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Diabetes researchers tend to be masters of understatement, but now they seem to be universally excited about a new drug that some are even calling “revolutionary” because it can delay the onset of type 1 diabetes (T1D).

Teplizumab is a new injectable drug from New Jersey-based Provention Bio that studies have found offsets the onset of T1D in a person at risk by as much as 2 to 5 years. In May 2021, an advisory committee of the Food and Drug Administration (FDA) recommended this treatment be approved by the full agency later in the year. And while the FDA on July 2 opted to not yet approve this as a treatment, excitement remains as Provention retools and pushes forward with what it believes could be a potential game-changer in recognizing and addressing T1D early.

“I will say with confidence that years from now, Teplizumab will widely be seen as revolutionary, and in fact for some, including myself, I have already seen it in such a light,” Dr. Mark Atkinson, American Diabetes Association Eminent Scholar for Diabetes Research and director of the University of Florida Diabetes Institute wrote in his testimony to the FDA. He called Teplizumab the most impactful diabetes breakthrough since home blood glucose meters replaced urine testing.

“We know this can have a blockbuster effect on the pre-diagnosed,” said Frank Martin, PhD, director of research at JDRF.

In other words, even the usually understated scientists are amped up about Teplizumab for use in the general public.

While many in the Diabetes Community had hoped the FDA would OK this drug on July 2, the agency wasn’t ready to give this the green light. Instead, the FDA issued a Complete Response Letter outlining a handful of areas it wanted the company to address before reconsidering Teplizumab.

This is the first-ever drug close to market with a real possibility of halting T1D, so there’s understandably a lot of excitement around it. The closest competitor would be Diamyd, developing a vaccine to halt the autoimmune attack in T1D, but that remains several years out from FDA submission.

Teplizumab, on the other hand, could potentially come to market as soon as next year.

First of all, the complicated name is pronounced TEP-LIH-ZOOM-AB.

It is an anti-CD3 monoclonal antibody drug that binds to the surface of T-cells in the body and helps suppress the immune system. Similar drugs are being tested for the treatment of other conditions like Crohn’s disease and ulcerative colitis.

Teplizumab is administered with injections given over a period of 2 weeks in an outpatient setting.

Studies in people with early onset T1D show that it appears to successfully reset the immune system, allowing the person’s insulin-producing beta cells to continue making insulin longer. One minor side effect is a skin rash.

Ways that it may help treat T1D include:

  • extending time without the need for insulin
  • longer periods without the organs in the body being attacked
  • more time for possible T1D patients and families to adapt to a full-blown diagnosis
  • the possibility of second doses down the road to delay T1D even longer
  • future possible use in restoring glycemic control in people who have already developed T1D

Based on these unprecedented possibilities, “I do think we are at a point in diabetes research that will be revolutionary,” said Provention Bio’s co-founder and CEO Ashleigh Palmer.

Teplizumab was born from a long line of drugs created and tested over more than three decades.

The idea took root in the labs of Dr. Kevan Herold and Dr. Jeffrey Bluestone at University of California (UC) San Francisco.

It was in 1989, when working with cancer patients, that Bluestone realized an anti-CD3 drug could be a key in stopping the progression of T1D because of how it helped transplant patients.

His theory seemed to hold up in small studies. Since T1D manifests when a person’s immune system gets confused and attacks their insulin-producing beta cells rather than protecting them, Bluestone surmised that by creating monoclonal antibodies in a lab that can be introduced into the body of a person on the verge of developing T1D, those will bind to the CD3 cells that are attacking the beta cells and stop the attack.

Over the years, researchers like Herold and Bluestone, along with companies like Tolerx, worked to find just the right level of anti-CD3 to make that effort a success.

Tolerx came close to approval of its drug about 10 years ago, but did not make it past Phase 3 trials with the FDA due to some significant side effects of flu-like symptoms.

Other trials fell short as well, which often happens as drug research progresses.

Four years ago, Provention Bio picked up the research and pushed it along more. They were frustrated, Palmer said, with how the medical system handles diagnoses of autoimmune diseases in general.

“The medical system waits for patients to exhibit symptoms. Very often, by that point, irreversible damage has been done,” Palmer said.

“Can you imagine,” he added, “a system in which a patient with kidney disease presents at the point of dialysis? Insulin therapy is pretty much the same as if we did that. We go right to the [intense and chronic] treatments at the start.”

At the point where Provention Bio took over, the global T1D screening research collaboration TrialNet was pumping some decent study participant numbers into the project, and more than 800 patients have received the treatment in multiple studies to date. With the work done over those past decades, it seemed they had found what Palmer calls the “Goldilocks” formula for the medication: “Not too little immune response alteration and not too much; just the right amount,” he said.

Some patients in the studies have had their need for insulin offset by 5 years, while 2 years is a strong average across the board.

Katie Killilea of Rhode Island told DiabetesMine that her son entered the Teplizumab trial at Yale in 2013, after she and her son were both tested via TrialNet at her other son’s diabetes camp.

Killilea herself was diagnosed shortly after. But her son, who was farther back in the progress toward T1D, was able to remain in the study as his body held off diagnosis for some time.

The challenges, she said, were that her son [along with his dad] had to spend 3 weeks up near Yale, a bit of a bump in the life of a 12-year-old, and a difficult set up for most families.

“It gives me hope, but the whole time [in 2013], I felt acutely aware of how difficult the Teplizumab trial was for families financially,” she said.

“You had to have a parent who could take time off from work, another parent to stay home with the other child or children. It seemed unrealistic for us, and maybe impossible for others to participate,” she said, stressing that these issues need to be worked out.

But the benefits were many, she said.

“Since he had the drug, his blood glucose returned to normal for a while. TrialNet did glucose tolerance tests every 6 months,” she said.

And while the time did come that her son developed T1D, she found it to be a more manageable transition as opposed to her other son’s previous diagnosis, Killilea told DiabetesMine.

“Although he was not able to keep T1D at bay forever, he did have a very gentle landing and was diagnosed with T1D before he needed to use insulin,” she said.

“He slowly had ‘more’ T1D and needed something silly like just 1 or 3 units of Lantus a day for a while. I remember his pediatric endo saying, ‘this dose is so small, I’m surprised it can do anything.’ But the speck was enough for a while. Then more Lantus was added — 5, then 7, then 10 units. Then an insulin pump with a very low basal rate, and maybe the bolus ratio was initially 1:100 or something. He never ate enough [carbs] to need a bolus dose initially.”

In other words, it was a slow progression instead of a shock. She wonders what could have been if he could have had a second round of the infusion treatment.

We may all find that out in the future.

In December 2020, JDRF launched a partnership that offers at-home tests to screen for the autoantibodies that are the most important markers for developing T1D (at a regular rate of $55 and discount rate of $10 per test for those in need).

Given that TrialNet offers testing for free, and there’s little you can do about it should you test positive for T1D risk, many wondered the point.

Now, it’s clear that these tests could pair up with the possible new ability to take action before diagnosis. If and when Teplizumab comes to market, those testing positive could begin with this prevention therapy right away.

While JDRF has pushed to build awareness around early detection, the organization’s research director says that currently, “medical people don’t really know what to do with a person with T1D risk.”

That’s why they’re so excited about the potential of Teplizumab.

If a person opts for an at-home test and has some antibodies come back positive now, their next step would be to reach out to TrialNet for screening there. Then, should the FDA grant approval, they could be guided toward this proactive treatment, the JDRF’s Martin said.

“Family history of the condition only impacts 15 percent of people with T1D in the United States,” he noted. That means 85 percent of people diagnosed have no reason to watch for symptoms or be on the lookout.

To make it something people think to do, he said, “Screening needs to be easy, accessible, and affordable… Our program has embedded educational material for all of this.”

The pandemic helped push the notion of at-home testing even more, he said.

One challenge? Seeing antibodies in tests can cause great anxiety. “We need to mitigate anxiety around finding out that you may be at risk,” Martin said. “This needs to have guidelines, so people know and understand how often to screen and what antibodies mean.”

It will make all the difference when there is a prevention that people can turn to, he said.

Provention Bio, the researchers, and the public at large were looking toward the July 2 meeting, hoping for FDA approval. But they were disappointed when the agency declined approval, citing concerns about how effective it might be and some other issues brought up during the regulatory review process.

During the May 2021 advisory committee’s meeting, it was a narrow 10 to 7 vote in favor of Teplizumab. That might have been the first clue that FDA approval wouldn’t be a guarantee initially. The FDA does not always follow the recommendations of subcommittees, and sometimes — as they have now done for Teplizumab — the agency required additional data and action before it would reconsider the drug.

In its response letter to Provention in early July, the FDA stated that a single, low-dose study for this medication used in healthy volunteers failed to adequately compare as it needed to. The FDA also cited other concerns about product quality, even though the company points out those have already been addressed or can be resolved in the short-term.

Additionally, the FDA also pointed to recent issues found during a general inspection of a Provention manufacturing facility, citing that as needing resolution before Teplizumab can be approved.

Some believe this could take 6 months to a year, to resubmit to the FDA.

Responding to the FDA’s decision, the JDRF expressed its disappointment but remains optimistic as the company and regulatory officials work through these additional issues.

“JDRF is thankful for the FDA’s designation of Teplizumab as a breakthrough therapy and ongoing consideration of this drug,” the JDRF statement says. “It is unfortunate that the FDA has not approved Teplizumab at this time and instead has requested additional information from the sponsor.”

Still, even with the FDA’s hesitancy in early July, many still believe one of the biggest diabetes breakthroughs in modern times could be at hand.

“Just the [fact] that this could offer a positive step to take from screening is huge,” Provention’s Palmer said. “Because why should a person developing T1D not have the opportunity to find out what is going on and take action when [their pancreatic cells] are not yet destroyed?”

Then, he hopes, they can dig into things like studying if a second treatment down the road could extend the offset even longer.

Martin also hopes this will one day change the lives of those already diagnosed by pairing with beta cell replacement or regeneration to reverse existing T1D.

“We want to stop people from having to live a life on insulin,” he said. “About 1.6 million people live with T1D and it’s a heavy burden. Your body fights against you. We want to cure all parts of disease points.”