FDA continues to make 2016 the year of the complete response letter, with three more CRLs announced in the past week.

Complete response letters had been declining for years, especially for new molecular entities and novel biologics, but FDA has already issued at least 10 since January. The CRL for Newron Pharmaceuticals SPA's Parkinson's disease therapy Xadago (safinamide), announced March 29, brings the number of non-approval actions for novel agents in 2016 to four.

FDA's Center for Drug Evaluation and Research brought its novel approval count to six with the clearance of Jazz Pharmaceuticals PLC's Defitelio (defibrotide) for a rare complication of stem cell transplantation on March 30.

Abuse Liability Assessment Delays Xadago

FDA wants to see more "clinical evaluation of the potential effect of safinamide on behaviors relating to abuse liability and dependence/withdrawal effects as required by the Controlled Substance Staff," Newron said in a March 29 release announcing an FDA complete response letter for the drug, known as Xadago.

Newron submitted Xadago, which inhibits dopamine uptake, monoamine oxidase-B, and glutamate release, in late December 2014 as add-on therapy to a stable dose of a single dopamine agonist in early Parkinson’s disease and in combination regimens for mid- to late-stage Parkinson’s. The submission was the second for Xadago; earlier in the year, FDA refused to file the company's first application. Additional information submitted during the review led to the user fee goal being extended from Dec. 29, 2015 to March 29, 2016.

The CRL comes less than two weeks after US WorldMeds LLC acquired US commercialization rights to Xadago from Zambon Co. SPA in a deal announced March 17 [See Deal]. Zambon, which acquired worldwide rights to safinamide outside of Asia in 2012, has launched the drug in the European Union and Switzerland.

Newron emphasized that FDA is not requiring any "additional new data/studies/analyses for efficacy or safety in patients with Parkinson's disease." The company plans to meet with FDA's neurology products division and the Controlled Substance Staff "to finalize plans for the additional experiments."

(See the Complete Response Letters chart on for more information on action letters sent by FDA.)

Rayaldee Held Up By Manufacturing

Deficiencies at a third-party contract manufacturer prompted FDA's complete response action on Opko Health Inc.'s Rayaldee (calcifediol), the firm announced March 30. Rayaldee is under review for treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease and vitamin D insufficiency. Opko reported that FDA has agreed on the package insert and all container labeling, and that the CRL did not cite any safety or efficacy issues or request any additional studies.

Furthermore, the issues at the St. Petersburg, Fla. site of Catalent Pharma, a major contract manufacturer, were not specific to Rayaldee manufacturing. The issues are “easily addressable” with a concrete action plan, and there were no systemic failures or a warning letter, Opko Exec VP-Administration Steven Rubin said during a March 30 call with investors ([A#14160330002]).

Rubin said that Catalent has committed to responding promptly to FDA's concerns “to ensure early resolution" and will prepare a plan to resolve the deficiencies by April 15, in accordance with FDA's request.

Brintellix Bid To Add Cognitive Function Data To Label Falters

FDA went against the recommendation of its Psychopharmacologic Drug Advisory Committee in issuing a CRL for Takeda Pharmaceutical Co. Ltd. and H. Lundbeck AS' supplemental application seeking to add data from two trials assessing cognitive function in patients with major depression to the labeling of Brintellix (vortioxetine).

The advisory committee voted 8-2 that substantial evidence supported a claim for the effectiveness of vortioxetine in treating cognitive dysfunction in major depressive disorder at its Feb. 3 meeting ([A#14160203006]). Brintellix is the first drug to try to add data specifying an effect on cognitive function in depressed patients to labeling.

The CRL was announced on March 29, the user fee goal for the Brintellix application. On the same day, the advisory committee considered another drug with a novel psychiatric claim, Acadia's Nuplazid for Parkinson's disease psychosis (see related story,[A#00160404013]).

Remoxy Rides Again

Pain Therapeutics Inc.'s Remoxy is back at FDA, almost a decade after the original submission. The sponsor was held up as former partner Pfizer Inc. returned rights to the extended-release, abuse-deterrent oxycodone product, which has had a rocky regulatory history Also see "Never Surrender: Pain Therapeutics Eyes 2016 Remoxy Filing" - Pink Sheet, 13 May, 2015.. Pfizer exited the collaboration after reviewing the clinical studies done to address a 2011 complete response letter, which cited concerns about manufacturing, bioequivalence and abuse potential Also see "Remoxy Development Not ‘Unmitigated Disaster,’ CEO Reassures; Hunt Begins For New Partner" - Pink Sheet, 28 October, 2014.. An earlier CRL, from 2008, sought reassurance that the Remoxy formulation could withstand common methods of tampering and misuse.

Pain Therapeutics has held its course, and says it "specifically developed Remoxy to make oxycodone difficult to abuse yet provide 12 hours of steady pain relief when used appropriately by patients." The product has a "thick, sticky, high-viscosity formulation [that] may deter unapproved routes of drug administration, such as injection, snorting or smoking."

The original NDA had priority review; Pain Therapeutics said it will announce the new user fee goal date in the next month.

(See the User Fee Goals chart on the FDA Performance Tracker for information on pending and recently approved applications.)

Lexicon Delivers On Technology-Driven Drug Development

Lexicon Pharmaceuticals Inc. has built its business on using gene science to discover and develop precision medicines, identifying more than 100 protein targets through its Genome5000 program, and has now submitted an NDA for telotristat etiprate for treatment of carcinoid syndrome, the firm announced March 30. The rare disease affects cancer patients with metastatic neuroendocrine tumors (mNET) that have spread to the liver and gastrointestinal tract.

Telotristat etiprate targets tryptophan hydroxylase, an enzyme that triggers the excess serotonin production within mNET cells that leads to carcinoid syndrome, the firm explains. "While existing treatments for carcinoid syndrome work to reduce the release of serotonin outside tumor cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells," it notes.

The NDA is supported by two 12-week Phase III trials; in TELESTAR the drug met the primary endpoint of a statistically significant reduction in the average number of daily bowel movements, and in TELECAST it met the primary endpoint of significantly reducing urinary 5-hydroxyindoleacetic acid (5-HIAA, the main metabolite of serotonin). Lexicon has requested a priority review.

Radius Tries To Join Osteoporosis Market

Radius is hoping to bring the first new bone anabolic treatment for osteoporosis to market since 2002, with the submission of abaloparatide-SC for once-daily treatment of osteoporosis in postmenopausal women, the firm announced March 30. The drug is a novel synthetic peptide that engages the parathyroid hormone receptor (PTH1); Radius selected the candidate for development based on favorable bone building activity.

The firm notes that abaloparatide-SC "met the primary and secondary endpoints essential for submission of the NDA, including the primary endpoint of reduction of vertebral fractures as well as key endpoints of reduction of nonvertebral, clinical and major osteoporotic fractures" in the 18-month Phase III ACTIVE trial in 2.463 patients and the first six months of the ACTIVExtend trial in 1.139 of the ACTIVE participants.

Under Jazz Direction, Defitelio Clears FDA

With FDA's approval of Defitelio, Jazz Pharmaceuticals PLC is introducing the first treatment for patients who develop a rare and life-threatening liver condition following stem cell transplantation. Defitelio (defibrotide) cleared FDA March 30 for use in adults and children with hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after a hematopoietic stem cell transplant.

FDA noted that fewer than 2% of patients develop severe hepatic VOD after HSCT, but as many as 80% of those do not survive. "The approval of Defitelio fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT,” Office of Hematology and Oncology Products Director Richard Pazdur said in a statement on the approval.

Data quality questions aborted an earlier NDA filing for defibrotide in 2011 by Gentium SPA. Jazz acquired Gentium in 2014 and resuscitated the product ([A#00151005009]).

(See all of CDER's new molecular entity and novel therapeutic biologic approvals in 2016 on the FDA Performance Tracker's Novel CDER Approvals chart.)

Keeping Track: FDA On A Complete Response Spree?

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