On the PDUFA date for Zynquista (sotagliflozin), the FDA delivered a complete response letter (CRL) to Lexicon Pharmaceuticals Inc. and partner Sanofi SA related to the NDA for the type 1 diabetes therapy, an oral dual inhibitor of sodium glucose transporter (SGLT) 1 and 2 that was previously known as LX-4211. Recro Pharma Inc. also found a CRL in its mailbox, related to the NDA for intravenous (I.V.) meloxicam for the management of moderate to severe pain.

The Woodlands, Texas-based Lexicon hosted a conference call Friday but cautioned that the CRL had just arrived and noted that Sanofi, of Paris, is the official holder of the NDA. Lexicon CEO Lonnel Coats said his firm would not be making any comments about the "nature or content" of the CRL, beyond that the FDA found Zynquista not approvable.

Questioners tried anyway.

Stephen Willey, analyst with Stifel, said he understood that Lexicon was "constrained with respect to what information you can provide," but wanted to know if it was "safe to say, given your reiteration [on the conference call] of 2019 guidance from a balance sheet and operating expenses perspective, that the contents of the CRL perhaps suggest these are not issues that can be remediated within the 2019 time frame?" Coats replied that "you have to plan wisely, and therefore we have given guidance in the most conservative way. Our efforts are only just beginning to engage with Sanofi and the FDA on this matter."

Willey pressed for news on the "intensity" of talks with U.S. gatekeepers since mid-January, when the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 8-8 on the question of whether the overall benefits of Zynquista outweighed the risks to support approval. He also sought an estimate regarding when the companies might engage next with the FDA. Coats said Sanofi and Lexicon will "follow the standard process" in dealing with a CRL and aims to "push forward as soon as possible" with talks. Regarding exchanges had so far, he said, "I would love to characterize those, but Sanofi is taking the lead in those discussions." (See BioWorld, Jan. 16, 2019.)

J.P. Morgan analyst Jessica Fye, in a March 13 research report, said that "after the split panel vote, we see a slightly better than 50-50 chance of first-pass approval in type 1 [diabetes] in the U.S.," pointing out that "management comments on the potential of a Zynquista approval have become increasingly conservative while the product has been under review by the FDA."

Lexicon's pivotal phase III trial showed that type 1 diabetes patients treated with sotagliflozin achieved statistically significant reductions in glycated hemoglobin, or A1C, at 24 weeks. Less favorable was a small incidence of diabetic ketoacidosis (DKA) in the treatment arms, an issue that has dogged SGLT2 inhibitors as a class. And that's where FDA briefing documents related to the panel meeting zeroed in, estimating that sotagliflozin was associated with an approximately eightfold increase in DKA risk vs. placebo.

Things have gone better for the candidate outside the U.S. At the start of this month, Lexicon said the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion on the type 1 diabetes marketing authorization of Zynquista. The CHMP recommended approval of sotagliflozin in the EU in a 200-mg and 400-mg dose for use as an adjunct to insulin therapy to improve blood sugar (glycemic) control in adults with a body mass index of ≥ 27 kg/m2, who have failed to achieve adequate glycemic control despite optimal insulin therapy.

The FDA has cleared SGLT-2 inhibitors for type 2 diabetes but none for type 1. Marketed are: Farxiga (dapagliflozin, Astrazeneca plc); Invokana (canagliflozin, Johnson & Johnson); Jardiance (empagliflozin, Boehringer Ingelheim GmbH); and Steglatro (ertugliflozin, Merck & Co. Inc.). The human amylin analog Symlin (pramlintide acetate, Astrazeneca plc), is approved for type 1 and type 2 disease.

The FDA's comments in the meloxicam CRL to Malvern, Pa.-based Recro focused on the onset and duration of the drug, noting that the delayed onset fails to meet the prescriber expectations for I.V. drugs. The letter also cited regulatory concerns about the role of the compound as a monotherapy in acute pain, as well as how it would meet patient and prescriber needs in that setting, given the FDA's interpretation of the trial data. Recro, which slated a conference call for this afternoon, said it "strongly disagrees" with the way regulators view the results, adding that no manufacturing issues were identified.

Shares of Lexicon (NASDAQ:LXRX) closed Friday at $6.20, down $1.74 or 22 percent. Sanofi (NASDAQ:SNY) dipped by $1.17 to $44.26. Recro's stock (NASDAQ:REPH) closed at $9.69, up 9 cents.

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