Complete Response Letters See Uptick With US FDA's Thumbs Down For Waylivra

In first half of 2018, CRLs were rarely issued for CDER-regulated novel agents, but FDA's rejection of Waylivra marks second in two weeks.

While novel product rebuffs by the US FDA's Center for Drug Evaluation and Research (CDER) have been rare occurrences for most of 2018, a complete response letter (CRL) for Akcea Therapeutics Inc.'s Waylivra (volanesorsen) was the second for a new molecular entity (NME) in two weeks, following that for Mallinckrodt PLC's stannsoporfin.

Waylivra, designed for the treatment of familial chylomicronemia syndrome (FCS), previously escaped a US FDA advisory committee meeting with a 12-8 vote in favor of approval. (Also see "Akcea Waylivra's Surrogate Endpoint Gains Support At US FDA Advisory Committee " - Pink Sheet, 10 May, 2018.) However, the agency struck a more skeptical tone in its briefing documents, where it raised questions about triglyceride levels as a surrogate endpoint, the adequacy of the pivotal trial and a thrombocytopenia safety signal. (Also see "Surrogate Endpoint, Safety Questions May Be Too Much For Waylivra To Overcome At US FDA Panel" - Pink Sheet, 9 May, 2018.)

FDA and advisory committee panelists who voted "no" were additionally concerned about whether even a strict REMS program would help to prevent severe thrombocytopenia, an event which lacks predictability. (Also see "The 'Dead Cat' Strikes Back: What Does US FDA Do With A Challenging Panel Outcome? " - Pink Sheet, 24 May, 2018.)

Akcea did not disclose in its Aug. 27 announcement which specific deficiencies FDA cited in the CRL. The company declined further comment to the Pink Sheet.

"We continue to feel strongly that Waylivra demonstrates a favorable benefit/risk profile in people with FCS as was reflected in the positive outcome from our Advisory Committee hearing in May," Akcea CEO Paula Soteropoulos said in an Aug. 27 statement. "We will continue to work with the FDA to confirm the path forward."

The theme of an unmet medical need was prominent at the advisory committee meeting, which included an emotional open public hearing, as there are no FDA-approved treatments for FCS, a rare genetic rare genetic syndrome characterized by a build-up of chylomicrons. However, it is possible that the safety profile was too much for the agency to look past given the uncertainty about the magnitude of the clinical benefit.

(Our FDA Performance Tracker’s Complete Response Letter chart lists publicly disclosed reasons for non-approval and sponsor activity in response.)

List Of Novel Product CRLs Starts To Grow

CDER had nearly a perfect batting average when it came to approving novel products in the first half of 2018. The one CRL that impacted the novel approval count went to Evolus Inc.'s DWP-450 (prabotulinumtoxinA), a potential competitor to Allergan PLC's Botox (onabotulinumtoxinA). (Also see "Keeping Track: A Diverse Array Of Approvals, A CRL For Evolus' Botox Competitor, And Coherus Refiles Neulasta Biosimilar" - Pink Sheet, 20 May, 2018.)

Achaogen Inc. additionally failed to pick up an indication for its aminoglycoside antibacterial Zemdri (plazomicin) to treat bloodstream infections (BSI), although FDA gave nod to the drug to treat complicated urinary tract infections (cUTI). (Also see "Achaogen Questioning Whether Others Will Pursue LPAD Pathway After Zemdri Misses Out " - Pink Sheet, 26 Jun, 2018.)

Biosimilars and 505(b)2 drugs had comprised most of the publicly announced CRLs so far this year. (Also see "US FDA Likely To Shatter Novel Approval Record In 2018" - Pink Sheet, 5 Jul, 2018.)

But that batting average has taken a dip so far in the second half of 2018 with the CRLs for Waylivra and stannsoporfin coming in back-to-back weeks. The CRL for stannsoporfin did not come as a surprise, as an advisory committee overwhelmingly voted against approval in May. (Also see "Keeping Track: Novel Approvals For Diacomit, Takhzyro And Oxervate; CRLs For Mallinckrodt And Allergan" - Pink Sheet, 24 Aug, 2018.)

CDER still has at least 30 novel agents in its pipeline with user fee goal dates in 2018.

(See the CDER 2018 Novel Approvals chart on the FDA Performance Tracker for all the novel agents approved by the agency's drug center. Detailed information on pending applications can be found in the Estimated User Fee Goals chart.)

Deciding Against Its Advisory Committee

The Waylivra CRL marks the first time in 2018 that FDA went against a positive vote from an advisory committee and declined to approve a drug.

It is not, however, the first time this year that the agency decided on a different outcome. The other instance followed a negative advisory committee vote for Pacira Pharmaceuticals Inc., which was seeking to add a nerve block indication to the labeling for its local anesthetic Exparel (bupivacaine liposome injectable suspension). (Also see "Pacira's Exparel: US FDA Panel Narrowly Rejects Nerve Block Claim" - Pink Sheet, 15 Feb, 2018.)

FDA ultimately granted approval to Exparel as an interscalene brachial plexus nerve block to produce postsurgical regional anesthesia, although the indication was narrower than what the company was initially seeking. (Also see "Pacira's Exparel Adds Nerve Block Indication For Shoulder Surgery In US" - Pink Sheet, 9 Apr, 2018.)