Praxis Bioresearch Presents Positive Preclinical Data for Novel Prodrug Stimulant with Abuse-Deterrent Properties at ACNP Annual Meeting

Study Results Demonstrate Favorable Preclinical Profile Through an Enzymatically-Activated Prodrug Approach to Combatting Intravenous and Oral Abuse

MENLO PARK, Calif., Dec. 07, 2017 (GLOBE NEWSWIRE) -- Praxis Bioresearch, a biopharmaceutical company focused on the discovery and development of novel therapeutics for chronic neuropsychiatric and neurodegenerative disorders, today reported positive preclinical data that demonstrated the desired pharmacokinetic (PK) profile and targeted activity for its lead product candidate, PRX-P4-003, a novel, abuse-deterrent prodrug stimulant.  PRX-P4-003 is being developed as a prodrug of fencamfamine, a well-tolerated Schedule IV stimulant that was formerly prescribed for decades in Europe and other countries, for a range of conditions including depressive daytime fatigue, lack of concentration, and lethargy. Praxis’ novel prodrug, which is selectively cleaved by gut enzymes, is designed to offer the therapeutic benefits of currently marketed stimulants, while reducing risk of abuse and diversion. These data were reported in a poster presentation at the annual meeting of the American College of Neuropsychopharmacology (ACNP), being held December 3-7, 2017, in Palm Springs, CA.

Presented study findings showed that prodrug PRX-P4-003 remained intact without releasing the parent compound (-)-FCF, a purified isomer of fencamfamine, when it was exposed to simulated gastric fluid. (-)-FCF was only released when the prodrug was metabolized following exposure to simulated intestinal fluid containing pancreatic enzymes. Importantly, data demonstrated that intact PRX-P4-003 lacked affinity for dopamine and norepinephrine transporters, whereas (-)-FCF demonstrated strong affinity for these key targets of stimulant therapy, as expected.  These findings suggest that orally dosed PRX-P4-003 possesses the desired profile to prevent rapid stimulant uptake and activity until it has passed through the stomach and reached the small intestine.

Once metabolized in the gut, orally dosed prodrug PRX-P4-003 demonstrated comparable exposure of (-)-FCF as equimolar oral dose of unmodified (-)-FCF. Additionally, oral doses of the prodrug resulted in dose-dependent increases in locomotor activity in rodents, as compared to vehicle.  This effect on locomotion suggests that PRX-P4-003 maintains the targeted stimulant-like activity following oral administration, which is the intended delivery route for the prodrug.

Researchers also evaluated the intravenous (IV) abuse-deterrent properties of PRX-P4-003. Findings demonstrated that plasma exposure of (-)-FCF was significantly lower with IV administration of the prodrug as compared to (-)-FCF exposure from a comparable dose of unmodified (-)-FCF delivered intravenously. Moreover, no stimulant-like activity was seen with PRX-P4-003 even when the prodrug was administered at a dose five times greater than unmodified (-)-FCF, which showed highly significant activity (P<0.001). This provides additional support for the mechanistic hypothesis that the prodrug is metabolized by the pancreatic lipase, an enzyme whose biological activity is almost exclusively limited to the gut. Less than 1% of the enzyme is expected to be active in the intravenous compartment thus limiting PRX-P4-003 activation following IV administration.  Taken together, these findings highlight the ability of Praxis’ prodrug to prevent abuse following IV administration, further supporting its abuse-deterrent potential.

“We are very encouraged by the aggregate results of this preclinical evaluation of our prodrug approach to developing an effective, yet low-risk stimulant to serve the therapeutic needs of patients with a range of CNS conditions,” said Sandeep Patil, PhD, MD, chief executive officer of Praxis Bioresearch. “In this study, we set out to establish that PRX-P4-003 has the capability to provide the established biological activity of stimulants, while pharmacokinetically limiting the potential for IV and oral abuse. We believe that these presented data show that we have achieved those objectives in animals and provide support for similar evaluation of the compound in human studies.” 

“While the epidemic of opioid abuse receives considerable public attention, somewhat similar issues and potential danger also exist with prescription stimulants.  As such, there is a significant need for novel abuse-deterrent stimulant formulations,” said Valentino J. Stella, distinguished professor emeritus, department of pharmaceutical chemistry at the University of Kansas and co-inventor of PRX-P4-003. “To my knowledge, this is the first prodrug that utilizes a gut-specific pancreatic lipase approach to limit intravenous activation by taking advantage of its asymmetric distribution.” 

Stimulants such as methylphenidate and amphetamines are among the most widely prescribed classes of medications, with an estimated 90 million annual prescriptions written for a range of central nervous system conditions including attention deficit hyperactivity disorder (ADHD) and binge eating disorder (BED). According to a report issued by Persistence Market Research, the stimulant market for ADHD alone is expected to grow to $25 billion annually in 2024. However, stimulants are classified as Schedule II controlled drugs due to risk of addiction. Accordingly, there is a significant unmet need for effective abuse-deterrent stimulant formulations.

Prodrug stimulant PRX-P4-003 is a novel, abuse-deterrent dopamine norepinephrine reuptake inhibitor incorporating an active isomer of fencamfamine. Having previously been prescribed for human use for decades, the clinical profile of fencamfamine is well established. PRX-P4-003 is specifically designed to produce therapeutic stimulant activity when delivered orally but lacks any such activity if injected. Translated into humans, this profile may assist in the deterrence of prescription stimulant abuse and diversion while providing effective treatment by the oral route.

About Praxis Bioresearch

Praxis Bioresearch, LLC, is a biopharmaceutical company focused on the discovery and development of therapeutics for chronic neuropsychiatric and neurodegenerative disorders. Praxis’ lead development candidate is PRX-P4-003, a novel prodrug stimulant designed to offer the proven clinical activity of currently marketed stimulants in an abuse-deterrent formulation.  For more information visit: www.praxisbioresearch.com.

 

Contact:
                    
                    Praxis Bioresearch, LLC			
                    Sandeep Patil, Chief Executive Officer
                    650-491-4347					
                    spatil@praxislscorp.com			
                    
                    Vida Strategic Partners (On behalf of Praxis)
                    Tim Brons (media)
                    646-319-8981
                    tbrons@vidasp.com