At the end of 2021, UK-based COMPASS Pathways shared positive results from its Phase IIb clinical trial of COMP360 psilocybin therapy for treatment-resistant depression (TRD). The study was the largest ever conducted with the psychedelic medicine, with 233 patients included at 22 sites across Europe and North America.
COMP360 psilocybin therapy
The trial demonstrated that patients who received a single 25mg dose of COMPASS’s proprietary psilocybin formulation, COMP360, with psychological support, experienced a significant reduction in depressive symptom severity after three weeks, with a rapid and sustained response lasting the 12 week duration of the trial.
To discuss the study, which COMPASS hopes will lead to COMP360 psilocybin therapy’s regulatory approval, PSYCH spoke with the company’s Chief Medical Officer, Dr Guy Goodwin.
‘Let’s start with the problem, which is major depression,’ said Goodwin. ‘Estimates vary, but it probably affects one in five to ten people at some point in their lifetime and the number of cases in the world is enormous – 300 million or more.
‘The challenge is that response to the standard first-line treatments, such as SSRI antidepressants or cognitive behaviour therapy (CBT), is about 50%. The usual approach after failure of an antidepressant is to offer a second-line treatment – some people will respond to that, but one in three still have an unsatisfactory response and remain depressed.
‘Depression has a major effect on people’s ability to concentrate, work, organise – people can lose their role in life which reinforces their depression.
‘These are the chronic states that, as psychiatrists, we are often trying to help, and it’s very common that people are partially responsive but still depressed. Primary care physicians don’t have a lot of time and don’t have a lot of familiarity with, or access to, additional options. The COVID-19 pandemic has increased rates of depression and anxiety, which has made the situation even worse.
‘COMPASS’s mission is to address those patients who have been failed by existing treatments. We are an ambitious company – we want to improve mental health, and we are starting with the most difficult-to-treat conditions.
‘Targeting treatment-resistant depression is the first step in that direction: we’ve got to do the essential clinical trials to get regulatory approval for the use of COMP360 psilocybin therapy in patients who need it the most.
‘Our view is that this is the most effective way to make these drugs available and accessible to the general population, by going through the same pathways other medicines do to demonstrate they work and are safe.
The positive Phase IIb results were welcomed by the scientific community, however some investors had questions over the treatment’s durability. PSYCH asked Goodwin to expand on the trial’s recruitment and results.
‘The patients we recruited came through conventional pathways and had documented failure by existing treatments. Over 90% of them were naive to the effects of psychedelics and the trial investigators, who were psychiatrists, were also using a psychedelic approach for the first time. So it was a big experiment into how we generalise our approach both in terms of patient population and the clinics providing the care.
‘The aim of the study was to identify the minimal effective dose of COMP360 psilocybin to investigate further in larger phase III trials, so we tested three different doses: 1mg, 10mg and 25mg. The results showed that 25mg COMP360, given in conjunction with psychological support from trained therapists, provides a significant reduction in depressive symptoms after three weeks, compared with the 1mg dose – a difference of six on the MADRS (Montgomery-Asberg Depression Rating Scale) score. This was an important and statistically significant result.
‘This effect is large when compared to trials of more conventional antidepressants. We had seen positive results from previous work done by academic centres, and we were excited to confirm the positive effect in a larger study with a more exacting protocol.
‘In terms of durability, a quarter of patients in the 25mg group maintained response at 12 weeks, the end of the trial period – this was after a single administration of COMP360 with no other antidepressant medication. This finding is unprecedented and remarkable. If people get to 12 weeks fully remitted, they often remain remitted for quite a long period of time, according to previous psilocybin studies. To determine how long, we are also following up as many patients as we can, to find out more.
‘The patients in this trial had been failed by existing treatments for some time, and results like these, in such a hard-to-treat area are very encouraging. Our next step will be a larger Phase III programme and then, if the results are positive, to seek regulatory approval.
‘We also reported results from a smaller study we completed last year, looking at COMP360 psilocybin therapy as an adjunctive treatment to SSRI antidepressants for patients with TRD. In our large Phase IIb clinical trial, patients were asked to come off their antidepressant medications, in line with the widely-held belief that SSRIs could interfere with psilocybin’s therapeutic effect.
‘We were interested to see the effect of COMP360 psilocybin therapy on patients who remained on their medications. The SSRI adjunctive study showed that the response to 25mg COMP360 psilocybin therapy was similarly positive and comparable to that of patients in the Phase IIb trial who had come off medication. This seems to offer us the potential to enable patients to choose whether they wish to remain on SSRIs, or come off them slowly, and still derive potential benefit from COMP360 psilocybin therapy – which will be important in the future development of our programme and good for patients.’
Mental health treatments have not seen significant innovation in decades. With Goodwin being an experienced researcher and the Emeritus Professor of Psychiatry at the University of Oxford, PSYCH was keen to learn how monumental he believes these trials could be.
‘I am conscious that the hopes and expectations around psychedelics have become magnified, perhaps to an unrealistic extent.
‘I think it’s important for COMPASS to focus on rigorous research and not create additional hype. We need results from large-scale, randomised controlled trials. We’ve made a start with our Phase IIb trial but there’s more to do and we’ll be looking at a number of key supplementary areas in our Phase III programme.
‘Psychedelics like psilocybin excite people as the drug mechanism is extremely powerful in revealing one’s mental mechanisms and apparently ‘opening one’s mind’. That has always attracted people as a way of solving deep-seated problems, and now we have the opportunity after many years to see if that promise can be fulfilled under conditions of clinical safety.
‘The story so far is certainly groundbreaking in the sense that we didn’t have evidence from such a large, well-controlled study before, but we need to complete our project properly if we are to be transformative for the whole mental health field, and bring this therapy successfully to patients.
Treatment-resistant depression is an illness that is notoriously difficult to manage. PSYCH asked Goodwin to speak about the challenges faced in treating the indication.
‘The risk of suicidality is always important when treating patients with depression – this is a big concern for psychiatrists and always has to be considered when designing clinical trials. We have to be aware that suicidality can emerge, remain vigilant, and so do everything we can to ensure patient safety. Unfortunately, suicidality is a threat in this patient population and adds to the suffering for patients and their families. This is what drives us every day – we want to change this.’
COMPASS is on a mission to change mental health care, with combating treatment-resistant depression the opening gambit. For the company’s investors, PSYCH was eager to learn which other illnesses the company was targeting.
‘COMPASS is ambitious in wanting to change how we treat serious mental health challenges, and treatment-resistant depression is just the start,’ declared Goodwin.
‘We are interested in treating areas of high unmet need in mental health. We have launched a study into PTSD and will be adding to this in 2022. We also provide our COMP360 psilocybin, free-of-charge, to a number of academic institutions who are running investigator-initiated studies in disorders including anorexia nervosa, bipolar depression, severe TRD, and suicidal ideation. If these provide promising signals they will help us shape our development programme.
‘Beyond COMP360 psilocybin therapy, we are developing new molecules and compounds through our Discovery Center and other partnerships, such as with Dr Matthias Grill of MiHKAL GmbH, as well as creating new digital solutions and technologies to support our innovations. Our ultimate goal is to develop innovations that address some of the hardest to treat mental health conditions, and make them available and accessible to the people who need them the most.’
To discuss the importance of a sustainable patient-first industry, COMPASS CEO George Goldsmith will take the stage at PSYCH Symposium: London 2022 – Europe’s premier psychedelic conference.
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