Lykos’ MDMA NDA Leads Upcoming Tests Of US FDA’s Psychedelics Draft Guidance

The US FDA will face some crucial tests for its nascent approach to regulation of psychedelic drug candidates in the coming year, headlined by an 11 August 2024 user fee goal for the first psychedelic-assisted therapy NDA for post-traumatic stress disorder: Lykos Therapeutics’ capsule formulation of MDMA, the active ingredient in the recreational drug commonly known as ecstasy or Molly.

Lykos – the newly adopted name of MAPS Public Benefit Corporation – is seeking priority review for its December 2023 NDA submission for midomafetamine capsules to treat of post-traumatic stress disorder in combination with psychological intervention, which includes psychotherapy and other supportive services from a “qualified healthcare provider.”

The NDA, which is being reviewed by the Center for Drug Evaluation and Research’s Division of Psychiatry, is the first psychedelic therapeutic submitted since the FDA put out a draft guidance in June 2023.

Reflecting the still-emerging contours of the space, the draft is titled “Psychedelic Drugs: Considerations for Clinical Investigations,” and notes that “there is limited experience as to the configuration of programs that may support approval of a psychedelic drug.” (A#PS148518])

The draft guidance “specifically outlines some of the foundational constructs that all sponsors, including academic sponsor-investigators, should consider when studying the therapeutic potential of psychedelic drugs,” CDER Division of Psychiatry director Tiffany Farchione told a recent Reagan-Udall Foundation meeting on psychedelic clinical study design.

Lykos’ forerunner, the Multidisciplinary Association for Psychedelic Studies (MAPS), is one of the most established institutions in the psychedelic drug development space. MAPS was founded in 1986, the year after MDMA was listed on Schedule I of the Controlled Substances Act, to support MDMA-assisted therapy research. MAPS received breakthrough therapy designation for midomafetamine from the FDA in 2017 and started Phase III in 2019.

In contrast to the lean decades for psychedelic development that MAPS pressed on through, the field is now growing at a dizzying pace. Farchione presented an internal FDA analysis of new psychedelic investigational new drug (IND) applications received just by the psychiatry division to illustrate the surge. (See chart below.)

Psychedelic drug programs have “become a sizable chunk of our overall workload,” the psychiatry division director declared. In addition, she noted, different groups in the FDA Office of New Drugs, like the Division of Anesthesia, Addiction Medicine and Pain Medicine, oversees other hot areas for psychedelic drug research.

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In another illustration of the relative youth of the psychedelic pipeline in clinical terms, very few product candidates are in pivotal trials. Phase II, on the other hand, is well populated.

After Lykos’ MDMA candidate, the next psychedelic to reach the NDA stage could be COMPASS Pathways’ COMP360, a synthetic formulation of the psychoactive ingredient in “magic mushrooms.” Two Phase III trials are underway for COMP360 plus psychological support for treatment-resistant depression.

Psychedelic Tomatoes

The FDA’s draft guidance uses the term “psychedelic” as “shorthand to include classic psychedelics, typically understood to be 5-HT2 agonists such as psilocybin and lysergic acid diethylamide (LSD), as well as entactogens or empathogens such as methylenedioxymethamphetamine (MDMA).”

The first psychedelic therapy approval is, however, generally considered to be Johnson & Johnson’s non-competitive NMDA antagonist Spravato (esketamine), the s-enantiomer of the anesthetic and dissociative hallucinogen ketamine.

Spravato nasal spray, self-administered under medical supervision, was approved for treatment-resistant depression in 2019 with an enhanced Risk Evaluation and Mitigation Strategy, and then added an indication for major depressive disorder with acute suicidal ideation and behavior in 2020. (Also see "Janssen’s Spravato Enters US Market With Enhanced REMS And Plans For A Monotherapy Trial" - Pink Sheet, 7 March, 2019.)

Like the tomato that is technically a fruit but behaves like a vegetable, Spravato’s review holds lessons for future psychedelic sponsors.

At the Reagan-Udall Foundation meeting, J&J Innovative Medicine VP Neuropsychiatry Clinical Development Carla Canuso praised the FDA’s “very clear and consistent feedback throughout the Spravato development program, given how little was known when it started.” The J&J program “was really based on a handful of single-dose studies with IV ketamine.”

“Collaborate early and often with regulators!” Canuso advised.

Spravato received a breakthrough therapy designations from the FDA in both the TRD and MDD with ASIB settings, which provided J&J with enhanced communication with the agency and high-level official involvement.

“Treatments with novel mechanisms of action and new dosing paradigms will require unique clinical development plans to inform labelling and clinical use,” she observed.

The need for medically supervised dosing of psychedelics with supportive psychotherapy is among the biggest challenges that the class poses to conventional drug development paradigms. “Consider how a treatment will be used in clinical practice and generate data to support this,” Canuso recommended.

Lykos MAPPs The Way

Lykos’ midomafetamine capsules are administered in combination with psychological intervention provided by a qualified healthcare provider, as defined by the draft guidance. The Phase III design starts with three 90-minute preparatory psychotherapy visits, followed by three treatment cycles spaced at least 21 days apart. Each treatment cycle includes a medication session with psychological intervention and three follow-up integration psychotherapy sessions.

“The dosing regimen incorporates split dose and dose escalation,” Lykos Chief Scientific Officer Berra Yazar-Klosinski said.

The company worked to standardize the psychotherapeutic component. “We’ve seen high levels of adherence to the treatment manual for MDMA-assisted therapy in both MDMA and placebo groups,” she reported.

The trials were able to use “standard endpoints for PTSD,” she observed. In both Phase III MAPP1 and MAPP2 trials, MDMA-assisted therapy demonstrated a significant reduction in PTSD severity.

No serious adverse events were reported in the MDMA group in the Phase III trials, while two patients in the placebo arm reported SAEs of suicide attempts or suicidal ideation (2.1%), Yazar-Klosinski reported.

Treatment-emergent AEs of at least moderate suicidal ideation were 13.1% for MDMA and 10.6% for placebo; cardiac palpitations were reported by 4% of MDMA and 2.1% of placebo patients. Suicidality and cardiac safety are common safety concerns for psychedelics.

Most AEs resolved within two days, the Lykos exec noted. “Generally, temporary dose-dependent increases in blood pressure and pulse were resolved by the end of the medication session without treatment.”

Compass Takes Psilocybin Into Phase III

Compass Pathways is putting together a “comprehensive package” to support an eventual NDA filing for its psilocybin candidate COMP360 in treatment-resistant depression, chief medical officer Guy Goodwin reported.

COMP360, which Goodwin described as a “synthetic high purity polymorphic crystalline formulation of psylocybine,” received a BTD for treatment-resistant depression in 2018.

The two ongoing Phase III trials in TRD make up “the largest randomized, controlled, double-blind psilocybin treatment clinical program ever conducted,” according to the company.

The Phase III COMP 006 trial, which kicked off in February 2023, is expected to enroll 568 patients. The international randomized parallel group, fixed repeat dose, double-blind controlled study will randomize patients to two administrations of COMP360 25mg, 10mg or 1mg. A three- to 10-week screening period precedes drug administration, followed by six weeks of follow-up.

The Phase III COMP 005 trial, which started in January 2023, is enrolling 255 patients randomized to 25mg COMP360 or placebo. The three-part trial starts with a six-week, single-dose, double-blind, placebo-controlled study, followed by a 20-week single-dose, double-blind re-treatment part and then a 26-week open-label treatment part.

Before the Phase III program, Compass Pathway’s Phase IIb study was the largest psilocybin trial to date at the time, with 233 patients enrolled. Each psilocybin therapy session lasted six to eight hours in the presence of two therapists. (Also see "COMPASS Psilocybin Depression Data Excite Despite Safety Issues" - Scrip, 10 November, 2021.)

At the end of Phase II, the company decided to “further standardize psychological support to ensure we are clearly measuring the drug effects and not the impact of differential behavior by therapists,” Goodwin told the Reagan-Udall meeting. “There are increasingly interesting emergent ways in which we can use AI to do that, and that’s something we are actively working on at the moment.”

The company published a retrospective study of an artificial intelligence model using natural language processing (NLP) to support COMP360 treatment in Psychopharmacology in August 2023. Compass created a machine learning algorithm to assess emotional sentiment in English-speaking patients from the Phase IIb trial in TRD, the company explained.

“The sentiment scores, as measured by valence (happiness to sadness) and arousal (intensity of emotion), were then used in the second stage of the machine algorithm to predict patient response as measured by the Montgomery-Asberg Depression Rating Scale (MADRS),” Compass said. The results “are exciting because they signal that we could potentially use AI technology to predict long-term patient response.”

Usona Up Next

The non-profit Usona Institute’s psilocybin candidate is the most recent BTD recipient among the psychedelics, having received the designation in 2019 for treatment of major depressive disorder.

Usona reported results from the 104-patient Phase II PSIL201 in August 2023, noting that at the time it was “largest Phase II randomized, double-blind placebo-controlled study of single-dose psilocybin to treat major depressive disorder.”

Based on the results, Usona is “diligently preparing to launch our next study,” the company said.

The Phase II compared a single 25mg dose of Usona’s psilocybin with an active control of niacin. The study used a Set and Setting (SaS) protocol “similar to the protocol that has been used in all modern studies of psilocybin,” the clinicialtrials.gov record for the PSIL201 study states. Patients met with facilitators in a preparatory session, and were then administered the drug in “an aesthetically pleasing room under the supervision of two facilitators.” Three post-dose integration sessions followed.

Cybin’s Deuterated Drug Strategy

Cybin Inc. is developing deuterated analogs of psychedelic drugs, leading with the deuterated psilocybin analog CYB003 for major depressive disorder.

The company is expecting a busy 2024 for the oral capsule drug. A placebo-controlled Phase I/IIa ascending oral dose study is complete, and in the first quarter of 2024 Cybin anticipates reporting long-term (three-month) efficacy data from a Phase II MDD trial. An end-of-Phase II meeting with the FDA to discuss pivotal development of CYB003 will follow.

The CYB003 Phase III program is expected to start in the second quarter of 2024.

Cybin has developed a psychological support model for all of its clinical trials, known as EMBARK. The model’s six-domain structure was designed to be a modular, transdiagnostic framework that can be adapted to address the full range of clinical indications that Cybin intends to study, according to the company.

Taming Anxiety With LSD And Ayahuasca

Cybin is also gearing up to start a Phase IIa study in generalized anxiety disorder in the first quarter of 2024 using CYB004, a deuterated dimethyltryptamine product. DMT is the psychoactive component of ayahuasca.

The CYB004 Phase IIa study will be randomized and double blind with an active control arm. The drug is delivered by IV.

In Phase I, CYB004 “demonstrated robust and rapid-onset psychedelic effects at lower doses compared to native DMT,” Cybin reported.

Working with the psychedelic effects of LSD, MindMed is developing the tartrate salt form of lysergide as MM-120 (lysergide D-tartrate) as a treatment for generalized anxiety disorder. The company says synthetic MM-120 offers “faster absorption, less variability and potentially shorter duration” of effect than the recreational drug.

“In 2024, we plan to continue working diligently and efficiently to advance our MM-120 program into Phase III,” MindMed stated on 8 January. The company expects to hold an End-of-Phase II meeting with the FDA in the first half of the year, and then to initiate Phase III in the second half of the year.

MindMed is planning for two Phase III trials with a 12-week randomized placebo-controlled primary efficacy study design. Open-label extensions will establish retreatment parameters.

Top-line results of a 198-patient Phase IIb dose optimization study announced in December 2023 showed statistically significant and clinically meaningful four-week results that “emphasize the critical role we believe the perceptual effects of MM-120 play in driving clinical outcomes,” the company said. Topline 12-week results are expected to be announced by the end of the first quarter.

No suicidal behavior or suicidality signals were seen in the Phase IIb trial.

MindMed does not anticipate changing the medication delivery protocol from Phase II to Phase III. Unlike many of the other late-stage psychedelic candidate sponsors, MindMed plans to demonstrate drug-only effects with no psychotherapeutic intervention.

MindMed exclusively licensed Catalent, Inc.’s Zydis orally disintegrating tablet technology for use with MM-120 in August 2023, noting that “ODT formulations have the potential to result in enhanced bioavailability and more rapid absorption, which could ultimately culminate in a shorter treatment session for MM-120.” Results of a pharmacokinetic bridging study of the MM-120 Zydis fast-dissolving ODT formulation are expected in the first quarter of 2024.

Taking On Major Depression

Seelos Therapeutics hopes to follow in Spravato’s footsteps with SLS-002 (intranasal racemic ketamine), although the drug fell short of its primary endpoint in a Phase II study in MDD patients with acute suicidal ideation and behavior (ASIB).

The company did not have funding to complete the planned Phase II study, but still found the data promising from the 147 patients who enrolled out of the planned 220 subjects. (Also see "Seelos Forges Ahead With SLS-002, Says Primary Endpoint Miss Due To Underpowered Trial" - Scrip, 20 September, 2023.)

At a recent end-of-Phase II meeting, the FDA agreed that “the primary endpoint in a Phase III trial could be the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Day 16, rather than the 24-hour timepoint that was selected in the Phase II SLS-002-201 study,” Seelos announced on 22 January. Change from baseline at 24 hours on a suicidality scale could be the key secondary endpoint, Seelos added.

“This agreement with the FDA gives Seelos further confidence for its Phase III development of SLS-002 as data in the Phase II study showed clinically significant treatment differences from placebo on both the Day 16 MADRS … and the 24-hour Sheehan- Suicidality Tracking Scale,” the company said.

Seelos’ intranasal racemic ketamine has also been selected by the Department of Defense for testing in its post-traumatic stress disorder (PTSD) master protocol.

The DoD’s adaptive platform trial started in late 2023 with already-marketed drugs – fluoxetine, vilazodone and Idorsia Pharmaceuticals Ltd’s Quviviq (daridorexant) – but will expand to novel drugs. The Phase II adaptive trial is expected to enroll 600 active-duty service members and veterans with PTSD.

Delix Therapeutics, Inc. is planning a Phase II study in MDD with its “third-generation psychoplastogen” DLX-001. (Also see "Delix Hits In Phase I And Plans To Prove Its Concept" - Scrip, 29 December, 2023.)

In Delix’s framework, ketamine and pilocybing are first-generation psychoplastogens, and chemically modified versions like Spravato and COMP360 are second-generation. Third-generation DLX-001 is non-hallucinogenic, non-dissociative and non-cardiotoxic, according to the company.

Combining Forces

The complexity of psychedelic administration protocols and the still-emerging regulatory framework for the drugs pose significant barriers for sponsors, and are only magnified by the limited resources of Seelos and the other emerging companies focused on psychedelics R&D.

Otsuka Pharmaceutical Co. Ltd. recently became one of the biggest companies in the space. After dipping its toe in psychedelic waters with a 2022 collaboration with Mindset Pharma, Inc., Otsuka jumped with both feet by acquiring MindSet in October 2023. (Also see "Otsuka Adds To CNS Pipeline With Mindset Acquisition" - Scrip, 1 September, 2023.)

Mindset’s lead candidate is a novel prodrug of psilocin, the active metabolite of psilocybin. MSP-1014 is in Phase II for MDD in the UK, testing three escalating doses of the drug in conjunction with Acceptance and Commitment Therapy (ACT).

The psilocin prodrug is in IND-enabling studies for end-of-life angst and treatment-resistant depression.

atai Life Sciences BV, which has one of the larger early-stage psychedelic pipelines in the industry, announced a strategic investment in private biotech Beckley Psytech Limited on 5 January 2024 in order to “accelerate” development of two Beckley short-duration psychedelic candidates, an intranasal benzoate derivative of DMT known as BPL-003 (mebufotenin or 5-MeO-DMT) and ELE-101, an IV formulation of psilocin, the active metabolite of psilocybin.

BPL-003 is the most advanced candidate from atai and Beckley, with a global Phase IIb trial in treatment-resistant depression that is expected to produce topline data in the second half of 2024. The Phase IIb study is testing the effects of medium and high doses of BPL-003 against an active placebo comparator in 225 patients with moderate-to-severe TRD.

In Phase I, BPL-003 produced a rapid onset of psychedelic effects (“within minutes,” the company said) with the resolution of all perceptual effects coming within 60-90 minutes.

Two small Phase IIa open-label studies of BPL-003 in TRD and alcohol use disorder are underway as well, with TRD data expected in the first half of 2024 and AUD data at mid-year.

Beckley Psytech’s ELE-101 is being studied in a Phase I/IIa for major depressive disorder, with initial results expected in the first half of the year. ELE-101, which Beckley Psytech gained with its 2022 acquisition of Eleusis Therapeutics Limited, has a “more consistent, controllable, and shorter treatment paradigm of less than two hours” when compared with psilocybin, the company said.

One of atai’s leading psychedelic candidates, PCN 101 (R-ketamine), failed a Phase IIa trial for treatment-resistant depression a year ago. In August, however, atai and its subsidiary Perception Neuroscience reported that a subsequent Phase I IV-to-subcutaneous bridging study supported “the concept of at-home use of PCN-101” as a rapid-acting antidepressant. The Phase I study suggested the potential for the single-isomer ketamine to produce lower rates of sedation and dissociation than Spravato.

atai also has psychedelic candidates at the Phase I stage. Oral EMP-01 (R-MDMA), designed to be better tolerated than racemic MDMA, is being studied for PTSD, with positive topline results of a single-ascending dose Phase I study results released 2 January. VLS-01, an oral transmucosal formulation of DMT “developed to induce a short duration of psychedelic effect of approximately 30 to 45 minutes,” is expected to begin enrollment in a Phase Ib study in the first half of 2024.

“In preparation of initiating a Phase II trial in TRD, we plan to further optimize VLS-01 by incorporating taste masking, an intrinsic backing layer, and enhancements to increase permeability,” atai said.

The company will discuss a proof-of-concept study of its oral formulation of ibogaine, DMX-1002, in opioid use disorder with regulatory authorities after reporting Phase I results last year.

Awakn Life Sciences Corp. signed a licensing agreement in December with Lohmann & Rauscher International GmbH & Co. KG for a sublingual oral thin film (OTF) formulation of S-ketamine, dubbed AWKN-002. LTS had successfully completed Phase I for the formulation, designed for “faster onset of action, more precise dosing, and reduced potential for adverse effects compared to conventional delivery.”

Awakn will develop AWKN-002 plus manualized relapse prevention cognitive behavioral therapy for AUD for the US market, with a pre-IND meeting with the FDA planned for the first half of 2024. Awakn’s earlier IV racemic ketamine program, AWKN-001, will be focused only on the UK market going forward.

Psychedelics Beyond Psychiatry

While most psychedelic drug development companies are focused on mental health, the category has drawn broader interest.

Tryp Therapeutics, for example, started a Phase IIa study in January in irritable bowel syndrome patients using its synthetic oral psilocybin candidate TRP-8802 in combination with psychotherapy. “The primary efficacy endpoint of the study will be improvement in abdominal pain which will be measured at four weeks post the final therapist-monitored psychedelic drug session, along with numerous other secondary endpoints including changes in brain connectivity,” Tryp said.

TRP-8803 is also being studied in a Phase IIa trial for binge eating disorder, and Phase IIa trials are planned to treat fibromyalgia and IBS-related abdominal pain.