Strike two against an antibody approach to treating type 1 diabetes. Otelixizumab, the protein GlaxoSmithKline and Tolerx were testing in phase III, failed to improve symptoms in recently diagnosed patients with the autoimmune form of the disease.
The failure was not judged as a surprise by some industry observers as a related molecule, teplizumab, failed for Eli Lilly and MacroGenics in October 2010. However, it is certainly a disappointment in terms of advancing new treatments for this disease - the product is one of just three late-stage candidates for type 1 that does not rely on insulin replacement.
Regulating immune response
As type 1 diabetics suffer from the body’s destruction of insulin-producing pancreatic beta cells, most medications for type 2 that rely on insulin stimulation, such as sulphonylureas, do not work. Treatment protocols therefore involve early intervention with human insulin or analogues.
The leading therapy for type 1 diabetes is Sanofi-Aventis’ long-acting insulin Lantus, which generates approximately $1bn a year in sales to these patients, analysts believe.
As with teplizumab, otelixizumab aimed to modulate destruction of insulin-producing pancreatic cells. It tried to do this by targeting the CD-3 molecule, a receptor that activates T-cells related to the immunological destruction of the body’s own tissues, inhibiting the course of the disease.
Otelixizumab’s Defend-1 trial in 240 newly-diagnosed type 1 diabetics aimed to demonstrate an increase in the body’s mealtime production of insulin biomarker C-peptide after 12 months of therapy with the monoclonal antibody alongside insulin; blood sugar and incidents of hyperglycaemia and hypoglycaemia were also measured.
GSK and privately held Tolerx of Massachusetts said otelixizumab failed to meet the primary endpoint, although no new safety issues were identified. They will suspend recruitment in the confirmatory Defend-2 trial, while the data is analysed further.
Consensus estimates from EvaluatePharmaput sales of the antibody at $327m in 2016, although these numbers will be heavily risk adjusted. UBS, which has top of the range figures, published a note March 9 putting its risk adjusted 2016 sales at £561m ($903m). In contrast the likes of Morgan Stanley and Nomura had assigned no value to the product in Glaxo's pipeline.
Those forecasts are now likely to be slashed or removed completely from models, although otelixizumab has further shots on goal with phase II ongoing for type II diabetes and rheumatoid arthritis, and a phase I in psoriasis. The news also has repercussions for BTG, which licensed the MAb to Tolerx in 2001 in return for 50% of Tolerx’s milestone and royalty payments.
There remains some hope that type 1 diabetes can yet be addressed by altering the body’s immunity. Diamyd Medical is expecting to report phase III data on its vaccine this spring (Event – High hopes for Diamyd’s diabetes vaccine, March 4, 2011). Meanwhile in the immunomodulation category, Andromeda Biotech is testing its T-cell modulator, DiaPep277, in a phase III trial expected to report results later this year.
Success would be welcome for a disease that has not seen the treatment advances of type 2 diabetes.