Rare Disease Report

Making Progress in Rare Diseases

JANUARY 08, 2017
Jeffrey S. Aronin, CEO and Chairman, Marathon Pharmaceuticals
After 30 years, the Orphan Drug Act is helping small companies innovate in small patient populations.

While rare diseases are, by definition, rare, they are hardly uncommon. Nearly one in 10 Americans suffers from one of the 7,000 diseases or conditions known as rare diseases, meaning they affect a population of 200,000 or fewer people. So while each disease in and of itself may be considered rare, the collective group of rare diseases impacts more of our family, friends, neighbors and colleagues than most of us realize.
Unfortunately, due to a variety of factors, the availability of treatments for rare diseases has, until recently, been scarce, denying hope to millions and cutting the lives of far too many far too short.

Orphan Drug Development is Challenging

Historically, even if a pharmaceutical company had a promising target drug for a rare disease, they might not pursue it. The costs of developing new treatments are extremely high. The number of patients living with a single rare disease is small, making it hard to even find participants for clinical trials. The costs of clinical trials are high. And the small patient population of each rare disease makes it hard for pharmaceutical companies to recoup those investments when a drug is approved for marketing. With those challenges, companies would often walk away from a development program for a drug that treated a rare disease, leaving the drug an ‘orphan.’
In other words, investing in orphan drugs is a risky business.
Recognizing these challenges, and spurred on by the work of tireless patient advocates, Congress enacted the Orphan Drug Act in 1983, which established several incentives to spur innovation in research, development and delivery of new therapies for rare diseases.  These incentives include a tax credit for clinical trial costs and seven years of market exclusivity.

A Critically Important Piece of Health Care Legislation

Thirty years on, and the Orphan Drug Act is, in the FDA’s own words, “a critically important piece of health care legislation.” Between 1967 and 1983, prior to the Act’s passage, the FDA had approved just 34 drugs for the treatment of rare diseases. In 2015 alone, the FDA approved 41.
In fact, the decade of the 2010s is the most fertile period of orphan drug development we have yet seen,  and that is a tremendous service to patients and the health care providers who care for them. In the first five years of this decade, the FDA received more requests for orphan drug designations, granted more of those requests, and approved more orphan drugs than in any prior decade. And we’re only halfway through. That is tremendous progress for the rare disease community who, for too long, saw little progress in the development of new treatments.  
The Orphan Drug Act has allowed for more players into the field – namely, small companies and private companies with limited capital who in the past could not afford to develop therapies for such small patient populations. In fact, many small and private companies have now developed niche markets in the rare disease space, driving innovation and progress. For small companies, incentives from the Orphan Drug Act counteract a limit in capital. For many private companies, they do not have to answer to investors as to why they are focusing on developing therapies for such a small patient population, essential latitude when undertaking high-risk efforts.
Of the 39 orphan drugs approved by the FDA in 2016, 12 were developed by small public or private companies.  This includes drugs for treatment of hereditary and acquired methemoglobinemia (by privately held Provepharm SAS), for treatment of keratoconus (by privately held Avedro, Inc.), for treatment of tyroseinemia type 1 (by publicly held Swedish Orphan), and for treatment of primary billary cirrhosis (by publicly held Intercept Pharmaceuticals, Inc.).
Drug development in rare diseases can transform patient care as well as dramatically improve the quality of life for patients. Take cystic fibrosis, for example. There are now six approved therapies for cystic fibrosis patients, up from just one two decades ago. There is also a robust pipeline of drugs in development that target different elements of the disease: drugs that restore CFTR function, anti-infectives, anti-inflammatories and drugs that aid mucociliary clearance. As a result, many of the more than 30,000 cystic fibrosis patients in the U.S. have new options – and the hope of new therapies still to come.

Duchenne Muscular Dystrophy

At Marathon, we’re hoping to be a part of a similar transformation in care for patients living with Duchenne muscular dystrophy, the most common and most severe form of muscular dystrophy. It affects about 15,000 patients in the U.S. and is primarily due to a mutation in the gene responsible for the generation of dystrophin, a structural protein in the muscle. I’ve met with parents and caregivers across the nation and I know first-hand their need for new treatments. 
Boys living with Duchenne have trouble moving beginning at an early age. As they get older, muscle weakness advances, and they are usually bound to a wheelchair sometime in their early teens. Later, their heart and respiratory muscles weaken. Most of these boys will not live past their 20s, primarily due to heart trouble, respiratory complications or infection.
In September, the FDA approved the first therapy for Duchenne, which treats the approximately 13% of Duchenne patients who carry a specific genetic mutation. It was developed by Sarepta Therapeutics, a small biopharmaceutical company.
Marathon is hoping to win FDA approval for the second treatment for Duchenne, the first that could potentially benefit patients with Duchenne regardless of the genetic etiology.  And it’s a therapy that’s the very definition of an orphan drug.
In 1995, a group of researchers conducted what was, at that time, the largest study in Duchenne muscular dystrophy. Unfortunately, the study was completed but never published. Several years ago, study investigators approached Marathon and convinced us that the drug – approved for use in other countries but never approved for use in treating Duchenne -- was effective. As a small, private company led by people who have spent our careers working in rare diseases, we saw potential in what this drug could mean to patients. With positive feedback from patient groups, we acquired rights to the investigational therapy. Over the past 6 years, we took it through a full pre-clinical and clinical program, including 17 studies, and helped the initial investigators find and reassemble missing lab data from the 1995 study. We submitted a New Drug Application to the FDA, which was accepted in August 2016. That same month, the pivotal study was published in Neurology. That study is one of the two studies in our pending NDA that establishes the efficacy of the drug for Duchenne.  A decision on the drug from the FDA is expected in early 2017.
We know if this drug is approved, it has the potential to make a difference in the lives of patients living with Duchenne. Making that a reality will require work on our part. We will need to educate doctors about its benefits and risks, based on the label the FDA will approve for marketing purposes. We will conduct additional studies to answer key questions about its use – at what age should patients start using it, and what is its impact in patients who are no longer ambulatory. And we will work to expand access to the drug so all who might benefit from it can do so.
A drug that was nearly abandoned in the past is now on the cusp of being the first drug approved for use in all patients living with Duchenne. That’s a proof point of the value of the Orphan Drug Act, and a sign of its lasting impact and its ongoing benefit to those who have too few treatment options to improve or extend their lives.
BIO: Jeffrey S. Aronin is the chairman and CEO of Marathon Pharmaceuticals, which develops, manufactures and commercializes high-need pharmaceutical products for patients with rare diseases.

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