FDA Was For PROCYSBI Orphan Drug Designation Based on Clinical Superiority Before It Was Against It . . . And Then For It Again

By Kurt R. Karst – 

“Driveway moments” – most of us have had them.  It’s that moment when we feel compelled to stay in the car and finish listening to something on the radio.  This blogger recently had such a moment commuting home from work on the subway and then into the parking garage to hop in the car, albeit in the context of reading an orphan drug designation file instead of listening to a segment on the radio.  So what kind of regulatory page-turner of a story could be so compelling and captivating that it was impossible to start up the car to head home?  It’s the years-long, winding road story of FDA’s designation of PROCYSBI (cysteamine bitartrate) Delayed-release Capsules as an orphan drug for the treatment of nephropathic cystinosis in adults and children age 6 years and older.  FDA approved the drug, from Raptor Therapeutics, Inc. (“Raptor”), on April 30, 2013 under NDA No. 203389, and then later awarded 7-year orphan drug exclusivity that expires on April 30, 2020.  (The Orange Book does not yet reflect that award of exclusivity, though we understand that it will soon.)  But it seems to have been quite a slog to get the exclusivity.

The story begins in September 2006 when the University of California, San Diego submitted to FDA a request that FDA designate enteric-coated cysteamine for the treatment of cystinosis, a rare lysosomal storage disease characterized by the abnormal accumulation of the amino acid cystine that eventually leads to intracellular crystal formation throughout the body.  FDA previously designated and approved as an orphan drug, in 1991 and 1994, respectively, another sponsor’s cysteamine drug for the treatment of cystinosis – specifically, Mylan Pharmaceuticals, Inc.’s CYSTAGON (cysteamine bitartrate) Capsules (NDA No. 020392).  As such, in order for a subsequent sponsor’s cysteamine drug for the treatment of cystinosis to be designated as an orphan drug, the sponsor was required to provide a plausible hypothesis of “clinical superiority.”  (To be awarded orphan drug exclusivity in such a context, FDA requires that the sponsor demonstrate clinical superiority, though that requirement is currently being challenged in court – see our previous post here.)

By way of background, once FDA approves a marketing application for a designated drug, the Agency may not approve another firm’s version of the “same drug” for the same disease or condition for seven years, unless the subsequent drug is “different” from the approved orphan drug, or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications.  (FDA may, however, approve a second application for the same drug for a different use.)  A drug is “different” from an approved orphan drug if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug.  FDA’s orphan drug regulations (21 C.F.R. Part 316) define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways: (1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials; (2) greater safety in a substantial portion of the target population; or (3) demonstration that the drug makes a major contribution to patient care (the so-called “MC-to-PC” basis for clinical superiority).  Clinical superiority was a topic of significant discussion in FDA’s recent clarification of the Agency’s orphan drug regulations (see our previous post here).

In October 2006, FDA awarded orphan drug designation based on a plausible hypothesis that enteric-coated cysteamine “may be safer (i.e., causes less side effects) than the approved formulation of cysteamine.”  Those side effects, according to a review from FDA’s Office of Orphan Products Development (“OOPD”), included less nausea and vomiting vis-à-vis CYSTAGON.  And as is typical when OOPD designates a drug based on a plausible hypothesis of clinical superiority, the Office noted in the letter granting designation that “[i]n order to obtain market exclusivity for your product . . . clinical studies submitted with the NDA must demonstrate that enteric-coated cysteamine is comparable in efficacy and safer than the approved formulation of cysteamine.”

A few years went by and a new owner of the drug and orphan drug designation, Raptor, approached OOPD about a second basis for designating enteric-coated cysteamine for the treatment of cystinosis: MC-to-PC.  Specifically, Raptor argued that enteric-coated cysteamine allows patients to be dosed with the drug every 12 hours instead of every 6 hours with CYSTAGON, and that as a result patients have an improved quality of life associated with improved patient compliance.  Why pursue MC-to-PC if designation has already been granted based on a plausible hypothesis of greater safety?  We’re not entirely certain, but we suspect it had something to do with the need to demonstrate superior safety vis-à-vis CYSTAGON to be granted orphan drug exclusivity.  A drug designated as an orphan drug on a MC-to-PC clinical superiority basis still has to demonstrate clinical superiority to be awarded exclusivity, but the demonstration is inherent in the characteristics of the drug that earned designation in the first place.  If those characteristics don’t change, then demonstrating clinical superiority seems to be in the bag.  In any case, OOPD concluded that a change from 6-hour dosing to 12-hour dosing does not meet the MC-to-PC regulatory threshold. 

Raptor, however, was not deterred.  The company came up with a new MC-to-PC theory: the company’s enteric-coated cysteamine causes less halitosis and body odor than CYSTAGON.  Both are effects of cysteamine treatment that clinicians have long recognized as interfering with patient compliance.  Still, OOPD was not convinced that Raptor provided adequate information to support a MC-to-PC clinical superiority decision, and the Office once again rejected the claim in December 2013 while Raptor’s NDA for enteric-coated cysteamine, known as PROCYSBI, was under review at FDA.

Raptor continued to press OOPD for a MC-to-PC designation that would guarantee them orphan drug exclusivity, even after FDA approved the company’s NDA for PROCYSBI, through the submission of additional correspondence and information.  Finally, OOPD’s threshold was met.  According to OOPD’s final review:

The determination of Clinical Superiority by a MC to PC is on a case-by-case basis considering the unique nature of the drug and the disease, among other factors.  Since it is recognized that cysteamine must be dosed at a strict q6h regimen to achieve its maximum benefit in cystinosis patients and that it is documented that many patients with cystinosis are unable to follow a strict q6h regimen throughout their lifetime, a q12h cysteamine product that can maintain cystine at the [white blood cell] levels to achieve maximum benefit can provide a MC to PC over a q6h cysteamine product.  The sponsor provides evidence . . . to show that the q12h delayed-release cysteamine product can maintain [white blood cell] cystine under 1.0 nmol/1/2 cystine/mg protein over 12 months in their long-term extension study RP103-04.

Not the type of “driveway moment” you might be familiar with . . . or were hoping for?  We understand; though to those of us who follow orphan drug issues closely, it is not only a story that gives us greater insight into FDA’s thinking on clinical superiority issues – and another precedent (see our previous post here) – but it has a good ending.