Rare Disease Report

Hartmann Wellhoefer, MD On Challenges Faced & Advances Made in Fight Against MPS

SEPTEMBER 28, 2018
Rare Disease Report® Editorial Staff
Hartmann Wellhoefer, MDIn a recent interview with Rare Disease Report®, Hartmann Wellhoefer, MD, vice president of medical affairs, Rare Diseases and Internal Medicine, at Shire, discussed the biggest challenges faced and advances being made in the fight against mucopolysaccharidosis (MPS), a group of rare, hereditary, and incurable conditions for which only a handful of treatments are available.

Dr. Wellhoefer also highlights key takeaways from the 15th International Symposium on MPS and Related Diseases (ISMPS) which was held from August 2-4, 2018 in San Diego, California. Through the symposium, the MPS community was provided with an opportunity to learn more about the latest research being conducted in the field as well as share personal experiences to boost awareness and improve patient care.

Rare Disease Report ®:  You recently attended the 2018 International Symposium on Mucopolysaccharidosis (MPS) and Related Diseases. Can you tell me about this conference?

Dr. Wellhoefer:  The ISMPS is one of the most unique congresses I’ve ever attended because of the presence of patient advocacy groups, patients, their families, and caregivers, as well as physicians and industry representatives. You actually hear children chatting and laughing in the hallways of the Congress, and more importantly, in the scientific sessions. It is these sounds that remind you it is all about the patient. This mix gives the event a very different atmosphere—almost a lightness, despite the fact that we’re talking about very serious and often life-threatening diseases.

At this Congress, there is also a tangible sense of hunger for new information. You walk the hallways and you see a global medical expert speaking with a patient and/or caregiver, having earnest conversations about MPS and sharing their perspectives.

The experience of attending and participating in this conference reinforces some of the major challenges of working in rare diseases, like MPS. Each of the MPS diseases—7 in total—are all very different in terms of the onset and type of symptoms. At ISMPS, because of the patient presence, you are able to see the individuality in each patient—or, to put it in medical terminology—the different phenotypes within each of the MPS diseases. This high level of variability within the same disease is the very challenge we have across almost all of the 7,000 or so rare diseases, some of which have treatments, most of which do not. This reminds us that there is much work to be done and that we have our work cut out for us—as an industry, and as a leader in rare diseases.

What were some of the major topics of discussion at the conference, and your biggest takeaways?

Front and center was the importance of patient engagement and the role of patients and caregivers as the champions of their own diseases. As a biotechnology company focused on rare diseases, it is absolutely critical to give patients the option to be included in what we are doing. More specifically, it is essential to include the voice of the patient in the drug development process. Patient-reported outcomes (PRO) really help in this regard to quantifying what’s important for an individual patient as far as his or her symptoms, reactions to the drug and the way he or she experiences the efficacy of a drug in a clinical trial setting. We want to—and have to—capture that in a quantitative way to help guide us in the drug development process.

The same applies to caregiver engagement. MPS diseases largely affect children, so how the caregiver sees the disease—and what problems or symptoms are important to them—might differ from what’s important to physicians and researchers.

To give you an example relating to Hunter syndrome (MPS II), from some parents’ perspective, the behavioral aspects of the disease are much more important than the neurocognitive aspects, including IQ. Caregivers see behavioral changes over time—such as aggression, or just the way MPS II boys connect with their environment—and for the parent, while a potential IQ decline is devastating, the child’s behavior can be a much bigger concern day-to-day.
We heard a lot about this theme during the conference.

What are some of the recent advances in MPS that have made a difference in the lives of physicians, patients, and their family members/caregivers?

There is a lot of talk about gene therapy. At Shire, we are also active in this field—looking at gene therapy as a potential option for the treatment of rare diseases. Overall, the discussions and presentations about it were cautiously optimistic about potential progress, but there remains quite a bit of healthy skepticism. The hurdles in gene therapy are still quite daunting.

What are the biggest challenges and hurdles for the MPS community and how are these being addressed?

There is a true hunger for updates, especially in terms of advances in treatment. In particular, patients and their families want to know how potential new therapies, delivery systems, or approaches can address the central nervous system (CNS) part of MPS diseases, such as cognitive decline, behavioral changes, impaired mobility, etc.

As many people know, about 9 months ago we shared some disappointing top-line results from our investigational intrathecal program (SHP609) for MPS II. SHP609 has not been approved for use by the US Food and Drug Administration, European Medicines Agency, or any other regulatory authorities. Our research and development team is working in close collaboration with the investigators, experts in the field, and regulatory authorities such as the FDA on a potential path forward. And we are continuing the extension study for this program.

Why is designing clinical trials for a rare disease such as MPS a major challenge? How are these challenges being addressed?

Clinical trials, in general, can be a challenge, but when you have just a small number of patients affected by a rare disease, the challenges multiply.

The first challenge is finding a homogenous group of patients—patients who have a similar set of symptoms, a similar history, and severity of the disease. Even if a group of these patients exists, they may not be located near a health care facility that includes physicians who have experience running clinical trials in rare diseases and administering investigational therapies.

The second challenge is demonstrating that the drug is effective and safe by determining endpoints that are meaningful for the patient, the family, the caregivers, and for regulatory authorities, as well as the institutions that will hopefully reimburse the drug at some point in time. In rare diseases, these endpoints are typically not well understood.

The third challenge in diseases like MPS is the fact that there may be a small window of opportunity to make a difference for patients who are rapidly deteriorating. Part of our research is identifying if there is a “window in time” where decline could be slowed. For example, in MPS II this might mean a young boy starts showing physical and behavioral symptoms but otherwise appears to be in a rather healthy cognitive status. In this scenario, there may be an opportunity to help.

The other challenge is that these clinical trials are typically double-blind, placebo-controlled trials. But in the case of a rare disease, where there may be no available treatment options, is it ethically and morally justifiable to provide some children with treatment and others with placebo with no opportunity to receive the investigational drug?

The good news is that regulatory authorities are more amenable to accept historical data and data from natural history studies to establish the natural course of a disease. However, we need to generate these natural history studies and establish what the course of the disease looks like to set as a comparator. It can be a race against the clock.

Can you elaborate on the importance of conducting more clinical trials in the rare disease space?

Clinical trials are the best approach to provide patients with a drug that we hope has the potential to be approved as safe and effective by regulatory authorities. Controlled clinical trials allow us to do everything we can to limit the potential risk to patients while finding signals for efficacy.

But what does efficacy mean? You may have to compare potential new drugs to standards of care—or, as is typical in rare diseases, to no treatment at all. And you may not be able to demonstrate efficacy in individual patients because each patient is different in terms of symptoms and stage of the disease. What might look like a signal of efficacy in one patient may end up being a reflection that he or she is relatively stable when compared with other patients, and not an indication of drug efficacy. And so, in order to establish efficacy, you need a very controlled environment—a clinical trial with a number of patients that may help assure researchers that what they observe is efficacy and not the natural history of individual patients.

Another essential part of this efficacy equation that is often forgotten is the dose. The clinical trials help us to establish if there is a safe and effective dosing level.

Unfortunately, we know that a lot of drugs that enter clinical trials are not successful. For example, on average only 1 in 10 succeed in making it from phase 1 to approval. These failures along the approval process can be for a number of reasons. Was the selected dose the right dose? Did the patient actually take the drug? If the drug is administered orally, you don’t always know. Was the right mechanism of action targeted? These are just some of the reasons that a drug may not make it to approval, which is why we need a controlled environment to identify these different variables.

Establishing safety, efficacy, and the right dose in a relatively small, homogeneous population is essential for gaining regulatory approval so that the treatment may be available to the larger patient population. While this may be a lengthy process from an individual patient or caregiver perspective, this process provides the fastest opportunity to find a viable treatment for as many patients as possible.

What is Shire’s mission in the rare disease space?

The rare disease community is relatively small compared to diabetes, hypertension, heart disease or oncology, but the unmet need is huge—their voices are strong, their mission is fervent, and their ability to work together to ensure advances in diagnosis, treatment, education, and support is incredible.

As a leader in rare disease, Shire wants to be the driving force in moving scientific innovation forward and finding and developing treatment options for unmet needs. We are committed to transparency and open engagement whenever possible and work every day to be a champion for patients, their families, and the community at large.

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