Temelimab: A Novel Disease-Modifying Agent for Diabetes Management

New disease state-modifying therapies could be on the way for management of type 1 diabetes. The autoimmune disease, which affects 1.6 million people in the United States, is characterized by destruction of the insulin-producing β cells, leading to severe metabolic conditions and even death.^1–3

Current therapies for type 1 diabetes are focused on supplementing insulin for glycemic control but does not impact the pathology of β cell destruction. GeNeuro is in phase 2 trials for their novel biologic, temelimab (GNbAC1), a monoclonal antibody used to preserve β cell function without impairing the immune system.

Temelimab is a recombinant humanized IgG4 monoclonal antibody, which blocks human endogenous retrovirus type W (HERV-W) protein.⁴ HERV-W is associated with the pathology of autoimmune disorders, such as multiple sclerosis (MS) and type 1 diabetes.⁵ Increased expression of HERV-W is linked to inflammation.⁵

HERV-W interacts with toll-like receptor 4 (TLR4) causing the release of inflammatory cytokines, such as IL-1β, IL-6, and TNF-α.⁵ Temelimab binds to HERV-W and prevents TLR4 activation; thus, reducing inflammation and attacks by the immune system.⁴

HERV-W makes up approximately 8% of the human genome; however, the level is found to be much higher in people with autoimmune diseases.⁴ HERV-W is seen in 60% of patients with type 1 diabetes and its expression occurs in 75% of postmortem type 1 diabetes patients.⁴

This increased expression of HERV-W can interact with β islet cells in the pancreas, which have TLR4 expression.⁴ This activates inflammatory markers to attack and cause damage to the β islet cells leading to decreased insulin secretion.⁴ Temelimab has been shown to neutralize HERV-W, which may preserve the remaining functional β cells.⁴

CHANGE MS was a double-blind, randomized, placebo control phase 2b trial comparing temelimab at varying doses versus placebo to examine whether suppression of HERV-W had any anti-inflammatory effects in patients with MS.⁶

Findings showed that temelimab did not achieve its main goal of reducing the number of active MRI brain lesions, even at the highest doses, but was well tolerated and showed potential anti-neurodegenerative effects.⁶

Angel-MS was a multicenter phase-2b study in patients with relapsing-remitting MS and is an extension of the CHANGE MS trial.⁷ The goal of the study was to determine long-term safety and efficacy of temelimab in terms of relapse rate, disability, and disease progression.⁷

The study included 220 patients who continued their regimen of temelimab from the previous trial to study its long-term safety effects over a total period of 96 weeks.⁷ The findings concluded that the medication was well-tolerated without any major adverse effects (AEs), with the most common AEs being nasopharyngitis and URIs.⁷

The RAINBOW-T1D (NCT03179423) phase 2a trial is currently evaluating the safety and tolerability of temelimab in patients with T1DM in combination with standard of care.⁸ The trial included 64 patients with an average use of 0.381 units/kg/day of insulin and found that temelimab was well-tolerated compared with placebo.⁴

Secondary endpoints evaluating levels of C-peptide, insulin use, or HbA1c between the groups found no differences between treatment groups.⁴ The temelimab group observed a statistically significant reduction in number of hypoglycemic events 2.09% vs 2.92%.⁴ The number of autoantibodies did not differ between groups; however, anti-insulin antibodies were found to be significantly reduced in the temelimab group at week 48 (5.14 vs 14.19).⁴

Although temelimab is still in its early stages of development, these results demonstrate tolerability and a positive pharmacodynamic response in the reduced number of hypoglycemic events. With these positive safety data, future trials focusing on efficacy in prevention of disease progression could solidify a potential therapeutic role in the early stages of disease.

Furthermore, trials looking into the efficacy of temelimab in type 2 diabetes progression could also be a future possibility considering the similar involvement of beta cell dysfunction. Disease-modifying agents may play a role in the future of diabetes management. Temelimab, as well as other biologics, may be another avenue to explore for the management of metabolic disease.

References

1. Association AD. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S15-S33. doi:10.2337/dc21-S002

2. Coexisting Conditions and Complications | Diabetes | CDC. Published August 7, 2020. Accessed September 7, 2021. https://www.cdc.gov/diabetes/data/statistics-report/coexisting-conditions-complications.html

3. Statistics About Diabetes | ADA. Accessed September 7, 2021. https://www.diabetes.org/resources/statistics/statistics-about-diabetes

4. Curtin F, Champion B, Davoren P, et al. A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes. Diabetes Obes Metab. 2020;22(7):1111-1121. doi:10.1111/dom.14010

5. Curtin F, Bernard C, Levet S, et al. A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody. Diabetes Obes Metab. 2018;20(9):2075-2084. doi:10.1111/dom.13357

6. Hartung H-P, Derfuss T, Cree BA, et al. Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study. Mult Scler J.:12.

7. GeNeuro-PR-ANGEL-MS-EN-VF.pdf. Accessed September 7, 2021. https://www.geneuro.com/data/news/GeNeuro-PR-ANGEL-MS-EN-VF.pdf

8. GeNeuro-T1D-562019-ENG-.pdf. Accessed August 27, 2021. https://www.geneuro.com/data/news/GeNeuro-T1D-562019-ENG-.pdf