From The Editor | May 22, 2017

AMO Pharma Addresses Rare Childhood Disease

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader

orphan rare disease

AMO Pharma is a virtual biotech with a focus on rare disease. The company’s CEO, Mike Snape, knows rare diseases have become an important healthcare issue, noting that everyone today knows someone whose life has in some way been impacted by a rare disease.

“Rare diseases are bad enough, but the ones that affect children are even more heartbreaking,” he says. “The medical need in these areas is greater than ever. They also present challenges for drug developers, especially with clinical trials.”

The children treated by AMO Pharma therapies have serious disorders that are life-threatening and have no treatment options. For that reason, the company searches for therapeutics which have had prior exposure to human beings. By doing so, the company is able to acquire compounds that have been “de-risked” and can reach patients in a timelier manner. By taking this approach, the company is moving as quickly as possible to get patients into a potentially life-saving clinical trial.

Recruitment Numbers Are Small

When you deal with rare diseases, finding patients can be a challenge. When you opt to focus on rare diseases impacting children, who represent only 20 percent of the population, you are taking a rare disease and making it even rarer.

“Over 350 million people have a rare disease, half of them are children, and 95 percent have no approved treatment,” says Ibraheem Mahmood, an advisor and non-executive director for AMO Pharma and president and CEO of DrugDev, a provider of clinical trial technology. “Many people don’t know that 80 percent of these diseases are genetic in origin. That’s an amazing opportunity, because once we determine the gap in the genetic code, we can begin to develop a solution. Given the tragic backdrop, it’s an exciting opportunity for companies such as AMO Pharma to find concrete solutions with the proper focus and dedication.”

AMO Pharma’s lead molecule is intended to treat congenital myotonic dystrophy. A quarter of children born with this defect will die in their first 18 months of life. Less than half of them will live to adulthood, and the ones who do will have significant mobility issues. They might not be able to walk, and they will almost always have cognitive disabilities and other life-threatening conditions. For that reason, AMO Pharma could potentially be conducting a clinical trial with less than 10 individuals.

“For a pharma company, that means we have to find the patients, we have to be careful about who we do and don’t allow in the trial, and we have to remain focused on the patients we have and think very carefully about them as the trial evolves. When you start with a small number of patients, you cannot afford to lose a single one.”

Although finding patients is difficult, this is both a challenge and opportunity for sponsor companies seeking to recruit them. Because these conditions are rare, the patients who are known to be afflicted will gravitate to a small number of specialist sites. There will also be motivated patient advocacy groups representing them and setting up registries.

On the flip side, the biggest obstacle is finding patients who have been properly diagnosed. Because these are rare diseases, it often takes time for physicians to recognize the disorder. In the U.K., there are two pediatric hospitals dealing with rare disease patients. This is where AMO Pharma does much of its recruiting. People with rare and fatal diseases are highly motivated. When a study offers even a slight amount of hope, word quickly gets around the patient community.

Measuring What Hasn’t Been Measured

Since AMO Pharma is working on diseases where there are no approved treatments, there will be no gold standard against which to measure. Therefore, the company spends a lot of time speaking to caregivers, patient groups, and expert physicians in the space to determine what it should be measuring in studies.

“Some of the things we are measuring have not been measured before,” states Snape. “The process we go through involves finding the right patients, thinking about the right outcome measures, doing what we can to keep those patients in the study, and thinking about what will happen to them at the end of the study. There are a lot of complex issues we have to consider that are specific to the rare disease space.”

The initial study in congenital myotonic dystrophy will be focused in the U.K. If the study meets the set objectives and offers proven benefit to patients, it will be expanded across multiple countries in order to recruit more patients. The patients participating in the trial will receive a drug that has been shown to cause the division and specialization of progenitor cells and stem cells. In layman’s terms, it enables patients to grow tissues where tissues haven’t grown previously. If a child fails to develop muscle tissues, the therapy stimulates the muscle cells to divide and differentiate into actual muscle tissue and then grow new muscles. The treatment is administered to the patients in the form of a strawberry-flavored drink. 

For Patients, Bad News and Good News

For sufferers of orphan diseases, there is both good news and bad news. First, orphan diseases tend to be ailments a person is born with. In essence, the afflicted children are often missing a piece of their biological machinery. This accounts for the relationship between children and orphan diseases. That’s the bad news.

The good news is, if the children are missing a piece of their biology, an understanding of the issue can be scientifically straightforward. Researchers or physicians can examine the patients and determine the missing biological component.

“I like to think of the human body as a series of dominos falling,” says Snape. “There is a series of biological events that happen, one after another, using things like enzymes. If that’s the case, then it is possible to use a drug to create an alternative pathway. You might even be able to replace the missing piece of machinery. If you look at Shire’s drug for Gaucher’s disease, it is just a replacement for the missing enzyme.”

With the congenital myotonic dystrophy program, AMO Pharma is not trying to prevent the condition from getting progressively worse. Rather, the goal is to reverse existing symptoms, and, ultimately, restore a patient to normal activity. One thing that will help demonstrate efficacy are natural history studies. They are usually run by patient groups, and there is a patient group for this condition. The group will collect information on patients to understand how the disorder is manifest and what outcomes one might measure. That information can then be converted into a rating scale.

Other tests, such as walking a specified distance, can also be used to show improvement. To check whether a patient has intellectual disabilities, there is an iPad-based test that is similar to a video game. By asking the children to identify various objects on the screen (e.g. a red dog), researchers can perform an assessment of the individual’s functional intellectual age. Various scanning techniques can also measure the amount of lean muscle mass that patients have in their torso, legs, arms, and toes. This allows researchers to determine whether patients are developing new muscle growth. 

In addition to trial design and treatment decisions, technology tools provided by companies such as DrugDev make it easier for sites and patients alike to participate in the trial. “Using electronic patient informed consent with animated videos that translate complex concepts into common language can have a significant educational impact for families,” says Mahmood. “In fact, across therapeutic areas, research shows this increased understanding leads to improved patient retention which is essential for rare disease trials.”

Online training modules, centralized support documents, awareness campaigns, and patient enrollment tracking tools are very helpful to keep the trial top of mind, and running smoothly, at global sites. As these systems become more ubiquitous in clinical research, sites are able to spend less time on operational details and more time focused on the patients and families who need their attention most.

The Need for Flexible Trials 

Another theme Snape believes applies to rare disease trials is the fact that the companies involved are exploring new frontiers. Every study is genuinely exploratory. “Everyone knows what they’re trying to measure when they’re running a cholesterol study or a diabetes study,” notes Snape. “But in a rare disease trial, we are always trying to work out exactly what we’re looking for and how to best measure it. Add in the limited number of patients, and it becomes clear researchers need to extract the most information possible from them. That creates the need to have a lot of flexibility in the trial design.”

For many drugs entering clinical trials there is a standard dose. It is not adjusted for the subject’s weight or other factors. In an orphan drug scenario, those factors are carefully considered to make sure the drug has its best chance to work. When 10 patients are available for a study, and all are at risk of death, you cannot afford to lose half the patients simply because they don’t meet the inclusion/exclusion criteria. In other trials, a person who is very thin or atrophic might be rejected from a more typical study. “With rare diseases, we cannot always afford to do that,” says Snape. “We have to be flexible and consider every patient to be a potential candidate. We have to be able to integrate more flexibility into these studies than you would find in a conventional study.”

Rejecting a sick child from a study also can create some uncomfortable conversations with parents and caregivers. If you are measuring cholesterol with a statin, you can easily send someone home if their cholesterol is not in the range that makes them a good candidate for the medication. The situation is different when a child has a disorder that is life-threatening. Even if the child does not meet a certain inclusion/exclusion criteria, it may be in the best interest of the patient – although not in best interest of the study – to give them the medication. In these cases, on an ethical level, turning down a patient is often not an option.

“How do you explain that to their parents?” asks Snape. “Sometimes you just can’t. Sometimes you say, ‘Your child is not the best candidate, but we are going to admit them into the study, or find another way to make the drug available to them.’ From a human point of view, we believe it would be wrong and irresponsible to not find a way to help.”