label studies: a phase 1/2 trial initiated in 2004 with 10 patients, and a phase 3 study with 20 patients that began in 2007. The inclusion criteria differed somewhat between the two studies, but all 30 patients had hypoglycemic unawareness. Mean follow-up was 7.8 years for the phase 1/2 trial and 4.7 years for the phase 3 trial.
For all of the patients, C-peptide levels were positive after transplant. The composite endpoint for success – an A1c level of ≤ 6.5% and the absence of severe hypoglycemic episodes for 1 year – was met by 19 patients (63.3%). For five patients (16.7%), the target A1c level was not achieved, and seven patients (23.3%) experienced a severe episode of hypoglycemia.
Twenty of the 30 patients achieved insulin independence for at least 1 year.
Improvements were also seen at 1 year in mixed meal test outcomes, fasting blood glucose levels, and overall glycemic control. Graft survival 10 years post transplant was achieved by 60% of patients, Dr. Oberholzer said.
Adverse events not unexpected, but still of concern
Two patients died, one as a result of fulminant sepsis at 20 months post transplant, and the other as a result of severe dementia 9 years post transplant. Three patients experienced four serious procedure-related events, including one liver laceration and two hepatic hematomas. Elevations in portal pressure occurred in two patients.
Most adverse events were associated with immunosuppression. These included 178 infections in 26 of the 30 patients. The most common of these were herpes virus infections, Epstein-Barr virus infections, oral candidiasis, and cytomegalovirus infections. Twelve infections were severe. Renal function declined persistently in two patients (20%), and six (20%) experienced new-onset proteinuria at 1 year.
The adverse events related to the procedure and the problems associated with immunosuppression were not unexpected and were consistent with those described for patients receiving whole pancreas transplants, FDA reviewer Patricia Beaston, MD, said in her review of the CellTrans data.
Panel members support treatment for a small group of patients
During the discussion, several panel members pointed out that the target patient population for this treatment will likely be smaller today than it was when the two studies were initiated, given advances in diabetes care. Those advances include continuous glucose monitoring devices with alarms and closed-loop insulin delivery systems – the “artificial pancreas” that automatically suspends insulin delivery to prevent hypoglycemia.
Panel chair Lisa Butterfield, PhD, a surgeon and immunologist at the University of California, San Francisco, voted in favor of approval. But, she added, “I do support postapproval gathering of data to learn more about the product. ... I don’t know how many patients will really benefit, but I think it’s to be determined.”
Christopher K. Breuer, MD, a general and pediatric surgeon at the Center for Regenerative Medicine, Nationwide Children’s Hospital, Columbus, Ohio, said he supported approval for “two very small subpopulations where it would provide the only viable therapy”: those who are eligible for pancreas transplant but cannot tolerate a major operation, and those who already use the latest automated insulin delivery systems and still do not achieve acceptable glycemic control.
Temporary voting member David Harlan, MD, director of the University of Massachusetts Diabetes Center of Excellence, Worcester, Mass., voted no.
He noted that only about 100 whole pancreas-only transplants are performed annually in the United States and that such transplants are “very effective, so we’re talking about patients who aren’t pancreas transplant candidates who might get this.”
Moreover, Dr. Harlan said, “I’ve seen the awful things that can happen in posttransplant recipients. It’s really hard to get that informed consent from someone when you’re asking them to consider a future that they don’t know. When it works, it’s great. When it doesn’t work, it can be catastrophic. I just worry about opening Pandora’s box.”
The only other diabetes specialist on the panel, temporary voting member Ellen Leschek, MD, said she “reluctantly voted yes because a few people could benefit, but I think it’s a much smaller number than the company may believe.”
Dr. Leschek, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said she’s concerned that “if it’s approved, too many people will get treated this way, when in fact, for a lot of those people, the risks will outweigh the benefits.”
Sandy Feng, MD, PhD, of the department of surgery at the University of California, San Francisco, pointed out that with regard to immunosuppressive therapy, “We’re concerned about the toxicity of what we currently use, but there are additional therapies being developed that might mitigate those toxicities that would be beneficial to this population.”
Dr. Feng, who voted yes, also said, “I do pancreas transplants. I can tell you that there is nothing that [patients with type 1 diabetes] like more than the freedom from dealing with the entire insulin issue. That has made a large impression on me over the last 20-plus years of clinical practice, so I do think this can help some people and will be incredibly meaningful to those people.”
FDA advisory panel members are vetted for conflicts of interest, and special waivers are granted if necessary. No such waivers were granted for this meeting.
A version of this article first appeared on Medscape.com.
A Food and Drug Administration advisory panel has endorsed a pancreatic islet cell transplant therapy for the treatment of people with type 1 diabetes that can’t be managed with current therapies.
On April 15, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 12 to 4 in favor of approval of donislecel (Lantidra). There was one abstention. The panel regarded the drug as having “an overall favorable benefit-risk profile for some patients with type 1 diabetes.” The product consists of purified allogeneic pancreatic islets of Langerhans derived from cadaveric donors and is infused into the portal vein of the liver.
Benefits of the treatment include the potential for insulin independence and elimination of severe hypoglycemia. Risks are those associated with the surgical procedure and with long-term immunosuppression.
The therapy is manufactured by CellTrans. According to Jose Oberholzer, MD, the founder of CellTrans, the proposed indication is for adults with “brittle” type 1 diabetes who meet the American Diabetes Association’s (ADA) criteria for whole-organ pancreas-alone transplant (i.e., transplant of pancreas but not kidney).
The ADA criteria include the following: frequent, severe hypoglycemia, hyperglycemia, and/or ketoacidosis that requires medical attention; clinical or emotional problems regarding the use of exogenous insulin; and consistent failure of insulin-based management to prevent acute diabetes complications.
Success in two-thirds of patients in small studies
Dr. Oberholzer presented data from two single-arm open-label studies: a phase 1/2 trial initiated in 2004 with 10 patients, and a phase 3 study with 20 patients that began in 2007. The inclusion criteria differed somewhat between the two studies, but all 30 patients had hypoglycemic unawareness. Mean follow-up was 7.8 years for the phase 1/2 trial and 4.7 years for the phase 3 trial.
For all of the patients, C-peptide levels were positive after transplant. The composite endpoint for success – an A1c level of ≤ 6.5% and the absence of severe hypoglycemic episodes for 1 year – was met by 19 patients (63.3%). For five patients (16.7%), the target A1c level was not achieved, and seven patients (23.3%) experienced a severe episode of hypoglycemia.
Twenty of the 30 patients achieved insulin independence for at least 1 year.
Improvements were also seen at 1 year in mixed meal test outcomes, fasting blood glucose levels, and overall glycemic control. Graft survival 10 years post transplant was achieved by 60% of patients, Dr. Oberholzer said.
Adverse events not unexpected, but still of concern
Two patients died, one as a result of fulminant sepsis at 20 months post transplant, and the other as a result of severe dementia 9 years post transplant. Three patients experienced four serious procedure-related events, including one liver laceration and two hepatic hematomas. Elevations in portal pressure occurred in two patients.
Most adverse events were associated with immunosuppression. These included 178 infections in 26 of the 30 patients. The most common of these were herpes virus infections, Epstein-Barr virus infections, oral candidiasis, and cytomegalovirus infections. Twelve infections were severe. Renal function declined persistently in two patients (20%), and six (20%) experienced new-onset proteinuria at 1 year.
The adverse events related to the procedure and the problems associated with immunosuppression were not unexpected and were consistent with those described for patients receiving whole pancreas transplants, FDA reviewer Patricia Beaston, MD, said in her review of the CellTrans data.
Panel members support treatment for a small group of patients
During the discussion, several panel members pointed out that the target patient population for this treatment will likely be smaller today than it was when the two studies were initiated, given advances in diabetes care. Those advances include continuous glucose monitoring devices with alarms and closed-loop insulin delivery systems – the “artificial pancreas” that automatically suspends insulin delivery to prevent hypoglycemia.
Panel chair Lisa Butterfield, PhD, a surgeon and immunologist at the University of California, San Francisco, voted in favor of approval. But, she added, “I do support postapproval gathering of data to learn more about the product. ... I don’t know how many patients will really benefit, but I think it’s to be determined.”
Christopher K. Breuer, MD, a general and pediatric surgeon at the Center for Regenerative Medicine, Nationwide Children’s Hospital, Columbus, Ohio, said he supported approval for “two very small subpopulations where it would provide the only viable therapy”: those who are eligible for pancreas transplant but cannot tolerate a major operation, and those who already use the latest automated insulin delivery systems and still do not achieve acceptable glycemic control.
Temporary voting member David Harlan, MD, director of the University of Massachusetts Diabetes Center of Excellence, Worcester, Mass., voted no.
He noted that only about 100 whole pancreas-only transplants are performed annually in the United States and that such transplants are “very effective, so we’re talking about patients who aren’t pancreas transplant candidates who might get this.”
Moreover, Dr. Harlan said, “I’ve seen the awful things that can happen in posttransplant recipients. It’s really hard to get that informed consent from someone when you’re asking them to consider a future that they don’t know. When it works, it’s great. When it doesn’t work, it can be catastrophic. I just worry about opening Pandora’s box.”
The only other diabetes specialist on the panel, temporary voting member Ellen Leschek, MD, said she “reluctantly voted yes because a few people could benefit, but I think it’s a much smaller number than the company may believe.”
Dr. Leschek, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said she’s concerned that “if it’s approved, too many people will get treated this way, when in fact, for a lot of those people, the risks will outweigh the benefits.”
Sandy Feng, MD, PhD, of the department of surgery at the University of California, San Francisco, pointed out that with regard to immunosuppressive therapy, “We’re concerned about the toxicity of what we currently use, but there are additional therapies being developed that might mitigate those toxicities that would be beneficial to this population.”
Dr. Feng, who voted yes, also said, “I do pancreas transplants. I can tell you that there is nothing that [patients with type 1 diabetes] like more than the freedom from dealing with the entire insulin issue. That has made a large impression on me over the last 20-plus years of clinical practice, so I do think this can help some people and will be incredibly meaningful to those people.”
FDA advisory panel members are vetted for conflicts of interest, and special waivers are granted if necessary. No such waivers were granted for this meeting.
A version of this article first appeared on Medscape.com.
A Food and Drug Administration advisory panel has endorsed a pancreatic islet cell transplant therapy for the treatment of people with type 1 diabetes that can’t be managed with current therapies.
On April 15, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 12 to 4 in favor of approval of donislecel (Lantidra). There was one abstention. The panel regarded the drug as having “an overall favorable benefit-risk profile for some patients with type 1 diabetes.” The product consists of purified allogeneic pancreatic islets of Langerhans derived from cadaveric donors and is infused into the portal vein of the liver.
Benefits of the treatment include the potential for insulin independence and elimination of severe hypoglycemia. Risks are those associated with the surgical procedure and with long-term immunosuppression.
The therapy is manufactured by CellTrans. According to Jose Oberholzer, MD, the founder of CellTrans, the proposed indication is for adults with “brittle” type 1 diabetes who meet the American Diabetes Association’s (ADA) criteria for whole-organ pancreas-alone transplant (i.e., transplant of pancreas but not kidney).
The ADA criteria include the following: frequent, severe hypoglycemia, hyperglycemia, and/or ketoacidosis that requires medical attention; clinical or emotional problems regarding the use of exogenous insulin; and consistent failure of insulin-based management to prevent acute diabetes complications.
Success in two-thirds of patients in small studies
Dr. Oberholzer presented data from two single-arm open-label studies: a phase 1/2 trial initiated in 2004 with 10 patients, and a phase 3 study with 20 patients that began in 2007. The inclusion criteria differed somewhat between the two studies, but all 30 patients had hypoglycemic unawareness. Mean follow-up was 7.8 years for the phase 1/2 trial and 4.7 years for the phase 3 trial.
For all of the patients, C-peptide levels were positive after transplant. The composite endpoint for success – an A1c level of ≤ 6.5% and the absence of severe hypoglycemic episodes for 1 year – was met by 19 patients (63.3%). For five patients (16.7%), the target A1c level was not achieved, and seven patients (23.3%) experienced a severe episode of hypoglycemia.
Twenty of the 30 patients achieved insulin independence for at least 1 year.
Improvements were also seen at 1 year in mixed meal test outcomes, fasting blood glucose levels, and overall glycemic control. Graft survival 10 years post transplant was achieved by 60% of patients, Dr. Oberholzer said.
Adverse events not unexpected, but still of concern
Two patients died, one as a result of fulminant sepsis at 20 months post transplant, and the other as a result of severe dementia 9 years post transplant. Three patients experienced four serious procedure-related events, including one liver laceration and two hepatic hematomas. Elevations in portal pressure occurred in two patients.
Most adverse events were associated with immunosuppression. These included 178 infections in 26 of the 30 patients. The most common of these were herpes virus infections, Epstein-Barr virus infections, oral candidiasis, and cytomegalovirus infections. Twelve infections were severe. Renal function declined persistently in two patients (20%), and six (20%) experienced new-onset proteinuria at 1 year.
The adverse events related to the procedure and the problems associated with immunosuppression were not unexpected and were consistent with those described for patients receiving whole pancreas transplants, FDA reviewer Patricia Beaston, MD, said in her review of the CellTrans data.
Panel members support treatment for a small group of patients
During the discussion, several panel members pointed out that the target patient population for this treatment will likely be smaller today than it was when the two studies were initiated, given advances in diabetes care. Those advances include continuous glucose monitoring devices with alarms and closed-loop insulin delivery systems – the “artificial pancreas” that automatically suspends insulin delivery to prevent hypoglycemia.
Panel chair Lisa Butterfield, PhD, a surgeon and immunologist at the University of California, San Francisco, voted in favor of approval. But, she added, “I do support postapproval gathering of data to learn more about the product. ... I don’t know how many patients will really benefit, but I think it’s to be determined.”
Christopher K. Breuer, MD, a general and pediatric surgeon at the Center for Regenerative Medicine, Nationwide Children’s Hospital, Columbus, Ohio, said he supported approval for “two very small subpopulations where it would provide the only viable therapy”: those who are eligible for pancreas transplant but cannot tolerate a major operation, and those who already use the latest automated insulin delivery systems and still do not achieve acceptable glycemic control.
Temporary voting member David Harlan, MD, director of the University of Massachusetts Diabetes Center of Excellence, Worcester, Mass., voted no.
He noted that only about 100 whole pancreas-only transplants are performed annually in the United States and that such transplants are “very effective, so we’re talking about patients who aren’t pancreas transplant candidates who might get this.”
Moreover, Dr. Harlan said, “I’ve seen the awful things that can happen in posttransplant recipients. It’s really hard to get that informed consent from someone when you’re asking them to consider a future that they don’t know. When it works, it’s great. When it doesn’t work, it can be catastrophic. I just worry about opening Pandora’s box.”
The only other diabetes specialist on the panel, temporary voting member Ellen Leschek, MD, said she “reluctantly voted yes because a few people could benefit, but I think it’s a much smaller number than the company may believe.”
Dr. Leschek, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said she’s concerned that “if it’s approved, too many people will get treated this way, when in fact, for a lot of those people, the risks will outweigh the benefits.”
Sandy Feng, MD, PhD, of the department of surgery at the University of California, San Francisco, pointed out that with regard to immunosuppressive therapy, “We’re concerned about the toxicity of what we currently use, but there are additional therapies being developed that might mitigate those toxicities that would be beneficial to this population.”
Dr. Feng, who voted yes, also said, “I do pancreas transplants. I can tell you that there is nothing that [patients with type 1 diabetes] like more than the freedom from dealing with the entire insulin issue. That has made a large impression on me over the last 20-plus years of clinical practice, so I do think this can help some people and will be incredibly meaningful to those people.”
FDA advisory panel members are vetted for conflicts of interest, and special waivers are granted if necessary. No such waivers were granted for this meeting.
A version of this article first appeared on Medscape.com.