Evoke Pharma Inc. and Intelgenx Corp. each received FDA complete response letters (CRL) regarding NDAs for products in their pipelines. Evoke's CRL for Gimoti states that the FDA cannot approve the NDA in its present form and provided recommendations to address two remaining approvability issues for an NDA resubmission.

For Intelgenx, the FDA cited issues related to the chemistry, manufacturing and controls portion of the application for Rizaport, but did not request a new bioequivalence study.

Shares of both companies closed sharply lower Tuesday.

The going has been tough for Evoke, especially in the past four weeks. The CRL is a follow-up to March 4's multidisciplinary review (DR) letter from the FDA that questioned if a review of Gimoti (metoclopramide) would be completed by its April 1 PDUFA date. (See BioWorld, March 5, 2019.)

Evoke's abbreviated new drug application (ANDA) for the investigational metoclopramide nasal spray, which was filed in June 2018, said it hoped to deliver the first new non-oral drug treatment option for diabetic gastroparesis in 40 years. The target market is female patients.

The CRL cites fewer issues than the DR and provided recommendations for addressing two remaining approvability issues in an NDA resubmission. No new clinical data were requested from the FDA and safety concerns were not raised, the company said.

Evoke's president and CEO, Dave Gonyer, remained upbeat: "We believe that the issues cited in the CRL, which were related to concerns over reproducible dose delivery, can be addressed. We look forward to meeting with FDA to gain a full understanding of the agency's requirements for approval and remain committed to bringing our novel nasal formulation of metoclopramide to patients."

The March DR has caused Evoke a lot of pain as company shares (NASDAQ:EVOK) dropped 57.2 percent on the day it was released. An H.C. Wainwright analysis on March 5 downgraded Evoke's stock to a neutral rating and questioned if the company's cash and equivalents were sufficient to take Gimoti to FDA approval. Tuesday's trading saw company shares drop dramatically again, closing at 90 cents per share, down 47 percent for the day.

March's DR raised questions about Gimoti's efficacy, chemistry and production, according to Evoke. The first was about chemistry, with the FDA commenting on the combination product quality control and reproducibility specific to the commercially available sprayer device Gimoti uses. Clinically, the FDA commented on a lack of information to support sex-based efficacy differences. There was also concern about maximum concentration (Cmax) of the medicine not being within the parameters for bioequivalence for the ANDA.

Solana Beach, Calif.-based Evoke's April 2 response noted that the "clinical pharmacology issue was specific to a low Cmax in subjects representing less than 5 percent of the total administered Gimoti doses in the pivotal pharmacokinetic (PK) study. The agency stated the overall lower mean Cmax was driven by the data from these few subjects. Without the aberrant doses, the company's analysis shows the data met the bioequivalence criteria for both men and women. The agency recommended a root cause analysis to determine the origin of the PK variability and mitigation strategies to address the issue.

"Additionally, FDA requested data from previously planned registration batches of commercial product to be manufactured by the company. These data were requested to provide additional support for the proposed acceptance criteria for droplet size distribution after actuation of the sprayer device."

According to Cortellis, eight drugs are in development for diabetic gastroparesis. After Gimoti, the most advanced competition includes Allergan plc's phase III relamorelin; the phase II Takeda Pharmaceutical Co. Ltd. candidates TD-8954 and TAK-906; CNSA-001, an orally bioavailable form of sepiapterin in development by Censa Pharmaceuticals and Retrophin Inc.; and Endologic LLC's renzapride.

Intelgenx's CRL for Rizaport

Intelgenx's CRL for Rizaport, for treatment of acute migraines, prompted President and CEO Horst G. Zerbe to state that the FDA's recommendations were manageable. "To that end," he added, "we expect to move quickly, with the objective of resubmitting the Rizaport NDA before the end of Q3 2019."

Tuesday's trading for Intelgenx shares (NASDAQ:IGXT) closed at 53 cents per share, down 22.2 percent for the day.

The Saint Laurent, Quebec-based company's partner in commercializing Rizaport in the U.S. is Gensco Pharma. Rizaport is designed to be taken orally and dissolve in the mouth so that patients do not have to drink water or swallow a pill.

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