Well, it has been a busy start to the year for the type 2 diabetes market, with both good and bad news from the FDA for some of the major players in this market. First came the news on the 19th of January that the FDA had issued a Complete Response Letter (CRL) for Bristol-Myers Squibb/AstraZeneca's dapagliflozin, the first-in-class sodium glucose cotransporter-2 (SGLT-2) inhibitor. This news actually came earlier than anticipated, because the drug's PDUFA date was scheduled for January 28th, 2012. But the news itself was not at all unexpected. As we discussed in our 'Dapagliflozin What Now?' blog post on July 20th, 2011 on July 19th 2011 an FDA Advisory Committee voted 9-6 against recommending approval of dapagliflozin. The Committee's concerns revolved around an excess number of cases of both breast and bladder cancer cases observed among patients taking dapagliflozin rather than a placebo or comparator drug, as well as a case of severe liver injury that was deemed to be likely to be caused by dapagliflozin. Although the overall number of cases of cancer was small, the FDA CDER's Office of Surveillance and Epidemiology (OSE) noted that the imbalance was statistically unlikely to have occurred by chance.
Following the Advisory Committee meeting, the FDA requested further data from recently completed and ongoing clinical trials of dapagliflozin, and pushed back the original scheduled PDUFA date from October 28th, 2011, to January 28th, 2012, in order to allow enough time for the data to be submitted and assessed. However, as we suspected, the data provided were insufficient to allay the FDA's concerns over dapagliflozin's safety, resulting in the issuance of the CRL. Although the precise details of the CRL have not been disclosed, AstraZeneca and BMS did report that the FDA has requested additional clinical data to allow a better assessment of the benefit-risk profile for dapagliflozin. These data will come from extensions of and follow-up to ongoing clinical trials (which we estimate will lead to a delay of up to two years before dapagliflozin is approved), but, crucially, new clinical trials may also be required. We assume that new clinical trials will only be required if the data from ongoing trials are insufficient to provide adequate reassurance of the safety of dapagliflozin. This seems unlikely, given that over 2,500 patients are still enrolled in five different trials or trial extensions, all due to finish by mid-2013. However, should one or more new clinical trials be required, then any such trial would most likely have to be large and lengthy, because the safety concerns noted so far are very rare. The expense of such a trial, and the inevitable delay to dapagliflozin's approval, may cast a question mark over dapagliflozin's further development. For now though, we assume that this will not be the case, and that dapagliflozin will be approved in the United States in 2014.
Another question that remains over the future of dapagliflozin is: what will happen in Europe. According to AstraZeneca's latest pipeline update, the European regulatory submission for dapagliflozin is slated to occur during the second half of 2012. By the time the EMA comes to make a decision on the drug, at least some of the data requested by the FDA will be available, and so a straight-forward approval (most likely with warnings on the drug's label) is more likely in Europe. And yet another question is the impact of this scrutiny of dapagliflozin's safety on other SGLT2 inhibitors in development, in particular Johnson & Johnson's canagliflozin and Boehringer Ingelheim/Eli Lilly's empagliflozin, both of which are in Phase III development and expected to launch in 2014. Until a detailed analysis of late-stage clinical trial data becomes available, it is impossible to say whether these drugs are also associated with the same safety concerns as dapagliflozin. What is certain, however, is that the developers of canagliflozin and empagliflozin can expect a high level of scrutiny of their drugs safety profile. These companies will be watching the dapagliflozin story unfold with great interest.
Amylin and Alkermes were the recipient of better news from the FDA; their drug Bydureon (a once-weekly version of the GLP-1 analogue Byetta), was finally approved in the United States on January 27th, 2012. The NDA for this drug was originally submitted in May 2009, but approval was delayed first by issues with the product label and manufacturing procedures (leading to a CRL in March 2010), and then by a request (in the form of a second CRL in October 2010) for further clinical data including data from a thorough QT (tQT) study. These data were submitted to the FDA in July 2011, and were sufficient for the drug to be deemed approvable in January 2012. This delay dearly cost Amylin and Alkermes (and, until November 2011 when the company terminated its involvement in Bydureon and Byetta, Eli Lilly; see our November 17th, 2011 blog post 'The End of the Road for Amylin and Lilly's Diabetes Pact' (for more on this), because it gave the once-daily GLP-1 analogue liraglutide (Novo Nordisk's Victoza), a significant head-start after its launch in February 2010.
Victoza has seen strong growth since its launch, resulting in blockbuster sales in 2011, its first full year on the market. However, Victoza now faces a serious challenger in the form of the once-weekly Bydureon. Although in the head-to-head DURATION-6 study Bydureon failed to demonstrate non-inferiority to Victoza on the primary endpoint of HbA1c reduction, Bydureon is tolerated better and only requires once-weekly injections rather than the once-daily injections required for Victoza. In the near term, we expect that Victoza's strong lead will allow it to stay well ahead of Bydureon in the race for leadership of the GLP-1 analogue space. Looking further ahead, at a ten-year horizon, the picture is somewhat different, with sales of Bydureon almost catching up with sales of Victoza. Who will be the ultimate winner is likely to be a close call that will depend heavily on the ability of the respective developers to market each drug. Given that both Victoza and Bydureon are expected to be blockbusters and big players within the type 2 diabetes space, it will be interesting to see how their relative fortunes fare.