Game Changer: Antibody First to Delay Type 1 Diabetes Onset in TrialNet 

Miriam E. Tucker

June 10, 2019

SAN FRANCISCO — For the first time, the onset of type 1 diabetes has been successfully delayed in those at high risk using teplizumab, an investigational anti-CD3 monoclonal antibody (Provention Bio). 

The findings were presented June 9 here at the American Diabetes Association (ADA) 2019 Scientific Sessions by lead investigator Kevan Herold, MD, professor of immunobiology and internal medicine at Yale University, New Haven, Connecticut, and simultaneously published in the New England Journal of Medicine.

In the phase 2, randomized, placebo-controlled trial of teplizumab in 76 pediatric and adult high-risk relatives of patients with type 1 diabetes — all had two or more autoantibodies and subclinical abnormal glucose tolerance — teplizumab infusions for 14 days delayed the development of type 1 diabetes by 2 years compared to placebo, without major adverse events.    

The drug modifies CD8+ T lymphocytes, which are thought to be involved in beta-cell destruction.   

The study was conducted by Type 1 Diabetes TrialNet, a US National Institutes of Health (NIH) funded research consortium that aims to prevent type 1 diabetes or slow its progression soon after diagnosis. 

Based on these encouraging phase 2 results, Ashleigh Palmer, CEO of Provention Bio, said in a company statement: "We are evaluating a regulatory path forward for teplizumab in at-risk individuals. We are also assessing teplizumab in newly diagnosed type 1 diabetes patients in our phase 3 PROTECT study, which commenced in April."

"At Face Value, It's Terrific"

The results are game changing, Herold said during a press briefing held at the meeting.

"This is the first time we have showed that immune therapy can delay progression to type 1 diabetes," he noted in an ADA press release. "Type 1 diabetes is one of the most common chronic diseases of childhood and is also diagnosed among adults. Our results offer great hope to family members, and possibly in the future, to the general public who may be at risk for developing type 1 diabetes."

"I think this changes the way we've thought about this in the past," he told assembled journalists. "There's been some reluctance on the part of families to engage in this sort of screening, to be identified [as high-risk], because the question has been, 'What do you do about it?' Now, we can say there's something we can do about it."

"Frankly, I think it changes the playing field entirely."

He also noted that although the delay in diagnosis among those who did eventually develop type 1 diabetes with teplizumab was only 2 years, that duration of not living with the condition makes a big difference.

"The 2-year delay to diagnosis, I would argue, is very clinically significant in light of the daily burden of disease management. Any time without clinical disease has significance, particularly in children."

In an interview with Medscape Medical News, study coauthor and TrialNet chair Carla Greenbaum, MD, director of the diabetes clinical research program at Benaroya Research Institute in Seattle, Washington, and chair of Diabetes TrialNet, urged clinicians to send families of patients with type 1 diabetes for TrialNet screening.

"We can identify people who are going to get diabetes. It's no longer they're at risk for it. We know they're going to progress to disease. That's critical. So for those treating people with type 1 diabetes, they should get their relatives tested because, if they're antibody positive, they can be in studies."

Asked to comment, Nelly Mauras, MD, chief of the division of endocrinology at Nemours Children's Health System, Jacksonville, Florida, told Medscape Medical News, "I think it's a step in the right direction. Some patients still got diabetes, but 2 years without diabetes is [significant]."

"So, if the morbidity of the drug was low, and it seems to have been, that's a really big deal that we can slow down the disease for 2 years. Whether or not it will stick, and whether or not it makes sense financially, remains to be seen. But at face value it's terrific."

Editorialists Add a Cautionary Note

In an accompanying editorial, associate editor Clifford J. Rosen, MD, Maine Medical Center Research Institute, Scarborough, and deputy editor of the journal, Julie R. Ingelfinger, MD, of Massachusetts General Hospital for Children, Boston, praise the findings but also express some caveats.

"Although the trial showed a marked delay in the onset of overt diabetes, the results should not be taken to imply that immune modulation constitutes a potential curative approach," they emphasize.

"Rather, these data provide strong albeit indirect evidence about the pathogenesis of beta-cell destruction and the potential to modify the course of type 1 diabetes with newer biologic agents. This trial will probably prompt the development of more refined screening criteria for the treatment of persons at highest risk, although challenges in using immune modulators for type 1 diabetes remain."

Herold acknowledged in his talk, "The question always comes up whether this prevents type 1 diabetes. The answer is we don't know...Those who didn't develop type 1 diabetes in the trial could have developed it the next day, or they may never develop it. That's still a question that needs to be answered."

Rosen and Ingelfinger also note that "this trial was small and involved only one 2-week treatment course. The duration and frequency of treatments, the long-term side effects of those therapies, the identification of subgroups of persons who do not have a response to the treatment, and the clinical course of persons who initially do have a response still need to be determined."

Nevertheless, they add, "We can finally say...that there has been substantial progress in modulating the early course of type 1 diabetes."

Fewer Developed Type 1 Diabetes With Teplizumab, Onset Delayed 2 Years

Family members of someone with type 1 diabetes have a 15 times greater risk of developing the disease than the general population.

The study involved 76 relatives (age ≥ 8 years) of patients with type 1 diabetes who had two or more autoantibodies known to be associated with the condition and abnormal glucose tolerance (but not meeting the threshold for diabetes). Most (72%) were children, and 64% were siblings of patients with type 1 diabetes.

They were randomized to 14 daily outpatient infusions of teplizumab (n = 44) or saline (n = 32) and then followed with oral glucose tolerance testing at 6-month intervals.

During this 7-year study, 43% (19/44) of patients in the teplizumab group were diagnosed with type 1 diabetes (as identified by an oral glucose tolerance test), compared with 72% (23/32) of patients who received placebo.

Further, the teplizumab group showed a lower annualized rate of type 1 diabetes of 14.9% compared to 35.9% in the placebo group.

The median time to diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group (hazard ratio [HR], 0.41; 95% CI, 0.22 - 0.78; P = .006), after adjusting for age and antibody status.

The largest effect of teplizumab occurred in the first year of the trial: just 7% (3/44) of those taking the drug were diagnosed with type 1 diabetes compared with 44% (14/32) of patients in the placebo group (unadjusted HR, 0.13). 

Adverse events, including low white blood cell count and rash, were expected based on previous trials of teplizumab in new-onset type 1 diabetes and were transient, Herold said.

Lymphocyte count decreased to a nadir of 72.3% by day 5. Fifteen patients in the teplizumab group developed lymphopenia, which resolved by day 45 in all but one individual, whose lymphocyte count returned to normal by day 105. 

A rash developed in 16 teplizumab recipients, but that too resolved. Infection rates were similar between the two groups.

TrialNet is currently testing other immunotherapeutic agents to determine whether they might also delay type 1 diabetes onset. 

Greenbaum, TrialNet chair, said in the ADA statement: “We hope to bring wider recognition to the fact that type 1 diabetes is an autoimmune disease that can be treated with immune therapy, similar to other autoimmune diseases.”

"We now understand that essentially all close relatives of people with type 1 diabetes and who also have multiple antibodies can be considered as having the early asymptomatic form of the disease."

"Just as we treat the asymptomatic presence of hypertension to prevent a heart attack or a stroke, these findings provide strong evidence we are approaching a future in which we can identify and treat type 1 diabetes long before symptoms occur."

Herold has reported receiving grants from the NIH and JDRF, personal fees from Provention Bio, Tiziana Life Sciences, Bristol Meyers Squibb, Eli Lilly, Merck, Forkhead Bio, Semma Bio, and Toleron, and grants from Merck. He also has a patent for a beta-cell death assay. Greenbaum has reported receiving grants from NIH/TrialNet, grants and personal fees from Novo Nordisk, personal fees and nonfinancial support from Bristol-Myers Squibb, grants from Janssen, and personal fees from Eli Lilly. Rosen and Ingelfinger are employed by the New England Journal of Medicine. Mauras has reported receiving research grant support from Medtronic and Novo Nordisk, and research supplies from Medtronic, LifeScan, and Johnson & Johnson.

N Engl J Med. Published online June 9, 2019. Full text, Editorial

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