EMA grants final approval to Sanofi/Lexicon’s Zynquista (sotagliflozin) for type 1 diabetes – April 26, 2019

Follows positive CHMP opinion in EU and Complete Response Letter from FDA; Restricted to BMI ≥27, equivalent to AZ’s Forxiga for type 1 in Europe; Both 200 and 400 mg doses approved with hypo benefit

Lexicon announced today that EMA has granted final approval to Sanofi-partnered SGLT-1/2 dual inhibitor sotagliflozin as an adjunct to insulin for adults with type 1 diabetes and BMI ≥27 kg/m2. This is equivalent to the approval granted to AZ’s Forxiga for type 1 in the EU. As with Forxiga, we expect the approval is also limited to physicians who are experienced in treating type 1 diabetes. We see this as a real win for patients – it will be tested in a smaller group of higher-BMI patients rather than “opening the floodgates” – but we believe it’ll be available to a larger group of patients eventually, if all goes well with this smaller population to start.

This extremely positive news follows a positive CHMP opinion (March 2019), but also a Complete Response Letter (CRL) from FDA (also March 2019). Sanofi commented today in its 1Q19 financial update that the company is currently seeking a meeting with FDA to determine next steps for sotagliflozin in the US. Given the significant unmet need in patients with type 1, we’re surprised that a meeting hasn’t yet happened but we are optimistic, long-term, that this therapy will be available to a sub-set of people with type 1 who have the right benefit/risk profile for the therapy.

FDA’s CRL was ostensibly based on concern over DKA risk and, to our observation, dissatisfaction at the sponsors’ risk mitigation strategy, both of which took center stage at a January Advisory Committee meeting. To be sure, DKA risk with SGLTs in type 1 is very real, but the vast majority thought leaders have expressed that (i) the benefits of SGLTs are too great to ignore; and (ii) proper strategies and protocols can minimize that risk meaningfully (see formal consensus). In its press release, Lexicon commented, “The risk of DKA will be addressed by careful selection of patients for treatment with sotagliflozin and through a risk-management plan and a mitigation strategy, including patient, healthcare professional and care giver educational activities, that will support its safe use” – we look forward to more details. One thing is for certain: FDA and EMA are approaching SGLTs in type 1 with different perspectives. AZ’s Farxiga remains under review for type 1 at FDA; a decision is expected later this year.

The BMI restriction placed on both Forxiga and Zynquista, at least as a starting point, has great promise. While we aren’t certain that longer-term, it needs to be quite as restricted as the initial label requires, we think it’s an excellent starting point that enables use in a large group of people with type 1 while not making it open to absolutely all. Shortly after CHMP proposed the restriction, DEPICT (AZ’s program for Forxiga in type 1) investigators presented a post-hoc analysis at ENDO 2019 showing that patients with BMI ≥27 saw substantially lower DKA rates than those <27. We view this as a valuable, data-driven way to safely limit the rollout of SGLTs for type 1 as researchers and clinicians work to learn more about DKA risk and prevention.

Per Lexicon, both the 200 and 400 mg doses of sotagliflozin have been approved. As a reminder, the CHMP opinion indicated that only the 200 mg tablet would be made available, meaning patients will take two tablets for the higher dose. To our knowledge, this is still the case. Additionally, as we understand it, there will be some sort of hypoglycemia benefit noted on the Sanofi/Lexicon label.

-- by Ann Carracher and Kelly Close