CEO Michael Wyand: Oxeia Interviews, Part 1
Michael Wyand is the CEO of Oxeia Biopharmaceuticals. Oxeia is a clinical-stage biotech company developing a drug treatment for concussion to address underlying neuro-metabolic dysfunction and axonal injury. OXE-103 is a synthetic form of the hormone ghrelin that is known for stimulating appetite. The company will be starting Phase 2 clinical trials in September 2020.
We also interviewed Dr. Vishal Bansal, Co-Founder of Oxeia, whose research into ghrelin for brain injury was the inspiration for the founding of Oxeia.
Concussion Alliance Co-Founders Malayka Gormally and Conor Gormally, and Leadership team member Julian Szieff interviewed Mr. Wyand in March about his work with OXE-103 and upcoming clinical trial. The interview has been edited for clarity and adapted for the Web by Cassidy Bins, with additional editing by Galen Moller.
Why was Oxeia founded? What makes the molecule ghrelin different from other molecules being studied for concussion therapy?
Conor Gormally
So the first question is the bigger picture, what do you see as the biggest challenges to the development of OXE-103, and any specific issues that you guys are starting to find with thinking about how Emergency Rooms are going to adopt this?
Michael Wyand
Dr. Vishal Bansal, the Co-Founder of Oxeia, was a trauma surgeon with the University of California San Diego. In the course of his research on TBI, he learned about the molecule ghrelin, and saw a profound effect in mTBI or concussion.
I joined Oxeia in 2017 when the company was ready to sign a license to the ghrelin technology from Daiichi Sankyo Co. Ltd. This Japanese pharmaceutical company had been working with ghrelin since its discovery in the late '90s.
Because Daiichi had performed preclinical animal studies and tested the drug extensively in people, there was a good database of safety data. This included all the pharmacokinetic and pharmacodynamic studies necessary to show how to dose the drug.
The challenge of being the first potential drug for concussion to go through the FDA review process
Michael Wyand
There are no approved drugs for concussion, so the FDA has never gone through a review process, and there are no other drugs to compare to. The investment community that supports biopharmaceutical development looks at what drugs come before, what the endpoints of trials are, how those drugs have performed. They look at your new technology to compare it to previous drugs.
Why concussion patients get lost in the medical system
Michael Wyand
Historically, the neurosurgeons have focused on more severe head trauma, including the people who were in comas or with severe physical disabilities that required months or years of physical therapy.
Most people do not go to the emergency room with concussions. If they do and a CT scan shows there is no brain bleed or other serious injury, a diagnosis of concussion is made, and more serious injuries demand the ED doctor's attention. Patients with concussions are typically instructed to "go home and rest."
Rest is not enough. In fact, rest is probably not the best thing to do. More recent studies suggest that it is important to continue to stimulate the brain, increase cardiovascular function, and provide blood and oxygen to the brain after the injury. As a result of these ED circumstances, patients go home and frequently get lost to the medical system.
Could ghrelin be the first drug specifically for concussions?
Michael Wyand
A significant percentage of people continue to experience concussion symptoms post-injury, and they seek further medical help from neurologists or sports medicine doctors.
There are some drug interventions that can treat specific symptoms. For example, there are drugs for headaches or depression. However, there are no drugs available that treat the basic injury and problems that occur following a concussion. Ghrelin may be the first drug to have a broad-spectrum effect on the injury.
What is the FDA looking for in a concussion drug?
Julian Szieff
What was your process with the FDA like, and where are you guys at in that process?
Michael Wyand
We have had what's called a Pre-IND meeting. The goal of this meeting is to ensure that the drug development plan and future trials are acceptable to the FDA. Among the feedback we received from the FDA discussion was that the drug should demonstrate 1) that it treats a constellation of symptoms and not just one or two symptoms and 2) that it has an effect on the way a patient feels and/or functions.
How will the trial measure whether OXE-103 helps concussion patients?
Michael Wyand
One of the major sets of endpoints we've chosen are patient-reported outcomes. Lots of neurologic drugs are approved based upon patient-reported outcomes. For example, migraine medications are based on how the patient has reported on their migraine symptoms and how they feel or function while on the migraine medication.
The second area for our trial are cognitive measurements: short-term memory, decision-making and cognition. Those can be measured with tests that are available on iPad-type devices that can quantitatively and objectively measure higher-level executive functions across a number of areas. Balance and stability can actually be assessed by holding an iPad and measuring your ability to stand up straight.
We'd also like to do some advanced MRI-type imaging in cohorts of our patients. There have been some very interesting studies that demonstrate that some of the advanced MRI techniques can detect metabolic changes 90 or 100 days after a single injury.
How is the trial going to measure the wide range of concussion symptoms?
Conor Gormally
I'm sure you're aware there's a laundry list of symptoms that can be associated with concussions and different injuries. Even different injuries in the same person can elicit different types or clusters of symptoms. A lot of what we heard at the 2020 North American Brain Injury Society (NABIS) conference was people trying to figure out what they're assuming are subtypes of concussions. For example, Geoffrey Manley (UCSF and TRACK-TBI NET) was talking about his estimate, based on some machine learning work they are doing with advanced imaging, that there are 25 different subtypes of concussions. This is a very rough estimate. But I'm curious which symptoms you are going to be asking your patients about in the clinical trial.
Michael Wyand
We are using a 22-symptom scale, the Post-Concussion Symptom Scale, that covers symptoms in the cognitive, emotional, and physical domains. Dizziness is an example of something in the physical domain, whereas depression is a symptom in the emotional domain.
It's clear that different types of symptoms will be emphasized or presented in different patients. One of the problems with a symptom scoring tool is that, if you have 10 symptoms scored at a 1, your score is a 10. If you have 2 symptoms that were severe and scored at a 5, you have still have a score of 10. These represent two very different patient populations.
We've looked carefully at work coming out of Michael McCrea's laboratory in Wisconsin. He's done some statistical studies looking at which symptoms tend to correlate most closely with the resolution of concussion. He's narrowed those symptoms down to 12. Further analysis showed that emotional symptoms are not easy to diagnose in the early parts of the injury. Depression and sleeplessness do not present immediately after a concussion. By removing the emotional symptoms, there are a smaller number of symptoms that can be measured in the first few days of the concussion.
Research showing that ghrelin has neuroprotective effects
Michael Wyand
The literature on ghrelin related to neuroprotective and neuroregenertive effects is extensive. Dr. Bashal has published some of that work based on research done in his laboratory. The pleiotropic [multiple] effects of OXE-103, and the naturally occurring ghrelin peptide, may significantly improve the way patients feel and function after receiving a concussion.
Treatment with OXE-103 has been shown in numerous animal and laboratory studies to restore normal energy metabolism, increase appetite, and reduce the toxic effects of reactive oxygen species that form in low energy states. OXE-103 also has effects on the axonal wiring system of the brain which improve information flow and increase the connections between nerve cells.
Phase 2 Trial: Collaborating with a neurologist at a concussion center
Malayka Gormally
I was wondering where you are on your timeline. You identified the challenges, such as raising money. We read your interview in S&P Global in 2018, and you listed a couple of stages: an observational trial, an open trial with 30 to 40 patients, and then the randomized control Phase 2 trial. I'm wondering where you are in that lineup.
Michael Wyand
We are ready to start a Phase 2 trial with a neurologist experienced in treating patients with persistent concussion symptoms. The trial will enroll 40 patients with significant concussion symptoms within 28-days of injury. Subjects who meet eligibility criteria will be randomized 1:1 to treatment with OXE-103 or placebo and followed through day 44. The trial will test the ability of OXE-103 to reduce concussion symptom burden over the study period. Measures of symptoms, cognition and balance will also be assessed to provide an objective assessment of recovery.
*The goal of a Phase 1 trial is to determine whether or not the drug is safe in humans. Oxeia has already undergone a Phase 1 trial. The goal of a Phase 2 trial is to determine whether or not the drug works as intended. Oxeia's Phase 2 trial is not double-blind or placebo-controlled.
Recruiting patients from the ER
[The first part of the Phase 2 trial will study concussion patients who have visited a specific neurologist at his/her concussion center. The second part will study ER patients who are referred to a study-specific neurologist by ER staff.]
Michael Wyand
We are currently raising money to study another group of patients in our Phase 2 trial. These are patients who have visited the emergency room, been diagnosed with concussion, and who will be treated within 24 hours of their injury. We want to look at the effect of treating patients who have a concussion within the first 24 hours of injury compared to patients treated days to weeks after the injury, following the same treatment regimen as in the first part of the Phase 2 trial.