Memorandum

Lexicon 3Q17 – FDA/EMA submission of SGLT-1/2 dual inhibitor sotagliflozin for type 1 diabetes in early 1H18; inTandem3 data makes NEJM– November 8, 2017

Executive Highlights

  • In Lexicon’s 3Q17 update today, management reiterated plans to file a New Drug Application (NDA) for SGLT-1/2 dual inhibitor sotagliflozin in 1H18, aiming for the earliest date possible and expressing confidence in the submission.
  • Lexicon highlighted inTandem3 results, published in the NEJM, showing that 29% of patients achieved an A1c <7% without severe hypoglycemia or DKA with 400 mg sotagliflozin. Management called into question some aspects of the DEPICT 1 study (AZ’s SGLT-2 inhibitor Farxiga in type 1 diabetes), but simultaneously acknowledged that success of other candidates in the adjunct therapy class will drive overall awareness and adoption.
  • The Sanofi-led phase 3 program for sotagliflozin in type 2 diabetes is now well underway, with several new study starts in 3Q17. In particular, Sanofi/Lexicon are focused on patients with type 2 diabetes and CKD, as SGLT-1 inhibition does not depend on kidney function (vs. SGLT-2 inhibition).

Lexicon provided its 3Q17 update this morning in a call led by CEO Mr. Lonnel Coats. Management remains very confident overall in SGLT-1/2 dual inhibitor sotagliflozin for type 1 diabetes, with FDA and EMA filings on track for 1H18. Management shared that Lexicon is targeting “the earliest part of 1H18,” which we suspect means 1Q18 as outlined during the company’s 2Q17 update. Moreover, management highlighted two recent sets of positive data on sotagliflozin: (i) inTandem3 results were presented in full at EASD 2017 (after a topline release in June) and were simultaneously published in the NEJM, while (ii) pooled CGM data from inTandem1 and inTandem2 was announced in early September just before EASD. On the call, Lexicon called particular attention to how sotagliflozin’s mechanism leads to its positive glycemic effects, explaining how SGLT-1 inhibition in the GI tract contributes to efficacy and safety, giving a reduction in mealtime glucose and more predictable glucose responses. On the topic of DEPICT 1 (AZ’s phase 3 study of SGLT-2 inhibitor dapagliflozin in type 1 diabetes, which also presented at EASD 2017), Lexicon management emphasized that the inTandem program did not exclude any substantial subset of the type 1 population, while DEPICT 1 only randomized patients with baseline A1c between 7.5%-10% (excluding 43% of patients at greatest risk for hypoglycemia). Management thus argued that Lexicon stands to address the whole market, while AZ’s Farxiga (dapagliflozin), if approved for a type 1 indication, would be available only to a subset of this population. We find this unlikely though that is pure speculation. There is extensive safety and efficacy data for dapagliflozin in type 2 diabetes (both RCT and real-world evidence, as Farxiga has been on the market for type 2 since 2013), and thought leader response to DEPICT 1 was decidedly positive at EASD and afterward. While we understand the stakes are very high for Lexicon with sotagliflozin, we’re disappointed to see any critical comments on Farxiga for type 1 diabetes – neither drug is approved for type 1 at this stage and there is more than enough room for both to be successful. An oral adjunct therapy for type 1 diabetes would be a huge win for patients, and we believe patient benefit will be compounded with any additional member in this class. Moreover, we imagine having the expertise of AZ and the familiarity of Farxiga (particularly to providers) join sotagliflozin in the “SGLT inhibitors for type 1 diabetes” class could actually promote sotagliflozin uptake. In fact, Lexicon’s presentation slides noted that other trials validate this class, and that class-wide success will drive awareness and adoption.  

  • DKA, especially euglycemic DKA, has emerged as the leading safety concern surrounding SGLT-1 and SGLT-2 inhibition in type 1 diabetes, but the narrative has become one of manageable risk, as long as care teams can offer strong patient education. In Lexicon’s presentation slides, the company cited T1D Exchange data showing a 5%-8% annual rate of DKA in patients with type 1 diabetes, higher than the rates of DKA seen across the inTandem studies (3% in the sotagliflozin arm of inTandem3 vs. 1% with placebo), and higher than the rates of DKA in DEPICT 1 (1%-2% in the dapagliflozin arm vs. 1% with placebo). Management emphasized that both clinical programs were able to manage DKA effectively with similar care instructions, though few details have been shared on the specific trial protocol surrounding this risk mitigation for the sotagliflozin studies. According to UNC’s Dr. John Buse, DKA-related education for inTandem3 participants was probably far from optimal. HCPs in DEPICT 1 were instructed to reduce total daily insulin dose by no more than 20%, which was a recommendation based on an earlier phase 2 pilot study of dapagliflozin in type 1. This may be behind the lack of DKA signal in DEPICT 1, but it’s important to keep in mind that the two programs (from Lexicon and AZ) cannot be directly compared because of differences in study population, differences in trial design and protocol, etc.
    • The question remains: What is “best practice” DKA risk management? Dr. Buse (citing Lexicon VP Dr. Paul Strumph, who “has thought about this more than anyone else on the planet”) believes that patient selection is key. Individuals who don’t monitor blood glucose, or those who are less engaged in their diabetes management, face higher risk, particularly for severe DKA. He’s noted that petite, insulin-sensitive (total daily dose <40 units) patients who avoid cards and exercise a lot are high-risk. Conceptually, Dr. Buse explains DKA associated with SGLT-1/2 inhibitors as accelerated starvation ketosis – in other words, feeding the body is one straightforward way to avoid DKA events. Pump therapy also appears to be a risk factor for this complication, and carb avoidance in general is problematic. Dr. Buse recommends daily ketonemia screening at least when starting SGLT inhibitors, and after any signs of fatigue, nausea, malaise, or anorexia. For treatment, he recommends fast-acting carbs with bolus insulin every hour or two until ketone levels subside, or correction doses targeting the lower end of the normal target range if the patient cannot eat. Additionally, Dr. Buse has suggested that these drugs be avoided when basal insulin rates will be lowered (i.e. during prolonged exercise, surgery, GI distress, fasting, dieting, and alcohol binges). Ultimately, he would like to see better mechanistic studies – stress tests under observation – to figure out basal rates and minimal carb intake parameters to prevent DKA.
  • Lexicon’s partner Sanofi has initiated phase 3 studies of sotagliflozin in type 2 diabetes, with several new trials added in 3Q17, though the NDA for a type 1 diabetes indication will certainly be submitted first. Within the type 2 program, sotagliflozin is being investigated as monotherapy, as an add-on to metformin, as an add-on to an SU, as an add-on to insulin, in patients with moderate to severe kidney impairment, and for CV outcomes (in the SCORED CVOT). Based on data collected so far, Lexicon management suggested that sotagliflozin could be differentiated from other SGLT-2 inhibitors based on its ability to reach type 2 patients with either stage 3 or stage 4 chronic kidney disease (CKD), comprising 15%-18% and 1%-2% of the type 2 diabetes population, respectively. To our understanding, this differentiation comes from the SGLT-1 inhibition of sotagliflozin, which acts on the gut rather than the kidneys to decrease glucose absorption. That said, Lilly/BI and AZ are also investigating their SGLT-2 inhibitor products specifically in CKD, so there is potential still for this broad class of therapy to be highly-effective in people with comorbid diabetes and kidney disease.
  • The phase 1a study of SGLT-1 inhibitor LX2761 in type 2 diabetes has completed, and phase 1b data is expected by 1H18. This candidate appears to cause no significant elevation in urinary glucose excretion, which would likely differentiate LX2761 in terms of side-effects, as genital mycotic and urinary tract infections should not occur as with SGLT-2 inhibitors. Lexicon has also initiated phase 1 studies of neuropathic pain candidate LX9211 (an AAK1 inhibitor). Management highlighted robust efficacy in preclinical models for this oral small molecule, and we’re glad to see Lexicon expanding into this area of huge unmet need.

Select Questions and Answers

Q: With the phase 3 type 1 program for sotagliflozin complete, what are the factors that could push filing earlier or later? When can we expect Sanofi to talk about sotagliflozin more?

A: I’d say Sanofi’s engagement has been quite remarkable, especially with how quickly they’re putting up phase 3 trials for type 2 diabetes. It’s our responsibility to push the type 1 program forward, and they’ve been integrated in that process and are now fairly in control of the filing process and positioned to do the work around type 2. In terms of the regulatory process, we’ve had the necessary meetings and also our pre-NDA meeting, and we’d characterize it as a very, very good meeting that inspired a lot of confidence in our program. Now we have to go out and audit sites, making sure CMC work is done and all the modules are completed. It’s all-hands-on-deck at Lexicon, and we’re trying to make submission in the earliest part of 1H18.

Q: With respect to the CVOT for sotagliflozin now posted, one of the endpoints is obviously CV death or hospitalization due to heart failure. That is now a labeled indication for Jardiance, and it’s been submitted for Invokana. Given that those two drugs have shown benefit, how does the context of a placebo arm in this study logistically work?

A: The main thing about this study is that it’s being done in patients with renal impairment. There isn’t robust evidence for SGLT-2 inhibitors in that population. We believe that by targeting that population it’s ethical to randomize to placebo, and the dosing scheme of starting at 200 mg and titrating to 400 mg was chosen because some will have heart failure at baseline and we want to make sure the drug is well-tolerated.

 

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