Keeping Track: Mitsubishi ALS NDA; Opko’s Rayaldee Approval; Avycaz Label Extension

The latest drug development news and highlights from our FDA Performance Tracker.

The summer season is off to a slow start at FDA.

FDA approved one new drug application (NDA), for a new extended-release formulation of a vitamin D prohormone, in the week following the first day of summer.

The agency also approved a supplemental NDA strengthening the labeling for an approved combination antibiotic.

Industry also reflected the slower pace, with one new molecular entity reaching FDA for review.

Mitsubishi Starts Road To Bigger US Presence With Edaravone Submission

The submission of a US NDA for edaravone, a free-radical scavenging nootropic and neuroprotective agent for amyotrophic lateral sclerosis (ALS), marks the start of what Mitsubishi Tanabe Pharma Corp.hopes will be a path to increased sales in a market where it has so far had only a limited direct presence.

Independent operations and expansion in the US specialty sector form a major pillar of MTP's new mid-term business plan, under which the company is aiming to generate total US sales of JPY80bn ($765m) by March 2021. Earlier this year, the company established a new US subsidiary, MT Pharma America Inc., to set up in-house specialty sales and marketing operations (Also see "MTP Building US Commercial Ops On Edaravone" - Scrip, 23 Feb, 2016.).

Edaravone would be the first launch for MT Pharma America. MTP anticipates launching the drug sometime in the fiscal year ending March 2017 (Also see "Big US Step For Mitsubishi Tanabe As Edaravone Filed For ALS" - Scrip, 20 Jun, 2016.).

The company announced the NDA submission on June 20, 2016. If the application receives priority review, the user fee goal would be expected to fall in February 2017.

The edaravone NDA is supported by clinical data from Japan, where the drug has been approved for inhibition of progression of functional disorders in ALS patients for about a year; it was launched for ALS in South Korea last December. The small molecule therapy has also been marketed as Radicut since 2001 for various types of acute cerebral infarction.

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

Opko Rayaldee Manufacturing Issues Resolved Quickly

Catalent Pharma Solutions, the third-party manufacturer for Opko Health Inc.’s Rayaldee (calcifediol), appears to have quickly resolved the issues that prompted a March 28, 2016 FDA complete response letter for the vitamin D3 analog. FDA approved Rayaldee on June 17, 2016, four months before the resubmitted NDA’s Oct. 22 user fee goal.

Since the complete response letter, Opko and Catalent have moved rapidly. The NDA was resubmitted on April 22, less than a month after the CRL. Opko has reported that the CRL’s sole issue related to FDA’s observations of deficiencies at a St. Petersburg, FL manufacturing site run by the contract manufacturer, and that the issues, including compliance procedures and quality controls, were “easily addressable” with a concrete action plan (Also see "FDA Hold-Up: Opko Scrambles To Fix Problems At Manufacturing Site" - Pink Sheet, 30 Mar, 2016.).

Rayaldee is an extended-release form of the vitamin D prohormone calcifediol, or 25-hydroxyvitamin D3, approved for treatment of secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. Labeling notes that Rayaldee is not indicated for patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis.

Opko sees a “large void in the current treatment options for SHPT in predialysis patients,” where the standard of care – high-dose vitamin D supplementation – is not approved by FDA. The company plans to launch Rayaldee with its dedicated renal sales force in the second half of 2016.

(Follow the progress of applications that have received action letters from FDA with the FDA Performance Tracker’s Complete Response Letters chart.)

FDA Lifts Limits On Avycaz’ Intra-Abdominal Infection Indication

On June 22, 2016, FDA approved new labeling strengthening the complicated intra-abdominal infection (cIAI) indication for Allergan PLC’s antibiotic Avycaz (ceftazidime and avibactam).

Avycaz was initially approved in February 2015 for cIAI and complicated urinary tract infections (cUTI), but the indications and usage section of labeling came with a caveat that use of the antibiotic should be reserved for patients who have “limited or no treatment options” because only limited clinical safety and efficacy data had been submitted (Also see "Actavis’ Avycaz Approval Shows How FDA Handles Limited-Data, Limited-Use Antibiotic" - Pink Sheet, 2 Mar, 2015.).

The limited indication helped FDA to see its way to approving the drug based on Phase II data (Also see "Flexibility Or Formal Pathway? Avycaz Suggests FDA Doesn't Need Congress To Expedite Limited Use Antibiotics" - Pink Sheet, 18 May, 2015.).

Allergan continued to conduct Phase III studies of Avycaz. The Phase III trial of Avycaz plus metronidazole in cIAI is now included in labeling, showing that clinical cure rates with Avycaz met the primary endpoint of statistical non-inferiority to meropenem.

FDA also allowed the addition of data to labeling from two subsets of the clinical trial patients: those infected with ceftazidime-resistant pathogens and those with pathogens that produce certain extended-spectrum beta-lactamases (ESBLs).

Avycaz’ label for treatment of cUTI still advises restricting use to patients who have limited or no alternatives. Allergan has completed Phase III studies in cUTI patients, and “the data is being analyzed for submission later this year,” the company said.

CDC Advises Against Use Of AstraZeneca’s FluMist Quadrivalent For 2016-2017 Season

AstraZeneca PLC is scrambling to defend the effectiveness of its nasal spray flu vaccine FluMist Quadrivalent after the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices issued guidance stating that the product should not be used in any setting in the 2016-2017 flu season.

The ACIP made its interim recommendation on June 22, 2016 based on CDC vaccine effectiveness data collected over the past three influenza seasons. CDC found that FluMist Quadrivalent did not demonstrate statistically significant effectiveness in children ages 2 to 17 years old.

AstraZeneca told the Pink Sheet that it has "initiated significant work to investigate overall vaccine effectiveness during the 2015-2016 season with the goal of improving vaccine effectiveness in future seasons.” AstraZeneca is also looking for a “potential explanation” for the CDC’s efficacy findings; the company said the CDC’s data conflict with its own studies, which found last year’s version of FluMist at the lower end of the efficacy range usually seen in children, but still acceptable (Also see "AstraZeneca Hopes To Save FluMist In US With Foreign Data" - Pink Sheet, 23 Jun, 2016.).

This will not be the first time AstraZeneca has fought for the quadrivalent formulation of FluMist. A trivalent formulation was approved in 2003, but when the company submitted a supplemental biologics license application (sBLA) in 2011, FDA refused to file it. AstraZeneca resorted to filing the sBLA over protest. In response to FDA concerns during the review, the company submitted more than 30 amendments to the sBLA, agency documents show. FDA approved the quadrivalent version of FluMist in February 2012.