FDA's decision not to approve AstraZeneca PLC's fixed-dose product combining two oral antidiabetic agents comes with a somewhat surprising request – more clinical data.

Both elements of the product – which combines the DPP-4 inhibitor Onglyza (saxagliptin) and the SGLT2 inhibitor Farxiga (dapagliflozin) for treatment of adults with type 2 diabetes – are already approved, yet FDA still appears to have safety or efficacy concerns about the fixed-dose combination.

FDA did not raise any concerns about the combination's risk for heart failure-related hospitalization or diabetic ketoacidosis, AstraZeneca said.

The company declined to say whether issues related to efficacy, safety or both were the reason behind the agency's data request, but the request for clinical data suggests that FDA's concerns extend beyond any potential formulation and manufacturing issues.

FDA's complete response letter "states that more clinical data are required to support the application. This includes clinical trial data from ongoing or completed studies and may require information from new studies," AstraZeneca said in an Oct. 16 press release.

The company said it will work with FDA to determine the appropriate next steps for the NDA and remains committed to development of the fixed-dose combination.

Lost Opportunity In The Billions?

AstraZeneca has focused on combination product development as a strategy for growing its diabetes franchise, which was previously partnered with Bristol-Myers Squibb Co. ([A#00150921017]).

Its portfolio of marketed diabetes treatments includes the GLP-1 receptor agonist Byetta (exenatide) and its long-acting follow-on Bydureon.

Saxagliptin and dapagliflozin already are approved in fixed-dose combinations with metformin extended-release as Kombiglyze XR and Xigduo, respectively. AstraZeneca has estimated peak year sales potential for the saxagliptin/dapagliflozin combination at $3bn.

However, the agency's brushback could put a dent in AstraZeneca's long-range revenue prediction of $8bn for its diabetes franchise by 2023 ([A#00140804008]).

The regulatory setback also would appear to put AstraZeneca at a competitive disadvantage to Eli Lilly & Co. and Boehringer Ingelheim GMBH.

In February, the companies' Glyxambi became the first fixed-dose combination of an SGLT2 inhibitor (empagliflozin) and a DPP-4 inhibitor (linagliptin) approved in the US ([A#14150202001]).

Empagliflozin subsequently got a further boost with the EMPA-REG OUTCOME study results, which showed a cardiovascular risk reduction benefit with the SGLT2 inhibitor that was driven by a reduction in CV death ([A#14150917005]).

Saxa, Dapa Have Their Own Safety Issues

One potential wrinkle for AstraZeneca's combination is that separate safety concerns have arisen for the two drugs.

Saxagliptin was approved in August 2009, making it one of the earliest approvals under FDA's December 2009 guidance requiring CV safety assessments for new type 2 diabetes treatments Also see "AstraZeneca/Bristol's Diabetes Drug Onglyza Cleared" - Pink Sheet, 31 July, 2009..

A large, post-marketing outcomes trial, SAVOR, showed neutral effects with the DPP-4 inhibitor on major adverse CV events. However, saxagliptin was associated with a 27% increased risk of hospitalization for heart failure, a statistically significant finding Also see "Alogliptin, Saxagliptin Show Neutral CV Effects In Outcomes Studies" - Pink Sheet, 2 September, 2013..

In April, an FDA advisory committee said Onglyza labeling should reflect language about the heart failure risk and describe baseline characteristics for those in SAVOR at highest risk of heart failure hospitalization ([A#14150414005]).

In August, the agency added a new warning about severe joint pain to the labels of all DPP-4 inhibitors.

Dapagliflozin was approved in January 2014, two years after its path to market was derailed by an FDA complete response letter stemming from concerns about an imbalance in bladder cancer cases ([A#14140108003]).

The delay enabled Johnson & Johnson's Invokana (canagliflozin) to win the race to market in the SGLT2 class.

FDA did not convene an advisory committee review of AstraZeneca's NDA for the saxagliptin/dapagliflozin combination.

Farxiga labeling includes a warning about the imbalance in bladder cancer cases, and FDA's approval included a requirement to conduct an animal study to assess bladder tumor promotion. That study is to be completed by November, with a final report due by August 2016, according to the approval letter.

In addition, the risk of bladder cancer is being examined in AstraZeneca's ongoing, 17,000-patient CV outcomes trial, DECLARE-TIMI58. The CV trial is expected to complete in 2019, while a bladder cancer sub-study with longer-term follow-up is targeted to complete in 2024, the approval letter states.

FDA is considering a class-wide labeling change for the SGLT2 inhibitors following reports of serious cases of ketoacidosis Also see "FDA Warning On SGLT-2 Drugs Raises Specter Of Labeling Change" - Pink Sheet, 15 May, 2015..

In addition, the agency is evaluating the risk of bone fracture with this class of drugs and has added a warning to the Invokana label.

An AstraZeneca spokeswoman said FDA did not raise any concerns about the saxagliptin/dapagliflozin combination's risk for hospitalization for heart failure or diabetic ketoacidosis.

"Based on the information available, the CRL is not expected to affect the individual components of saxagliptin or dapagliflozin, which are approved for the treatment of adult patients with type 2 diabetes," AstraZeneca said.

The agency's regulatory action also does not affect ongoing interactions with other health authorities including in the EU, where the fixed-dose combination is under review, the company added.

Notably, FDA's rejection of AstraZeneca's NDA came in the absence of an advisory committee review of the combination product.

Similarly, on Oct. 14 FDA rejected an expanded indication for Pfizer Inc.'s JAK inhibitor Xeljanz (tofacitinib) without convening an advisory committee for the application. Pfizer sought approval for adults with moderate to severe chronic plaque psoriasis.

AstraZeneca Diabetes Combo Needs More Clinical Data, FDA Says

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