ADA Takes to the Streets in New Orleans

Enthusiasm for the host of clinical data released at the ongoing American Diabetes Association (ADA, June 5-9) meeting has simmered down as the FDA’s long-term safety concerns will weigh heavily on whether these drugs will actually make it to market. New data on weekly versions of GLP-1’s, Phase II data from Roche’s aleglitazar, and data for a novel class of drugs that aim to treat diabetes by blocking IL-1β were all important developments in the fight against diabetes, but they are unlikely to boost the shares of the companies developing them in the near term.

New weekly GLP-1 data. Will the FDA change its stance on this class?

During ADA GlaxoSmithkline, NovoNordisk and Lilly unveiled new data on their respective GLP-1 analogues: Syncria (albiglutide), Victoza (liraglutide) and Byetta LAR (exenatide). While the new data was not especially different from data previously released, it adds evidence of the strong benefits that this class can offer: weight reduction, compliance benefit, and balanced glycemic control. The key benefits of this class should be supported by longer clinical studies in a large population, which could compel the FDA to re-evaluate its view on the risk-reward profile of GLP-1s. Despite no evidence of thyroid cancer in the clinical trials, the FDA remains concerned about the association of thyroid cancer with GLP-1’s given the strong evidence seen in trials in rats, and the fact that medullar thyroid cancers are slow progressing. Longer clinical trials are required to prove either way.

Pushing Aleglitazar into PhIII is a risky bet

Phase II data on Roche’s aleglitazar is in line with the data of other PPAR agonists (strong efficacy but safety concerns), which have been discontinued in the past. It demonstrated a dose-related increase in serum creatinine levels; thus it seems to be a risky bet to push this compound into Phase III. Aleglitazar faces concerns similar to AstraZeneca’s dual PPAR agonist, Galida, which was discontinued in 2006 because of a larger than acceptable rise in creatinine levels. The rise in creatinine levels associated with aleglitazar is smaller than those seen with Galida, but still might not be acceptable, as the increase is dose-dependent and we could see a continuing rise over time.

Promising data for XOMA 052 (novel IL-1β blocker, PhI)

Xoma 052 (anakinra), an IL-1β blocker, will be discussed at ADA as a potential disease modifying therapy for Type 2 Diabetes Mellitus. Rather than focusing on insulin, this novel approach to diabetes treatment aims to block the master inflammatory cytokine, IL-1β, which when elevated can lead to impaired insulin secretion, decreased cell proliferation, and apoptosis. Progress with this mechanism raises hopes for Novartis’ IL-1β blocker for Type 2 Diabetes Mellitus, ACZ-885 (PhII)

  • Strong efficacy data: Single dose of Xoma 052 reduced HbA1c by a median of 1.1% with a maximum of 2.2% in three months. In contrast, the placebo treated subjects showed an increase of 0.1%. The treatment arm also showed a continuous increase in insulin production at one and three months compared to baseline as measured by the i.v. stimulation test, while placebo treated subjects showed no improvement.
  • Safety may be a concern: The adverse effect profile will be an area to watch out for, as IL-1β is an important signal for the inflammatory response of the body against infection. Thus, blocking IL-1β may increase the susceptibility of infections. The role of IL-1β is also established in hematopoesis, so IL-1β blockers can possibly reduce the production of natural erythropoietin, which can lead to anemia. However, clinical data from Phase I published in New England Journal of Medicine suggests a clean safety profile.

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