AZ files SGLT-2 inhibitor Forxiga for type 1 diabetes in Japan, ahead of planned 2H18 submission – May 21, 2018

This morning, AZ announced that an sNDA for SGLT-2 inhibitor Forxiga (dapagliflozin) in type 1 diabetes has been submitted to Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). According to AZ’s 1Q18 results announcement (page 45), this filing was slated for 2H18, and now comes ahead of schedule. Assuming a standard 10-12 month review period, a decision from PMDA is expected in 2Q19.

This supplementary application requesting a new indication for Forxiga (the drug is already marketed for type 2 diabetes) is based on positive results from the global DEPICT program in type 1, as well as a dedicated trial of Forxiga in Japanese patients with type 1. At EASD 2017, 24-week data from DEPICT 1 was presented to positive reception: The 5 mg and 10 mg doses of dapagliflozin were associated with 0.4% and 0.5% greater drops in A1c vs. placebo (baseline A1c 8.5%, both p<0.0001), with 3% and 4% weight loss (baseline BMI 28 kg/m², both p<0.0001 vs. placebo), and with an additional ~2.2 and ~2.6 hours of time-in-range. This last benefit, in particular, is incredible, and we’re eager for more type 1s to have access to this adjunct oral treatment (many patients with type 1 diabetes are already taking an SGLT-2 inhibitor off-label).

We now await 52-week results from DEPICT 1 as well as data from DEPICT 2, which completed in April 2018 according to ClinicalTrials.gov. AZ has noted that both datasets have been available in-house since 4Q17. We can’t wait for these readouts later this year (potentially at ADA or EASD 2018). AZ’s announcement of the Japan sNDA mentions significant reductions in A1c, body weight, and total daily insulin dose with both 5 mg and 10 mg Forxiga at both 24 and 52 weeks, but no specific data was given.

Japan represents an interesting market for an adjunct type 1 diabetes therapy. The country has a relatively low rate of type 1 diabetes, with a prevalence of ~13.5/100,000 persons, translating to ~17,000 type 1s based on Japan’s current population. While this is not a trivial number of patients, it’s much smaller than, for example, the >1 million people with type 1 in the US. That said, we understand that reimbursement and pricing (and thus, profitability) are favorable in Japan. AZ could benefit by being first-to-market in the country. Read more about other oral adjuncts for type 1 below.

On March 5, AZ announced that the EMA had accepted an equivalent submission (Forxiga for type 1) for active review; a decision for the EU market is expected in 1Q19. A filing of Farxiga for type 1 with the US FDA is still expected in 2H18.

Adjunct Oral Treatment & DKA

• In DEPICT 1, DKA events rates were 1% in the 5 mg group (four patients), 2% in the 10 mg group (five patients), and 1% in the placebo group (three patients). This suggested no significant risk with dapagliflozin vs. placebo. That said, Lexicon management and Dr. Satish Garg wrote in an NEJM comment that DEPICT reported only “definite” DKA, suggesting that event rates would have been higher had investigators also recorded “possible” DKA. For comparison, the inTandem program for Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin considered both probable or possible DKA. The NEJM response concludes that when all levels of certainty are considered, the DKA rates were very similar between the dapagliflozin and sotagliflozin programs. In our view, DKA is a small but very significant risk with use of all SGLT inhibitors in type 1 diabetes. Rather than debating relative risk between incomparable trials, the field’s attention should shift to how to best minimize DKA risk. To be sure, there are ways to use these agents safely in type 1 diabetes care, meeting a severe unmet need, but we need to spread awareness of and education on these best practices. We gathered some early ideas on how to manage DKA in the real world from Dr. John Buse and Professor Thomas Danne shortly after sotagliflozin was submitted to FDA and EMA – read their thoughts here, and write to us with your own. These include wallet cards identifying patients with type 1 on an SGLT inhibitor, emphasizing to providers that treatment requires glucose + insulin both, courses that patients have to take prior to receiving an SGLT prescription, and more.

Competitive Landscape

• We’re not aware of any plans from Sanofi/Lexicon to submit sotagliflozin in Japan in the near future, so it seems reasonable to expect that Forxiga will be first-to-market there for a type 1 indication, pending approval. Forxiga has been submitted to EMA, and sotagliflozin has been submitted to both EMA and FDA; we expect decisions on all three in 1Q19. Pending regulatory approval, we imagine sotagliflozin could be first-to-market in the US, as AZ likely won’t file with FDA for Farxiga’s type 1 indication until sometime in 2H18. Meanwhile, launch in the EU will be more neck-and-neck. Much will depend on approval and launch timing/logistics, and we expect an Advisory Committee meeting in the US for each candidate. While Sanofi/Lexicon have been very positive about their interactions with FDA so far, we are uncertain of how the agency will approach the DKA data and how much clout will be given to CGM data and time-in-range benefit (in our view, this is the most notable advantage to adjunct therapy for type 1s). Commercially speaking, we wonder if Farxiga could have a leg up on sotagliflozin, at least initially, since the product is already well-established in type 2 diabetes, especially outside the US. All this said, we see more than enough room for both products to be successful on the market. In fact, sotagliflozin and Farxiga could benefit from each other’s presence on the market, from a joint effort by the manufacturers to spread safety information/education surrounding DKA, and from the emergence of a new “SGLT inhibitors for type 1” class. We understand that thousands of type 1s are already taking SGLT-2s off-label, and this practice could be so much safer with regulatory approval and with public safety protocols in place. To this end, we would love to see AZ and Sanofi/Lexicon work together to the extent possible to raise awareness, address safety and regulatory concerns, and eventually build quality reimbursement.

• Lilly/BI have promised phase 3 results from the EASE program (Jardiance in type 1) in 2018. Both EASE-2 (n=730) and EASE-3 (n=977) evaluated SGLT-2 inhibitor empagliflozin in adults with type 1 diabetes, for 52 and 26 weeks, respectively. Both trials are complete (as of September and October 2017), and we’ll keep an eye out for topline results and full presentations.

-- by Ann Carracher, Payal Marathe, and Kelly Close