Reviva: Developing a novel therapeutic for schizophrenia and bipolar disorders
Reviva Pharmaceuticals has successfully completed the Phase I clinical study with RP5063, its novel molecule for schizophrenia and schizoaffective disorders, the most advanced compound in a pipeline of new therapeutics for clinically validated targets. When asked, Laxminarayan Bhat, PhD, President and CEO of Reviva stated, “We are very excited by the results we have obtained since this product provides a safe and effective next generation dopamine-serotonin system stabilizer that meets the unmet medical needs of approved drugs for this disease.”
As Bhat explained, the drugs currently marketed in the USA for schizophrenia and bipolar disorders have serious side effects that include cardiac problems, dose-limiting central nervous system issues, weight gain, risk of diabetes and hyperlipidemia. In addition, side effects as muscle stiffness and diminished libido make patients unwilling to take the drug regularly. “These are off-target problems and we know what causes them, so we can address them by using the same therapeutic targets while designing and optimizing new chemical entities to mitigate the side effects,” Bhat said. RP5063 displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively, and this balancing may ameliorate both psychosis and mood or cognition in schizophrenia and depression.
Results from Phase I trials of RP5063 in both healthy volunteers and schizophrenia patients indicate that drug is well tolerated with a very favorable profile, excellent predictable pharmacokinetics suited for once-a-day dosing schedule. Preliminary data shows a much milder side effect profile compared to other drugs in this class in schizophrenia patients. Preliminary results from the 32-patient Phase Ib multiple ascending dose (MAD) trial suggest good acceptance by subjects and disease stabilization, and improvements in cognition including frontal lobe executive function. Serious dose-limiting toxicities previously noticed with other schizophrenic drugs were not observed. A larger Phase II clinical study is set to launch in December in the US, Europe and Asia. “The unique receptor balance of this dopamine-serotonin stabilizer produced a very clean profile with excellent safety and initial efficacy in these placebo-controlled Phase I trials,” said Marc Cantillon, MD, medical advisor.
The compound has blockbuster potential, given a global schizophrenia therapy market of USD 24 billion and a US market of more than USD 14 billion. “Even if we capture only 10 to 15 percent of the market, that is approximately USD 1 billion in sales,” Bhat pointed out.
The same development strategy that Reviva used for schizophrenia is also applied to other drugs in its pipeline. Bhat explained that “rather than investing in high risk endeavors, Reviva focuses on developing novel drugs that are safer, more effective and best-in-class drugs for clinically validated targets.” He elaborated, “This approach for new chemical entities allows a faster discovery with low attrition and high success rates.” When combined with an accelerated development program, this extends a drug’s effective patent life by bringing a compound to market much sooner than can normally be achieved.
Speed without sacrificing quality is one of the hallmarks of Reviva’s product development model. “Other companies spend seven to eight years in the research discovery stage exploring the possibilities of novel, unvalidated receptors, but only a very few advances to the late preclinical stage,” Bhat noted. “Then, despite several more years of preclinical work, approximately 70 percent of drugs fail to advance to the clinic because of pharmacologic or safety issues.”
Reviva’s approach shortens the pre-clinical phase to less than four years. “Our schizophrenia compound went from concept to clinical trials in 30 months,” Bhat pointed out. After receiving investigational new drug (IND) approval from the FDA in October 2010, Reviva started the Phase I clinical trial in the USA in December, which was completed in early September 2011. By focusing on clinically validated targets with new molecular entities, if we fail, it will most likely be in the preclinical stage, well before expensive clinical studies. The risk of the target engagement by the drug not translating to clinical efficacy is nonexistent, thus once exposure is confirmed in humans the odds of failure due to lack of pharmacology is very low. Based upon the projected timeline, Bhat says he expects to file a new drug application (NDA) for the schizophrenia compound, RP5063, in September 2014.
Reviva was founded in 2006 and during this period has gained a substantial patent position in the US and worldwide. Reviva’s product pipeline includes compounds for seven indications. The schizophrenia compound will begin Phase II trials in December 2011. Compounds for obesity and depression are in the preclinical stage, and compounds for Alzheimer’s, dyslipidemia, gastroesophageal reflux disease (GERD) and pain are in the research stage.
Reviva is located in the state of the art San Jose BioCenter, which was rated one of the best technology incubators in the world in 2009 by the National Business Incubation Association. The key benefit of this location is access to core analytical equipment, cell culture and in vitro pharmacology laboratories. Access to these facilities allows Reviva to put its money into its development program, thereby building value for the company.
Reviva is financed by Bhat and angel investors comprising medical doctors and professionals associated with the pharmaceutical and high tech industries. “Many of the investors have clinical experience, and some have considerable experience in conducting clinical trials during their careers,” according to Bhat. The company received an additional boost last year in the form of a USD 250,000 research grant from the Department of Health & Human Services to advance its schizophrenia program.
As the company grows, Bhat envisions continued cash flow based upon partnering and licensing agreements. “Reviva intends to partner at least the first two clinical stage INDs with major pharmaceutical companies to complete the clinical studies and successfully bring them to market,” Bhat said. We project that we will have three drugs in the clinic by 2014–two in late stage and one in early stage development.” Based upon industry-standard figures for partnering deals and royalties, milestone projections show a steady revenue growth for Reviva. “Our goal is to become a fully-integrated–concept to market–pharmaceutical company by 2015,” Bhat noted.
Going into the BIO-Europe 2011 partnering event, the emphasis is upon commercialization and marketing resources. The company is open to a variety of partnering options, but, as Bhat, underscored, “We have the development capital we need. We are looking to partner with a large company to bring compounds to market since with many large pharmaceutical companies facing patent expirations of blockbuster drugs in 2015, Reviva’s novel compounds for clinically validated targets provides them with unique and exciting opportunities.”
Bhat has more than 15 years experience in drug discovery and development, in the therapeutic areas of central nervous system, cardiovascular, metabolic and cancer therapies, gained at XenoPort, ARYx Therapeutics and Higuchi Biosciences. He holds more than 20 patents. To build upon that foundation, he has assembled a knowledgeable executive research and development team that has substantial experience at big pharmaceutical companies as well as a successful record of taking several drugs through the development process and to FDA market approval.