Lilly faces setback as FDA pushes back Bydureon to 2012
This article was originally published in Scrip
Lilly has suffered another blow to its late-stage pipeline after the US FDA unexpectedly issued another complete response letter for Bydureon, Lilly/Amylin/Alkermes' once-weekly formulation of the twice-daily injectable type 2 diabetes drug Byetta (exenatide).
Bydureon, which had already been hit with a previous complete response letter in March (which had raised questions about the product's labelling, the risk evaluation and mitigation strategy (REMS) and manufacturing processes) now faces at least an additional 18-month delay to the US market. Amylin's shares had plunged 49% on Nasdaq by mid-morning on 20 October, while Alkermes' shares dropped by 28% and Lilly's shares by 4%.
Lilly/Amylin plan to submit their reply to the complete response letter for Bydureon by the end of 2011, pending discussions with the FDA. Based on the requirements for additional data, this will likely be considered a Class 2 resubmission requiring a six-month review. In the complete response letter, the FDA requested a thorough QTc study (QTc is a risk marker for rare cardiac arrhythmias) with exposures of exenatide higher than typical therapeutic levels of Bydureon.
Additionally, the FDA has now requested the results of the DURATION-5 study to evaluate the efficacy, and the labelling of the safety and effectiveness, of the commercial formulation of Bydureon. DURATION-5 was a Phase III trial in which Bydureon was superior to Byetta in controlling blood sugar.
It is the QTc study which will is the main reason for Bydureon's delay. On a conference call, Amylin indicated that the FDA's particular issue with QTc prolongation may revolve around the potential risks with higher exenatide exposures in patients with renal impairment.
Jefferies analysts, who say that the QTc study requirement is a major surprise, believe that the FDA is concerned with a randomized, placebo-controlled QTc study of Byetta in healthy volunteers presented at the American Diabetes Association meeting in 2009, in which one set of data suggests that higher exenatide levels may prolong the QTc interval. However, based on the totality of the data, they do not believe that QTc prolongation will prevent approval of Bydureon.
They note that the company has not seen a similar QTc effect at all with Bydureon in the DURATION-1 data, including in the subset of patients with mild-moderate renal impairment; the extrapolation of the data from the Byetta QTc study out to serum concentration levels of 500-600 pg/mL (2-3x the steady state concentration levels of Bydureon) does not surpass the 10msec threshold, which has been an important cutoff for historical QT precedents; and Bydureon may be predicted to have a more benign effect on QTc than Byetta given the lack of insulin spikes at steady state that can cause a spurious QTc effect.
rivals
Lilly had been hoping that Bydureon would make up for some of the lost sales of Byetta, which had sales of $669 million last year. The first-in-class GLP-1 receptor agonist was launched in the US in 2005, but has recently lost market share to Novo Nordisk's once-daily, injectable Victoza (liraglutide), the second GLP-1 drug to reach the market. Other than its being once instead of twice-daily, Novo Nordisk cites its more convenient administration as an advantage over Byetta, and in a head-to-head trial published in the Lancet in June, it demonstrated better blood sugar control.
According to Novo Nordisk, Victoza accounted for more than a quarter of all prescriptions in the GLP-1 class in its first five months on the market (as of 30 June). Analysts see Victoza as the biggest beneficiary of the Bydureon delay, and other rival GLP-1 drugs in late-stage development could also benefit.
These include GlaxoSmithKline/Human Genome Sciences' once-weekly Syncria (albiglutide) and Sanofi-Aventis's once-daily lixisenatide. Roche/Ipsen had been developing their once-weekly GLP-1 analogue taspoglutide, but it has had issues with gastrointestinal tolerability and hypersensitivity and anaphylactic reactions. If taspoglutide still makes it to the market, its arrival is not expected for many years. Meanwhile, Lilly is also developing once-weekly dulaglutide, an engineered GLP-1 Fc fusion protein, in Phase III.
Convenience has been a major reason for the lower uptake of Byetta, compared with the other new class of type 2 diabetes drugs, the oral DPP-4 inhibitors, such as Merck's Januvia (sitagliptin). Januvia was launched in the US in 2006 and reached sales of $1.9 billion last year, while Janumet (sitagliptin plus metformin) also had sales of $658 million last year.
Lilly, which is facing one of the biggest patent cliffs in the industry, suffered earlier this year when another big pipeline hope, its gamma secretase inhibitor semagacestat, failed in Phase III and the company ceased development of the drug.