Rare Diseases, When Taken Together, Are Are Together, When Taken Diseases, Rare to According at All

Home , Amatuximab, Arimoclomol, Bimagrumab, Biovest, Carcinoid syndrome, Catridecacog

2013 REPORT 7 7 2 6 4 8 52 56

ontents C Orphan Drugs Innovative ...... in the Pipeline ...... Orphan Drug Approvals ...... Trials Challenges in Clinical Act Drug User Fee Prescription ...... (PDUFA) and Statistics...... Facts Disease Rare ...... Orphan Drugs in Development Glossary...... Drug Development/ ...... Process Approval A major area of this research targets targets of this research A major area than more for accounting cancers, rare in medicines disease of all rare one-third areas research Other top development. - neurologi include genetic disorders, and diseases infectious cal conditions, disorders. autoimmune research victories, Despite some recent is a diseases rare for treatments into This ongoing innovation daunting quest. in medicines of new and the hundreds - hope that physi offer now development options treatment new cians will have disease. rare a patients confronting for -

ipeline ipeline Rare diseases, when taken together, are are together, when taken diseases, Rare to according at all. In fact, rare that not (NIH), of Health the National Institutes one of the 30 million Americans have officially that are diseases 7,000 nearly each because alone they “rare” deemed people in than 200,000 fewer affect only Sometimes, States. the United to known patients are hundred a few disease. a particularhave rare a diagnosis of a rare Simply receiving a frustrating often becomes disease nev doctors have may many quest, since the disease. of or seen heard er before a time of great however, This is, Biopharmaceutical and hope. progress era new is entering an exciting research understanding of the with a growing Scientific advances human genome. to tools new researchers given have often which are diseases, rare explore diseases. than common complex more 13 orphan drugs were alone, In 2012 including diseases, rare for approved therapies cystic for Cushing disease, America’s and Gaucher disease. fibrosis companies research biopharmaceutical with 452 that progress continuing are in development and vaccines medicines listedThe medicines diseases. rare for either in clinical trials in this report are and Drug the Food by or under review (FDA). Administration More Than 450 Medicines in Development for for in Development Medicines Than 450 More Diseases Rare

t men

20 y

Diseases

ator

s s

Respir der

Disor

ological ological

28 Neur

Diseases

ectious ectious

Inf der 85

Disor

Genetic

Blood

, ,

Application Submitte Phase III Phase II Phase I er

er Canc

105 Orphan Drugs in Development Canc

presented by america’s biopharmaceutical research companies biopharmaceutical research america’s by presented Rare Diseases Rare A Report P Drugs in the on Orphan icines in Develop icines Med *Some medicines are listed in more than one category. in more listed are *Some medicines Key Issues

Innovative Orphan Drugs in the function and, as dystrophin expression increases, there have been demonstrated improvements in patients’ ability to walk. Pipeline for Rare Diseases Potential New Treatment for a Genetic Disease in Infants The 452 medicines and vaccines in development for rare dis- —Hypophosphatasia is a rare inherited bone disease that eases employ exciting new scientific and technical knowledge. results from a genetic mutation which hinders the forma- Many of the medicines, which offer hope for those suffering tion of bones and teeth and can result in substantial skeletal from one of the nearly 7,000 rare diseases, represent innova- abnormalities. Severely affected infants often have persistent tive new ways to target disease, including: bone disease or die from respiratory insufficiency due to Targeted RNAi Therapy Approach for Duchenne Muscular progressive chest deformity from poorly developed bones. Dystrophy—In clinical trials, RNAi therapies have shown po- Currently, there are no approved medicines for this disease. tential in treating neuromuscular disorders such as Duchenne One therapy in development delivers the enzyme necessary muscular dystrophy (DMD), which affects about 1 in every for proper bone growth that patients with hypophosphatasia 3,500 to 6,000 male births each year in the United States. are missing. In DMD, DNA deletions cause mutations in important genes Treatments for Patients with Debilitating Lung Disease— that encode for dystrophin, a structural protein found in Idiopathic pulmonary fibrosis (IPF) is a debilitating and almost normal muscle. The loss of this protein causes muscle fibers uniformly fatal disease in which patients experience progres- to disintegrate faster than they can be regenerated. One sive difficulty breathing due to scarring of the lungs. There medicine in development targets restoration of dystrophin are currently no effective treatment options available, and

Medicines in Development By Disease and Phase

Some medicines are listed in more than one category.

Autoimmune Disorders 18 Application Submitted Blood Disorders 7 Phase III Cancer 105 Phase II Cancer, Blood 65 Phase I Cancer-Related 10 Cancer, Skin 15

Cardiovascular Diseases 4

Digestive Disorders 14 Eye Disorders 16 Genetic Disorders 85

Growth Disorders 7 Infectious Diseases 28

Neurological Disorders 32 Respiratory Disorders 20 Skin Conditions 2

Transplantation 14 Other 35

2 Medicines in Development Rare Diseases 2013 Key Issues

ALS: Fighting a Devastating Disease—Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is a progressive RARE DISEASES BIG IMPACT neurodegenerative disease that causes the brain to lose control over body movement, ultimately resulting in paralysis and death. The one drug approved to treat ALS can mod- estly slow progression of the disease, but new treatments are needed. As our scientific understanding of the disease has grown, researchers are pursuing many new approaches to halt or slow progression, including the use of the patient’s own bone marrow stem-cells to create healthy neuron-like cells to replace diseased neurons. Other trials are studying 00 ways to prompt the immune system to protect neurons af- 7,0 fected by ALS. RARE DISE DE Two Targets to Fight Leukemia—A potential first-in-class ASES WORLDWI medicine for acute lymphoblastic leukemia (ALL) is a bispecific T-cell engager antibody designed to focus the body’s cell destroying T-cells against cells expressing CD19, a Source: National Institutes of Health protein found on the surface of B-cell-derived leukemia and lymphoma. The modified antibodies are designed to engage two different targets simultaneously, linking the T-cells to the average patient with IPF dies within three years of diag- cancer cells. nosis. A medicine in development targets connective tissue growth factor, which is elevated in the lungs of IPF patients. Combination Vaccine Treatment for Pancreatic Cancer—A Researchers recently announced promising results from a potential treatment for pancreatic cancer is a combination of Phase II trial in which 60 percent of IPF patients were able two therapeutic vaccines. The treatment combines a Listeria- to stabilize their disease or experience improvement in lung based vaccine that has been engineered to express the function.

Orphan Drug Act of 1983— RARE DISEASES BIG IMPACT A Success Story Recognizing the scarcity of medicines to treat rare diseases with very small patient populations, the Orphan Drug Act of 1983 provided incentives to companies developing rare disease treatments. BY DEFINITION, A RARE DISEASE AFFECTS Over the last 30 years, more than 400 medicines representing 447 separate indications have been approved to treat rare diseases, compared to <200,000 fewer than 10 in the 1970s. As of September 15, 2013, the FDA has granted the orphan drug patients in the United States designation to 2,899 potential therapies.

Source: National Institutes of Health

Medicines in Development Rare Diseases 2013 3 Key Issues

tumor-associated antigen mesothelin and allogeneic pancreatic cancer cells that are genetically-modified to secrete the immune-stimulant, granulocyte-macrophage colony stimu- RARE DISEASES BIG IMPACT lating factor (GM-CSF). The cells are irradiated to prevent further cell growth although they stay metabolically active. Sequential administration of the vaccines in animal studies have demonstrated enhanced tumor-specific T-cell and anti- tumor responses. IN TOTAL, RARE DISEASE IMPACT Orphan Drug Approvals for 30 MILLION Rare Diseases

Since passage of the Orphan Drug Act in 1983, more than 400 medicines for rare diseases have been brought to mar- ket. Below are some key approvals for rare diseases in recent years that represent new technologies or a more defined 1 IN 10 AMERICANS patient population target. Source: National Institutes of Health Zelboraf® (vemurafenib), a personalized medicine, was approved for the treatment of unresectable or metastatic melanoma that expresses a gene mutation called BRAF protein is involved in regulating cell growth but a mutated V600E. It was approved with a first-of-its-kind companion form is found in about half of the late-stage melanoma diagnostic (4800 BRAF V600 Mutation Test) to help de- cases. Zelboraf is able to block the function of the V600E- termine if a patient has the gene mutation. A normal BRAF mutated BRAF protein.

Seeking New Treatments for Children with a Rare Disease

The National Institutes of Health estimates that 50 percent of people affected by rare diseases are children, making rare diseases a particularly deadly and debilitating concern for children worldwide. Rare diseases are responsible for 35 percent of deaths in the first year of life and 30 percent of children with a rare disease will not live to see their fifth birthday.

Encouragingly, one in three of the nearly 3,000 treatments with orphan designation are for children. In addition to the Orphan Drug Act, two other laws have made a significant impact on pediatric research. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) have resulted in a wealth of useful information about dosing, safety, and efficacy. According to the FDA, BPCA and PREA have resulted in 467 pediatric labeling changes since 1988. Together, BPCA and PREA have helped foster research and greatly advanced our ability to treat pediatric patients.

BPCA and PREA were permanently reauthorized by the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA). By providing a predictable regulatory environment, the permanent reauthorization will help ensure that pediatric research by biopharmaceutical companies continues to advance children’s medical care. FDASIA also required the FDA to hold a public meeting and issue a report on encouraging and accelerating development of new therapies for pediatric rare diseases.

4 Medicines in Development Rare Diseases 2013 Key Issues

cally, Ilaris was approved to treat two types of CAPS: familial “In the last five years, one-third of all new cold-auto-inflammatory syndrome (FACS) and Muckle-Wells syndrome (MWS). CAPS is a serious auto-inflammatory drug approvals were for rare diseases” disease that lasts a lifetime with symptoms such as fever, —FDA headache, fatigue, skin rash, painful joints and muscles. CAPS is caused by a single gene mutation that leads to overproduction of interleukin-1 beta, which causes sustained Adcetris® (brentuximab vedotin), the first in a new class of inflammation and tissue damage. Ilaris rapidly and selectively antibody-drug conjugates (ADCs), was approved to treat blocks production of interleukin-1 beta. Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL), a rare type of lymphoma that represents only Kalydeco™ (ivacaftor) was the first medicine approved to 3 percent of all non-Hodgkin lymphomas. ADCs combine treat the underlying cause of cystic fibrosis (CF) and not just a monoclonal antibody and a therapeutic drug, where the the symptoms of the disease. It targets a defective protein antibody directs the therapeutic to target the cancerous cells. to help achieve sustained improvement in lung function. It is also the first FDA-approved drug for Hodgkin lymphoma Kalydeco was approved for use in people with cystic fibrosis in more than 30 years and the first to specifically treat ALCL. (ages 6 and older) who have at least one copy of the G551D Adcetris is composed of an anti-CD30 monoclonal antibody mutation in the CF transmembrane conductance regula- and a microtubule disrupting agent, allowing it to release its tor (CFTR) gene. The defect affects a small portion of CF therapeutic drug once inside the CD30-expressing tumor cells. patients—about 5 percent or 1,200 of the 30,000 CF suf- ferers—but it also provides hope that knowledge gained will Ilaris® (canakinumab), a fully human monoclonal antibody, lead to treatments that will help even more CF patients. was approved to treat adults and children as young as age 4 with cryopyrin-associated periodic syndrome (CAPS). Specifi-

RARE DISEASES BIG IMPACT Patient Engagement The biopharmaceutical research industry is committed to close collaboration and regular coordination with rare disease patient groups N DRU SINCE 1983, NEARLY and other rare disease stakeholders. We must A G work together towards building a positive policy H A environment to help us meet the public health

P C R T challenges that rare diseases present.

O 2,900 ORPHAN DRUG 1983 DESIGNATIONS

Source: Office of Orphan Products Development, RESEARCH Food and Drug Administration PROGRESS HOPE

Medicines in Development Rare Diseases 2013 5 Key Issues

found genes associated with diseases such as myotonic dystrophy, ALS, cystic fibrosis, progeria and neurofibromatosis RARE DISEASES BIG IMPACT types 1 and 2. These breakthroughs are a crucial step toward new treatments. TREATMENTS FDA400 APPROVED Evolving genetic research may offer a solution to the challenges of clinical development. Genetic markers may make it possible to identify a patient population in advance and allow clinical trials with a smaller number of participants.

Before a potential new treatment can be approved, it must be tested in clinical trials. It is often difficult to find patients to volunteer in clinical trials, and rare diseases pose an even greater challenge. Specific rare disease patient populations A GOOD START, but are very small, geographically dispersed and often include RARE DISEASES children. The biopharmaceutical sector is working with pa- of tient advocacy organizations to identify and advance better <5% HAVE A TREATMENT ways to connect patients to biopharmaceutical and academic Source: Food and Drug Administration, researchers conducting clinical trials. EveryLife Foundation for Rare Diseases Physicians and patients can find out about clinical trials being conducted all over the country in collaboration with local Challenges in Clinical Trials for institutions by accessing www.clinicaltrials.gov, a database Rare Diseases sponsored by the National Institutes of Health. Information on clinical trials and medicines in development is also avail- Advances in science and technology, such as personalized able on www.phrma.org. medicine, are creating new opportunities to improve and expand research into rare diseases and the development of new treatments. While personalized medicine is just begin- ning to impact patients, the Personalized Medicine Coalition RARE DISEASES BIG IMPACT estimates that available personalized medicines, treatments and diagnostic products increased from 13 in 2006 to 72 by 2011. In just 10 years since the human genome was mapped, real progress has been made.

The sequencing of the human genome and the analysis of critical proteins in the blood have profoundly impacted bio- 452 pharmaceutical research and are yielding important new tools medicines for understanding and treating a wide range of conditions. & vaccines in These tools are proving critical for taking on rare diseases, development which are often more complex than more common diseases. Many rare diseases will require new tactics to find effective treatments.

Researchers are increasingly able to identify much more targeted patient populations and this new knowledge is allowing clinicians to discover whether a patient is developing or Source: PhRMA, 2013 Rare Diseases Report will develop an illness much earlier. Already researchers have

6 Medicines in Development Rare Diseases 2013 Key Issues

Prescription Drug User Fee Act PDUFA V Advances Regulatory (PDUFA) Continues To be a Success Science for Patients and Medical Innovation Through PDUFA V, FDA will have dedicated resources to develop and apply new scientific tools and approaches to as- Since 1992, the Prescription Drug User Fee Act (PDUFA) sess the safety and effectiveness of new medicines. has provided additional resources to FDA to help make safe and effective new medicines available to patients in a • Additional FDA resources will help to better address timely manner. In its first 20 years, PDUFA brought more submissions that involve pharmacogenomics and qualified than 1,500 new medicines to Americans; increased FDA’s biomarkers. staffing and resources; helped improve the consistency, predictability and efficiency of FDA reviews; encouraged • FDA will support the development of treatments for rare medical innovation and economic growth; and preserved diseases by increasing outreach to the patient commu- and strengthened FDA’s high safety standards. PDUFA nity, providing specialized training for agency staff, and has been reauthorized and amended four times since its developing guidance and policy related to advancing and original passage in 1992—in 1997, 2002, 2007, and most facilitating the development of medicines for rare diseases. recently in 2012 as PDUFA V. • Dedicated FDA staff will evaluate and define best practic- PDUFA V encompasses several provisions that will positively es for the conduct of meta-analyses and to inform guid- impact research and development of treatments for rare ance on commonly accepted and standardized method- diseases. ologies to be used in drug review and safety monitoring.

• Dedicated FDA staff will support the advancement of the use of patient-reported outcomes and other outcomes assessment tools.

Rare Disease Facts and Statistics

Here are a few statistics and facts to illustrate the breadth • In the United States, a condition is considered “rare” if of the rare disease challenge in the United States and it affects fewer than 200,000 people. worldwide. • About 80 percent of rare diseases are genetic in origin, • There are approximately 7,000 different types of rare and thus are present throughout a person’s life, even if diseases and disorders, with more being discovered symptoms do not immediately appear. each day. • The prevalence distribution of rare diseases is • 30 million people in the United States are living with skewed— 80 percent of all rare disease patients are rare diseases. This equates to 1 in 10 Americans or affected by approximately 350 rare diseases. 10 percent of the population. • According to the EveryLife Foundation for Rare Dis- • It is estimated that 350 million people worldwide suf- eases, 95 percent of rare diseases lack a single FDA fer from rare diseases. approved treatment.

• If all of the people with rare diseases lived in one Source: The Global Genes Project, a program of The country, it would be the world’s third most populous R.A.R.E. Project country.

Medicines in Development Rare Diseases 2013 7 Orphan Drugs in Development

Autoimmune Disorders

Product Name Sponsor Official FDA Designation* Development Status**

Actemra® Genentech treatment of systemic sclerosis to be Phase II tocilizumab South San Francisco, CA a separate disease or condition from www.gene.com localized scleroderma

apremilast Celgene treatment of Behcet’s disease Phase II (CC-10004) Summit, NJ www.celgene.com

ARA290 Araim Pharmaceuticals treatment of neuropathic pain in Phase II Ossining, NY patients with sarcoidosis www.araim.org

ARG201 arGentis Pharmaceuticals treatment of diffuse systemic sclerosis Phase II (type 1 native bovine skin collagen) Memphis, TN www.argentisrx.com

caplacizumab Ablynx treatment of thrombotic Phase II (ALX-0081) Ghent, Belgium thrombocytopenic purpura www.ablynx.com

Diamyd® Diamyd Medical treatment of type I diabetes with Phase III autoimmune diabetes vaccine Stockholm, Sweden residual beta cell function www.diamyd.com

DiaPep277® Andromeda Biotech for use in type 1 diabetic mellitus Phase III (peptide vaccine) Ness Ziona, Israel patients with residual beta-cell www.andromedabio.com function

E5501 Eisai treatment of idiopathic Phase III (avatrombopaq) Woodcliff Lake, NJ thrombocytopenic purpura www.eisai.com

Firdapse™ Catalyst Pharmaceutical treatment of Lambert-Eaton Phase III amifampridine Coral Gables, FL myasthenic syndrome www.catalystpharma.com (Breakthrough Therapy)

gevokizumab XOMA treatment of Behcet’s disease Phase III (XOMA 052) Berkeley, CA (see also eye) www.xoma.com

Gilenya® Novartis Pharmaceuticals treatment of chronic inflammatory Phase III fingolimod East Hanover, NJ demyelinating polyneuropathy www.novartis.com

IBC-VS01 Orban Biotech treatment of type 1 diabetes patients Phase I (insulin B-chain vaccine) Brookline, MA with residual beta cell function www.orbanbiotech.com

Oralgam™ Latona Life Sciences treatment for juvenile rheumatoid Phase II completed human gammaglobulin oral Scottsdale, AZ arthritis www.latonalifesciences.com

Pomalyst® Celgene treatment of systemic sclerosis Phase II pomalidomide Summit, NJ (see also cancer, related) www.celgene.com

*The designation is issued by the FDA’s Office of Orphan Products Development while the drug is still in development. The designation makes the sponsor of the drug eligible for entitlements under the Orphan Drug Act of 1983. The entitlements include seven years of marketing exclusivity following FDA approval of the drug for the designated use.

**For more information about a specific medicine or company in the report, please use the website provided.

8 Medicines in Development Rare Diseases 2013 ORarerphan Diseases Drugs in Development

Autoimmune Disorders

Product Name Sponsor Official FDA Designation Development Status

Prochymal® Osiris Therapeutics treatment of type 1 diabetes patients Phase II remestemcel-L Columbia, MD with residual beta cell function www.osiris.com (see also transplantation)

Simponi® Janssen Biotech treatment of sarcoidosis Phase II golimumab Horsham, PA (see also digestive) www.janssenbiotech.com

Stelara® Janssen Biotech treatment of chronic sarcoidosis Phase II ustekinumab Horsham, PA www.janssenbiotech.com ------treatment of primary biliary cirrhosis Phase II www.janssenbiotech.com

teplizumab MacroGenics treatment of recent-onset type 1 Phase III (anti-CD3 mAb) Rockville, MD diabetes www.macrogenics.com

Blood Disorders

Product Name Sponsor Official FDA Designation Development Status

fedratinib Sanofi US treatment of secondary and primary Phase III Bridgewater, NJ myelofibrosis www.sanofi.com ------treatment of polycythemia vera Phase II www.sanofi.com

human prothrombin complex Octapharma USA reversal of anticoagulation therapy in application submitted concentrate Hoboken, NJ patients needing treatment of serious www.octapharma.us or life-threatening bleeding and/or needing urgent surgery or invasive procedures

Jakafi® Incyte treatment of polycythemia vera Phase III ruxolitinib Wilmington, DE (Fast Track) www.incyte.com (see also cancer) ------treatment of essential Phase II thrombocythemia www.incyte.com

LY2784544 Eli Lilly treatment of myeloproliferative Phase II (gandotinib) Indianapolis, IN disorders (polycythemia vera, www.lilly.com essential thrombocythemia and myelofibrosis)

Medicines in Development Rare Diseases 2013 9 Orphan Drugs in Development

Blood Disorders

Product Name Sponsor Official FDA Designation Development Status

pacritinib Cell Therapeutics treatment of myeloproliferative Phase III Seattle, WA disorders with the JAK2 V617F mutation www.celltherapeutics.com

simtuzumab Gilead Sciences treatment of myelofibrosis Phase II (anti-LOXL2 mAb) Foster City, CA (see also cancer, respiratory) www.gilead.com

SPD602 Shire treatment of chronic iron overload in Phase II (iron chelator) Wayne, PA patients with transfusion-dependent www.shire.com anemias

Cancer

Product Name Sponsor Official FDA Designation Development Status

Abraxane® Celgene treatment of pancreatic cancer Phase III paclitaxel protein-bound particles Summit, NJ (see also cancer, skin) www.celgene.com for injection suspension, (albumin-bound)

ABT-414 AbbVie treatment of glioblastoma multiforme Phase I (EGFR ADC) North Chicago, IL (GBM) www.abbvie.com

ADI-PEG20 Polaris Pharmaceuticals treatment of hepatocellular Phase III (pegylated arginine deiminase) San Diego, CA melanoma www.polarispharma.com (see also cancer, skin)

ADXS-HPV Advaxis treatment of HPV-associated anal Phase I/II Princeton, NJ cancer www.advaxis.com

AEZS-108 AEterna Zentaris treatment of ovarian cancer Phase II completed (zoptarelin doxorubicin) South San Francisco, CA www.aezsinc.com

Afinitor® Novartis Pharmaceuticals treatment of hepatocellular Phase III everolimus East Hanover, NJ carcinoma www.novartis.com

aldoxorubicin CytRx treatment of soft tissue sarcoma Phase II Los Angeles, CA www.cytrx.com ------treatment of adenocarcinoma of the Phase II pancreas www.cytrx.com

algenpantucel-L NewLink Genetics treatment of pancreatic cancer Phase III Ames, IA (Fast Track) www.linkp.com

10 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

alisertib Millennium Pharmaceuticals treatment of ovarian cancer Phase II completed (MLN8237) Cambridge, MA (see also cancer, blood) www.millennium.com

AMG 102 Amgen treatment of gastric cancer including Phase III (rilotumumab) Thousand Oaks, CA gastroesophageal junction www.amgen.com adenocarcinoma

amrubicin Celgene treatment of small-cell-lung cancer Phase III Summit, NJ www.celgene.com Dainippon Sumitomo Pharma Osaka, Japan

ARC-100 Archer Biosciences treatment of gliomas Phase II (abeotaxane inhibitor) New York, NY www.archerbiosciences.com ------treatment of pediatric neuroblastoma Phase I/II www.archerbiosciences.com

Archexin® Rexahn treatment of pancreatic cancer Phase II antisense oligonucleotide Rockville, MD www.rexahn.com

astuprotimut-R GlaxoSmithKline treatment of MAGE-A3 positive Phase III Rsch. Triangle Park, NC non-small-cell lung cancer www.gsk.com (see also cancer, skin)

ATR-101 Atterocor treatment of adrenocortical Phase I Ann Arbor, MI carcinoma www.atterocor.com

AVO113 Activartis Biotech treatment of malignant glioma Phase II (dendritic cell cancer Vienna, Austria www.activartis.com immunotherapy)

Avastin® Genentech therapeutic treatment of patients application submitted bevacizumab South San Francisco, CA with ovarian cancer www.gene.com

Azedra™ Progenics Pharmaceuticals treatment of neuroendocrine tumors Phase II iobenguane I-131 Tarrytown, NY (Fast Track) www.progenics.com

BAY 94-9343 Bayer HealthCare Pharmaceuticals treatment of mesothelioma Phase I (anti-mesothelin-ADC) Wayne, NJ www.bayerpharma.com

BC-819 BioCancell Therapeutics treatment of pancreatic cancer Phase II (gene therapy) Jerusalem, Israel (Fast Track) www.biocancell.com

Medicines in Development Rare Diseases 2013 11 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

CBP501 CanBas for use in combination with cisplatin Phase II (peptide mimetic) Shizouka, Japan and pemetrexed for the treatment of www.canbas.co.jp patients with mesothelioma

Ch14.18 mAb United Therapeutics treatment of neuroblastoma Phase III Silver Spring, MD www.unithers.com

CO-1686 Clovis Oncology treatment of non-small-cell lung Phase I/II (EGFR receptor antagonist) Boulder, CO cancer and mutations in the www.clovisoncology.com epidermal growth factor receptor

Cotara® Peregrine Pharmaceuticals treatment of glioblastoma multiforme Phase II TNT-1B mAB Tustin, CA and anaplastic astrocytoma www.peregrineinc.com

CP-613 Cornerstone Pharmaceuticals treatment of pancreatic cancer Phase I/II Cranbury, NJ www.cornerstonepharma.com

CPP-1X Cancer Prevention Pharmaceuticals treatment of neuroblastoma Phase II (eflornithine) Tucson, AZ www.canprevent.com

crenolanib AROG Pharmaceuticals treatment of malignant glioma Phase I (CP-868-596) Dallas, TX (see also cancer, blood) www.arogpharma.com

CRS-207/GVAX Pancreas Aduro Biotech treatment of pancreatic cancer Phase II (listeria monocytogenes) Berkeley, CA www.adutobiotech.com

CVac™ Prima Biomed treatment of ovarian cancer Phase II/III intradermal cancer vaccine Sydney, Australia www.primabiomed.com

DCVax®-Brain Northwest Biotherapeutics treatment of primary brain malignant Phase III dendritic cell vaccine Bethesda, MD cancer www.nwbio.com

EGEN-001 Expression Genetics treatment of ovarian cancer Phase II Huntsville, AL www.egeninc.com

ENMD-2076 EntreMed treatment of ovarian carcinoma Phase II Rockville, MD www.entremed.com

ensituximab Precision Biologics treatment of pancreatic cancer Phase I/II (NPC-1C) Dallas, TX www.precision-biologics.com

Estybon® Onconova Therapeutics treatment of pancreatic cancer Phase III rigosertib Newton, PA (see also cancer, blood) www.onconova.com

12 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

etirinotecan pegol Nektar Therapeutics treatment of ovarian cancer Phase II (NKTR-102) San Francisco, CA www.nektar.com

FANG™ Vaccine Gradalis treatment of ovarian cancer Phase II autologous tumor cell vaccine Carrollton, TX (see also cancer, skin) www.gradalisinc.com

farletuzumab Eisai treatment of ovarian cancer Phase III (MORAb-003) Woodcliff Lake, NJ www.eisai.com

G-202 GenSpera treatment of of hepatocellular Phase II San Antonio, TX carcinoma www.genspera.com

G-203-2c Genus Oncology treatment of pancreatic cancer Phase I (synthesized peptide) Vernon Hills, IL www.genusoncology.com

G-series prophage vaccine Agenus treatment of glioma Phase II (vitespan) Lexington, MA www.agenusbio.com

GL-0810 Gliknik treatment of HPV-16-expressing head Phase II (HPV-16 cancer vaccine) Baltimore, MD and neck squamous cell carcinoma www.gliknik.com

GL-0817 Gliknik treatment of MAGE-A3-expressing Phase II (MAGE-A3 cancer therapeutic Baltimore, MD head and neck squamous cell www.gliknik.com Trojan peptide vaccine) carcinoma

GliAtak® Advantagene treatment of malignant brain tumors Phase II gene therapy Auburndale, MA www.advantagene.com

glufosfamide Eleison Pharmaceuticals for treatment of pancreatic cancer Phase III St. Petersburg, FL (Fast Track) www.eleison-pharma.com

Havalen® Eisai treatment of advanced soft tissue Phase III eribulin Woodcliff Lake, NJ sarcoma www.eisai.com

ICT-107 ImmunoCellular Therapeutics treatment of glioblastoma or brain Phase II (dendritic cancer vaccine) Calabasas, CA stem glioma www.imuc.com

IMA901 immatics biotechnologies treatment of renal cell carcinoma in Phase III (peptide vaccine) Tuebingen, Germany HLA-A*2-positive patients www.immatics.com

IMGN901 ImmunoGen treatment of small-cell lung cancer Phase II (maytansinoid DM-1-conjugated Waltham, MA (see also cancer, blood) www.immunogen.com mAb)

Medicines in Development Rare Diseases 2013 13 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

IRX-2 IRX Therapeutics neoadjuvant therapy in patients with Phase II completed New York, NY squamous cell carcinoma of the head www.irxtherapeutics.com and neck (Fast Track)

Jakafi® Incyte treatment of pancreatic cancer Phase II ruxolitinib Wilmington, DE (see also blood) www.incyte.com

lenvatinib Eisai treatment of follicullar, medullary, Phase III Woodcliff Lake, NJ anaplastic cancer and metastatic or www.eisai.com locally advanced papillary thyroid

Lutathera® Advanced Accelerator Applications treatment of gastro-entero-pancreatic Phase III DOTA-Tyr3 octreotide Saint Genis Pouilly, France neuroendocrine tumors www.adacap.com

masitinib AB Science treatment of malignant Phase III (AB-1010) Short Hills, NJ gastrointestinal stromal tumors www.ab-science.com ------treatment of patients with pancreatic Phase III cancer www.ab-science.com

mibefradil Tau Therapeutics treatment of glioblastoma multiforme Phase I Charlottesville, VA www.tautherapeutics.com

mifamurtide Millennium Pharmaceuticals treatment of osteosarcoma Phase III Cambridge, MA www.millennium.com

milciclib Nerviano Medical Sciences treatment of thymic epithelial tumors Phase II Nerviano, Italy www.nervianoms.com

MK-1775 Merck treatment of ovarian cancer Phase II (WEE1 tyrosine kinase inhibitor) Whitehouse Station, NJ www.merck.com

MM-111 Merrimack Pharmaceuticals treatment of HER2-expressing Phase II (bispecific antibody mAb) Cambridge, MA advanced adenocarcinoma of the www.merrimackpharma.com stomach and gastroesophageal junction ------treatment of HER2-expressing Phase II adenocarcinoma of the esophagus www.merrimackpharma.com

MM-398 Merrimack Pharmaceuticals treatment of pancreatic cancer Phase III (nanoliposomal irinotecan) Cambridge, MA www.merrimackpharma.com

MORAb-004 Eisai treatment of soft tissue sarcoma Phase II Woodcliff Lake, NJ www.eisai.com

14 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

MORAb-009 Eisai treatment of mesothelioma Phase II (amatuximab) Woodcliff Lake, NJ www.eisai.com

MORAb-066 Eisai treatment of pancreatic cancer Phase I Woodcliff Lake, NJ www.eisai.com

Multikine® CEL-SCI neoadjuvant therapy in patients with Phase III leukocyte interleukin Vienna, VA squamous cell carcinoma of the head www.cel-sci.com and neck

Nexavar® Bayer HealthCare Pharmaceuticals treatment of medullary thyroid application submitted sorafenib Wayne, NJ cancer, anaplastic thyroid cancer, and www.bayerpharma.com recurrent or metastatic follicular or papillary thyroid cancer

NGF-hTNF MolMed treatment of malignant pleural Phase III (recombinant fusion protein) Milan, Italy mesothelioma www.molmed.com

niraparib TESARO treatment of ovarian cancer Phase III (ADP-ribose PARP inhibitor) Waltham, MA www.tesarobio.com

onartuzumab Genentech treatment of gastric cancer including Phase III South San Francisco, CA gastroesophageal cancer www.gene.com

Oncophage® Agenus treatment of renal cell carcinoma Phase III prophage cancer vaccine Lexington, MA (Fast Track) www.agenusbio.com

Opaxio® Cell Therapeutics treatment of glioblastoma multiforme Phase II paclitaxel poliglumex Seattle, WA www.celltherapeutics.com

oregovomab Quest PharmaTech treatment of epithelial ovarian cancer Phase II (B43.14 mAb) Edmonton, Canada www.questpharmatech.com

OSE2101 OSE Pharma treatment of non-small-cell lung Phase III Paris, France cancer in patients expressing HLA-A2 www.osepharma.com

perifosine AEterna Zentaris treatment of neuroblastoma Phase I Basking Ridge, NJ www.aezsinc.com

Perjeta® Genentech treatment of gastric cancer Phase III pertuzumab South San Francisco, CA www.gene.com

pexastimogene devacirepvec Jennerex, Inc. treatment of hepatocellular Phase II (Pexa-Vac; JX-594) San Francisco, CA carcinoma www.jennerex.com

Medicines in Development Rare Diseases 2013 15 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

pimasertib EMD Serono treatment of pancreatic cancer Phase II (MEK inhibitor-1) Rockland, MA www.emdserono.com

polyclonal antibody stimulator Cancer Advances treatment of gastric cancer Phase III (G17DT immunogen) Durham, NC www.canceradvancesinc.com ------treatment of adenocarcinoma of the Phase III pancreas www.canceradvancesinc.com

Poly-ICLC Emory University treatment of primary brain tumors Phase II Atlanta, GA www.oncovir.com Oncovir Washington, DC University of California San Diego, CA

PV-10 Provectus Pharmaceuticals treatment of hepatocellular Phase I (rose bengal disodium) Knoxville, TN carcinoma www.provectus.com (see also cancer, skin)

ramucirumab Eli Lilly treatment of gastric cancer application submitted Indianapolis, IN www.lilly.com ------treatment of hepatocellular Phase III carcinoma www.lilly.com

rindopepimut Celldex Therapeutics treatment of EGFRvIII-expressing Phase II/III Phillipsburg, NJ glioblastoma multiforme (Fast Track) www.celldextherapeutics.com

rucaparib Clovis Oncology treatment of ovarian cancer Phase II (PARP inhibitor) Boulder, CO www.clovisoncology.com

salirasib Kadmon treatment of panreatic cancer Phase II (KD032) Warrendale, PA www.kadmon.com

simtuzumab Gilead Sciences treatment of pancreatic cancer Phase II (anti-LOXL2 mAb) Foster City, CA (see also blood, respiratory) www.gilead.com

Somatuline® Ipsen Biopharmaceuticals treatment of symptoms associated Phase III lanreotide acetate Basking Ridge, NJ with carcinoid syndrome www.ipsen.com ------treatment of neuroendocrine tumors Phase III www.ipsen.com

SP1049C Supratek Pharma treatment of gastric cancer Phase II Montreal, Canada www.supratek.com

squalamine Ohr Pharmaceutical treatment of ovarian cancer refractory Phase II New York, NY or resistant to standard chemotherapy www.ohrpharmaceutical.com

16 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

tegafur/gimeracil/oteracil Taiho Pharma USA treatment of gastric cancer Phase III Princeton, NJ www.taiho.co.jp

telatinib ACT Biotech treatment of gastric cancer Phase II (VEGFR/PDGFR/KIT inhibitor) San Francisco, CA www.actbiotech.com

telotristat etiprate Lexicon Pharmaceuticals management of symptoms of Phase III (LX1032) The Woodlands, TX carcinoid syndrome associated with www.lexgen.com carcinoid tumor

TH-302 EMD Serono treatment of soft tissue sarcoma Phase III (hypoxia-activated prodrug) Rockland, MA www.emdserono.com Threshold Pharmaceuticals www.thresholdpharm.com South San Francisco, CA

ThermoDox® Celsion treatment of hepatocellular Phase III lyso-thermosensitive liposomal Lawrenceville, NJ carcinoma (Fast Track) www.celsion.com doxorubicin

Toca 511 & Toca FC combination Tocagen treatment of glioblastoma multiforme Phase I/II San Diego, CA www.tocagen.com

trans sodium crocetinate Diffusion Pharmaceuticals treatment of glioblastoma in Phase I/II (TSC) Charlottesville, VA conjunction with radiotherapy www.diffusionpharma.com

trebananib Amgen treatment of ovarian cancer Phase III (AMG 386) Thousand Oaks, CA www.amgen.com

TVA-Brain-1 TVAX Biomedical treatment of primary central nervous Phase II Lenexa, KS system malignancies www.tvaxbiomedical.com

Tykerb® GlaxoSmithKline treatment of ErbB2-positive Phase III lapatinib Rsch. Triangle Park, NC esophageal cancer www.gsk.com ------treatment of ErbB2-positive Phase III gastric cancer www.gsk.com

VAL-083 Del Mar Pharmaceuticals treatment of malignant gliomas Phase I/II Vancouver, Canada www.delmarpharma.com

VB-111 Vascular Biogenics treatment of malignant glioma Phase I/II Or Yehuda, Israel www.vblrx.com

Medicines in Development Rare Diseases 2013 17 Orphan Drugs in Development

Cancer

Product Name Sponsor Official FDA Designation Development Status

VB4-845 Viventia Biotech treatment of Ep-CAM-positive Phase II (recombinant fusion protein) Winnipeg, Canada squamous cell carcinoma of the head www.viventia.com and neck (Fast Track)

veliparib AbbVie treatment of epithelial ovarian cancer Phase II completed North Chicago, IL in combination with DNA-damaging www.abbvie.com agents (see also cancer, skin)

Votrient® GlaxoSmithKline treatment of ovarian cancer Phase III pazopanib Rsch. Triangle Park, NC www.gsk.com

VS-6063 Verastem treatment of mesothelioma Phase II (defactinib) Cambridge, MA www.verastem.com

Y-90 clivatuzumab Immunomedics treatment of pancreatic cancer Phase II Morris Plains, NJ (Fast Track) www.immunomedics.com

Yondelis® Janssen Research & Development treatment of patients with ovarian Phase III trabectedin Raritan, NJ cancer www.janssenrnd.com ------treatment of soft tissue sarcoma Phase III www.janssenrnd.com

Zybrestat™ OXiGENE treatment of ovarian cancer Phase II fosbreyabulin South San Francisco, CA (Fast Track) www.oxigene.com

Cancer, Blood

Product Name Sponsor Official FDA Designation Development Status

ACE-536 Acceleron Pharma treatment of myelodysplastic Phase II (recombinant fusion protein) Cambridge, MA syndromes www.acceleronpharma.com Celgene (see also genetic) www.celgene.com Summit, NJ

Adcetris® Seattle Genetics treatment of patients with Phase III brentuximab vedotin Bothell, WA peripheral T-cell lymphoma, not www.seattlegenetics.com otherwise specified (Fast Track) (see also cancer, skin)

18 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer, Blood

Product Name Sponsor Official FDA Designation Development Status

AFM-13 Affimed Therapeutics treatment of Hodgkin lymphoma Phase I (anti-CD30/CD16A mAb) Heidelberg, Germany www.affimed.com

alisertib Millennium Pharmaceuticals treatment of peripheral T-cell Phase III (MLN8237) Cambridge, MA lymphoma www.millennium.com (see also cancer)

allogeneic mesenchymal Mesoblast treatment of insufficient hematopoietic Phase III precursor cells New York, NY stem cell production in patients with www.mesoblast.com (stem cell therapy) hematologic malignancies who have failed treatment with conventional chemotherapy

AT-101 Ascenta Therapeutics treatment of chronic lymphocytic Phase II (R-(-)-gossypol) Malvern, PA leukemia www.ascenta.com

AT9183 Astex Therapeutics treatment of acute myeloid leukemia Phase I/II completed Dublin, CA www.astx.com

belinostat Spectrum Pharmaceuticals treatment of peripheral T-cell Phase II Henderson, NV lymphoma (Fast Track) www.sppirx.com

BI-505 BioInvent International treatment of multiple myeloma Phase I (anti-cellular adhesion Lund, Sweden www.bioinvent.com molecule-1 mAb)

BiovaxID® Biovest International treatment of follicular lymphoma Phase III dasiprotimut-T Tampa, FL (Fast Track) www.biovest.com ------treatment of mantle cell lymphoma Phase II www.biovest.com

BL-8040 BioLineRx treatment of acute myeloid leukemia Phase II (CXCR4 chemokine receptor) Jerusalem, Israel www.biolinerx.com

blinatumomab Amgen treatment of acute lymphocytic Phase II Thousand Oaks, CA leukemia www.amgen.com

BP 100-1-01 Bio-Path treatment of chronic myelogenous Phase I (liposomal Grb-2) Houston, TX leukemia www.biopathholdings.com

BT-062 Biotest Pharmaceuticals treatment of multiple myeloma Phase I/II (indatuximab ravtansine) Boca Raton, FL www.biotestpharma.com

Medicines in Development Rare Diseases 2013 19 Orphan Drugs in Development

Cancer, Blood

Product Name Sponsor Official FDA Designation Development Status

CNDO-109 Coronado Biosciences treatment of acute myeloid leukemia Phase I/II (activated allogeneic natural killer Burlington, MA www.coronadobiosciences.com cells)

CPX-351 Celator Pharmaceuticals treatment of acute myeloid leukemia Phase III (cytarabine/daunorubicin liposome Ewing, NJ www.celatorpharma.com injection)

crenolanib AROG Pharmaceuticals treatment of acute myelogenous Phase II (CP-868-596) Dallas, TX leukemia www.arogpharma.com (see also cancer)

Dacogen® Eisai treatment of acute myeloid leukemia Phase II decitabine Woodcliff Lake, NJ www.eisai.com

daratumumab Janssen Research & Development treatment of multiple myeloma Phase I/II Raritan, NJ (Fast Track) www.janssenrnd.com (Breakthrough Therapy)

darinaparsin Solasia treatment of peripheral T-cell Phase I (ZIO-101) Tokyo, Japan lymphoma www.ziopharm.com ZIOPHARM Oncology Boston, MA

dinaciclib Merck treatment of chronic lymphocytic Phase III (MK-7965) Whitehouse Station, NJ leukemia www.merck.com

elotuzumab AbbVie treatment of multiple myeloma Phase III North Chicago, IL www.abbvie.com Bristol-Myers Squibb www.bms.com Princeton, NJ

epratuzumab Immunomedics treatment of non-Hodgkin Phase II Morris Plains, NJ lymphoma www.immunomedics.com

EPZ-5676 Epizyme treatment of acute lymphoblastic Phase I (DOT1L protein inhibitor) Cambridge, MA leukemia (ALL) www.epizyme.com

Estybon™ Onconova Therapeutics treatment of myelodysplastic Phase III rigosertib Newton, PA syndromes www.onconova.com (see also cancer)

forodesine BioCryst Pharmaceuticals treatment of T-cell non-Hodgkin Phase II (PNP inhibitor) Durham, NC lymphoma www.biocryst.com Mundipharma www.mundipharma.com Cambridge, United Kingdom

20 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer, Blood

Product Name Sponsor Official FDA Designation Development Status

ibrutinib Janssen Biotech treatment of chronic lymphocytic application submitted Horsham, PA leukemia (Fast Track) www.janssenbiotech.com Pharmacyclics (Breakthrough Therapy) www.pharmacyclics.com Sunnyvale, CA ------treatment of mantle cell lymphoma Phase III (Breakthrough Therapy) www.janssenbiotech.com ------www.pharmacyclics.com treatment of multiple myeloma ------Phase II www.janssenbiotech.com www.pharmacyclics.com

idelalisib Gilead Sciences treatment of chronic lymphocytic Phase III (PI3K delta inhibitor) Foster City, CA leukemia www.gilead.com

IMGN901 ImmunoGen treatment of multiple myeloma Phase I (maytansinoid DM1-conjugated Waltham, MA (see also cancer) www.immunogen.com mAb)

inotuzumab ozogamicin Pfizer treatment of B-cell acute Phase III (CD22-targeted cytotoxic agent) New York, NY lymphoblastic leukemia www.pfizer.com

interleukin-21 Bristol-Myers Squibb treatment of stage II (T4), III or IV Phase I (rIL-21) Princeton, NJ malignant melanoma www.bms.com

IPI-145 Infinity Pharmaceuticals treatment of follicular lymphoma Phase II (PI3K δ/γ inhibitor) Cambridge, MA www.inpi.com

ISF35 Memgen treatment of chronic lymphocytic Phase II (gene encoding chimeric CD40 San Diego, CA leukemia www.memgen.com ligand)

lestaurtinib Teva Pharmaceutical treatment of acute myeloid leukemia Phase II (CEP-701) North Wales, PA www.tevapharm.com

midostaurin Novartis Pharmaceuticals treatment of acute myeloid leukemia Phase III (PKC412) East Hanover, NJ (see also other) www.novartis.com

milatuzumab Immunomedics treatment of chronic lymphocytic Phase I/II Morris Plains, NJ leukemia www.immunomedics.com

MLN4924 Millennium Pharmaceuticals treatment of acute myelogenous Phase I (NAE inhibitor) Cambridge, MA leukemia www.millennium.com ------treatment of myelodysplastic Phase I syndromes www.millennium.com

MLN9708 Millennium Pharmaceuticals treatment of multiple myeloma Phase III (ixazomib citrate) Cambridge, MA (see also other) www.millennium.com

Medicines in Development Rare Diseases 2013 21 Orphan Drugs in Development

Cancer, Blood

Product Name Sponsor Official FDA Designation Development Status

mocetinostat Mirati Therapeutics treatment of Hodgkin lymphoma Phase II (MGCD0103) San Diego, CA www.mirati.com

mogamulizumab Kyowa Hakko Kirin Pharma treatment of patients with cutaneous Phase III Princeton, NJ T-cell lymphoma www.kyowa-kirin-pharma.com ------treatment of adult T-cell leukemia/ Phase II lymphoma (ATLL) www.kyowa-kirin-pharma.com ------treatment of peripheral T-cell Phase II lymphoma www.kyowa-kirin-pharma.com

moxetumomab pasudotox AstraZeneca treatment of hairy cell leukemia Phase III Wilmington, DE www.astrazeneca.com MedImmune Gaithersburg, MD

NiCord® Gamida Cell for use as hematopoietic support Phase I/II stem cell therapy Jerusalem, Israel in patients with myelodysplastic www.gamida-cell.com syndromes

obinutuzumab Genentech treatment of chronic lymphocytic application submitted South San Francisco, CA leukemia www.gene.com (Breakthrough Therapy) ------treatment of diffuse large B-cell Phase III lymphoma www.gene.com

ocaratuzumab MENTRIK Biotech treatment of follicular lymphoma Phase II Dallas, TX www.mentrik.com

otlertuzumab Emergent BioSolutions treatment of chronic lymphocytic Phase II (anti-CD37 mAb) Rockville, MD leukemia www.emergentbiosolutions.com (TRU-016)

OXi4503 OXiGene treatment of acute myelogenous Phase I (combretastatin A 1 diphosphate) South San Francisco, CA leukemia www.oxigene.com

panobinostat Novartis Pharmaceuticals treatment of multiple myeloma Phase III East Hanover, NJ www.novartis.com

plitidepsin PharmaMar USA treatment of multiple myeloma Phase III (cyclic depsipeptide) New York, NY www.pharmamar.com

22 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer, Blood

Product Name Sponsor Official FDA Designation Development Status

quizartinib Ambit Biosciences treatment of acute myeloid leukemia Phase II (FLT3 inhibitor) San Diego, CA www.ambitbio.com

Revlimid® Celgene treatment of chronic lymphocytic Phase III lenalidomide Summit, NJ leukemia www.celgene.com ------treatment of diffuse large B-cell Phase III lymphoma www.celgene.com ------treatment of follicular lymphoma Phase III www.celgene.com

sapacitabine Cyclacel treatment of acute myelogenous Phase III Berkeley Heights, NJ leukemia www.cyclacel.com ------treatment of myelodysplastic Phase II syndromes www.cyclacel.com

SHP-141 Shape Pharmaceuticals treatment of cutaneous T-cell Phase I (HDACi inhibitor) Cambridge, MA lymphoma www.shapepharma.com

siltuximab Janssen Research & Development treatment of Castleman’s disease application submitted Raritan, NJ www.janssenrnd.com ------treatment of multiple myeloma Phase II www.janssenrnd.com

SL-401 Stemline Therapeutics treatment of acute myeloid leukemia Phase I/II (recombinant fusion protein) New York, NY www.stemline.com

SNS01-T Senesco Technologies treatment of diffuse large B-cell Phase I/II (DNA plasmid vector) Bridgewater, NJ lymphoma www.senesco.com ------treatment of mantle cell lymphoma Phase I/II www.senesco.com ------treatment of multiple myeloma Phase I/II www.senesco.com

StemEx® Gamida Cell for use as hematopoietic support in Phase III carlecortemcel-L Jerusalem, Israel patients with relapsed or refractory www.gamida-cell.com hematologic malignancies who are receiving high-dose therapy (Fast Track)

Medicines in Development Rare Diseases 2013 23 Orphan Drugs in Development

Cancer, Blood

Product Name Sponsor Official FDA Designation Development Status

Synribo® Teva Pharmaceutical treatment of myelodysplastic Phase II omacetaine mepesuccinate North Wales, PA syndromes www.tevapharm.com

tabalumab Eli Lilly treatment of multiple myeloma Phase II/III Indianapolis, IN www.lilly.com

Telintra® Telik treatment of myelodysplastic Phase II ezatiostat Palo Alto, CA syndromes www.telik.com

tosedostat Cell Therapeutics treatment of acute myeloid leukemia Phase II Seattle, WA www.celltherapeutics.com Chroma Therapeutics Oxon, United Kingdom

ublituximab TG Therapeutics treatment of chronic lymphocytic Phase I/II (TG-1101) New York, NY leukemia www.tgtherapeutics.com ------treatment of nodal marginal zone Phase /II lymphoma www.tgtherapeutics.com ------treatment of extranodal marginal Phase I/II zone lymphoma (mucosa-associated www.tgtherapeutics.com lymphatic tissue, MALT)

veltuzumab Immunomedics treatment of chronic lymphocytic Phase I/II Morris Plains, NJ leukemia www.immunomedics.com

Vidaza® Celgene treatment of acute myeloid leukemia Phase III azacitidine Summit, NJ www.celgene.com

vosaroxin Sunesis Pharmaceuticals treatment of acute myeloid leukemia Phase III (SNS-595) South San Francisco, CA (Fast Track) www.sunesis.com

Xalkori® Pfizer treatment of anaplastic large-cell Phase I crizotinib New York, NY lymphoma www.pfizer.com

24 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer, Related Conditions

Product Name Sponsor Official FDA Designation Development Status

Captisol-Enabled® melphalan Spectrum Pharmaceuticals high dose conditioning treatment Phase II/III Henderson, NV prior to hematopoietic progenitor www/sppirx.com (stem) cell transplantation

E-0316 Elorac topical treatment of pruritus Phase II (naloxone topical) Vernon Hills, IL associated with mycosis fungoides www.eloracpharma.com (Fast Track)

FT-1050 Fate Therapeutics enhancement of stem cell Phase II (stem cell stimulant) San Diego, CA engraftment through ex-vivo www.fatetherapeutics.com treatment of human allogeneic hematopoietic stem cells (treatment of neutropenia, thrombocytopenia, lymphopenia, and anemia)

GC-4419 Galera Therapeutics prevention of radiation- or Phase I completed (superoxide dismutase mimetic) Malvern, PA chemotherapy-induced oral mucositis www.galeratx.com in cancer patients

LG631 Lentigen for bone marrow protection in the Phase I (stem cell gene therapy) Gaithersburg, MD treatment of glioblastoma multiforme www.lentigen.com

momelotinib Gilead Sciences treatment of myelofibrosis Phase II (JAK inhibitor) Foster City, CA www.gilead.com

Pomalyst® Celgene treatment of persons with myelo- Phase III pomalidomide Summit, NJ proliferative neoplasm-associated www.celgene.com myelofibrosis and anemia who are red blood cell tranfusion dependent (see also blood)

sodium thiosulfate (STS) Adherex Technologies prevention of platinum-induced Phase III Rsch. Triangle Park, NC ototoxicity in pediatric patients www.adherex.com

Xerecept® Celtic Pharma treatment of peritumoral brain edema Phase III corticotropin-releasing factor Hamilton, Bermuda www.celticpharma.com

Xgeva® Amgen treatment of hypercalcemia of Phase II denosumab Thousand Oaks, CA malignancy www.amgen.com

Medicines in Development Rare Diseases 2013 25 Orphan Drugs in Development

Cancer, Skin

Product Name Sponsor Official FDA Designation Development Status

Abraxane® Celgene treatment of stage IIB to IV melanoma Phase III paclitaxel protein-bound particles Summit, NJ (see also cancer) www.celgene.com for injection suspension (albumin-bound)

Adcetris® Seattle Genetics treatment of mycosis fungoides Phase III brentuximab vedotin Bothell, WA (see also cancer, blood) www.seattlegenetics.com

ADI-PEG20 Polaris Pharmaceuticals treatment of invasive malignant Phase II (pegylated arginine deiminase) San Diego, CA melanoma www.polarispharma.com (see also cancer)

astuprotimut-R GlaxoSmithKline treatment of MAGE-A3-positive stages Phase III Rsch. Triangle Park, NC IIB to IV malignant melanoma www.gsk.com (see also cancer)

Cavatak™ Viralytics treatment of stage II (T4), stage III, Phase II coxsackievirus A21 Sydney, Australia and stage IV melanoma www.viralytics.com

FANG™ Vaccine Gradalis treatment of stage IIB to IV melanoma Phase II autologous tumor cell vaccine Carrollton, TX (see also cancer) www.gradalisinc.com

Marqibo® Spectrum Pharmaceuticals treatment of metastatic uveal Phase II vincristine liposomal Henderson, NV melanoma www.sppirx.com

melapuldencel-T California Stem Cell treatment of stage IIIB through IV Phase II (autologous dendritic cell vaccine) Irvine, CA metastatic melanoma www.californiastemcell.com

MK-3475 Merck treatment of stage IIB through IV Phase II (lambrolizumab) Whitehouse Station, NJ malignant melanoma www.merck.com (Breakthrough Therapy)

nivolumab Bristol-Myers Squibb treatment of stage IIB to IV Phase III (anti-PD-1 mAb) Princeton, NJ melanoma (Fast Track) www.bms.com

POL-103A Polynoma treatment of stage IIB to stage IV Phase III (polyvalent melanoma vaccine) San Diego, CA melanoma www.polynoma.com

PV-10 Provectus Pharmaceuticals treatment of metastatic melanoma Phase II (rose bengal disodium) Knoxville, TN (see also cancer) www.pvct.com

talimogene laherparepvec Amgen treatment of stage IIB-stage IV Phase III Thousand Oaks, CA melanoma www.amgen.com

trametinib and dabrafenib GlaxoSmithKline treatment of stage IIB through IV application submitted Rsch. Triangle Park, NC melanoma www.gsk.com

26 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Cancer, Skin

Product Name Sponsor Official FDA Designation Development Status

veliparib AbbVie treatment of malignant melanoma Phase II North Chicago, IL stages IIB through IV www.abbvie.com (see also cancer)

Cardiovascular Diseases

Product Name Sponsor Official FDA Designation Development Status

ixmyelocel-T Aastrom Biosciences treatment of dilated cardiomyopathy Phase II Ann Arbor, MI www.aastrom.com

plasmin (human) Grifols Therapeutics treatment of acute peripheral arterial Phase II Los Angeles, CA occlusion www.grifolsusa.com

SRM003 Shire prevention of arteriovenous fistula or Phase II Wayne, PA arteriovenous graft failure in patients www.shire.com with end-stage renal disease receiving hemodialysis or preparing for hemodialysis (Fast Track)

tafamidis meglumine Pfizer treatment of symptomatic Phase III New York, NY transthyretin (TTR) amyloid www.pfizer.com cardiomyopathy (see also genetic) Digestive Diseases

Product Name Sponsor Official FDA Designation Development Status

Aes-210 AesRx topical treatment of children and Phase II (clotrimazole) Newton, MA adults with pouchitis www.aesrx.com

alicaforsen Atlantic Healthcare treatment of pouchitis (Fast Track) Phase III Essex, United Kingdom www.atlantichc.com

budesonide Meritage Pharma treatment of patients with Phase II oral suspension San Diego, CA eosinophilic esophagitis www.meritagepharma.com

EUR-100 Aptalis Pharma US treatment of pediatric and adult Phase I/II (fluticasone propionate) Bridgewater, NJ eosinophilic esophagitis www.aptalispharma.com

Medicines in Development Rare Diseases 2013 27 Orphan Drugs in Development

Digestive Diseases

Product Name Sponsor Official FDA Designation Development Status

Humira® AbbVie treatment of pediatric Crohn’s disease Phase III adalimumab North Chicago, IL www.abbvie.com

Lialda® Shire treatment of ulcerative colitis in Phase I mesalamine controlled release Wayne, PA pediatric patients www.shire.com

metronidazole 10% topical SLA Pharma topical treatment of active perianal Phase II ointment Liestal, Switzerland Crohn’s disease www.slapharma.com

naltrexone low-dose TNI BioTech treatment of Crohn’s disease in Phase II Bethesda, MD pediatric patients www.tnibiotech.com

orBec® Soligenix treatment of gastrointestinal Phase I beclomethasone oral Princeton, NJ symptoms with chronic graft versus www.soligenix.com host disease in patients undergoing allogeneic hematopoietic cell transplantation

reslizumab Teva Pharmaceutical treatment of children with Phase III North Wales, PA eosinophilic esophagitis www.tevapharm.com

SGX203 Soligenix treatment of pediatric patients with Phase I Princeton, NJ ulcerative colitis www.soligenix.com

Simponi® Janssen Biotech treatment of pediatric ulcerative Phase I golimumab Horsham, PA colitis www.janssenbiotech.com (see also autoimmune)

Soliris® Alexion Pharmaceuticals treatment of Shiga toxin-producing Phase II eculizumab Cheshire, CT Escherichia coli hemolytic uremic www.alxn.com syndrome (see also eye)

Uceris® Santarus treatment of ulcerative colitis in Phase II budesonide San Diego, CA pediatric patients aged 0 through www.santarus.com 16 years

28 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Eye Disorders

Product Name Sponsor Official FDA Designation Development Status

CODA-001 CoDa Therapeutics treatment of persistent corneal Phase II (antisense oligonucleotide) San Diego, CA epithelial defects www.codatherapeutics.com

EryDex EryDel treatment of ataxia-telangiectasia Phase I erythrocyte-encapsulated Urbino, Italy www.erydel.com dexamethasone

gevokizumab XOMA treatment of non-infectious Phase III (XOMA 052) Berkeley, CA intermediate, posterior or pan uveitis, www.xoma.com or chronic non-infectious anterior uveitis (see also autoimmune)

LIPO-102 Lithera treatment of symptomatic Phase II (salmeterol/fluticasone) San Diego, CA exophthalmos associated with thyroid www.lithera.com related eye disease

Mitosol® Mobius Therapeutics prevention of recurrence of pterygium application submitted mitomycin St. Louis, MO after its surgical excision www.mobiustherapeutics.com

NT-501 CNTF Neurotech USA treatment of retinitis pigmentosa Phase II/III (ciliary neurotrophic growth factor) Cumberland, RI (Fast Track) www.neurotechusa.com ------treatment of macular telangiectasia Phase I type 2 (MacTel) www.neurotechusa.com

plasminogen concentrate Kedrion treatment of ligneous conjunctivitis Phase II/III (human) Barga, Italy www.kedrion.com

QLT091001 QLT treatment of retinitis pigmentosa Phase I (synthetic retinoid) Menlo Park, CA (see also genetic) www.qltinc.com

QPI-1007 Quark Pharmaceuticals treatment of ischemic optic Phase I (synthetic double-stranded siRNA) Fremont, CA neuropathy www.quarkpharma.com

retinal pigment epithelium Advanced Cell Technology treatment of Stargardt’s macular Phase I/II cell therapy Santa Monica, CA dystrophy www.advancedcell.com

RV001 River Vision treatment of active (dynamic) phase Phase II (teprotumumab) New York, NY Grave’s orbitopathy

sirolimus opthalmic Santen treatment of chronic/refractory Phase III (DE-109) Emeryville, CA anterior noninfectious uveitis, www.santen.com noninfectious intermediate uveitis, noninfectious panuveitis and non-infectious uveitis affecting the posterior of the eye (NICUPS)

Medicines in Development Rare Diseases 2013 29 Orphan Drugs in Development

Eye Disorders

Product Name Sponsor Official FDA Designation Development Status

Soliris® Alexion Pharmaceuticals treatment of neuromyelitis optica Phase II eculizumab Cheshire, CT (see also digestive) www.alxn.com

StarGen™ Sanofi US treatment of Stargardt disease Phase I/II gene therapy Bridgewater, NJ www.sanofi.com

UshStat® Sanofi US treatment of retinitis pigmentosa Phase I/II gene therapy Bridgewater, NJ associated with Usher syndrome www.sanofi.com 1B gene defect

Vibex™/KXL™ System Avedro treatment of corneal ectasia following application submitted riboflavin ophthalmic solution Waltham, MA refractive surgery www.avedro.com ------treatment of keratoconus application submitted www.avedro.com Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

AAV1-FS344 Milo Biotechnology treatment of Duchenne and Becker Phase I/II (gene therapy-delivered myostatin Cleveland, OH muscular dystrophy www.milobiotechnology.com inhibitor)

ABH001 Shire treatment of epidermolysis bullosa Phase III human fibroblast-derived Wayne, PA (Fast Track) www.shire.com dermal substitute

Abilify® Otsuka Pharmaceutical treatment of Tourette’s syndrome Phase III aripiprazole Rockville, MD www.otsuka.com

ACE-536 Acceleron Pharma treatment of B-thalassemia Phase II (recombinant fusion protein) Cambridge, MA (see also cancer, blood) www.acceleronpharma.com Celgene www.celgene.com Summit, NJ

Aeroquin® Aptalis Pharmaceuticals treatment of pulmonary infections Phase III levofloxacin Birmingham, AL due to Pseudomonas aeruginosa and www.aptalispharma.com other bacteria in patients with cystic fibrosis

Aes-103 AesRx treatment of sickle cell disease Phase II Newton, MA www.aesrx.com

30 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

afamelanotide Clinuvel Pharmaceuticals treatment of erythropoietic Phase III New York, NY porphyrias www.clinuvel.com

ALN-TTR02/GENZ438027 Alnylam Pharmaceuticals treatment of familial amyloidotic Phase II (siRNA oligonucleotide) Cambridge, MA polyneuropathy www.alnylam.com Sanofi US (Genzyme) www.sanofi.com Bridgewater, NJ

alpha1-proteinase inhibitor Grifols Therapeutics treatment of cystic fibrosis Phase II (human) Los Angeles, CA www.grifols.com

Alprolix™ Biogen Idec for the control and prevention of application submitted recombinant factor IX fusion Weston, MA hemorrhagic episodes in patients www.biogenidec.com protein with hemophilia B (congenital factor IX deficiency or Christmas disease) (Fast Track)

ALXN1101 Alexion Pharmaceuticals treatment of molybdenum cofactor Phase I (cPMP replacement therapy) Cheshire, CT deficiency type A (MoCD) www.alxn.com

AMG 145 Amgen treatment of homozygous familial Phase III (evolocumab) Thousand Oaks, CA hypercholesterolemia www.amgen.com

AMT060 uniQure treatment of hemophilia B Phase I/II (factor IX gene therapy) Amsterdam, Netherlands www.uniqure.com

arbaclofen Seaside Therapeutics treatment of the behavioral Phase III (STX209) Cambridge, MA abnormalities associated with fragile www.seasidetherapeutics.com X syndrome

Arikace® Insmed treatment of bronchopulmonary Phase III liposomal amikacin for inhalation Monmouth Junction, NJ Pseudomonas aeruginosa infections in www.insmed.com cystic fibrosis patients (see also infectious)

asfotase alfa Alexion Pharmaceuticals treatment of hypophosphatasia Phase II/III Cheshire, CT (Fast Track) www.alxn.com (Breakthrough Therapy)

Medicines in Development Rare Diseases 2013 31 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

ataluren PTC Therapeutics treatment of muscular dystrophy Phase III (PTC124) South Plainfield, NJ resulting from premature stop www.ptcbio.com mutations in the dystrophin gene (Fast Track) ------for use in the treatment of cystic Phase III fibrosis resulting from a nonsense www.ptcbio.com (premature stopcodon) mutation in the cystic fibrosis transmembrane conductance regulatory gene (Fast Track)

BAX111 Baxter International treatment of von Willebrand disease Phase III (rhVWF) Deerfield, IL www.baxter.com

beloranib Zafgen treatment of Prader-Willi syndrome Phase II Cambridge, MA www.zafgen.com

BMN-701 BioMarin Pharmaceutical treatment of Pompe disease Phase II (IGF2-GAA) San Rafael, CA www.bmrn.com

Bronchitol® Pharmaxis for use to facilitate clearance of mucus application submitted mannitol inhalation Exton, PA in patients with bronchiectasis and in www.pharmaxis.com patients with cystic fibrosis at risk for bronchiectasis (Fast Track)

CEQ508 Marina Biotech treatment of familial adenomatous Phase I/II (RNA interference) Bothell, WA polyposis www.marinabio.com

ciprofloxacin dry powder Bayer HealthCare Pharmaceuticals management of pulmonary infection Phase II inhalation (DPI) Wayne, NJ due to Pseudomonas aeruginosa in www.bayerpharma.com Novartis Pharmaceuticals cystic fibrosis patients www.novartis.com East Hanover, NJ

CPP-IX/sul Cancer Prevention Pharmaceuticals treatment of familial adenomatous Phase II (eflornithine plus sulindac) Tucson, AZ polyposis www.canprevent.com

CSL654 CSL Behring treatment of patients with congenital Phase II/III (rIX-FP) King of Prussia, PA factor IX deficiency (hemophilia B) www.cslbehring.com

CSL689 CSL Behring treatment and prophylaxis of Phase I (rVIIa-FP) King of Prussia, PA bleeding episodes in patients with www.cslbehring.com congenital hemophilia and inhibitors to coagulation factor VIII or IX ------treatment of congenital factor VII Phase I deficiency which includes treatment www.cslbehring.com and prophylaxis of bleeding episodes in patients with congenital factor VII deficiency

32 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

drisapersen GlaxoSmithKline treatment of Duchenne muscular Phase III (GSK2402968) Rsch. Triangle Park, NC dystrophy www.gsk.com Prosensa Therapeutics (Breakthrough Therapy) Leiden, Switzerland

duvoglustat Amicus Therapeutics treatment of Pompe disease Phase II (AT2220) Cranbury, NJ www.amicusrx.com

ecopipam Psyadon Pharmaceuticals symptomatic treatment of self Phase III (PSYRX101) Germantown, MD injurious behaviors in patients with www.psyadonrx.com Lesch-Nyhan disease ------treatment of Tourette’s syndrome in Phase II children 0-16 years old www.psyadonrx.com

EDI1200 Edimer Pharmaceuticals treatment of X-linked hypohidrotic Phase II Cambridge, MA ectodermal dysplasia (Fast Track) www.edimerpharma.com

eliglustat tartrate Sanofi US (Genzyme) treatment of Gaucher disease Phase III (glucosylceramide synthase Bridgewater, NJ www.sanofi.com inhibitor)

Eloctate™ Biogen Idec treatment of hemophilia A application submitted recombinant human factor VIII-FC Weston, MA (Fast Track) www.biogenidec.com

EPI-743 Dainippon Sumitomo Pharma treatment of inherited mitochondrial Phase II/III (vatiquinone) Osaka, Japan respiratory chain diseases www.ds-pharma.com Edison Pharmaceuticals www.edisonpharma.com Mountain View, CA

eteplirsen Sarepta Therapeutics treatment of Duchenne muscular Phase II (antisense oligonucleotide) Cambridge, MA dystrophy (Fast Track) www.sareptatherapeutics.com

EXR-101 ExSAR treatment of GM-2 gangliosidoses Phase II (pyrimethamine) Monmouth Junction, NJ (Tay-Sachs disease and Sandhoff www.exsar.com disease)

EXR-202 ExSAR treatment of Gaucher disease Phase I (ambroxol) Monmouth Junction, NJ www.exsar.com

GNE lipoplex Gradalis treatment of hereditary inclusion Phase I Carrollton, TX body myopathy-2 www.gradalisinc.com

GSK2696273 GlaxoSmithKline treatment of severe combined Phase III (ex-vivo stem cell gene therapy) Rsch. Triangle Park, NC immunodeficiency due to adenosine www.gsk.com MolMed deaminase deficiency Milan, Italy

Medicines in Development Rare Diseases 2013 33 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

GZ402665 Sanofi US (Genzyme) treatment of acid sphingomyelinase Phase I (rhASM) Bridgewater, NJ deficiency (Niemann-Pick disease) www.sanofi.com

halofuginone hydrobromide Halo Therapeutics treatment of Duchenne muscular Phase I/II Newton, MA dystrophy www.halotherapeutics.com

HGT1110 Shire treatment of metachromatic Phase I/II (cerebroside sulfatase) Wayne, PA leukodystrophy www.shire.com

HGT1410 Shire for treatment of Sanfilippo syndrome Phase I/II (sulfamidase enzyme Wayne, PA (MPS IIIA) www.shire.com replacement therapy)

HQK-1001 HemaQuest Pharmaceuticals treatment of beta thalassemia Phase II San Diego, CA www.hemaquest.com ------treatment of sickle cell disease Phase II www.hemaquest.com

human-cl rhFVIII Octapharma USA immune tolerance induction in Phase III Hoboken, NJ hemophilia A patients with inhibitors www.octapharma.com

human coagulation factor X Bio Products Laboratory treatment of hereditary factor X Phase III Herst, United Kingdom deficiency www.bpl.co.uk

idebenone Santhera Pharmaceuticals treatment of Duchenne muscular Phase III Liestal, Switzerland dystrophy www.santhera.com ------treatment of mitochondrial Phase II myopathy, encephalopathy, lactic www.santhera.com acidosis with stroke-like episodes syndrome (MELAS)

ISIS-TTRRX Isis Pharmaceuticals treatment of familial amyloid Phase III (antisense oligonucleotides) Carlsbad, CA polyneuropathy (Fast Track) www.isispharm.com

L-glutamine Emmaus Medical treatment of sickle cell disease Phase III Torrance, CA (Fast Track) www.emmausmedical.com

LCI699 Novartis Pharmaceuticals treatment of Cushing’s disease Phase II (aldosterone synthase inhibitor) East Hanover, NJ www.novartis.com

LentiD® bluebird bio treatment of andrenoleukodystrophy Phase II/III gene therapy Cambridge, MA www.bluebirdbio.com

34 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

LentiGlobin® bluebird bio treatment of B-thalassemia major and Phase I/II gene therapy Cambridge, MA intermediate www.bluebirdbio.com

LUM001 Lumena Pharmaceuticals treatment of alagille syndrome Phase II (sodium bile acid cotransporter San Diego, CA www.lumenapharma.com inhibitor) ------treatment of primary biliary cirrhosis Phase II www.lumenapharma.com ------treatment of primary sclerosing Phase I cholangitis www.lumenapharma.com ------treatment of progresssive familial Phase I intrahepatic cholestasis www.lumenapharma.com

mavoglurant Novartis Pharmaceuticals treatment of fragile X syndrome Phase II/III (AFQO56) East Hanover, NJ www.novartis.com

migalastat Amicus Therapeutics treatment of Fabry disease Phase III Cranbury, NJ www.amicusrx.com GlaxoSmithKline www.gsk.com Rsch. Triangle Park, NC

Mirapex® Boehringer-Ingelheim Pharmaceuticals treatment of Tourette syndrome in Phase III completed pramipexole Ridgefield, CT pediatric patients www.boehringer-ingelheim.com

MST-188 Mast Therapeutics treatment of sickle cell anemia Phase III (purified poloxamer 188) San Diego, CA (Fast Track) www.masttherapeutics.com

NKTT120 NKT Therapeutics treatment of sickle cell disease Phase I (rhIgG1k mAb) Waltham, MA www.nktrx.com

NN7999 Novo Nordisk routine prophylactic administration Phase III (N9-GP) Princeton, NJ for prevention of bleeding in patients www.novonordisk.com with hemophilia B (Christmas disease)

NovoThirteen® Novo Nordisk for the prevention of bleeding application submitted catridecacog (rFXIII) Princeton, NJ associated with congenital FXIII www.novonordisk.com deficiency ------treatment of congenital FXIII application submitted deficiency www.novonordisk.com

OB-1 Baxter International treatment and prevention of episodic Phase III (recombinant porcine factor VIII) Deerfield, IL bleeding in patients with inhibitor www.baxter.com antibodies to human coagulation factor VIII (Fast Track)

Medicines in Development Rare Diseases 2013 35 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

PEG-PAL BioMarin Pharmaceutical treatment of hyperphenylalaninemia Phase III (PEGylated recombinant San Rafael, CA www.bmrn.com phenylalanine ammonia lyase)

pegylated carboxyhemoglobin Sangart treatment of acute painful sickling Phase I San Diego, CA crises in patients with sickle cell www.sangart.com disease

PF-05280602 Catalyst Biosciences routine prophylaxis to prevent Phase I (rhFVIIa) South San Francisco, CA bleeding episodes in patients with www.catalystbiosciences.com Pfizer hemophilia A and B patients with www.pfizer.com New York, NY inhibitors

pradigastat Novartis Pharmaceuticals treatment of hypertriglyceridemia in Phase III (LCQ908) East Hanover, NJ the setting of type I www.novartis.com hyperlipoproteinemia, also known as familial chylomicronemia syndrome

pridopidine Teva Pharmaceutical treatment of Huntington’s disease Phase II/III North Wales, PA www.tevapharm.com

QLT091001 QLT treatment of Leber congenital Phase I (synthetic retinoid) Menlo Park, CA amaurosis (LCA) due to inherited www.qltinc.com mutations in RPE65 (encoding the protein retinal pigment epithelial protein 65) or LRAT (encoding the enzyme lecithin:retinol acyltransferase) genes (see also eye)

rAAV1-CB-hAAT AGTC treatment of alpha1-antitrypsin Phase II (adeno-associated Alachua, FL deficiency www.agtc.com virus vector-mediated gene therapy)

rAAV2-CB-hRPE65 AGTC treatment of type II Leber’s congenital Phase II (gene therapy) Alachua, FL amaurosis www.agtc.com

RG2833 Repligen treatment of Friedreich’s ataxia Phase I (HDAC3 inhibitor) Waltham, MA www.repligen.com

RG7090 Roche treatment of fragile X syndrome Phase II Nutley, NJ www.roche.com

36 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

RGN-137 topical RegeneRx Biopharmaceuticals treatment of epidermolysis bullosa Phase II completed (thymosin beta 4) Rockville, MD www.regenerx.com

rivipansel GlycoMimetics treatment of vaso-occlusive crisis in Phase II (GMI-1070) Gaithersburg, MD patients with sickle cell disease www.glycomimetics.com Pfizer (Fast Track) www.pfizer.com New York, NY

Ruconest® Santarus treatment of (acute attacks of) application submitted conestat alfa San Diego, CA angioedema caused by hereditary www.santarus.com or acquired C1-esterase inhibitor deficiency ------prophylactic treatment of Phase II angioedema caused by hereditary www.santarus.com or acquired C1-esterase inhibitor deficiency

SD-101 Scioderm treatment of skin blistering and Phase II (allantoin) Durham, NC erosions associated with inherited www.sderm.com epidermolysis bullosa (Breakthrough Therapy)

sebelipase alfa Synageva BioPharma treatment of lysosomal acid lipase Phase III Lexington, MA deficiency (Fast Track) www.synageva.com

SelG2 Selexys Pharmaceuticals treatment of vaso-occlusive crisis in Phase II (humanized IgG2 antibody) Oklahoma City, OK patients with sickle cell disease www.selexys.com

S-nitroglutathione N30 Pharmaceuticals management of cystic fibrosis Phase I (N6022) Boulder, CO patients to improve airway clearance www.n30pharma.com and to improve or stabilize pulmonary function

Spiriva® HandiHaler® Boehringer Ingelheim Pharmaceuticals to improve pulmonary function in Phase III tiotropium bromide Ridgefield, CT conjunction with standard therapy www.boehringer-ingelheim.com in the management of patients with cystic fibrosis

tafamidis meglumine Pfizer treatment of familial amyloid application submitted New York, NY polyneuropathy www.pfizer.com (see also cardiovascular)

TD-101 TransDerm treatment of pachyonychia congenita Phase I (small interfering RNA) Santa Cruz, CA www.transderm.com

Medicines in Development Rare Diseases 2013 37 Orphan Drugs in Development

Genetic Disorders

Product Name Sponsor Official FDA Designation Development Status

UX001 Ultragenyx Pharmaceutical treatment of hereditary inclusion Phase II (sailic acid extended release) Novato, CA body myopathy www.ultragenyx.com

Vimizim™ BioMarin Pharmaceutical treatment of mucopolysacharidosis application submitted elosulfase alfa Novato, CA type IV A (Morquio A syndrome) www.bmrn.com

VX-809/ivacaftor Vertex Pharmaceuticals treatment of cystic fibrosis Phase III Cambridge, MA (Fast Track) www.vrtx.com (Breakthrough Therapy)

Xenobilox® Sigma-Tau Pharmaceuticals treatment of cerebrotendinous application submitted chenodeoxycholic acid Gaithersburg, MD xanthomatosis www.sigmatau.com

Zavesca® Actelion Pharmaceuticals treatment of the neurological application submitted miglustat South San Francisco, CA manifestations of Niemann-Pick www.actelion.com disease, type C

Growth Disorders

Product Name Sponsor Official FDA Designation Development Status

BMN-111 BioMarin Pharmaceutical treatment of achondroplasia Phase I (modified recombinant human San Rafael, CA www.bmrn.com C-type natriuretic peptide)

macimorelin acetate AEterna Zentaris diagnosis of growth hormone Phase III (AEZS-130) South San Francisco, CA deficiency www.aezsinc.com

MOD-4023 PROLOR Biotech treatment of growth hormone Phase III (hGH-CTP) Ness Ziona, Israel deficiency www.prolor-biotech.com

octreotide (oral) Chiasma for the oral treatment of acromegaly Phase I Jerusalem, Israel www.chiasmapharma.com

Signifor® LAR Novartis Pharmaceuticals treatment of acromegaly Phase III pasireotide East Hanover, NJ www.novartis.com

testosterone undecanoate (oral) SOV Therapeutics treatment of constitutional delay in Phase II Morrisville, NC growth and puberty in adolescent www.sovtherapeutics.com boys (14-17 yrs of age)

38 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Growth Disorders

Product Name Sponsor Official FDA Designation Development Status

triptorelin pamoate Debiopharm treatment of central precocious Phase III (Debio 8206 CPP) Lausanne, Switzerland puberty www.debiopharm.com

Infectious Diseases

Product Name Sponsor Official FDA Designation Development Status

AB-103 Atox Bio treatment of necrotizing soft tissue Phase II (synthetic peptide) Ness Ziona, Israel infections (NSTI) www.atoxbio.com Fast Track Drugs and Biologics (Fast Track) North Potomac, MD

anthrax immune globulin (human) Cangene treatment of toxemia associated with Phase III Winnipeg, Canada inhalational anthrax www.cangene.com

Anthrivig™ Emergent Biosolutions treatment of inhalation anthrax Phase III anthrax immune globulin Rockville, MD disease (Fast Track) www.emergentbiosolutions.com

Arestvyr™ SIGA treatment of orthopoxvirus infections Phase II tecovirimat New York, NY (Fast Track) www.siga.com

AriKace® Insmed treatment of bronchiectasis in Phase II completed liposomal amikacin for inhalation Monmouth Junction, NJ patients with Pseudomonas www.insmed.com aeruginosa or other susceptible microbial pathogens (see also genetic) ------Phase II treatment of infections caused by www.insmed.com non-tuberculous mycobacteria (Fast Track)

ASP0113 Astellas Pharma US prevention of clinically significant Phase III (cytomegalovirus DNA vaccine) Northbrook, IL cytomegalovirus (CMV) viremia, www.astellas.com (VCL-CB01) CMV disease and associated complications in at-risk hematopoietic cell transplant populations ------prevention of clinically significant Phase II cytomegalovirus (CMV) viremia, CMV www.astellas.com disease and associated complications in solid transplant populations

Medicines in Development Rare Diseases 2013 39 Orphan Drugs in Development

Infectious Diseases

Product Name Sponsor Official FDA Designation Development Status

AVI-7288 Sarepta Therapeutics prophylaxis following documented or Phase I (antisense oligonucleotide) Cambridge, MA suspected exposure to Marburg virus www.sareptatherapeutics.com (Fast Track)

Cayston® Gilead Sciences improvement of respiratory symptoms Phase III completed aztreonam Foster City, CA in patients with bronchiectasis and www.gilead.com gram-negative bacteria in the airways

Civacir® Biotest Pharmaceuticals prophylaxis of hepatitis C infection in Phase III hepatitis C virus immune globulin Boca Raton, FL liver transplant recipients www.biotestpharma.com (human)

delamanid Otsuka Pharmaceutical treatment of pulmonary tuberculosis Phase III (OPC-67683) Rockville, MD www.otsuka.com

Dificid® Optimer Pharmaceuticals treatment of pediatric Clostridium Phase II fidaxomicin Jersey City, NJ difficile infection www.optimerpharma.com

ETI-204 Elusys Therapeutics treatment of exposure to B. anthracis Phase I (recombinant chimeric mAb) Pine Brook, NJ spores (Fast Track) www.elusys.com

isavuconazole Astellas Pharma US treatment of invasive aspergillosis Phase III Northbrook, IL www.astellas.com Basilea Pharmaceutica Basel, Switzerland

maribavir ViroPharma treatment of clinically significant Phase II Exton, PA cytomegalovirus viremia and disease www.viropharma.com in at-risk patients (Fast Track)

MBX-400/cyclopropavir Microbiotix treatment of active cytomegalovirus Phase I (nucleoside DNA polymerase Worcester, MA infections www.microbiotix.com inhibitor)

miltefosine Paladin Therapeutics treatment of leishmaniasis application submitted St-Laurant, Canada www.paladin-labs.com

MK-8228 Merck prevention of human Phase II (letermovir) Whitehouse Station, NJ cytomegalovirus viremia and disease www.merck.com in at-risk populations (Fast Track)

Nabi-HB® Biotest Pharmaceuticals prophylaxis against hepatitis B virus application submitted hepatitis B immune globulin Boca Raton, FL reinfection liver transplant patients www.biotestpharma.com (human)

40 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Infectious Diseases

Product Name Sponsor Official FDA Designation Development Status

nifurtimox Bayer HealthCare Pharmaceuticals treatment of Chagas disease Phase I Wayne, NJ (American typanosomiasis) caused www.bayerpharma.com by T. cruzi

Nuartez™ Sigma-Tau Pharmaceuticals immediate treatment of malaria Phase III completed artesunate injection Gaithersburg, MD www.sigmatau.com US Army Medical Materiel Development Activity Ft. Detrick, MD

RiVax™ Soligenix prevention of ricin intoxication Phase I ricin toxin pre-exposure vaccine Princeton, NJ www.soligenix.com

SQ109 Sequella treatment of tuberculosis Phase II (ethylenediamine) Rockville, MD (Fast Track) www.sequella.com

sutezolid Sequella treatment of tuberculosis Phase II Rockville, MD www.sequella.com

tafenoquine GlaxoSmithKline treatment of malaria Phase II (8-aminoquinoline) Rsch. Triangle Park, NC www.gsk.com

TCN-202 Theraclone Sciences prevention of congenital Phase I (mAb) Seattle, WA cytomegalovirus (CMV) infection www.theraclone-sciences.com following primary CMV infection in pregnant women

Thravixa™ Emergent BioSolutions for post-exposure prophylaxis and Phase I human anthrax mAb Rockville, MD treatment of inhalation anthrax www.emergentbiosolutions.com

Valtorim® PharmAthene treatment of anthrax infection Phase I anthrax anti-toxin mAb Annapolis, MD (Fast Track) www.pharmathene.com

vancomycin inhalation powder Savara Pharmaceuticals treatment of persistent methicillin- Phase II Austin, TX resistant S. aureus lung infection in www.savarapharma.com patients with cystic fibrosis Neurological Disorders

Product Name Sponsor Official FDA Designation Development Status

ADX-N05 Aerial BioPharma treatment of narcolepsy Phase II (neurotransmitter modulator) Morrisville, NC www.aerialbio.com

AmiKet™ Immune Pharmaceuticals treatment of postherpetic neuralgia Phase II completed amitriptyline/ketamine Tarrytown, NY www.immunepharmaceuticals.com

Medicines in Development Rare Diseases 2013 41 Orphan Drugs in Development

Neurological Disorders

Product Name Sponsor Official FDA Designation Development Status

arimoclomol ALS Association treatment of amyotrophic lateral Phase II/III Richmond, VA sclerosis www.alsa.org FDA Office of Orphan Products Development Silver Spring, MD University of Miami Miami, FL

ATI355 Novartis Pharmaceuticals treatment of acute spinal cord injury Phase I (anti-Nogo-A mAb) East Hanover, NJ www.novartis.com

autologous bone marrow-derived TCA Cellular Therapy treatment of amyotrophic lateral Phase I mesenchymal stem cells Covington, LA sclerosis www.tcacellulartherapy.com

BA-210 BioAxone BioSciences treatment of acute spinal cord injury Phase II (recombinant fusion protein) Cambridge, MA (Fast Track) www.bioaxonebio.com

Captisol-enabled™ CURx Pharmaceuticals treatment of partial onset or primary Phase I topiramate injection San Diego, CA generalized tonic-clonic seizures for www.ligand.com Ligand Pharmaceuticals hospitalized epilepsy patients who are La Jolla, CA unable to take oral topiramate

Circadin® Neurim Pharmaceuticals treatment of non-24-hour sleep-wake Phase III melatonin controlled-release Tel-Aviv, Israel disorder in blind individuals without www.neurim.com light perception

civamide Winston Laboratories treatment of postherpetic neuralgia Phase III Vernon Hills, IL www.winstonlabs.com ------treatment of postherpetic neuralgia Phase II of the trigeminal nerve www.winstonlabs.com

CPP-115 Catalyst Pharmaceutical Partners treatment of infantile spasms Phase I (GABA-AT inhibitor) Coral Gables, FL www.catalystpharma.com

diazepam intranasal spray Acorda Therapeutics management of patients with acute Phase III Ardsley, NY repetitive seizures www.acorda.com

Duopa® AbbVie treatment of late-stage Parkinson’s application submitted levodopa/carbidopa intranuodenal North Chicago, IL disease (Fast Track) www.abbvie.com

Eladur™ DURECT relief of persistent pain associated Phase II bupivacaine transdermal Cupertino, CA with postherpetic neuralgia www.durect.com

ganaxolone Marinus Pharmaceuticals treatment of infantile spasms Phase II New Haven, CT www.marinuspharma.com

42 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Neurological Disorders

Product Name Sponsor Official FDA Designation Development Status

H.P. Acthar® Gel Quesctor Pharmaceuticals treatment of amyotrophic lateral Phase II repository corticotropin injection Anaheim Hills, CA sclerosis www.questcor.com subcutaneous

intravenous carbamazepine Lundbeck treatment of epilepsy patients who Phase III Deerfield, IL cannot take anything by mouth (NPO) www.lundbeck.com

ISIS-SMNRX Biogen Idec treatment of spinal muscular atrophy Phase II (antisense oligonucleotide) Weston, MA www.biogenidec.com Isis Pharmaceuticals www.isispharm.com Carlsbad, CA

midazolam intranasal Upsher-Smith Laboratories rescue treatment of seizures in Phase III (USL-261) Maple Grove, MN patients who require control of www.upsher-smith.com intermittent bouts of increased seizure activity (e.g., acute repetitive seizures, seizure clusters) (Fast Track)

NH001 NeuroHealing Pharmaceuticals for the treatment of patients in a Phase II (apomorphine subcutaneous) Waban, MA vegetative state orminimally www.neurohealing.com conscious state for up to 12 months following a severe traumatic brain injury (traumatic or spontaneous) (Fast Track)

Northera® Chelsea Therapeutics treatment of neurogenic symptomatic application submitted droxidopa Charlotte, NC orthostatic hypotension in patients www.chelseatherapeutics.com with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine-beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy (Fast Track)

NP001 Neuraltus Pharmaceuticals for slowing the progression of Phase II Palo Alto, CA amyotrophic lateral sclerosis www.neuraltus.com

NSI-566 Neuralstem treatment of amyotrophic lateral Phase II (human spinal cord-derived neural Rockville, MD sclerosis www.neuralstem.com stem cells)

NurOwn™ BrainStorm Cell Therapeutics treatment of amyotrophic lateral Phase II (GDNF-producing stem cell New York, NY sclerosis www.brainstormcell.com therapy)

ozanezumab GlaxoSmithKline treatment of amyotrophic lateral Phase II (anti-nogo-A mAb) Rsch. Triangle Park, NC sclerosis www.gsk.com

Medicines in Development Rare Diseases 2013 43 Orphan Drugs in Development

Neurological Disorders

Product Name Sponsor Official FDA Designation Development Status

PF-06687859 Pfizer treatment of spinal muscular atrophy Phase I (mRNA decapping enzyme New York, NY (Fast Track) www.pfizer.com inhibitor)

progesterone infusion BHR Pharma for early intervention in the treatment Phase III (BHR-100) Herndon, VA of moderate to severe closed-head www.bhrpharma.com traumatic brain injury (Fast Track)

RP103 Raptor Therapeutics treatment of Huntington’s disease Phase II/III (cysteamine) Novato, CA www.raptorpharma.com

RTL-1000 Artielle ImmunoTherapeutics treatment of multiple sclerosis Phase I completed (recombinant T-cell receptor San Mateo, CA patients who are both HLA-DR2- www.artielle.com ligand) positive and autoreactive to myelin oligodendrocyte glycoprotein residues 35-57

SEN196 Siena Biotech treatment of Huntington’s disease Phase I (SIRT-1 inhibitor) Siena, Italy www.sienabiotech.com

tasimelteon Vanda Pharmaceuticals treatment of non-24 hour sleep/wake application submitted Washington, DC disorder in blind individuals without www.vandapharma.com light perception

tirasemtiv Cytokinetics treatment of amyotrophic lateral Phase II South San Francisco, CA sclerosis (ALS) (Fast Track) www.cytokinetics.com

Vanquix® Pfizer management of selected, Phase III diazepam auto-injector New York, NY refractory patients with epilepsy www.pfizer.com on stable regimens of antiepileptic drugs, who require intermittent use of diazepam to control bouts of increased seizure activity Respiratory Disorders

Product Name Sponsor Official FDA Designation Development Status

Adempas™ Bayer HealthCare Pharmaceuticals treatment of pulmonary arterial application submitted riociguat Wayne, NJ hypertension www.bayerpharma.com

AIR001 Aires Pharmaceuticals treatment of pulmonary arterial Phase II (sodium nitrite) San Diego, CA hypertension www.airespharma.com

44 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Respiratory Disorders

Product Name Sponsor Official FDA Designation Development Status

ARD-3150 Aradigm management of bronchiectasis Phase III (liposomal ciprofloxacin) Hayward, CA www.aradigm.com

aviptadil THERAMetrics treatment of acute respiratory distress Phase I (vasoactive intestinal peptide) Stans, Switzerland syndrome www.therametrics.com

beraprost 314d United Therapeutics treatment of pulmonary arterial Phase III Silver Spring, MD hypertension www.unither.com

BMS-986202 Bristol-Myers Squibb treatment of idiopathic pulmonary Phase II (LPA1 receptor antagonist) Princeton, NJ fibrosis www.bms.com

Esbriet® InterMune treatment of idiopathic pulmonary Phase III pirfenidone Brisbane, CA fibrosis (Fast Track) www.intermune.com

FG-3019 FibroGen treatment of idiopathic pulmonary Phase II (CTGF mAb inhibitor) San Francisco, CA fibrosis www.fibrogen.com

GeNosyl™ GeNO treatment of persistent pulmonary application submitted nitric oxide Waltham, MA hypertension in newborns www.genollc.com

INOmax® Ikaria to reduce the risk of chronic lung Phase III nitric oxide inhalation Hampton, NJ disease in premature neonates www.ikaria.com ------treatment of pulmonary arterial Phase I hypertension www.ikaria.com

IW001 ImmuneWorks treatment of idiopathic pulmonary Phase I (purified bovine type V collage) Indianapolis, IN fibrosis www.immuneworks.com

nintedanib Boehringer Ingelheim Pharmaceuticals treatment of patients with idiopathic Phase III (triple kinase inhibitor) Ridgefield, CT pulmonary fibrosis www.boehringer-ingelheim.com

Opsumit® Actelion Pharmaceuticals treatment of pulmonary arterial application submitted macitentan South San Francisco, CA hypertension www.actelion.com

PRM-151 Promedior treatment of idiopathic pulmonary Phase II (recombinant human pentraxin-2 Lexington, MA fibrosis www.promedior.com protein)

SAR156597 Sanofi US treatment of idiopathic pulmonary Phase II (IL4/IL13 bi-specific antibody) Bridgewater, NJ fibrosis www.sanofi.com

selexipag Actelion Pharmaceuticals treatment of pulmonary arterial Phase III South San Francisco, CA hypertension www.actelion.com

Medicines in Development Rare Diseases 2013 45 Orphan Drugs in Development

Respiratory Disorders

Product Name Sponsor Official FDA Designation Development Status

simtuzumab Gilead Sciences treatment of idiopathic pulmonary Phase II (anti-LOXL2 mAb) Foster City, CA fibrosis www.gilead.com (see also blood, cancer)

STX-100 Biogen Idec treatment of idiopathic pulmonary Phase II (anti-integrin alphaVbeta6 mAb) Weston, MA fibrosis www.biogenidec.com

Surfaxin® Discovery Laboratories treatment of acute respiratory distress Phase II completed lucinactant Warrington, PA syndrome in adults (Fast Track) www.discoverylabs.com

tralokinumab AstraZeneca treatment of idiopathic pulmonary Phase II (anti-interleukin-13 mAb) Wilmington, DE fibrosis www.astrazeneca.com MedImmune Gaithersburg, MD Skin

Product Name Sponsor Official FDA Designation Development Status

Debrase® MediWound debridement of acute, deep dermal Phase II completed bromelain topical Yvane, Israel burns in hospitalized patients www.mediwound.com

StrataGraft™ Stratatech treatment of hospitalized patients Phase I/II skin replacement therapy Madison, WI with complex skin defects resulting www.stratatechcorp.com from partial and full thickness skin burns requiring excision and grafting Transplantation

Product Name Sponsor Official FDA Designation Development Status

anti-T-lymphocyte immune Fresenius Biotech prevention of graft versus host Phase III globulin Waltham, MA disease (GVHD) www.fresenius-biotech.com

ASC-101 America Stem Cell to improve homing to bone Phase I/II Floresville, TX (treatment of myeloablation) in www.americastemcell.com patients receiving hematopoietic stem cell transplantation

46 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Transplantation

Product Name Sponsor Official FDA Designation Development Status

BB3 Angion Biomedica to improve renal function and prevent Phase II (HGF mimetic) Uniondale, NY delayed graft function following renal www.angion.com transplantation (Fast Track)

emricasan Conatus Pharmaceuticals treatment of patients undergoing Phase II San Diego, CA solid organ transplantation (hepatic www.conatuspharma.com fibrosis)

HSV-TK cell therapy MolMed immunotherapy for acceleration Phase III Milan, Italy of T-cell reconstitution in patients www.molmed.com undergoing allogeneic hematopoietic stem cell transplantation

humanized IgG4 mAb Opsona Therapeutics prevention of ischemia/reperfusion Phase II (OPN-305) Dublin, Ireland injury associated with solid organ www.opsona.com transplantation

liposomal alpha REGiMMUNE prevention of graft versus host Phase I/II galactosylceramide Santa Clara, CA disease www.regimmune.com (RGI-2001)

Multistem® Athersys prophylaxis of graft versus host Phase I stem cell therapy Cleveland, OH disease www.athersys.com

NX001 NephRx treatment of delayed graft function in Phase I Kalamazoo, MI renal transplant recipients www.nephrx.com ------prevention of delayed graft function Phase I in renal transplant recipients www.nephrx.com

Prochymal® Osiris Therapeutics treatment of acute graft versus host Phase III remestemcel-L Columbia, MD disease (Fast Track) www.osiris.com (see also autoimmune)

QPI-1002 Quark Pharmaceuticals prophylaxis of delayed graft function Phase II (siRNA oligonucleotide) Fremont, CA in renal transplant patients www.quarkpharma.com

reparixin Dompe prevention of graft loss in pancreatic Phase II (IL-8A/B receptor antagonist) Milan, Italy islet transplantation www.dompe.com

Medicines in Development Rare Diseases 2013 47 Orphan Drugs in Development

Transplantation

Product Name Sponsor Official FDA Designation Development Status

TOL101 Tolera Therapeutics prophylaxis of acute rejection of solid Phase I/II (anti T-cell receptor murine mAb) Kalamazoo, MI organ transplantation www.tolera.com

TXA127 Tarix Pharmaceuticals to accelerate engraftment of Phase II (angiotensin 1-7) Cambridge, MA hematopoietic cells (treatment of www.tarixpharma.com neutropenia, thrombocytopenia, lymphoma, and anemia) in hematopoietic stem cell transplants ------treatment of patients requiring stem Phase I completed cell transplantation to accelerate www.tarixpharma.com the mobilization of hematopoietic stem cells (CD34+) from the bone marrow to the peripheral blood when combined with a granulocyte colony-stimulating factor Other

Product Name Sponsor Official FDA Designation Development Status

Ampligen® Hemispherx Biopharma treatment of chronic fatigue Phase III completed rintatolimid Philadelphia, PA syndrome www.hemispherxbiopharma.net

BIO300 Humanetics prevention of acute radiation Phase I Minneapolis, MN syndrome www.humaneticscorp.com

BMN-190 BioMarin Pharmaceutical treatment of neuronal ceroid Phase I/II (rhTPP1) San Rafael, CA lipofutscinosis type 2 www.bmrn.com

BYM338 Novartis Pharmaceuticals treatment of inclusion body myositis Phase II (bimagrumab) East Hanover, NJ (Breakthrough Therapy) www.novartis.com

CYT-107 Cytheris treatment of progressive multifocal Phase II (glycosylated recombinant Rockville, MD leukoencephalopathy www.cytheris.com human interleukin-7)

Defitelo™ Gentium for the treatment of hepatic Phase III defibrotide Villa Guardia, Italy veno-occlusive disease (Fast Track) www.sigmatau.com Sigma-Tau Pharmaceuticals Gaithersburg, MD

48 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Other

Product Name Sponsor Official FDA Designation Development Status

DigiBind® Glenveigh Medical treatment of severe preeclampsia and Phase II digoxin immune fab (ovine) Chattanooga, TN eclampsia (Fast Track) www.glenveigh.com

ELAD® Vital Therapies treatment of fulminant hepatic failure Phase III immortalized human liver cells/ San Diego, CA (acute liver failure) www.vitaltherapies.com extracorporeal liver assist device

entolimod Cleveland BioLabs prevention of death following a Phase I Buffalo, NY potentially lethal dose of total body www.cbiolabs.com irradiation during or after a radiation disaster

fresolimumab Sanofi US treatment of primary focal segmental Phase II (TGF-beta antagonist) Bridgewater, NJ glomerulosclerosis www.sanofi.com

human heterologous liver cells Cytonet treatment of urea cycle disorders Phase II Durham, NC www.cytonetllc.com

Ilaris® Novartis Pharmaceuticals treatment of TNF receptor-associated Phase II canakinumab East Hanover, NJ periodic syndrome (TRAPS) www.novartis.com

Kiacta™ Auven Therapeutics treatment of secondary amyloidosis Phase III eprodisate New York, NY www.auventx.com

Lucassin® Ikaria treatment of hepatorenal syndrome application submitted terlipressin Lebanon, NJ (Fast Track) www.ikaria.com

metreleptin Amylin Pharmaceuticals treatment of metabolic disorders application submitted San Diego, CA secondary to lipodystrophy (Fast Track) www.bms.com ------treatment of leptin deficiency second- application submitted ary to generalized lipodystrophy and www.bms.com partial familial lipodystrophy (Fast Track)

midostaurin Novartis Pharmaceuticals treatment of mastocytosis Phase II (PKC412) East Hanover, NJ (see also cancer, blood) www.novartis.com

MLN9708 Millennium Pharmaceuticals treatment of systemic light chain (AL) Phase III (ixazomib citrate) Cambridge, MA amyloidosis www.millennium.com (see also cancer, blood)

Natpara® NPS Pharmaceuticals treatment of hypoparathyroidism Phase III recombinant human parathyroid Bedminster, NJ www.npsp.com hormone (rhPTH)

Medicines in Development Rare Diseases 2013 49 Orphan Drugs in Development

Other

Product Name Sponsor Official FDA Designation Development Status

Neo-Urinary Conduit™ Tengion treatment of bladder dysfunction Phase I Winston-Salem, NC requiring incontinent urinary www.tengion.com diversion

NT-100 Nora Therapeutics prevention of implantation failure Phase II (rhGCSF) Palo Alto, CA www.noratherapeutics.com

obeticholic acid Intercept Pharmaceuticals treatment of primary biliary cirrhosis Phase III (OCA) New York, NY www.interceptpharma.com

OCR-002 Ocera Therapeutics treatment of hyperammonemia and Phase II (ornithine phenylacetate) San Diego, CA resultant hepatic encephalopathy www.ocerainc.com (HE) in patients with acute liver failure (Fast Track)

Octaplas LG® Octapharma USA treatment of thrombotic application submitted human coagulation active plasma, Hoboken, NJ thrombocytopenic purpura www.octapharma.com solvent/detergent treated

OrbeShield™ Soligenix prevention of death following a Phase I/II beclomethasone dipropionate Princeton, NJ potentially lethal dose of total body www.soligenix.com irradiation during or after a radiation disaster (Fast Track)

Oxabact® OxThera treatment of primary hyperoxaluria Phase II/III oxalobacter formigenes Stockholm, Sweden www.oxthera.com

PRT-201 Proteon Therapeutics prevention of arteriovenous fistula Phase II (recombinant human type I Waltham, MA maturation and arteriovenous graft www.proteontherapeutics.com pancreatic elastase) failure in patients with endstage renal disease who are receiving hemodialysis or preparing for hemodialysis (Fast Track)

Ravicti™ Hyperion Therapeutics for intermittent or chronic treatment Phase II glycerol South San Francisco, CA of patients with cirrhosis and any www.hyperiontx.com grade hepatic encephalopathy

recilisib Onconova Therapeutics treatment of acute radiation Phase I Newton, PA syndrome www.onconova.com

Samsca™ Otsuka Pharmaceuticals treatment of autosomal dominant application submitted tolvaptan Rockville, MD polycystic kidney disease www.otsuka.com (Fast Track)

SAR100842 Sanofi US treatment of patients with systemic Phase II (LPA-1/LPA-3 antagonist) Bridgewater, NJ sclerosis www.sanofi.com

50 Medicines in Development Rare Diseases 2013 Orphan Drugs in Development

Other

Product Name Sponsor Official FDA Designation Development Status

Serelsa™ Autism Therapeutics treatment of autism Phase III fluoxetine rapid dissolve New York, NY (Fast Track) www.autismtherapeutics.com (AT001)

triheptanoin Ultragenyx treatment of fatty acid disorders Phase II Novato, CA www.ultragenyx.com

uridine triacetate Wellstat Therapeutics an antidote in the treatment of Phase III (PN401) Gaithersburg, MD 5-fluorouracil poisoning www.wellstattherapeutics.com

XEN402 Teva Pharmaceutical treatment of erythromelalgia Phase II (sodium channel inhibitor) North Wales, PA www.tevapharm.com Xenon Pharmaceuticals www.xenon-pharma.com Burnaby, Canada

Xiaflex® Auxilium Pharmaceuticals treatment of Peyronie’s disease application submitted collagenase clostridium Chesterbrook, PA www.auxilium.com hystolyticum

The content of this report has been obtained through public, government (FDA’s Orphan Drug Product designation database) and industry sources, and the Adis “R&D Insight” database based on the latest information. Report current as of September 23, 2013. The medicines in this report include medicines being developed by U.S. based companies conducting trials in the United States and abroad, PhRMA-member companies conducting trials in the United States and abroad, and foreign companies conducting clinical trials in the United States. The information in this report may not be comprehensive. For more specific information about a particular product, contact the individual company directly or go to www.clinicaltrials.gov. The entire series of Medicines in Development is available on PhRMA’s website. A publication of PhRMA’s Communications & Public Affairs Department. (202) 835-3460 www.phrma.org | www.innovation.org | www.pparx.org Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 2013 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.

Pharmaceutical Research and Manufacturers of America • 950 F Street, NW, Washington, DC 20004

Medicines in Development Rare Diseases 2013 51 Glossary

adenocarcinoma—Cancer of glandular muscles of the hips, pelvic area, thighs cutaneous—Pertaining to the skin. tissue, or tumor of which gland-derived and shoulders. BMD is similar to Duch- cystic fibrosis—A genetic disorder of the cells form gland-like structures. enne MD but often much less severe. exocrine glands (such as sweat glands or adjuvant—A substance or drug that aids The disease progresses slowly and with kidneys) that causes abnormal mucous another substance in its action. variability but can affect all voluntary secretions that obstruct glands and ducts muscles. BMD primarily affects boys and in various organs. alpha 1-proteinase inhibitor deficiency— men, who inherit the disease through Although it is a rare condition, some their mothers. Most with BMD survive cytomegalovirus (CMV)—A DNA virus people are congenitally deficient in alpha well into mid- to late adulthood. that can cause infection without symp- 1-proteinase inhibitor (or alpha 1-tryp- toms or with mild flu-like symptoms. sin, a glycoprotein), which predisposes Breakthrough therapy—A designation assigned by the U.S. Food and Drug diabetes—A chronic disease in which the them to pulmonary emphysema early in body does not produce or properly use life, even in the absence of exposure to Administration that is intended to expedite the development and review insulin, a hormone that is needed to con- substances (like cigarette smoke) that vert sugar, starches and other food into interfere with lung-defense mechanisms. of drugs for serious or life-threatening conditions. The criteria for breakthrough energy needed for daily life. Symptoms amyotrophic lateral sclerosis (ALS)— therapy designation require preliminary may include excessive thirst, hunger, Also known as Lou Gehrig’s disease, the clinical evidence that demonstrates the urination and weight loss. The cause most common of the motor neuron dis- drug may have substantial improvement of diabetes continues to be a mystery, eases, a group of rare disorders in which on at least one clinically significant end- although both genetics and environ- the nerves that control muscular activity point over available therapy. A break- mental factors such as obesity and lack degenerate within the brain and spinal through therapy designation conveys all of exercise appear to play roles. Type 1 cord causing weakness and wasting of of the Fast Track designation features, as diabetes, the more severe form, results the muscles. well as more intensive FDA guidance on from the body’s failure to produce insu- anaplastic thyroid carcinoma—An an efficient drug development program. lin, which “unlocks” the cells of the body, allowing glucose to enter and fuel them. aggressive, invasive form of cancer of carcinoma—Cancer. Squamous cell the thyroid gland. It occurs most often It is estimated that 5 percent to 10 carcinoma is one of the three most com- percent of Americans who are diagnosed in people over age 60. The cause is mon types of skin cancer, arising from unknown. Anaplastic cancer accounts with diabetes have type 1, which requires the flattened, scale-like cells in the skin insulin treatment. for only about 1 percent of all thyroid and resulting primarily from long-term cancers and is a very rare disease. exposure to the sun. Duchenne muscular dystrophy—An inherited disorder that involves rapidly application submitted—An application chronic fatigue syndrome—The symp- for marketing has been submitted by the worsening muscle weakness. Other toms of this illness include debilitating muscular dystrophies get worse much company to the Food and Drug Admin- fatigue, interference with the ability to istration (FDA). more slowly. Duchenne’s is caused by a concentrate, and, in some cases, a low- defective gene. Because of the way the aspergillosis—Infection caused by asper- grade fever and swelling of the lymph disease is inherited, males are more likely gillus, a fungus sometimes found in old nodes. Many possible causes have been to develop symptoms than are women. buildings or decaying plant matter. implicated, but the true cause remains unknown. epidermolysis bullosa—A rare, inherited B-cell—A class of white blood cells im- condition in which blisters appear on portant to the body’s immune system. Clostridium difficile—A bacterium that the skin after minor damage. It mainly Becker muscular dystrophy (BMD)— produces an irritating toxin that causes a affects young children and has a wide One of nine types of muscular dystro- form of colitis characterized by profuse, range of severity. watery diar¬rhea with cramps and low- phy, a group of genetic, degenerative —A genetic metabolic grade fever. Fabry disease diseases primarily affecting voluntary disorder that causes build-up of certain muscles. It’s caused by an insufficient Crohn’s disease—A subacute chronic lipids. It becomes clinically apparent in production of dystrophin, a protein that gastro¬intestinal disorder, involving the childhood and adolescence with fe- helps keep muscle cells intact. Onset can small intestine, characterized by patchy ver, pain and small vascular tumors. It occur during adolescence or adulthood. deep ulcers that may cause fistulas and a progresses to central nervous system Symptoms include generalized weak- narrowing and thickening of the bowel. disturbances and renal and cardiac failure ness and wasting, which first affects the Cushing disease— in mid-life.

52 Medicines in Development Rare Diseases 2013 Glossary

Fast Track—A process designed to Friedreich’s ataxia—An inherited graft versus host disease—In bone facilitate the development and expedite disease that causes progressive dam- marrow transplantation, normal bone the review of drugs to treat serious age to the nervous system resulting in marrow is used to replace malignant diseases and fill an unmet medical need. symptoms ranging from gait disturbance or defective marrow. In an allogeneic The status is assigned by the U.S. Food and speech problems to heart disease. transplantation, healthy marrow is taken and Drug Administration. The purpose “Ataxia,” which refers to coordination from a donor; in an autologous trans- is to get important new drugs to the problems such as clumsy or awkward plantation, the patient’s own healthy patient earlier. Fast Track addresses a movements and unsteadiness, occurs in marrow is used. In graft vs. host disease, broad range of serious diseases. Gener- many different diseases and conditions. a complication of such transplants, im- ally, determining factors include whether The ataxia of Friedreich’s ataxia results mune system cells attack the transplant the drug will have an impact on such from the degeneration of nerve tissue in recipient’s tissues. factors as survival, day-to-day function- the spinal cord and of nerves that con- hematopoietic support—Helping the ing, or the likelihood that the disease, if trol muscle movement in the arms and body to form blood or blood cells. left untreated, will progress from a less legs. The spinal cord becomes thinner severe condition to a more serious one. and nerve cells lose some of their myelin hemophilia A and B—Hemophilia A, Filling an unmet medical need is defined sheath—the insular covering on all nerve the “clas¬sic” hemophilia, is a genetic as providing a therapy where none exists cells that helps conduct nerve impulses. bleeding disorder due to deficiency of or providing a therapy which may be The condition, although rare, is the the coagulation factor VIII. Hemophilia potentially superior to existing therapy. most prevalent inherited ataxia, affecting B, or “Christmas” disease, is caused by Once a drug receives Fast Track designa- about 1 in every 50,000 people in the deficiency of coagulation factor IX. tion, early and frequent communication United States. hepatic—Related to the liver. between the FDA and a drug company is FXIII deficiency (congenital)—A rare hepatitis—Inflammation of the liver encouraged throughout the entire drug disease that affects 1 out of every 3-5 with accompanying liver cell damage development and review process. The million people in the United States, or or death, caused most often by viral frequency of communication assures that approximately 150 people. The condi- infection (e.g., types B and C), but also questions and issues are resolved quickly, tion is characterized by blood that clots by certain drugs, chemicals or poisons. often leading to earlier drug approval normally, but the clots are unstable, so Hepatitis may be either acute (of limited and access by patients. bleeding recurs. FXIII deficiency can duration) or chronic (continuing). —One of the most cause umbilical cord bleeding in some fragile X syndrome hepatocellular—Pertaining to the cells in common causes of inherited mental newborns, soft tissue bruising, mucosal the liver. retardation and neuropsychiatric disease bleeding and potentially fatal intracranial in human beings, affecting as many as 1 hemorrhage (ICH). Studies have shown hepatocellular cancer/carcinoma—A in 2,000 males and 1 in 4,000 females. that up to 60 percent of people with cancer that begins in the liver cells. The syndrome is also known as FRAXA FXIII deficiency experience at least one hereditary angioedema—A rare but (the fragile X chromosome itself) and as ICH during their lifetime. serious problem with the immune system the Martin-Bell syndrome. However, the Gaucher disease—An inherited disease that is passed down through families. It preferred name is fragile X syndrome. caused by a lack or deficiency of an en- is caused by low levels or improper func- The characteristic features of the fragile zyme (glucocerebrosidase). Primarily af- tioning of a protein called C1 inhibitor, X syndrome in boys include prominent or fects the liver, spleen and bone marrow. which affects the blood vessels. People long ears, a long face, delayed speech, with hereditary angioedema can develop large testes, hyperactivity, tactile defen- glioblastoma multiforme—The most rapid swelling of the hands, feet, limbs, siveness, gross motor delays, and autis- common and most malignant of the as- face, intestinal tract, or airway (larynx or tic-like behaviors. Much less is known trocytomas. The tumor grows so fast that trachea). about girls with fragile X syndrome. it increases pressure in the brain, produc- HPV (human papillomavirus)—Viral Only about half of all females who carry ing headaches, slowed thinking, and if agent of warts, believed to be conta- the genetic mutation have symptoms severe enough, sleepiness and coma. gious and usually harm-less, but it can themselves. Of those, half are of normal glioma—A type of brain tumor arising lead to cervical cancer. intelligence, and only one-fourth have from the supporting glial cells within an IQ under seventy. Few fragile X girls the brain. Gliomas make up about 60 Huntington’s disease—Huntington’s have autistic symptoms, although they percent of all primary brain tumors and chorea is an uncommon, inherited dis- tend to be shy and quiet. are frequently malignant. ease in which degeneration of the basal

Medicines in Development Rare Diseases 2013 53 Glossary

ganglia (structures deep in the brain) tigue, and problems with the heart, eyes, the lymph nodes and spleen, multiply results in chorea (rapid, jerky, involuntary and various other systems. unchecked. Lymphomas fall into two movements) and dementia (progressive Juvenile rheumatoid arthritis—Refers to categories: One is called Hodgkin’s dis- mental impairment). Symptoms do not arthritis or an arthritis-related condition ease, characterized by a particular kind usually appear until the age of 35 to 50. (rheumatic disease) that occurs by age of abnormal cell. All others are called hypercholesterolemia (homozygous 15 or younger. non-Hodgkin’s lymphomas, which vary in their malignancy according to the nature familial)—An inherited metabolic dis- Leber congenital amaurosis (LCA)—An order resulting in an abnormal amount and activity of the abnormal cells. B and inherited retinal degenerative disease T-cell lymphomas are caused by prolifer- of cholesterol in the blood. It can lead characterized by severe loss of vision to accelerated atherosclerosis and early ation of the two principal types of white at birth. A variety of other eye-related blood cells, called B- and T-lymphocytes. heart attack. Dietary treatment seldom abnormalities including roving eye move- helps in these cases. Mycosis fungoides is a type of lym- ments, deep-set eyes, and sensitivity to phoma that primarily affects the skin of hypophosphatasia—A rare, inherited bright light also occur with this disease. the buttocks, back or shoulders but can disease that results in decreased activ- Some patients with LCA also experience also occur in other sites. The cause is ity of the enzyme alkaline phosphatase, central nervous system abnormalities. unknown. which assists in the metabolism of phos- Lesch-Nyhan syndrome (LNS)—A rare, phate that is present in many tissues, in- melanoma—A cancer made up of pig- inherited disorder caused by an enzyme mented skin cells. cluding bones and teeth. The illness may (HPRT) deficiency. LNS is present at occur during infancy or as an adult. The birth in baby boys. The lack of HPRT metastatic—Secondary cancers that infantile form of hypophosphatasia is causes a build-up of uric acid in all body have spread from the primary or original fatal in 50 percent of cases. Symptoms fluids, leading to symptoms such as cancer site. of hypophosphatasia in infants include severe gout, poor muscle control, and mucositis—The swelling, irritation, and poor feeding, failure to gain weight, moderate retardation, which appear in ulceration of the mucosal cells that line failure to thrive, delayed development, the first year of life. A striking feature of the digestive tract. Mucositis can occur loss of teeth, and bone pain. Adults LNS is self-mutilating behaviors–char- anywhere along the digestive tract from who develop hypophosphatasia have acterized by lip and finger biting–that the mouth to the anus. It can be a very a normal life expectancy. Symptoms in begin in the second year of life. Ab- troublesome and painful side effect of adults include premature loss of teeth, normally high uric acid levels can cause chemotherapy. fractures, and bone pain. sodium urate crystals to form in the multiple myeloma—A malignant condi- idiopathic thrombocytopenia purpura— joints, kidneys, central nervous system, tion characterized by the uncontrolled A condition in which there is destruc- and other tissues of the body, leading to proliferation and disordered function of tion of blood platelets by the immune gout-like swelling in the joints and severe plasma cells (a type of white blood cell) system. The reduced number of platelets kidney problems. Neurological symptoms in the bone marrow. It occurs in middle may result in abnormal bleeding into the include facial grimacing, involuntary to old age and leaves patients vulnerable skin (purpura) and other parts of the writhing, and repetitive movements of to increased infections and anemia. body. the arms and legs similar to those seen in Huntington’s disease. multiple sclerosis (MS)—Progressive inherited mitochondrial diseases—A disease of the central nervous system in group of systemic diseases caused by leukemia—A form of cancer involving which scattered patches of the covering inherited or acquired damage to the mi- abnormally growing white blood cells, of nerve fibers (myelin) in the brain and tochondria, which are small, energy-pro- which dominate the bone marrow and spinal cord are destroyed. Symptoms ducing structures found in every cell in prevent it from making enough normal range from numbness and tingling to the body that serve as the cells’ “power blood cells. This leaves the patient highly paralysis and incontinence. plants.” When the mitochondria are not susceptible to serious infections, anemia working properly, there is an energy and bleeding episodes. The cells increase neuroblastoma—A tumor of the adrenal shortage within those areas of the body in the blood, interfering with the func- glands or sympathetic nervous system that consume large amounts of energy tion of other organs. (the part of the nervous system responsible for certain automatic body func- such as the muscles, brain, and heart. lymphoma—Cancers in which the cells The result is often muscle weakness, fa- tions, such as the control of heart rate). of lymphoid tissue, found mainly in Neuroblastomas are the most common

54 Medicines in Development Rare Diseases 2013 Glossary

extra-cranial (outside the skull) solid or completely eliminate this essential abnormal oxygen-carrying pigment tumors of childhood. enzyme. Excessive amounts of glycogen called hemoglobin S, resulting in chronic, neuropathic pain—Caused by disease, accumulated everywhere in the body, severe anemia and the characteristic inflammation, or damage to the periph- but the cells of the heart and skeletal sickle shape of the red cell. Caused by eral nerves, which connect the central muscles are the most seriously affected. mutation of the gene that codes for nervous system (brain and spinal cord) to The symptoms of Pompe disease can hemoglobin. the sense organs, muscles, glands, and vary widely in terms of age of onset and spinal cord injury—Damage to the spinal internal organs. severity depending on the degree of cord which can cause loss of sensation, enzyme deficiency. neuropathy—Disease, inflammation, or muscle weakness or paralysis. damage to the peripheral nerves, which postherpetic neuralgia—A burning pain systemic—Affecting the whole body. that may recur at the site of an attack of connect the central nervous system to thalassemia—Not just one disease the sense organs, muscles, glands, and shingles months or even years after the illness. but rather a complex series of genetic internal organs. (inherited) disorders all of which involve Parkinson’s disease—Chronic neurologic prophylaxis—Treatment intended to underproduction of hemoglobin, the disease of unknown cause, characterized preserve health and prevent the spread indispensable molecule in red blood cells by tremors, rigidity and an abnormal of disease. that carries oxygen. gait. The most common variety is idio- pulmonary—Pertaining to the lungs. Tourette syndrome (TS)—A neurologi- pathic Parkinson’s disease. pulmonary arterial hypertension—High cal disorder characterized by repetitive, Phase 0—First-in-human trials conduct- blood pressure in the arteries supplying involuntary movements and vocalizations ed in accordance with FDA’s 2006 guid- the lungs due to increased resistance to called tics. The early symptoms of TS are ance on exploratory Investigational New blood flow through the lungs. typically noticed first in childhood, with Drug (IND) studies designed to speed up renal—Relates to kidneys. the average onset between the ages of development of promising drugs by es- 3 and 9. TS occurs in people from all tablishing very early whether the tested respiratory distress syndrome (RDS)— ethnic groups; males are affected about compound behaves in human subjects as Lung disorder of premature infants three to four times more often than was anticipated from preclinical studies. characterized by respiratory distress and females. It is estimated that 200,000 cyanosis (lack of oxygen in blood). RDS Americans have the most severe form Phase I—Safety testing and pharmaco- is caused by a deficiency of surfactant, logical profiling in humans. of TS, and as many as 1 in 100 exhibit a substance that coats the inner lining milder and less complex symptoms such Phase II—Effectiveness and safety test- of the lungs and prevents them from col- as chronic motor or vocal tics. Although ing in humans. lapsing during exhalation. TS can be a chronic condition with Phase III—Extensive clinical trials to retinitis pigmentosa—Degeneration in symptoms lasting a lifetime, most people demonstrate safety and efficacy in both eyes of the rods and cones of the with the condition experience their worst humans. retina—the light-sensitive membrane that tic symptoms in their early teens, with improvement occurring in the late teens Pompe disease—A rare (estimated at lines the inside of the back of the eye and continuing into adulthood. 1 in every 40,000 births), inherited on which images are cast by the cornea and often fatal disorder that disables and lens. Usually has a genetic basis. ulcerative colitis—A chronic inflamma- the heart and muscles. It is caused The first symptom is usually night blind- tion and ulceration of the lining of the by mutations in a gene that makes an ness, progressing to a ring-shaped area colon and rectum. It causes bloody diar- enzyme called alpha-glucosidase (GAA). of blindness that gradually extends to rhea and mainly involves the left colon. lessen the field of vision. Normally, the body uses GAA to break uveitis—Inflammation of the uvea, the down glycogen, a stored form of sugar sickle cell anemia/disease—Inher- middle layer of the eye. used for energy. But in Pompe disease, ited blood disorder in which red cells mutations in the GAA gene reduce are abnormal in shape and contain an

Medicines in Development Rare Diseases 2013 55 The Drug Discovery, Development and Approval Process

Developing a new medicine takes an average of 10-15 years; For every 5,000-10,000 compounds in the pipeline, only 1 is approved. Drug Discovery and Development: A LONG, RISKY ROAD

DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW LG-SCALE MFG Y

5,000–10,000 250 5 VEILLANCE ONE FDA-

VER COMPOUNDS APPROVED O DRUG

PHASE PHASE PHASE ARKETING SUR 1 2 3 -M ST NUMBER OF VOLUNTEERS PRE-DISC 20–80 100–300 1,000–3,000 A SUBMITTED 0.5–2 IND SUBMITTE D 3–6 YEARS6–7 YEARS ND

YEARS PHASE 4: PO The Drug Development and Approval Process The U.S. system of new drug approvals is in people. The IND shows results of previous ate statistically significant evidence to confirm perhaps the most rigorous in the world. experiments; how, where and by whom the new its safety and effectiveness. They are the lon- studies will be conducted; the chemical structure gest studies, and usually take place in multiple It takes 10-15 years, on average, for an experi- of the compound; how it is thought to work in sites around the world. mental drug to travel from lab to U.S. patients, the body; any toxic effects found in the animal according to the Tufts Center for the Study of New Drug Application (NDA)/Biologic License studies; and how the compound is manufac- Drug Development. Only five in 5,000 com- Application (BLA). Following the completion tured. All clinical trials must be reviewed and ap- pounds that enter preclinical testing make it to of all three phases of clinical trials, a company proved by the Institutional Review Board (IRB) human testing. And only one of those five is analyzes all of the data and files an NDA or BLA where the trials will be conducted. Progress approved for sale. with FDA if the data successfully demonstrate reports on clinical trials must be submitted at both safety and effectiveness. The applications On average, it costs a company $1.2 billion, least annually to FDA and the IRB. contain all of the scientific information that the including the cost of failures, to get one new Clinical Trials, Phase I—Researchers test the company has gathered. Applications typically medicine from the laboratory to U.S. patients, drug in a small group of people, usually between run 100,000 pages or more. according to a recent study by the Tufts Center 20 and 80 healthy adult volunteers, to evaluate for the Study of Drug Development. Approval. Once FDA approves an NDA or BLA, its initial safety and tolerability profile, deter- the new medicine becomes available for physi- Once a new compound has been identified in mine a safe dosage range, and identify potential cians to prescribe. A company must continue the laboratory, medicines are usually developed side effects. to submit periodic reports to FDA, including as follows: Clinical Trials, Phase II—The drug is given any cases of adverse reactions and appropriate Preclinical Testing. A pharmaceutical company to volunteer patients, usually between 100 and quality-control records. For some medicines, conducts laboratory and animal studies to show 300, to see if it is effective, identify an optimal FDA requires additional trials (Phase IV) to biological activity of the compound against the dose, and to further evaluate its short-term evaluate long-term effects. targeted disease, and the compound is evalu- safety. Discovering and developing safe and effective ated for safety. Clinical Trials, Phase III—The drug is given to a new medicines is a long, difficult, and expensive Investigational New Drug Application (IND). larger, more diverse patient population, often process. PhRMA member companies invested an After completing preclinical testing, a com- involving between 1,000 and 3,000 patients estimated $48.5 billion in research and develop- pany files an IND with the U.S. Food and Drug (but sometime many more thousands), to gener- ment in 2012. Administration (FDA) to begin to test the drug