A high-potential drug for type 1 diabetes may not have received regulation this year, but it sparked vital conversation among experts.
The promise of breakthrough agents and treatments can have tremendous impacts for specialists and patients in that specific field—an avenue to reduce its burden and an advancement to improve quality of life.
But, with the idea of a singular event such as this, the level of hope does not always meet its intended promise and sometimes questions still remain, despite being an overall worthwhile step forward.
This year, the field of type 1 diabetes (T1D) had moments that may have shifted the possibility care and how many people may suffer from the disease. Of course, thinking in the context of 100 years from the discovery of insulin, it might make these moments feel monumentally larger and potentially fall farther when they do not match expectations.
Still, the conversation surrounding the T1D agent teplizumab proved to be one of the biggest stories of the year in medicine and experts shared their opinions on what it represented in the state of diabetic care opportunities in 2021.
Earlier this year in May, the US Food and Drug Administration (FDA) reviewed the Biologics License Application (BLA) for teplizumab, an investigational candidate for the delay of T1D in at-risk individuals. The agent is an investigational anti-CD3 monoclonal antibody developed for the delay of clinical T1D.
The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) reviewed the safety and efficacy of the BLA for teplizumab intravenous infusion, submitted by Provention Bio, Inc.
Its application was based on the TN-10 study that observed a single 14-day course of teplizumab delayed the clinical disease and insulin-dependence by at least 2 years in pre-symptomatic patients with stage 2 T1D, when compared to placebo. The analysis showed the agent had the ability to preserve beta-cell function shown by C-peptide in ≥800 assessed patients.
After a series of assessments and analyses, the committee voted 10-7 to support the benefit-risks of teplizumab for delaying T1D, noting its major clinical need and benefit. However, they did note uncertainties regarding the target population, safety issues, and limited data set.
As stated above, an advancement a century removed from the discovery of insulin may hold some greater weight in that context.
In an interview with HCPLive this year, Lou Philippson, MD, Director, Kovler Diabetes Center, University of Chicago, was candid about the progress of the field since its greatest breakthrough in 1921.
“As I said in my FDA testimony, diabetes sucks, and it doesn't suck any less now that we're 100 years from the discovery of insulin,” he said. “It is not a condition, it's not a thing. It's a chronic illness, which is not unlike cancer, or perhaps HIV. That leads by itself to numerous complications.”
Philipson was one of the speakers at the EMDAC Meeting; he expressed to HCPLive the effect the disease has on finances, quality of life for patients and their families, and some of its larger consequences, including divorce and suicide.
“The toll of a chronic illness like this is not obvious to people who are not embedded in those who either have the disease or have a loved one with the disease or take care of people with the disease,” Philipson said.
He provided some insight into the history of the agent, being developed almost 30 years prior, as well as the potential patient population. Those who are diagnosed with diabetes in adolescence may have poorly controlled sugars in adulthood, leading to adverse events such as blindness and kidney failure.
Although advances in technology have helped curb those adversities, persons of a lower socioeconomic standing or those on dialysis may have difficulty maintaining their diabetes. Philpson questioned the idea of a risk-benefit in that situation.
He pointed out the question of what the comparative to T1D is in this debate, noting cancer therapies are successful in turning an acute death into a chronic illness. If T1D is a lifelong illness, there will be inherent severe downsides over that time period, despite the potential issues in tolerability with the agent.
“I think we have a cognitive dissonance with risk benefit in some situations, especially when it comes to children, and decision making,” he said. “But the downsides of T1D are spectacular and a certain amount of risk. That’s understood, I think it’d be tolerated.”
For patients whose child gets diabetes and is suddenly sick, they have a short period of time to decide to use an investigational drug. He noted that even its approval may lead to a Phase 4 marketing study aspect, the current protocol is multiple days of infusion in a row, which may give parents pause.
“It’s a little complicated, it has side effects, andits schedule can be disruptive, but there’s never a great time to get T1D,” Philipson said.
The discussion continued into the American Diabetes Association (ADA) 2021 Scientific Sessions, where both Elaine M. Apperson, MD, Prisma Health-Upstate and Stephen W. Ponder, MD, Texas A&M School of Medicine expressed their hope of what an agent to delay T1D could represent for pediatric populations.
Apperson indicated that while she is not sure if this agent would be the end-all be-all, everything counts to extend the window of time until diagnosis, potentially up to 5 years. In that time, advancements may extend to the point of a panacea for the complications of T1D.
But, with the arena of innovative technologies, such as hybrid-closed loop therapy, she noted that patients may not experience adverse events such as dysglycemia to any significant extent.
“My understanding of the way that type one will be ultimately prevented from an immune standpoint is that it's not going to be a single agent, it's going to be like cancer therapy, it's going to be a concoction,” Apperson said. “Because the immune system doesn't lend itself to single agent therapies, most often.”
For teplizumab, she would be in favor of the approval of the agent, making it widely available—but it may not represent the only solution. If clinicians and experts in the field are only waiting for the resolution of disease for their patients, it may ultimately be detrimental in what can currently be offered to improve their quality of life in the meantime.
On the other hand, Ponder went on to explain that the effort to slow the progression of T1D has been a goal his entire career, particularly during his fellowship. He called it a “holy grail” in his profession.“I was very encouraged by those studies, and disappointed by the fact it didn't get approved,” Ponder said. “But that doesn't mean it's not going to happen in another version or another form.”
He noted that the advancements in biologics have made the goal for a therapy considerably more realistic, where the advancement may come in the next few years, rather than a future goal that will take time to be met.
“I think that if we can even buy some time for our patients, so I'm not starting insulin pumps on 2-year-olds, maybe if they're now 7, or 8, and maybe a little bit older, to able to better able to manage at that age, or hopefully never, I'm all for that,” he said. “As a person that's lived with this condition for 56 years, I am very much a proponent of anything that can delay or prevent this condition.”
What ultimately happened?
Ultimately, in July, the FDA issued a Complete Response Letter (CRL) to Provention Bio for teplizumab. The FDA stated that the company failed to show Provention Bio failed to show pharmacokinetic (PK) comparability in the clinical trials.
They cited a single, low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in healthy volunteers comparing planned commercial products originating from drug substances manufactured for historic clinical trials failed to show PK comparability.
Additionally, the CRL addressed considerations related to product quality, which Provention Bio indicated has been addressed.
However, there were no clinical deficiencies in the efficacy and safety data submitted in the BLA, but the FDA requested a safety update in the resubmission in the BLA.
As of November of this year, the company met with the FDA to discuss the compatibility between the planned teplizumab commercial product and the clinical drug product used in historical trials.
They discussed the population pharmacokinetic model (popPK) model to be used for planned commercial and clinical drug product comparison.
During that meeting, the FDA approved Provention’s proceeding to populate the popPK model with data from patients receiving teplizumab in a PK/PD substudy of the ongoing PROTECT phase 3 trial.
Their preliminary analysis from the popPK model showed results on the geometric mean of the ratio of commercial to clinical drug product (90% Confidence Interval). The data show 83.2% AUC Infinity (90% CI, 76.9 - 89.9), 85.3% AUC Day 13 (90% CI, 78.0 - 93.3), 86.5% CMAX (90% CI, 83.9 - 89.3).
Though, for now, it seems like a waiting game and a watershed moment that may not have met its breakthrough promise this year.