Expert Financial Analysis and Reporting

Purpose of Report

I recently initiated coverage of Catalyst Pharmaceutical Partners (CPRX). This report is a follow-on to that report which focuses on the clinical trials that have been conducted to date with CPP-109 (vigabatrin) in cocaine addiction. This provides perspective on the all-important ongoing US phase IIb trial. The company hopes to duplicate the results shown in a well conducted phase II trial in Mexico, which is described in this report. If the US phase IIb trial is successful, it hopes that it can file for approval based on the US study using the Mexican study as a supporting trial. The topline results should be available in 2H, 2012 and if they are positive, it potentially could enable an NDA to be filed in 2H, 2013.

I have also included some additional comments on CPP-115. This drug works by the same mechanism of action as vigabatrin. This suggests that CPP-115 may then be useful in treating cocaine addiction; the disease states in which vigabatrin is now approved such as partial complex epileptic seizures and infantile spasms; and potentially other CNS diseases and addictions. The pre-clinical studies suggest that it has the potential to be safer and more effective than vigabatrin, but these are not necessarily predictive of how the drug will perform in humans. It is just entering phase I trials and is probably 5+ years from approval if all goes well in the development program. If the clinical development gods smile on this product and it is successfully developed, it could have blockbuster sales potential with patent protection through 2028.

Early Proof of Concept Trials for CPP-109 for Treating Cocaine Addiction

Proof of concept trials for the use of CPP-109 in treating cocaine addiction came from two small open label studies performed in Mexico in 2003 and 2004. These trials were done in conjunction with weekly supportive psychotherapy in an outpatient setting. There were 20 cocaine dependent patients in the first study and in a 10 week study eight were abstinent for at least 4 successive weeks during the 10 week study. In a second study of 30 patients with methamphetamine and/or cocaine dependence, 16 were abstinent for at least 3 successive weeks over 9 weeks of treatment. The most common adverse effects were transient sleepiness and headache; no serious events occurred in either study.

Phase II Randomized Study in Mexico was Encouraging

Based on the two small studies, a larger phase II trial was conducted. The study subjects were parolees from a Mexico City prison who had a history of cocaine dependence. In the trial, 50 subjects were randomly assigned to CPP-109 and 53 to placebo. The trial lasted for 9 weeks after which patients were followed for another four weeks. The primary endpoint was full abstinence for the last 3 weeks of the trial. Cocaine use was determined by testing urine samples that were taken twice a week.

The CPP-109 daily dose of 3 grams was dissolved in 250 ml of orange juice according to a fixed titration and placebo patients were given identical bottles of juice. The patients were required to visit the treatment center twice a week to give urine and at that time were given their daily dose under observation. For the other five days of the week, they self-administered the drug. All patients received weekly behavior therapy focused on supporting abstinence.

Fourteen (28%) of the CPP-109 treated patients were abstinent for the final three weeks of the trial as compared to only 4 (8%) of the placebo patients. This primary endpoint of the study was successfully achieved with p<0.05. A secondary end point of partial abstinence (reduced cocaine consumption) was reached by 17 (34%) vigabatran patients and 5 (9%) of placebo patients for a p<0.01. Interestingly, 10 (20%) of vigabatran patients stated that they were also abstinent from alcohol at the end of the trial versus 1(2%) of the placebo group for which the p value was <0.01.

Through the four week follow-up period, 12 of the 14 vigabatran patients who reached the primary endpoint of the trial and 2 of the 4 placebo patients remained abstinent. In the vigabatran arm, 62% of patients completed the trial versus 44% in the placebo arm. However, there were no differences between the two groups in drug craving, depression or anxiety. Side effects for vigabatrin and placebo were comparable.

The full details of this study were reported in the American Journal of Psychiatry in November 2009.

The Phase II US Trial Disappointed

These favorable Mexican studies led to the initiation of a phase II trial in the US which was similar in design to the phase II Mexican trial. This trial failed to produce positive topline results. However, researchers generally felt that this disappointment was attributable to the trial design rather than lack of activity of the drug.

The US trial included 186 patients from 11 medical centers who were randomly assigned to 3 grams of vigabatran given in two daily doses or placebo. The trial ran for 12 weeks and patients received computerized behavioral therapy and counseling once a week. Urine specimens were collected three times a week to test for cocaine use. The primary endpoint was being abstinent in weeks 11 and 12 of the 12 week study. This was determined by patient self-reporting and also measuring levels of benzoylecgonine, the major metabolite of cocaine, in urine samples. Treatment adherence was evaluated through pill counts and patient self-reporting.

The study failed to meet its primary endpoint. There were 61 dropouts so that 125 patients completed 12 weeks of therapy for a dropout rate of about 33%, which is common for addiction trials. In a post hoc analysis which looked at urine samples, it was found that 48% of the 61 CPP-109 patients that stayed in the trial were not compliant with their medication. This lack of compliance had a profound negative influence on the trial outcome

Catalyst performed an analysis of the 32 patients who were compliant with their medication for the entire trial. Because of the small numbers of patients involved in the study, there was not enough statistical power to reach significance on the primary abstinence endpoint. However, there was also encouragement on a secondary endpoint as CPP-109 patients used consistently less cocaine as determined by measuring benzoylecgonine (the major metabolite of cocaine) levels; the p value was 0.006.

Catalyst believes that the US trial failed because the US patients were less motivated than the Mexican patients. Mexican patients were observed by their parole officers or health care personnel taking their medication for 2 of 7 days each week. The subjects in the Mexican study were also parolees from prison, and showing up at least once per week at the CPP-109 study treatment center was necessary to meet the requirements for parole. The American study consisted of patients who had been recruited by academic medical centers through radio and TV ads and who were paid for their participation. US patients were generally unobserved taking their medicine and were less motivated overall to take their medication.

Proof of Concept Trial in Methamphetamine Addiction

A proof of concept trial in methamphetamine users enrolled 29 patients on CPP-109 and 28 on placebo. There was a 2.5 times higher rate of abstinence in the last two weeks (weeks 11 and 12) of the study in the CPP-109 group versus placebo. This was not statistically significant due to the small number of patients enrolled, but it was encouraging.

The Next Step, New US Trial in Process

In February of 2010, Catalyst began a new phase IIb study of CPP-109 in which 200 patients will be enrolled. This time the trial is only enrolling truly motivated patients who have a strong incentive to quit, e.g. keeping their family together and/or retaining their job. Patients will receive no payment for participating in the trial. The endpoint of the study is abstinence at 8-9 weeks with patients then being followed through 24 weeks in total. The company believes that topline data will be available in 2H, 2012 and if the trial is positive an NDA could be filed in 2H, 2013 with possible approval in 3Q, 2014.

More on CPP-115

Pre-clinical work in rats with CPP 115 has been very encouraging. PET imaging scans have shown that in rats given cocaine, the dopamine levels are increased 550% with placebo, 325% with CPP-109 and 250% with CPP-115. Remember that less dopamine leads to less cocaine induced pleasure. Other types of rat studies have also indicated that rats received less cocaine dependent pleasure reward when using this drug. The pre-clinical data was reported in the Journal of Medicinal Chemistry.

The pre-clinical profile of the product indicates that the drug is not metabolized which reduces the potential for interactions with other drugs. This is important for epilepsy patients who are often on multiple therapies. It also appears to have little off targeting binding which should reduce the side effect potential. No cardiovascular or respiratory effects were observed. One of the most important findings was that in rat models it appears to have much less effect on vision acuity than CPP-109.

Sabril (vigabatran or CPP-109) was approved in 2009 in the US to treat infantile spasms, a very severe form of epilepsy that affects infants. The incidence in the US is about 2000 children per year and the prevalence is about 4,000. The prevalence is also about 4,000 in Europe. The US market size is about $100 million divided between Questcor’s Acthar Gel at about $60 million and Sabril at $40 million. CPP-115 in pre-clinical studies has shown significant advantages over Sabril. It suppresses seizures at doses 100 times lower than Sabril, has longer time of control over seizures and doesn’t appear to cause severe sedation. It could be a significant advance for treating this dangerous disease and could provide a quick path to approval.

In Europe, Sabril is indicated for and widely used for treating complex partial epileptic seizures. These are epilepsy patients who generally lose consciousness during their seizures and are unable to recall that they have had a seizure. There are about 1.5 million such epilepsy patients in the US who are treated and about 30% are refractory to therapy. Based on the experience of Sabril, CPP-115 may be effective as monotherapy in refractory patients and as add on therapy for many of the effectively treated patients. This could be a very large market opportunity.