FDA Law Blog: The Third Time’s the Charm for RAVICTI and Orphan Drug Designation: Another “Greater Safety” Clinical Superiority Precedent

FDA Law Blog: The Third Time’s the Charm for RAVICTI and Orphan Drug Designation: Another “Greater Safety” Clinical Superiority Precedent

The Third Time’s the Charm for RAVICTI and Orphan Drug Designation: Another “Greater Safety” Clinical Superiority Precedent Posted: 25 Jul 2016 08:04 PM PDT By Kurt R. Karst –      We recently posted on an orphan drug clinical superiority precedent we came across: PURIXAN (mercaptopurine) Oral Suspension, 20 mg/mL, for the treatment of Acute Lymphoblastic Leukemia in pediatric patients. It’s the sixth “greater safety” orphan drug clincial superiority precedent we know of (see our scorecard of precedents here).  Today we give you the seventh precedent, as promised in our previous post: Hyperion Therapeutics Inc.’s (“Hyperion’s”) RAVICTI (glycerol phenylbutyrate) Oral Liquid, 1.1 grams/mL, which FDA approved on February 1, 2013 under NDA 203284 “for use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.” We’ll spare you all of the legal background – you can refer to our previous posts (linked to above) for that – and cut right to the chase. . . . Hyperion initially requested orphan drug designation of RAVICTI, which is also referred to as “GT4P,” in March 2005 for “maintenance treatment of patients with deficiencies in enzymes of the urea cycle.” But FDA’s Office of Orphan Products Development (“OOPD”) didn’t grant designation – at least not initially.  FDA’s previous approvals of BUPHENYL (sodium phenylbutyrate) under NDA 020572 (Tablets; approved on May 13, 1996) and NDA 020573 (Powder; approved on April 30, 1996) for use “as adjunctive therapy in the chronic management of patients with urea cycle disorders” were an obstacle to obtaining orphan drug dersignation. Although BUPHENYL and RAVICTI contain different active ingredients, glycerol phenylbutyrate is an esterified prodrug of phenylbutyrate, and is considered by OOPD to be the same drug under FDA’s orphan drug regulations.  As such, Hyperion needed to provide a plausible hypothesis of clinical superiority to obtain orphan drug designation. In September 2006, OOPD informed Hyperion that the company failed to provide a plausible hypothesis of clinical superiority to BUPHENYL under any of the three available bases (i.e., greater efficacy, greater safety, or a major contribution to patient care): We find no reason to believe that GT4P may confer greater safety or greater effectiveness than Buphenyl in the treatment or urea cycle disorders. Moreover, we find a lack of objective evidence to support your claim that GT4P, at the proposed dosages, would have comparable safety and effectiveness profiles as those of Buphenyl. . . . You indicate that GT4P is clinically superior to phenylbutyrate since it can be administered in smaller daily dosing volume, is odorless and tasteless, and lacks the inherent sodium load. At issue is whether these advantages, in light of the current lack of preclinical and/or clinical evidence showing that the drug is as safe and effective as Buphenyl, are sufficient for considering that GT4P makes a major contribution to patient care for purposes of orphan-drug designation under § 316.3(b)(3)(iii), or they just simply render the drug an acceptable alternative to Buphenyl.  First, with respect to the daily dosing volume, while four teaspoons of liquid GT4P may be better received than 40 Buphenyl tablets, it is difficult to believe that they really represent a significant advantage over four tablespoons of Buphenyl powder per day.  Second, while the sodium burden and the objectionable taste and odor of phenylbutyrate are obvious drawbacks, we find no evidence that these disadvantages prevent the use of phenylbutyrate in an extraordinary number of patients, nor is there any evidence to show that a substantial proportion of patients discontinue treatment as a result. Hence, it is not readily apparent that these advantages of GT4P, per se, rise to the level of a major contribution to patient care to be considered a different drug than Buphenyl for purposes of orphan-drug designation. Therefore, for us to consider your request to designate GT4P on the basis of a major contribution to patient care, you should first demonstrate with reasonable certainty that GT4P, at the proposed dosages, would offer at least comparable safety and effectiveness profiles as those of Buphenyl, and that it would be well tolerated by most patients in chronic use. Second, you need to present clear and convincing evidence that Buphenyl, due to its taste, odor, and sodium load, cannot be used, or is so poorly tolerated that its effectiveness is significantly compromised, in a substantial number of patients with urea cycle disorders. Hyperion got back to OOPD several months later, in May 2006, with new information and clinical superiority arguments. But OOPD shot Hyperion down for a second time, in October 2006, saying, among other things, that “no clinical evidence [supports] your suggestion that the currently recommended doses of Buphenyl produce too high a level of [phenylacetate] in UCD patients.” Some time passed, and Hyperion eventually went back to OOPD (in December 2008) for a third time, but armed with new data and analyses. According to Hyperion: HPN-100 is not just a re-formulation of sodium phenylbutyrate. It is a new chemical structure, a triglyceride that exhibits delayed release characteristics.  It is a nearly odorless and tasteless, more concentrated drug (providing three 4-phenylbutyrate molecules for every mole of drug), which enables the overall drug volume to be reduced and eliminate the need for G-Tubes that are placed solely for drug administration.  It will ease the comfort of drug administration thereby reducing the emotional/psychological trauma that patients/caregiver deal with on a daily basis due to drug administration issues.  Because it is a triglyceride, it should the symptoms consistent with oral mucositis and the upper GI side effects patients struggle with on a regular basis due to BUPHENYL® (sodium phenylbutyrate).  In addition HPN-100 removes the noxious excipient sodium.  Finally, data suggests that has the potential to offer more effective nitrogen-scavenging and superior ammonia control compared to BUPHENYL. Out of all of this, OOPD latched on to the last point above: sodium load. OOPD states in an April 2009 Memorandum: The sponsor claims that HPN-100 is different than the approved product because it is more efficacious, safer, and a major contribution to patient care. However, the only salient aspect of the amendment that is relevant to the potential designation of HPN-100 for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle is the difference in the sodium content of the approved product, Buphenyl, compared to HPN-100. The approved labelingfor Buphenyl states that each tablet contains 62 mg of sodium (corresponding to 124 mg of sodium per gram of sodium phenylbutyrate) and that Buphenyl powder contains 11.7 gm of sodium, corresponding to 125 mg of sodium per gram of sodium phenylbutyrate.  The recommended total daily dose of Buphenyl is 9.9 to 13.0 g/M2/d in patients weighing more than 20 kg.  For an average size adult (1.7M2), this means that a person would need to take as many as 44 tablets per day which would contain 2.728 g of sodium.  This is a significant sodium load and in the Warnings section of the labeling for Buphenyl, it states that “Buphenyl should be used with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states in which there is sodium retention with edema.” In contrast, HPN-100 contains no sodium. The current recommended daily allowance of sodium is less than 2.4 g per day.  When dietary intake of sodium is added to the sodium intake from Buphenyl, a person could be taking over 5 gm of sodium every day. As noted by the sponsor, there are no reports of the clinical effects of the high sodium content of Buphenyl in patients with urea cycle disorders. However, Buphenyl has been used to treat other diseases in which the sodium content of the drug adversely impacted patient health. . . . Although [reports provided by Hyperion] are not in patients with urea cycle disorders, the clinical effects attributed to the sodium content in Buphenyl highlight the risk associated with the drug. The risk of high sodium intake leading to hypertension and eventual heart disease is well recognized in the medical community.  Therefore, HPN-100, with no sodium in the formulation, is safer than Buphenyl and should be considered a different drug for purposes of orphan designation. Hyperion’s persistence paid off. FDA approved RAVICITI on February 1, 2013 and granted a period of orphan drug exclusivity that expires on February 1, 2020.