By Sam Falsetti

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, a rare disease is defined as a condition that affects fewer than 200,000 people, while in the European Union, a disease is defined as rare when it affects fewer than one in 2,000 people. The US Orphan Drug Act was enacted in 1983 to stimulate investment into therapeutic development for rare diseases through financial incentives, tax credits, user fee waivers and marketing exclusivity. Similar legislation has also been passed in Europe and Japan, illustrating an increased focus by regulatory bodies around the world on providing improved therapeutic options for these patients.

Although there are more than 7,000 rare diseases identified, only a fraction of them have approved therapies available. Advances in DNA sequencing have led to the identification of the genetic cause of several rare diseases, which can potentially lead to better understanding of the disease and development of targeted therapies.

In addition to the development of novel therapies for patients with specific rare diseases, orphan drug development programs can also provide a unique opportunity to understand other disorders that may be more common. For example, the study of lipodystrophies, a set of conditions where patients lack adipose tissue, has provided tremendous insights into the role of adipose-derived hormones such as leptin. Similarly, lessons learned from studying therapies that can improve metabolism and satiation response in patients with Prader-Willi syndrome, a rare disease affecting one out of every 15,000 live births, can be hugely beneficial in developing novel drugs for general obesity.

As with all drug discovery, basic research into understanding the etiology, pathophysiology and genetics is the first step toward identifying viable targets with a validated role in disease biology. While drug discovery and development is laden with intricacies, there are four overall areas of consideration that must be considered in the context of rare disease programs: a validated therapeutic target (or at least an identified compound through phenotypic assays), a clinical data set to base clinical trial development on, a potential regulatory path forward, and an addressable patient population both for clinical trials and to support commercial feasibility.

In rare monogenic diseases, the nature of the underlying genetic basis of disease can provide a clear path to the development of cellular and animal models that mimic human biology. However, even in monogenic disorders with validated biological models, the path to development of a clinical therapy is highly complex. Lysosomal storage disorders (LSDs) represent an addressable group of diseases with a validated treatment paradigm. In these conditions, a lack of a specific lysosomal enzyme leads to lysosomal dysfunction and underlies disease pathology. Replacement of the deficient enzyme (also known as enzyme replacement therapy) has been approved for multiple LSDs. However, many LSDs remain unaddressed often due to the relatively small size of specific populations or from a lack of clinical data needed to develop approvable trials.

To address these challenges in the US, the National Institutes of Health provides many resources to facilitate the development of new drugs for rare diseases. The National Center for Advancing Translational Sciences’ Therapeutics for Rare and Neglected Diseases program. This initiative supports preclinical development of new treatments to advance them to an Investigational New Drug. Another example is The Rare Diseases Clinical Research Network program, which advances medical research of rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment, and data sharing.

Due to the nature of rare diseases, finding a patient is often one of the biggest challenges in rare disease programs. Often, only a small fraction of the estimated population for a given rare disease is comprised of diagnosed patients. Many patients go through a long diagnostic journey before they receive a correct diagnosis. It takes, on average, more than seven years for a patient with a rare disease to get a diagnosis and often involves four to eight physicians and two to three misdiagnoses. For many patients, the end of this diagnostic journey raises more questions than answers as a formal diagnosis does not always guarantee that a therapy is available. A well elucidated natural history can provide understanding into disease progression and clinical management. Shortening this diagnostic journey and enhancing rates of diagnosis are critical to both increase the number of patients able to access a clinical trial and improve the commercial feasibility of these programs.

Targeted disease education for physicians and patients is the first step toward raising awareness and encouraging identification of these patients. Mapping the patient journey can reveal key diagnostic inflection points for a sponsor to improve awareness and catalyze diagnosis. Often, hallmark signs and symptoms can present early in disease manifestation to suspect-refer audiences that have low awareness of the condition. Beyond increasing awareness with these accessory target audiences at key points in the patient journey, it is necessary to assist with providing a clear path of referral to a center of excellence that can provide an accurate diagnosis and multidisciplinary clinical management.

Beyond the patient journey, another critical step for a sponsor to undertake is early synergistic engagement with patient advocacy organizations. In rare disease, these groups play an essential role in program development. Often, these groups are deeply involved in the drug discovery and development process, as well as disease education for patients and physicians. For example, the Cystic Fibrosis Foundation’s novel venture philosophy model-based partnership between the foundation and a for-profit pharmaceutical company, Aurora Biosciences (now Vertex Pharmaceuticals), led to development and approval for Kalydeco, the first drug to treat the underlying cause of cystic fibrosis. Developing a patient advocacy engagement plan prior to first-in-human trials is essential as these groups can both provide greatly needed visibility into the clinical development program and inform the potential commercial feasibility of a program.

Nowhere is the importance of advocacy group engagement more pronounced than in considerations regarding enrollment and completion of clinical trials. This can be a daunting task in any disease area due to the many logistical challenges of finding and recruiting patients, as well as ensuring patient adherence to dosing and other restrictions, such as diet or medications. The complexities of finding the patients are even more pronounced when the disease for which the treatment is being tested affects a limited number of patients or a significant proportion of pediatric patients, or if many of the patients go undiagnosed for a long period of time. Unfortunately, many of these circumstances occur in the rare community.

Trials can place large burdens on patients in terms of travel to the site, time missed from work or school, and physical effects of the treatment itself. Patient-centric trial design is becoming more popular and is especially important for rare disease trials. Pharmaceutical companies often partner with patients and patient advocacy groups to gather input to strike a balance of minimally burdensome design while ensuring the generation of meaningful data.

Endpoint selection in rare-disease clinical trials can be particularly challenging since often there is a large gap in understanding of the disease pathophysiology and clinical manifestations over time. These elements, combined with lack of treatments or clinical trial precedents, can create a puzzle. During this process, it is important to identify biomarkers that correlate with clinical endpoints and can be linked to long-term benefits for the patient. Choosing an endpoint that demonstrates the clinical benefit of the drug is vital to ensure post-market adoption of the treatment.

In lieu of a randomized controlled trial, orphan drugs can also be approved based on data collected through compassionate use programs due to a clear unmet need and the resulting generation of sufficient data showing safety and efficacy of the drugs in the patient populations. For example, Cholbam for bile acid synthesis disorders and Zellweger spectrum disorder, and Myalept for lipodystrophy each had more than 10 years of data in patients before Food and Drug Administration (FDA) approval.

The regulatory landscape for rare disease development is evolving as more drugs enter clinical trials. Currently, the regulatory environment is favorable with both FDA and the European Medicines Agency (EMA), as they offer incentives for the development of orphan drugs. As such, the number of rare disease therapies approved has increased exponentially in the last two decades.

In 2015, FDA updated guidance for rare disease drug development to help industry sponsors create successful drug development programs that address the particular challenges posed by each disease. The guidance recommends that pharmaceutical companies invest in understanding disease pathophysiology and progression—initial symptoms, diagnosis, surrogate markers and clinical outcomes. This will help in designing more efficient clinical development programs, as well as influencing decisions regarding reimbursement and formulary placement.

The challenges in the rare disease market extend beyond a successful clinical trial and approval for use. In cases of treatments where the endpoint is based on surrogate markers or other non-outcomes-based measures, establishing the value of the drug can be difficult. Many agencies have specific decisionmaking thresholds based on criteria of cost-effectiveness and evidence quality. For example, the UK’s National Institute for Health and Clinical Excellence considers patients’ quality of life and the length of life they will gain as a result of an intervention. The health benefits are expressed as quality-adjusted life years (QALYs). Health technologies with an incremental ratio of less than £20,000 ($25,600) per QALY gained are considered cost effective and are highly likely to be reimbursed; those with a ratio in excess of £30,000 ($38,500) would require other conditions to be met in order for them to be funded.

Orphan drugs rarely meet these criteria, so they pose a unique problem for reimbursement decisionmaking. There is currently a lack of specific protocols to assess reimbursement-related determinations for these therapies. The epidemiology and natural history of rare diseases are not well understood, so extrapolating from surrogate markers or other clinical trial endpoints to evaluate long-term benefits can be hard to definitively measure. Successful commercialization of an orphan drug, therefore, requires several components, including demonstration of value during the course of clinical development, thoughtful trial design, and understanding the natural history and long-term outcomes of the disease.

Patients with rare diseases are a largely underserved population with a huge unmet need in terms of awareness, diagnosis, and available therapies and medical management. Just as science has adapted and introduced new techniques to address the unique challenges of rare disease drug development, all the stakeholders—policy makers, payors, patients and pharmaceutical companies—have to adapt and engage with one another for continued success in developing new drugs and ensuring market access. Ultimately, our commitment to rare disease research and tackling the large unmet need in this small population is a reflection of our values as a society. Much progress has been made, but much more needs to be done.

Sam Falsetti is head of medical strategy and product innovation and Usha Iyer is senior medical director at Cambridge BioMarketing, a Cambridge, MA full-service advertising and communications agency serving pharmaceutical and biotech clients.

By Sam Falsetti

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