Search

Fanconi anemia (FA) is characterized by chromosome fragility, bone marrow failure (BMF) and predisposition to cancer. As reverse genetic mosaicism has been described as "natural gene therapy" in patients with FA, we sought to evaluate the clinical course of a cohort of FA mosaic patients followed at referral centers in Spain over a 30-year period. This cohort includes patients with a majority of T cells without chromosomal aberrations in the DEB-chromosomal breakage test. Relative to non-mosaic FA patients, we observed a higher proportion of adult patients in the cohort of mosaics, with a later age of hematologic onset and a milder evolution of (BMF). Consequently, the requirement for hematopoietic stem cell transplant (HSCT) was also lower. Additional studies allowed us to identify a sub-cohort of mosaic FA patients in whom the reversion was present in bone marrow (BM) progenitor cells leading to multilineage mosaicism. These multilineage mosaic patients are older, have a lower percentage of aberrant cells, have more stable hematology and none of them developed leukemia or myelodysplastic syndrome when compared to non-mosaics. In conclusion, our data indicate that reverse mosaicism is a good prognostic factor in FA and is associated with more favorable long-term clinical outcomes.

The incentives provided under the Orphan Drug Act (ODA) have been credited for catalyzing the marketing approval of drugs for the treatment of rare diseases by the US Food and Drug Administration. Orphan drug designation, the granting of special status to drugs or biologics (“drugs”) for the treatment of rare diseases, one of the ODA's key incentive programs, has seen major increases in volume over recent years. The new era of precision medicine and the development of therapies directed toward smaller “orphan” subsets of common diseases have been suggested as being a major driver. We evaluated the basis for orphan drug designations and orphan subsets in relation to the impact of precision medicines. We found that the increasing numbers of orphan drug designation determinations were not driven by precision medicines separating common diseases into orphan subsets and that orphan subsets overall also represented a relatively small proportion of designations.

Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1–6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs., Eileen Nicoletti is an employee of Rocket Pharmaceuticals, Inc. Gayatri Rao is an employee of Rocket Pharmaceuticals, Inc. Juan A. Bueren is the head of the Hematopoietic Innovative Therapies Division at Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT) which receives funding for Fanconi Anemia (FA) gene therapy and has licensed the PGK-FANCAWpre* lentiviral vector to Rocket Pharmaceuticals, Inc. He is also a consultant for Rocket Pharmaceuticals, Inc. Paula Río is a member of the Hematopoietic Innovative Therapies Division at Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT) which receives funding for Fanconi Anemia (FA) gene therapy and has licensed the PGK-FANCA-Wpre* lentiviral vector to Rocket Pharmaceuticals, Inc. Susana Navarro is a member of the Hematopoietic Innovative Therapies Division at Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT) which receives funding for Fanconi Anemia (FA) gene therapy and has licensed the PGK-FANCAWpre* lentiviral vector to Rocket Pharmaceuticals, Inc. Jordi Surrallés does not have any conflicts of interest. Grace Choi is an employee of Rocket Pharmaceuticals, Inc. Jonathan D. Schwartz is an employee of Rocket Pharmaceuticals, Inc.

Background: Fanconi anemia (FA) is a disorder of defective deoxyribonucleic acid (DNA) repair, progressive bone marrow failure (BMF), and a predisposition to hematologic malignancies and solid tumors. Approximately 60 to 70% of all cases result from a mutation in the Fanconi Anemia Complementation Group A (FANCA) gene (FA-A). 80% of FA patients experience BMF within the first decade of life. Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative for BMF; however, its efficacy is limited by human leukocyte antigen (HLA)-matched sibling donor availability and transplant-related toxicities. Lentiviral mediated gene therapy utilizing autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) confers a proliferative advantage to gene-corrected HSPCs as demonstrated in preclinical studies and the FANCOLEN-I clinical trial conducted in Madrid, Spain. We report results from ongoing RP-L102 studies using "Process B" manufacturing optimizations including transduction enhancers, commercial grade vector, and modified cell processing. Methods: Patients (pts) with a FANCA gene mutation, age ≥1 year with no HLA-matched sibling donor and at least 30 CD34+ cells/µL in bone marrow (BM) are eligible. Peripheral blood (PB) mononuclear cells are collected via leukapheresis on 2 consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. CD34+ HSPCs are enriched, transduced with a lentiviral vector encoding for the FANCA gene (PGK-FANCA-WPRE) and infused without cryopreservation or conditioning. Patients are followed for 3 years post-infusion for safety assessments (replication competent lentivirus [RCL], insertion site analysis [ISA]) and to ascertain evidence of efficacy (increasing PB and BM vector copy number [VCN] and mitomycin-C [MMC] resistance in BM colony forming units [CFUs]), along with stabilization/correction of cytopenias. Results: As of March 2021, 9 pts (aged 2 to 6 years) have received RP-L102. Evidence of engraftment has been identified in 6 pts with ≥6 months of follow up as indicated by PB VCN. 2 of 3 pts with follow up of ≥12 months have shown increased MMC resistance in BM CFUs. 1 pt developed BMF requiring alloHSCT after influenza B infection. 1 pt had a serious Grade 2 transient RP-L102 infusion-related reaction. Updated safety and efficacy data for pts with ≥12 months of follow-up will be presented. Conclusions: RP-L102's safety profile remains favorable. Increasing evidence of engraftment has been confirmed in 6 subjects as demonstrated by PB VCN; without conditioning, 12+ months of follow up is likely required to observe the proliferative advantage of transduced HSPCs. Disclosures Czechowicz: Editas Medicine: Current equity holder in publicly-traded company; Rocket Pharmaceuticals, Inc.: Research Funding; Global Blood Therapeutics: Current equity holder in publicly-traded company; Stemodontics: Consultancy, Current equity holder in publicly-traded company; GV: Consultancy, Current equity holder in publicly-traded company; Spotlight Therapeutics: Consultancy, Current equity holder in publicly-traded company; Beam Therapeutics: Consultancy, Current equity holder in publicly-traded company; Magenta Therapeutics: Current equity holder in publicly-traded company, Other: Intellectual property rights; Decibel Therapeutics: Current equity holder in publicly-traded company; Forty Seven Inc.: Divested equity in a private or publicly-traded company in the past 24 months; Gilead Sciences: Other: intellectual property rights; Jasper Therapeutics: Other: Intellectual property rights. Sevilla: Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Sevilla is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, and may be entitled to receive financial benefits from the licensing of such patents., Patents & Royalties: J. Sevilla is a consultant and has licensed medical products from Rocket Pharmaceuticals, Inc. ; Amgen: Consultancy; Novartis: Consultancy; Miltenyi: Consultancy; SOBI: Consultancy. Booth: GSK: Honoraria; Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Río: Rocket Pharmaceuticals: Current equity holder in publicly-traded company, Other: Paula Rio has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Research Funding. Navarro: Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: Dr. Navarro has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Beard: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Wagner: Magenta Therapeutics: Consultancy; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company; Vertex Pharmaceuticals: Consultancy; ASC Therapeutics: Consultancy; Bluebird Bio: Consultancy. Rao: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schwartz: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren: Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Bueren is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, may be entitled to receive financial benefits from the licensing of such patents and receives funding for research., Patents & Royalties, Research Funding.

Background: Pyruvate kinase deficiency (PKD) is a rare inherited hemolytic anemia caused by mutations in the PKLR gene resulting in decreased red cell pyruvate kinase activity and impaired erythrocyte metabolism. Manifestations include anemia, reticulocytosis, splenomegaly and iron overload, and may be life-threatening in severely affected individuals. PKD represents a significant unmet medical need as current treatments are palliative and limited to blood transfusions, chelation therapy, and splenectomy which are associated with significant side effects. Preclinical studies in a clinically relevant PKD murine model have demonstrated that infusion of gene-modified Lin− bone marrow (BM) cells may ameliorate PKD phenotype. Based on compelling preclinical data, a global Phase 1 clinical trial RP-L301-0119 (NCT04105166) is underway to evaluate the feasibility and safety of lentiviral mediated gene therapy in adult and pediatric subjects with severe PKD. Methods: Six adult and pediatric patients with severe PKD (defined as severe and/or transfusion-dependent anemia despite prior splenectomy) will be enrolled. Peripheral blood (PB) hematopoietic stem cells (HSCs) are collected on 2 consecutive days via apheresis after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. HSCs are enriched, transduced with PGK-coRPK-WPRE lentiviral vector (LV), and cryopreserved. Following release testing of the investigational product (IP), RP-L301, myeloablative therapeutic drug monitoring (TDM) busulfan is administered over 4 days. RP-L301 is then thawed and infused. Patients are followed for safety assessments, including replication competent lentivirus (RCL) and insertion site analysis (ISA), and for efficacy parameters including PB and BM genetic correction, decrease in transfusion requirements, clinically significant improvement in anemia, and reduction of hemolysis for 2 years post-infusion. Results: As of May 2021, 2 adult patients with severe anemia have received RP-L301. Patient 1 (age 31 years) received 3.9x106 CD34+ cells/kg with mean vector copy number (VCN) of 2.73. Patient 2 (age 47 years) received 2.4x106 CD34+ cells/kg with mean VCN of 2.08. Despite baseline hemoglobin (Hb) levels in the 7.0-7.5 g/dL range, both patients displayed normal-range hemoglobin (Hb), improved hemolysis markers, and have required no red blood cell transfusions post-engraftment at 9- and 6- months follow-up. Both report improved quality of life. PB mononuclear cell VCNs for both patients were >2.0 at last evaluated timepoint (6- and 3-months post-treatment, respectively). No serious adverse events have been attributed to RP-L301. Updated safety and efficacy data will be presented. Conclusions: Hematopoietic stem cell mobilization using G-CSF and plerixafor is feasible and effective in adult PKD patients. RP-L301 was successfully manufactured to meet the required specifications for the Phase 1 clinical study and administered without short-term infusion related complications. Efficacy was demonstrated by normalized Hb associated with engraftment confirmed by PB and BM VCN. Disclosures Shah: OrchardTherapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Dr. Shah currently serves on the medical advisory board for Orchard Therapeutics . Navarro: Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: Dr. Navarro has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Sevilla: Miltenyi: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Sevilla is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, and may be entitled to receive financial benefits from the licensing of such patents.; SOBI: Consultancy. Glader: Agios: Consultancy. Quintana Bustamante: Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company. Beard: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Rao: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren: Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Bueren is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, may be entitled to receive financial benefits from the licensing of such patents and receives funding for research., Patents & Royalties, Research Funding. Schwartz: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Segovia: Rocket Pharmaceuticals, Inc.: Consultancy, Research Funding.

Background: Leukocyte Adhesion Deficiency-I (LAD-I) is a rare disorder of neutrophil adhesion resulting from ITGB2 mutations encoding for the β2-integrin component, CD18. Severe LAD-I (CD18 Methods: Pediatric patients ≥ 3 months old with severe LAD-I are eligible. HSCs are collected via apheresis after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor and transduced with Chim-CD18-WPRE-LV. Myeloablative therapeutic drug monitoring (TDM) busulfan conditioning precedes RP-L201 infusion. Patients are followed for safety and efficacy (i.e., survival to age 2 and at least 1-year post-infusion, increase in PMN leukocyte CD18 expression to at least 10%, peripheral blood [PB] vector copy number [VCN], decrease in infections/hospitalizations, and resolution of skin or periodontal abnormalities). Results: Seven patients (ages 5mos-9yrs) have received RP-L201; all with follow-up ≥3 to 18 months. RP-L201 cell doses ranged from 2.8x106 to 6.5x106 CD34+ cells/kg with VCN from 1.8-3.8 copies/cell. No serious RP-L201 related treatment-emergent adverse events were reported. PB PMN CD18 expression in Patient 1 at 18-months post-treatment was 40% (vs. < 1% at baseline), with PB VCN of 1.44. Baseline skin lesions resolved with no new lesions reported. CD18 expression in the subsequent 6 patients has been 25-80% in neutrophils and stable for each patient from 3 to up to 18 months post-treatment. No new infections have been reported in patients post-infusion. The safety profile of RP-L102 remains highly favorable with no serious adverse events (SAEs) attributed to the investigational product (IP). Conclusion: RP-L201 leads to durable neutrophil CD18 expression and improved clinical course. Additional patient treatment is ongoing in 2021. Disclosures Kohn: UC Regents: Patents & Royalties; Pluto Immunotherapeutics: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; ImmunoVec: Membership on an entity's Board of Directors or advisory committees; Lyrik Therapeutics: Membership on an entity's Board of Directors or advisory committees; MyoGene Bio: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sangamo Biosciences: Membership on an entity's Board of Directors or advisory committees. Booth: GSK: Honoraria; Takeda: Honoraria; SOBI: Consultancy, Honoraria; Orchard Therapeutics: Consultancy, Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Sevilla: Miltenyi: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Sevilla is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, and may be entitled to receive financial benefits from the licensing of such patents.; SOBI: Consultancy. Rao: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Almarza: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. de Oliveira: Orchard Therapeutics: Research Funding; Bluebird Bio: Research Funding. Law: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Beard: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bueren: Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Bueren is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, may be entitled to receive financial benefits from the licensing of such patents and receives funding for research., Patents & Royalties, Research Funding. Schwartz: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company.

Introduction: LAD-I is a rare inherited disorder of leukocyte (primarily neutrophil) adhesion to endothelial cell surfaces, migration, and chemotaxis resulting from ITGB2 gene mutations encoding for the β2-integrin component, CD18. Severe LAD-I (i.e., CD18 expression on Methods: Pediatric patients ≥ 3 months old with severe LAD-I (demonstrated by CD18 expression on Results: Two patients (ages 9 and 3) were treated in Phase 1. Both have a history of recurrent severe infections, documented ITGB2 mutations, and baseline CD18, CD11a, and CD11b expression < 1%. Mobilization and apheresis procedures were performed successfully and busulfan was administered at the target AUC. Investigational product comprised of 4.2x106 CD34+ cells/kg with VCN of 3.8 copies/cell (liquid culture) for Patient 1 and 2.8x106 CD34+ cells/kg with VCN of 2.5 for Patient 2 and were infused without complications. No serious treatment-emergent adverse events were reported. Neutrophil engraftment was observed in < 3 weeks in both patients. For Patient 1, PB PMN CD18 expression 6 months post-treatment was 47% (sustained from 45% at 3-months, vs. < 1% at baseline), with PB VCN of 1.3. Skin lesions present at baseline were resolving with no new lesions. Replication competent lentiviral (RCL) testing at 3 months and 6 months post-infusion were negative. Safety and efficacy data 12-months post-treatment for Patient 1 and 6-months post-treatment for Patient 2 will be available at the time of presentation. Conclusion: Initial results from Phase 1 demonstrate preliminary safety and efficacy of RP-L201 for reversal of severe LAD-I. Enrollment of patients in the Phase 2 study is underway. Disclosures Kohn: Allogene Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Patents & Royalties, Research Funding. Rao:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Almarza:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Beard:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sevilla:Novartis: Other: Advisory Board; Sobi: Other: Advisory Board; Rocket Pharma: Consultancy; Amgen: Other: Advisory Board. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from this company., Patents & Royalties, Research Funding. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company.

Introduction: Pyruvate Kinase Deficiency (PKD) is a rare inherited hemolytic anemia that is caused by mutations in the PKLR gene leading to decreased red cell pyruvate kinase (RPK) activity and impaired erythrocyte metabolism. The disorder is characterized by anemia, reticulocytosis, splenomegaly and iron overload, and may be life-threatening in severely affected individuals. PKD represents a significant unmet medical need as current therapies are palliative and limited to chronic blood transfusions, iron chelation therapy, and splenectomy. The side effects of these supportive treatments include iron overload, end-organ damage and increased infection risks. AG-348, an allosteric activator of RPK, is under evaluation in clinical trials, predominantly in less severely-afflicted transfusion-independent patients. Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed in selected cases and resulted in transfusion independence, suggesting that the disorder may be reversed when an adequate level of hematopoietic stem and progenitor cells (HSPCs) harboring a corrected PKLR gene engraft in the bone marrow (BM). The therapeutic efficacy of allogeneic transplant is limited by the availability of a suitable donor and transplant-associated toxicities. Preclinical studies conducted in a clinically relevant PKD murine model have demonstrated the safety and efficacy of Lin- BM cells transduced with the therapeutic lentiviral vector, PGK-coRPK-WPRE, in ameliorating the PKD phenotype. More specifically, transplantation of transduced cells resulted in increased erythrocyte survival, decreased reticulocytosis, and improvement in the secondary manifestations of hemolytic anemia, including splenomegaly and hepatic iron overload. Based on compelling preclinical data, a global Phase 1 clinical trial RP-L301-0119 (clinicaltrials.gov#NCT04105166) is underway to evaluate the feasibility and safety of lentiviral mediated gene therapy in adults and pediatric subjects with severe PKD. Methods: 6 subjects with severe PKD (defined as having a history of severe and/or transfusion-dependent anemia despite prior splenectomy) will be enrolled in the Phase 1 study; the first 2 subjects will be adults (age ≥18- Results: An adult female PKD subject (age 31 years) with significant anemia and transfusion requirement has received treatment as of July 2020. Mobilization and apheresis procedures were performed successfully and busulfan conditioning was administered at the target area under the curve (AUC). IP consisted of 3.9×106 CD34+ cells/kg body weight, with a mean vector copy number (VCN) of 2.73. Safety and preliminary efficacy results will be available at the time of presentation. Conclusions: Efficacy in pre-clinical models indicates promising potential for clinical gene therapy in severe PKDHematopoietic stem cell mobilization using G-CSF and plerixafor appears feasible and effective in adult PKD patientsIP was successfully manufactured to meet the required specifications for the Phase 1 clinical study and administered without short-term infusion related complications Disclosures Navarro: Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: SN has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Sevilla:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Beard:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from this company., Patents & Royalties, Research Funding. Rao:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Segovia:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from the Company., Patents & Royalties, Research Funding.

Rare diseases (RD) affect approximately 30 million Americans, half of whom are children. This study is the first to comprehensively evaluate their medical device needs via a survey of physicians. The study sought to identify and document the presumed unmet diagnostic and therapeutic device needs for RD management; clarify the magnitude of the potential unmet need; and generate meaningful data to inform medical device stakeholders. A cross-sectional nonprobability survey was conducted. The study population was drawn from the membership files of four groups: FDA Medical Devices Advisory Committee, Pediatric Advisory Committee, Pediatric Device Consortia, and National Institutes of Health (NIH) Rare Diseases Clinical Research Network. Only physician respondents with experience or knowledge regarding RD were eligible. Among eligible respondents, 90% confirmed the need for innovative devices to care for people with RD. Over 850 device needs were identified for 436 RD, with 74% of needs related to children. Pediatric physicians (OR = 2.11, 95% CI 1.01–4.39, P = 0.046) and physicians with more RD experience reflected greater dissatisfaction with existing devices (OR = 4.49, 95% CI 2.25–8.96, P

Scientific advances, in combination with government incentives and commercial opportunity, have fuelled strong investment in orphan drugs, resulting in many innovative therapies. Here, we discuss the approach of the FDA to a range of issues that remain crucial to maintaining this momentum, such as the use of the totality of evidence in evaluating orphan drugs.

The Food and Drug Administration's (FDA) Humanitarian Device Exemption (HDE) is a unique marketing approval pathway for medical devices targeting diseases affecting small (rare) patient populations. In an effort to increase the utilization and success of this pathway, the FDA has analyzed data from HDE approvals from 2007 to 2015 to identify factors that have contributed to a successful HDE marketing application. There were 28 HDE approvals during the analysis period and were based on a broad range of data constituting valid scientific evidence. Most had at least one prospectively conducted clinical trial to support safety and probable benefit. An analysis of these HDE approvals demonstrates that the FDA exercises a high degree of flexibility when reviewing HDE applications.

O1 The European Social Preferences Measurement (ESPM) study project: social cost value analysis, budget impact, commercial life cycle revenue management, and the economics of biopharmaceutical Research & Development (R&D) Michael Schlander, Soren Holm, Erik Nord, Jeff Richardson, Silvio Garattini, Peter Kolominsky-Rabas, Deborah Marshall, Ulf Persson, Maarten Postma, Steven Simoens, Oriol de Sola Morales, Keith Tolley, Mondher Toumi, Harry Telser O2 Newborn Screening: the potential and the challenges James R Bonham O3 Untreatable disease outcomes - how would we measure them? Helmut Hintner, Anja Diem, Martin Laimer O4 Taking Integrated Care Forward: Experiences from Canada to inspire service provision for people living with rare disease in Europe Rejean Hebert O5 Listening to the patient’s voice: social media listening for safety and benefits in rare diseases Nabarun Dasgupta, Carrie E. Pierce, Melissa Jordan O6 Via Opta: Mobile apps making visually impaired patients’ lives easier Barbara Bori, Mohanad Fors, Emilie Prazakova O7 A report of the IRDiRC “Small Population Clinical Trial” Task Force Simon Day O8 HAE patient identification and diagnosis: An innovative, ‘game changing’ collaboration Thomas J. Croce Jr. O9 Co-creating with the community: primary packaging & administration for people with haemophilia Jonas Fransson, Philip Wood O10 Go with Gaucher, taking forward the next generation. How to involve young people to create a new generation of patient advocates Anne-Grethe Lauridsen, Joanne Higgs, Vesna Stojmirova Aleksovska P1 ODAK – Orphan Drug for Acanthamoeba Keratitis Christina Olsen, Ritchie Head, Antonio Asero, Vincenzo Papa, Christa van Kan, Loic Favennec, Silvana Venturella, Michela Salvador, Alan Krol P5 Rare Navigators help people living with rare diseases to manage the social – and healthcare systems Stephanie J. Nielsen, Birthe B. Holm P6 The eAcademy for Tay-Sachs & Sandhoff disease app Daniel Lewi, Patricia Durao P10 The role of a patient organisation in driving the research agenda in a rare disease Heather Band, Andrea West P13 Expertise for rare diseases mapped Marinda J.A. Hammann, Marije C. Effing-Boele, Hanka K. Dekker P14 The hidden costs of rare diseases: a feasibility study Amy Hunter, Amy Simpson P15 FDA’s new natural history grant program: support to build a solid foundation for development of products for rare diseases Gumei Liu, Katherine Needleman, Debra Lewis, Gayatri Rao P17 Understanding the wider impact of adrenal insufficiency: patient organisation involvement in the TAIN project Amy Simpson, Amy Hunter, Martin J Whitaker P20 Bridging the gaps between medical and social care for people living with a rare disease Raquel Castro