AMO Pharma Works With FDA To Advance CNS Trials

By Ed Miseta, Chief Editor, Clinical Leader

AMO Pharma is developing treatments for serious and debilitating diseases including rare genetic disorders. The company currently has three products in its pipeline addressing Phelan-McDermid syndrome, congenital myotonic dystrophy, and Rett syndrome. 

Congenital myotonic dystrophy is a genetic disease that is present at birth. The most challenging symptoms are predominantly CNS related and include difficulty with thinking and problem solving, weakened muscles, and difficulty with speech, hearing, and vision. Conducting clinical trials with these patients is difficult, and that challenge has heightened with the precautions arising from the COVID-19 pandemic.

“For our Phase 3 clinical trial we opted to focus on children with symptoms that were present at birth,” says Mike Snape, PhD, CSO of AMO Pharma. “That means we will treat children or adolescents who may have cognitive and learning disabilities. They may have speech problems or have difficulty staying awake. Many will be unable to simply interact effectively with the world and understand what's going on in it.”

Those children will generally be brought into a clinical trial environment by a caregiver. They may also have mobility issues. Therefore, taking part in a clinical trial is difficult. For both the patient and caregiver, just getting out of the house can be an enormous challenge. 

A Patient Centric Approach

When COVID-19 began to impact trials in March 2020, sponsor companies began a search for patient centric approaches that would facilitate continued participation. AMO Pharma was no exception. In fact, because of the condition of the patient population, it was even more vital to keep them safe. Snape notes AMO Pharma was implementing patient-centric measures even before the pandemic hit.   

“We always felt it was important for things like at-home safety assessments to be built into our trials,” he says. “But that raises other interesting questions. For example, if someone is at home sheltering in place, will they want someone from the outside coming into their home? There are some things you can do via telemedicine visits, but there are measurements, like an EKG monitor to check heart function, that cannot. It is also no secret that the ideal assessment of whether a drug has efficacy is performed in a clinic. I think the ideal situation is to implement things like telemedicine and home visits as an insurance policy. The primary objective should be finding sites that are safe and accessible for patients.”

For CNS disorders, the challenges of implementing virtual technologies are related to both the patients and the technologies. Years ago, a patient would enter a clinic and a physician would take measurements and record them on a case form which could be properly anonymized. Today, the security and privacy of the patient is a greater concern. 

“There are many questions to answer,” says Snape. “How do you demonstrate to a regulator that telemedicine visits actually took place? What is the source document? How was it timestamped? How was it recorded? And how does a hospital ensure something that must be recorded was done to proper standards of confidentiality and anonymization? I feel the industry is not ready to answer all of those questions.”

A Technology And Training Problem

Performing virtual visits is still a challenge. There are two issues and the first is technology. Snape notes there is no single solution for remotely connecting with patients. Zoom is a great platform, but it is not a validated, FDA-compliant system. Hospitals can establish their own systems by taking a commercial offering and making it valid and compliant. They could also build something from scratch or purchase a proprietary platform that is FDA validated.  

“There is no one solution for everyone to use,” he says. “We have worked very hard with a specific provider to get a solution that's acceptable to all of the sites that we want to use in our clinical study. We are close to having the solution in place, but it was not an easy undertaking. This is a technology problem the entire industry is dealing with.”

Even with a technology solution in place, another challenge remains. Snape believes the best way to gather FDA-acceptable data on developmental disorders is to have a clinician or a caregiver be specifically trained to implement a scoring system. That scoring system would capture the severity of a specific symptom. The question is, can a clinician perform that task over a telemedicine platform?

“I believe you can,” states Snape. “But, to make it work properly, there needs to be a very specific training system to do that. This is true even if the assessment is being performed in the clinic. So, what we need is a very specific training system to do that over a telemedicine platform. We need to roll that out, validate it, and have the FDA accept it. That issue will continue to be a challenge.”

Protocol Development

Every successful CNS trial begins with designing an effective protocol. Snape believes his team is in a good position to do that. He notes the team has experienced success in gaining FDA approval for pediatric neurology products. Those approvals involved capturing data on developmental disorders. The management team also has close family involvement with the target conditions. The main question is always determining how to measure the condition of a patient.

“The rest of the clinical trial design is pretty straightforward,” says Snape. “You decide if you need a placebo group and how long you should treat the patients. Those things are easy to determine. The central issue in a rare genetic developmental disorder is the measurement method. We are treating a small number of patients and dealing with a rare developmental disorder that half the world has never heard of. For those diseases, unlike hypertension or diabetes, there is no defined way of performing the measurements.”

The measurements require accuracy and the approval of regulators. For some, it may seem counter-intuitive to have trained physicians look at the cardinal features that differentiate a developmental condition and characterize and score them. Some in the industry also believe if there is no gold standard for measuring a patient’s condition, then you pick the next best option. For example, if there is not a standard for measuring syndrome A, but you know those patients suffer from anxiety, then you use the best anxiety measure that is available. Or if you know those patients also have severe muscle issues, there are ways of measuring muscle function. Unfortunately, neither of those approaches really get at the heart of what the FDA would like you to measure.

For example, in the past the AMO Pharma team has worked closely with other companies that also have an interest in a condition known as fragile X syndrome. When the team got involved with the disease there was no FDA agreed way of measuring symptoms. Other companies working in the disease were using a variety of methods to measure anxiety, hyperactivity, and other disease symptoms. Working with the FDA, experts in the field, and all published literature on the disease, the team was able to build a specific rating instrument that would capture all of the characteristics that clinically define someone as having fragile X syndrome.

“FDA was able to approve use of this measure,” says Snape. “And that is also what we have been able to do with congenital myotonic dystrophy. That is important for a couple of reasons. Our investigational medicine treats the very biological basis of this disorder and it penetrates all organs of the body. What we are trying to prove is that the drug could potentially improve any symptom, if not all the symptoms that a patient has.”

A Better Measurement System

Of course, if researchers use a computer to measure the strength in the right index finger of every patient, that method of measurement will not determine whether a patient’s autism, learning disabilities, or any other symptom has improved. Measuring any functional task adjacent to the disorder is, by definition, too limited to explore the main benefits regulators and the community are interested in.

Additionally, it may seem that using a computer measure will make measurements less prone to human error. Although that thinking seems perfectly reasonable, Snape notes that even though a computer gathered the information, the human factor involved in putting a patient in front of a computer or keeping them attending to a computer introduces just as much human error.

“If we set up a very specific set of instructions, training, and qualification for the caregivers or clinicians as to how to assign a number to each of the symptoms that characterize this disorder, we can come to information very accurately and detect change very sensitively. We are also doing it in a way that FDA recommends.”

Snape also recommends working closely with the FDA. He notes regulators have seen all current development programs and know what works and what does not. When the FDA provides guidance on their current thinking, Snape strongly advises reading the guidance document and making that your starting point.

Partners Assist With Trial Conduct

AMO Pharma’s treatment for congenital myotonic dystrophy is a liquid that patients drink once a day. AMO has completed a Phase 2 study and has a Phase 3 study planned for the fourth quarter of 2020. COVID-19 has necessitated greater involvement with the FDA and forced the company to introduce some telemedicine components to protect the safety of patients.

AMO worked with technology provider iTakeControl to implement a telemedicine platform that helped keep patients safe. The platform allowed AMO to collect data while remotely engaging with patients.

“iTakeControl is a boutique firm that specializes in rare diseases and genetic disorders,” says Snape. “We wanted any solution we implemented to be audited, compliant, and validated. iTakeControl met all of those requirements and it provided training and relevant information to our trial participants and provided mobile notifications and alerts, and could capture text, audio, and video recordings.”

AMO does work with CROs although Snape notes he prefers to work with smaller, more boutique firms specific to the areas in which the company is conducting a trial, such as Australia or New Zealand.

“We really use them to operationalize the site-specific activities on our behalf,” says Snape. “The smaller CROs tend to have something special about them. For example, if you wanted to conduct a trial in Canada, you can find a small CRO that is incredibly good at working in Canada. That does not mean the larger CROs can’t do the same thing, but they may not have that specific expertise. You may also find one that has a lot of expertise in your therapeutic area, such as developmental disorders. Their study coordinators will know the industry experts and understand the language of the disease. That expertise is very helpful to us.”

Snape concedes there is also the fear that a large CRO partner might land a massive contract from a top 5 pharma company, which could pull staff away from your project. Higher rates of staff turnover can be an issue with larger CROs as well. He believes smaller sponsor companies would have a hard time competing with the bigger companies because of the money being spent.

“With some of the smaller boutique CROs, I have been their only client,” he says. “That means at any given time I am getting 100 percent of their attention.”