Raptor Pharmaceutical Corp. announced 36-month efficacy results from a phase 2/3 clinical trial evaluating RP103 for the potential treatment of Huntington's disease, called CYST-HD, conducted in collaboration with the Centre Hospitalier Universitaire d'Angers (CHU d'Angers), France.

Data from the study revealed that there was a slowing in the rate of change in the Total Motor Score (TMS) component of the Unified Huntington's Disease Rating Scale (UHDRS) at 36 months of treatment favoring earlier RP103 treatment (RP103-RP103) versus delayed start of RP103 treatment (placebo-RP103). The 25% treatment effect in TMS favoring subjects treated with RP103 for the full 36 months as compared to the placebo/RP103 arm, while not statistically significant, is regarded by clinical leaders in the field as clinically meaningful. The TMS data were consistent with observed effects in key functional measures including Total Functional Capacity (TFC) and Independence Scale. There was statistically significant improvement in the Independence Scale.

Huntington's disease is a rare, inherited, neurodegenerative disorder that causes motor, cognitive and behavioral dysfunction, deterioration and premature death. There is no currently approved drug that slows disease progression.

"The 36-month efficacy results from the CYST-HD study are clinically meaningful and suggest that RP103 may play an important role in the treatment of Huntington's disease," said Dominique Bonneau, M.D., Professor of Medical Genetics at the CHU d'Angers and principal investigator for CYST-HD. "These data warrant further assessment as there remains a clear need for new, safe and tolerable therapies to treat this disease."

CYST-HD was a randomized, placebo-controlled, multi-center trial evaluating the long-term efficacy, safety and tolerability of RP103 for the treatment of Huntington's disease. Placebo subjects crossed over to open-label treatment at 18 through 36 months. This phase of the study examined the effect of RP103 in Huntington's disease subjects treated earlier, beginning at Month 0 (RP103/RP103) compared to subjects with a delayed start to treatment, beginning at Month 18 (placebo/RP103). The primary efficacy endpoint for this study was the change from baseline at 18 months in the TMS component of the UHDRS between placebo/RP103 and RP103/RP103-treated subjects. Analysis of this endpoint was also completed in the open-label phase of the study at 36 months. Key secondary endpoints evaluating function included the UHDRS-TFC and Independence Scale. 88 subjects entered the open-label period and 78 subjects completed 36 months of treatment. The full analyses set included all randomized subjects from Month 0 to Month 36.

An evaluation of the change in the progression of the UHDRS-TMS at Month 36 from baseline in the full analyses set in the trial showed a 25% slower progression [10.0 (1.7) vs. 13.3 (1.8), respectively; p=0.18] in patients treated earlier with RP103 relative to those patients on a delayed start. In a completers analysis, these effects were more pronounced with a 35% slower progression [9.2(1.7) vs. 14.1(1.9), respectively p=0.06] in the earlier treatment with RP103 relative to those patients on a delayed start. These changes in the TMS were consistent across a number of subscale components of the measure including voluntary movements favoring earlier  treatment. These effects on the TMS were consistent with improvements in functional measures including the UHDRS-TFC and the Independence Scale. A 23% slowing in the rate of decline in TFC [-2.0 (0.33) vs. -2.6 (0.35); p=0.25] and a 46% slowing in the rate of deterioration on the Independence Scale [-6.9(1.45) vs. -12.7 (1.54); p=0.008] was observed, favoring earlier treatment relative to a delayed start of RP103.

"We are excited to be advancing a treatment that has the potential to slow the rate of motor and functional decline in Huntington's disease patients," said Julie Anne Smith, Raptor's President and CEO. "Such a therapy holds promise to be transformational for patients and is perfectly aligned with our strategic focus to develop and commercialize therapies that bring significant relief to patients and families living with life-threatening diseases. We look forward to discussing the 36-month data with the regulatory authorities and to advancing RP103 in a confirmatory study."

"These promising data along with substantial pre-clinical data support the treatment potential of RP103 in individuals with Huntington disease," said Christopher Ross, M.D., Ph.D., Professor of Psychiatry, Neurology, Pharmacology and Neuroscience; Director of Division of Neurology; Director of the Baltimore Huntington's Disease Center, Johns Hopkins University School of Medicine and Co-chair Scientific Affairs Committee of the Huntington Study Group (HSG). "The HSG is excited to partner with Raptor on the future development of RP103 in Huntington  disease."

The safety profile observed for RP103 was generally consistent with what has been previously reported. The most common adverse events included nausea, vomiting, diarrhea, headache and breath odor. Three deaths due to suicide occurred during the open-label period, including two deaths that occurred in subjects in the placebo/RP103 group and one death in the RP103/RP103 group. Deaths due to suicide were generally consistent with background rates, with over 25% of  patients with Huntington's disease attempting suicide at least once and accounting for 5% to 7% of deaths, per published estimates. Suicides have not been observed in any other RP103 clinical trials or in any patients on clinical or commercial drugs.

Raptor initiated regulatory discussions with the FDA and the EMA starting in 2014 and most recently received feedback from the EMA through a Scientific Advice procedure. The outcome of these interactions indicated that an additional study would be required. Raptor has already engaged with the EMA on the confirmatory study design through a Protocol Assistance procedure and the EMA was in agreement with key aspects of the confirmatory study design. Raptor intends to update both regulatory agencies with the 36-month data and to discuss a trial design that would support marketing authorization.

The CYST-HD study enrolled 96 patients who were randomized in a double blind, 1:1 ratio to RP103 or placebo for an initial 18-month treatment period followed by an 18-month open-label treatment with RP103. 89 patients completed the first 18-month phase. The study enrolled Stage 1 patients showing early disease symptoms with a Unified Huntington Disease Rating Scale (UHDRS), Total Motor Score (TMS) = 5, Total Functional Capacity (TFC) > 10 and a CAG repeat > 38. The trial was conducted at eight clinical sites throughout France under a collaboration agreement between Raptor and CHU d'Angers. Clinical expenses of the study were covered by a grant from the French government (PHRC 2004-03bis CYST-HD).

The objective of the study was to evaluate the effectiveness, safety and tolerability of RP103 in the treatment of Huntington's disease. The primary endpoint of the study was the change from baseline in the TMS sub-scale of the UHDRS at 18 months of treatment in the placebo- and RP103-treated groups. Due to the duration of the study, patients were permitted to continue taking their normal medication regime which included tetrabenazine, a vesicular monoamine transporter 2 inhibitor.

Data through Month 18 were reported in February 2014. Analysis of all 96 patients enrolled in the trial showed a positive trend towards slower progression of TMS in patients treated with RP103 versus those patients on placebo, the primary endpoint of the study. TMS progression was 32% slower in patients treated with RP103 versus those treated with placebo after 18 months of treatment (4.51 vs. 6.68, respectively; p=0.19) in the per protocol population. In 66 patients not taking tetrabenazine, RP103 treatment resulted in a statistically significant slower progression in TMS versus the placebo group (2.84 points vs. 6.78, respectively; p=0.03). Adverse events were similar in the two groups and were comparable to what has been observed in other studies in this patient population. RP103 was well tolerated with 48/52 patients experiencing at least one adverse event during the 18-month study versus 38/44 on placebo. There were five patients treated with RP103 who experienced serious adverse events compared with four patients treated with placebo.

RP103 is Raptor's proprietary delayed and extended release oral medication designed to treat the underlying metabolic cause of several rare diseases and disorders including cystinosis. RP103 is in clinical development for Huntington's and mitochondrial diseases based on a number of proteostatic and antioxidative properties demonstrated in multiple animal models.

PROCYSBI is a cystine depleting agent that is approved in the US for the management of nephropathic cystinosis in adults and children ages two years and older. It is contraindicated in patients with a hypersensitivity to penicillamine. The most commonly reported side effects are vomiting, abdominal pain/discomfort, headaches, nausea, diarrhea, anorexia/decreased appetite, breath odor, fatigue, dizziness, skin odor and rash.

Raptor Pharmaceutical Corp. is a global biopharmaceutical company focused on the development and commercialization of transformative therapeutics for rare, debilitating and often fatal diseases.