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ORPHAN DRUG APPROVALS ON THE RISEDiseases with a prevalence of less than 200,000 af ected individuals in the United States and less than approximately 250,000 af ected individuals in the European Union (EU) can be designated as orphan diseases. T e passage of the U.S. Orphan Drug Act in 1983 provided regulatory, tax, and com-mercial incentives to companies develop-ing drugs for orphan diseases in the United States. Similar legislation was passed in the EU in 2000, and several other countries now provide regulatory and commercial benef ts to products for rare diseases. Activism by rare-disease advocacy organizations—for example, the National Organization for Rare Disorders (NORD) and Rare Diseases Europe (EURORDIS)—and patient asso-ciations, as well as the cooperation between academic institutions, companies, and reg-ulatory agencies, has led to an increase in the number of orphan drug designations over time. In the United States, the U.S. Food and Drug Administration (FDA) des-ignated 1 orphan drug in 1983, 70 in 2000, and 199 in 2011. In the EU, the EMA des-ignated 10 orphan drugs in 2000 (f rst year of designations) and 104 in 2011 (www.fda.gov and www.ema.europa.eu, respectively; a single drug may have an orphan designa-tion for more than one indication). T ree areas within orphan diseases have the most orphan drug approvals: pediatric indica-tions, rare types of cancer, and genetic dis-eases. Protein replacement therapies have proven to be a valuable treatment for rare monogenic diseases.

T e f rst monogenic protein replace-ment therapies (MPRTs) in the orphan drug space to receive regulatory approval in

the United States and EU were blood fac-tors and enzyme replacement therapies for lysosomal storage disorders. T ese MPRTs introduced a new commercial model called “orphan drug pricing,” in which high pre-miums are applied to life-changing thera-pies. Currently, the annual cost for MPRTs, such as Fabrazyme, Elaprase, and Nagla-zyme, generally exceeds $200,000 (1), and sales of orphan MPRTs exceed $100 million per year.

T ere has been considerable attention given to the high prices of orphan drugs and the challenges with reimbursement (2, 3). MPRTs are reimbursed in the United States, in many countries of the EU, and in Japan, and they are of en supplied at no cost in the developing world or through patient assistance programs. In order to continue to support orphan drug pricing and obtain reimbursement, it is important for devel-opers of MPRTs to make a case to payers for cost-ef ectiveness of these therapies. Although certain MPRTs have shown long-term safety, clinical ef cacy, and improve-ments in health-related quality of life (4–6), more data are needed to demonstrate cost-ef ectiveness (a net reduction in health-care costs from MPRTs) to justify reimburse-ment in certain countries (2).

LOW DEVELOPMENT RISKT e Tuf s Center for the Study of Drug De-velopment (CSDD) has published several reports on clinical approval success rates. In 2010, DiMasi et al. published the results of a study evaluating the clinical approval success rates for investigational compounds that entered clinical testing between the mid-1990s and the early 2000s from the 50 largest pharmaceutical f rms (as deter-mined by 2006 sales) (7). T is study strati-f ed data by product type (large versus small molecule). T e authors reported the overall probability of clinical approval success at 19%, with biologic drugs having a higher

success rate (32%) than that of small-molecule drugs (13%). Tu% s CSDD also published a report in 2010 that looked spe-cif cally at approval probabilities for orphan drugs. In this study, sponsors engaged in orphan grant–funded development report-ed that 22% of their clinical programs led to approvals (8). T e probability of regulatory approval for MPRTs, which comprise only a small fraction of the total number of ap-proved drugs, has not been determined.

We conducted an analysis to determine whether MPRTs would have a higher prob-ability of success through clinical trials, compared with all orphan drugs and all other drug classes. If these therapies have a higher probability of success than those of other new molecular entities (NMEs), a case could be made for expanded invest-ment to develop MPRTs for orphan diseases that currently have no approved therapeu-tic products.

MPRT: APPROVED OR TERMINATED?To conduct our analysis, we consulted sev-eral data sources. We began by reviewing all U.S. and EU orphan product designations and identifying monogenic protein replace-ment therapy candidates (www.fda.gov and www.ema.europa.eu). Because companies may not seek orphan designations for cer-tain protein replacement therapies (for example, follow-on therapies or plasma-derived therapies reviewed at the national level in the EU), we supplemented our or-phan drug designated product search by conducting candidate searches in the Adis R&D Insight database (http://bi.adisinsight.com), reviewing public domain candidate data from Tu% s CSDD (http://csdd.tu% s.edu/research/databases), reviewing prod-uct listings from the World Federation of Hemophilia (www.wf .org), and by review-ing the pipelines of companies we know are active in the MPRT space. Our analy-ses were restricted to MPRTs for the treat-ment of orphan diseases that had entered or completed clinical trials, f led for or re-ceived regulatory approval as of 30 Novem-ber 2011. For inclusion in the study group, therapies had to meet certain criteria, as described in the Supplementary Methods.

We identif ed 144 replacement thera-pies approved or investigated for 40 unique proteins that are def cient or dysfunctional owing to mutations in a single gene associ-ated with an orphan disease (table S1). We then determined whether these therapies were at the preclinical stage, clinical stage,

R E G U L AT O R Y S C I E N C E

Protein Replacement Therapies for RareDiseases: A Breeze for Regulatory Approval?Jennifer A. Gorzelany1* and Mark P. de Souza2

*Corresponding author. E-mail: jen@laurelwoodbio.com

1Laurelwood Biopartners, Boston, MA, 02115, USA. 2Lotus Tissue Repair, a wholly owned subsidiary of Shire Human Genetic Therapies, Lexington, MA 02421, USA.

Protein replacement therapies for rare monogenic diseases have a higher probability of regulatory approval compared with biologics, small molecules, and grant-funded orphan drugs.

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or currently marketed. For those in clinical trials, we determined whether the candi-dates were active or terminated. Candi-date status was recorded as the most ad-vanced clinical phase or approval in either the United States or EU. To determine the probability of approval for candidates that

have entered clinical trials, the 23 active preclinical programs (for 21 protein tar-gets) were not included in the analysis. T e removal of these candidates le% 121 total therapies directed to 29 targets. Eighty-f ve of these therapies have received regulatory approval for 21 monogenic diseases, and 25

are active clinical candidates directed to 14 targets (Table 1). Eleven terminated candi-dates were identif ed. Our analysis shows that once MPRTs enter clinical trials, the probability of regulatory approval is 88%, compared with Tu% s CSDD’s rates of 19% for all drugs (7) and 22% for grant-funded

Table 1. MPRTs that have entered clinical development or received regulatory approval. The number of candidates and development or approval status is listed by biological target. Plasma-derived products identifi ed here may be approved in the EU at the national level and sold in individual EU countries. The full data set analyzed is in table S1.

Replacement protein Disease Candidate status Terminated(phase)

Total candidates directed to target

Phase 1 Phase 2 Phase 3 Approved

Factor VIIa Factor VII defi ciency - - - 4 4

Factor VIII Hemophilia A 2 - 6 25 2 (P2) 35

Factor IX Hemophilia B - 1 4 13 1 (P1) 19

Factor X Factor X defi ciency - - 1 1 2

Factor XI Factor XI defi ciency - - - 2 2

Factor XIII Factor XIII defi ciency - - 1 1 2

vWF von Willebrand disease - - 1 5 6

Protein C Protein C defi ciency - - - 2 2

Antithrombin III Antithrombin defi ciency 1 - - 7 8

Fibrinogen Fibrinogen defi ciency - - - 2 2

C1-esterase inhibitor Hereditary angioedema - - - 5 5

Alpha-1 proteinase inhibitor (α1-PI)

α1-PI defi ciency - - - 4 2 (P2) 6

Glucocerebrosidase Gaucher disease - - 1 3 1 (P1) 5

Alpha-L-iduronidase Mucopolysaccharidosis I - - - 1 1

Iduronate sulfatase Mucopolysaccharidosis II - - - 1 1

N-acetylgalactosamine-4-sulfatase

Mucopolysaccharidosis VI - - - 1 1

N-acetylgalactosamine-6-sulfatase

Mucopolysaccharidosis IVA - - 1 - 1

Heparan sulfate sulfatase Mucopolysaccharidosis IIIA - 1 - - 1

Alpha-galactosidase A Fabry disease - - - 2 1 (P2) 3

Alpha-glucosidase Pompe disease 1 - - 2 1 (P1), 1 (P2) 5

Acid sphingomyelinase Niemann-Pick type B disease 1 - - - 1

Alpha-mannosidase Alpha-mannosidosis - 1 - - 1

Arylsulphatase A Metachromatic leukodystrophy

- - - - 1 (P2) 1

Lysosomal acid lipase (LAL) LAL defi ciency - 1 - - 1

Sucrase-isomaltase Sucraseisomaltase defi ciency - - - 1 1

Adenosine deaminase (ADA) ADA defi ciency - - - 1 1

Insulin-like growth factor 1 (IGF-1)

Primary IGF-1 defi ciency - - - 2 2

Alkaline phosphatase Hypophosphatasia - 1 - - 1

Porphobilinogen deaminase Acute intermittent porphyria - - - - 1 (P2) 1

Total: 29 protein targets for 29 monogenic diseases

5 5 15 85 11 121

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orphan drugs (8). [T e probability of regu-latory approval for monogenic protein re-placement therapies of 88% was calculated as follows: (85 × 100) / (85 + 11).]

To reduce the inf uence of the large number of approved candidates for Factor VIII and Factor IX, we also calculated the probability of approval for a f rst-in-class protein replacement therapy. Here, we con-sidered the number of targets that had at least one approved MPRT (21 targets) with the total number of targets for which a can-didates’ ultimate fate (approval or termina-tion) was known (23 targets). Only two tar-gets, arylsulphatase A and porphobilinogen deaminase, had candidates terminated in clinical trials, with no approved therapies (table S1). T us, f rst-in-class MPRTs have a 91% probability of regulatory success.

BLOOD FACTORS AND LYSOSOMAL ENZYMES DOMINATEIf we consider the 27 targets from Table 1 that have active clinical stage and/or approved programs, 85% of MPRTs to these targets can be classif ed as blood components (12 targets) or lysosomal enzymes (11 targets). T e remaining 15% of MPRTs are targeted to metabolic disorders. T ese target classes may represent the “low-hanging fruit,” and the >85% probability of regulatory success for MPRTs is high because the clinical patho-genesis, mechanism of action, and ability to manufacture the MPRT are well understood for blood components and many lysosomal enzymes. It is possible that the probability of regulatory success of MPRTs for targets out-side of these classes will decrease with chal-lenging targets, such as structural proteins, or di& cult methods of delivery, such as for central nervous system disorders.

Similarly, lysosomal enzymes and blood products make up 78% of the identif ed pre-clinical programs (18/23), with 22% (5 pro-grams) directed toward targets outside of these classes. New MPRT preclinical targets include structural proteins in dermatology (collagen VII in dystrophic epidermolysis bullosa and ectodysplasin-A1 in X-linked hypohidrotic ectodermal dysplasia), mito-chondrial enzymes (thymidine phosphory-lase in mitochondrial neurogastrointestinal encephalopathy and frataxin in Friedreich’s ataxia), and a nonlysosomal metabolic en-zyme [lecithin-cholesterol acyltransferase (LCAT) in LCAT def ciency].

CLINICAL AND COST ADVANTAGESMPRTs have the advantage of receiving regulatory approval with smaller clinical trials and a% er shorter development times. For example, the total number of patients evaluated in clinical trials for the MPRTs Elaprase, Vpriv, Fabrazyme, and Nagla-zyme, were 108, 94, 73, and 56, respectively. Clinical trials for biologics in larger indi-cations generally evaluate >1000 patients. Additionally, the time from Investigational New Drug (IND) application to approval for the MPRTs above were 5.6, 6.2, 6.0, and 4.7 years, respectively, compared with 8.3 years, which is the median time reported for NMEs and signif cant biologics for the period from 1980 to 2009 (Supplementary Methods) (9).

Paul et al. (10) developed an R&D model to estimate the cost of discovering and de-veloping a single new molecular entity from lead discovery through preclinical and clin-ical studies to commercial launch. If the high (88%) probability of clinical success for MPRTs was used in this model, it would substantially reduce the out-of-pocket costs and total capitalized costs for the clinical development of an MPRT, compared with small molecules and other biologics.

OPPORTUNITIES REMAINT e commercial potential of MPRTs and the unmet need for new drugs for orphan diseases has led to increasing attention from the pharmaceutical and biotechnol-ogy industries, as well as from the invest-ment community owing to the potential returns within this sector. Several compa-nies that focused on the development and commercialization of MPRTs have been ac-quired for large sums. For instance, in 2011 Sanof -Aventis acquired Genzyme for ~$20 billion, and Alexion acquired Enobia for ~$1.1 billion.

T ere are many monogenic diseases that do not have approved protein replace-ment therapies. Federal agencies such as the National Institutes of Health and the FDA have developed specif c guidelines to accelerate regulatory approval and provide incentives for orphan drug development. In addition to the commercial success of MPRTs, we hope the observation that MPRTs demonstrate a high probability of regulatory approval will provide another incentive to develop additional MPRTs for

diseases for which no therapy is available, as well as to create improved follow-ons for existing treatments.

SUPPLEMENTARY MATERIALSMethodsTable S1. Active MPRT preclinical candidates and MPRTs that have entered clinical development or received regulatory ap-proval.

REFERENCES AND NOTES 1. H. Hyde, D. Dobrovolny, Orphan drug pricing and payer

management in the United States: Are we approaching the tipping point? Am. Health Drug Benef ts. 3, 15–23 (2010).

2. M. Schlander, M. Beck, Expensive drugs for rare disor-ders: To treat or not to treat? The case of enzyme replace-ment therapy for mucopolysaccharidosis VI. Curr. Med. Res. Opin. 25, 1285–1293 (2009).

3. D. A. Hughes, B. Tunnage, S. T. Yeo, Drugs for exception-ally rare diseases: Do they deserve special status for funding? QJM 98, 829–836 (2005).

4. M. Rohrbach, J. T. Clarke, Treatment of lysosomal storage disorders: Progress with enzyme replacement therapy. Drugs 67, 2697–2716 (2007).

5. M. Connock, A. Burls, E. Frew, A. Fry-Smith, A. Juarez-Garcia, C. McCabe, A. Wailoo, K. Abrams, N. Cooper, A. Sutton, A. O’Hagan, D. Moore, The clinical eff ectiveness and cost-eff ectiveness of enzyme replacement therapy for Gaucher’s disease: A systematic review. Health Tech-nol. Assess. 10, iii–iv, ix-136 (2006).

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7. J. A. DiMasi, L. Feldman, A. Seckler, A. Wilson, Trends in risks associated with new drug development: Success rates for investigational drugs. Clin. Pharmacol. Ther. 87, 272–277 (2010).

8. Tufts Center for the Study of Drug Development, U.S. orphan product designations more than doubled from 2000-02 to 2006-08. Impact Report. 12 (2010); available at http://csdd.tufts.edu/fi les/uploads/2010_jan-feb_summary.pdf.

9. K. I. Kaitin, J. A. DiMasi, Pharmaceutical innovation in the 21st century: New drug approvals in the fi rst decade, 2000-2009. Clin. Pharmacol. Ther. 89, 183–188 (2011).

10. S. M. Paul, D. S. Mytelka, C. T. Dunwiddie, C. C. Persinger, B. H. Munos, S. R. Lindborg, A. L. Schacht, How to improve R&D productivity: The pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov. 9, 203–214 (2010).

Acknowledgments: The authors thank J. Fordyce, J. Reichert, P. Reilly, and B. Ruch for reviewing the manuscript and provid-ing helpful edits and comments and Sagient Research Sys-tems for providing access to the orphan drug sales data in its BioMedTracker database. Competing interests: None.

Citation: J. A. Gorzelany, M. P. de Souza, Protein replacement therapies for rare diseases: A breeze for regulatory approval? Sci. Transl. Med. 5, 178fs10 (2013).

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DOI: 10.1126/scitranslmed.3005007, 178fs10178fs10.5Sci Transl Med

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