Teplizumab surprise puts spotlight on type 1 diabetes antibodies

Type 1 diabetes has proven an R&D graveyard, with approaches ranging from therapeutic vaccines to anti-inflammatory compounds failing to have a disease-modifying effect on the autoimmune disease. So positive phase II results for a once-abandoned antibody could raise hopes of some progress in preserving pancreatic function.

In an investigator-led study, MacroGenics’ teplizumab slowed the decline in patients’ blood levels of C-peptide, a biomarker for insulin production. A scan of pipeline data in EvaluatePharma finds three other candidates still listed in active development for type 1 diabetes in the same drug class, an anti-CD3 monoclonal antibody, and all are preclinical (see table). Thus, if Macrogenics or its academic or potential commercial partners can design a successful study, the project might have an open field, although it still seems a long shot.

If at first you don't succeed

MacroGenics’ partner Lilly had handed back rights to teplizumab in 2010 after failure of the phase III Protégé trial – two 14-day courses had no effect on insulin use or blood sugar one year after completion of dosing. This presaged the failure of a similar candidate, Tolerx and GlaxoSmithKline’s otelixizumab, in 2011 (Otelixizumab another disappointment in type 1 diabetes, March 14, 2011).

Anti-CD3 antibodies bind to an epitope on T-cells, modulating their activity in attacking insulin-secreting beta cells, although the trials so far have not shown any significant effect on outcomes.

But the new study, backed by Yale University and the National Institutes of Health, dosed 63 patients with teplizumab for 14 days at the beginning of treatment and again after one year. Patients in the treatment arm saw their C-peptide levels remain significantly higher two years after initial treatment – the investigators have also identified subgroups that see greater benefit, which could help future trial design.

The approach – preserving beta-cell function – is by no means a cure in that it would only be effective in patients with beta cells to preserve. For many type 1 diabetics this would not be an option – but newly diagnosed patients might benefit. That population includes more than 15,000 people under 20 years of age each year in the US, for example.

The biggest-selling pharma product to treat type 1 diabetes is Sanofi’s long-acting insulin Lantus, with 19% of its forecast $8.66bn in sales in 2018 attributable to the insulin-dependent form of the condition.

Mirror image

The late-stage R&D pipeline for type 1 diabetes looks quite a lot like that of type 2, with new insulins and small molecules like sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists awaiting pivotal results. These are intended to be used as supplements to insulin in improving glucose control and could help reduce dependence on insulin.

But, because of its autoimmune and biological aspects that differ from type 2 diabetes, many developers are attempting to address disease progression in type 1. Cell therapies are one approach – Osiris Therapeutics has completed enrolment into a phase II trial of its stem cell therapy Prochymal, which has been approved in Canada and New Zealand for graft vs host disease. The treatment has been shown to suppress immune response; the hope is that it will assist in beta cell regeneration.

Andromeda Biotech’s DiaPep277, derived from the heat shock protein 60, illustrates another approach, using a peptide therapy to preserve beta cell function by suppressing immune response. And therapeutic vaccines have been tried, with Diamyd Medical’s eponymous candidate failing to demonstrate preservation of beta cell function.

Antibody approach

With monoclonal antibodies being such a common technology in other autoimmune diseases like rheumatoid arthritis and multiple sclerosis, it is not surprising to see them being attempted in type 1 diabetes – perhaps it is more surprising that they have failed so far. The anti-CD3 class has had difficulty finding a suitable therapeutic window – adverse events seen in phase I trials have required lower doses in phase II and III trials, reducing the efficacy of candidates.

Otelixizumab, the only other anti-CD3 MAb to reach pivotal studies, is probably a dead letter; developer Tolerx was liquidated after its failure. Interestingly, it remains in active development at GlaxoSmithKline in rheumatoid arthritis.

In the anti-CD3 category only three candidates besides teplizumab have been proposed for type 1 diabetes, and all are listed as preclinical (see table): Tolera Therapteutics’ TOL101, which is mostly being touted as an organ transplant candidate, and two from Columbia University.

As far as antibodies go, the pipeline is little bigger. Xoma has put the anti-interluekin 1 antibody gevokizumab into phase II in type 1 diabetes, and has a back-up agent in XMetA – the latter’s target has not been disclosed. As a target, interleukin 1 also has a role in inflammatory disease; however, a recently published investigator-led study tested a similar antibody, Ilaris, against the IL-1 receptor antagonist Kineret, a protein therapeutic, and found that neither significantly reduced C-peptide levels.

Even assuming that MacroGenics could interest a new partner in teplizumab, it is a long way from the market or indeed the initiation of a phase III trial. Yet the fact that investigators were able to learn from failure and identify responders suggests that it is not yet time to give up on the antibody approach.

Understanding of the role of blood sugar control and managing complications like cardiovascular disease has helped to extend the life expectancy of type 1 diabetics; a treatment that would preserve beta cell function could help even more.

Monoclonal antibodies in development for type 1 diabetes
Project Pharmacology class Company Status
Otelixizumab Anti-CD3 MAb GlaxoSmithKline Abandoned
Teplizumab Anti-CD3 MAb MacroGenics Phase II
TOL101 Anti-CD3 MAb Tolera Therapeutics Phase II*
Gevokizumab Anti-interleukin-1 beta (IL-1b) MAb XOMA Phase II
XMetA Anti-diabetic MAb XOMA Preclinical
hOKT3gl Anti-CD3 MAb Columbia University Research project
Diabetes MAb Research Project Anti-CD3 MAb Columbia University Research project
*Privately held Tolera has only disclosed the development status of TOL101 in organ transplant. It has orphan drug status in type 1 diabetes.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @JonEPVantage on Twitter

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