Probuphine is Titan’s novel subdermal implant formulation designed using its ProNeura technology to deliver six months of buprenorphine hydrochloride (“buprenorphine”) following a single treatment. Probuphine is being developed for the treatment of opioid dependence and is the first long acting product using buprenorphine, an approved daily dosed compound with U.S. sales of approximately $1.5 billion in 2013 that is designed to maintain a stable, round-the-clock blood level of the drug buprenorphine, for six months following a single treatment.
Probuphine has been shown to be effective with an acceptable safety profile in the following clinical studies:
The goal of any therapy for an addictive disorder is to reduce the use of the substance over time and to engage the patient in treatment long enough for therapeutic gains to be consolidated. In a clinical study, the effectiveness of a treatment for opioid dependence is primarily evaluated by testing a patient’s urine samples for the presence of opioids over the treatment period. In both placebo-controlled Phase 3 studies of Probuphine, every participant was required to provide urine samples three times a week, essentially on alternate days. Any missed sample was considered a positive result (i.e. urine testing positive for illicit opioid). In these studies, the primary effectiveness of the treatment with Probuphine (i.e. the primary endpoint) was established by statistically comparing the proportion of negative urine results (i.e. urine testing negative for illicit opioid) between the Probuphine and placebo arms. The patients in the Probuphine arm showed a clinically meaningful and statistically significant difference in the negative urines as compared to the placebo arm in both studies, with Probuphine treated patients being significantly more successful in reducing their usage of illicit opioids as compared to those treated with placebo implants. These favorable results for Probuphine were also confirmed by a significant difference over the placebo arm in other secondary measures such as retention in treatment, control of withdrawal symptoms and craving for opioids, all of which are monitored by clinicians to see if a treatment is providing clinically meaningful benefit to the patients.
Results for the first double-blind, placebo-controlled safety and efficacy study have been published in the Journal of the American Medical Association (JAMA, October 2010), and results for the second controlled study have been published in the journal Addiction (Addiction, September 2013).
Patients who completed the controlled studies were eligible for enrollment in the six-month re-treatment studies, which provided important safety and efficacy data for up to one full year of treatment. The pharmacokinetic safety study has provided important data on the level of buprenorphine in the blood during the treatment period and demonstrated a good profile of the safety of Probuphine. Data from the clinical development program have been regularly presented at key medical and scientific meetings and congresses including the International Society of Addiction Medicine (ISAM), The American Society of Addiction Medicine (ASAM), The American Association of Addiction Psychiatry (AAAP), The American Psychiatric Association (APA), The College on Problems of Drug Dependence (CPDD) and the American College of Neuropsychopharmacology (ACNP).
These studies are part of a registration-directed program intended to obtain marketing approval of Probuphine for the treatment of opioid dependence in the U.S. and in Europe. Following a review of the NDA submitted in October 2012, the FDA issued a Complete Response Letter (CRL) and requested one additional clinical study which is expected to be completed by mid 2015, followed by a resubmission of the NDA later in 2015.
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The continuous drug delivery system consists of a small, solid rod made from a mixture of ethylene-vinyl acetate (“EVA”) and a drug substance. The resulting product is a solid matrix that is placed subcutaneously, normally in the inner part of the upper arm in a simple office procedure, and is removed in a similar manner at the end of the treatment period. The drug substance is released slowly, at continuous levels, through the process of dissolution. This results in a stable blood level similar to intravenous administration. Such long-term, linear release characteristics are generally desirable as this avoids peak and trough level dosing that poses problems for many Central Nervous System (“CNS”) and other disease settings.
This continuous drug delivery technology was developed to address the need for a simple, practical method to potentially provide continuous drug administration on an outpatient basis over extended periods of up to 6-12 months. In addition to Probuphine, which is the first product to complete clinical testing that has utilized this proprietary continuous drug delivery technology, Titan has conducted initial non-clinical studies with long-term delivery of dopamine agonists demonstrating the potential of this product in the treatment of Parkinson’s disease in non-clinical models of the disease.
Fanapt (iloperidone) is an atypical antipsychotic approved by the FDA for the treatment of schizophrenia currently being marketed by Novartis Pharma AG (“Novartis”) in the U.S. Titan is entitled to a royalty of 8-10% of net sales of Fanapt under a sublicense agreement with Novartis that is based on a U.S. patent which expires in October 2016 (does not include a possible six-month pediatric extension).
Titan has entered into several agreements with Deerfield Management LP (“Deerfield”), which entitle Deerfield to most of the future royalty revenues related to Fanapt in exchange for cash and debt considerations, the proceeds of which have been used to advance the development of Probuphine and for general corporate purposes. Titan has retained a portion of the royalty revenue from net sales of Fanapt in excess of specified annual threshold levels; however, based on sales levels to date, it is unlikely that Titan will retain any revenue from Fanapt in the next several years, if ever. Titan does not incur any ongoing expenses associated with this product.