FDA Action Alert: Avenue, Merck, Sol-Gel, Protalix and Chiesi, and Ardelyx


The U.S. Food and Drug Administration (FDA)’s schedule for April has several PDUFA dates scattered across the rest of the month. Here’s a look.

Avenue’s Resubmission of IV Tramadol

Avenue Therapeutics has a target action date of April 12, 2021, for its resubmission of its New Drug Application (NDA) for IV tramadol. On October 12, 2020, the FDA issued a Complete Response Letter (CRL) over the NDA, stating that although the pivotal Phase III trials demonstrated statistically significant outcomes for all of the primary and many secondary endpoints, the agency could not approve the application in its present form. It indicated further that IV tramadol, which was designed to treat patients in acute pain who require opioids, was not safe for the intended patient population. More specifically, if a patient required analgesia between the first dose of IV tramadol and the onset of analgesia, a rescue analgesic would be needed, which would likely be another opioid. The additional opioid would increase the risk of opioid-related adverse effects.

The company held a Type A meeting with the FDA in November 2020 and resubmitted the NDA, which incorporated revised language associated with the proposed product label and data about terminal sterilization validation.

Merck’s Keytruda for Metastatic Esophageal and Gastroesophageal Junction Cancer

Merck had a target action date of April 18 for its Keytruda (pembrolizumab) plus chemotherapy as first-line therapy for locally advanced unresectable or metastatic esophageal and gastroesophageal junction cancer. This submission was based on data from the KEYNOTE-590 trial. The checkpoint inhibitor was approved on March 23 for that indication. The KEYNOTE-590 trial demonstrated significant improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for the drug plus fluorouracil (FU) and cisplatin versus FU and cisplatin alone, regardless of histology or PD-L1 expression.

“Because Esophageal cancer generally has poor survival rates, new first-line therapies are urgently needed for these patients,” said Peter Enzinger, director, Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women’s Cancer Center. “Today’s approval of this indication for Keytruda introduces a new option, which has shown a superior survival benefit compared to FU and cisplatin alone, for newly diagnosed patients with locally advanced or metastatic esophageal or GEJ carcinoma that is not amenable to surgical resection or definitive chemoradiation, regardless of PD-L1 expression status and tumor histology.”

Sol-Gel Tech’s Epsolay for Rosacea

Sol-Gel Technologies has a target action date of April 26 for its NDA for Epsolay to treat inflammatory lesions of rosacea. Epsolay is a 5% single-agent benzoyl peroxide drug. The NDA was based on two positive, identical Phase III trials that compared the drug to vehicle (placebo) in patients with papulopustular rosacea. The drug showed a statistically significant improvement in both co-primary endpoints of number of patients achieving “Clear” or “Almost Clear” in the Investigator Global Assessment (IGA) scale and absolute mean reduction from baseline in inflammatory lesion count beginning as early as Week 2 and running through Week 12.

Protalix and Chiesi’s Pegunigalsidase Alfa for Fabry Disease

Protalix Biotherapeutics and Chiesi Global Rare Diseases, a business unit of Chiesi Farmaceutici S.p.A., have a target action date of April 27. This was moved back from an original PDUFA date of January 27, 2021. The stated reason was the FDA wanted to inspect the company’s manufacturing plant and a third-party facility in Europe that performs fill and finish for PRX-102. Because of COVID-19-related FDA travel restriction, the agency advised that it couldn’t conduct the inspections before the PDUFA date and pushed it back three months. The date is for the companies’ Biologics License Application (BLA) for accelerated approval of pegunigalsidase alfa for adults with Fabry disease.

Pegunigalsidase alfa is a plant cell culture-expressed and chemically modified stabilized form of the recombinant alpha-Galactosidase-A enzyme. Fabry disease is a rare genetic disorder where the body cannot produce the enzyme alpha-galactosidase A, which breaks down a type of fat, globotriaosylceramide (Gb3 or GL-3) into building blocks that can be used by the body’s cells.

Ardelyx’s Tenapanor for Chronic Kidney Disease

Ardelyx has a target action date  of April 29 for its NDA of tenapanor for control of serum phosphorus in adults with chronic kidney disease (CKD) on dialysis. The NDA was built on data from three successful Phase III trials of more than 1,000 patients. These included two monotherapy trials, as well as a long-term study, to control serum phosphorus in CKD dialysis patients, and one with a dual-mechanism approach in dialysis patients whose hyperphosphatemia was difficult to control despite being on phosphate binder therapy.

Tenapanor is a first-in-class oral drug with a unique mechanism of action that acts in the gut to inhibit the sodium hydrogen exchanger 3 (NHE3). This causes a conformational change in the epithelial cell junctions, reducing paracellular uptake of phosphate at the primary pathway of phosphate absorption.

In September 2020, when the FDA accepted the NDA for review, Mike Raab, president and chief executive officer of Ardelyx said, “The acceptance of our NDA is extremely exciting as it represents the next critical step towards bringing to market a completely new approach to the management of hyperphosphatemia, an area where a significant unmet need exists.”

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