Ovid Therapeutics & Graviton Bioscience Announce Topline Data From Phase 1 Clinical Trial Studying a Potential First-In-Class Therapy for Cerebral Cavernous Malformations

Ovid Therapeutics Inc. and Graviton Bioscience Corporation recently announced the results from their Phase 1 healthy volunteer study evaluating the safety, tolerability, and pharmacokinetic (PK) profile of multiple ascending doses of OV888/GV101 capsule. Ovid and Graviton plan to progress to a Phase 2 clinical study in cerebral cavernous malformations (CCM) later this year.

“The safety data support progression to a proof-of-concept study in people with CCM, a community that has no FDA-approved pharmacologic treatment available today. The standard of care for people diagnosed with CCM is often ‘watchful waiting’ or high-risk brain surgery for eligible symptomatic patients. We hope to bring an oral, potentially first-in-class, highly selective ROCK2 inhibitor to this community,” said Dr. Jeremy Levin, DPhil, MB BChir, Chairman and CEO of Ovid Therapeutics. “Our collaboration with Graviton Bioscience is both successful and exciting. We are unpacking the therapeutic potential of inhibiting ROCK2. This mechanism of action has broad potential applications in multiple additional neurovascular and neuro-inflammatory conditions, which we look forward to pursuing together in the future.”

“Today’s data reinforce our conviction that OV888/GV101 capsule has the potential to become the first oral treatment for CCM,” added Samuel Waksal, PhD, CEO and founder of Graviton. “Based on nonclinical data, we believe the highly selective inhibition of ROCK2 by OV888/GV101 capsule could have a three-pronged effect in CCM: firstly, to restore the barrier function of brain endothelial cells and prevent future bleeds; secondly, to reduce inflammation; and thirdly, to stop consequent fibrosis in the lesions.”

The Phase 1 study was a single-center, double-blinded, randomized, placebo-controlled, multiple ascending dose (MAD) trial to evaluate the safety, tolerability, and PK profile of OV888/GV101 capsule in healthy adult volunteers. OV888/GV101 capsule or placebo was administered once daily for seven days. The MAD cohorts evaluated doses of 100 mg, 200 mg, 400 mg, and 600 mg. OV888/GV101 capsule met the study’s primary safety and tolerability objectives and characterized its PK properties.

Well tolerated at all tested doses. There were no serious adverse events (SAEs) and no participants met the preset trial stopping criteria. All drug-associated clinical adverse events (AEs) were mild (Grade 1) and resolved. The most commonly reported clinical AE was headache, which occurred in 23% of participants. All participants reporting headaches had transient cases, which resolved. One subject discontinued the study early due to mild headache and nausea, which resolved after study drug discontinuation. Most clinical AEs resolved within 24 hours, all resolved within the study period. There were no AEs reported in the placebo cohort.

Target engagement achieved. There was a dose dependent decrease in proinflammatory cytokines IL-17 and IL-21 secretion by stimulated peripheral blood mononuclear cells. These decreases are markers of selective ROCK2 inhibition. These findings indicate that OV888/GV101 is biologically active in humans at the target clinical dose and elicits a pharmacodynamic response.

Exposure and half-life findings supportive of daily dosing. Topline data show a dose dependent increase in C_max and AUC_0-24 up to the 400 mg target dose. The average half-life is approximately 12 hours suggesting that OV888/GV101 capsule may be well suited for once daily dosing.

Laboratory results. In the study period, there were two asymptomatic laboratory findings rated Grade 2 or higher, which occurred in at least 5% of treated subjects relative to placebo. Increases in total bilirubin without direct hyperbilirubinemia were reported in 30% of participants. These elevations were clinically insignificant and are consistent with the understood effect of ROCK2 inhibition on UGT1A1 enzyme. Importantly, no concurrent liver enzyme elevations were observed. Creatine phosphokinase elevations without muscle pain or weakness were reported in 7% of participants. There were no reported related clinical impacts for either laboratory finding, and all participants normalized during the study period.

Ovid and Graviton expect to initiate a Phase 2 proof-of-concept study in people living with CCMs in the second half of 2024. Additionally, under the collaboration agreement between Ovid and Graviton, the parties have agreed to develop an intravenous formulation of OV888/GV101 for undisclosed neurological indications.

CCMs are one of the most common vascular malformations in the central nervous system (CNS), with a prevalence of approximately 400,000 symptomatic individuals in the seven major markets. CCMs are clusters of abnormal mulberry-shaped blood vessels with thin walls. CCMs can cause blood to leak into the brain, resulting in a variety of symptoms, including: headaches, seizures, and other focal neurological deficits. Surgical resection is the only recommended treatment for CCM hemorrhage, as there are no approved pharmacological treatments. However, surgical intervention is dependent on the location of the lesion and is not an option for many individuals with CCM.
OV888/GV101 capsule is a highly selective and potent inhibitor of ROCK2. Proper regulation of ROCK2 pathway has been shown to be important for vascular endothelial function, as abnormal activation of this pathway has been demonstrated to be a key component of CCM pathogenesis, including bleeding and formation of lesions in the brain and the spinal cord. In preclinical studies, OV888/GV101 capsule has been shown to be blood-brain-barrier penetrant and highly selective for ROCK2. OV888/GV101 capsule has the potential to be a first- and best-in-class oral therapy for CCM and other rare CNS diseases.

Graviton Bioscience Corporation is a clinical-stage drug discovery and development company, dedicated to engineering and developing best-in-class therapeutics for treating CNS, autoimmune, fibrotic, and other serious diseases where ROCK2 and its other therapeutic compounds play a pivotal role in pathology. Graviton’s first drug candidate, GV101, is in clinical studies, with additional assets advancing through the preclinical pipeline. Leading Graviton is Dr. Samuel Waksal, the founder, and former Chairman and CEO of Kadmon Pharmaceuticals (acquired by Sanofi). Dr. Waksal is also the founder and former CEO of ImClone Systems (acquired by Eli Lilly) and a founder of MeiraGTx.  For more information, visit www.gravitoncorp.com.

Ovid Therapeutics Inc. is a New York-based biopharmaceutical company that is dedicated to meaningfully improving the lives of people affected by certain epilepsies and brain conditions with seizure symptoms. The company is advancing a pipeline of novel, targeted small molecule candidates that modulate the intrinsic and extrinsic factors involved in neuronal hyperexcitability causative of seizures and other neurological symptoms. Ovid is developing: OV888/GV101 capsule, a potent and highly selective ROCK2 inhibitor capsule, for the potential treatment of cerebral cavernous malformations and other rare CNS diseases; OV329, a GABA-aminotransferase inhibitor, a potential therapy for treatment-resistant seizures; and OV350, a direct activator of the KCC2 transporter, for the potential treatment of epilepsies and other psychiatric conditions. For more information, visit www.ovidrx.com.