Tell us about the scientific foundation behind the Spectris ADTM device.
Our non-invasive investigational Spectris ADTM device evokes 40 Hz brain gamma oscillations through audiovisual stimulation. It’s delivered in a daily one-hour treatment at home. There are a number of scientific principles behind the use of light and sound to generate this activity. Those 40 Hz oscillations are a resonant frequency known to be essential for everyday cognitive functions like sensory processing, learning memory consolidation and basic housekeeping functions like maintaining network coherence, brain plasticity and glymphatic functioning.
After a number of initial clinical experiences in human studies, we were able to show in our OVERTURE feasibility study that there was significant preservation of daily behavioral function, network function and brain structures in terms of brain volume.
How did you design clinical trials for this device and approach?
The choice of Alzheimer's disease was driven by preclinical and preliminary clinical research, with the design of Spectris ADTM then based on extensive user experience research. We essentially designed a simple, intuitive system that could be used by people with Alzheimer’s-related cognitive impairment every day at home and we found it was a good fit for the technology we were developing. We completed the 74-patient feasibility study and then designed and have almost fully enrolled a 670-patient pivotal study (HOPE).
We designed the HOPE study as a traditional double-blind Alzheimer’s study where we use a randomization of active treatment and sham. We kept the one hour per day treatment that we used in OVERTURE to minimize any differences there. We also used a similar population: for OVERTURE the MMSE range was 14-26 and in the HOPE study the MMSE range is 15-28 inclusive. We’re studying mild-to-moderate Alzheimer’s. The main functional outcomes we are looking for include the ADCS-ADL, which is a 23-item scale used by many trials to measure daily functioning and cognition as measured by the MMSE, a cognitive scale widely used in clinical trials and medical practice. We then combine them into a composite in our study as an outcome measure where we use an equally weighted mix of ADCS-ADL and MMSE (iADMARS), similar to what Eli Lilly did with iADRS, in a trial where they combined iADL with ADAS-Cog. It’s a very traditional approach to Alzheimer’s trials.
"At the end of the day, the most important piece of a trial, regardless of the modality, is patient safety and data quality."
How has your trial design evolved from feasibility to pivotal?
There are a few key differences. The feasibility study was a six-month randomized trial with a 12-month open label extension. Our pivotal study is a 12-month randomized trial with a 12-month open label extension, which will provide us a total of 24 months of experience with the treatment to better measure its durability.
What lessons did you learn in going from a 74-patient study to a 600+ patient study?
Aside from the obvious additional workforce we needed to make this happen, because this is a device trial, there were some specific considerations that needed to be put in place. We need a dedicated tech support function integrated with the clinical trial. Its role is to onboard patients, provide device training and monitor adherence. This team also interacts with participants if they have any questions about the device or if we see that there is an adherence issue or to provide customer support that returns calls within 24 hours. The device itself also has audio prompts that take people through the treatment each day, which is probably the most important piece to ensuring adherence.
The other piece that's really important is that we evaluate the device in each participant for tolerance and gamma response (T/GR) to confirm target engagement prior to study randomization. We optimize the device settings for each person so that we know everyone in the trial has a response confirmed at the outset of their inclusion. With drug trials, adherence and compliance are very challenging. We have an advantage as a device because we can measure device use real-time while maintaining study blinding.
"We cannot forget that our goal is not simply to advance science but to address patient needs using scientific approaches."
As someone who has been CMO both of a therapeutics company and device company, what are some of the similarities and differences?
A big difference between my prior roles – which were mostly in complicated biologics and specialty pharma drugs – and my current role is that the adverse event profile of biologics and drugs is very different than a non-invasive device. Cognito had a much easier time than in some of the pharmacological approaches in terms of safety. It’s also easier to provision the device and send it to people’s homes when compared to the complicated process of provisioning autologous cell therapies.
At the end of the day, the most important piece of a trial, regardless of the modality, is patient safety and data quality. And we've put into place a lot of very important measures, including source data verification and optical character recognition to prevent keystroke errors and transcription errors of the data. We also monitor the data to make sure that there are no unusual changes in scores. And we do intensive MRI monitoring of treatment outcomes, which is important as an objective measure of treatment efficacy to support clinical outcomes that are clearly important to patients. All of this while having procedures in place to maintain study and data integrity, including blinding.
How did patient input influence the design of your trials?
In the study design itself, we wanted to minimize participant burden as much as possible. Therefore, we have been very cognizant about using clinically relevant outcome instruments that require less time and are less burdensome. Also, the nature of our treatment lends itself to be patient friendly. The patients in our trial expressed a strong interest in being part of a non-invasive device treatment as opposed to a pharmacological treatment.
We cannot forget that our goal is not simply to advance science but to address patient needs using scientific approaches. We need to start with the patient and find out what they need and adapt the science so we can give them a usable solution.
"I don’t think there’s a magic formula but maximizing diversity needs to be one of your mission objectives."
How can CMOs better engage diverse populations of patients?
We’ve been fortunate to partner with a Global Alzheimer’s Platform (GAP) with a clinical site network across regions. This has allowed us to thoughtfully select sites that match our criteria and that already have community outreach connections with diverse populations. We have also done our own advertising for our study through diversity organizations as well as hosted local events where people of all backgrounds can learn about options to treat Alzheimer’s.
It’s a lot of hard work. I don’t think there’s a magic formula but maximizing diversity needs to be one of your mission objectives.
Anything else?
As a community, when thinking about finding solutions for a disease, we need to work backwards from the patient. What do patients and their families find important? Taking that approach will lead to more meaningful results.
