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contents
February 2019, 23rd

FEATURE STORY
●  Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy
GENE THERAPY
● Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model
● Long-term correction of hemophilia B using adenoviral delivery of CRISPR/Cas9
RARE DISEASES
● Characterization and treatment of congenital thrombotic thrombocytopenic purpura
● Targeting angiogenesis in Duchenne muscular dystrophy
CLINICAL TRIALS - DATA
● Catabasis Pharmaceuticals: new data supporting edasalonexent as a potential treatment for Duchenne Muscular Dystrophy
INDUSTRIAL LANDSCAPE & AGREEMENTS
● AOP Orphan announces EU marketing authorization for ropeginterferon alfa-2b for rare blood cancer
MISCELLANEOUS
● Patient access to orphan drugs in France 
● The Orphan Drug Act revisited
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FEATURE STORY
Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a monogenic disorder and a candidate for therapeutic genome editing. There have been several recent reports of genome editing in preclinical models of Duchenne muscular dystrophy, however, the long-term persistence and safety of these genome editing approaches have not been addressed. A group has just shown that genome editing and dystrophin protein restoration is sustained in the mdx mouse model of Duchenne muscular dystrophy for 1 year after a single intravenous administration of an adeno-associated virus that encodes CRISPR (AAV-CRISPR). The researchers also show that AAV-CRISPR is immunogenic when administered to adult mice; however, humoral and cellular immune responses can be avoided by treating neonatal mice. Additionally, they describe unintended genome and transcript alterations induced by AAV-CRISPR that should be considered for the development of AAV-CRISPR as a therapeutic approach. The results appeared in February 18th online issue of Nat Med
Related Informations/Publications
- Hum Gene Ther. 2019 Jan 16. Questions answered and unanswered by the first CRISPR editing study in the canine model of Duchenne muscular dystrophy. Wasala NB et al. One Hospital Drive, M610 Medical Sciences Bldg, Columbia, Missouri, USA
Results/Comments: Future large-scale, long-term, and comprehensive studies are warranted to establish the safety and efficacy of CRISPR editing therapy in large mammals. Link: Abstract
-J Pers Med. 2018 Nov 24;8(4). Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy. Lim KRQ et al. University of Alberta, 8812-112 St., Edmonton, AB T6G 2H7, Canada
Results/Comments: This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.
Link: AbstractFull Text
-OCT 2017: Sarepta Therapeutics Signs Exclusive Global Collaboration with Duke University for Gene Editing CRISPR/Cas9 Technology to Develop New Treatments for Duchenne Muscular Dystrophy (DMD) Results /Comments: Exclusive license option grants Sarepta rights to Duke intellectual property for CRISPR/Cas9. Link: Press Release 
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GENE THERAPY
Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model
In humans, inner ear development is completed in utero, with hearing onset at ∼20 weeks of gestation. However, genetic forms of congenital deafness are typically diagnosed during the neonatal period. Gene therapy approaches in animal models should therefore be tested after the period of hearing onset, to determine whether they can reverse an existing deafness phenotype. Researchers have used a mouse model of DFNB9, a human deafness form accounting for 2–8% of all cases of congenital genetic deafness. They show that local gene therapy in the mutant mice not only prevents deafness when administered to immature hearing organs, but also durably restores hearing when administered at a mature stage, raising hopes for future gene therapy trials in DFNB9 patients. The results appeared in February 19th online issue of PNAS.  
Related Informations / Publications
- Front Mol Neurosci. 2018; 11: 221. Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success. Zhang W et al. Zhongnan Hospital of Wuhan University, Wuhan, China. Link: AbstractFull Text 
 Mol Ther. 2016 Feb; 24(1): 17–25. Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice. Wade W et al. National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, Maryland, USA. Link: Full Text
Long-term correction of hemophilia B using adenoviral delivery of CRISPR/Cas9
Hemophilia B (HB) is a life-threatening inherited disease caused by mutations in the FIX gene, leading to reduced protein function and abnormal blood clotting. Due to its monogenic nature, HB is one of the primary targets for gene therapy. Indeed, successful correction of HB has been shown in clinical trials using gene therapy approaches. However, application of these strategies to non-adult patients is limited due to high cell turnover as young patients develop, resulting in vector dilution and subsequent loss of therapeutic expression. Gene editing can potentially overcome this issue by permanently inserting the corrective gene. Integration allows replication of the therapeutic transgene at every cell division and can avoid issues associated with vector dilution. In this study, American researchers have explored adenovirus as a platform for corrective CRISPR/Cas9-mediated gene knock-in. They determined as a proof-of-principle that adenoviral delivery of CRISPR/Cas9 is capable of corrective gene addition, leading to long-term augmentation of FIX activity and phenotypic correction in a murine model of juvenile HB. The results appeared in February 13th online issue of J Control Release
Related Informations / Publications
- DEC 2018 : uniQure Announces Long-Term Clinical Data from Ongoing Phase I/II Trial of AMT-060 and Confirms Dose for AMT-061 Pivotal Study in Hemophilia B. Link: Press Release 
-Stem Cell Res Ther. 2018 Apr 6;9(1):92. Targeted genome engineering in human induced pluripotent stem cells from patients with hemophilia B using the CRISPR-Cas9 system.
Lyu C et al. Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China. Results/Comments: The iPSC technique is a good tool for genetic therapy for human hereditary diseases. CRISPR-Cas9 is versatile, convenient, and safe to be used in iPSCs with low off-target effects. Link: Abstract Full Text 
-F1000Res. 2018 Apr 24;7. Emerging therapies for hemophilia: controversies and unanswered questions. Arruda VR et al. The Children's Hospital of Philadelphia, Philadelphia, PA, USA Results/Comments: The researchers here review these emerging therapies with a focus on controversies and unanswered questions in each category. Link: AbstractFull Text 
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RARE DISEASES
Characterization and treatment of congenital thrombotic thrombocytopenic purpura
Congenital Thrombotic Thrombocytopenic Purpura (cTTP) is an ultra rare thrombomicroangiopathy caused by an inherited deficiency of ADAMTS13. There is limited data on the genotype-phenotype correlation and no consensus on treatment. Researchers have reviewed the largest cohort of cTTP cases, diagnosed in the UK, over the past 15 years. 73 cases of cTTP were diagnosed, confirmed by genetic analysis. 93% were alive at the time of review. 36% had homozygous mutations and 64% compound heterozygous mutations. Two presentation peaks were seen, childhood (median diagnosis age 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age 31 years). Genetic mutations differed by age of onset with pre-spacer mutations more likely to be associated with childhood-onset (p=0.0011). 69% of adult presentations were associated with pregnancy. Fresh Frozen Plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. 88% of patients with normal blood counts but headaches, lethargy or abdominal pain reported symptom resolution with prophylactic therapy although the most common currently used regimen of three weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. The results appeared in February 15th online issue of Blood
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Related Informations / Publications
-J Thromb Haemost. 2019 Feb 14. Risk of diagnostic delay in congenital thrombotic thrombocytopenic purpura. Ferrari B et al. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy Results/Comments: Early diagnosis can avoid recurrences and long-term organ damage with long-term sequelae. Link: Abstract
-N Engl J Med. 2019 Jan 24;380(4):335-346. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. Scully M et al. National Institute for Health Research UCLH-UCL Biomedical Research Center, London, UK. Link: Abstract
 -Res Pract Thromb Haemost. 2018 Nov 16;3(1):26-37. Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine.. Coppo B et al. Centre de Référence des Microangiopathies Thrombotiques Paris France. Link: AbstractFull Text 
Targeting angiogenesis in Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) represents one of the most devastating types of muscular dystrophies which affect boys already at early childhood. Despite the fact that the primary cause of the disease, namely the lack of functional dystrophin is known already for more than 30 years, DMD still remains an incurable disease. Thus, an enormous effort has been made during recent years to reveal novel mechanisms that could provide therapeutic targets for DMD, especially because glucocorticoids treatment acts mostly symptomatic and exerts many side effects, whereas the effectiveness of genetic approaches aiming at the restoration of functional dystrophin is under the constant debate. Taking into account that dystrophin expression is not restricted to muscle cells, but is present also in, e.g., endothelial cells, alterations in angiogenesis process have been proposed to have a significant impact on DMD progression. Indeed, already before the discovery of dystrophin, several abnormalities in blood vessels structure and function have been revealed, suggesting that targeting angiogenesis could be beneficial in DMD. In this review, researchers summarize current knowledge about the angiogenesis status both in animal models of DMD as well as in DMD patients, focusing on different organs as well as age- and sex-dependent effects. The review appeared in February 15th online issue of Cell Mol Life Sci
Related Informations / Publications
-J Orthop Res. 2018 May 22. Stem cells, blood vessels, and angiogenesis as major determinants for musculoskeletal tissue repair. HuardJ, The University of Texas Health Science Center, 1881 East Road, 3SCR6.3618, Houston, Texas, 77054., USA. Link: Abstract
¬Front Physiol. 2014 Feb 18;5:50. Angiogenesis as a novel therapeutic strategy for Duchenne muscular dystrophy through decreased ischemia and increased satellite cells. Shimizu-Motohashi Y & Asakura A, University of Minnesota Medical School Minneapolis, MN, USA.
Results/Comments: Researchers here focus on angiogenesis, reviewing the background, vascular endothelial growth factor (VEGF)/VEGF receptor-pathway, effect, and concerns of this strategy in DMD.
Link: Abstract Full Text 
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CLINICAL TRIALS - DATA
Catabasis Pharmaceuticals: new data supporting Edasalonexent as a potential treatment for Duchenne Muscular Dystrophy
Catabasis Pharmaceuticals, a clinical-stage biopharmaceutical company, shared on February 19th additional clinical results from the MoveDMD trial of edasalonexent. In the Phase 2 MoveDMD trial and open-label extension, boys with Duchenne muscular dystrophy (DMD) treated with edasalonexent on average grew in line with the growth of unaffected boys in the same age range. These data were presented on Sunday, February 17, 2019, at the XVII International Conference on Duchenne and Becker Muscular Dystrophy in Rome, Italy. In the MoveDMD trial, boys treated with edasalonexent grew an average of 2.1 inches taller per year and gained 2.9 pounds per year, and their overall body mass index decreased from 70th percentile of unaffected boys to the 55th percentile over 72 weeks of treatment, approaching the average body mass index for unaffected boys. Boys treated with corticosteroids, the standard of care in DMD, typically experience excess weight gain and curtailed growth. For further information 
Related Informations / Publications
-JAN 2019 : Catabasis Pharmaceuticals Phase 3 PolarisDMD Clinical Trial for Edasalonexent in Duchenne Muscular Dystrophy Progress Update and Additional Trial Sites Open for Enrollment
Results/Comments: Patient Enrollment Underway in U.S. with Nine Locations Open for Enrollment. Global Start-Up Activities Ongoing with Clinical Trial Application Approvals Received in Canada and Multiple European Countries Link: Press Release
- J Neuromuscul Dis. 2019;6(1):43-54. Phase 1 Study of Edasalonexent (CAT-1004), an Oral NF-κB Inhibitor, in Pediatric Patients with Duchenne Muscular Dystrophy. Finanger E et al. Oregon Health Sciences University Pediatrics, Portland, OR, USA
Results/Comments: This first report of edasalonexent oral administration for one week in male pediatric patients with Duchenne muscular dystrophy showed that treatment was well tolerated and inhibited NF-kB pathways. Link: Abstract
-J Clin Pharmacol. 2017 May;57(5):627-639. A Novel NF-κB Inhibitor, Edasalonexent (CAT-1004), in Development as a Disease-Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects. Donovan JM et al. Catabasis Pharmaceuticals, Inc, Cambridge, MA, USA
Link: AbstractFull Text 
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INDUSTRIAL LANDSCAPE&AGREEMENTS
AOP Orphan announces EU marketing authorization for Ropeginterferon alfa-2b for rare blood cancer
PharmaEssentia announced on February 20th that the European Commission (EC) has approved Besremi® (ropeginterferon alfa-2b, P1101) as monotherapy in adults for the treatment of polycythaemia vera without symptomatic splenomegaly. The European market authorization makes Besremi the first and only approved treatment for polycythemia vera (PV) independent of previous hydroxyurea exposure based on Phase III clinical data. The Marketing Authorization Holder for Besremi® in Europe is AOP Orphan Pharmaceuticals AG (AOP Orphan). Ropeginterferon alfa-2b is a novel, long-acting, predominately (>98%) single isomer mono-pegylated proline interferon (ATC L03AB15) with improved pharmacokinetic properties and demonstrated tolerability and convenience. It is administered once every 2 weeks, or once every 4 weeks during long-term maintenance, and is the first interferon approved for PV. Ropeginterferon alfa-2b was discovered by and is manufactured by PharmaEssentia in Taichung Taiwan plant that was cGMP certified by the EMA in January 2018. For further information 
Related Informations / Publications
-DEC 2018: AOP Orphan announces positive CHMP opinion for Ropeginterferon alfa-2B. Link: Press Release
-DEC 2018: AOP Orphan Pharmaceuticals AG (AOP Orphan) announces latest follow-up results on Ropeginterferon alfa-2b in patients with Polycythemia Vera (PV) from CONTINUATION-PV presented at ASH 2018. Link: Press Release
 - Clin Adv Hematol Oncol. 2018 Nov;16(11):750-757. Novel therapeutic approaches in polycythemia vera. Foucar CE, Stein BL. Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA Results/Comments: Early-phase clinical trials have also suggested that MDM2 inhibitors such as idasanutlin and histone deacetylase inhibitors should continue in their development. If these novel agents are able to modify the natural history of PV, the treatment paradigm in newly diagnosed patients will evolve from risk-adapted or reactive treatment toward early interventions. Link: Abstract  
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miscellaneous
Patient access to orphan drugs in France
Since incentives were introduced to promote orphan drugs in Europe, several dozens of drugs have been registered at the European level. However, patient access on a national level remains very heterogeneous across Europe. This can be explained by healthcare organization and drug reimbursement, which are within the purview of each Member State. French researchers have studied access to orphan drugs in France from the patients’ point of view, including marketing but also ease of supply from patients’ perspective, financial and time-based dimensions. They identified 91 registered orphan drugs in Europe, corresponding to 115 orphan drug–therapeutic indication pairs. In France, 78.3% (90/115) of these pairs were marketed: 100% were available to inpatients and 75.6% were available to outpatients. The median period between granting of the European marketing authorization and publication of the reimbursement decision was 360 days. The broadest availability—through community pharmacies—was guaranteed in only 31.1% of cases. Prescriptions were mainly restricted either to hospital-based doctors or to specialists. Inpatients were not financially responsible for these prescriptions and 72% of the orphan drug–therapeutic indication pairs available to outpatients were fully covered by national health insurance in France. The analysis appeared in February 18th online issue of Orphanet J Rare Dis
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Related Informations / Publications
- Orphanet J Rare Dis. 2018 Nov 6;13(1):184. The European challenges of funding orphan medicinal products. Szegedi M et al. Semmelweis University, H 1083 Tömő u, Budapest, 25-29, Hungary
Results/Comments: Standard and special reimbursement techniques play different roles in participant countries. The number of accessible OMPs indicated an equity gap between Eastern and Western Europe.
Link: Abstract - Full Text
Value Health. 2018 May;21(5):553-560. Patient Access to Medicines for Rare Diseases in European Countries. Detiček A et al. Faculty of Pharmacy, University of Ljubljana, Slovenia
Results/Comments: Patient access to medicines for rare diseases varies largely across Europe. Patients in Germany, Scandinavian countries, Switzerland, France, and the United Kingdom can access larger numbers of medicines in shorter time. Link: AbstractFull Text
Eur J Clin Pharmacol. 2018 Jul;74(7):895-902. Policies and availability of orphan medicines in outpatient care in 24 European countries. Sarnola K et al. Faculty of Health Sciences, Kuopio Campus, University of Eastern Finland Results/Comments: In most of the 24 countries, special policies were not implemented in the assessment of reimbursement status (22 countries) or in the pricing (20 countries) of orphan medicines. Link: Abstract  
The Orphan Drug Act revisited
The Orphan Drug Act (ODA) was first passed in 1983 to address the concern that pharmaceutical manufacturers were not pursuing drug development for diseases that affect limited patient populations. The concern was in part that companies viewed pursuing these therapies as undesirable because the markets for them are small in comparison with the markets for more widespread chronic diseases. To promote the development of orphan drug therapies, the ODA provided companies that engaged in research for drugs with populations of fewer than 200 000 patients with tax incentives, research subsidies, and extended patent protection. With the new incentives in place, drug companies began developing more of these drugs. As of August 2018, a total of 503 new orphan therapies had been approved following the passage of the act. While the ODA was successful at inducing drug companies to conduct research and develop therapies for rare diseases, there are some concerns that the success of the ODA has adversely affected the overall pharmaceutical market and the integrity of the US system for drug approval. The incentives established by the act are so appealing, and the requirements of traditional drug approval so onerous, that some pharmaceutical companies have disproportionately shifted their focus to orphan drug development. Rare diseases, as defined in the Act, affect less than 10% of individuals in the United States.3 However, between 2015 and 2016, therapies focused on these diseases constituted 30 products (45%) of the 67 new drugs approved by the Food and Drug Administration (FDA).
The analysis appeared in February 19th online issue of JAMA 
Related Informations / Publications
- Orphanet J Rare Dis. 2018 Oct 22;13(1):183. Investigating the landscape of US orphan product approvals. Miller KL et al. US Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD, 20903, USA. Results/Comments: The data suggest that the Orphan Drug Act appears to have stimulated significant drug development for rare diseases. Additionally, approvals of orphan indications have been increasing over time
Link: Abstract - Full Text
- Health Aff (Millwood). 2018 May;37(5):732-737. Evaluating The Impact Of The Orphan Drug Act's Seven-Year Market Exclusivity Period. Sarpatwari A et al. Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital, both in Boston, Massachusetts, USA
Link: Abstract  
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