AZ's Farxiga nabbed its Type 1 nod in EU. But after Zynquista's rebuff, how will it fare at FDA?

Farxiga
AstraZeneca’s Farxiga just won European Commission approval in Type 1 diabetes, but a tough FDA review lies ahead. (AstraZeneca)

AstraZeneca’s Farxiga just won European approval in Type 1 diabetes, but its prospects in the U.S. are less certain. The FDA’s rejection of Sanofi and Lexicon Pharmaceuticals’ would-be rival Zynquista may serve as an ill omen in Type 1 for the entire SGLT class.

Both Farxiga (marketed as Forxiga in Europe) and Zynquista previously secured positive opinions from the European Medicines Agency. But clearly the FDA has other ideas about Zynquista, having rejected the SGLT1/2 dual inhibitor on Friday.

Zynquista’s complete response letter was not a total surprise, considering an FDA advisory panel was split on its approval. Increased incidence of diabetic ketoacidosis (DKA)—a potential life-threatening complication when the body produces high levels of blood acids—among Zynquista trial patients was a major concern for some of the expert panelists. And it’s a risk that’s seen across SGLT inhibitors, including Farxiga.

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In its pivotal Depict clinical program in Type 1 diabetes, Farxiga, as an add-on to insulin, did significantly lower HbA1c, a standard blood glucose measure, compared with placebo, and it also demonstrated a weight-loss benefit. But DKA events in the Farxiga groups were notably higher than the number observed in the control group. Specifically, 4.0% and 3.4% on two different doses of Farxiga versus 1.9% on placebo at 52 weeks, or 2.6% and 2.2% in Farxiga versus 0% in placebo at 24 weeks.

Though not for direct comparison, Zynquista, in its inTandem phase 3 program, also showed a similar 3% to 4% DKA rate, while the control group had less than 1%. Zynquista also reduced patients’ A1c levels and body weight.

European regulators gave their thumbs-ups to Farxiga and Zynquista, allowing their use only in overweight people who have a body mass index (BMI) of 27 kg/m2 or above and limiting its recommendation to exclude patients with low insulin requirements.

AstraZeneca expects to get word on the type 1 diabetes application during the second half of the year, a company spokesperson said via email. "We remain confident in the positive benefit-risk profile of dapagliflozin and dapagliflozin-containing products, as outlined in the prescribing information," the spokesperson said.

RELATED: FDA stiff-arms Sanofi and Lexicon's Type 1 diabetes hopeful Zynquista

On a Friday analyst call after Zynquista's FDA rebuff, Lexicon CEO Lonnel Coats said he couldn’t characterize the problem because Lexicon had not seen the CRL itself and noted that its partner Sanofi will talk with the FDA to get a better understanding of the path forward.

DKA is a problem that's cropped up across the SGLT class in Type 1 diabetes, not just for Farxiga and Zynquista, because the drugs lower blood sugars separately from insulin. Eli Lilly and Boehringer Ingelheim’s Jardiance, in its phase 3 Ease program, also recently reported a statistically significant increase in DKA numbers in the main 10-mg and 25-mg groups. Upon unveiling the data last October, the pair said they have initiated regulatory discussions. Johnson & Johnson’s Invokana was no exception, as investigators in a 2016 study noted serious DKA in 4.3% of Type 1 diabetes patients on 100 mg of Invokana and 6.0% in the 300-mg group.

At this point it's unclear whether the FDA rejected Zynquista because of the DKA risk, but it looks like a likely scenario. Declining to give any specific speculations on future SGLT applications, Coats said: “Whatever we’re dealing with, you can always assume that any others who come after us will certainly have to deal with the same.”

Editor's note: This story was updated with comments from AstraZeneca.

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