RL-007: a pharmacologically unique, clinically de-risked procognitive compound being developed for the treatment of CIAS

Updated: September 2024

With this series of weekly blog posts, I will highlight our clinical-stage compounds and why we are so excited about their potential in mental health indications.

Schizophrenia is a chronic psychiatric disorder characterized by a heterogeneous combination of symptoms including psychosis, social withdrawal, flattened affect and cognitive impairment. It is one of the most debilitating mental illnesses known, estimated to impact over 24 million people globally and approximately 2.8 million people in the United States.

While antipsychotics are commonly used to treat the psychotic symptoms of schizophrenia, they fail to address the cognitive and negative symptoms of this condition. Currently, there are no drugs approved for the specific treatment of Cognitive Impairment Associated with Schizophrenia (CIAS).

Background on atai

Our company, atai Life Sciences (Nasdaq: ATAI), is a clinical-stage biopharmaceutical company aiming to accelerate the development of new medicines to achieve clinically meaningful and sustained behavioral change in mental health patients.?

We have a pipeline of 4 clinical-stage drug development programs; 3 are psychedelic and 1 is non-psychedelic in nature. In addition, we use AI-based computational and medicinal chemistry approaches as part of our drug discovery efforts to generate the next generation of psychedelic and related molecules.

Overview

Cognitive function is moderately to severely impaired in patients with schizophrenia, and this impairment is the prime driver of the significant disabilities in occupational, social, and economic functioning in these patients. We are attempting to address this unmet need with our lead compound, RL-007. This compound has been assessed in ten Phase 1 and 2 clinical trials, involving over 500 participants to date, with no evidence of safety issues. In the two Phase 1 and two Phase 2 clinical trials where cognition was assessed, RL-007 administration resulted in a consistent pattern of pro-cognitive effects, with improvements in verbal memory and attention noted.

We are developing this compound for the treatment of Cognitive Impairment Associated with Schizophrenia (CIAS), with the potential to expand to Autism and Alzheimer’s dementia. There are currently no drugs approved for the specific treatment of CIAS.

Non-Clinical Evidence

RL-007 has been shown to be active in a broad range of non-clinical models, consistently exhibiting pro-cognitive, anxiolytic, antinociceptive and anticonvulsant effects. Although the precise molecular target and mechanism of action for RL-007 has not been elucidated, studies with co-delivered antagonists suggest that RL-007 modulates both inhibitory and excitatory neuronal signaling through GABA-B and cholinergic mediated mechanisms.

Studies in several species have demonstrated that RL-007 can improve cognition in non-impaired animals, reverse age-related cognitive decline, and reverse the effects of scopolamine, a muscarinic antagonist that induces temporary cognitive impairment. For example, as summarized in the figure below, investigators observed enhanced learning and memory, assessed using the Delayed Non-Matched to Position (DNMP) task, in both normal and scopolamine challenged dogs with RL-007 administration. The benefits reached statistical significance at the 1 mg/kg dose and were diminished at higher doses, consistent an inverted U-shaped dose-response.

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Phase 1 Scopolamine Challenge Study

A third-party Phase 1 study enrolled 23 healthy volunteers to evaluate the effects of RL-007 in the scopolamine-induced cognitive impairment model. RL-007 was administered three-times-a-day (“TID”) for one day and then co-administered with scopolamine on Day 2. Cognitive function was assessed on Day 2 using a battery of tasks from the Cognitive Drug Research (CDR) computerized assessment system. As shown in the figure below, the administration of RL-007 resulted in a statistically and clinically significant reversal of scopolamine-induced cognitive impairment on the Continuity of Attention composite score and Delayed Word Recall task. Notably, and consistent with non-clinical evidence, an inverted U-shaped dose response was seen, with the most significant changes observed at the 30mg dose-level.

Phase 2 Study in Diabetic Peripheral Neuropathic Pain (DPNP)

A third-party conducted a Phase 2 study that enrolled 181 patients with DPNP in a randomized, double-blind, placebo-controlled study. Cognitive function was assessed as an exploratory endpoint using a standard computerized cognitive test battery (Cogstate) which assessed attention, concentration, verbal learning and memory, working memory and global cognitive functioning. In the cohort receiving RL-007 at the lower dose (40 mg TID for one week, then 80 mg TID for three weeks), subjects exhibited an improvement in verbal learning (Cohen’s d = 0.31) and memory (Cohen’s d = 0.36), once again consistent with the inverted-U shaped dose response noted above.?

Phase 2a Study in CIAS

Recognify conducted a Phase 2a proof-of-mechanism study in the United States of RL-007 in 32 CIAS patients, positive results of which were announced in December 2021. The study was designed to evaluate the safety and tolerability of RL-007 in this population, as well as its effects on cognition, as assessed using several subscales of the MATRICS Consensus Cognitive Battery (MCCB), a validated regulatory endpoint for measuring cognitive function in CIAS.

RL-007 was well tolerated and demonstrated a clinically meaningful pro-cognitive profile consistent with previous clinical trials involving compound. The figure below highlights the results of RL-007 administration on the key cognitive endpoints of the Hopkins Verbal Learning Task (HVLT), symbol coding and category fluency.?Consistent with previous results, an inverted U-shaped dose-response curve was seen, with the largest benefits across tasks seen with the intermediate 20mg and 40mg TID doses. ?On symbol coding at the 20mg dose, a Cohen’s d of approximately 0.8—consistent with a large effect size—was observed.

“Symbol coding response is at a level that would correlate with better work/school performance” – Keith Nuechterlein, Ph.D. (Semel Institute for Neuroscience and Human Behavior)

Currently Ongoing Phase 2b Study in CIAS

In the first quarter of 2023, we announced the dosing of the first patient in the Phase 2b proof-of-concept clinical trial for RL-007 in CIAS. The Phase 2b trial is a randomized, placebo-controlled, double-blind, three-arm study evaluating 20mg and 40mg doses of RL-007 in approximately 230 patients. The primary endpoint of the study is the MCCB neurocognitive composite score at 6-weeks.

We aim to make a meaningful difference with our lead compound RL-007 for patients suffering from CIAS.

Learn more about our programs?here.