FDA approves AZ’s Qtern (fixed dose saxagliptin/dapagliflozin) the second time around – March 1, 2017

In very exciting news, AZ announced yesterday that the FDA has approved fixed-dose combination product Qtern, which combines DPP-4 inhibitor Onglyza (saxagliptin) and SGLT-2 inhibitor Farxiga (dapagliflozin) into a once-daily oral tablet. The label indicates Qtern for adults with type 2 diabetes who are inadequately controlled on Farxiga alone, or those who are already being treated with both Onglyza and Farxiga separately. This is similar to the EMA-approved indication for the product (European approval came in 2Q16), but notably, Lilly/BI’s first-in-class Glyxambi (linagliptin/empagliflozin) was FDA-approved for use in any adult with type 2 diabetes for whom treatment with both agents is appropriate. Glyxambi was EMA-approved in 4Q16 for adult patients inadequately controlled on metformin and/or sulfonylureas plus one of the individual agents, or for people already being treated with both components separately.

The timing of the US approval of Qtern is in line with company expectations of a 1Q17 decision at the time of the product’s resubmission. The product received a Complete Response Letter (CRL) in October 2015, when the FDA requested more clinical data “to support various dosing regimens.” Since then, AZ has conducted an additional clinical trial of Qtern in close correspondence with the FDA. According to management, the drug was approved based on (i) a phase 3 trial (n=315 patients inadequately controlled on ≥1,500 mg metformin daily) investigating A1c reductions with saxagliptin/dapagliflozin treatment over 24 weeks (baseline A1c between 7%-10.5%) and (ii) a pooled safety analysis (n=1,169, 492 treated with Qtern) of phase 3, placebo-controlled studies out to 52 weeks. Management has also asserted that the initial CRL was not due to DKA or heart failure risk associated with dapagliflozin and saxagliptin, respectively. While uptake of Glyxambi in the US has so far been slow, AZ management has expressed clear confidence in Qtern and in the Farxiga franchise more generally. Based on this, we expect AZ will invest more heavily in promotion and access for Qtern (whereas Lilly management has acknowledged that its investment in Glyxambi has been limited thus far). We’re excited to see how US launch proceeds.

In our view, AZ is well-positioned to carry forward commercial success of a product in this class: (i) Sales growth for Farxiga has been impressive (could very well hit $1 billion blockbuster status in 2017), and the therapy leads the SGLT-2 inhibitor class by volume; (ii) AZ has a smaller diabetes portfolio than Lilly, which could allow for more resources to be allocated to Qtern compared to Glyxambi; and (iii) We’ve heard strong optimism from management on Qtern’s potential to improve the lives of people with type 2 diabetes – after all, it is a convenient oral medicine that offers both DPP-4 and SGLT-2 inhibition for better glycemic control and weight loss. “We have a focus on the SGLT-2 inhibitor class,” management said of its portfolio priorities, “with Farxiga as the primary driver for the dapagliflozin family, but the approval of Qtern is good news for patients who may benefit from adding a DPP-4 inhibitor to an SGLT-2 inhibitor in a convenient, once-daily tablet.” All in all, the company seems wholly committed to invest in this advanced therapy within its diabetes portfolio, so we have high hopes for how Qtern will fare in the US, the largest market for diabetes globally.

• Price is an immediate and important question that comes to mind with any new drug approval, diabetes or otherwise. AZ management shared that the company is committed to making Qtern widely accessible. We’re happy to hear this early stance on pricing from AZ, and we eagerly await more specific pricing information, which will be decided closer to launch date.
• Overall, Glyxambi seems to have an advantage over Qtern in terms of compelling CV benefits. Cardiovascular effects are an increasingly important consideration for choice of diabetes therapy. While combination products have not been explicitly evaluated in CVOTs, we take stock of the CV effects of each component. The FDA recently approved an updated label for Glyxambi that includes positive CV data from EMPA-REG OUTCOME, which demonstrated that empagliflozin significantly reduces risk for CV death – though, notably, the label update did not include the expanded indication for cardiovascular death that Jardiance’s label features. Meanwhile, the DECLARE trial evaluating CV effects of dapagliflozin isn’t scheduled to complete until April 2019 – any changes to the Farxiga or Qtern labels would come even later. Turning to the DPP-4 inhibitor component of each combination therapy, while the SAVOR-TIMI study for Onglyza demonstrated CV safety overall, the trial also found a worrisome 27% increased risk of hospitalization for heart failure with Onglyza therapy (p=0.007) that led to the addition of warnings for heart failure on the standalone product’s label. The CARMELINA (expected to complete January 2018) and CAROLINA (expected to complete March 2019) CVOTs for Tradjenta (linagliptin) are ongoing.
  
  • All this said, we anticipate that competition in this particular drug class will be more heavily influenced by marketing strategy, at least in the short term. Glyxambi sales have been sluggish to-date, even with EMPA-REG OUTCOME results published – of course we’ll have to wait and see if 1Q17 sales show any positive impact of the label change, which was only approved in early January. Qtern, we think, will derive huge advantage from AZ’s sheer commitment to making it a clinical and commercial success. Moreover, we imagine that US launch will be informed by the product’s roll-out in the UK (launch in other European countries is slated for 2017).
• Before year-end, we may see a third product in this class of fixed-dose DPP-4 inhibitor/SGLT-2 inhibitor therapies – Merck/Pfizer’s combination of Januvia (sitagliptin) and ertugliflozin. Standalone SGLT-2 inhibitor ertugliflozin, an ertugliflozin/metformin fixed-dose combination, and an ertugliflozin/sitagliptin fixed-dose combination were all submitted as New Drug Applications to the FDA in 4Q16, based on positive results from the VERTIS clinical program. A CVOT for ertugliflozin, VERTIS CV, is underway and is scheduled to complete in October 2019. Januvia boasts the only resoundingly neutral CVOT data currently available within the DPP-4 inhibitor class and we expect this fact, coupled with Merck’s experience in the diabetes field and its familiarity among primary care providers especially, will be a boon for the Merck/Pfizer combination. Ultimately, we’re excited by the convenience that accompanies a single, oral medicine with both DPP-4 and SGLT-2 inhibition, and we look forward to how this class may enhance diabetes care for many patients.

Close Concerns Questions

Q: What’s the launch timing for Qtern in the US, now that the long-awaited (!) FDA approval has been announced?

Q: What is AZ’s strategy for marketing the product, and for educating patients and healthcare providers?

Q: How will US launch be informed by launch of Qtern in the EU? Will AZ take any lessons from Glyxambi’s launch and marketing to-date?

Q: Will the broader indication for Glyxambi compared to Qtern have any impact on the prescription volume of each therapy?

Q: How will cardiovascular outcomes factor into marketing of Qtern? Will the lack of a completed CVOT (vs. Glyxambi’s label featuring EMPA-REG OUTCOME data) impede sales or uptake of the newly-approved combo therapy?

-- by Payal Marathe, Helen Gao, and Kelly Close