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SAN FRANCISCO – Teplizumab, an experimental anti-CD3 monoclonal antibody (Provention Bio), has been successfully delayed in high-risk individuals.
The findings were presented on June 9th here at the 2019 Scientific Sessions of the American Diabetes Association (ADA) by senior researcher Kevan Herold, MD, professor of immunobiology and internal medicine at the University. Yale of New Haven, Connecticut, and published simultaneously in the New England Journal of Medicine.
In Phase 2, the randomized, placebo-controlled trial of teplizumab in 76 high-risk adults and adults with type 1 diabetes – all had two or more autoantibodies and abnormal abnormal glucose tolerance and subclinical – 14-day infusions delayed the development of type 1 diabetes at 2 years of age compared with placebo, without major adverse events.
The drug modifies CD8 + T cells, which would be involved in the destruction of beta cells.
The study was conducted by Type 1 TrialNet, a research consortium funded by the National Institutes of Health (NIH) of the United States, which aims to prevent type 1 diabetes or slow its progression shortly after diagnostic.
Based on these encouraging results from Phase 2, Ashleigh Palmer, CEO of Provention Bio, said in a statement, "We are evaluating a regulatory pathway for teplizumab in people at risk." We are also evaluating teplizumab in newly diagnosed patients. diagnosed with diabetes in our Phase 3 PROTECT study, which began in April. "
"At first glance, it's awesome"
The results are changing the game, said Herold during a press briefing at the meeting.
"That's the first time we 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 in adults. Our results offer great hope to family members and eventually to the general public, who are likely to develop type 1 diabetes. "
"I think that changes the way we think in the past," he told reporters. "There has been some reluctance on the part of families to engage in this type of screening, to identify [as high-risk]because the question was, "What are you doing about it?" Now, we can say that we can do something about it. "
"Frankly, I think it completely changes the playing field."
He also noted that although the delay in diagnosis in people with type 1 diabetes with teplizumab was only 2 years, the duration of the absence of disease with this disease makes a big difference.
"The delay of 2 years before the diagnosis, in my opinion, is very important clinically considering the daily burden of managing the disease.Any period without clinical illness has significance, especially in children."
In an interview with Medscape Medical News, co-author of the study and TrialNet Chair, Carla Greenbaum, MD, director of the Clinical Diabetes Research Program at the Benaroya Research Institute in Seattle, Washington, and President of TrialNet Diabetes , urged clinicians to send families of type 1 diabetic patients to TrialNet screening.
"We can identify people who are going to get diabetes. It is no longer that they run the risk of becoming so. We know that they will evolve into the disease. It's essential. Thus, people who treat people with type 1 diabetes should their loved ones have been tested because, if they are antibody positive, they can participate in studies. "
Invited to comment, Nelly Mauras, MD, chief of the endocrinology division of the Nemours Children's Health System, in Jacksonville, Florida, said Medscape Medical News"I think it's a step in the right direction. Some patients still have diabetes, but 2 years without diabetes is [significant]. "
"So, if the morbidity of the drug was low, and that seems to have been the case, we can really slow down the disease for 2 years, whether it remains or not, and whether it has financial meaning or not, remains to be seen." at first glance, it's great. "
Editorialists add a warning
In an editorial, editor Clifford J. Rosen, MD, Maine Medical Center Research Institute, Scarborough, and the newspaper's associate editor, Julie R. Ingelfinger, MD, of the Massachusetts General Hospital for children, Boston, praise the results, but also express some caveats.
"Although the trial has shown a marked delay in the onset of reported diabetes, the results should not be interpreted to imply that immune modulation is a potential curative approach," they point out.
"These data provide rather strong, though indirect, evidence for the pathogenesis of beta cell destruction and the potential for changing the course of type 1 diabetes with new biological agents." will probably prompt the development of more specific screening criteria for the treatment of diabetes – the people most at risk, although the use of immunomodulators for type 1 diabetes remains a challenge. "
Herold acknowledged in her speech: "The question that arises is whether this prevents type 1 diabetes. The answer is that we do not know it … Those who have not developed type diabetes 1 during the test could have developed it the next day, or they may never develop it.It is always a question that must be answered. "
Rosen and Ingelfinger also note that "this trial was small and involved only a two-week treatment.The duration and frequency of treatments, the long-term side effects of these treatments, the identification of subgroups of people who do not respond to treatment, and the clinical course of people who initially have an answer has yet 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."
Less type 1 diabetes developed with Teplizumab, delayed start of 2 years
Family members of a person with type 1 diabetes are 15 times more likely to develop the disease than the general population.
The study included 76 family members (≥ 8 years old) of type 1 diabetes patients with two or more autoantibodies associated with the disease and abnormal glucose tolerance (but not did not meet the diabetes threshold). Most (72%) were children and 64% were siblings of patients with type 1 diabetes.
They were randomized to receive 14 daily infusions of teplizumab (n = 44) or saline (n = 32) outpatients, followed by an oral glucose tolerance test at 6-month intervals.
In this 7-year study, 72% (19/44) of patients in the placebo group were diagnosed with type 1 diabetes (identified by an oral glucose tolerance test), compared with 43% (23 / 32) teplizumab patients.
In addition, the teplizumab group had an annualized rate of lower type 1 diabetes, 14.9%, compared with 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 (risk ratio [HR]0.41; 95% CI, 0.22 to 0.78; P = 0.006), after adjustment for age and antibody status.
The most important effect of teplizumab occurred in the first year of the trial: only 7% (3/44) of people taking the drug had been diagnosed with type 1 diabetes, compared to 44% (14/32) patients in the placebo group (unadjusted). HR, 0.13).
Adverse events, including a decrease in the number of white blood cells and rashes, were expected based on previous trials on teplizumab in newly emerged type 1 diabetes and were transient, said Herold.
The number of lymphocytes decreased to reach a nadir of 72.3% at day 5. Fifteen patients in the teplizumab group developed lymphopenia, which resolved on day 45 in all but one individual, whose number of lymphocytes returned to normal on day 105.
A rash developed in 16 recipients of teplizumab, but it also resolved. Infection rates were similar between the two groups.
TrialNet is currently testing other immunotherapeutic agents to determine if they could also delay the onset of type 1 diabetes.
Greenbaum, president of TrialNet, said in a statement from the ADA: "We hope to better understand that type 1 diabetes is an autoimmune disease that can be treated with immune therapy, similar to d?" other autoimmune diseases. "
"We now understand that essentially everyone close to people with type 1 diabetes and having multiple antibodies may be considered to have the early asymptomatic form of the disease."
"Just as we treat the asymptomatic presence of hypertension to prevent a heart attack or stroke, these findings provide strong evidence that we are approaching a future in which we will be able to identify and treat diabetes from type 1 well before the symptoms appear. "
Herold indicated that she received funding from NIH and JDRF, personal fees from Provention Bio, Tiziana Life Sciences, Bristol Meyers Squibb, Eli Lilly, Merck, Forkhead Bio, Semma Bio and Toleron, as well as grants from Merck. He also has a patent for a beta cell death test. Greenbaum reported receiving grants from NIH / TrialNet, Novo Nordisk grants and personal honoraria, personal fees and non-financial support from Bristol-Myers Squibb, Janssen grants, and Eli Lilly's personal fees. Rosen and Ingelfinger are employed by the New England Journal of Medicine. Mauras said he has received a research grant from Medtronic and Novo Nordisk, as well as research supplies from Medtronic, LifeScan and Johnson & Johnson.
N Engl J Med. Posted online June 9, 2019. Full text, Editorial
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