Rare Diseases, Orphan Drugs

By Steven Duncan

The diagnosis of a rare and life-threatening condition can come as a devastating blow to patients and their families. Discovering there are no treatments currently available only makes matters worse. Unfortunately, this situation is the economic reality for many Americans living with rare conditions. Most biomedical research is funded by industry and companies prefer to invest in large populations that can turn a profit.1 When relatively few patients are affected, commercial demand is low and private drug companies are less motivated to sponsor development projects.

Thankfully, when a disease is officially classified as rare (affecting less than 200,000 people in the United States), related pharmaceutical research may qualify for special status and government incentives as outlined by the federal Orphan Drug Act which passed in 1983.2 This law has allowed hundreds of new ‘orphan drugs’ to be developed and approved by the FDA for the treatment of rare diseases.3

Despite the modest progress made thus far, only five percent of the existing 7,000 rare diseases have an FDA-approved treatment.4 Many patients suffer and succumb to their illness without any legitimate medical options. Going forward, advocates for orphan drug development must promote measures that ensure sustainability for future investment in the rare disease sector. Despite the barriers that hindered investment in the past, researching orphan drugs can be a sustainable endeavor because 1) rare drug development contributes valuable understanding to the field of medicine and may show a generalized benefit later, 2) helping the marginalized is part of the moral responsibility of researchers and physicians, and 3) orphan drugs may be more economically profitable than previously believed.5

A Historical Perspective

At present in the United States, the Center for Disease Control estimates over one million people are infected with human immunodeficiency virus (HIV).6 Over the past 30 years, the market for antiretroviral therapy has grown to be valued at nearly 25 billion dollars.7 Despite its current prevalence, HIV was once a rare disease that originated with a singular ‘patient zero’. Although certainly a unique example, HIV illustrates the potential for a rare disease affecting very few people to become an epidemic. The demand for and subsequent value of knowledge gained through research can increase unexpectedly.

The study of HIV also brought about generalizable advancements in virology. Antiretroviral medications were developed in the early 1980s for the treatment of HIV by targeting the enzyme reverse transcriptase. Later, it was discovered that these medications are effective against hepatitis B virus which coincidentally encodes the same enzyme.

While treatments for infectious diseases are often versatile, approximately 70% of rare diseases are genetic with childhood onset.9 Even still, several drugs originally developed to treat non-infectious rare conditions have shown promise in other areas of medicine. One such drug is rituximab.

Rituximab is a monoclonal antibody directed against CD20 antigen on B lymphocytes. It was developed to treat Non-Hodgkin’s lymphoma, but the ability to inhibit B lymphocytes has broad implications in the clinical field of immunology. The drug has now received eight additional FDA approvals for a variety of conditions including rheumatoid arthritis, pemphigus vulgaris, chronic lymphocytic leukemia and granulomatous vasculitides.10 Complement-directed therapeutics like eculizumab have also shown great promise and been granted multiple FDA approvals. The potential to repurpose medical knowledge and find multiple homes for orphan drugs is an important contributor to the future sustainability of rare disease research.

Helping the Helpless

The inverse care law, introduced in 1971 by Dr. Julian Hart, emphasized the role of market forces on healthcare. He posited that “those who need medical care the most are the least likely to get it."11,12 This maxim holds true for patients with rare diseases, especially those without means to pay for healthcare. While no individual is directly responsible for a broken system, clinicians and researchers have a duty to their patients. Rare diseases and rare cancers are almost uniformly life-threatening, which heightens the necessity of high-quality care.

As pre-medical students interview for medical school, they are called upon to demonstrate passion and some awareness of the challenges that lie ahead in their training. For many, medicine is a calling and an identity. When the hours are long and the paperwork even longer, humanistic values from deep within must become the sustaining force.13 The simple fact that someone chose medicine in the first place shows their commitment to help others over their own self-interest.

Herein lies the sustainability of rare disease research: it matters. There is something sustainable about doing meaningful and fulfilling work. In fact, physicians report more satisfaction when they are intrinsically motivated and interested by their work.14,15 The weighty tasks of curing disease and alleviating suffering will always draw upon talented and highly motivated individuals who are more interested in saving lives than engineering a more profitable statin. Rare disease research will find the necessary manpower among medical professionals whose passion is helping those who really need it. A cultural shift in the direction of choosing fulfillment over monetary compensation will spur forward the development of orphan drugs.

Finding A Market

Innovation in biomedical research is also at an all-time high; the FDA set another record by approving 59 new drugs in 2018.16 Rare disease treatments have become just as lucrative as drugs aimed at large patient populations, and drug manufacturers are taking notice. The reason why these drugs still make money despite their small consumer base is the price tag. Orphan drugs are expensive, in part because most (60%) are ‘biologics’, a moniker for pharmaceuticals that are derived from living organisms and require more costly technology to manufacture than traditional small molecule drugs.17,18 Patients may have no other option than to pay full price because a generic version does not exist. This is not an ideal situation for affected individuals and their families, although these exorbitant prices are one reason behind the favorable economic equilibrium. Orphan drugs have come to represent a multibillion-dollar industry.19

There are many reasons why development of orphan drugs is becoming increasingly sustainable. History has shown that rare diseases are subject to change their scope and should not be ignored. Medical knowledge can also be reallocated to more generalizable causes down the line. Patients with rare diseases are a marginalized group who deserve to be helped, and medical professionals have a moral responsibility to address their needs. Medicine attracts service-oriented, empathic people who will pursue a fulfilling path over a more assuredly lucrative one. Finally, market research indicates that orphan drugs have unforeseen economic potential and represent a growing industry. All of these factors promise security and sustainability in the field of drug development for rare conditions. Common diseases and standard treatments will always occupy the interests of pharmaceutical companies, but now it is time to share the spotlight with orphan drugs.