Approaching a cure: Treatments offer promise to delay, improve life with type 1 diabetes
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For people living with type 1 diabetes and the clinicians and researchers who treat and study the disease, 2021 was a year of groundbreaking achievements and cause for optimism. Though as with any new experimental treatments, caveats abound.
Developments in the fields of beta-cell regeneration, investigational cell therapy, stem cell transplantation and immunotherapy, among others, have yielded big gains in type 1 diabetes research during the past year, seemingly month after month. In April, the FDA granted breakthrough therapy designation for an oral, once-daily glucokinase activator (vTv Therapeutics) as an adjunct to insulin shown to improve glycemic control without increasing risk for hypoglycemia. That same month, an FDA advisory panel voted in favor of the investigational cell therapy donislecel (Lantidra, CellTrans), shown to increase insulin independence and decrease the number of severe hypoglycemic events among patients with difficult-to-control type 1 diabetes.
In May, an FDA advisory panel recommended approval of the immunotherapy teplizumab (Provention Bio), shown to delay development of type 1 diabetes for some high-risk children and adults, in some cases by years, although the agency ultimately declined to approve the therapy.
In October, Vertex announced positive 90-day data for the first patient in a phase 1/2 clinical trial dosed with VX-880, a novel investigational stem cell-derived therapy for type 1 diabetes. The patient, lauded in news reports, has been described as the first person “cured” of diabetes after receiving an infusion of cells.
“What was different about 2021 was that, for the first time, we finally started moving outside of our thinking of the past 100 years,” Kevan Herold, MD, the C.N.H. Long Professor of Immunobiology and Medicine at Yale School of Medicine, told Endocrine Today. “Our treatment strategy has been that we will give you insulin and watch your diet, and then we will figure out new ways of giving insulin. It has been the same story for 100 years. Developments like hybrid closed-loop insulin pumps are absolutely changing the way we treat diabetes. But it’s the same approach.”
Advancements in insulin formulations and wearable technologies have substantially improved quality of life and lessened the risk for severe hypoglycemia for people with type 1 diabetes. However, the latest devices or insulins still fail to restore normal physiologic control of blood glucose. Of the 1.6 million people living with type 1 diabetes in the U.S., fewer than one-third regulate and maintain glucose targets consistently.
“Despite these technologies in the box, the average HbA1c for a person with type 1 diabetes rarely meets even American Diabetes Association standards of care,” Herold said. “We clearly need something to change the paradigm, and that is where we are heading.”
Some advancements, however, come with their own risks. Stem cell therapy, for example, comes with risks for autoimmunity and alloimmunity. Chronic immunotherapy has been associated with possible risk for cancer. More work also must be done to know how long new beta cells will survive, whether such approaches will work for everyone with type 1 diabetes, and how to make such treatments scalable for the nearly 20 million people in the world living with type 1 diabetes.“The advances are exciting. The way to look at these are as first steps, but the devil is in the details,” Irl B. Hirsch, MD, professor of medicine at the University of Washington School of Medicine in Seattle, told Endocrine Today. “We have these wonderful tools, but to me the real story is how do we do a better job for type 1 diabetes with implementing what we already have? Teplizumab, stem cell therapies, all those things are great — but the average person may never have access to these, ever. I hope I am wrong.”
Progress accelerating
For decades, the pace of developments in the type 1 diabetes space has been slow and methodical, despite past promises to the contrary. Recent progress in genetics, technology and data collection has allowed increased collaboration and faster discoveries.
“I spent 10 years cloning a gene and purifying a protein. Now, you don’t even do that. You just go online and it’s right there, thanks to the genome project,” Andrew F. Stewart, MD, director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, told Endocrine Today. “Now we are developing tools to understand 3D organization of the genome on a whole cell basis. Bioinformatics and data have advanced immensely. You might see something and go after it for your project; I see something and go after it for my project. Then we put those together and we both see things you cannot see alone. That is why things are accelerating.”
The type 1 diabetes therapies getting attention this year have been decades in the making, according to Dawn Belt Davis, MD, PhD, professor in the division of endocrinology at the University of Wisconsin-Madison, section chief of endocrinology at the William S. Middleton Memorial Veterans Hospital, director of the UW-Madison Comprehensive Diabetes Center, and an Endocrine Today Editorial Board Member.
“On the preclinical side, we have been investigating the concept of stem cell therapy or islet transplant therapy for decades, coming up with better ways to improve outcomes and minimize the negative impact of immunosuppression,” Davis told Endocrine Today. “The same goes for the glucokinase activator. That is a concept looked at for many years in type 2 diabetes, and now we are looking at application for type 1. Obviously, there have been some big advances this year finally getting that early-stage clinical trial data; however, we must recognize this is a long time coming, and a lot of work brought us to this point.”
‘It’s not a fantasy ... it can happen’
Announcing positive 90-day data from its phase 1/2 trial, Vertex said a patient with type 1 diabetes was treated with a single infusion of VX-880 human embryonic stem cell-derived islet product at half the target dose, in conjunction with immunosuppression, through intraportal cell delivery. In the 1 year before treatment, the patient experienced five severe hypoglycemic episodes and was treated with 34 U insulin per day. Fasting and stimulated C-peptide levels were undetectable.
After treatment, the patient achieved successful engraftment and demonstrated “rapid and robust improvements” in multiple measures, including increases in fasting and stimulated C-peptide, improvements in glycemic control, including HbA1c, and decreases in exogenous insulin requirement. VX-880 was generally well tolerated.
“People have been trying to turn stem cells — embryonic stem cells, tissue stem cells, any stem cells — into beta cells for years,” said Stewart, whose work focuses on inducing remaining human pancreatic beta cells in people with type 1 and type 2 diabetes to regenerate using orally administered drugs. “The goal has always been to figure out how to turn any stem cell into a mature beta cell. What this study says to me is it is possible. It’s not a fantasy; it’s not a cocktail party discussion. It can happen. That is huge. This is thanks to really good people working hard for a long time, not letting up.”
A need for lifelong immune suppression, however, carries its own risks for nephrotoxicity, infection and cancer. When transplants are carried out in people with type 1 diabetes, preventing recurrent autoimmune islet destruction remains a challenge with some patients. The risk that comes with immunosuppression must be balanced with the daily risks of living with type 1 diabetes, particularly during a time when developments in insulin delivery and technology have helped to ease disease burden, Davis said.
“The burden of chronic immunosuppression is also something we have to take seriously,” said Davis, whose institution is a participating site in the Vertex trial. “We worry about trading one burden — living with type 1 diabetes — for another with immunosuppression, essentially. This is [a treatment] to help those people who are not doing well with the current options, who for many reasons may not be able to participate in meaningful improvements in their care. The great news is we have made improvements on both sides of the fence. That means that, maybe, there may be less people who need this type of aggressive treatment moving forward, because they can manage more effectively on their own now.”
Ongoing research includes efforts to protect stem cell islets from immune attack. One approach, involving both gene deletions and additions to protect cells, is expected to be tested in clinical trials in coming months. The goal for researchers is to one day transplant cells successfully without the need for immune suppression.
“It is exciting to be moving to this phase for the first time and be a part of it,” Davis said. “It is getting a lot of national press, but again, we want to caution that this is something for a very specific subset of patients with type 1. Not every person with type 1 diabetes should receive immunosuppressive therapy for a transplant. There are many known risks with that.”
Teplizumab: Promise of delayed diagnosis
In May, an FDA advisory panel voted 10-7 in favor of recommending approval of the humanized anti-CD3 monoclonal antibody teplizumab to delay development of type 1 diabetes in high-risk children and adults, although most committee members also expressed some concerns about trial size and safety.
In casting their votes, most members of the Endocrinologic and Metabolic Drugs Advisory Committee said they struggled with their decision. A randomized clinical trial showed teplizumab delayed the median time to development of type 1 diabetes by 2 years in children as young as age 8 years after a single 14-day course of the drug. Members weighed the importance of reducing the disease burden and complications of type 1 diabetes with questions of efficacy and potential safety concerns.
In July, the FDA issued a complete response letter for teplizumab, stating a study failed to show pharmacokinetic comparability. In a press release, Provention Bio said the FDA stated that a single, low-dose pharmacokinetic/pharmacodynamic bridging study in healthy volunteers to compare the planned commercial product with the drug product originating from drug substance manufactured for historic clinical trials failed to show pharmacokinetic comparability.
Herold is hopeful teplizumab will be approved by FDA later this year.
“Like many families with individuals at risk for developing type 1 diabetes, I hope there is approval in 2022,” Herold said. “The issue captured in the complete response letter had to do with a new lot of drug. It had nothing to do with efficacy or any of the clinical data. It was what I consider to be a manufacturing matter with the new production of the monoclonal antibody.”
If FDA ultimately approves the treatment, the decision will “change the playing field,” Herold said, offering people at high risk for developing type 1 a chance to delay disease onset, perhaps by years.
“If you are about to go into elementary school, and now you are not going to get diabetes until 3 years later, your opportunities to mature and grow and manage your disease are tremendous,” Herold said. “Likewise, if you are about to go into middle school, and now you’re not going to get diabetes until high school, that is a big deal. For a child, this is meaningful, not just in terms of maturation, but the way we treat diabetes this year is not the way we treated diabetes 3 years ago or even 5 years ago. If nothing else, to put a hold on things and allow developments to occur is undoubtedly better.”
Not every patient who received an infusion of teplizumab experienced delay of disease onset, and Herold points out the need for more research to learn who are the optimal responders to treatment.
“For all drugs, some people do not respond, whereas other have very robust responses,” Herold said. “Some people are beyond 7 years and still do not have diabetes. If you asked anyone with diabetes what they would give to not have diabetes for 7 years, they would tell you almost anything. The effects are huge for the people who live with it.”
Ensuring access to new discoveries
The newest treatments have generated media attention and talk of a possible “cure” within reach; however, access to diabetes therapies must be addressed, according to Hirsch. In 2022, many patients continue to struggle to afford insulin and other essential diabetes supplies. Many more lack access to comprehensive diabetes care.
“I have no interaction with any of these companies, and [the treatments] are exciting,” Hirsch said. “But at the very best, they are the future. I worry about reimbursement. ... [I worry that these therapies] are not going to be for the 50% of adults with type 1 diabetes getting therapy in primary care. Those patients do not have access to what we have now, not to mention the expertise.”
What may help many people with type 1 diabetes soon is new technology that could allow the use of FDA-approved therapies with an indication for type 2 diabetes, such as SGLT2 inhibitors, which can significantly reduce risks for adverse cardiovascular and renal outcomes, Hirsch said. Drugs such as sotagliflozin (approved in the European Union as Zynquista and developed by Lexicon), a dual SGLT 1/2 inhibitor, and the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca), have failed to earn the backing of an FDA advisory panel for a type 1 indication due to concerns about increased risk for diabetic ketoacidosis.
“All of these other therapies are great, but we also have therapies right under our nose, and quite frankly, it’s a shorter distance to get to them, use them in type 1, and have a greater impact on more people,” Hirsch said.
In a first-in-human study published in April in the Journal of Diabetes Science and Technology, researchers demonstrated that a continuous ketone monitor (Abbott), similar to a continuous glucose monitor, performed well against capillary ketone values in measuring interstitial fluid ketone levels for 14 days in 12 healthy adults assigned low-carbohydrate diets. Such technology could allow people with type 1 diabetes to safely use therapies currently approved for people with type 2, Hirsch said.
“The big issue is many of us feel that we are going to need technology like that to safely mitigate using SGLT2 inhibitors in type 1 diabetes, for glucose control but maybe also for kidney disease and heart failure,” Hirsch said. “We do not use them in type 1 diabetes now because of the DKA risk. I am more interested in that, because those drugs are reasonably affordable and could be deployed right away, as opposed to cell transplants that approach $300,000 per year.”
Herold, who agreed it is “too much” to promise a cure for type 1 diabetes at this point, said researchers are working during a time of pivotal discoveries.
“The currently available therapies, especially those that use new technologies and even insulin itself, are expensive,” Herold said. “The costs of these transformative therapies, whatever they will be, needs to be balanced with the financial, physical, personal costs of living with diabetes.”
Herold, who serves as chair of TrialNet, an international network of institutions and health care teams offering screening for type 1 diabetes, said eligibility criteria to enter have been broadened beyond first-degree relatives of people with type 1 diabetes.
“At TrialNet, we have taken the success of TN-10 trial to be a charge to action,” Herold said. “We are trying to expand the number of individuals we can screen. You can now get into TrialNet even if in the general population. We want to broaden our reach. It is important to recognize that this is not over yet. There is work to be done, and we need to use what we have learned from the trials to take us to the next step. This is not just by chance. We can figure out how to make the therapies we have impactful for families and patients. We are in a place we have never been before.”
- References:
- Alva S, et al. J Diabetes Sci Technol. 2021;doi:10.1177/19322968211008185.
- FDA Briefing Document: Cellular, Tissue and Gene Therapies Advisory Committee Meeting. Available at: www.fda.gov/media/147525/download. Published April 15, 2021. Accessed Jan. 18, 2022.
- Sanofi: FDA issues complete response letter for sotagliflozin. Available at: www.sanofi.com/en/media-room/press-releases/2019/2019-03-22-19-15-00. Published March 22, 2019. Accessed Jan. 18, 2022.
- Sims EK, et al. Sci Transl Med. 2021;doi:10.1126/scitranslmed.abc8980.
- Vertex press release. Available at: news.vrtx.com/press-release/vertex-announces-positive-day-90-data-first-patient-phase-12-clinical-trial-dosed-vx?_ga=2.151952570.2012838280.1641583258-906097575.1640196292. Published Oct. 18, 2021. Accessed Jan. 18, 2022.
- For more information:
- Dawn Belt Davis, MD, PhD, can be reached at dbd@medicine.wisc.edu; Twitter: @DawnDavisLab.
- Kevan Herold, MD, can be reached at kevan.herold@yale.edu.
- Irl B. Hirsch, MD, can be reached at ihirsch@uw.edu.
- Andrew F. Stewart, MD, can be reached at andrew.stewart@mssm.edu.
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