Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.
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The authors acknowledge M. Lanthier and K. Miller, who helped formulate FDA data, and M. Gomar Mengod, who helped formulate EMA data for the figures presented. The authors acknowledge work done by the combined teams of C. J. Mungall (Lawrence Berkeley National Laboratory), M. A. Haendel (Oregon Health Sciences University and Oregon State University), P. J. Robinson (Jackson Laboratories) and D.-T. Nguyen (US National Institutes of Health National Center for Advancing Translational Sciences) for Fig. 1 and J. Holmes and S. L. Mathias (University of New Mexico) for the figure related to the rare disease proteome in Box 2. The authors also sincerely acknowledge the help of F. Sasinowsky for the sections on ASOs, natural history and patient engagement, and of E. Powers for the gene and cell therapy section. The authors thank D. Spencer for rereading and commenting on the article. NIH grants U24 CA224370, U24 TR002278, U01 CA239108, UL1 TR001449 and P30 CA118100 provided funding to T.I.O.
The authors declare no competing interests.
The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of regulatory agencies or organizations with which they are employed/affiliated.
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Drug repurposing hub: https://clue.io/repurposing
E-Rare. E-Rare-3 call for proposals 2016: www.erare.eu/joint-call/e-rare-3-call-proposals-2016-jtc-2016-clinical-research-new-therapeutic-uses-already-0
EURORDIS Rare Diseases Europe: https://www.eurordis.org
European Lead Factory: https://www.europeanleadfactory.eu/
European Medicines Agency. Committee for Orphan Medicinal Products: https://www.ema.europa.eu/en/committees/committee-orphan-medicinal-products-comp
European Medicines Agency. Orphan designation overview: https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designation-overview
European Medicines Agency. Rare diseases, orphan medicines. Getting the facts straight: https://www.ema.europa.eu/en/documents/other/rare-diseases-orphan-medicines-getting-facts-straight_en.pdf
FDA Rare Diseases Program: https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/rare-diseases-program
Genetic and Rare Diseases Information Center of the US National Institutes of Health: https://rarediseases.info.nih.gov/
IRDiRC. Datamining and repurposing: http://www.irdirc.org/activities/task-forces/data-miningrepurposing
Mondo disease ontology: https://mondo.monarchinitiative.org/
National Institutes of Health Bridging Interventional Development Gaps Program: https://ncats.nih.gov/bridgs
National Institutes of Health Drug Record. Livertox: enzyme replacement therapy: https://www.ncbi.nlm.nih.gov/books/NBK548796/
Orphanet, an online database of rare diseases and orphan drugs: http://www.orpha.net
Rare Diseases Registry (RaDaR) Program: https://rarediseases.info.nih.gov/radar
- Lipinski’s rule of five
These guidelines identify several physicochemical properties to be considered for small molecules that are intended for oral delivery: molecular mass 500 Da or less; five or fewer hydrogen-bond donors; fewer than 10 hydrogen-bond acceptors; and calculated octanol–water partition coefficient (a surrogate for the ability of a molecule to cross biological membranes) of 5 or less.
Gene encoding the cystic fibrosis transmembrane conductance regulator protein, an ion channel in the membrane of cells that produce mucus, sweat, saliva, tears and digestive enzymes. Mutations in CFTR that affect the production, processing or function of the protein underlie cystic fibrosis.
- ‘Umbrella trial’
A clinical trial design in which a single drug is evaluated in more than one disease simultaneously.
A type of single-domain antibody fragment.
- Good manufacturing practice
A system for ensuring that products are consistently produced and controlled according to defined quality standards.
Attaching polyethylene glycol chains to therapeutics, particularly proteins, can improve characteristics such as immunogenicity and pharmacokinetics. For example, pegylation has been used to extend the half-life of factor VIII replacement therapies for haemophilia.
- Intrathecal injection
Delivery of a substance directly to the spinal fluid (intrathecal space) through a drug delivery system comprising a pump and a catheter.
- Haematopoietic stem cells
(HSCs). Cells that can replenish all blood cell types. HSCs derived from bone marrow have been used for many years to treat cancer; patients receive a myeloablative conditioning regimen to remove diseased cells before transplantation, with the transplanted HSCs then reconstituting the haematopoietic system. A similar strategy can also be used to treat inherited blood disorders.
- Adeno-associated virus (AAV) vectors
AAV vectors are based on wild-type AAV, which has a single-stranded circular genome of roughly 4.7 kilobases. The AAV genome contains two open reading frames bounded by inverted terminal repeats into which a transgene of up to approximately five kilobases can be inserted.
A protein shell that originally encloses the viral genome.
- Fast track pathway
This can expedite the review of products to treat serious conditions. The process allows sponsors to have more frequent meetings and communications with the FDA to address appropriate data collection and design of clinical trials. It also allows a sponsor to be eligible for priority review and a rolling review of the application.
- Accelerated approval
This allows a product for a serious condition to be approved on the basis of a surrogate end point or an intermediate clinical end point. Confirmatory postmarketing trials will be needed to verify this benefit.
- Priority review
This is a designation that allows the FDA to act on a marketing authorization application in 6 months (compared with 10 months for standard reviews). To be eligible for priority review, the intended medicine should offer significant advancements in safety and efficacy of treatment, diagnosis or prevention of a serious condition.
- Breakthrough therapy deignation
This FDA designation can expedite development of drugs for which preliminary clinical evidence indicates that they may offer substantial advantages over existing treatment options for patients with serious or life-threatening diseases. Designated drugs are eligible for the expedited processing that fast track designation offers, as well as intensive guidance on efficient development from the FDA.
- Regenerative medicine advanced therapy designation
This FDA designation is similar to the breakthrough threapy designation and is available for cell therapies, therapeutic tissue engineering products, human cell and tissue products and combination products if the product is intended to treat serious or life-threatening diseases.
- Conditional marketing authorization
This European Medicines Agency pathway is similar to the accelerated approval process in the United States. Applicants may be granted a conditional marketing authorization for medicines for which the benefit of immediate availability outweighs the risk of less comprehensive clinical data than normally required.
- Approval under exceptional circumstances
In exceptional cases, a reduced data set is acceptable by the European Medicines Agency for candidate drugs for a rare indication with a high medical need if it is difficult to obtain sufficient data to fulfil the requirements of a full dossier for marketing authorization in a reasonable time frame. Annual review of clinical data obtained after such approval is required, with the potential to maintain or withdraw the authorization.
- Accelerated assessment
The evaluation of a marketing authorization application under the centralized procedure in the European Union can take up to 210 days. On request, the time frame can be reduced to 150 days if the applicant provides sufficient justification that the medicinal product is expected to be of major public health interest, particularly in cases of therapeutic innovation.
- Priority Medicines (PRIME) scheme
A scheme in the European Union that provides early and enhanced scientific and regulatory support for medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.
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Tambuyzer, E., Vandendriessche, B., Austin, C.P. et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat Rev Drug Discov 19, 93–111 (2020). https://doi.org/10.1038/s41573-019-0049-9
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