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contents
August 2018, 28th

FEATURE STORY
●    Inotersen: First global approval 
GENE THERAPY   
●  Advances in the gene therapy of Fanconi Anemia
RARE DISEASES
●    Emerging pharmacotherapies in cystic fibrosis
● Epigenetic changes associated with the expression of Amyotrophic Lateral Sclerosis causing genes
CLINICAL TRIALS
● A randomized placebo controlled clinical trial to evaluate the efficacy and safety of minocycline in patients with Angelman Syndrome 
INDUSTRIAL LANDSCAPE & AGREEMENTS 
● Rare-disease, health-record startup RDMD raises $3M 
● Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector
● Shire announces FDA approval of lanadelumab-flyo for Hereditary Angioedema 
MISCELLANEOUS
● Parents of children with rare diseases' experiences of navigating the healthcare system 
● AVXS-101 and Nusinersen for Spinal Muscular Atrophy: effectiveness and value
●  Economic burden limiting proper healthcare delivery, management, and improvement of patient outcomes
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FEATURE STORY
Inotersen: First global approval
Ionis Pharmaceuticals and Akcea Therapeutics have developed inotersen (Tegsedi™), an antisense oligonucleotide inhibitor of mutant and wild-type human transthyretin (TTR), for the treatment of hereditary transthyretin amyloidosis ( hATTR ). Mutation of the TTR gene results in accumulation of TTR protein fragments as amyloid deposits throughout the organs in patients with hATTR, including the peripheral nervous system and the heart. Treatment with inotersen, which selectively binds to TTR mRNA, prevents the synthesis of TTR protein in the liver, thus reducing further amyloid deposition throughout the body. Subcutaneous administration of inotersen significantly reduced neurological progression and improved health-related quality of life in patients with hATTR and polyneuropathy in a phase III trial. Based on these results, inotersen was recently approved in the EU for the treatment of stage 1 or 2 polyneuropathy in adult patients with hATTR and is under evaluation in the USA and Canada for a similar indication.
The review appeared in August 17th online issue of Drugs  
Related Informations/Publications
- Hosp Pharm . 2018 Jul;53(4):236-238. New Medications in the Treatment of Hereditary Transthyretin Amyloidosis. Walker S, Prescribe Right, LLC, Wildwood, MO, USA
Results / Comments: There are a few drugs in development to treat hereditary transthyretin amyloidosis either by stabilizing the abnormal protein or by decreasing production of transthyretin
Link: Abstract   
- N Engl J Med . 2018 Jul 5;379(1):22-31. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. Benson MD et al. Indiana University School of Medicine, Indianapolis, USA
Results / Comments: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring.
 Link: Abstract
-AUG2018: Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults
Link: Press Release  
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GENE THERAPY
Advances in the gene therapy of Fanconi Anemia 
Fanconi anemia ( FA ) is a rare inherited disease associated with bone marrow failure (BMF) and cancer predisposition. Previous clinical trials have shown the difficulties of treating BMF of FA patients by gene therapy. Nevertheless, the discovery of new drugs capable of efficiently mobilizing hematopoietic stem cells (HSC) and the development of optimized procedures for transducing HSCs with safe integrative vectors, have markedly improved the efficiency for correcting the phenotype of hematopoietic repopulating cells from FA patients. Additionally, thanks to these achievements it has been possible to demonstrate the in vivo proliferation advantage of gene-corrected FA repopulating cells in immunodeficient mice. Significantly, new gene therapy trials are nowadays ongoing with the purpose of progressively replacing the hematopoiesis of FA patients with gene corrected autologous HSCs. Further experimental studies are focused on the ex vivo transduction of non-purified FA HSCs using new pseudotyped vectors with HSC tropism.
The review appeared in August 17th online issue of Hum Gene Ther 
Related Informations / Publications  
-Exp Hemato l. 2018 Jul 19. Functional analysis of Fanconi anemia mutations in China. Li N et al. Shanghai Children's Medical Center, China
Link: Abstract  
-F1000Res . 2018 Jan 24;7:105. Recent advances in understanding hematopoiesis in Fanconi Anemia. Bagby G, Oregon Health & Science University, Portland, Oregon, USA.
Link: Abstract  -  Full Text  
- Br J Haematol . 2018 Jan;180(1):100-109. Transplant results in adults with Fanconi anaemia. Bierings M et al. Utrecht University Children's Hospital, Utrecht, The Netherlands.
Link: Abstract - Full Text
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RARE DISEASES
Emerging pharmacotherapies in cystic fibrosis
Cystic fibrosis ( CF ) is an autosomal dominant chloride channelopathy caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that results clinically in a multisystem disorder. The major source of morbidity and mortality in CF is lung disease, which is characterized by recurrent cycles of inflammation and infection and progressive respiratory decline. Therapeutics have traditionally focused on the downstream effects of the primary genetic defect. However, recent advances have shifted attention to modulation of upstream pathways and the defective CFTR protein itself. Areas covered: A recent review focuses on emerging pharmacotherapeutics for CF lung disease, with an emphasis on the evidence for CFTR modulators and a summary of emerging modulator therapies currently in phase II and III clinical trials as of July 2018. Results of relevant trials reported in peer-reviewed journals, scientific conference abstracts and sponsor press releases are included.
The review appeared in August 21st online issue of Experts Rev Respir Med  
Related Informations / Publications
- Expert Rev Respir Med . 2018 Aug 17. Cystic fibrosis respiratory microbiota: unraveling complexity to inform clinical practice. Caverly LJ et al. Medical Center Dr., Ann Arbor , MI , 48109, USA
Link: Abstract  
- Expert Opin Biol Ther. 2018 Aug 10:1-14. Lessons learned from lung and liver in-vivo gene therapy: implications for the future. van Haasteren J et al. University of Oxford, Oxford , UK
Link: Abstract 
- Front Pharmacol . 2018 Apr 20;9:396. Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique. Marangi M & Pistritto G, Italian Medicines Agency, Rome, Italy
Results / Comments: CRISPR-Cas9 approach may represent a valid tool to repair the CFTR mutation and hopeful results were obtained in tissue and animal models of CF disease.
Link: Abstract   - Full Text
Epigenetic changes associated with the expression of Amyotrophic Lateral Sclerosis causing genes
Neurodegenerative disorders, including Amyotrophic Lateral Sclerosis ( ALS ), have been associated to alterations in chromatin structure resulting in long lasting changes in gene expression. ALS is predominantly a sporadic disease and environmental triggers may be involved in its onset. In this respect, alterations in the epigenome can provide the key to transform the genetic information into phenotype. In a recent paper, Italian researchers demonstrate that two modifications associated with transcriptional activation, namely dimethylation of lysine 4 on H3 tail (H3K4me2) and phospho-acetylation of serine 10 and lysine 14 on H3 tail (H3K14ac-S10ph), and two modifications associated to transcriptional repression, namely trimethylation of lysine 9 on H3 tail (H3K9me3) and DNA methylation are selectively altered in cellular and animal model of ALS. These results reinforce the idea that epigenetic therapy may represent a potential and attractive approach for ALS treatment.
The results appeared in August 19th online issue of Neuroscience .
Related Informations / Publications
- Stem Cells . 2018 Apr 15. Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis. Thomsen GM et al. Cedars-Sinai Medical Center, Los Angeles, California, USA.
Results / Comment : The data suggest that introducing cortical astrocytes releasing GDNF represents a novel promising approach to treating ALS
Link: Abstract 
-Fron t Mol Neurosci . 2017 Dec 7;10:405. Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis. Tosolini et al. University College London, London, United Kingdom.
Link: Abstract -  Full Text
- Curr Opin Neurol . 2018 Jul 19. Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis. Ly CV et al. Washington University, Saint Louis, Missouri, USA.
Results / Comments: Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated.
Link: Abstract  
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CLINICAL TRIALS
A randomized placebo controlled clinical trial to evaluate the efficacy and safety of minocycline in patients with Angelman Syndrome
Minocycline is an old tetracycline antibiotic that has shown antiinflammatory and antiapoptotic properties in different neurological disease mouse models. Previous single arm study in humans demonstrated benefits in individuals with Angelman Syndrome ( AS ); however, its efficacy in patients with Angelman Syndrome has not been assessed in a controlled trial. This was a randomized, double-blind, placebo-controlled, crossover trial in individuals with AS, aged 6 years to 30 years (n = 32, mean age 12 [SD 6·29] years). Participants were randomized to minocycline or placebo for 8 weeks and then switched to the other treatment (a subset of 22 patients) or to receive minocycline for up to 16 weeks (10 patients). After week 16, all patients entered a wash-out 8-week follow-up period. Thirty-six subjects were screened and 34 were randomized. Thirty two subjects (94·1%) completed at least the first period and all of them completed the full trial. Intention-to-treat analysis demonstrated the lack of significantly greater improvements in the primary outcome, mean changes in age equivalent of the development index of the Merrill-Palmer Revised Scale after minocycline compared with placebo. No serious adverse events occurred on minocycline.
The results appeared in August 20th online issue of Orphanet J Rare Dis
Related Informations / Publications
- Patient . 2018 Jul 10. A Conceptual Model of Angelman Syndrome and Review of Relevant Clinical Outcomes Assessments. Grieco JC et al. Ovid Therapeutics, New York, NY, USA
Link: Abstract
- Int J Mol Sc i. 2018 Apr 5;19(4). Taurine Administration Recovers Motor and Learning Deficits in an Angelman Syndrome Mouse Model. Guzzetti S et al. Istituto Auxologico Italiano, IRCCS, 20145 Milano, Italy
Results/ Comments: The study indicates taurine administration as a potential therapy to ameliorate motor deficits and learning difficulties in AS
Link: Abstract -  Full Text 
- BMC Neurol. 2014 Dec 10;14:232. An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome. Grieco JC et al. Ovid Therapeutics, New York, NY, USA
Link: Abstract - Full Text  
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INDUSTRIAL LANDSCAPE & AGREEMENTS
Rare-disease, health-record startup RDMD raises $3M
San Francisco-based startup RDMD , which is focused on rare diseases and personal health records, said on August 22nd that it has reaped $3 million in a seed funding round. Participating in the fundraising were Lux Capital, Village Global, First Round’s Healthcare Co-op, Garuda, Shasta Ventures and unidentified angel investors, the company said. The funds will be used for developing the company’s platform, additional hiring and expanding the scope of rare diseases it targets (neurofibromatosis type II, https://ghr.nlm.nih.gov/condition/neurofibromatosis-type-2). RDMD wants to gather, under one roof, the far-flung medical data of people with rare diseases—sometimes only a few dozen people are afflicted per disease. The company is using tech tricks to convert a range of health records in different formats, such as doctor’s notes, medical images, and hospital charts, into a single repository that researchers can use to push drug development forward. For further information 
Related Informations / Publications
- J Child Neurol . 2018 Jan;33(1):82-91. Neurofibromatosis Clinical Trial Consortium. Packer RJ et al. Children's National Health System, Washington, DC, USA
Results / Comments: The NFCTC has now been expanded to 19 sites in the United Stated and Australia. Mechanisms have been put in place to work closely with other consortia, foundations, and industry to expeditiously translate preclinical discoveries into clinical trials.
Link: Abstract  
- J Med Genet . 2017 Oct;54(10):657-664. Genetic Severity Score predicts clinical phenotype in NF2. Halliday D et al. Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.
Link: Abstract - Full Text
Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector
Ophthotech said on August 22nd that preclinical data for its adeno-associated virus gene therapy for the treatment of rhodopsin-mediated autosomal dominant retinitis pigmentosa ( RHO-adRP ) was recently published. In a naturally-occurring canine disease model of RHO-adRP, the treatment suppressed expression of the endogenous RHO RNA while the human RHO replacement transgene produced up to 30 percent of normal RHO protein levels. Ophthotech plans to continue IND-enabling studies with plans to start a clinical trial in 2020.
The results appeared in August 20th online issue of PNAS
Related Informations / Publications
--JUN2018 : Ophthotech Enters into Gene Therapy Agreements with the University of Florida and the University of Pennsylvania
Link BusinessWire
- PLoS One. 2015 Feb 19;10(2):e0115723. Exclusion of the unfolded protein response in light-induced retinal degeneration in the canine T4R RHO model of autosomal dominant retinitis pigmentosa. Marsili S et al. University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America
Link: Abstract -  Full Text 
Shire announces FDA approval of lanadelumab-flyo for Hereditary Angioedema
Shire announced on August 23rd that following priority review, the FDA has approved Takhzyro™ (lanadelumab-flyo) injection, for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years of age and older. HAE is a rare, genetic and potentially life-threatening disorder that can result in recurrent attacks of edema (swelling) in various parts of the body.Although several new therapies to both treat acute hereditary angioedema (HAE) attacks and provide prophylaxis for patients with recurrent episodes have been introduced in the past several years, HAE remains a disease with a substantial physical, psychosocial, and economic burden to both affected patients and society in general. Not all treatments work for all patients, and research is ongoing to improve HAE diagnosis and selection of therapy for individual patients to optimize outcomes. But the disease has a significant economic impact with high direct and indirect costs, and high charges related to the new therapies developed for patients to reduce symptoms and attack recurrence. Overall, effective management of HAE is often complicated by clinical and economic barriers to optimal patient outcomes that must be overcome to provide the best care possible and prevent future attacks and complications associated with this rare disease. The analysis appeared in August 24th online issue of Am J Manag Care . For further information  
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Related Informations / Publications
- Am J Manag Care . 2018 Aug;24(14 Suppl):S299-S307. Current and emerging therapies to prevent hereditary angioedema attacks. Lumry WR, University of Texas Southwestern Medical School, private practice, Dallas, TX, USA
Link: Abstract 
- Allergy Asthma Proc . 2018 Aug 14. Subcutaneous C1-esterase inhibitor to prevent hereditary angioedema attacks: Safety findings from the COMPACT trial. Li HH et al. Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, China
Link: Abstract
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MISCELLANEOUS
Parents of children with rare diseases' experiences of navigating the healthcare syste
A disorder is considered a rare disease if it affects 1 in 2000, hence, while independently unique, collectively, these conditions are quite common. Many rare diseases are diagnosed during childhood, and therefore parents become primary caregivers in addition to their parental role. Despite the prevalence of rare diseases among children, there has been little research focused on parents' experiences of navigating the healthcare system, a gap Canadian researchers begin to address in a recent study. Guided by an interpretive description methodology, participants were recruited through online listservs and posting flyers at a pediatric hospital in Western Canada. Sixteen parents (15 mothers and 1 father) participated in in-depth, semi-structured interviews between April 2013 and March 2014. Data were analyzed inductively, generating the main study themes. Findings illuminated the challenges parents' experienced on their child's diagnostic journey-from seeking, to receiving, to adjusting to the rare disease diagnosis. Following diagnosis, gaps, and barriers to services resulted in parents pursuing services that could support their child's unique care needs, which often resulted in out-of-pocket payments and changes to employment. Parents found peer support, both online and in person, to be an effective resource. This study illustrates the common challenges experienced by parents of children with rare diseases as they navigate the healthcare system.
he results appeared in August 21st online issue of J Genet Counsel 
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Related Informations / Publications
-Nat Rev Genet . 2018 May;19(5):253-268. Paediatric genomics: diagnosing rare disease in children. Wright CF et al. Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
Link: Abstract
-Adv Exp Med Biol. 2017;1031:197-205. Post-approval Studies for Rare Disease Treatments and Orphan Drugs. Mayer WC et al. Translation & Innovation Hub, London, W12 0BZ, UK
Results / Comments: Many rare diseases have strong patient advocacy groups that can in aid the design and execution of rare disease registries
Link: Abstract
AVXS-101 and Nusinersen for Spinal Muscular Atrophy: effectiveness and value
The Institute for Clinical and Economic Review ( ICER ) has posted on August 23rd a draft-scoping document outlining a planned review of the comparative clinical effectiveness and value of Bannockburn, Ill.-based Avexis Inc.’s AVXS-101 and Spinraza (nusinersen) from Cambridge, Mass.-based Biogen Inc. for the treatment of spinal muscular atrophy ( SMA ). The document will be open to public comment until 5 p.m. EST on Sept. 12, 2018. Nusinersen was approved in 2016 for treatment of SMA in both children and adults. AVXS-101 is a gene therapy currently being studied for use in infants with SMA, and an FDA decision is expected in the first quarter of 2019. ICER’s report on these therapies will be the subject of a March 2019 meeting of the New England Comparative Effectiveness Public Advisory Council, one of ICER’s three independent evidence appraisal committees.
For further information  
Related Informations / Publications
-AUG2018 : ICER to evaluate comparative effectiveness of Biogen and Novartis SMA drugs
Link: Thepharmaletter
-APR2018 : Biogen’s Spinraza Sales Slow as AveXis and Novartis Pursue SMA Gene Therapy
Link: Talks 
Economic burden limiting proper healthcare delivery, management, and improvement of patient outcomes
Although several new therapies to both treat acute hereditary angioedema ( HAE ) attacks and provide prophylaxis for patients with recurrent episodes have been introduced in the past several years, HAE remains a disease with a substantial physical, psychosocial, and economic burden to both affected patients and society in general. Not all treatments work for all patients, and research is ongoing to improve HAE diagnosis and selection of therapy for individual patients to optimize outcomes. But the disease has a significant economic impact with high direct and indirect costs, and high charges related to the new therapies developed for patients to reduce symptoms and attack recurrence. Overall, effective management of HAE is often complicated by clinical and economic barriers to optimal patient outcomes that must be overcome to provide the best care possible and prevent future attacks and complications associated with this rare disease.
The analysis appeared in August 24th online issue of Am J Manag Care  
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