As the neuroscience treatment landscape continuously evolves towards the wider use of precision treatment options, biomarker-led trials are emerging as a great way to facilitate better treatment outcomes for patients with psychiatric disorders.
Traditionally, trials in the realm of psychiatry have relied on either self-reported patient or clinician-rated endpoints, which have proven challenging to interpret. This is largely due to the subjectivity of the patient experience, which can cause significant variation in recorded outcomes when interpreting trial data.
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Because of this, sponsors are increasingly exploring the potential of more objective, biomarker-driven trials, which some are touting as the next frontier in patient retention.
While Dr Hans Eriksson, CMO at HMNC Brain Health and seasoned frontline psychiatry and drug development expert, backs the use of biomarker-led trials, he notes that there are hurdles that must be overcome before studies of this nature become the norm in psychiatry.
This interview has been edited for length and clarity.
Annabel Kartal-Allen (AKA): Why are sponsors increasingly opting to use biomarkers to enrol patients in psychiatry clinical trials?
Dr Hans Eriksson (HE): Psychiatric drug developers have long been looking for baseline characteristics that may predict response, which could be anything from sex and ethnicity to the severity or duration of a patient’s disorder. However, the results up to now have been quite bleak, so something more drastic needs to be done to identify patients who will benefit from treatment.
In the example of depression, which is often hereditary, it makes sense to look at the genetic makeup of patients, which remains consistent throughout their lives. By assessing this aspect, we can develop biomarkers that more accurately predict if a patient will have a positive response to a certain therapy.
Combining the efforts of good genetic guidance with non-drug approaches like cognitive behavioural therapy (CBT) will likely constitute the best approach. Biological markers can go a long way to help us, but they won’t allow us to completely solve the problem, as external factors can often have a notable influence on psychiatric disorders.
AKA: How can biomarkers help to better assign patients to the right therapies?
HE: Using a genetic test to determine if a patient has a suitable biomarker profile for treatment will allow physicians to determine which treatment will have the highest likelihood of offering benefit.
In our case, we are developing a vasopressin 1b inhibitor that we picked up from the drug’s previous developer, Sanofi. While this medicine has already demonstrated a strong efficacy signal, it seems that our genetic test, focused on components of vasopressin signalling, is able to identify a subset of individuals who are likely to obtain better outcomes from the therapy.
The vision is that when patients seek treatment for depression, the clinician can make a diagnosis and take a genetic test to determine which therapy has the highest likelihood of benefiting that specific individual. It will never provide absolute certainty, but it will allow patients and physicians to make more informed choices.
AKA: How are biomarker-led trials conducted?
HE: There are two ways to conduct a biomarker trial: one way is to assess the biomarker before the trial and use that information to assign a patient to a certain treatment, and the other is to take a sample before the trial and analyse the biomarker post-study to see how it contributed to the treatment effect. While this may sound like a trivial difference, it isn’t, as regulators aren’t keen on using non-validated biomarkers to assign patients to treatment.
In our case, we have conducted the trials in large cohorts of patients and analysed the biomarkers after the trial. While the trial was ongoing, no one knew the characteristics of each patient, and we did not use biomarkers to assign individuals to a certain treatment arm. In the current regulatory climate, I think that’s the way one has to do it.
This approach may delay results for some time, but it will allow a sponsor to obtain information on the linkage between a certain biomarker and an outcome.
AKA: What challenges may sponsors face when running biomarker-led trials?
HE: There’s a fair amount of hype around precision psychiatry approaches, which show great efficacy in a small subset of patients. When a patient goes to a clinician for treatment, that practitioner has the option to perform a test on the patient to see if they will benefit from treatment, but it takes around three weeks all-in to find out if an individual is a suitable candidate for treatment.
I think the pragmatics and clinical implementation of these precision measures pose a significant challenge, and for a method like this to become successful, you need to find a relatively large cohort of patients who will benefit from a treatment.
It’s about striking a balance between sensitivity and specificity, as you want to find a reasonably sized cohort that will gain a meaningful benefit from treatment, but you don’t want to use selection tools that will narrow your cohort down so much that you only find a very small number of patients who will benefit. It’s about finding some sort of sweet spot and thinking about what can be done to enhance treatment outcomes over the standard of care without losing too many from the addressable population.
AKA: How are regulators dealing with the shift to drug-diagnostic trials?
HE: I would say regulators have quite a modern approach to this, and there are no longer such rigid rules on how they can be used. Agencies are acknowledging that there are a number of ways you can address biology with different study designs.
Of course, regulators want to have clear evidence of efficacy and safety, but there’s a higher degree of flexibility. In the US, you can secure approval for a new antidepressant based on two positive short-term trials – typically six to eight weeks in duration, as long as you commit to run a long-term trial as a post-approval commitment.
European regulators, however, generally require long-term data to award an approval, which typically results in delayed patient access, but provides documented proof that a drug offers long-term benefit; it’s all about striking a balance here, though my preference would be more of a US approach.
AKA: How is the psychiatric market and drug development space currently looking, and what are the current trends shaping the space?
HE: The first golden age of neuropsychopharmacology was the 1950s, when the first antipsychotic, antidepressant and anxiolytic medications were developed. Currently, I’d say we’re in the midst of a second event of this nature – driven by smaller companies and startups looking to embrace the potential of drugs like psilocybin and LSD that were previously relegated to the ‘bad boy bench’ and largely abandoned.
This revolution in industry interest around psychedelic medicines is largely driven by startups and smaller companies that are looking to embrace the potential of medicines that don’t have the typical patent protection that big pharma is embracing.
However, the initial hype around psychedelics, driven by very high overall efficacy in early studies, has not necessarily materialised in larger clinical trials, and functional unblinding is still a challenge that requires overcoming.
The recent introduction of Johnson & Johnson’s (J&Js) Spravato (esketamine) as a therapy for treatment-resistant depression (TRD) also contradicted all the common know-how in the depression space, which suggested that you need to be treated for four to six weeks before you see efficacy; now there’s a medication that can make some patients feel better tomorrow.
