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contents

February 2019, 11th
*FEATURE STORY* ● Luxturna®: FDA documents reveal the value of a costly gene therapy GENE THERAPY ● The application of Adeno-Associated Viral vector gene therapy to the treatment of Fragile X Syndrome ● Adeno-associated virus vector as a platform for gene therapy delivery *DISRUPTIVE TECHNOLOGIES* ● Integrative analysis of pooled CRISPR genetic screens using MAGeCKFlute *CLINICAL TRIALS - DATA* ● GenSight's LHON gene therapy fails to meet endpoints at week 48 ● UniQure announces first patient treated in HOPE-B pivotal trial of AMT-061 in patients with hemophilia B ● Solid Bio is hit by another setback as initial biopsies spotlight a flop for Duchenne muscular dystrophy ● Sangamo Therapeutics: in vivo genome editing in patients with MPS II treated with SB-913 *INDUSTRIAL LANDSCAPE & AGREEMENTS* ● EdiGene completes $10 million round for gene editing-based discovery *MISCELLANEOUS* ● β-thalassemia: cost-efficacy analysis of gene therapy versus allogenic hematopoietic stem cell transplantation

February 2019, 11th

FEATURE STORY

● Luxturna®: FDA documents reveal the value of a costly gene therapy
GENE THERAPY
● The application of Adeno-Associated Viral vector gene therapy to the treatment of Fragile X Syndrome
● Adeno-associated virus vector as a platform for gene therapy delivery
DISRUPTIVE TECHNOLOGIES
● Integrative analysis of pooled CRISPR genetic screens using MAGeCKFlute
CLINICAL TRIALS - DATA
● GenSight's LHON gene therapy fails to meet endpoints at week 48
● UniQure announces first patient treated in HOPE-B pivotal trial of AMT-061 in patients with hemophilia B
● Solid Bio is hit by another setback as initial biopsies spotlight a flop for Duchenne muscular dystrophy
● Sangamo Therapeutics: in vivo genome editing in patients with MPS II treated with SB-913
INDUSTRIAL LANDSCAPE & AGREEMENTS
● EdiGene completes $10 million round for gene editing-based discovery
MISCELLANEOUS
● β-thalassemia: cost-efficacy analysis of gene therapy versus allogenic hematopoietic stem cell transplantation

FEATURE STORY

Luxturna®: FDA documents reveal the value of a costly gene therapy

In 2017, the FDA approved Luxturna® (voretigene neparvovec-rzyl), a gene therapy used to treat inherited retinal diseases caused by RPE65 mutations. Widely described as a curative treatment that 'restores vision', it was priced at US$850 000. Although voretigene neparvovec-rzyl represents a substantial therapeutic advance, most reports have failed to adequately describe study outcomes as documented by FDA reviewers. These documents reveal that the drug is not expected to restore normal vision, that only about half of treated patients met the FDA's threshold for minimally meaningful improvement, that improvements might not persist, that the original endpoint was abandoned after yielding mixed results, and that two patients experienced permanent vision loss. Over US$100 million of additional publicly -funded costs are not reflected in the US$850 000 figure. The analysis appeared in January 31st online issue of Drug Discov Today

Related Informations/Publications

-NOV 2018 : European Commission approves Spark Therapeutics’ Luxturna® (voretigene neparvovec), a one-time gene therapy for inherited retinal disease caused by confirmed biallelic RPE65 mutations. Link: Press Release
-Br J Ophthalmol. 2019 Jan 18. Estimation of impact of RPE65-mediated inherited retinal disease on quality of life and the potential benefits of gene therapy. Lloyd A et al. Acaster Lloyd Consulting, London, UK Results/Comments: This is the first study to report health-related quality of life weights (or utilities) for health states describing different levels of vision loss in patients with IRD, specifically those with RPE65-mediated disease.
Link: Abstract
-Lancet. 2017 Aug 26;390(10097):849-860. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Russell L et l. Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA Link: Abstract – Full Text

GENE THERAPY

The application of Adeno-Associated Viral vector gene therapy to the treatment of Fragile X Syndrome

Viral vector-mediated gene therapy has grown by leaps and bounds over the past several years. Although the reasons for this progress are varied, a deeper understanding of the basic biology of the viruses, the identification of new and improved versions of viral vectors, and simply the vast experience gained by extensive testing in both animal models of disease and in clinical trials, have been key factors. Several studies have investigated the efficacy of adeno-associated viral (AAV) vectors in the mouse model of fragile X syndrome where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. These studies have demonstrated a range of efficacies in different tests from full correction, to partial rescue, to no effect. Collectively, the findings to date from the mouse studies on fragile X syndrome, and data from clinical trials testing AAVs in other neurological conditions, indicate that AAV-mediated gene therapy could be a viable strategy for treating fragile X syndrome. The review appeared in February 02nd online issue of Brain Sci.

Related Informations / Publications

-Brain Sci. 2019 Jan 21;9(1). pii: E17. CRISPR to the Rescue: Advances in Gene Editing for the FMR1 Gene. Yrigollen CM & Davidson B, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Results / Comments: The rapidly growing field of CRISPR therapeutics is providing a myriad of approaches to target a gene, pathway, or transcript for modification. As cures for FXADs have remained elusive, CRISPR opens new avenues to pursue. Link : Abstract
-Neuropsychopharmacology. 2014 Dec;39(13):3100-11. Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice. Gholizadeh S et al. University of Toronto, Toronto, ON, Canada
Results / Comments: The results provide the first proof of principle that gene therapy can correct specific behavioral abnormalities in the mouse model of FXS. Link: Abstract - Full Text

Adeno-associated virus vector as a platform for gene therapy delivery

Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success. The review appeared in February 01st online issue of Nat Rev Drug Discov.

Related Informations / Publications

-Mol Ther Methods Clin Dev. 2018 Mar 16; Emerging Issues in AAV-Mediated In Vivo Gene Therapy. Colella et al. Genethon, INSERM U951 INTEGRARE, University of Evry, University Paris-Saclay, 91001 Evry, France. Link: Full Text
-Hum Gene Ther. 2017 Nov 1; 28(11): 1061–1074. Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial. Vandamme C et al. Institute of Clinical Medicine, University of Eastern Finland , Kuopio, Finland.
Results/Comments: While the knowledge generated has contributed to yield impressive clinical results, several important questions remain unanswered, making the study of immune responses to AAV a priority for the field of in vivo transfer. Link: Abstract - Full Text
-Viruses. 2019 Jan 25;11(2). pii: E102. doi: 10.3390/v11020102. Adeno-associated Virus (AAV) versus Immune Response. Rabinowitz J et al. Rare Disease Research Unit, Pfizer Inc., 7030 Kit Creek Road, Morrisville, NC 27560, USA
Results/Comments: While the immune responses to rAAV remains a major challenge in translating experimental drugs to approved medicine, and will likely require more than a single solution, researchers think that they now know better understand the hurdles to formulate and test experimental solutions to surmount them. Link: Abstract - Full Text

DISRUPTIVE TECHNOLOGIE

Integrative analysis of pooled CRISPR genetic screens using MAGeCKFlute

Genome-wide screening using CRISPR coupled with nuclease Cas9 (CRISPR-Cas9) is a powerful technology for the systematic evaluation of gene function. Statistically principled analysis is needed for the accurate identification of gene hits and associated pathways. In a recent publication, researchers describe how to perform computational analysis of CRISPR screens using the MAGeCKFlute pipeline. MAGeCKFlute combines the MAGeCK and MAGeCK-VISPR algorithms and incorporates additional downstream analysis functionalities. MAGeCKFlute is distinguished from other currently available tools by its comprehensive pipeline, which contains a series of functions for analyzing CRISPR screen data. This protocol explains how to use MAGeCKFlute to perform quality control (QC), normalization, batch effect removal, copy-number bias correction, gene hit identification and downstream functional enrichment analysis for CRISPR screens. The results appeared in February 01st online issue of Nat Protoc.

Related Informations / Publications

-Genome Biol. 2015 Dec 16;16:281. Quality control, modeling, and visualization of CRISPR screens with MAGeCK-VISPR. Li W et al. Harvard T.H. Chan School of Public Health, Boston, MA, 02215, USA.
Results/Comments: The algorithm uses a generalized linear model to deconvolute different effects, and employs expectation-maximization to iteratively estimate sgRNA knockout efficiency and gene essentiality. MAGeCK-VISPR also includes VISPR, a framework for the interactive visualization and exploration of QC and analysis results. MAGeCK-VISPR is freely available at https://bitbucket.org/liulab/mageck-vispr. Link: Abstract - Full Text

CLINICAL TRIALS - DATA

GenSight's LHON gene therapy fails to meet endpoints at week 48

GenSight Biologics, a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, announced on February 04th results from the first scheduled readout, at Week 48, of the RESCUE Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 39 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) occurred up to 6 months prior to study treatment. These subjects received GS010 in one eye and a sham injection in the other eye, with drug treatment randomized between best- and worst-affected eyes. Visual loss in LHON usually progresses such that vision reaches a nadir in 3 to 5 months, before stabilizing; the duration of this progression to nadir varies from patient to patient. These figures incorporate a recovery from the nadir of vision loss for drug- and sham-treated eyes: mean improvement over the nadir of vision loss was +13 ETDRS letters equivalent in GS010-treated eyes and +11 ETDRS letters equivalent in sham-treated eyes. The primary efficacy endpoint, defined as a +15-letter difference in visual acuity improvement for GS010-treated eyes compared to sham-treated eyes at 48 weeks, was not met. For further information, see Press Release

Related Informations / Publications

-Curr Opin Neurol. 2019 Feb;32(1):99-104. Treatment strategies for Leber hereditary optic neuropathy. Jurkute et al. NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, UK
Results/Comments: Although disease-modifying treatment options remain limited, a better understanding of the underlying disease mechanisms in LHON is paving the way for complementary neuroprotective and gene therapeutic strategies for this mitochondrial optic nerve disorder. Link: Abstract
-DEC 2018 : GenSight Biologics reports sustained quality of life improvements at Week 72 of Phase III REVERSE clinical trial of GS010 for the treatment of Leber Hereditary Optic Neuropathy (LHON). Link: Press Release
-Adv Ther. 2018 Oct;35(10):1510-1518. Current and Emerging Treatment Modalities for Leber's Hereditary Optic Neuropathy: A Review of the Literature. Theodorou-Kanakari A et al. National and Kapodistrian University of Athens, Athens, Greece.
Results /Comments: Treatment modalities for LHON include nutritional supplements, activators of mitochondrial biogenesis, brimonidine, and symptomatic and supportive treatment, but nowadays attention is being paid to idebenone and gene therapy or stem cells. Link: Abstract - Full Text

UniQure announces first patient treated in HOPE-B pivotal trial of AMT-061 in patients with hemophilia B

UniQure announced on February 04th that it has treated the first patient in its HOPE-B pivotal trial of AMT-061, an investigational AAV5-based gene therapy incorporating the patent-protected FIX-Padua variant for the treatment of patients with severe and moderately severe hemophilia B. AMT-061 has been granted Breakthrough Therapy Designation by the FDA and access to Priority Medicines (PRIME) regulatory initiative by the European Medicines Agency. The global HOPE-B Phase III clinical trial will evaluate the efficacy and safety of AMT-061. Approximately 50 adult patients with hemophilia B classified as severe or moderately severe will be enrolled in a six-month observational period, during which time they will continue to use their current standard of care to establish a prospective comparator. After the six-month lead-in period, patients will receive a single intravenous administration of AMT-061. The primary outcome measure is the assessment of Factor IX activity 26 weeks after AMT-061 dosing. Secondary outcome measures include annualized bleeding rate (ABR) and usage of Factor IX replacement therapy over a 52-week time frame, as well as other efficacy and safety aspects. Post-treatment, patients will be followed for 5 years. The Dutch biotech has presented almost simultaneously updated clinical data from its phase IIb study of AMT-061 for this indication. These data show that all three patients have demonstrated increasing and sustained FIX levels after the one-time administration of AMT-061. For further information, see Press release

Related Informations / Publications

-JAN 2019 : uniQure Announces FDA Clearance of Investigational New Drug Application for AMT-130 in Huntington’s Disease. Link: Press Release
- Blood. 2019 Jan 31;133(5):407-414. Update on clinical gene therapy for hemophilia. Perrin GQ et al. Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL, USA
Results /Comments: The current review provides a summary and update on advances in clinical gene therapies for hemophilia and its continued development. Link: Abstract
- Mol Ther Nucleic Acids. 2018 Dec 20;14:364-376. Viral Vector-Based Delivery of CRISPR/Cas9 and Donor DNA for Homology-Directed Repair in an In Vitro Model for Canine Hemophilia B. Gao J et al. Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany. Link: Abstract
-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

Solid Bio is hit by another setback as initial biopsies spotlight a flop for Duchenne muscular dystrophy

Solid Biosciences announced on February 07th preliminary findings from IGNITE DMD, the company’s Phase I/II dose-ascending clinical trial evaluating the safety and efficacy of SGT-001 microdystrophin gene transfer for the treatment of Duchenne muscular dystrophy (DMD). Initial three-month biopsy data showed low levels of microdystrophin protein expression. The company is currently engaging with the appropriate parties to dose escalate as planned and as soon as possible. Preliminary analyses are based on three-month biopsy data from the first three patients dosed with 5E13 vg/kg of SGT-001, the lowest dose outlined in the study protocol. In one patient, microdystrophin was detected via western blot below the five percent level of quantification of the assay and in approximately 10 percent of fibers via immunofluorescence. There were also signs of co-localization of neuronal nitric oxide synthase (nNOS) and beta-sarcoglycan associated with microdystrophin expression. In the second and third patients,microdystrophin was detected via immunofluorescence at very low levels, but it was undetectable via western blot. For further information, see Press Release

Related Informations / Publications

-Mol Ther. 2019 Jan 25. pii: S1525-0016(19)30005-X. Development of Novel Micro-dystrophins with Enhanced Functionality. Ramos JN et al. University of Washington School of Medicine, Seattle, WA 98195, USA
Results/Comments: Two miniaturized micro-dystrophins (μDys) designs were identified that led to increased force generation compared with previous μDys while also localizing neuronal nitric oxide synthase to the sarcolemma. An AAV vector expressing the smaller of these (μDys5) from the CK8e RC is currently being evaluated in a DMD clinical trial. Link: Abstract
-JUN 2018: Solid Biosciences Announces FDA Removes Clinical Hold on SGT-001. Link: Press Release
-Nat Commun. 2017 Jul 25;8:16105. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Le Guiner et al . Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech, Nantes, France. Link: Abstract - Full Text

Sangamo Therapeutics : in vivo genome editing in patients with MPS II treated with SB-913

Sangamo Therapeutics reported on February 07th preliminary molecular and enzymatic evidence of editing of the human genome in vivo. These findings are part of the interim results from the Phase 1/2 CHAMPIONS Study evaluating SB-913, a zinc finger nuclease (ZFN) in vivo genome editing product candidate for the treatment of patients with Mucopolysaccharidosis Type II (MPS II). These interim results were presented at the WORLDSymposium 2019 being held in Orlando, Florida. Also reported were interim results (announced separately) evaluating SB-318 for the treatment of MPS I. Sangamo believes data from these two studies provide complementary evidence supportive of a favorable safety profile and of the activity of the ZFN in vivo genome editing technology used in both SB-913 and SB-318. For further information see Press Release

Related Informations / Publications

-SEP 2018: Sangamo Announces 16 Week Clinical Results Including Reductions In Glycosaminoglycans In Phase 1/2 Trial Evaluating SB-913, A Zinc Finger Nuclease Genome Editing Treatment For MPS II (Hunter Syndrome) Link: Press Release
-Curr Gene Ther. 2018;18(2):90-95. Genetics and Gene Therapy in Hunter Disease. Sestito S et al. Pediatrics Unit, University "Magna Graecia", Catanzaro, Italy. Link: Abstract
-Mol Ther. 2018 Apr 4;26(4):1127-1136. Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing. Laoharawee K et al. University of Minnesota, Minneapolis, MN, USA
Results/Comments: Researchers here conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases.
Link: Abstract

INDUSTRIAL LANDSCAPE&AGREEMENTS

EdiGene completes $10 million round for gene editing-based discovery

EdiGene, a Beijing-Cambridge, MA company that uses gene editing technology to develop novel therapeutics, announced on February 04th that it has completed a $10 Million Series pre-B Plus financing. The latest round was led by new investor Shenzhen Green Pine Capital Partners. Founded in 2015, EdiGene combines its CRISPR/Cas 9 gene editing technologies with high-throughput genomic screening and functional big data of underlying biology. It is developing a portfolio of candidates to treat genetic diseases and cancer. The company also offers CRO discovery services based on its CRISPR/Cas 9-based screening platforms.
For further information, see ChinaBio Today

Related Informations / Publications

-Genome Biol. 2019 Jan 24;20(1):20. Guide RNAs with embedded barcodes boost CRISPR-pooled screens. Zhu S et al. Peking University, Beijing, 100871, China. Link: Abstract - Full Text
-AUG 2018: Genome Editing Biotech EdiGene Raises $15 Million in Series pre-B Financing
Results /Comments : The financing is led by new investor Lilly Asia Ventures (LAV). New investor HuagaiCapital participated in this round. Series A lead investor IDG Capital, Series A investor WI Harper Group and other insiders also participated in this round. Link: Press Release

miscellaneous

β-thalassemia: cost-efficacy analysis of gene therapy versus allogenic

Seventy-five percent of β-thalassemic patients do not have Human Leukocyte Antigen (HLA) matched siblings and had until recently no access to a curative treatment Gene therapy is a promising treatment that can be proposed to these patients. This study estimates its cost and efficacy. In a recent analysis, researchers have compared in a mono-centric retrospective study and cost-efficacy analysis the two-year outcomes and costs of β-thalassemic patients treated by gene therapy and HSCT. Grade III and IV complications, hospitalizations and length of stay were extracted from the hospital discharge data. Costs were estimated from hospital accounting information and national cost studies. The results appeared in January 31st online issue of Hum Gene Ther .

Related Informations / Publications

-Mol Diagn Ther. 2019 Jan 30. doi: 10.1007/s40291-019-00383-4. Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges. Ghiaccio V et al. Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
Results/Comments: In this review, researchers aim to establish the potential benefits of gene therapy for BH, to summarize the status of the ongoing trials, and to discuss the possible improvement or direction for future treatments.
Link: Abstract
-Mol Ther Methods Clin Dev. 2018 Dec 18;12:102-110. Engineering Globin Gene Expression. Davis R et al. Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA. Link: Abstract - Full Text

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