24 August 2010

Avandia squeaks through an FDA Advisory Panel. But can the pharmaceutical/biotechnology industry develop better insulin sensitizers?

By |2010-08-24T00:00:00+00:00August 24, 2010|Drug Development, Drug Discovery, Metabolic diseases, Strategy and Consulting|

Avandia (rosiglitazone)

On July 15, 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to leave the diabetes drug rosiglitazone  (GlaxoSmithKline’s  Avandia) on the market, with some new restrictions (e.g., closer supervision and new label warnings). This is the same committee that voted against FDA approval of Vivus’ anti-obesity drug Qnexa on the same day, as discussed in our August 4 blog post. (Some commentators believe that the Qnexa rejection is connected to the decision on Avandia. We shall reserve judgment on that question.)

The FDA usually follows the advice of its advisory panels, but does not always do so.

Of the 33-member panel, 10 voted to keep Avandia on the market under close supervision, seven voted to keep it on the market but with stronger label warnings, and three voted to keep the drug on the market with no new restrictions. Twelve voted to remove Avandia from the market. One member abstained.

One factor in the recommendations of several panelists to add restrictions or to eliminate Avanida from the market altogether is that a competing drug of the same thiazolidinedione (TZD) class, pioglitazone (Takeda’s Actos), appears to have similar efficacy to Avandia, but fewer adverse effects.

The panel members’ decisions were based on their analysis of large amounts (18 presentations worth) of contradictory data.

TZDs are agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that controls glucose metabolism and adipocyte differentiation. In treatment of type 2 diabetes, TZD modulation of PPARγ results in decreased insulin resistance. (Insulin resistance is the inability of tissues such as muscle and fat to utilize insulin efficiently for the uptake of glucose.) Thus treatment with these drugs can result in decreased levels of serum glucose, and amelioration of diabetes. Agents that work by decreasing insulin resistance are known as “insulin sensitizers”.

We have been following safety issues with agonists of PPAR receptors for quite some time. For example, there are two articles (here and here) published in 2006 (and available on our website) that include discussion of PPAR agonist safety.

As discussed in these two articles, Steven Nissen, M.D. (now Chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH) has been a leading critic of Avandia’s cardiac safety. This began with his 2007 meta-analysis of clinical studies of the drug, published in the New England Journal of Medicine. This meta-analysis indicated that treatment with Avandia was associated with a significant increase in the risk of myocardial infarction (MI), and an increase in the risk of cardiovascular death that had borderline significance. A 2010 meta-analysis by Dr. Nissen and his colleagues (published online ahead of print in the Archives of Internal Medicine on June 28) indicated that treatment with Avandia was associated with a significant increase in the risk of MI, but no increased risk of cardiovascular death or all-cause mortality. The results also suggest an unfavorable benefit to risk ratio for Avandia.

A retrospective study by FDA researchers of Medicare recipients published in the Journal of the American Medical Association in July 2010 indicated that Avandia treatment is associated with an increased risk of the composite of AMI, stroke, heart failure, and all-cause mortality as compared with Actos, in patients 65 years or older.

The consensus of multiple studies is that both Avandia and Actos induce weight gain, and carry an increased risk of edema and heart failure as compared with placebo, but that Avandia has a higher risk of MI than Actos. (Few studies directly compared the two drugs, however. The 2010 FDA study is an exception). However, some studies presented to the FDA Advisory Committee indicated that the risk of cardiovascular events were comparable between Avandia, Actos, and diabetes medications of other classes.

The panel’s decision was a compromise, based not only on the contradictory nature of the evidence, but also on the contention that Avandia may be a better choice than Actos (or other diabetes drugs) for certain groups of patients, but not others. However, the continuing bad publicity about Avandia’s risks have significantly reduced its sales.

The continuing unfavorable safety findings for Avandia, as well as the findings that both Avandia and Actos induce weight gain in type 2 diabetics (who are usually obese to begin with), and carry an increased risk of edema and heart failure, have given new ammunition to critics who believe that physicians treating diabetes should stick to combinations of the older, cheaper drugs–insulin, metformin, and sulfonylureas, and avoid using not only TZDs, but also newer agents. This point of view also suggests that there is no need to discover and develop new antidiabetic agents.

However, the arguments in our 2008 Genetic Engineering News (GEN) article on diabetes (available on our website) still apply. There are still major unmet needs in type 2 diabetes, especially the need to prevent weight gain in diabetes treatment (and even to promote weight loss), and the need to prevent long-term loss of pancreatic beta-cell function. It is the loss of beta-cell function that results in the progression of type 2 diabetes, such that patients who initially succeed in reaching glycemic goals even with multidrug treatment with older antidiabetics eventually experience poor glycemic control on the same regimens.

As we discussed in earlier blog posts, some of the newer antidiabetics, namely the incretin mimetic exenatide (Amylin/Lilly’s Byetta) and liraglutide (Novo Nordisk’s Victoza), may give increased glycemic control while promoting weight loss. There is also evidence from animal studies that these drugs might help to preserve beta-cell function.

Ironically, despite the major safety issues with TZDs, there is both animal model and human evidence that these agents may work to preserve and/or enhance beta-cell function. Moreover, insulin resistance is a major factor in the pathogenesis of type 2 diabetes. Therefore, it would be very advantageous, and perhaps essential, for physicians and patients to have access to safer insulin sensitizers, especially if they work to prevent diabetes progression by preserving and enhancing beta-cell function.

Might it be possible to discover and develop better, safer insulin sensitizers than the TZDs? We shall discuss this question in Part 2 and Part 3 of this series.

24 August 2010

Aileron Therapeutics partners with Roche

By |2010-08-24T00:00:00+00:00August 24, 2010|Chemistry, Drug Development, Drug Discovery, Strategy and Consulting|


On November 27, 2009, we posted an article on this blog about the use of stapled peptides in targeting intracellular pathways. This technology was originally developed by Dr. Gregory Verdine (Department of Chemical Biology, Harvard University, Cambridge MA, and the Dana-Farber Cancer Institute, Boston MA) and his colleagues. A biotechnology company, Aileron Therapeutics (Cambridge, MA) was founded (with Dr. Verdine among its founders) in 2005 to develop and commercialize stapled peptide drugs. Aileron’s most advanced compounds, which are being developed for the treatment of solid and hematological tumors, are only in the preclinical stage.

On August 24, 2010, Aileron and Roche announced that they had entered into a collaboration to discover, develop, and commercialize stapled peptide drugs designed to address up to five undisclosed targets. These targets are selected from Roche’s key therapeutic areas of interest–oncology, viral diseases, inflammation, metabolic diseases, and central nervous system diseases.

Under the agreement, Roche will provide Aileron guaranteed funding of at least $25 million in R&D support and technology access fees. Aileron will also be eligible to receive up to $1.1 billion in discovery, development, regulatory, and commercialization milestone payments, if drug candidates are developed against all five targets. Aileron will also receive royalties on any future sales of marketed products that result from the collaboration.

In our November 2009 article, we discussed the design of stapled peptides, in which hydrocarbon moieties are used to constrain, or “staple” peptide sequences into an α-helical conformation. These sequences are designed to mimic key binding domains of proteins that are involved in intracellular signaling pathways. We gave two examples of pathways that were addressed by specific stapled peptides: the Notch pathway and a Bcl-2-related apoptotic pathway. In both cases, the stapled peptides modulated protein-protein interactions that are considered “undruggable” by conventional small-molecule drugs.

According to Roche, It is “as yet intractable” intracellular protein-protein interactions that are of special interest to the company in collaborating with Aileron.

According to Aileron, the new alliance with Roche validates the broad potential of their stapled peptide technology platform across multiple therapeutic areas and classes of targets. The alliance also provides Aileron with capital to advance its internal R&D.

The Roche agreement represents Aileron’s first Big Pharma strategic alliance. However, a venture capital consortium that included GlaxoSmithKline, Novartis, Roche, and Lilly invested $40 million in Aileron in June 2009.

As we said in our November 2009 article, stapled peptides represent an exciting and innovative technology with the potential to address “undruggable” protein-protein interactions, even though the therapeutic value of stapled peptides has not yet been confirmed in the clinic. (We have discussed several other means of addressing protein-protein interactions in various articles in this blog–these targets represent an area of opportunity for companies that are innovative enough to pursue it.) And as we discussed in a more recent article, Roche is one of the Big Pharma companies that continues to be focused on innovative drug discovery and development, in an era of Big Pharma R&D retrenchment. The Aileron-Roche partnership therefore appears to be an ideal match.

Go to Top