Sanofi submits LixiLan (lixisenatide/insulin glargine) to the FDA – December 28, 2015

Sanofi announced last week that it has submitted a New Drug Application (NDA) for its fixed-ratio combination of insulin glargine and lixisenatide to the FDA. While the announcement notes that the brand name for the combination is still pending, Sanofi has previously referred to the product as LixiLan in its quarterly updates and recent “Meet Sanofi Management” seminar. The announcement also shared that Sanofi redeemed a priority review voucher (PRV) with the submission, which grants an expedited six-month review process rather than the standard 10-month review process. As a result, a regulatory decision would be expected by mid-2016 (August 2016 at the latest, assuming the FDA takes the full allowed 60 days to accept the NDA). This timeline puts LixiLan neck-and-neck with Novo Nordisk’s Xultophy (insulin degludec/liraglutide) in the race to be the first GLP-1 agonist/basal insulin fixed-ratio combination to reach the US. Xultophy was submitted to the FDA at the end of September 2015 and will likely receive a regulatory decision in 3Q16. Presumably both would have advisory board meetings and we expect FDA may combine these (pure speculation however – we don’t know).

Sanofi highlighted LixiLan as one of its main commercialization priorities in its new strategic plan, unveiled during its November “Meet Sanofi Management” seminar. Given the similarity in expected approval timelines for LixiLan and Xultophy, the negotiations over 2017 formulary access will be crucial for the two combinations’ near-term prospects in the US. Novo Nordisk has previously stated that it does not intend to sacrifice price for immediate broad access for Xultophy. Recent history suggests that Sanofi may take a different approach, as it accepted a relatively high level of rebates for Lantus (insulin glargine) in exchange for stronger formulary positioning for Toujeo (U300 insulin glargine) for 2015. That said, Novo Nordisk management has expressed confidence that Xultophy has a superior clinical profile compared to LixiLan, and Xultophy could benefit from having a more established presence in Europe, though our understanding is that penetration is still fairly limited there – and our belief is that payers in the EU aren’t eager to make reimbursement more widely available for virtually any new compound, regardless of clinical profile. Despite this, we’re very excited for the GLP-1 agonist/basal insulin class as a whole and are particularly optimistic about its potential to reduce dosing burden, prompt weight neutrality or weight loss (as opposed to weight gain), reduce hypoglcyemia, and consolidate copays for patients.

• The NDA is supported by the phase 3 LixiLan-O and LixiLan-L trials, which both reported topline results in the second half of 2015. The LixiLan-O trial (n=1,170) demonstrated statistically superior A1c reductions with LixiLan vs. Lyxumia (lixisenatide) or Lantus (insulin glargine) in patients with type 2 diabetes on oral agents. The LixiLan-L trial (n=736) found that LixiLan produced statistically superior A1c reductions vs. Lantus in patients with type 2 diabetes on basal insulin. Secondary endpoints were not reported. We eagerly await full results, particularly for body weight, hypoglycemia, and GI side effects, when they are presented “in an appropriate scientific forum.” Presumably ADA 2016 is a possibility.
• Sanofi appears to be positioning LixiLan both as a first injectable therapy or as an intensification option for patients not at target with basal insulin alone. We’ve heard quite a bit on the conference circuit (including at EASD 2015 and CODHy 2015) on the logic behind adding a short-acting GLP-1 agonist like lixisenatide for postprandial glucose control on top of basal insulin. Since short-acting GLP-1 agonists generally have stronger effects on postprandial glucose, the fact that LixiLan includes a short-acting GLP-1 agonist could differentiate it from Xultophy, which includes the longer-acting GLP-1 agonist liraglutide along with insulin degludec. Novo Nordisk plans to target Xultophy initially to patients on basal insulin but believes the appropriate population could expand over time. We wonder how Sanofi’s launch strategy will compare. MDI seems very hard for many doctors to learn and train patients on and even patients with access to educators don’t find mealtime insulin particularly easy to learn. We think the GLP-1/basal combination, used optimally (and particularly used early) will be very helpful for patients and could enable many patients to take one therapy over a much longer-than-usual time. When SGLT-2s are generic, we would imagine the three used together could be a very good combination for many (before then, reimbursement may be challenging though we expect some to take it).
• Interestingly, the projected decision date for LixiLan is fairly close to the projected FDA decision date for standalone lixisenatide. Sanofi submitted an NDA for Lyxumia in July and the FDA accepted the NDA in September. Assuming the standard ~10-month review process, a decision would be expected in late July 2016.
• Sanofi has previously stated that it intends to submit LixiLan for regulatory approval in the EU in 1Q16. Xultophy is already available in several European countries, including the UK, Germany, Switzerland, and Sweden.

Close Concerns Questions

Q: How will LixiLan be priced, reimbursed, and rebated relative to Xultophy and Toujeo?

Q: Will Sanofi seek exclusive formulary access with the major pharmacy benefits managers?

Q: What does LixiLan’s clinical profile look like compared to Xultophy?

Q: What does the safety profile and body weight data look like in the phase 3 program for LixiLan?

Q: Which patient populations will Sanofi initially target?

Q: Are there any plans for a “Lixi-Toujeo” combination in the future?

-- by Helen Gao, Emily Regier, and Kelly Close