Sanofi Sustaining Innovation Analyst Day 2017 – Once-weekly GLP-1 efpeglenatide projected to be as efficacious as semaglutide, new autoinjector debuted; Sotagliflozin type 2 filing by 2020; Sanofi entering obesity/NASH with GLP-1/glucagon dual agonist – December 13, 2017

Sanofi hosted an analyst day early this morning in Paris, France, discussing the company’s R&D strategy and pipeline across therapeutic areas. CEO Mr. Olivier Brandicourt set the tone when he described Sanofi’s mixed commercial performance over the past couple of years – the company’s diabetes portfolio has been hit with major challenges primarily related to access, but we certainly see cause for optimism based on what’s coming up in pipeline and we certainly hope data improvements will help justify much greater use of compounds. See below for our top four highlights on the day’s Diabetes and Cardiovascular updates, and/or check out the webcast, presentation slides, and press release in full. 

Top Four Highlights

1. Once-Weekly GLP-1 Agonist Efpeglenatide Enters Phase 3 with Hefty Expectations – Equivalent Efficacy to Semaglutide?; Sanofi Nixes Once-Monthly Dosing Prospects; Autoinjector Already Developed

Management expressed serious confidence in phase 3 GLP-1 agonist efpeglenatide, presenting modeled data indicating that the once-weekly candidate would offer A1c-lowering efficacy equivalent to Novo Nordisk’s recently-approved Ozempic (semaglutide). This is an ambitious claim, as semaglutide has already shown superiority head-to-head against existing once-weekly GLP-1s Trulicity (Lilly’s dulaglutide) and Bydureon (AZ’s exenatide). Anticipating a market entry when Ozempic and Trulicity will be the major players in the GLP-1 market, Sanofi compared phase 2 efpeglenatide data to published data on the other two molecules. The resulting model shows that dulaglutide would be the least efficacious option (offering ~1.2% A1c reduction), while efpeglenatide 6 mg would give a similar ~1.5% A1c reduction as semaglutide 1 mg. We temper this projection with the fact that efpeglenatide’s phase 3 program isn’t even recruiting yet, and safety/efficacy in phase 3 can look markedly different from safety/efficacy in phase 2. Nonetheless, we’re excited to see this candidate moving forward, and phase 2 data was admittedly impressive (in fact, we wonder why it took Sanofi so long to initiate phase 3, delayed from the original expectation of 4Q16). Management acknowledged that there’s no room for inferiority when it comes to the GLP-1 agonist class – for example, GSK ceased production of Tanzeum (albiglutide) earlier this year, citing clinical data that wasn’t up to the same standard as other GLP-1 molecules. As we wrote when the 400-person trial for efpeglenatide was posted to ClinicalTrials.gov, competition is fierce in the GLP-1 agonist market, and Sanofi’s once-weekly will be facing two well-established once-weekly formulations (and maybe even oral semaglutide) by the time this trial wraps up in January 2020. On the other hand, there’s plenty of room for whole class growth when it comes to GLP-1 agonists (these agents comprised only 7% of second-line type 2 diabetes prescriptions in the US in 2016). Lilly management mentioned today that positioning GLP-1 as the first injectable for patients instead of basal insulin could be a significant growth opportunity. And ultimately, we see no reason why multiple once-weekly GLP-1 products can’t be successful. We note that Sanofi hasn’t invested extensively in its once-daily GLP-1 Adlyxin (lixisenatide), perhaps because the focus has been on combining that agent with basal insulin for fixed-ratio Soliqua, but efpeglenatide could make the company a much bigger player in the GLP-1 market specifically.

• Mr. Klaus Henning Jensen (Head, Diabetes Development) announced that Sanofi has developed its own proprietary autoinjector for efpeglenatide, the MARS platform. The device has a removable cap and auto-injects when placed against the skin. Our suspicion is that Sanofi might use this autoinjector in its phase 3 program, which would be a smart move. Lowering the burden of self-administered injections could substantially improve patient adherence in the trial and could therefore lead to better results on A1c and weight loss. Indeed, one lesson learned from the EXSCEL trial for AZ’s Bydureon, which used single-dose reconstitution kits, is that a more complicated, burdensome injection process can decrease adherence, which can reduce effect size on important clinical outcomes (this CVOT narrowly missed the threshold for CV superiority). That an autoinjector is already prepared for efpeglenatide could be instrumental in its eventual commercial success – Lilly’s Trulicity comes with a very patient-friendly, IDEO-designed autoinjector and this has in part contributed to strong uptake, while AZ developed an autoinjector for Bydureon after product launch, only recently-approved as Bydureon BCise. The prompt debut of Sanofi’s efpeglenatide autoinjector is certainly notable.
• Sanofi will not be pursuing a once-monthly formulation of efpeglenatide – this very notable announcement came across during Q&A. Management attributed this decision to concerns over efficacy. Presumably, efpeglenatide might not be long-acting enough to sustain its glycemic effects over four weeks instead of one. Previously, Sanofi has discussed the potential for once-monthly efpeglenatide dosing, so we’re definitely struck by this turn of events. That said, this has no bearing on the promise of once-weekly efpeglenatide in phase 3.
• Based on current data, management characterized efpeglenatide’s GI tolerability as superior to other GLP-1 agonists. With all agents in this class, GI side-effects improve over time – they appear to improve more rapidly with efpeglenatide, though management offered no specific numbers. We’ll be curious to see if this trend holds up in phase 3, and we also wonder if this effect could have anything to do with the “Lapscovery” technology the molecule uses (licensed from Hanmi). This could be a big factor in patient adherence, satisfaction, and quality of life scores (although we’re unsure whether any patient-reported outcomes will be collected in the upcoming phase 3). As we understand it, GI side-effects are a big deterrent up front for many patients starting GLP-1 agonist treatment (on top of cost and injection burden).

2. Nine-Trial Phase 3 Program for SGLT-1/2 Dual Inhibitor Sotagliflozin in Type 2 Diabetes Underway; Management Anticipates Regulatory Filing for Type 2 Late 2019 or Early 2020; Type 1 Submission Imminent (1H18)

Sanofi anticipates filing SGLT-1/2 dual inhibitor sotagliflozin for type 2 diabetes near the end of 2019/beginning of 2020, and is very committed to collecting high-quality CVOT data. We noticed the SCORED CVOT (among other phase 3 trials for sotagliflozin in type 2) on ClinicalTrials.gov during Sanofi’s 3Q17 update, when management mentioned plans to focus on cardioprotection and renal protection from the get go with this newly-launched phase 3 program. Management reaffirmed these plans during Analyst Day, explaining how SCORED will include a sufficient number of patients with renal impairment to adequately capture sotagliflozin’s effects on kidney function and in patients with baseline renal impairment. We imagine this could be a wise decision in terms of demonstrating CV benefit as well, since patients with impaired kidney function face higher residual risk for CV events, offering a greater margin for cardioprotection. Two studies in the phase 3 program are dedicated entirely to comorbid diabetes/kidney disease (SOTA-CKD3 enrolls patients with moderate renal impairment, while SOTA-CKD4 enrolls patients with severe renal impairment). We’ve also heard from Sanofi management in the past that SCORED might be powered for superiority, and based on the ClinicalTrials.gov page, the study has co-primary endpoints – non-inferiority for the classic three-point MACE (non-fatal MI, non-fatal stroke, or CV death) and superiority for a composite of CV death/hospitalization for heart failure. Mr. Jensen expressed hope that the phase 2 trial of sotagliflozin in patients with worsening heart failure (severely affected patients who have been hospitalized) will also show efficacy in this patient population. He noted that other SGLT-2 inhibitors have shown compelling benefit in heart failure. Indeed, DECLARE for AZ’s Farxiga (dapagliflozin) includes heart failure in its primary endpoint, and AZ and Lilly/BI have launched new outcomes studies of their SGLT-2 inhibitors in people with heart failure with and without diabetes (Dapa-HF for dapagliflozin and the EMPEROR program for empagliflozin). We think Sanofi’s approach here is very smart, focusing on outcomes in a large, pre-approval CVOT – as the bar rises for new diabetes drugs, sotagliflozin will likely have to show efficacy beyond glucose-lowering, and CV and renal risk reduction are both becoming central considerations in best practice diabetes care. The company also seems to have capitalized on recent interest in SGLT-2s for heart failure and CKD to inform its clinical program around sotagliflozin, which as you’ll see from the table below, is quite robust.

Phase 3 Program for Sotagliflozin in Type 2 Diabetes

• From a scientific perspective, management expects that the dual inhibition of sotagliflozin will confer increased benefit over other SGLT-2 inhibitors, particularly in patients with reduced kidney function. On top of the increased glucose excretion caused by SGLT-2 inhibition, sotagliflozin reduces glucose uptake along the GI tract, which seems to reduce postprandial glucose excursions and to elevate GI hormones independent of renal function. Clinical evidence shows a dose-dependent effect of sotagliflozin on A1c, but not on urinary glucose excretion, supporting the added glycemic benefit of dual inhibition. Evidence also supports efficacy in patients with reduced kidney function. Regardless of added benefit, phase 2 found a ~0.9% A1c reduction at 12 weeks with a 400 mg daily oral dose of sotagliflozin in patients with type 2 diabetes, putting it in good position to compete at least on par with currently available SGLT-2 inhibitors.
• Sanofi’s partner Lexicon conducted phase 3 studies of sotagliflozin in type 1 diabetes. Sanofi is now leading the regulatory filing process for a type 1 indication, planned for 1H18 (and as early as possible). In type 1 diabetes, sotagliflozin is a potential first-in-class drug, offering A1c and weight reduction and significant improvements in time-in-range. The SGLT-1/2 inhibitor would also be the first oral adjunct therapy for type 1 diabetes (AZ’s Symlin is injectable, and hasn’t seen much commercial success), and we note that many patients with type 1 already take SGLT-2 inhibitors off-label (the horse is out of the barn, as we’ve been saying – we don’t think we’ll ever be in a position that type 1 patients who can get access won’t pursue this compound). Sotagliflozin in type 1 wasn’t a major focus on this call, but see our Lexicon 3Q17 report for the latest. 

3. Sanofi Looks to Diabetes-Adjacent Indications – GLP-1/Glucagon Dual Agonist for Obesity (Phase 3 in 2H18) & NASH (Phase 2 Planned); Impressive Four-Week Weight Loss Results in Phase 1

Eager to break into obesity, Sanofi announced plans to carry GLP-1/glucagon dual agonist SAR425899 into phase 3 trials in 2H18, with a 270-person phase 2 trial in type 2 diabetes completing this month. Two large phase 3 trials will assess SAR425899 in (i) patients with overweight/obesity and comorbidities, and in (ii) patients with overweight/obesity and type 2 diabetes. Another phase 3b study will enroll patients with overweight/obesity and prediabetes. It’s too soon for these studies to appear on ClinicalTrials.gov, but nonetheless, we appreciated this early glimpse at the details. Sanofi’s candidate joins a few others in the GLP-1/glucagon competitive landscape targeting an obesity indication, but it’s one of the more advanced (OPKO Health also has a GLP-1/glucagon agent in phase 2 for obesity, while Zealand/BI and Novo Nordisk have candidates in phase 1 – click here for the complete picture). Expressing optimism that Sanofi’s products will be able to make a real difference in obesity – and that someone will be willing to pay for them – management contrasted obesity to diabetes, where there are already many solutions on the market (this echoes commentary from Novo Nordisk CSO Dr. Mads Thomsen, who has alluded to the vastly under-treated populations with diabetes-adjacent indications like obesity and NASH). Mr. Jensen reviewed compelling weight loss data with SAR425899, demonstrating ~13 lbs weight loss at four weeks with the highest dose. Much longer trials will be needed to show that this rapid weight loss is sustainable, but we are encouraged by the early results. Moreover, we were struck my Sanofi’s clear inclination toward obesity – we listened to Lilly’s 2018 financial guidance call the same morning, and we were reminded that the company has historically been laser focused on type 1 and type 2 diabetes rather than obesity. Lilly will continue this trend by launching phase 3 studies of high-dose GLP-1 agonist dulaglutide in type 2 diabetes even though there’s huge potential for GLP-1 therapy (especially at high doses) in obesity.

• Sanofi is also in the process of moving SAR425899 into phase 2 trials for NASH, another diabetes-adjacent indication that management highlighted as a significant opportunity. The dual agonist is believed to have a specific beneficial effect on the liver, while also promoting weight loss, which makes it an ideal candidate for NASH therapy. The NASH competitive landscape is quite robust and it’s noteworthy that Sanofi is throwing its hat into the ring – no NASH treatments are FDA-approved, and this is a huge therapeutic area of unmet need.

4. Praluent: Topline Results from ODYSSEY Outcomes Still Expected in 1Q18; CV Indication Filing Anticipated for 3Q18

Dr. Jay Edelberg (VP, PCSK9 Strategic Development & Launch Unit) reiterated that topline results from the ODYSSEY Outcomes CVOT for Regeneron-partnered PCSK-9 inhibitor Praluent (alirocumab) are expected in 1Q18. He also shared that Sanofi hopes to file for a CV indication in the US and EU by 3Q18 – a swift turnaround. We anticipate that full results from ODYSSEY Outcomes may be presented at ACC 2018 in Orlando, FL, following suit with the FOURIER presentation (for Amgen’s PCSK9 inhibitor Repatha) at ACC 2017. Sanofi/Regeneron’s CVOT, closing out now, enrolled ~18,000 patients 1-12 months after an acute coronary event and evaluated Praluent on top of maximally-tolerated statin therapy. Median exposure time was 33 months, and notably, this trial is longer than FOURIER and could shed more light on how PCSK9 inhibitor reduces risk for CV death. Amgen’s Repatha (evolocumab) gained a CV indication earlier this month based on FOURIER results. Now, positive findings from ODYSSEY Outcomes would point to a CV class effect for this new category of lipid-lowering drugs, which could only improve their extremely poor reimbursement status – we’ve seen data that 96% of prior authorizations for PCSK-9 inhibitors are denied. Amgen has recognized that positive ODYSSEY Outcomes results should be a boon for the class overall (making their patent infringement lawsuit against Sanofi/Regeneron confusing), and we’re looking forward to getting longer-term follow-up data than FOURIER offered. As we’ve gathered from thought leaders, FOURIER was a shorter trial (median follow-up 26 months), which may be the reason that evolocumab didn’t show significant risk reduction for CV death (HR=1.05, 95% CI=0.88-1.25), with only 251 deaths in the treatment arm and 240 in the placebo arm. Sanofi/Regeneron were first to report results on their PCSK9 inhibitor specifically in a diabetes patient population (see our coverage from ADA 2017), although Amgen followed with a subgroup analysis of FOURIER focused on diabetes at EASD 2017. Diabetes and hyperlipidemia together present extremely high CV risk, and we thus see major potential applications of PCSK9 inhibitors for people with diabetes (a theme that came up at AHA 2017), though reimbursement and access will have to be improved first and foremost.

Questions and Answers

Q: Could you rephrase your intention with efpeglenatide? When you enter the market, best-in-class will be Ozempic, first-in-class will be Trulicity, and maybe cheapest will be Bydureon. What role do you plan to play in this market?

Mr. Klaus Henning Jensen (Head, Diabetes Development): Modeling shows efficacy as strong as the best product out there, but with the GI adverse events profile, weight benefits, and particularly the device we’re going to deliver the drug in is going to make this a very attractive combined product. In diabetes and GLP-1 agonists, we’ve seen that efficacy matters. If efficacy is as good, I believe we can make a good competitive business out of the other benefits we provide.

A: The once-weekly GLP-1 agonist segment is probably the most attractive segment in diabetes. It’s the fastest growing segment and it has just started. With more products going into the category, that’s something we expect to continue.

Q: Is a once-monthly formulation still in development for efpeglenatide? And do you have any reason to think your dual agonist will be better than others in development?

Mr. Jensen: Efpeglenatide has been investigated by Hanmi for once-monthly use, but here, we cannot compromise on efficacy. If we become more convenient but less efficacious, that’s not a place we want to go. We could give larger injections but there’s still a period where GLP-1 agonist exposure is reduced. Our focus is once-weekly.

Mr. Jensen: In terms of the dual agonist, we’re coming into a market where competition is going to be increasing. Right now, what’s available gives 5%-8% weight loss across the board. Also, now semaglutide is planning to go into obesity, but it’s hard to project what weight loss the higher once-daily dose they’re investigating will give. I believe the two complementary mechanisms in our dual agonist will make it very competitive.

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