ATAI Life Sciences N.V. (atai) operates as a clinical-stage biopharmaceutical company aiming to transform the treatment of mental health disorders.
The company is dedicated to efficiently developing and investing in innovative therapeutics to treat depression, anxiety, addiction, and other mental health disorders. By pooling resources and best practices, the company intends to responsibly accelerate the development of new medicines to achieve clinically meaningful and sustained behavioral chang...
ATAI Life Sciences N.V. (atai) operates as a clinical-stage biopharmaceutical company aiming to transform the treatment of mental health disorders.
The company is dedicated to efficiently developing and investing in innovative therapeutics to treat depression, anxiety, addiction, and other mental health disorders. By pooling resources and best practices, the company intends to responsibly accelerate the development of new medicines to achieve clinically meaningful and sustained behavioral change in mental health patients.
Model and Strategy
The company has a team of experienced drug discoverers, developers and innovators working to heal mental health disorders. At atai, the company has a robust portfolio of drug development programs that have either been acquired through strategic investments or created de novo through the company’s drug development platform. To continue to grow the company’s business and to aid in the development of the company’s various programs, the company intends to continue to incubate, acquire and invest in companies that share the company’s intention of advancing transformative treatments for patients that suffer from mental health disorders.
Programs
The company has built a diversified pipeline of drug and discovery development programs, including psychedelic and nonpsychedelic compounds. Psychedelics are emerging as novel breakthrough therapies for mental health disorders, such as depression, and with growing scientific support, recent regulatory advancements and increasing patient and physician acceptance. There is a growing body of clinical evidence that supports the potential efficacy and safety profile of psychedelics, which may have potential therapeutic benefits, such as a rapid onset of effect and sustained efficacy after a short-course of administration. These programs, which include new molecular entities, as well as variants of known compounds with unique pharmacology, have the potential to address unmet needs in mental health disorders.
These programs vary across stage of development, indication and mechanism of action, which will improve the commercial potential and risk profile of the company’s pipeline in the aggregate. The company also prioritizes the development of compounds and compound classes that have shown potential for efficacy and safety in prior clinical trials or observational studies.
Strategic Investments
COMPASS Pathways plc (‘COMPASS’) is developing its investigational COMP360 psilocybin therapy, which comprises the administration of COMP360 with psychological support from specially trained therapists, with an initial focus on treatment-resistant depression (‘TRD’). COMPASS is conducting a Phase 3 pivotal program composed of two pivotal trials, each of which will have a long-term follow-up component. Top-line pivotal data for the first and second trials are expected in the fourth quarter of 2024 and mid-2025, respectively. The company’s interest in the product candidates of COMPASS is limited to the potential appreciation of the company’s equity interest.
Beckley Psytech Psytech Limited (‘Beckley Psytech’) is developing its investigational compounds, BPL-003 5 Methoxy N,N-dimethyltryptamine benzoate (‘5-MEO-DMT’) for the treatment of TRD and Alcohol Use Disorder (‘AUD’) and ELE-101 psilocin therapy for the treatment of Major Depressive Disorder (‘MDD’). Beckley Psytech is conducting a Phase 2b controlled study of BPL-003 in patients with TRD, with an anticipated readout in second half of 2024. Initial results from the BPL-003 open-label Phase 2a in TRD were announced in March 2024. Initial results from the BPL-003 open-label Phase 2a study in AUD are anticipated mid-2024. Initial results from the current ELE-01 Phase 1/2a study are anticipated in the first half of 2024. In January 2024, the company invested in Beckley Psytech resulting in a 35.5% ownership stake and 1:1 warrant coverage at a 30% premium on the primary issuances. The company holds a time-limited right of first refusal on a future sale of the company and an indefinite right of first negotiation for BPL-003 and ELE-101. atai and Beckley Psytech also agreed to collaborate on digital therapeutics, commercial and market access activities in preparation for future potential commercialization. The company’s interest in the product candidates of Beckley Psytech is limited to the potential appreciation of the company’s equity interest.
Enabling Technologies and Drug Discovery Platforms
The company is developing enabling technologies that have the potential to support the programs in the company’s pipeline. The company has enabling technologies housed at its atai companies, as well as IntelGenx Technologies, a strategic investment of the company. While many of these technologies remain in early stage development, in October 2023, the company announced the completion of a Phase 1 study in healthy participants, in which pharmacokinetic (‘PK’) and pharmacodynamic (‘PD’) data confirmed systemic delivery of VLS-01 via, a proprietary oral transmucosal film (‘OTF’) formulation of N,N-dimethyltryptamine (‘DMT’), via the oral, transmucosal route at levels comparable to those achieved with 30 mg intravenous (‘IV’) administration of DMT.
In addition, the company conducts early-stage drug discovery through the company’s discovery platform. Expanding intellectual property has been essential to the company’s strategy, with key investments made to unlock NCEs. The company has made substantial progress in its drug discovery efforts to date, synthesizing and screening approximately 700 compounds and identifying novel scaffolds that display potential in targeting mental health disorders.
Pipeline
The company’s pipeline consists of therapeutic candidates across multiple neuropsychiatric indications, including depression, anxiety, opioid use disorders (‘OUD’), and cognitive impairment associated with schizophrenia (‘CIAS’).
Psychedelic Programs & Strategic Investments
COMP360 (via Strategic Investment in COMPASS)
Product Candidate Concept: COMP360 is a proprietary psilocybin formulation that includes pharmaceutical-grade polymorphic crystalline psilocybin, optimized for stability and purity. By activating a distinct set of receptors in brain areas critical to mood and cognition, psilocybin acts to induce a range of downstream effects that may have important, sustained effects on brain function. In this way, evidence of the molecular, cellular, and systemic effects of psilocybin in the CNS supports the potential for psilocybin in the treatment of mental health conditions. At the molecular level, psilocybin is rapidly metabolized to its active metabolite psilocin, which is a partial agonist at several 5-hydroxytryptamine (serotonin), or 5-HT, receptors, also known as serotonin receptors, including 5-HT2A, 2C, and 1A receptors. This means that psilocin binds to and activates these receptors, all of which are expressed in neurons in different areas of the CNS. In particular, many of the prominent acute effects of psilocybin, such as changes in emotion and cognition, are thought to be mediated by 5-HT2A receptor stimulation, an interpretation that is supported by the fact that blocking the 5-HT2A receptor prevents the psychedelic effects of psilocybin in humans. COMP360 is being evaluated in a pivotal program in patients with TRD with additional Phase 2 studies being conducted in post-traumatic stress disorder and anorexia.
Prior Clinical Evidence
Phase 1 Healthy Volunteer Study
In its initial Phase 1 healthy volunteer trial, COMPASS observed that COMP360 was generally well-tolerated and supported continued progression of Phase 2b studies. The trial also showed the feasibility of simultaneous administration of COMP360 to up to six people in the same facility, with 1:1 therapist support. In August 2020, the FDA approved COMPASS's request for a 1:1 model of therapist support.
Phase 2b Study in Patients with TRD
COMPASS evaluated COMP360 in conjunction with psychological support in a Phase 2b trial that concluded in July 2021 and reported its positive Phase 2b data for its proprietary psilocybin COMP360 for TRD in November 2021. The 233-patient trial met its primary endpoint, showing a 6.6-point reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to 3 weeks when comparing the 25mg dose to the 1mg dose. COMP360 also showed both rapid response and durability of efficacy and was generally well tolerated.
Recent Advancements: At the beginning of 2023, a Phase 3 program evaluating COMP360 psilocybin treatment in TRD was initiated. The Phase 3 program is composed of two pivotal trials, each with a long-term follow-up component. The pivotal program design is as follows: Pivotal trial 1 (COMP005) (n=255): a single dose (25mg) monotherapy compared with placebo. This trial is designed to replicate the treatment response seen in the company’s Phase 2b trial (n=233). Top-line data is expected in the fourth quarter of 2024. Pivotal trial 2 (COMP006) (n= 568): a fixed repeat dose monotherapy using three dose arms: 25mg, 10mg and 1mg. This trial is designed to investigate whether a second dose can increase treatment responders and whether a second dose can improve responses observed in the company’s Phase 2b trial and to explore the potential for a meaningful treatment response from repeat administration of COMP360 10mg. Top-line data is expected by mid-2025. The primary endpoint in both pivotal trials is the change from baseline in the MADRS (Montgomery-Åsberg Depression Rating Scale) total score at week 6.
BPL-003 (via Strategic Investment in Beckley Psytech)
Product Candidate Concept: BPL-003 is a dry powder, intranasal formulation of the benzoate salt form of 5-MeO-DMT, a psychoactive indolealkylamine derivative of tryptamine. 5-MeO-DMT is a serotonergic psychedelic due to its ability to bind to a variety of serotonin (5-HT) receptors where it predominantly acts as an agonist. Its agonist activity at 5-HT receptors is considered to be the mechanism for its psychoactive effects and, although it has affinity for a broad range of 5-HT receptors, its actions at serotonin 1A (5-HT1A) and serotonin 2A (5-HT2A) receptors are considered to be the most important for the majority of its reported activities. The lead indication for BPL-003 is TRD, with on-going Phase 2a and 2b studies. There is also an on-going Phase 2a study in AUD.
Prior Clinical Evidence
Phase 1 Study of BPL-003 in Healthy Volunteers
A two-part, phase 1, single ascending dose study was conducted to evaluate the safety, tolerability and PK profile of BPL-003 in healthy subjects. BPL-003 was safe and well-tolerated in the study, with a PK profile that was approximately dose linear. In this study assessments were made of PD endpoints that are thought to be predictive of efficacy outcomes in TRD subjects. Literature data indicate that the 30-item Mystical Experience Questionnaire (MEQ-30) data may be used as a surrogate marker of potential future psychiatric efficacy, and so was the key PD outcome measure conducted. A score of =3 was defined to be the threshold to elicit a significant experience. A score of =3 in all four subdomains of the MEQ-30 was defined as a complete Mystical Experience. The mean subject MEQ-30 scores generally increased with BPL-003 dose, with levels =3 being observed at doses of 6 mg and above in at least one sub-domain or total MEQ-30 score. The highest MEQ-30 scores were attained with 12 mg BPL-003, and three of five subjects (60%) achieved a complete Mystical Experience at 10 mg and 12 mg doses.
Recent Advancements: BPL-003 is being investigated in an on-going Phase 2a open-label study and an on-going Phase 2b double-blind, randomized, controlled study in people living with TRD. In addition, the company is also conducting an open-label Phase 2a study in patients with AUD.
In March 2024, the company announced initial results from Part 1 of the on-going Phase 2a open-label study in patients with moderate to severe TRD. The Phase 2a study investigated the safety, tolerability and efficacy of a single 10mg dose of BPL-003 alongside psychological support in patients who were not taking concomitant antidepressants. 12 subjects were dosed, and 11 met the criteria for per-protocol analysis. Patients were followed for 12 weeks post-dosing, with assessments conducted at multiple points throughout the study. Efficacy was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS). Initial analysis showed that a single dose of BPL-003 induced a rapid antidepressant response (=50% reduction in MADRS score) in 55% of patients on the day after dosing. The antidepressant effect was durable, with the 55% response rate maintained at weeks 4and 12. There were 55% of patients in remission (MADRS score =10) at week 4 and 45% in remission at week 12.
BPL-003 demonstrated a promising safety profile and was well tolerated. Adverse events (AEs) were predominantly mild or moderate and the most common (>10%) AEs were nasal discomfort, headaches, nausea and vomiting, broadly consistent with Phase 1 findings. No serious AEs were reported. The acute effects of BPL-003 resolved on average in less than two hours. These data suggest that BPL-003 could offer a shorter treatment time when compared to other psychedelic treatments in development.
A Part 2 extension of this Phase 2a open-label study is now enrolling patients with TRD who are on stable doses of oral antidepressants to assess the safety and efficacy of BPL-003 co-administration.
A randomized, quadruple-masked, controlled Phase 2b study of BPL-003 is underway. The study is investigating the effects from a single 12mg or 8mg dose of BPL-003 against a sub-perceptual dose of 0.3mg in 225 patients with TRD. Efficacy will be assessed by masked raters using the MADRS scale at several time points with the primary endpoint at week 4 and final assessment at week 8. Top-line results are expected in H2 2024.
Lastly, BPL-003 is also being investigated in the open-label Phase 2a study in AUD, with initial data expected mid-2024.
VLS-01 (N,N-Dimethyltryptamine; (‘DMT’) for TRD
Product Candidate Concept: VLS-01 is an oral transmucosal film (‘OTF’) formulation of DMT. Pharmacologically, DMT is a partial agonist of the 5-HT-1A/2A/2C receptors, developed to induce a short duration of psychedelic effect of approximately 30 to 45 minutes, with a serum half-life estimated at less than 10 minutes. Intravenous (‘IV’) DMT administration results in rapid-acting antidepressant effects in patients with major depressive disorder. VLS-01’s OTF may eliminate the need for IV infusion.
Prior Evidence – Non-Clinical and Clinical Data
VLS-01 Non-Clinical
Neural plasticity is considered to be a critical mechanism by which serotonergic psychedelics exert antidepressant effects. DMT acts as a partial agonist of the 5-HT 1A/2A/2C receptors, primarily in cortical neurons and the limbic system, where it is believed to increase neuroplasticity and decrease functional connectivity. In vitro and in vivo assays for neuritogenesis and synaptogenesis in the prefrontal cortex of adult rats demonstrated DMT’s potential to significantly increase dendritic arbor complexity along with functionality (assessed by ex-vivo slice recordings of excitatory postsynaptic currents (‘EPSCs’), suggesting the potential to restore prefrontal cortex deficits observed in the pathophysiology of depression.
In a series of behavioral experiments conducted in male rats, a single intraperitoneal injection of 10 mg/kg DMT, a hallucinogenic dose based on rodent drug discrimination data, demonstrated an antidepressant-like effect in the forced swim test, as indicated by a significant reduction in immobility and increase in swimming.
DMT has limited oral bioavailability, and current clinical studies conducted by third parties typically involve either IV or inhaled routes of administration. Given the challenges—both commercial and safety—with these routes, the company is developing VLS-01 as an OTF formulation, which is expected to provide a more convenient and acceptable route of administration. The company’s improved proprietary formulation has demonstrated good mucosal penetration of DMT when tested in vitro in a standard model involving pig mucosal tissue.
Phase 2a Study of IV DMT fumarate in Major Depressive Disorder
The third-party Phase 2a study investigated the safety and efficacy of DMT fumarate with supportive therapy compared to placebo with supportive therapy, in 34 patients with moderate/severe MDD. Patients were administered a short IV infusion of 21.5mg of DMT fumarate, resulting in a 20 to 30-minute psychedelic experience. The study met the primary and key secondary endpoints, demonstrating a placebo-adjusted reduction of -10.8 (p=0.002) and -7.4 (p=0.02) in MADRS scores at one- and two-weeks post-dose, respectively. DMT fumarate was well tolerated with no drug-related serious adverse events reported, including no reports of suicidal ideation or behavior. There were no clinically significant safety concerns in any treatment group, including with vital signs, electrocardiogram (‘ECG’) or clinical laboratory findings.
This study provides strong proof of concept data for DMT as a potential treatment for depression and supports the development of the OTF formulation of DMT, VLS-01, which may simplify in-clinic administration relative to an IV formulation.
Recent Advancements: In March 2024, the company dosed the first participant in the Phase 1b study of VLS-01. The study is expected to explore doses up to 240 mg with an optimized OTF that incorporates taste masking, an intrinsic backing layer, and enhancements designed to increase permeability with goals of further improving the participant experience and PK. Top-line results are expected in the second half of 2024.
ELE-101 (via Strategic Investment in Beckley Psytech)
Product Candidate Concept: ELE-101 is the benzoate-salt form of psilocin, the active metabolite of psilocybin, which is being evaluated as an IV formulation. ELE-101 is a serotonergic psychedelic, and as such, primarily acts as a partial agonist of the 5-HT2A receptor. Psilocin plasma concentrations are highly correlated with serotonin 5-HT2A receptor occupancy and corresponding psychedelic effect. Studies using oral psilocybin have shown its therapeutic utility and have begun exploring its mechanism of action. However, they also highlighted that the conventional oral formulation has its limitations; PK variability, prolonged duration of treatment effect and difficulty in optimizing or halting the treatment. IV delivery of psilocin enables consistent drug concentrations to be achieved rapidly and in a controlled manner.
Prior Evidence
Recent Advancements: ELE-101 is being studied in a two-part Phase 1/2a study. The Phase 1 portion (Part 1) of the study is a randomized, double-blind, placebo-controlled study to assess safety, tolerability, PK and PD of single ascending IV doses of ELE-101 in healthy volunteers. The Phase 2 portion of the study will evaluate a range of PD effects of a single IV dose of ELE-101 in patients with MDD. Initial results from the Phase 1/2a study are anticipated in the first half of 2024.
IBX-210: (ibogaine) for Opioid Use Disorder (‘OUD’)
Product Candidate Concept: IBX-210is an intravenous formulation of ibogaine, a naturally occurring oneirogenic and psychedelic compound isolated from a West African shrub with cholinergic, glutamatergic and monoaminergic receptor modulatory activity which the company is developing for the treatment of OUD. The company was previously developing DMX-1002, an oral formulation of ibogaine.
The company is initially focused on OUD, a form of SUD characterized by uncontrolled and persistent self-administration of opioids, resulting in significant impairment, distress, and mortality.
Prior Clinical Evidence
2018 Publication of Investigator Initiated Case Studies of an Oral Ibogaine Formulation (Mash et. al.)
A single dose of another formulation of ibogaine has been shown in several case series to be an effective treatment for acute opioid withdrawal, from both the physiological and psychological perspectives. A 2018 publication authored by the founder of DemeRx IB describes the results of clinical use of ibogaine to treat SUD in over 180 patients. In this clinical study, treatment of 75 opioid-dependent and 81 cocaine-dependent patients with single doses of 8 mg/kg to 12 mg/kg ibogaine led to significant and durable reductions in ratings of craving at discharge on day 12 and at one-month post-treatment. In addition, both opioid- and cocaine-dependent patients reported improved mood from as early as five days after dosing up to at least one-month follow-up.
Ibogaine was generally well tolerated when administered in a highly controlled clinical setting. All patients experienced a hallucinatory, dream-like state which typically resolved between six and 12 hours after dosing, though subjective effects were observed up to 24 hours after dosing in some subjects. There were no serious adverse events or deaths that occurred from administration of ibogaine to drug dependent patients in the dose range used in this trial.
Opioid-dependent patients reported significant decreases in drug craving as measured by all Heroin Craving Questionnaire-29 subscales at discharge and at one-month follow-up. Similarly, assessments of mood (The Beck Depression Inventory (‘BDI’), The Profile of Mood States, or POMS, depression subscale, Symptom Checklist-90 depression subscale) revealed significant reductions in depression, as well as improvement in mood scores from baseline to post-dose and at one-month follow-up (p<0.01 for all).
2014 Publication of a Double Blind, Placebo Controlled Study of Ibogaine in Cocaine Use Disorder (Prior et. al.)
A double blind, placebo controlled study was conducted with 20 patients (N=20), split in 2 groups: the ibogaine group received a single dose of 1800 mg of encapsulated ibogaine extract and the placebo group received a single capsule of sugar powder. All patients were followed for a 24-week period, with biweekly visits to a psychiatric professional, in which a urine sample was collected in order to detect cocaine use. Data analyzes was performed using ANOVA for repeated measures for comparison of data between groups and between members of the same group. Urine samples were compared (positive results) using measure ANOVA statistical tests with the Least Squares Difference for post hoc two group comparisons. Statistical significance was 5% (P< 0.05) for all the referred tests.
Phase 1 Study of DMX-1002 (Ibogaine) in Opioid Use Disorder
A phase 1/2a study was initiated to assess safety, tolerability, PK, and potential for clinical activity in health volunteers and patients with OUD. In August 2023, the company announced the results from the Phase 1 portion of the study. The single-blinded Phase 1 study assessed the safety, tolerability and PK of single-ascending doses of DMX-1002 in healthy volunteers. Oral doses of 3 mg/kg, 6 mg/kg & 9 mg/kg were evaluated in 20 participants. Results of the Phase 1 trial demonstrated that oral doses of DMX-1002 at 9 mg/kg achieved plasma concentrations in line with those described in previous studies1,2 in which subjects reported psychedelic experiences and obtained therapeutic benefit in OUD. However, a marked interpatient variability in the PK of both ibogaine and its major metabolite, noribogaine, were noted.
The treatment-related adverse events (‘AEs’) were similar to those observed in prior trials of DMX-1002, and nearly all (>94%) were rated mild-to-moderate in severity. There were no serious adverse events reported. QT prolongation was observed at all three doses tested, and on one of the two participants who received 9 mg/kg of DMX-1002, QT prolongation reached levels near those seen at the 10 mg/kg dose in the published literature3 (median change: 95ms). In this participant, a QTcF prolongation of 90-94ms was observed with a QTcF interval of 493-501ms. The patient was asymptomatic, with no cardiac arrythmias, and the QTc change resolved without intervention or sequalae.
Recent Advancements: Based on the analysis of the Phase 1 results, atai is exploring IBX-210, a novel IV formulation of ibogaine, that is designed to improve safety, reduce PK variability and lead to a shorter and more predictable time in-clinic that is anticipated to improve scalability and patient access relative to oral ibogaine (DMX-1002). The company plans to engage regulatory authorities to assess progressing IBX-210 into an efficacy study in patients with OUD.
EMP-01: R-3,4-methylenedioxy-methamphetamine (‘R-MDMA’)
Product Candidate Concept: EMP-01 is an oral formulation of an R-MDMA.
Recent Advancements: In January 2024, the company announced positive top-line results from the Phase 1 study. EMP-01 was well-tolerated, and treatment-related adverse events (AEs) were all expected and generally dose dependent. There were no study discontinuations, and no serious or severe AEs were observed in the study. The PK profile of EMP-01 was dose-proportional. PD measures included both subjective reports and blood-based biomarkers. Significant, consistent, and dose-dependent changes were seen on several of these exploratory PD measures. EMP-01 administration resulted in a differentiated subjective experience compared to racemic MDMA on standard psychedelic experience questionnaires. Further, dose dependent changes on measures of emotional breakthrough, a phenomenon thought to be a key mediator of the long-term psychological changes associated with psychedelics, were noted in this healthy volunteer population.EMP-01 was well-tolerated in all cohorts. The company is evaluating next steps for the development of EMP-01.
EGX-A and EGX-B: Novel 5-HT2A Receptor Agonists
Product Candidate Concept: EGX-A and EGX-B are lead candidates from atai’s internal drug discovery engine, which were discovered using an artificial intelligence/machine learning-driven approach. They are psychedelic-like with novel, non-tryptamine structures with differentiated 5-HT receptor pharmacology compared to traditional psychedelics.
Recent Advancements: As part of atai’s drug discovery effort, novel 5-HT2A receptor agonists were discovered that are non-hallucinogenic based on animal studies. The molecules are being further optimized and studied in animal models to assess therapeutic potential.
Non-Psychedelic Programs
RL-007
Product Concept: RL-007 is an orally bioavailable compound that has demonstrated pro-cognitive effects in multiple pre-clinical and clinical studies, including two Phase 1 and two Phase 2 trials. Although the precise molecular target and mechanism of action for RL-007 has not yet been fully elucidated, RL-007 has been demonstrated to modulate the cholinergic, glutamatergic and GABA neurotransmitter systems. Overall, RL-007 putatively alters the excitatory/inhibitory balance in the brain. The compound has been assessed in ten completed Phase 1 and Phase 2 clinical trials. As of December 31, 2023, over 500 participants have been dosed with no evidence of safety issues. The company is initially developing this compound for the treatment of CIAS.
Prior Evidence - Non-Clinical & Clinical Data
Non-Clinical
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.
Studies with co-delivered antagonists suggest that RL-007 modulates both inhibitory and excitatory neuronal signaling through the gamma-aminobutyric acid B (GABAB) and nicotinic a4ß2 receptor complexes.
In contrast to other compounds that are agonists of GABAB receptors, RL-007 does not appear to induce the classic GABA side effects such as sedation (in animal models), suggesting the involvement of additional pharmacological mechanisms.
Studies in several species have demonstrated that RL-007 can reverse the effects of scopolamine, a muscarinic antagonist that induces temporary cognitive impairment, and can also improve performance in complex memory tasks in aged animals, bringing their performance to a comparable level as young animals. For example, in an in vivo model in normal and scopolamine challenged dogs, RL-007 demonstrated enhanced effects on cognition. In the figure below, investigators observed enhanced learning and memory with an inverted U-shaped dose response.
Phase 1 Scopolamine Challenge
A Phase 1 study enrolled 23 healthy volunteers to evaluate the effect of RL-007 on the scopolamine cognition model in healthy volunteers. RL-007 was administered ter in die, or three times a day (‘TID’) for one day and then co-administration with scopolamine on Day 2 to induce a temporary cognitive impairment. RL-007 was well tolerated. A statistically and clinically significant reversal of the scopolamine-induced cognitive impairment was observed with the 30 mg TID dose. Additionally, marked changes in quantitative encephalogram (‘qEEG’) were found at all doses tested. Notably, and consistent with non-clinical evidence, the dose response was inverted U-shaped, with the most significant changes observed at the 30mg dose-level.
Phase 2 Study in Diabetic Peripheral Neuropathic Pain (‘DPNP’)
A Phase 2 study that enrolled 181 patients with DPNP in a double-blind, randomized, placebo-controlled study to evaluate the efficacy of RL-007 to address neuropathic pain in subjects with diabetes. While unsuccessful in demonstrating a clinically meaningful effect on pain scores with RL-007, as part of this trial, cognitive function was assessed using a standard computerized cognitive test battery, Cogstate, which assessed cognitive abilities such as attention, concentration, verbal learning and memory, working memory and global cognitive functioning. In addition, investigators observed subjects in the lowest dose cohort (40/80 mg) exhibited an improvement in verbal learning (Cohen’s d = 0.31) and memory (Cohen’s d = 0.36), underscoring the effects on cognition and inverted-U dose response observed in prior clinical and non-clinical studies.
Phase 2a Study in CIAS
Recognify initiated a Phase 2a proof-of-mechanism study in the United States for RL-007 in 32 CIAS patients. The study was designed to evaluate the safety and tolerability of RL-007, as well as effects on clinical activity endpoints, including a subset of the MATRICS Consensus Cognitive Battery (‘MCCB’) to assess cognition. In December 2021, the company announced positive clinical data from the Phase 2a study of RL-007 in CIAS patients. RL-007 was well tolerated and demonstrated a clinically meaningful pro-cognitive profile consistent with previous Phase 1 and Phase 2 trials of this compound.
The company shows the results on a subset of the MATRICS Consensus Cognitive Battery (MCCB) demonstrating an inverted-U dose response on the key cognitive endpoints of HVLT, symbol coding and category fluency. On symbol coding at the 20mg dose, a Cohen’s d of 0.79 was observed. The MCCB is recognized by the FDA as an approvable endpoint for measuring cognitive function in CIAS.
The totality of the results observed in this Phase 2a study supported the progression of RL-007 in clinical development to further demonstrate the pro-cognitive benefit of RL-007 in CIAS.
Recent Advancements: In the first quarter of 2023, the company 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 of RL-007 compared to placebo in approximately 230 patients The primary endpoint of the study is the MCCB neurocognintive composite score at 6 weeks. The company anticipates reporting top-line results from this study by mid-2025.
GRX-917 (deuterated Etifoxine)
Product Candidate Concept: GRX-917 is a novel compound that potentiates neurosteroidogenesis, that is being developed as a treatment for Generalized Anxiety Disorder (‘GAD’).
GRX-917 is a deuterated form of etifoxine (Stresam), an anxiolytic drug approved in France and other countries. Etifoxine has demonstrated rapidity of onset and magnitude of efficacy comparable to benzodiazepines in the treatment of anxiety-related disorders. Additionally, etifoxine’s safety profile has been reported to be superior to benzodiazepines, with less sedation, cognitive impairment, amnesia or ataxia, and minimal human abuse liability.
In contrast to benzodiazepines, etifoxine and GRX-917 appear to produce their anxiolytic effects by enhancing neurosteroidogenesis and thus increasing the concentration of endogenous brain neurosteroids, including allopregnanolone. Allopregnanolone is a potent positive allosteric modulator of the GABAA receptor which, in the presence of GABA, results in further attenuation of neuronal activity. GRX-917 does not activate the GABAA receptor at clinically efficacious concentrations.
The pharmacological profile of GRX-917 has been evaluated and compared to etifoxine in a series of pre-clinical studies, which have demonstrated that GRX-917 has similar efficacy and pharmacology to etifoxine. GRX-917 has been observed to have improved metabolic stability conferred by deuteration compared to etifoxine.
Prior Evidence – Non-Clinical & Clinical Data
Etifoxine & GRX-917 Non-Clinical
Etifoxine and GRX-917 have shown anxiolytic effects in the elevate plus maze (‘EPM’) mouse model. Finasteride, an inhibitor of neurosteroid biosynthesis, was able to fully inhibit the anxiolytic activity of GRX-917 and etifoxine in the EPM model, suggesting that both compounds work via modulation of neurosteroidogenic activity. In humans, the anxiolytic activity of etifoxine hydrochloride is not inhibited in the presence of the benzodiazepine antagonist flumazenil (Schlichter et al, 2000), supporting the notion that etifoxine’s anxiolytic effects are not driven by the direct activation of the benzodiazepine site of the GABAA receptor.
GRX-917’s half-life in human and rat liver microsomes is increased by 82% compared to etifoxine. In rats, this enhanced in-vitro metabolic stability translated in-vivo to a 1.7-fold increase in maximum concentration (i.e. Cmax) and a 2.5 fold increase in exposure (i.e. AUC) for the GRX-917 compared to etifoxine. Terminal half-life was also increased by 20%. The effect of deuterium substitution on enhancing microsome stability is identical (+82%) in rats and humans, pointing to a similar metabolic pathway. Therefore, GRX-917’s superior rat PK profile is expected to translate to humans.
Phase 1 Safety, Tolerability and PK Study of Etifoxine
In 2020, GABA Therapeutics completed a Phase 1 study of etifoxine to evaluate the safety, tolerability, PK and PD (via qEEG) of single (100 mg) and multiple doses (100 mg, twice a day (‘BID’) for seven days) of oral etifoxine in normal healthy volunteers. The results quantified the PK of etifoxine and served as a benchmark for the single and multiple ascending dose study GRX-917.
Phase 1 Single and Multiple Ascending Dose Study
In June 2021, GABA initiated a Phase 1 single and multiple ascending dose trial of GRX-917. The Phase 1 trial was a randomized, double-blind, placebo-controlled study of the safety, tolerability and PK of single and multiple-ascending doses of GRX-917 up to 500mg as single doses and 300mg given every twelve hours for seven days, respectively.
In January 2023, Phase 1 results were announced from the study of GRX-917 in healthy volunteers. GRX-917 was well-tolerated, in all dose cohorts with no dose-limiting toxicities and sedation compared to placebo.
Additionally, the data confirmed an improved PK profile including longer half-life and increased bioavailability compared to etifoxine. Quantitative electroencephalography (‘qEEG’) data showed dose-dependent increases in frontal beta power, providing evidence of target engagement. These qEEG data from the Phase 1 study were detailed in April 2023 in a poster at the Society for Biological Psychiatry (‘SOBP’) Annual Meeting.
Regulatory Authorities Pharmacovigilance assessments of Etifoxine
An analysis of the safety profile of etifoxine (2000-2012) was completed by the French National Agency for the Safety of Medicines and Health Products (‘ANSM’) France showed that the profile of Adverse Drug Reaction (ADR) is globally similar to that expected and there were no new safety data regarding the risks identified in the spontaneous reporting data. In over 14 million prescriptions of Stresam between 2000 and 2012, there was a low ADR rate of ~ 21 per million treatments. There were only sporadic reports of ADRs relating to abuse, misuse or dependence. Data from this pharmacovigilance study were reviewed by the ANSM and this resulted in a confirmation of the favorable risk-benefit assessment subject to the conduct of additional studies. As risk mitigation measures, revisions were made to the label information and a letter was sent to healthcare professionals in 2014.
Further to the ANSM’s study, in 2021 the ANSM initiated a referral towards the European Medicines Agency (‘EMA’) leading to a review of Stresam’s (etifoxine) benefit-risk based on additional available data including the results of a new study. The review was carried out by the EMA’s Committee for Medicinal Products for Human Use (‘CHMP’) which concluded that Stresam can continue to be used for the treatment of anxiety disorders, but it must not be used in patients who previously had severe skin reactions or severe liver problems after taking etifoxine.
Third-Party Non-Inferiority Study of Etifoxine vs. Lorazepam
A third-party conducted a study to compare the efficacies of etifoxine (50mg TID) and lorazepam (.5 – 1mg BID) monotherapies in the treatment of adjustment disorder with anxiety over a period of 28 days. The study demonstrated that etifoxine works as rapidly as lorazepam, with etifoxine continuing its effects beyond the treatment period, while lorazepam shows rebound post-treatment.
Recent Advancements: Following Phase 1 results announced in January 2023, the company is actively looking for partnership and external funding opportunities for this program. The goal is to proceed GRX-917 into a Phase 2 study in patients living with anxiety disorder.
Other Clinical Program
Perception Neuroscience: PCN-101 (R-Ketamine) for TRD
Product Candidate Concept: PCN-101, a subcutaneous formulation of R-ketamine, as a therapy for psychiatric indications, initially focused on TRD. PCN-101 is being evaluated as a rapid-acting antidepressant therapy with potential benefits over S-ketamine, including a non-dissociative profile that has the potential to allow for at-home-use.
Prior Clinical Evidence: In a third-party, open-label clinical trial, another formulation of R-ketamine was observed to produce a rapid and durable response with limited dissociative side effects in a small number of patients with TRD.
In January 2023, results from the Phase 2a proof-of-concept study were announced. The objective of this study was to assess the efficacy of PCN-101 for the two doses, 30 mg and 60 mg, which were sub-dissociative and non-sedating based upon Phase 1 results. To achieve a sufficiently differentiated and commercially viable treatment in TRD in line with the company’s internal target product profile, the company set the following targets for the single dose Phase 2a study. On efficacy, the company targeted a placebo adjusted change from baseline of 5 or more points on the MADRS at 24 hours, the primary endpoint. On safety/tolerability, the company targeted sedation and dissociation comparable to placebo, operationalized as a risk ratio of less than 2. The observed mean change from baseline on the MADRS at 24 hours was -15.3 for PCN-101 60 mg and -13.7 for placebo (placebo adjusted change of -1.6; p-value 0.5). The magnitude of both the placebo effect and the drug effect were comparable to that seen in several other acute antidepressant trials incorporating inpatient overnight stays. The efficacy of the 60 mg dose was greater when considering only U.S. sites at the 24-hour time point, though the placebo effect was similar to that observed in the full sample set (-19.2 MADRS mean change from baseline on 60mg PCN-101 vs. -14.4 on placebo; p-value 0.32). However, it should be noted that the number of patients in the U.S.-only subset was small (9 on PCN-101 and 8 on placebo). The single 60 mg dose of PCN-101 showed an efficacy signal at each timepoint over the 2-week timeframe of the study, potentially indicating a sustained duration of effect. The results did reach statistical significance (p-value 0.04) at the 15-day endpoint in the U.S.-only subset in an exploratory analysis. PCN-101 was generally well-tolerated with rates of sedation and dissociation comparable to placebo.
Recent Advancements
In August 2023, the company reported results from the Phase 1 open-label bridging study designed to assess the safety, tolerability, and PK profile of 60mg, 90mg and 120mg of PCN-101 delivered subcutaneously (‘SQ’) as compared to 60mg of PCN-101 delivered via IV.
PK analysis indicated that 120mg of PCN-101 delivered SQ resulted in an approximate doubling of drug exposure (‘AUC’) while maintaining approximately the same maximum concentration (‘Cmax’) as the 60mg IV dose.
At the highest SQ dose of 120mg, rates of sedation (defined as MOAA/S score <5) and dissociation (defined as CADSS total score >4 and change from baseline >0) were each 14%. Overall, the data supports testing the concept of at-home use of PCN-101 in future studies.
The company continues to work collaboratively with Perception Neuroscience to explore strategic partnership opportunities.
Intellectual Property
As of December 31, 2023, the company’s intellectual property portfolio included 33 issued U.S. patents, 223 issued non-U.S. patents, 45 pending U.S. patent applications, 111 pending non-U.S. patent applications, 20 pending U.S. provisional applications, and 28 PCT applications.
A description of the company’s patents as of December 31, 2023, follows below:
BPL-003
Beckley Psytech owns two issued U.S. patents, three foreign issued patents in Europe, two issued patents in the United Kingdom, two U.S. pending patent applications, nine foreign pending patent applications in Australia, Brazil, Canada, China, Europe, Israel, Japan, South Korea and New Zealand, two PCT patent applications and numerous pending United Kingdom priority patent applications covering benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT benzoate), methods of synthesis, methods of use, crystalline forms and formulations thereof. Atai Therapeutics, Inc. has a strategic investment in Beckley Psytech to accelerate the clinical development of short-duration psychedelics.
VLS-01
ATAI Therapeutics, Inc. owns one issued U.S. patent, three U.S. pending patent applications and two PCT patent application, two U.S. provisional patent applications and twenty nine foreign pending patent applications in Argentina, Taiwan, Australia, Brazil, Canada, Chile, China, EP, Israel, India, Japan, South Korea, Mexico, New Zealand, Russia, and UAE, covering (i) DMT compositions exhibiting unique PK profiles following transmucosal administration (ii) new DMT salts and polymorphic forms, including DMT succinate (VLS-01), (iii) DMT parenteral formulations, and (iv) oral transmucosal films of DMT. Any patents issuing from these pending patent applications, if granted, are expected to expire between 2042 and 2044, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. ATAI Therapeutics Inc. owns one issued U.S. patent, eight U.S. pending patent applications, five PCT patent applications, one U.S. provisional patent applications and seventeen pending foreign applications in Australia, Brazil, Canada, Chile, China, EP, Israel, India, Japan, South Korea, Mexico, New Zealand, Russia, UAE, Argentina, and Taiwan, covering novel analogues, products and conjugates of dimethyltryptamine, methods and pharmaceutical compositions thereof. Any patents issuing from these pending patent applications, if granted, are expected to expire between 2042 and 2044, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.
ELE-101
Beckley Psytech owns two issued U.S. patents, two U.S. pending patent applications, one PCT patent application and nine foreign pending patent applications in Australia, Brazil, Canada, China, Europe, Israel, Japan, South Korea and New Zealand. Beckley Psytech also co-owns with Board of Supervisors of Louisiana State of University and Agricultural and Mechanical College one U.S. pending patent application and one foreign pending patent application in Europe covering methods of use of 4-hydroxy-N,N-dimethyltryptamine (psilocin) and 3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate (psilocybin). Atai Therapeutics, Inc. has a strategic investment in Beckley Psytech to accelerate the clinical development of short-duration psychedelics.
IBX-210
ATAI Therapeutics, Inc. owns five issued U.S. patents and six foreign issued patents in Europe, Australia, Canada and Hong Kong, six U.S. pending patent applications, and two foreign pending patent applications in Australia and South Africa covering methods of treatment using ibogaine (IBX-210). DemeRx IB’s issued patents and any patents issuing from the pending applications, if granted, are expected to expire in 2035, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. Atai Therapeutics, Inc. owns one pending U.S. patent application and one pending PCT patent application, covering methods of improving the therapeutic effectiveness and safety profile of ibogaine. Any patents issuing from these pending patent applications, if granted, are expected to expire in 2042, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.
EMP-01
EmpathBio Inc. owns one issued U.S. patent, eight U.S. pending patent applications, six PCT patent applications and two U.S. provisional patent applications, covering MDMA enantiomers and processes for the preparation of MDMA, its enantiomers and derivatives thereof. Any patents issuing from these pending patent applications, if granted, are expected to expire between 2042 and 2044, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. ATAI Therapeutics Inc. owns one U.S. pending patent application, one PCT patent application, and one provisional application covering salts of R-MDMA and polymorphic forms and compositions comprising R-MDMA and methods of treating with the same. Any patents issuing from this pending patent application, if granted, are expected to expire between 2043 and 2044, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. ATAI Therapeutics Inc. owns one U.S. pending patent applications, one PCT patent applications and four U.S. provisional patent applications, covering uses of MDMA for treating stress related disorders, increasing exposure of R-MDA, and modulating aggression responses. Any patents issuing from these pending patent applications, if granted, are expected to expire between 2043 and 2044, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.
EGX-A & EGX-B
Atai Therapeutics, Inc. owns one issued U.S. patent, two U.S. pending patent applications, four PCT patent applications, fourteen foreign pending patent applications in Australia, Brazil, Canada, Chile, China, Europe, Israel, India, Japan, South Korea, Mexico, New Zealand, Russia and UAE and four U.S. provisional patent applications covering novel 5-HT2A agonists. Atai Therapeutics, Inc, owns two U.S. pending patent applications, one PCT patent application and one U.S. provisional patent application covering non-hallucinogenic 5-HT2A agonists. Atai Therapeutics, Inc. owns two U.S. provisional patent applications covering EGX-A/EGX-B development related filings. Any patents issuing from these pending patent applications, if granted, are expected to expire between 2041 and 2044, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.
RL-007
Recognify in-licenses twelve issued U.S. patents and 36 foreign issued patents in Europe, Australia, Brazil, Canada, China, Hong Kong, Israel, South Africa, India, Japan, Republic of Korea, Mexico, New Zealand and Russia, covering RL-007, including the pharmaceutical composition of and methods of using RL-007. The patents licensed to Recognify are expected to expire between 2026 and 2034, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.
GRX-917
GABA Therapeutics owns four issued U.S. patents, two U.S. pending patent applications, eleven issued foreign patents in Australia, Brazil, Canada, China, Europe, Mexico, Israel, Japan, Republic of Korea and Mexico and one foreign pending patent application in Israel and one PCT application, covering the pharmaceutical composition and corresponding methods of use of the deuterated analogs of etifoxine (GRX-917). GABA Therapeutics’ issued patents and any patents issuing from the pending patent applications, if granted, are expected to expire between 2036 and 2044, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.
PCN-101
Perception Neuroscience in-licenses three issued U.S. patents, three foreign issued patents in Japan and two foreign issued patents in Europe and Canada, four U.S. pending patent applications and fifteen foreign pending patent applications in Brazil, Canada, China, Europe, Hong Kong, and Japan covering the composition of and methods of using R-ketamine (PCN-101) for the treatment of depressive symptoms in mental disorders, neurological disorders and substance abuse. Perception Neuroscience also in-licenses one U.S. pending patent application and one foreign issued patent in Australia and seven foreign pending patent applications in Brazil, Canada, China, Europe, Hong Kong, Israel and Japan covering the composition of matter of S-Norketamine for the treatment of depressive symptoms. Perception Neuroscience also owns one issued U.S. patent, one U.S. pending patent application, one foreign issued patent in Mexico, and seven foreign pending patent applications in Australia, Canada, China, Europe, Hong Kong, Japan and Mexico covering the method of using R-ketamine (PCN-101) for the treatment of depressive symptoms in mental disorders and substance abuse, as well as two pending PCT application directed to R-Ketamine salts and pharmaceutical compositions and one PCT application directed to methods of administering R-Ketamine. Perception Neuroscience’s owned and in-licensed issued patents and any patents issuing from the owned or in-licensed pending patent applications, if granted, are expected to expire between 2034 and 2043, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.
Government Regulation and Product Approval
The FDA, the U.S. Department of Health and Human Services Office of Inspector General, Centers for Medicare and Medicaid Services, or CMS, DEA, and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs such as those the company is developing.
Research and Development
The company’s research and development expenses were $62.2 million for the year ended December 31, 2023.
History
Atai Life Sciences N.V., formerly known as Adripa Holding B.V., was founded in 2018. The company was incorporated pursuant to the laws of the Netherlands in 2020.
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