I take care of rare diseases, one of which is hereditary angioedema (HAE). Before the origin of this condition was identified to be a genetic mutation of a gene in families that encodes for C1 esterase inhibitor protein, important for regulating the production of bradykinin, a strong dilator of blood vessels that leads to swelling. Patients with this rare disease have repeated swelling attacks of their extremities, abdomen, face, lips, tongue and on occasion their throat, which can lead to asphyxiation and death. Because this condition was designated as an “orphan” disease affecting less than 200,000 people in the US, pharmaceutical companies couldn’t justify the cost of research to develop treatments for this condition.
Before 1983, patients with HAE had to be managed with androgens (male hormone), which worked to increase C1INH partially in some patients but caused significant side effects. These patients often required narcotics to control the pain associated with these attacks that led them to be labeled as drug seekers by physicians. Most families with HAE can tell stories of loved ones who died or were intubated due to throat swelling, and all HAE patients can elaborate on how this disease has impaired their quality of life. The Orphan Drug Act (ODA) was established in 1983 to encourage pharmaceutical companies to commit time and money to develop therapies for rare diseases by offering tax incentives for clinical trials, waivers of FDA fees and seven years of market exclusivity. Apathy for developing therapies for rare diseases soon turned into the golden age of biotechnology for drug development. For HAE patients and many other orphan diseases, therapies quickly emerged to stop a sudden attack from progressing and to prevent the onset of an attack with the first being intravenous replacement therapy for C1INH, which is the missing protein required to stop swelling. This was quickly followed by preventative medications like subcutaneous C1INH replacement therapy, subcutaneous and oral kallikrein inhibitors and now longer acting novel therapies. In addition, newer subcutaneous and oral on-demand treatments that can prevent the progression of a swelling episode have been developed. In fact, we are now on the verge of a potential cure using CRISPR technology that can permanently knock out the gene in liver cells that stops the production of kallikrein, a critical protein for bradykinin production. For HAE patients who have witnessed “famine to feast” over the past 33 years, this has been astounding progress. For the first time, these patients could now lead normal lives. They could travel without concerns of having an attack, engage in athletics and other leisure activities and never worry about being in close proximity to a hospital.
This story has been replicated hundreds of times since 1983. The FDA has now approved over 800 drugs for rare diseases, which is an increase from only 38 treatments before the ODA was approved. The development of novel therapies for many of these diseases has led to astonishing research breakthroughs using new novel technologies that has allowed us to better understand disease pathogenesis and mechanistic targets for other poorly controlled diseases. However, the same incentives that transformed these patients’ lives have begun to strain our healthcare system. Because the market for rare diseases is small, the cost of these novel therapies has been priced high so companies can recoup their research costs. While orphan drugs treat a relatively small number of individuals in the US, they often cost hundreds of thousands of dollars sometimes exceeding $500,000 per patient, per year. Thus, an unintended but predictable outcome of the ODA has led to massive burdens on patients, physicians and insurers.
As a clinical investigator who helps to bring these therapies to patients, I see firsthand the “double edged sword” that has occurred since the ODA was approved. In one circumstance it has saved countless lives and has been critical for advancing scientific knowledge. On the flip side, it is driving up healthcare premiums for everyone and requiring increased time and effort by physician offices to get prior authorization approval for these treatments. Today, the challenge is to reform the ODA perhaps by limiting exclusivity and the high-cost monopolies of truly rare conditions while ensuring that it continues to serve those patients intended to benefit. We must continue to strive to find ways to help these patients without making the healthcare system an orphan of unsustainable costs.
