Psychedelic: Exclusive talk with biopharma company Definium

In this edition of “Psychedelic”, The Fly conducted an exclusive interview with Rob Barrow, Chief Executive Officer, and Daniel Karlin, Chief Medical Officer, at Definium Therapeutics (DFTX), a late-stage clinical biopharmaceutical company developing therapeutic product candidates to address underlying causes of psychiatric and neurological disorders. Here are some highlights:

PSYCHEDELIC DRUG DEVELOPMENT: Definium, which hosted an Analyst & Investor Day on April 22, is on a mission to forge a new era of psychiatry by applying scientific rigor to psychedelics, with the goal of developing accessible treatments that unlock healing at scale. The company is working on an evidence-based pipeline of product candidates, striving to deliver on the therapeutic potential of psychedelics and other novel compounds to address unmet needs in Generalized Anxiety Disorder, Major Depressive Disorder, Post-Traumatic Stress Disorder, and Autism Spectrum Disorder.

“We are making sure that we are staying true to the science and staying true to our mission, which is to really recognize the full potential of the opportunity in front of us,” Barrow said. He added Definium sets itself apart from other companies in the space in its approach to going after major market indications.

“Virtually every program in this area has siloed themselves into this ‘Treatment-Resistant Depression’ indication,” the CEO said. “We take issue with even the labeling of that because it implies that there is some biological entity that is unique to some segment of people suffering from depression. The reality is that the drugs we have today don’t work particularly well and a lot of people are going to be underserved by those treatments because they don’t work well.”

The company’s approach to focusing on GAD, MDD and the full markets speaks to the way Definium thinks about the opportunity available and what the company can ultimately accomplish, he said. “That is how we approach development programs as well,” Barrow said. “We have tried to do very thoughtfully designed studies that have complementary findings, but at their core give us clean answers about questions of efficacy. We have taken an approach where we give a single dose of drugs without concurrent psychotherapy and we have been able to demonstrate not only the largest, but the longest duration efficacy of any late-stage trials in this area.”

DT120 ODT: Definium’s lead candidate is DT120 orally disintegrating tablet, a pharmaceutically optimized proprietary formulation of lysergide D-tartrate. The drug is an ergoline derivative belonging to the group of classic serotonergic psychedelics, which acts as a partial agonist at specific serotonin receptors, causing its distinctive transient perceptual and emotional effects.

“What we have established through our Phase 2 programs is that we have real confidence in our ability to treat GAD, because that’s what we did in Phase 2 in a robust, rapid, endurable way,” Karlin said. “What we also saw in the Phase 2 was a significant movement in the Montgomery–Asberg Depression Rating Scale, the major depression scale.”

He noted GAD and MDD are conditions that both definitionally overlap one another and epidemiologically have a very high degree of comorbidity. “Phase 2 gave us a lot of confidence to go into Phase 3 programs in both GAD and MDD,” the CMO said. “We have readouts from Phase 3s coming very soon here. By the end of this half of this year, we’ll have an MDD readout and then we have two GAD readouts in the second half of this year. We’re confident that the drug will continue to perform in GAD and MDD the way that we saw it perform in Phase 2 and the way it has in historical studies.” If those studies are successful, the data will enable Definium to approach regulators regarding labels to treat both conditions, he said.

“The dynamics of the drug, the way that it works, the durable efficacy without need for daily drugs, all of this sets DT120 apart from everything that’s currently available from a psychopharmacological standpoint,” Karlin said. “We think it will open up the ability for psychiatry to really operate in a whole new way.”

PHASE 3 STUDIES: Definium is currently conducting the Phase 3 Voyage study of DT120 for the treatment of GAD, the Phase 3 Panorama study of DT120 in GAD, the Phase 3 Emerge study of DT120 in MDD and the Phase 3 Ascend study of DT120 in MDD.  At Analyst Day, the company said it expects topline data for Emerge in late Q2, Voyage in early Q3 and Panorama in late Q3. Definium also expects first patient dosing for Ascend in Q2.

“We’re now in the second quarter, so it’s a matter of months at this point for Emerge data,” Barrow said. “We announced the trial was fully enrolled and 149 patients were randomized 1:1 in that study. When we look at the landscape, there has always been other physical data with other psychedelics. What we have seen there, and as it relates to with those drugs, is in line with historical averages for anti-depression, which are around 3.5 or so points delta over placebo on the MADRS.”

In pursuing development of DT120 for MDD, the company sought a path to deliver data that exceeds that mark, he said.  

“If our data delivers four or more points separation from placebo, we’re going to be talking about one of the best drug outcomes, if not the best drug outcomes, we have ever seen for this indication,” the CEO said. “While the study would be able to detect differences that are smaller than that, we certainly think given the magnitude of the response we saw in Phase 2, that exceeding a four-point bar, would be incredibly exciting, not only for us, but for the entire field.”

For the Phase 3 Ascend study of DT120 in MDD, dosing is expected to begin this quarter. The trial is expected to enroll approximately 175 participants randomized 2:1:2 to receive DT120 ODT 100 micrograms, DT120 ODT 50 micrograms control, or placebo.

“While the macroenvironment is obviously evolving, we think the best thing to do is the standard two studies per indication, even if that’s not really required for a regulatory approval,” Karlin said. “There are other audiences for these studies than the regulators and if we are approved, we need to have evidence to convince the healthcare providers who will be the prescribers of the drug, the dosing session monitors and the referrals to care. We need to build real confidence in that community.”

The company will also have to convince private payors, commercial payors and public payors, he said, in order for patients to get access to the drug and have their payor cover it.

“And then of course the patients too,” the CMO said. “We need the folks who could benefit from the drug to have real confidence in the evidence that we built. We are absolutely moving forward with Ascend, the second MDD study. And in each of the second studies in the indications, we have an additional control condition to build further confidence that the effects being measured from the drug are really due to the drug.”

Definium has also been progressing Panorama and Voyage, the Phase 3 studies on DT120 in GAD, as guided, he said.

“We are very pleased with the operational efficiency and integrity of those studies,” Karlin said. “The output of Panorama we expect to be very similar to the output of Voyage. Panorama has this additional control condition, which again just gives us another methodological argument for the robustness of the science and the integrity of the findings. All of these studies together taken in concert are meant to build an incontrovertible body of evidence for the efficacy of this drug across these two conditions.”

Along with Analyst Day, the company also announced the expansion of the DT120 ODT program into PTSD with the Haven Phase 3 study expected to enroll approximately 200 participants randomized 1:1 with a primary of the Clinician-Administered PTSD Scale for DSM-5 at Week 8. Study initiation is expected in 2027.

DT120 MARKET OPPORTUNITY: GAD and MDD, are two of the largest drivers of psychiatric disease burden, with approximately 26M adults in the U.S. living with GAD and 41M adults in the U.S. living with MDD. These disorders represent a massive and growing unmet need as current psychiatry is limited by available treatment options.

“The market is so staggeringly large in terms of patients affected,” Barrow said. “One in five U.S. adults, about 50M U.S. adults, are affected by anxiety or depression. When we go through all of the filtering and look at patients who have been diagnosed, sought treatment and had multiple treatment options be inadequate to give them relief, we are talking about mid-single digits, 4M or 5M patients in that population.”

Early market research has indicated that that population would be the most eager for new treatment options and ready for adoption of these products, he said.  

“When we think about it, we’re talking about millions of patients in need with a high degree of enthusiasm,” the CEO said. “And this excitement is not only from patients, but also from providers and in our conversations, the willingness to pay for such treatment by payors. We’re following a huge opportunity in the number of patients we can treat, but also as an organization a huge opportunity in the value that we can create.”

DT402: Definium is also developing DT402, the R-enantiomer of MDMA, to target the core symptoms of ASD, specifically addressing social communication challenges. The company initiated a Phase 2a study in Q4 and initial data from the study is anticipated in 2026.

“Folks who are following the space will be familiar with MDMA as it was previously studied as an adjunct to psychotherapy in the treatment of PTSD,” Karlin said. “We take a very different approach with our MDMA, which is to say we are not thinking of it as a session-based drug, or a drug that someone would use in concert with some type of therapy, but instead we’re seeing it as a daily drug that someone with ASD could take in order to help with social and communication difficulties associated with that illness.”

He noted the model for 402 is very similar to the model of psychostimulants in Attention-Deficit Hyperactivity Disorder, where a person that has ADHD can take a drug to increase their ability to focus.

“If they take it, they get the benefit of the drug, but if they don’t take it, nothing happens,” the CMO said. “We think of 402 as very much that. Someone takes the drug and while the drug is onboard it provides some benefit to emotional cognition, emotional recognition, social recognition and social communication. Then when the drug comes off, the person is as they were before. It is a very different model than our DT120 and it’s a very different model than what has been used with MDMA-based compounds in the past.”

PSYCHEDELIC EXECUTIVE ORDER: On Saturday, President Donald Trump signed an Executive Order accelerating research and improving access to psychedelic drugs as promising treatments for serious mental illnesses. The order directs coordinated federal action to prioritize mental health therapies, streamline regulatory pathways, and expand cross-agency collaboration, consistent with the Administration’s policy to accelerate innovative research models and appropriate drug approvals to increase access to psychedelic medicines that could help save lives and address the serious mental health crisis in America.

“It’s incredibly encouraging to see the degree of focus on the mental health epidemic,” Barrow said. “That’s the thing first and foremost that everyone should realize is, regardless of what drugs we’re talking about and where they are in development, the fact we are having that conversation about the magnitude of need and the urgency that is needed to treat these conditions is huge in and of itself. Beyond that, given what we believe is an incredible opportunity to really change the direction of that problem with our program and other programs that are in development with psychedelics, we think this is a real opportunity for a paradigm shift in psychiatry. To see a path being charted and a degree of alignment to facilitate this as efficiently as possible is incredibly encouraging and we’re very excited for the path forward.”

CHALLENGES: When asked about the largest hurdles facing the psychedelic biopharma space, the CEO pointed out that with any novel product, there has historically been a lack of aligned forethought on well-executed implementation.

“Not from us, not from companies, but in looking at everyone that needs to be involved in facilitating adoption of the actual impact that we think is possible,” he said. “Oftentimes policies, regulations and ways of approaching novel products are reactive or haven’t really been thought through with all the implications.”

He said Definium has been in discussions with legislators, the executive branch and patient advocacy organizations and all parties are looking to facilitate a thoughtful conversation of balancing the safe delivery of these products with the urgency and the magnitude of the need.

“Putting up artificial barriers that make it too onerous, make it hard for anyone to actually benefit from these products, wouldn’t actually get us to the goal as an industry and as a field,” Barrow said. “Certainly given the breadth of engagement involved that is needed to get there, it’s a big push, a big thing that we all hopefully navigate together.”

OPPORTUNITIES: As the psychedelic biopharma industry develops and matures, the CEO said the biggest opportunities lie in delivering physical data, moving toward FDA filings and getting drugs on the market.

“That’s the ultimate goal is to get these treatments to patients and get them out there in a major way,” he said. “The opportunity to do that, do that well and do that better than anyone is what we aspire to.”

Barrow noted the company is also excited about the near-term opportunity in MDD and to address the underappreciation of the opportunities of DT120 in depression.

“We don’t have a Phase 1 study in MDD, although we saw really strong results in depression symptoms in the GAD population in our Phase 2 program,” he said. “We have data in late Q2 that will answer that question on the magnitude and durability of the effects on MDD. To get that data out there, we are of course incredibly excited for and data that is positive would only broaden out the opportunity and broaden out the appreciation for what can be accomplished here.”

OTHER PSYCHEDELIC STOCKS: Publicly-traded companies in the space include Algernon Health (AGNPF), AtaiBeckley (ATAI), BetterLife (BETRF), Bright Minds (DRUG), Clearmind (CMND), Compass Pathways (CMPS), Enveric Biosciences (ENVB), Filament Health (FLHLF), GH Research (GHRS), Helus Pharma (HELP), Incannex (IXHL), MIRA Pharmaceuticals (MIRA), NRx Pharmaceuticals (NRXP), Numinus Wellness (NUMIF), Pasithea Therapeutics (KTTA), PharmAla Biotech (MDXXF), PharmaTher (PHRRF), Psyence Biomedical (PBM), Relmada Therapeutics (RLMD), Revive Therapeutics (RVVTF) and Silo Pharma (SILO).