The US FDA shows its teeth

With the advent of PDUFA V nearly four years ago the US regulator heralded a new era of unprecedented collaboration and transparency, and drug approvals rose. Biopharma applicants and investors alike would have been excused for thinking that happy days were here again, and the stage was set for the biotech bull market.

But after the agency's issuing of two refuse-to-file letters in the past seven days, for Catalyst Pharmaceuticals’ Firdapse and PTC Therapeutics’ Translarna, the message now seems to be that enough is enough (see tables below).

It could be that drug applicants had simply become too complacent in putting together data packages in an approval-friendly climate. But refuse-to-file (RTF) letters had become such a rarity after 2011 that for two to have been issued in the space of a week seems a remarkable coincidence.

The actual details of the FDA slapdowns are confidential, so we have to take Catalyst and PTC’s word for it that both were the result of incomplete dossiers. Still, it is noteworthy that these are two of only five major disclosed RTF letters to have been issued since PDUFA V took effect in October 2012.

Until that point RTF letters had been relatively common, and an analysis by Leerink suggested that their issuance rose between 1998 and 2011, with deficiencies in clinical data, chemistry manufacturing and controls, and the electronic file the most common reasons.

Key disclosed US refuse-to-file letters since 2010
Project Company Indication Reason given by applicant Date
Translarna PTC Therapeutics Duchenne muscular dystrophy Not sufficiently complete 23 Feb 2016
Firdapse Catalyst Lambert Eaton myasthenic syndrome Not sufficiently complete 17 Feb 2016
Dronabinol Insys Anorexia in Aids patients Inadequate paediatric study plan  15 Oct 2014
Safinamide Newron Parkinson's disease Organisation and navigation problems 29 Jul 2014
Undisclosed Flamel Undisclosed Reformatting datasets 7 May 2013
Lemtrada Genzyme Multiple sclerosis Presentation of datasets 27 Aug 2012
Perampanel Eisai Epilepsy seizures Reformatting/reanalyses of datasets  29 Jul 2011
Vyndaqel Pfizer Transthyretin familial amyloid polyneuropathy Not sufficiently complete 4 Apr 2011
Farydak Novartis Relapsed/refractory Hodgkin's lymphoma  None given Q1 2011
Rhucin Santarus & Pharming Hereditary angioedema  Not sufficiently complete 28 Feb 2011
Melphalan Delcath Metastatic melanoma in the liver Plant inspection, sterilisation and safety  22 Feb 2011
Truvada & TMC278 Gilead HIV-1 infection Analytical methodology/qualification data  25 Jan 2011
Kadcyla Roche Breast cancer Failed to meet accelerated approval standard 27 Aug 2010
Ceplene EpiCept AML remission maintenance Therapeutic contribution not established 23 Aug 2010
Exelbine Adventrx NSCLC Insufficient data 1 Mar 2010
Pradaxa Boehringer Ingelheim Stroke prevention Data integrity issues 12 Feb 2010
Menveo Novartis Meningococcal disease in infants Procedural concerns 31 Jan 2010

Those hoping that the past week’s developments are just a blip could argue that it is solely incompetence on the part of Catalyst and PTC that is to blame. But these letters have previously been issued to Pfizer, Novartis and Roche, companies who theoretically should know better.

Earlier RTF letters included those for Merck KGaA’s cladribine, Pharmacyclics’ Xcytrin and – most notoriously of all – Imclone Systems’ Erbitux in 2001, leading ultimately to the conviction and jailing of the group’s chief executive, Sam Waksal, for securities fraud.

The FDA lists several reasons for issuing a RTF letter, with materially incomplete or inadequately organised applications top of the list. Intriguingly, relying on a single trial if prior communication had “determined the need for more than one” is also given.

Profound absence

Cowen yesterday said that there was probably a profound absence of some type of required pivotal data in PTC’s Translarna package, pointing to the FDA’s emphasis on dystrophin production in its recent damning briefing documents for Sarepta’s eteplirsen; dystrophin is the only pivotal data type that PTC’s study did not produce.

PTC shares crashed 62% yesterday, and investors in other Duchenne stocks took the hint, sending Sarepta and BioMarin down 7% and 4% respectively.

The implication, of course, is that the US regulator is no pushover after all, even when it comes to debilitating, poorly treated diseases. While the PTC slapdown, eteplirsen briefing papers and Kyndrisa rejection level the Duchenne playing field, rivals can only bemoan their coincidence with the market downturn.

The Duchenne muscular dystrophy pipeline
Project Company Pharmacology class
US filed
Translarna PTC Therapeutics Transcription modulator
Kyndrisa BioMarin Muscular dystrophy antisense
Eteplirsen Sarepta Muscular dystrophy antisense
Phase III
PF-06252616 Pfizer Anti-myostatin MAb
Raxone Santhera Coenzyme Q10
Cialis Lilly PDE5 inhibitor
SRP-4045 & SRP-4053 Sarepta Muscular dystrophy antisense
Deflazacort Marathon Corticosteroid
Phase II
Myostatin adnectin Bristol-Myers Squibb Myostatin (GDF-8) antagonist
BMN 045, BMN 044 & BMN 053 BioMarin Exon 45-skipping antisense
FG-3019 FibroGen Anti-CTGF MAb
Givinostat Italfarmaco HDAC inhibitor
CAT-1004 Catabasis  NF-kB modulator
CAP-1002 Capricor  Cardiovascular cell therapy agent
AAV1-Follistatin Milo Biotechnology Myostatin inhibitor
TXA127 Tarix Orphan Angiotensin (1-7)
NPC-14 Nobelpharma Unknown
HT-100 Akashi/Grünenthal Unknown
Source: EvaluatePharma

To contact the writers of this story email Jacob Plieth or Edwin Elmhirst in London at [email protected] or follow @JacobPlieth or @EPVantage on Twitter

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