AstraZeneca Investor Day 2014 – Phase 3 trial of exenatide/dapagliflozin; Emphasis on triple therapy; Saxa/dapa submission by end of year – November 20, 2014

AstraZeneca hosted an Investor Day yesterday, featuring over five hours of presentations and discussions led by CEO Mr. Pascal Soriot. Below we include our top five highlights from the presentations, as well as an honorable mention.

1. A major highlight of the event was the news that a phase 3 trial of exenatide/dapagliflozin combination therapy is currently recruiting participants.

2. The need for early, aggressive combination therapy for type 2 diabetes was a recurring theme of the day; to that end, AZ highlighted the progress of the company’s saxagliptin/dapagliflozin/metformin fixed-dose combination (FDC).

3. Management confirmed that AZ’s saxagliptin/dapagliflozin FDC should be submitted by the end of 2014.

4. We learned that the first patient has been dosed in a phase 3 trial of Farxiga (dapagliflozin) in type 1 diabetes.

5. Management highlighted the strong global launch of Forxiga, noting that it has been the most successful launch of any diabetes product in many emerging markets.

Top Five Highlights

1. A major highlight of the event was the news that a phase 3 trial of exenatide/dapagliflozin combination therapy is currently recruiting participants. The double-blind trial (ClinicalTrials.gov Identifier: NCT0229396) aims to enroll 660 patients with type 2 diabetes on background metformin who will be randomized to receive either combination therapy with exenatide once weekly and dapagliflozin once daily or treatment with either component alone. The primary endpoint is change in A1c from baseline at 28 weeks; secondary endpoints include change in body weight, blood pressure, and fasting and postprandial glucose. The trial also includes a 24-week extension phase following the initial 28-week treatment period; primary completion is expected in June 2016 and study completion in February 2017. In AZ’s 2Q14 update, management commented during Q&A that “there is a very strong logic to combining a GLP-1 agonist and Farxiga (dapagliflozin)” and indicated that the company would be “exploring” that possibility, but this is the first we have heard of a specific trial. We have been hearing more and more discussion at conferences about the potential of GLP-1 agonist/SGLT-2 inhibitor combinations to provide impressive (even synergistic) A1c reductions and weight loss (see our coverage of Professor Anthony Barnett’s [University of Birmingham, Birmingham, UK] comments on the subject at EASD) and we are pleased to see AZ taking the lead in this arena.

2. The need for early, aggressive combination therapy for type 2 diabetes was a recurring theme of the day. To that end, AZ highlighted two ongoing clinical trials (ClinicalTrials.gov Identifiers: NCT01646320 and NCT01619059; n=280 for each) of triple therapy with saxagliptin, dapagliflozin, and metformin. Both are randomized, double-blind, placebo-controlled trials; the control groups will receive triple therapy with placebo substituted for either saxagliptin or dapagliflozin. Both studies have a primary endpoint of change in A1c from baseline and secondary endpoints including change in body weight and fasting and postprandial glucose; they are expected to complete in February 2015, and management indicated that a regulatory submission of a potential triple fixed-dose combination (FDC) would not occur until 2017 at the earliest. More aggressive use of combination therapy to replace the current “treat to failure” model of type 2 diabetes pharmacotherapy has emerged as a theme at recent conferences – at EASD, Dr. Bernard Zinman (Mount Sinai Hospital, Toronto, Canada) called for such a paradigm shift during an AZ-sponsored symposium, and Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX), one of the most vocal advocates of triple therapy over the years, concluded a presentation on Lilly/BI’s empagliflozin/linagliptin FDC by suggesting that the two compounds could eventually be combined in one tablet with metformin.

3. Management confirmed that the company’s saxagliptin/dapagliflozin FDC should be submitted by the end of 2014. This is consistent with guidance from AZ’s 2Q14 update indicating that the product would be submitted by the end of the year, but during the company’s 3Q14 update, management said only that a filing would occur in the next few months, suggesting that it might have been pushed into 2015. Lilly/BI’s empagliflozin/linagliptin FDC was submitted in the US in April and will likely be filed in Europe in 2015. Phase 3 data for both “saxa/dapa” and “empa/lina” showed significantly greater A1c reductions with the combinations compared to either component alone, though the results fell short of the additive or even synergistic efficacy that some had predicted. Future GLP-1 agonist/SGLT-2 inhibitor combinations would likely offer even more powerful efficacy, although the need for injections could be a barrier for some patients. In the meantime, we believe SGLT-2 inhibitor/DPP-4 inhibitor combinations will be a valuable new option for patients with type 2 diabetes, offering unprecedented efficacy for an oral medication, minimal risk of hypoglycemia, and the potential for weight loss, although cost could pose a significant obstacle for some patients depending on how the products are priced.

4. We learned that the first patient has been dosed in a phase 3 trial (ClinicalTrials.gov Identifier: NCT02268214) of Farxiga in type 1 diabetes. The double-blind, randomized, placebo-controlled trial (n=768) has a primary endpoint of change in A1c from baseline at 24 weeks and secondary endpoints including change in daily insulin dose, body weight, and, excitingly, the percentage of CGM readings within range (70-180 mg/dl) – we are encouraged to see time in range becoming more common as an endpoint in clinical trials, as we believe it provides a much more complete picture of glycemic control than A1c alone. Primary completion for the trial is expected in May 2017. BMS/AZ presented phase 2 results at ADA 2013 showing that Farxiga reduced total daily insulin dose in patients with type 1 diabetes, and we were excited to hear the announcement this past May that AZ planned to initiate a phase 3 trial in 2014. AZ is currently farthest along in its pursuit of a type 1 diabetes indication for an SGLT-2 inhibitor, but other companies are close behind: J&J has an ongoing trial of Invokana (canagliflozin) in type 1 diabetes (primary completion expected May 2015) and Lexicon has a fairly comprehensive phase 2 program investigating its SGLT-1/2 dual inhibitor sotagliflozin (LX4211) in type 1 diabetes patients, including those who are younger and more poorly controlled. We believe the SGLT-2 inhibitor class could offer valuable benefits for the type 1 patient population, including reductions in insulin dose and improvements in body weight and blood pressure, and we are glad to see more products closer to reaching these patients (though some may already be experiencing these benefits due to apparently common off-label use).

5. Management highlighted the strong global launch of Forxiga (dapagliflozin’s ex-US trade name), noting that it has been the most successful launch of any diabetes product in many emerging markets. As noted in AZ’s 3Q14 update, Farxiga’s launch in the US has also been very successful, with weekly total prescriptions (TRx) climbing to 22,000 as of late October. There was some discussion during Q&A regarding Farxiga’s pricing in the US, as one analyst inquired about ways to transition away from the cost-savings program that allows many patients with commercial insurance to access the drug for free (J&J and Lilly/BI offer comparable programs for Invokana and Jardiance [empagliflozin], respectively). Management responded that the program was not intended to be indefinite but that more time was needed to see how the currently very competitive SGLT-2 inhibitor market develops before making any predictions on pricing. As of our last update on Forxiga sales in Europe, growth was fairly modest (sequential growth of $1-$2 million in 2013 back when BMS broke out revenues), but the re-launch in Germany following successful arbitration over pricing may have accelerated growth in recent quarters.

Honorable Mention

AZ highlighted a new preclinical candidate, “Protein X,” for type 2 diabetes that could potentially modify beta cell function. While the product is still in the very early stages of development, it has shown promise in reducing glucose and improving beta cell function in animal models, and management expressed hope that it could eventually prove to be a disease-modifying agent. We were glad to get a rare glimpse into AZ’s early-stage pipeline, as the company’s quarterly updates typically focus only on later-stage products; management also hinted that several other early-stage molecules for metabolic disease will be moving forward within the next 12-18 months.

-- by Emily Regier, Manu Venkat, and Kelly Close