The FDA has set up a debate among outside experts over Sanofi’s ($SNY) combo diabetes drug LixiLan today by raising a series of red flags over potential safety issues that could arise if the combination is allowed to reach the market.
In particular, regulatory insiders say that Sanofi’s proposed dose range for the combo, a mix of Lantus and lixisenatide--now dubbed "iGlarLixi"--would likely create some confusion over dosing among physicians, as well as expose some patient groups to adverse risks. The regulator's docs also noted the clear possibility that the final trial data were biased by inadequate dosing of insulin.
The stakes are high for both companies, with Sanofi--which used a $245 million priority review voucher to try to gain an edge over a competing product from Novo Nordisk ($NOVO)--in particular facing a tough task in getting its blockbuster diabetes franchise back on track after some shaky quarters. Just as the FDA was issuing its review of the Sanofi combo, the pharma giant announced that, among other senior exec changes, its diabetes chief Pascale Witz is out and Peter Guenter is in.
Novo Nordisk, one of Sanofi’s chief rivals in the huge diabetes market, was hit with its own FDA critique of IDegLira on Friday. Novo claimed that their combination of a GLP-1 drug and basal insulin--Victoza and Tresiba--proved superior to either of the two treatments provided to patients alone. But an internal assessment at the agency concluded that the trial design was biased in favor of the combo, making it impossible for the FDA to agree on that point regarding its superiority to Tresiba alone.
Novo’s response will come tomorrow (Tuesday 24 May) as an FDA panel convenes to discuss its recommendations on an approval, followed by Sanofi’s turn at bat on Wednesday. And Sanofi’s regulatory team can expect some tough questions about the way this kind of combination will play out in the real world, where millions of patients are involved.
“In fact, the dose range proposed for the GLP-1 component in the combination product includes doses that were not effective when used alone,” states the review by Jean-Marc Guettier, the director of the Division of Metabolism and Endocrinology Products inside CDER. “Although these low doses may be useful to ensure safe titration of one or both of the components, it is possible that specific patient populations (i.e., insulin sensitive individuals who require low doses of the combination for control) could be exposed to one component that provides no therapeutic benefit and causes specific adverse reactions.”
“The majority of participants in studies never reached the intended plasma glucose target (for reasons that were not captured) suggesting product dosing may have been inadequate,” he continued. “Inadequate dosing of the insulin in the studies could have biased the estimate of efficacy in favor of the combination product. This would further confound interpretability of a clinical superiority claim for the combination against the insulin comparator.”
Switching patients from one of these treatments to a combination of both also requires that they get a lower dose of the therapy they had been on. “(S)witching to the combination product may translate to a loss of glycemic control compared to addition of the second component administered independently.”
“FDA is clearly a little uncomfortable with the combos,” noted Bernstein’s Ronny Gal this morning. “Like the Xultophy documents, the main concerns raised are: (i) the logic of exposing patients to side effects of two drugs, when one may do; (ii) having patients already on GLP1 or insulin reduce the existing drug dose as they titrate up the fixed ratio combo; (iii) lack of rigor in proof that combination is better than Tresiba/Lantus alone. That said, the FDA has not faulted the actual results for both products and kept a neutral tone. In short, approval for both products seems likely with the question being primarily whether it would be approved for use only in injectable-naïve patients or in patients already on GLP1 or insulin.”