DMX-1002: Ibogaine as a potential treatment for OUD

With my weekly blog series, I will do a deep dive into each of our clinical compounds and illustrate why we are excited about their potential in mental health indications. You can read earlier blogs here: RL-007, GRX-917, VLS-01, and EMP-01.

Opioid Use Disorder (OUD) is a form of Substance Use Disorder (SUD) characterized by uncontrolled and persistent self-administration of opioids, resulting in significant impairment, distress, and mortality. Between 1991 and 2011, the U.S. saw a threefold spike in annual opioid prescription rates (from 76 to 219 million) [1]. OUD was estimated to impact 6-7 million adolescents and adults in the United States in 2019 [2].

OUD’s societal effects are extremely far-reaching as the condition burdens multiple stakeholders, and a retrospective secondary analysis attributed $787 billion societal cost to OUD in the U.S. [3]. Unfortunately, there are currently only limited pharmacological agents available to treat OUD, and these therapies suffer from a number of limitations, including high relapse rates, inconvenient treatment regimens, and access.

Ibogaine, a naturally occurring psychoactive compound found in the root bark of an African shrub, is believed to have used for hundreds – if not thousands – of years in ceremonial and spiritual settings in African communities [4]. Pharmacologically, ibogaine is complex and multimodal, with opioidergic, cholinergic, glutamatergic and monoaminergic receptor modulatory activities demonstrated.

While ibogaine is not approved for any indication in any regulatory jurisdiction, it is currently administered (typically as an extract) in over 70 clinics and retreats worldwide for the treatment of acute opioid withdrawal symptoms and to promote and support remission in patients with OUD. In several published case series, a single dose of ibogaine has shown to reduce both acute and chronic cravings for opioids and to improve mood. ?

We hypothesize that a single administration of ibogaine, administered in an appropriately supervised setting, could be safe, well‐tolerated, and could facilitate acute withdrawal from opioids and improve longer term abstinence rates. DMX-1002, our formulation of ibogaine, is in an ongoing Phase 1/2 trial to evaluate its safety, tolerability, pharmacokinetics, and efficacy. We expect topline results from the Phase 1 component of this trial being conducted in recreational drug users and healthy volunteers in the first half of 2023.

Background on atai

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

We have a pipeline of five clinical-stage drug development programs, several of which are envisioned to be paired with a proprietary, internally developed digital therapeutics platform. Of these five clinical drug candidates, three are psychedelic and two are 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. As of our latest publicly filed report, we also have a 22.4% stake in COMPASS Pathways (separately listed on Nasdaq; CMPS).

Overview of SUDs and OUD

Substance Use Disorders (SUDs) are characterized by an individual’s inability to control their use of a legal or illegal drug, medication, or other psychoactive compound. SUDs typically occur following prolonged, repeated use of a substance at high doses and/or high frequencies.?Opioid Use Disorder (OUD) is a form of SUD characterized by uncontrolled and persistent self-administration of prescription and/or illicit opioids. Over 20 million Americans live with a SUD, and, since the start of the drug epidemic in 1999, there have been over 900,000 overdose fatalities [5]. ?COVID-19 severely exacerbated the crisis for people with SUDs; drug overdose deaths shot up ~30% with close to 93,000 deaths in 2020, nearly 70,000 of which involved opioids [5].

Current treatment options

Present day pharmacological options to treat OUD are limited and have numerous deficiencies.?Current treatment options for OUD are divided into two classes: (i) synthetic mu opioid receptor agonists, such as buprenorphine and methadone, and (ii) mu opioid antagonists, such as naltrexone and naloxone. These therapies’ shortfalls include high relapse rates, inconvenient treatment regimens, and accessibility issues. In addition to these limitations, current treatment options have low rates of efficacy; approximately 75% of patients undergoing OUD therapy experience relapse within one year of treatment.

This is where we believe ibogaine enters the scene. This little-known substance has been quietly building a reputation for treating aspects of opioid addiction without the pitfalls of current market options.

History of Ibogaine

Ibogaine was first isolated from the Tabernanthe iboga plant by Jan Dybowski and Edouard Landrin and, independently, by Haller and Heckel in 1901. George Büchi would go on to synthesize ibogaine in 1966 [7]. ?Between 1930 and the 1960s, ibogaine – in the form of an extract from the Tabernanthe manii plant – was marketed as Lambarène in France, purporting efficacy as a both a mental and physical stimulant.

Despite enjoying great popularity among athletes, it was withdrawn from the market when all ibogaine-containing medicines were declared illegal in France [8]. The United States Food and Drug Administration assigned it Schedule I status, indicating no accepted medical use and high potential for abuse [9].

Early promising evidence

Yet anecdotal evidence regarding ibogaine’s therapeutic effects continued to emerge.??In 1962, Howard Lotsof began experimenting with ibogaine and found the compound significantly reduced both cravings and withdrawal symptoms for seven heroin addicts. All seven said they were no longer in heroin withdrawal, and five of them lost their desire to use heroin for six months or longer [10].

Shortly after his inadvertent discovery of ibogaine’s anti-addictive properties, Howard Lotsof began working with a Belgian company to produce a tablet form of ibogaine for clinical trials in the Netherlands and received a U.S. patent for the product in 1985.?Multiple studies soon followed, corroborating ibogaine’s apparent efficacy in alleviating addiction not only for opioids, but cocaine [11] ?and alcohol [12] as well.

Today, though ibogaine remains illegal in the United States, some countries including Canada, Mexico, and the United Kingdom, allow its administration by a clinician for anti-addiction therapy in limited circumstances. Nevertheless, for a range of reasons including the lack of availability of GMP-grade drug product, large scale studies have not been undertaken. However, anecdotal evidence has continued, suggesting the potential ibogaine may have in treating the increasingly global issue of addiction in all forms.

How Ibogaine works

Ibogaine affects a variety of neurotransmitter systems directly or indirectly, and it appears to have particularly high affinity for the sigma-2 receptor [13]. ?Ibogaine is metabolized by humans into noribogaine [14] by the cytochrome P450 2D6 enzyme [15]. Noribogaine – like ibogaine – is a weak NMDA receptor antagonist, as well as a moderate k-opioid receptor agonist and weak μ-opioid receptor agonist [16]. Although exact mechanisms to produce ibogaine’s dissociative psychedelic effects are unclear, many speculate that action at the kappa opioid receptor contributes significantly.?Additional effects may come from noribogaine’s function as a potent serotonin reuptake inhibitor.

Clinical evidence

In several case series, a single dose of ibogaine has been shown to be an effective treatment for acute opioid withdrawal from both the physiological and psychological perspectives. One large observational study of ibogaine’s potential benefits reported that of 88 subjects interviewed, 80% stated treatment either reduced or eliminated their withdrawal symptoms. At the time of the survey, which took place more than 6-months after treatment, 41% reported total abstinence; and though 70% of the sample eventually reported a relapse following treatment, 48% of those reported decreased use and 11% eventually achieved abstinence [17]. Interestingly, those that responded to the treatment, reported their ibogaine experiences as more spiritually meaningful, mirroring similar findings with psilocybin [18].

In a clinical study published in 2018, 75 opioid-dependent and 81 cocaine-dependent patients were treated with single doses of 8 mg/kg to 12 mg/kg ibogaine.?The patients experienced significant and durable reductions in ratings of craving at discharge on day 12 and at one-month post-treatment. Both patient types reported improved mood from as early as five days after dosing up to one-month post-dose [19].

As shown in the graph below, opioid-dependent patients reported significant decreases in drug cravings, measured by 29 subscales at discharge and at one-month follow-up. Similarly, assessments of mood 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).

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 patients. In the study, no serious adverse events or deaths occurred from administration of ibogaine to drug dependent patients in the dose range used in this trial.

Finally, ibogaine is also being investigated in conditions outside of the SUDs.?As an example, Stanford University is currently running a pre-post study evaluating the safety and efficacy of Ibogaine with magnesium treatment therapy in 30 veterans with traumatic brain injury resulting from repeated blast exposure. The study is assessing the safety profile of the compound by examining unexpected or serious adverse events related to dosing. The primary endpoint of the study is the change in the World Health Organization Disability Assessment Schedule 2.0 (WHODAS) from baseline to post-treatment. In addition to psychological and cognitive testing, study participants will also receive magnetic resonance imaging (MRI) and electroencephalography (EEG) to explore possible brain changes associated with its use. The study expected to be completed by August this year [20].

DMX-1002 (Ibogaine) for OUD

We are currently testing DMX-1002, atai’s oral formulation of ibogaine, in an ongoing Phase 1/2 trial to evaluate its safety, tolerability, ?pharmacokinetics, and efficacy. We expect initial data from the Phase 1 SAD study, being conducted in healthy volunteers and recreational drug users, in the first half of 2023.

We regard ibogaine as a unique development candidate for the potential treatment of opioid use disorder, with possible single administration providing ?potential benefit in this difficult to treat indication.

Learn more about our programs?here.

Forward-Looking Statements

Please note that the information provided above contains forward-looking statements.?We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy, short-term and long-term business operations and objectives, and financial needs. These forward-looking statements are subject to a number of important factors that could cause actual results to differ materially from those in the forward-looking statements, including the risks, uncertainties, and assumptions described under "Summary Risk Factors" below, “Risk Factors” in Item 1A of Part I, “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in Item 7 of Part II and elsewhere in our Form 10-K for the year ended December 31, 2022, filed with the Securities and Exchange Commission.

Any forward-looking statements made herein speak only as of the date of this communication, and you should not rely on forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee that the future results, performance, or achievements reflected in the forward-looking statements will be achieved or will occur. Except as required by applicable law, we undertake no obligation to update any of these forward-looking statements for any reason after the date hereof or to conform these statements to actual results or revised expectations.

Sources

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20. ClinicalTrials.gov ?“Pre-post Evaluation of the Safety and Efficacy of Ibogaine-Magnesium Therapy in Veterans With Repeated Blast Exposure “

“Effect of Ibogaine on Naloxone-precipitated Withdrawal Syndrome in Chronic Morphine-dependent Rats.” PubMed, 1 Aug. 1988.