On the 5th August, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to teplizumab (anti-CD3) for the prevention or delay of clinical type 1 diabetes (T1D) in individuals at risk of developing the disease. This is quite amazing and has implications way beyond T1D.
The question in relation to anti-CD3 treatment is this ‘true prevention’ or simply a disease-modifying effect, i.e. a treatment that prevents the end-organ damage that eventually leads to clinical T1D? These were all antibody-positive subjects at very high risk of developing T1DM; i.e. they had a ~85% chance of developing T1DM and arguably had subclinical inflammation or autoimmune attack ongoing in their pancreas when they were treated with anti-CD3.
In the MS space, this study would analogous to treating radiologically-isolated syndrome and delaying RIS patients from having their first clinical attack.
The question for MSers is that if we could identify who of your children or siblings are at very high risk of getting MS – for argument’s sake let’s say they had a >50% risk of getting MS – would you volunteer them to participate in an anti-CD3 MS prevention trial?
The difference between T1D and MS is that endocrinologists have insulin; i.e. when the end-organ fails you simply replace insulin. In MS when the end-organ fails you become disabled with all its socio-economic consequences. Type 1 diabetics do so much better than MSers; in short, the stakes are so much higher for MSers.
I wonder how the EMA will respond to teplizumab? Breakthrough Therapy Designation (BTD) is an FDA program designed to expedite the development and review of therapeutic candidates intended to treat serious or life-threatening diseases. I predict that the European regulators arguing that in the modern era T1D is not a serious or life-threatening disease. We need to push back against such criticisms as they may use similar arguments if we ever get to this position in relation to MS.
I am so envious of the T1 diabetologists. I have a dream of being in a position one day of either offering people at high risk of developing MS, or members of the general public, an intervention to either reduce their risk or prevent them from developing MS. The question I have is society, the MS community and the regulators ready for MS prevention studies?
Herold et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613.
BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.
METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.
RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization – 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.
CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).