AZ files SGLT-2 inhibitor Forxiga (dapagliflozin) for type 1 diabetes with EMA – March 5, 2018

AZ announced this morning that the EMA has accepted an application for SGLT-2 inhibitor Forxiga (dapagliflozin) in type 1 diabetes. Assuming a standard 10-12 month review period, a decision is expected in 1Q19. This regulatory submission comes on time with plans shared in AZ’s 4Q17 update (page 48), and if the program continues on schedule, the company will file Farxiga for a type 1 indication with FDA in 2H18.

Dapagliflozin could be the first-to-market oral adjunct therapy for type 1 diabetes, though Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin is close behind, and stands as most likely to be first-to-market in the US. During Lexicon’s 4Q17 update, management confirmed that an NDA is on track for 1Q18, meaning it should be submitted in the next four weeks. Sanofi/Lexicon aim to file sotagliflozin with the EMA by end of 1Q18 as well.

It’s interesting that AZ is pursuing a type 1 indication for Forxiga in Europe ahead of the US. This could be a sign that the EMA will offer a smoother path for an oral adjunct treatment though this is speculation. Indeed, EMA’s recently-released draft guidance for diabetes drugs includes a new section on oral therapies to supplement insulin for type 1s, suggesting that the agency is ready to evaluate these incoming applications. The proposal recommends hypoglycemia as a co-primary endpoint to A1c reduction – this is critical, in our view and we’d also like to see weight loss considered. We’d also like to see EMA take this one step further by advocating for CGM use in these clinical trials to collect time-in-range data, which could illuminate the greatest benefit for patients. Notably, EMA is accepting comments on the draft guidance until August 15, 2018: just fill out this template and email it to CVSWPSecretariat@ema.europa.eu.

The language in EMA’s draft guidance surrounding adjunct therapies/DKA risk is relatively neutral; the text simply requests that DKA events be recorded throughout clinical development. We suspect this safety concern will loom large for FDA in evaluating sotagliflozin and dapagliflozin for type 1, though this is only our speculation for now, and it remains to be seen how both regulatory bodies approach the DKA data on these candidates. We sincerely hope that DKA doesn’t overshadow the key advantages of oral adjunct treatment in type 1 diabetes care: additional A1c-lowering and more time-in-range, less hypoglycemia (where insulin causes hypo and fear of hypo), and greater weight loss (where insulin causes weight gain). The hypoglycemia, in particular, is so important for patients with type 1 diabetes - we can’t emphasize that enough.

Competitive Landscape

• While AZ’s Farxiga and Sanofi/Lexicon’s sotagliflozin lead the competitive landscape for oral adjunct therapy, Lilly/BI will also announce phase 3 results from the EASE program in 2018. Two clinical trials, EASE-2 and EASE-3, investigated SGLT-2 inhibitor Jardiance (empagliflozin) in a population with type 1 diabetes. J&J completed a phase 2 study of SGLT-2 Invokana (canagliflozin) in type 1, which was presented at ADA 2016, but it’s unclear if/when the company will move forward with phase 3. We wonder if Farxiga and Jardiance, which are already established as type 2 diabetes drugs, will have an edge over sotagliflozin in terms of early commercial uptake. Importantly, we see more than enough room for all of these products to be successful on the market, and we anticipate that each drug will benefit from the emergence of the whole class. Our sense is that many type 1s in the real world are already taking SGLT-2 inhibitors off-label (Dr. Anne Peters shared a powerful patient testimonial at ADA Postgrad 2016), so there is clearly demand, and this practice will only become safer with (hopeful) EMA and FDA approvals for type 1 diabetes. In other words, this should not be a story about within-class competition – rather, we’d love to see these companies work together to address regulatory concerns and, later on, to build up strong payer reimbursement.

DEPICT Clinical Program

• AZ’s EMA submission is based on 52-week data from DEPICT 1 and 24-week data from DEPICT 2. The company announcement indicates that Farxiga (at 5 mg or 10 mg once-daily) showed statistically significant reductions in A1c, body weight, and total daily insulin dose in both placebo-controlled trials. We have yet to see full results from the DEPICT 1 trial extension or from DEPICT 2, but these findings became available internally at AZ in 4Q17, and we look forward to presentations at scientific meetings later this year.
• Preliminary 24-week data from DEPICT 1 was featured in an EASD symposium and was published simultaneously in the Lancet Diabetes & Endocrinology. The study enrolled 833 patients with type 1 diabetes, randomizing them 1:1:1 to 5 mg dapagliflozin, 10 mg dapagliflozin, or placebo. From a baseline 8.5%, A1c declined 0.4% with 5 mg Farxiga vs. placebo and declined 0.5% with 10 mg Farxiga vs. placebo (both p<0.0001). Percent change in body weight vs. placebo was -3% with low-dose Farxiga and -4% with high-dose Farxiga (both p<0.0001); participants started the study with a baseline BMI of 28 kg/m², indicating overweight. From a baseline of 60 units, total daily insulin dose fell 9% (>5 units) with 5 mg Farxiga vs. placebo and fell 13% (nearly 8 units) with 10 mg Farxiga vs. placebo (both p<0.0001). These efficacy results are highly statistically significant and clinically-meaningful, and the DEPICT 1 trial extension out to one year will reveal the durability of these effects. We were intrigued by Dr. Paresh Dandona’s suggestion at EASD that weight loss will be amplified with longer follow-up (since there was very little flattening of the weight loss curves in the first 24 weeks), and we’ll be looking for this when 52-week DEPICT 1 data reads out.
  
  • Although hypoglycemia was balanced across all three treatment arms in DEPICT 1, time-in-range improved meaningful for people on Farxiga vs. placebo. CGM showed 52% (12.5 hours), 55% (13.2 hours), and 44% (10.6 hours) time-in-range with 5 mg dapagliflozin, 10 mg dapagliflozin, and placebo, respectively. This corresponds to an extra 2-3 hours in-range with the SGLT-2 inhibitor vs. placebo, and that’s a win for patients no matter how you look at it – consider the 2-3 extra hours each day someone with type 1 could spend feeling well, not working to get back in range, experiencing higher quality of life.
  • DKA occurred in 1% of the 5 mg treatment arm (four patients; two due to pump failure; one due to missed insulin dose), in 2% of the 10 mg treatment arm (five patients; one due to pump failure; three due to missed insulin dose; one due to alcohol), and in 1% of the placebo arm (three patients; one due to pump failure, one due to missed insulin dose; one due to stress). Our sense is that at least some of the favorable DKA outcomes in DEPICT 1 can be attributed to the protocol that total insulin should only be reduced up to (but no more than) 20%. Study participants were advised to eat more carbs and dose insulin if they weren’t taking a certain amount daily. Our understanding is that less insulin reduction is crucial in mitigating DKA risk, and we’re curious to see how this will be incorporated into guidelines for real-world HCPs prescribing new oral adjuncts to their patients with type 1. This is another example of where all the SGLT manufacturers can collaborate in making their emerging drug class a commercial success. We caution against over-comparison of the DKA results (or any results, for that matter) from the DEPICT program vs. the inTandem program for sotagliflozin vs. the EASE program for Lilly/BI’s empagliflozin (which will report later this year). Differences in study population and trial design preclude such comparisons, and in any case, we don’t believe ranking these agents is necessary or worthwhile at this stage. Oral adjunct therapy has long been an unmet need in type 1 diabetes care, and now that products are finally nearing the market, we imagine this class as a whole can gain traction. We’re excited about dapagliflozin for type 1, sotagliflozin for type 1, and empagliflozin for type 1, and we maintain that DKA risk should be manageable in the real world with diligent monitoring and patient education. Whether or not REMS should be required is a question that we hope to see answered; there are multiple other questions, including some very basic ones – how to ensure that patients have ketone monitors and know how to use them and can gain access to this technology easily (the strips are not cheap). Many (many!) thought leaders have maintained that managing SGLT-related DKA is manageable, including Drs. John Buse, Anne Peters, Irl Hirsch, and Julio Rosenstock – we hope to show that this is so, including, again, the basics of monitoring and assessing ketone levels.

-- by Payal Marathe and Kelly Close