Helus Shares Experience Studying Adjunctive Psychedelic For Major Depressive Disorder

A conversation between Helus Pharma Chief Medical Officer Amir Inamdar, MBBS, DNB (Psych), MFPM, and Clinical Leader Executive Editor Abby Proch

As psychedelic therapies move into late-stage development, trial design decisions take on heightened importance — particularly in complex real-world settings like major depressive disorder (MDD).

In this interview, CMO Amir Inamdar discusses the strategic rationale behind Helus Pharma’s HLP003 Phase 3 program, including its adjunctive-treatment approach, patient population selection, and endpoint strategy. He also outlines how the team addressed well-known challenges in psychiatric and psychedelic trials, from placebo response and functional unblinding to site capacity and rater consistency.

Beyond design, the conversation explores operational execution, site selection and training, as well as dose selection. Combined, his insights offer a practical look at how sponsors can align psychedelic research with regulatory expectations and real-world clinical practice.

Clinical Leader: How did Helus Pharma decide which target patient population should anchor its Phase 3 program of HLP003 for MDD?

Amir Inamdar MBBS, DNB: MDD represents a larger addressable patient population compared to treatment-resistant depression (TRD). A TRD label generally places a product after multiple treatment failures and addresses the most treatment-refractory patients. An adjunctive MDD indication could position HLP003 earlier in the patient treatment journey — before they become resistant.

A study investigating adjunctive treatment for MDD also aligns with real-world prescribing, where many patients are already being treated with antidepressants, potentially avoiding the need to titrate off existing antidepressants.

What, then, was the core rationale for pursuing it as an adjunctive treatment rather than a monotherapy?

An adjunctive treatment trial design potentially offers several benefits over a monotherapy trial design in MDD.

Adjunctive therapy aligns with real world clinical practice, whereas many as 70% of treated patients are on background antidepressants like SSRIs/SNRIs.

Patients maintained on a stable antidepressant regimen may experience withdrawal symptoms if they need to discontinue their medication or taper off too quickly. Adjunctive treatment may allow patients to continue benefiting from their background medications without the need to taper off existing treatment.

HLP003, as an adjunctive therapy, has the potential to provide improved outcomes for patients who are experiencing a partial or insufficient response to anti-depressant therapy alone.  

In short, the adjunctive approach better matches real-world conditions, lowers barriers to adoption, and allows patients to avoid withdrawal symptoms and stay on their existing medications, if beneficial, while offering new options and opportunities for improvement beyond background therapy effects.

Why was the Montgomery-Åsberg Depression Rating Scale (MADRS) the right primary efficacy measure for this program, and what would have been lost by choosing a different endpoint?

MADRS is a widely used, clinician-rated 10-item scale used to assess the severity of depressive symptoms and changes in symptoms following treatment.

In major depressive disorder clinical studies, changes from baseline in MADRS total score is a common efficacy endpoint and has been accepted by the FDA as a primary endpoint in Phase 3 trials.

MADRS was designed to be more sensitive to treatment-related changes in depressive symptoms and is considered less weighted toward somatic or vegetative symptoms than the Hamilton Rating Scale for Depression (HAM-D), for example.

In a psychiatric trial where placebo response can be high, what did you do to preserve assay sensitivity?

We have several measures in place to support signal-detection in our Phase 3 pivotal program.

First, we have a rigorous patient screening process to help ensure that enrolled participants meet the appropriate inclusion and exclusion criteria. This includes structured clinical interviews and the SAFER interview: a remote, centralized assessment designed to strengthen diagnostic consistency and reduce enrollment variability.

Second, consistent with FDA guidance on psychedelic drug development, we use central, independent, blinded raters who assess efficacy without knowledge of participants’ treatment assignment.

Third, our Phase 3 program includes two complementary pivotal studies: APPROACH, a placebo-controlled study, and EMBRACE, a dose-response study with high-dose, mid-dose, and placebo arms. This design helps characterize efficacy, safety, and dose response while addressing known challenges in psychedelic trials, including functional unblinding, expectancy effects, and interpretability of treatment effect.

How did site training, rater consistency, and visit conduct factor in?

All our site staff have been trained in the conduct of the clinical trial, on the protocol, and on the study drug. Sites and site staff are trained in ICH-GCP, and we took measures to support consistency across sites and raters.

Session monitors must also complete a structured training and qualification program before they are permitted to oversee dosing visits. This helps ensure that participants are supported consistently and that study procedures are conducted in accordance with the protocol.

We follow FDA guidance on the qualifications and role of session monitors in psychedelic drug studies. Our in-house EMBARK training program is designed to prepare session monitors to support participants before, during, and after dosing, using standardized evidence-informed practices.

Also, how did you manage enrollment, retention, and visit adherence in a study population that may be dealing with fluctuating symptoms and concurrent background therapy?

For enrollment, we prioritized sites with demonstrated experience in MDD and high‑touch patient management, coupled with targeted outreach strategies (i.e., innovative patient navigator) and prescreening to ensure appropriate patient identification and expectation setting from the outset.

To support retention, we implemented proactive engagement practices, including consistent patient communication, flexible scheduling, and the use of site staff trained specifically in managing individuals with depressive symptoms. We also emphasized continuity by minimizing patient burden where possible (i.e., patient travel and reimbursement) and reinforcing the importance of study participation alongside ongoing background therapy.

For visit adherence, we incorporated reminder systems, real‑time tracking of visit compliance, and rapid follow‑up on missed or at‑risk visits. Sites were empowered with clear escalation pathways and supported by centralized oversight to identify and address early signals of disengagement. Importantly, we ensured coordination with patients’ existing treatment regimens to minimize disruption and reduce competing demands.

Together, these measures allow us to effectively manage the complexities of this population while maintaining strong enrollment momentum, retention rates, and protocol adherence.

How do you balance efficacy signals against tolerability when selecting the dose that will actually be used in practice?

Selections were informed by preclinical and dose-ranging studies showing efficacy and tolerability at higher doses.

We have seen evidence of a threshold effect, wherein symptom improvements are correlated with an emotional breakthrough we believe is triggered at and beyond certain dose levels.

Accordingly, we selected doses intended to provide exposures that balance tolerability with the potential to achieve clinically meaningful effects.

What role did durability of effect play in deciding whether repeated dosing or re-dosing should be part of the development strategy?

Durability was an important consideration in our development strategy. In Phase 2, two 16-mg doses administered three weeks apart were associated with durable improvement in depressive symptoms, including 71% remission at 12 months.

Mechanistically, we believe the first dose may open a period of increased psychological and neurobiological flexibility, during which participants can begin to reframe maladaptive patterns of thought. The second dose may help reinforce, deepen, or consolidate that process.

That said, we do not view repeated dosing as something to do indefinitely or on a fixed chronic schedule. The goal is to achieve durable benefit with limited, intermittent dosing. Additional dosing in the Phase 3 long-term extension is reserved for eligible participants who relapse or do not respond, allowing us to evaluate whether re-dosing can restore or extend benefit while balancing efficacy, tolerability, and treatment burden.

What were the biggest operational risks in running a psychiatric Phase 3 program, and which ones were most underappreciated before the trial began?

Psychedelic Phase 3 studies are operationally intensive compared with conventional daily-dosing psychiatric trials. Each participant requires substantial site resources, including trained session monitors, dedicated dosing and observation time, and careful adherence to protocol-specific administration requirements.

One of the most underappreciated risks was site capacity. These trials compete for experienced psychiatric trial sites, qualified raters, and trained session monitors at a time when multiple depression and psychedelic studies are being conducted in parallel. That creates real pressure on site resources.

Another challenge is training consistency. Each sponsor may have its own protocol, manuals, and monitor training requirements, which can be demanding for sites to implement. Over time, we have developed a much clearer understanding of these operational demands and have built additional training, qualification, and site support processes around them.

Finally, what are the most important planning lessons for sponsors that need to run a complex adjunctive program without sacrificing the trial timeline?

The biggest lesson is that infrastructure matters. For a complex program like this, sponsors should invest early in site relationships, training systems, session monitor capacity, and repeatable operational processes. The goal is to avoid rebuilding from scratch for each study. If you can train and qualify a pool of session monitors and continue working with experienced sites across studies, you reduce redundancy and improve execution discipline.

The adjunctive design also creates specific planning challenges. It is not enough for participants simply to be on background antidepressant therapy; that therapy needs to be stable. If a participant’s background medication or dose has changed recently, it becomes harder to interpret where the clinical effect is coming from.

That can create real operational friction. In practice, many patients who are not responding adequately may have had recent medication changes, or their clinician may be considering a dose adjustment or switch. Those participants may need additional time before they can be randomized, and some may be lost during that stabilization period. So, sponsors need to plan for longer screening timelines, clear eligibility criteria, and close site coordination from the outset.

About The Expert:

Amir Inamdar, MBBS, DNB (Psych), MFPM, is the chief medical officer of Helus Pharma and a qualified psychiatrist and pharmaceutical physician with more than 20 years of clinical and drug development experience. He has advanced numerous candidate medicines through preclinical development, early-phase clinical trials and proof-of-concept studies. Dr. Inamdar has also led global teams developing novel therapies across psychiatric and neurological indications, including treatment-resistant depression, narcolepsy, anxiety, schizophrenia, bipolar disorder, and substance use disorders.