Chief clinical development officer of HMNC Brain Health, Hans Eriksson, speaks to Psychedelic Health about how the company’s formula, ‘Ketabon’, will provide the therapeutic benefits of ketamine without the ‘trip.’
In June 2022, HMNC and Develco Pharma’s Phase 2 oral prolonged-release ketamine (Ketabon) Study dosed its first patient. The trial aims to understand if ketamine can help people living with treatment-resistant depression (TRD) who have not responded to a minimum of two standard antidepressants in their current major depressive episode.
Based on the data, HMNC believes the pharmacokinetic profile of its prolonged release Ketabon formulation could significantly improve tolerability and patient convenience by minimising dissociative effects compared with the currently applied intravenous and intranasal therapies.
HMNC’s proprietary formulation of ketamine is an oral formulation of ketamine that is taken up slowly by the body, with its concentration peaking at around six to eight hours.
The formulation, delivered in pill form, contains both enantiomers of ketamine – (S)-ketamine and (R)-ketamine – explains Eriksson.
“Since it’s taken orally, everything will essentially pass by the liver, so, quite a lot of the parent compound, ketamine – an active compound – is metabolised, as we get the relatively higher contribution of some of the downstream active metabolites,” said Eriksson.
“We believe that some of the advantages that we expect to find with Ketabon come from the pharmacokinetic properties, both the slow concentration buildup and also the relatively high first-pass metabolism.”
In its Phase 1 study, results demonstrated that patients with chronic pain conditions that were exposed to this compound had good tolerability.
A smaller Phase 2 study in treatment-resistant depression was conducted in an academic setting at the University of Zurich in Switzerland, although the study was terminated early due to difficulties in recruiting participants during the pandemic.
“This study still gave us lots of encouragement because we saw a clear signal of clinical efficacy,” said Eriksson.
With HMNC’s larger Phase 2 study underway, a clinical data readout is expected during the first half of next year. This study is being carried out with 117 patients in three different treatment arms as an add-on to standard antidepressant treatment in three countries in Europe. It is also being run as an outpatient study, which is not very usual for ketamine.
The first dose in the study is being given under medical supervision to ensure safety. While the study aims to demonstrate efficacy and safety, it is also an exploratory study, says Eriksson, as HMNC believes that three weeks may not be essential to achieve maximum efficacy.
“We believe that sometime during the time after three weeks there will be maximum efficacy,” said Eriksson. “That’s probably the induction phase that we will use going forward as there is quite a lot of compelling evidence that maintenance treatment in individuals who have responded to ketamine, or (S)-ketamine, doesn’t have to be given on a daily basis.
“We can see that for instance with spravato [a nasal (S)-ketamine spray] and in many other regimens, where the frequency of dosing becomes lower and lower.”
Ketamine without the trip
Ericsson says HMNC believes that its Ketabon formulation has a low likelihood of causing clinically significant dissociative side effects.
Currently, whether or not the “trip” aspect of psychedelic therapy, and ketamine therapy, is necessary for clinical benefits is being debated.
“For the dissociative effects of ketamine, I actually don’t think it’s absolutely needed,” said Eriksson. “In our small study in Switzerland, it was indeed possible to get an efficacy signal without dissociation. And there is also some data from academic studies out there looking at oral administration that look pretty encouraging.
“Our hypothesis is that with the dose we have chosen, we will get the antidepressant efficacy, but we will not get the dissociative side effects. In our study, under the Clinician Administered Dissociative States Scale, which is one of the standard scales to look at dissociation – a common side effect of ketamine – the high dose of our drug was similar to the placebo.
“It was placebo level dissociation and there were also no signs of blood pressure increase, which is another typical consequence of giving ketamine intravenously or giving (S)-ketamine as a nasal spray.”
The company is aiming to develop the medication as a take-at-home medicine to over come the current challenges faced when delivering ketamine treatment. With IV ketamine treatment causing strong dissociative effects – patients must be treated in-clinic and supervised by a medical professional for a number of hours.
“I think there are two consequences of not having dissociative side effects,” said Eriksson. “One is that it will be good for patients, because many patients really disliked the dissociative experiences and they are quite unpredictable as well.
“On a practical level, it will change things because if you’re taking a medicine like intranasal (S)-ketamine, which is a good medicine, you need to come into a physician’s office of the hospital several times during the treatment, once per week, twice per week and so on, and you need to stay there for several hours.
“It’s really a complex treatment compared to if you can take the medicine at home. Our take-at-home approach has the potential to become a game changer for ketamine treatment.
“When you take psychedelic medicines that necessitate lots of staff and a controlled setting, meaning they become limited to a more severe end of the spectrum, which I think is natural.
“If it will be possible to develop this medicine to something that gives efficacy with a very benign tolerability profile, then there is the potential to as a next step, continue developing the medicine for a broader use in psychiatric disorders, not necessarily only the treatment-resistant disorders.”
As Ketabon is an oral medication, Ericsson says HMNC will likely run a full effect study to find out whether the uptake is influenced by the food a patient is eating.
So far, HMCN has spoken to several regulatory agencies and is aiming to take its treatment to the US and Europe, with development programmes designed to be fit for purpose for each market.
“We believe that ketamine is a good antidepressant and that we can use Ketabon’s pharmacokinetic properties to disentangle the beneficial antidepressant effects from sometimes disturbing dissociative and cardiac effects,” Said Eriksson.
“That opens up the potential for a broader use of the medicine.”
Psilocybin analogue shows positive results in Phase 2 depression study
Cybin has announced positive Phase 2 topline safety and efficacy data for its proprietary deuterated psilocybin analogue – CYB003 – for the treatment of major depressive disorder (MDD).
Results from Cybin’s study have shown that 79% of patients were in remission from depression at six weeks after receiving two doses of CYB003.
CYB003 demonstrated a large improvement in symptoms after one dose and a total of 79% of patients were responsive to the treatment. The compound also demonstrated an excellent safety profile in doses tested, with all reported adverse events mild to moderate and self–limiting.
Additionally, Cybin has stated that the magnitude of improvement was superior compared to approved antidepressants and recently reported data with other psychedelics, stating that the effects translate into an unprecedented effect size.
The company has said that the results compare favorably to pooled data from 232 industry studies of current standard-of-care antidepressants, SSRIs, submitted to the FDA.
The announcement follows Phase 2 interim results in early November 2023, which demonstrated that CYB003 saw a “rapid, robust and statistically significant reduction in symptoms of depression three weeks following a single 12mg dose compared to placebo”.
Cybin CEO, Doug Drysdale, stated: “We are delighted to share that CYB003 achieved the primary efficacy endpoint in this study and showed rapid and statistically significant improvements in depression symptoms after a single dose, with a clear incremental benefit of a second dose, resulting in four out of five patients in remission from their depression at six weeks.
“This is an impressive finding and follows on from the unprecedented interim results we announced earlier this month.”
Drysdale emphasised that the strength of the data will support CYB003 into Phase 3 of the study.
Cybin CMO, Amir Inamdar, added: “The significant reduction in depression symptoms observed in our Phase 2 study is highly gratifying.
“At the three-week primary efficacy endpoint, a single 12mg dose of CYB003 showed a rapid, robust, and highly statistically significant improvement in depression symptoms compared to placebo, with a -14.08 point difference in change from baseline in MADRS.
“This translated into a very large effect size. Similar significant and robust effects were also seen with a single 16mg dose, which resulted in an improvement in symptoms of depression as measured using the MADRS total score by about 13 points versus placebo.
“These effects were evident on day one with the 16mg dose and were also highly statistically significant. When data from 12mg and 16mg are pooled, these robust effects are maintained. Further, with two doses, response and remission rates in excess of 75% were observed with CYB003 (12mg).
“With these findings in hand, we are encouraged by the potential of CYB003 to help those with MDD and look forward to progressing to a multinational, multisite Phase 3 study early next year.”
Cybin is planning on submitting topline data to the FDA with an aim to hold a Phase 2 meeting in Q1 of 2024, with further 12-week durability data from Phase 2 CYB003 expected in Q1, and recruitment for the Phase 3 study anticipated to begin by the end of Q1 2024.
Clerkenwell Health calls for volunteers to support groundbreaking psychedelic research
Mental health research provider Clerkenwell Health is calling for volunteers to join its groundbreaking clinical trials that will research whether psychedelics can provide effective treatments for complex mental health conditions.
Clerkenwell is seeking a diverse group of volunteers from across the UK between 18 and 65 years old to take part in the trials if they suffer from a relevant condition.
The trials, which will be conducted at Clerkenwell Health’s purpose-built facility near Harley Street in London, are being run in partnership with a number of world-leading drug developers to test whether psychedelic drugs – often combined with talking therapy – can offer a new approach to treating a variety of mental health illnesses.
Clerkenwell Health is seeking volunteers for trials that look to find cures for a range of conditions, including PTSD, depression, alcohol use disorder and anorexia.
Many of the conditions have few successful treatment options and Clerkenwell’s innovative methods of combining psychedelics with therapy aim to to treat these problems more holistically, providing long-term quality of life for patients.
Chief Scientific Officer at Clerkenwell Health, Dr Henry Fisher, said: “With the current system for treating mental health disorders simply not working, we’re calling for patients to help identify the next wave of treatments.
“These have the potential to be groundbreaking for the millions of people across the UK who are affected by poor mental health.
“The status quo for mental health treatment has not only resulted in patients experiencing debilitating side-effects, huge waiting lists and high relapse rates, but is costly, complicated and broadly ineffective.
“By participating in upcoming clinical trials, patients have an opportunity to make a valuable contribution to growing research which will support the development of the next generation treatments for mental health conditions.”
According to MIND, approximately 1 in 4 people in the UK will be affected by a mental health condition each year and with a significant rise in people contacting mental health services in recent years, there has never been a more desperate need to identify new and innovative treatments.
Given the challenges facing the country’s health service and with mental health challenges on the rise, the search for volunteers to test effective treatments has never been more pressing.
Clerkenwell has stated, in this regard, that it has gone national with its search for volunteers in an effort to deliver medical breakthroughs in mental health akin to the Polio clinical trials in the 20th Century.
Paper explores extended difficulties following psychedelic trips
A new paper has explored the extended difficulties experienced by some people following psychedelic drug use and discusses psychedelic harm reduction.
While multiple studies have shown that psychedelics can be safe when administered appropriately, some people experience difficulties following their use. These difficulties can last anywhere from a few days to years.
With a rise in clinical research surrounding these compounds, there is a drive to change drug policy and several places have already implemented progressive approaches to accessing these therapies such as decriminalisation or including them on authorised medical access schemes.
In light of these developments, it is vital to understand the potential risks associated with psychedelic use and what actions can be taken to reduce these risks.
The paper has been published in Plos One and authored by a team of leading psychedelic scientists from the Universities of Exeter, Greenwich and Queen Mary, University College London and Royal Holloway, New York University and the Perception Restoration Foundation.
Extended difficulties following psychedelic use
The team of researchers has gathered data on the context of use, nature and duration of these difficulties and explored risk factors and perceived causes that may contribute to these experiences.
The most common forms of extended difficulty that the team uncovered include symptoms such as anxiety/fear and existential struggle, as well as social disconnection, depersonalisation and derealisation.
“For approximately one-third of the participants, problems persisted for over a year, and for a sixth, they endured for more than three years,” the authors write.
The findings revealed that the length of time these experiences last following psychedelic use could be predicted by the participants’ knowledge of dose and drug type, and that the experiences were shorter if a participant had taken part in a guided psychedelic experience.
Additionally, the most common length of time such difficulties lasted was between one and three years. When asked about mental illness onset following the psychedelic experience, 18.8% said they had gone on to be diagnosed with a mental illness, while 76.8% said they had not.
The authors write: “Our findings support the results of Simonsson et al., who found that anxiety was the most common enduring difficulty, based on quantitative questionnaire data and Bouso et al’s study of the Global Ayahuasca Survey, in which ‘feeling nervous, anxious or on edge’ was the second most common adverse mental health effect. Our findings also suggest that a Sense of disconnection from others was within the top five most prevalent themes, as did the studies by Simonsson et al. and Bouso et al.
“Some extended adverse effects that were quite common in other studies weren’t so common in our data set–for example, feeling a harmful connection to the spirit world was reported by 14% of respondents to the Global Ayahuasca Survey but by less than 4% of our data set, which may suggest some forms of difficulty are particularly associated with certain psychedelic substances and/or their associated cultures.”
Reducing risk factors
The authors suggest a number of actions that could be taken to reduce these risks.
Highlighting that, as anxiety and fear are some of the most commonly reported difficulties, the authors suggest that all legal psychedelic experience providers give guidance on methods for “self-soothing and overcoming bouts of anxiety following the retreat, clinical trial or ceremony.”
Further suggestions include informing participants of potential harms and risks and advising participants that the integration process may take some time, and what practices can be done to help people cope with difficulties. The authors say these practices will be explored in an upcoming paper.
The team writes: “We envisage using the information in this study, and accompanying future papers that focus on social support and forms of coping used by those with enduring difficulties, to provide structured guidance and training to psychedelic retreats, therapists and clinical trial centers about the potential for adverse experiences, what the potential risk factors are and what can be done to help individuals who report such extended difficulties.”
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