Guest Column | April 22, 2024

Bucking Convention: How Analog Ibogaine Could Help Conquer CNS Disorders

A conversation with EQUULUS Cofounder and CEO Robert Discordia

teenager taking medication-GettyImages-1049816548

Developing new therapies for central nervous system (CNS) disorders, which are currently treated by a multitude of therapies ranging from antipsychotics to antidepressants to mood stabilizers and more, can be a challenging endeavor for most any pharma. But if you’re a startup just coming out of stealth mode and seeking a program rooted in hallucinogenics, that journey just got a little tougher — but all the more worthwhile.

For EQUULUS, the path is new, but the plan has been set. In this Q&A, EQUULUS Cofounder and CEO Robert Discordia discusses his company’s pursuit of an analog ibogaine as a potential therapy for CNS disorders, exploring how this non-hallucinogenic can impact patients and ways in which the company hopes to work with and earn approval from regulators.

What are some of the key challenges in developing effective CNS disorder treatments?

The multifaceted nature of CNS disorders and the unique hurdles that must be crossed in order to deliver therapeutics accurately and selectively to the brain are top issues in CNS drug development. EQUULUS’ transdiagnostic disease construct recognizes the key issues that occur across and are common to critical psychiatric illnesses and presents treatment opportunities to help in patients’ journey back to health and quality of life.

Can you give us an overview of EQUULUS' current pipeline and the CNS disorders you are targeting?

Our pipeline includes our ibogaine analog program, which consists of our lead preclinical asset, a non-hallucinogenic, non-cardiotoxic analog of ibogaine for the treatment of a range of substance use disorders. Our second program focuses on dual-action CB1R neutral antagonist/CB2R agonists. Our lead asset is being developed for nicotine dependence/addiction. We intend to investigate its safety and efficacy in obese smokers, the subpopulation of smokers with the highest rate of premature mortality.

Of note, EQUULUS identified a lead portfolio asset in conjunction with our agreement with the Research Triangle Institute, which provides EQUULUS with access and development rights to a library of over 750 serotonin-releaser compounds and other novel molecular scaffolds. The library holds the potential for new drug development candidates with superior safety and efficacy profiles for the treatment of PTSD as well as other molecules that could be useful for a wide range of CNS disorders. EQUULUS has also established an agreement with Küleon Biosciences for access to their novel ibogaine analogs and selective 5HT1/2 compounds arising from their discovery efforts. We also have a partnership with the NIH’s NIDA/Addiction Treatment and Discovery Program in which they are performing preclinical assessments of several of our lead assets.

What is ibogaine (and its analog)? Why is EQUULUS pursuing it as a therapy, and what are some of the regulatory considerations for eventually bringing it to clinical trials?

Ibogaine is a natural product isolated from Tabernanthe iboga, a tree common to Central Africa that exhibits unique pharmacological properties beneficial in treating addictions, in particular, addiction to opioids, as well as other substances such as stimulants, alcohol, and nicotine. However, when ingested, ibogaine produces delirium-like hallucinations for six to 10 hours and its effects may last for up to 24 hours. Ibogaine is also known to be a dangerous substance due to its ability to cause dangerous or even fatal arrythmias (just 19 reported over its more than 20-year history).

While there are some companies looking into advancing ibogaine as a prescription medication, EQUULUS believes ibogaine is too unsafe to be developed into a drug and that the regulatory approval path forward is through the discovery and development of synthetic analogs of ibogaine that have been specifically designed to eliminate the known toxic attributes while retaining or even improving upon its anti-addictive efficacy. Several companies have active ibogaine analog programs. MindMed previously advanced MM-110, its ibogaine analog, also known as 18-MC (18-methoxycoronaridine),) through Phase 1 clinical trials for opioid withdrawal in late 2021, when it then halted further development in August 2022 after the FDA requested additional preclinical characterization of the drug. EQUULUS has an active ibogaine analog program, which includes our lead development compound EQL-101 that we plan to advance into clinical trials.

How does EQUULUS' approach to CNS disorder treatment differ from conventional methods?

EQUULUS is taking a transdiagnostic approach to the development of therapeutics for CNS disorders, which involves identifying and targeting fundamental factors that transcend standard diagnostic categories and are tied to clear disease-driving physiology. This approach is supported by evidence that mental health disorders are composed of clusters of symptoms that vary between patients and overlap with other disorders. Focusing on the key criteria and underlying mechanisms of CNS disorders allows us to get below the surface of the symptoms and address the crucial origin of the disease. EQUULUS is also, in parallel, working toward the development and application of biomarkers to aid in drug development. Doing so will increase development success rates and generate highly valued therapeutics that more completely treat the target disorders.

When it comes to the development and application of new biomarkers for CNS, what factors must you consider for regulatory acceptance and eventual widespread industry use?

Key among considerations for biomarker development and deployment is the demonstration of robustness and reliability, validating the biomarker’s clear correlation with clinical endpoints and therapeutic outcomes. The lack of translation from basic scientific research into clinical studies required for new medicines is a major challenge in CNS drug development. While some fluid-based biomarkers are preserved across species, an issue that often arises with humans is that these biomarkers are much more variable as they are influenced by external factors like stress, diet, and lifestyle, and so robust measurements can be very challenging.

It is also imperative to address ethical considerations pertaining to patient safety and privacy, adhering to stringent ethical and regulatory guidelines. Regulatory acceptance hinges on the collection of comprehensive data substantiating the clinical utility and predictive value of the biomarker, which necessitates extensive preclinical and clinical validation studies.

In one example, advances in the use of quantitative machine learning EEG algorithms as biomarkers in certain neurological and neurodegenerative disorders could help to bridge proof-of-concept preclinical studies to clinical trials and also help to provide evidence of efficacy while reducing potential placebo effects by providing objective measurements of brain function. EQUULUS is interested in contributing to this critical area of CNS drug development. Successful regulatory approval sets the stage for widespread industry adoption, facilitated by publication, educational initiatives, and collaborative partnerships. The establishment of clear guidelines and standards for biomarker development and utilization will promote consistency and will facilitate their integration into clinical practice, thereby advancing drug development efforts and improving patient care within the realm of CNS therapeutics.

What are some of the most promising developments in CNS disorder treatment that you foresee in the near future?

The rebirth of psychedelics has opened a new frontier of discovery. The initial wave of investigations over the past five to seven years by pioneering scientists and companies laid important groundwork.  This new phase we are now entering is leveraging those initial efforts and creating therapeutics that will be highly prized by mainstream pharmaceutical companies because they will be highly desired by physicians and patients and, crucially, will fit into the payer/reimbursement systems of global healthcare systems. By moving in this direction, we are creating turnkey drug development pipeline assets that will be highly sought after by pharma companies as in-licensing or acquisition targets.

How does EQUULUS plan to navigate the regulatory landscape for CNS disorder treatments?

EQUULUS is an advocate for innovative regulatory approaches, similar to those used in other therapeutic areas, that should be applied to their full potential to medicines being developed for CNS disorders, such as transdiagnostic approaches, real-time review (RTR), and optimizing use of Breakthrough Therapy designation (BTD), coupled with advancement in innovative trial designs. To successfully traverse the regulatory requirements and ensure compliance and approvals, EQUULUS will build a close rapport and maintain close communication with regulatory agencies. EQUULUS is fortunate to have a highly experienced regulatory leader on our team who has many years of experience as a reviewer within the Office of Neuroscience (ON) at the FDA and, subsequently, in the pharma services industry. 

About The Expert:

Robert Discordia, Ph.D. is a 30-year veteran of the biopharmaceutical and biotech industry. He was previously chief operating officer and head of pharmaceutical development at Corbus Pharmaceuticals before starting his own biotech, Avanzarx Pharmaceuticals, focusing on pulmonary inflammation and fibrosis. Most recently, he was chief scientific officer at CaaMTech, Inc., a privately-held pharmaceutical drug discovery company focused on creating and optimizing next-generation psychedelic-inspired medicines to treat mental health conditions. Discordia led a 26-year career in pharmaceutical development at Bristol Myers Squibb where he played critical roles in the integrated development and commercialization of the key brands Taxol, Entecavir, and Eliquis.  He also served as executive director in business operations in business operations where he was responsible for the management of external services to the global pharmaceutical development and manufacturing organizations, overseeing seven global sites, 55 employees, and an annual budget of $700 million. Bob is a father of two and resides with his wife Krista near Charlotte, NC.