Guest Column | November 16, 2023

Trial Site Selection And Design Insights For Neurodegenerative Diseases

Telemedicine human brain recovery-GettyImages-1397367749

For the past decade, Amylyx Pharmaceuticals has incorporated a myriad of voices from the neurodegenerative disease community in designing its clinical trials for NDD therapies. And now, it’s poised to commence what could be the largest progressive supranuclear palsy (PSP) trial to date with ORION, a planned global Phase 3 clinical trial of AMX0035.

Here, Amylyx’s head of global clinical development Lahar Mehta, MD, talks multi-stakeholder trial design, purposeful site selection, the importance of caregiver burden, and the benefits of an open label extension (OLE), among other contributing factors in what he hopes will be the successful execution of ORION.

Clinical Leader: The ORION trial was created with the help of patients, advocates, clinicians, researchers, and other experts. In what specific ways did their input inform the trial’s design?

Lahar Mehta, MD: Since Amylyx was founded in 2013, our decisions have been made with and for the broader neurodegenerative disease community, and we are deeply grateful for their ongoing participation in and support of our clinical programs, and for sharing their experiences with us. For ORION, we collaborated with patient advocacy groups (PAGs) and nonprofits who are dedicated to the advancement of support and care for people living with PSP, including new treatments. Additionally, we are working with a world-class expert steering committee of 13 members of the broader PSP community from across the globe, and both groups have provided their input and insights into the trial design itself as well as the identification of global trial sites that have deep experience in PSP care and trial initiation.

One example of the insights gathered was related to trying to reduce the burden of assessments for participants, some of which can be quite tiring. We evaluated several quality-of-life instruments and based on feedback from our steering committee, we selected ones that minimized the burden and were not redundant. Another example is the need to advance the scientific field. Every participant further contributes to the understanding of PSP. Hence, we heard from our steering committee that we should also collect fluid and imaging biomarkers in ORION so that this data can help with our knowledge of PSP in the future.

In designing the ORION trial, we also brought forward learnings from the development of AMX0035 for the treatment of amyotrophic lateral sclerosis (ALS), including the implementation of a participant-centric clinical trial design to accommodate the specific needs of our participants. For example, in ORION, we allowed for safety and survival data to be collected remotely, to help reduce time at the clinic as longer sessions can be challenging for people living with PSP (many of whom experience fatigue).

With an enrollment goal of 600 participants across North America, Europe, and Japan, ORION is poised to become the largest clinical trial for PSP. How has Amylyx arrived at that goal, and why is reaching that many patients a priority?

There is an incredible unmet need within the PSP community for new and effective treatment options, as there are currently no disease-modifying therapies approved for the treatment of the disease. As a company rooted in ALS research, we understand the urgency to move as quickly as possible across our pipeline to advance research and potential new solutions for these communities who don’t have time to wait.

The previous trials we’ve run for AMX0035 have answered the key questions that a Phase 2 trial seeks to address (including validating efficacy and further evaluating safety) so that we could swiftly move into a large Phase 3 trial. We determined effective dosing as part of our Phase 2 CENTAUR trial of AMX0035 in ALS, generated safety and tolerability data, and clinical outcome data in ALS, and separately in the Phase 2 PEGASUS trial in Alzheimer’s disease observed that AMX0035 significantly lowers tau and generated safety and tolerability data.

We also felt since PSP is rapidly progressing, we would lose vital time by separately conducting a Phase 2 study for two years and then take another two or three years to conduct a Phase 3. Since we have seen a clinical effect in ALS, which is another devastating condition, it was natural for Amylyx to seek to reduce development time. We are excited about the strong scientific rationale supporting AMX0035 in PSP and the best way to evaluate this potential efficiently is by running a large Phase 3 study with a validated endpoint that is well-powered. 

The ORION trial will include patient populations in three distinct areas of the world. What is the significance of including these patient populations and markets?

PSP is a global disease affecting about seven in 100,000 people worldwide. As neurodegenerative diseases have no geographical boundaries, we are working as quickly and efficiently as possible to advance our R&D efforts around the world where there continues to be a significant unmet need. We took learnings from previous large, global, multicenter PSP trials and applied them to our approach in designing and operationalizing our ORION trial.

The ORION trial has inclusion and exclusion criteria consistent with past PSP studies and we’re identifying the same investigators and sites that participated in past studies. We believe that this established network, along with our collaboration with the PSP advocacy community, will enable us to enroll the trial effectively across the U.S., Canada, Europe, the United Kingdom, and Japan with the goal of recruiting around 600 participants, which would make ORION the largest clinical trial in PSP to date.

There are several factors that we consider when choosing countries for our clinical trials, including:

  • Strong support from the broader community, including advocacy associations and clinicians, for new, safe, and effective treatment options.
  • Access to concentrated populations of study participants, for established example centers of excellence with active interest in trial participation and enough people to recruit for the trials.
  • Regulatory pathways that are clear and achievable.

The study design incorporates several criteria, including the need for a study partner. How did your trial design plan for and accommodate the needs of a study partner? In other words, what elements of trial design, such as any decentralized components or reimbursement options, did you incorporate?

Given the unique challenges that a person living with PSP may face, including issues with mobility or speech, it was important to accommodate a study partner who may be a caregiver, friend, or family member in this context to provide support to during the 52-week trial.

Our primary and secondary endpoints aren’t captured remotely - having them measured during the clinic visits would help ensure standardization of collection and measurement of these endpoints.

We do also allow for reimbursement for reasonable expenses  (such as travel or meals) for both the participants and their caregivers so that out of pocket costs are not a barrier to trial completion.

Caregiver burden is also among the list of exploratory outcomes to be assessed from baseline to week 52 of the trial. Interestingly, this is an outcome not experienced first-hand by the patient, which is most typical, but instead by the caregiver. How is that outcome measured, and why is that considered important to the overall success of the investigational therapy?

For a neurodegenerative condition such as PSP that is looking to measure the rate of disease progression compared to placebo, it is important to also recognize and assess the impact of the disease on caregivers.

We will measure caregiver burden using the Zarit Burden Interview (ZBI), a self-report questionnaire that consists of 22 items that assess the caregiver’s perceived emotional, physical health, social life, and financial consequences of caregiving. Each item is scored on a 5-point Likert scale, with higher scores indicating greater burden. The total score for the ZBI ranges from 0 to 88, with higher scores indicating greater overall caregiver burden.

We hope that these data will elucidate the potential impacts of the drug beyond the participants and provide valuable insights to the community.

The trial is followed by a 52-week open label extension phase for continued access to AMX0035. How did Amylyx arrive at the decision to embark on an OLE? And how does this impact the potential success of the drug as well as the participants who’ve completed the randomized portion of the trial?

For neurodegenerative conditions, we believe that open label extensions offer opportunities to study PSP in a different way. First, we ask a lot for participants to volunteer their time and take the chance of being on a placebo for 52 weeks. So, it is appropriate to offer them the chance to receive AMX0035 after the double-blind treatment period. Second, data from an OLE can examine if there are benefits in starting a disease modifying therapy early or if it would be beneficial to wait. This is often a question that comes up in clinical practice. Thus, an OLE can provide insight into how those who were on continuous treatment (started earlier) fared compared to those who started later (i.e., participants who switched from placebo to active drug). Third, open label extension phases have been incorporated into our trial programs in ALS, for both our completed Phase 2 trial (CENTAUR) and our ongoing Phase 3 trial (PHOENIX).

About The Expert:

Lahar Mehta, MD, is currently head of global clinical development at Amylyx Pharmaceuticals. He has over 11 years of biopharmaceutical clinical development experience in several organizations including Alder Biopharmaceuticals, Amgen, and Biogen. Mehta has led clinical development team activities across a variety of CNS conditions including multiple sclerosis, stroke, and migraine. He has represented clinical development for successful U.S. regulatory approvals for both VYEPTI (eptinezumab) in migraine prevention and RELYVRIO (sodium phenylbutyrate and taurursodiol) in amyotrophic lateral sclerosis. Mehta received his medical degree from Meharry Medical College and completed his neurology residency at the University of Utah. He completed his postdoctoral training in neuroimmunology and experimental therapeutics at the University of Rochester.