• Chinese (Simplified, PRC)

February 29 is Rare Disease Day, a day we set aside to raise awareness about rare diseases and their impact on patients' lives. In honor of this noteworthy event, I think it’s important to explore the myths and realities of rare/orphan drug research.

In the past, rare and orphan disease research was eschewed by biopharma as too complicated and offering too little return on investment to pursue outside of philanthropic efforts. And they weren’t entirely wrong. These trials can be difficult to recruit for, face innumerable unknown risks, and have a much smaller consumer population, making them appear less attractive from a business standpoint. However, changes in the commercial, economic and regulatory landscape have made rare disease research more appealing for biopharma companies in recent years. These development efforts now are encouraged by fast tracking initiatives, tax breaks, longer exclusivity, and the opportunity to be the first to market to solve an unmet medical need. Thanks to these incentives, rare disease research is coming to the fore, with dozens of orphan drugs gaining approval and seeing commercial success every year.

In each of the past two years, the US Food and Drug Administration approved more orphan drugs for rare diseases than in any previous year in its history. In 2014, 41% of all novel new drugs approved in the US were for the treatment of rare diseases, including Sylvant™ to treat Castleman’s disease, and Impavido™ to treat forms of the tropical disease, leishmaniasis. In 2015, that rate rose to 47%, with 21 of 45 novel drugs addressing rare diseases, including Orkambia™, a therapy for cystic fibrosis, and Unituxin™ to treat pediatric patients with high-risk neuroblastoma.

Although these drugs may have smaller target patient populations, their commercial potential can still be significant. The orphan oncology drug Rituxan™, for example, is second only to Lipitor in profitability, and is expected to garner more than $150 billion in revenue over its lifetime, the majority of which is for orphan indications. And it’s not alone. Worldwide, orphan drug sales are forecast to total $178 billion by 2020, with many of these drugs achieving blockbuster status.

And there are many un-explored development paths yet to be taken. According to the National Institutes of Health (NIH), there are 7,000 rare diseases – defined in the US as those that affect fewer than 200,000 people – affecting a total of 350 million people worldwide. That means the dozens of drugs that win approval each year are barely scratching the surface of what still needs to be done.

Five benefits of orphan drug research

Meeting an unmet medical need while achieving bottom-line results is the Holy Grail for most biopharma research teams, though it is important to acknowledge that these projects won’t be easy. Most rare diseases have few if any treatments developed for the condition, which means there will be no well-defined development pathway and there may be no or few validated outcome measures. Recruiting is also a challenge as these patient populations are small and widely dispersed. These diseases also often impact pediatric populations, adding additional emotional, logistical, and regulatory challenges, including requirements for extra toxicology studies to prove the safety of the treatments before patients can enroll. Finally, biomarkers to identify patients for trials and to guide development may not be as widely available in rare diseases as they are in more common diseases due to decades of research underfunding in this space.

But there are several upsides to this research that you won’t find in mainstream drug development projects.

  1. Little competition. Because these diseases have few or no treatment options, biopharma companies don’t have to demonstrate that their drug is better, cheaper, or more valuable than the competitors. Improvement in quality of life or life expectancy can be enough to win approval, premium pricing, and favorable reimbursement. There may or may not be competition for patients to enter trials depending on which rare disease is explored; even in cases in which several sponsors wish to study a drug, developers are exploring novel cross-company collaborations in which, for example, a single, ‘shared’ placebo group is used. There will also be lower marketing costs and faster uptake of drugs for rare diseases once they hit the market, as patients and physicians are often in desperate need of new treatments.
  2. Financial incentives. Regulators want biopharma to pursue this research, and they are willing to do their part to defray the costs. The Orphan Drug Act in the US includes several financial provisions, including annual grant funding for trials, and significant tax credits. They are also open to smaller trials when patient populations don’t warrant massive studies, which further cuts time and cost from the trial experience. Elaprase™, for example, was approved for Hunter syndrome after a 96-patient Phase II/III trial. These incentives can significantly reduce trial costs compared to non-orphan drug trials. Similar incentives are available in Europe.
  3. Accelerated regulatory pathways. Regulators are eager to safely speed drugs for unmet medical needs to market, and they are creating avenues to fast track development, with most drugs qualifying for at least one expedited program. FDA, offers a Fast Track process that typically culminates in a Priority Review  to sponsors of products being developed to address an unmet medical need for a serious condition. This means researchers have greater access to regulators for feedback, and their submissions will get quicker reviews, cutting months from the approval process. Similarly, the European Medicines Agency (EMA) has its Adaptive Pathway and Accelerated Approval for drugs to address unmet medical needs. The program provides for approval for specific patient populations, allowing sponsors to subsequently expand the patient population or to reduce uncertainty for the initial patient population through post-approval data collection. In the first 10 months of this program, EMA received 34 applications for the adaptive pathway pilot, including 12 orphan products. Although orphan designation does not directly translate into reduced regulatory requirements, regulatory authorities are also often more amenable to non-standard approaches for orphan drugs.
  4. Longer exclusivity. To help generate a strong return on investment for orphan drug research, these drugs are awarded seven years of Orphan Drug Exclusivity (ODE) by the FDA, and 10 years by EMA. Extended exclusivity can also start running later in the product’s life cycle for a new indication that is approved after the initial launch.
  5. Non-orphan commercial potential. An orphan drug can also be developed subsequently for other orphan or non-orphan indications; conversely, a drug developed for a non-orphan indication can gain orphan status for a new indication which meets orphan criteria. While the benefits of orphan designation (additional exclusivity, research tax credits, etc,) only apply to the orphan indication, a drug developed for both orphan and non-orphan indications provides biopharma companies with additional commercial benefit, including potentially earlier market access to cultivate brand recognition. Drugs including Avastin™, Enbrel™, Herceptin™, Humira™ and Remicade™, have all benefited from such orphan designations.

Rare disease research is difficult but rewarding, and with the right partners and a clear understanding of the science and regulatory environment, it can also be a lucrative path to follow. In an era where blockbuster drugs are a rarity, this research path should be hard to pass up.

Topics in this blog post: Rare Disease Day, Rare Diseases, Biopharma, R&D