Donny Wong, Ph.D. Director, Metabolic Disorders
Last week, we examined key happenings in the diabetes drug development arena from the first half of 2011. According to Decision Resources’ Metabolic Disorders team, here are the most influential events to impact the diabetes market in the second half of 2011.
To read part one of this list, click here
4. In June 2011, the French and German regulatory agencies withdrew Takeda’s PPAR-gamma agonist Actos because of bladder cancer concerns. These concerns arose after several registry studies, including the FDA's Adverse Event Reporting System and the French national health insurance body's database, linked use of Actos to an increased risk of developing bladder cancer. The drug remains on the market in other European countries, Japan, and the United States, although cautions about its use in patients with known or suspected bladder abnormalities have been added to the drug's prescribing information.
Winners and losers: While at the surface level it looks like the withdrawal of Actos from France and Germany is a loss for Takeda, the fact that the drug was allowed to remain on the market in the United States (and in Japan) is a win considering that French and German sales for Actos comprised only 2% of total G7 major-market sales for Actos. Similar to how Januvia benefited from the decline of Avandia following the publication of several meta-analyses linking Avandia to elevated cardiovascular risk, the negative publicity surrounding Actos and the elevated risk for bladder cancer will be a boon for the DPP-IV inhibitors, which are viewed by many physicians as safer options. However, the real losers will be the generics manufacturers who have lined up to market generic pioglitazone once the drug loses marketing exclusivity in Q3 2012; these companies will face diminishing demand for pioglitazone. Other drugs in the diabetes pipeline may also end up on the losing side, as the bladder cancer issue will cause regulators to increase their level of scrutiny for cancer signals, as we observe for the SGLT-2 inhibitor dapagliflozin (see #5 below).
5. In July 2011, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee cast a 9-6 vote against approval of Bristol-Myers Squibb's and AstraZeneca's (potentially) first-in-class SGLT-2 inhibitor dapagliflozin. The negative vote resulted primarily from an imbalance in the number of breast and bladder cancer cases observed from pooled Phase II and III data in patients exposed to dapagliflozin, and a possible case of Hy's law (signifying potential drug-induced liver injury). The original PDUFA date for dapagliflozin was October 28, but was delayed by the FDA until January 28, 2012 following a request for additional data from ongoing clinical trials. Mechanistically, the imbalance in the cancer cases doesn’t make a lot of sense. But regulators cannot deny the numerical imbalance (18 breast and bladder cancers in the dapagliflozin group, 1 case in the control group) and therefore we anticipate that the additional data that BMS and AstraZeneca have delivered to the FDA will be insufficient. Instead, we expect that dapagliflozin will receive a complete response letter from the FDA requesting a safety study to demonstrate that there is no elevated cancer risk or hepatoxicity. We expect that fulfilling this request will result in at least a two-year delay for dapagliflozin.
Winners and losers: BMS and AstraZeneca stand to lose the lucrative first-in-class advantage for dapagliflozin owing to the regulatory delays we are anticipating. This opens the door for Johnson & Johnson's canagliflozin and Boehringer Ingelheim and Eli Lilly's empagliflozin, which are both in Phase III development—and we now expect all three drugs to launch around the same time. This delay will also benefit the DPP-IV inhibitors, which will not face the challenges posed by a new drug class until the first SGLT-2 inhibitors enter the market in 2014. However, the burden of proof is on other developers of SGLT-2 inhibitors to demonstrate that their compounds are not associated with elevated cancer risk—and if subsequent imbalances are found, then the entire class may be at risk.
6. In September 2011, Novo Nordisk filed applications for regulatory approval of insulins Degludec and Degludec Plus in the United States and in Europe. Degludec has a longer halflife than Lantus or Novo Nordisk’s Levemir, and is therefore a truer once-daily long-acting insulin analogue than either Lantus or Levemir. Also, Degludec is associated with a 25% lower rate of nocturnal hypoglycemia than Lantus and can be dosed more flexibly (i.e., at any point in the day).
Winners and losers: I would have to go out on a limb and say that Novo Nordisk will end up the most likely loser here. The company also has the most to gain, but there are too many chips stacked against widespread use of Degludec. Do we really need another long-acting insulin, especially as biosimilar formulations of insulin glargine are looming in the not-too-distant future? Novo Nordisk has also been fairly quiet about the thrice-weekly option that they had been championing over the past couple of years. While the need for fewer injections will be welcomed by patients, the thrice weekly option left most physicians scratching their heads, as a weekend “drug holiday” doesn’t exactly help a patient’s best interests. However, the proof will be whether payers will reimburse for what boils down to just improved safety and convenience. The one wild-card will be the Degludec-Victoza combination, which is currently in Phase III development. This duo will become a strong contender if it demonstrates good safety and efficacy (which we expect based on each drug’s individual profiles), and if the dosing can be optimized (i.e., via a single injection). The Degludec-Victoza combination also got a boost when Sanofi announced a delay to the development of its own basal insulin + GLP-1 analogue combination (Lantus + Lyxumia).
7. In September 2011, Eli Lilly and Boehringer Ingelheim announced that they were delaying the launch of Trajenta (linagliptin) in Germany due to ongoing discussions about reimbursement with German reimbursement authorities following the passing of AMNOG (Germany’s Pharmaceutical Restructuring Act) earlier in the year. The companies’ concern was that generic antidiabetic drugs such as metformin or the sulfonylureas might be used for reference pricing for Trajenta, which would result in a low price for Trajenta. However, why the rest of the pharmaceutical industry needs to take notice of this development is that there can be serious repercussions beyond Germany, given that many other countries use German pricing as an external reference.
Winners and losers: In the short term Eli Lilly and Boehringer Ingelheim are losing revenue to other DPP-IV inhibitors by not launching Trajenta in Germany. However, the entire pharmaceutical industry may end up being the losers in the long term if German reimbursement officials do end up benchmarking novel therapies like Trajenta against low-cost generics like metformin or the sulfonylureas. The only potential winner here is the German healthcare system. One potential fallout to keep an eye open for is the possibility that BI and Eli Lilly will refuse to launch Trajenta in Germany at all. We’ve seen this happen in the past when AstraZeneca abandoned its plans to launch Crestor (rosuvastatin) in Germany in 2005. (However, AstraZeneca did eventually launch the drug in 2008, a full five years after its first launch in other European markets).