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As of September 30^th, 2024, Reviva held $5.6 million in cash on its balance sheet. 3Q:24 cash burn was ($4.2) million while cash flows from financing were $3.6 million related to the August underwriting agreement.

OLE Update

Following the conclusion of the RECOVER study, patients were given the opportunity to continue on brilaroxazine to gather long term safety and tolerability in an open label extension (OLE) study. As part of the safety study and a prerequisite for the NDA, 12 months of safety data is required for 100 patients.

The OLE was designed to take place in parallel with RECOVER and evaluate the long-term safety of brilaroxazine. It must evaluate at least 100 subjects and can enroll patients that were part of the RECOVER trial. The study is listed under the identifier NCT05184335 on clinicaltrials.gov in an entry that is shared with the RECOVER trial. It will evaluate flexible doses of brilaroxazine of 15, 30 or 50 mg. Management’s qualitative assessment is that the drug has been generally well-tolerated across patients with acute and stable schizophrenia.

On November 12^th, Reviva provided an update to the open label extension (OLE) study, which was and extension of the RECOVER trial intended to evaluate the effect and safety of brilaroxazine in patients with acute schizophrenia compared to placebo. Of the patients enrolled in the global trial, 108 have completed one year of treatment and 250 have completed six months of treatment. Results so far show that brilaroxazine continues to be generally well-tolerated across patients. Reviva expects to report topline from the study in December 2024 and to complete the OLE by 1Q:25.

Peer Approvals

Interest in the schizophrenia space has been elevated over the last year with two transactions taking place in December 2023. These were the first transactions that included a schizophrenia asset in many years and represented a return of interest in the space. The first of these transactions was announced on December 6^th, 2023 in a press release by AbbVie. It highlighted AbbVie’s goal of building out its pipeline in psychiatric and neurological disorders with a focus on emraclidine, AbbVie offered and paid $8.7 billion for the asset. The other transaction occurred a few weeks later where Bristol Myers picked up Karuna and its candidate KarXT. This asset was valued even higher at $14 billion, illustrating the potential upside for a promising asset in this space.

Emraclidine

Emraclidine is in clinical trials for treating mental health disorders, particularly schizophrenia. It’s a selective muscarinic acetylcholine receptor modulator, specifically targeting the M4 receptor subtype. This receptor type is found in areas of the brain involved in cognition, mood, and sensory processing, which are often disrupted in conditions like schizophrenia. The drug works by modulating the activity of M4 receptors without directly mimicking or blocking acetylcholine. This selective approach aims to enhance therapeutic effects while minimizing side effects. In a November 11, 2024 press release, AbbVie updated stakeholders on the emraclidine Phase II trials, EMPOWER-1 and EMPOWER-2. It reported that the trials did not meet their primary endpoint. While three of the four emraclidine arms were better than placebo for PANSS total score at week six, none were statistically significant.

KarXT (Cobenfy)

The other recent CNS transaction was between Bristol Myers and Karuna. The deal was announced on December 22^nd, 2023. The transaction acquired KarXT, a first-in-class M1 / M4 muscarinic receptor agonist for the treatment of schizophrenia. The acquisition was auspicious, as KarXT was approved by the FDA a few months later in September 2024. It was the first novel schizophrenia drug approved in 35 years targeting a new set of receptors, specifically the M1 and M4 muscarinic receptors. KarXT is a combination of two muscarinic ligands, xanomeline, a muscarinic agonist and trospium chloride, a muscarinic antagonist.

Given the enthusiasm around the recent approval for KarXT, now branded Cobenfy, and the anticipated $1 billion+ expected revenues in 2027 and the over $2 billion expected revenues in 2029, the recently approved treatment for schizophrenia is attracting attention. Following the approval on September 26^th, the shares of Bristol-Myers rose by about 6% over the next week compared to flat for the S&P500. This is a change in market cap of about $6 billion.

Receptor Binding

The muscarinic receptor is a type of acetylcholine receptor found in the cell membranes of certain neurons and other cells. the primary natural ligand for these receptors is acetylcholine, a neurotransmitter. These receptors play a role in regulating the heart rate, controlling smooth muscle contraction, modulating neurotransmitter release and affecting memory and attention. This last characteristic led to investigation of xanomeline in Alzheimer’s disease where the drug showed evidence of improving behavior and cognition. Despite the benefits, the drug also was associated with unpleasant side effects including diarrhea, sweating and hypersalivation leading to high discontinuation rates. The drug was able to cross the blood brain barrier, which is a critical feature for any drug that addresses a brain disease; however, the side effects led to high discontinuation rates and the drug was eventually abandoned.

Xanomeline’s side effect profile was problematic, causing patients to struggle with nausea, vomiting, diarrhea, excessive salivation and sweating. Karuna solved the side effect problem by adding trospium, a muscarinic antagonist, to block the binding of xanomeline from the muscarinic receptors outside the brain. Trospium is not able to cross the BBB, and does not bind to the M1 or M4 receptors in the CNS but does bind to the muscarinic receptors in the other parts of the body acting as an antagonist thereby reducing the xanomeline-related adverse events.

A Concept of an Idea

Cobenfy emerged from Karuna co-founder Andrew Miller’s investigations into one of Eli Lilly’s failed drugs for Alzheimer’s disease (AD). Dr. Miller knew that only a minority of patients with schizophrenia were well treated and that new targets were necessary.^[2],[3] Typical antipsychotics block the dopamine pathway, but Cobenfy’s key constituent, xanomeline, is an M1 and M4 muscarinic agonist that provides antipsychotic benefits. However, side effects, particularly gastrointestinal ones such as nausea, vomiting and diarrhea, kept many candidates off the drug. To block the cholinergic side effects of xanomeline, it was combined with trospium. Trospium is a non-selective muscarinic receptor antagonist which does not cross the blood brain barrier and is a competitive antagonist that binds to muscarinic acetylcholine receptors (mAChRs), specifically blocking all five muscarinic receptor subtypes (M1-M5). This activity blocks xanomeline from binding outside of the brain and thereby avoiding its unwanted side effects.

What About Other Schizophrenia Candidates?

The excitement about the first new drug for schizophrenia in decades and the anticipated revenue opportunity shifts our attention to other important late-stage products such as Reviva’s brilaroxazine. The candidate has produced impressive Phase II and Phase III data so far and only needs to complete one more successful Phase III before submitting a new drug application (NDA) with the FDA. We take a side by side look at brilaroxazine and Cobenfy to evaluate the relative efficacy of each. We compare on several domains including CGI-S total score. PANSS total score, PANSS positive symptoms, PANSS negative symptoms and discontinuation among other metrics.

Brilaroxazine and Cobenfy Comparison

While comparing results from two different trials carries numerous caveats and limitations, it can provide an indication of the relative safety and efficacy of two competing products. Looking at the PANSS total score, brilaroxazine produced reduced symptoms relative to both Emergent trials by 0.5 to 1.8 points. With respect to positive PANSS score, brilaroxazine demonstrated a slight advantage relative to the Emergent 2 trial but was behind the Emergent 3 trial. Results for negative symptoms using the PANSS score were more conclusive, however, with the 2-point improvement over Emergent 2 and lack of any statistically significant improvement in Emergent 3. Another critical element that deserves substantial attention is the discontinuation rate. Discontinuation rates are important because no matter how good a medication may be, if a patient stops taking it, there is no benefit. On this metric, brilaroxazine had a 16% discontinuation rate in the 50 mg dose, a 19% rate in the 15 mg dose and a 22% rate in placebo. For Cobenfy, in Emergent 2, discontinuation was 21% vs. 25% in placebo and in Emergent 3, discontinuation was 37% vs. 29% in placebo.

Brilaroxazine Safety

As reported in multiple Reviva posters, overall treatment-emergent adverse events (TEAEs) rates were 34.5% for brilaroxazine 15 mg, 35.5% in 50 mg and 30% in placebo. Common TEAEs were headache (<6%) and somnolence (≤7.5%), which were generally transient in nature. No serious adverse events (SAEs) were reported for brilaroxazine. With respect to metabolic factors, no significant change in body weight and blood glucose levels vs placebo were observed and there was a significant decrease in cholesterol and LDL and increase in HDL vs placebo. Specific adverse events:

• Neuroleptic: 0.7% Akathisia and 0.7% EPS in 50 mg, none in 15 mg and placebo

• Endocrine: Significant decrease in prolactin and no change in thyroid levels vs placebo

• Cardiac and GI: Similar to placebo

• No incidence of suicidal ideation or suicides

• Discontinuation rate 16% in 50 mg, 19% in 15 mg, and 22% in placebo

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^{[1] We use restated data for our comparisons.}

^{[2] How Karuna's schizophrenia med KarXT went from a 'serendipitous clinical finding' to the FDA in 25 not-so-short years. October 2023.}

^{[3] For Bristol Myers Squibb's newly approved schizophrenia drug, what a long, strange trip it's been. October 2024.}