Orchard Therapeutics plc operates as a global gene therapy company.
The company is dedicated to transforming the lives of people affected by rare diseases through the development of potentially curative gene therapies. Its ex vivo autologous hematopoietic stem cell, or HSC, gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. The company seeks to achieve this outcome by utilizing a len...
Orchard Therapeutics plc operates as a global gene therapy company.
The company is dedicated to transforming the lives of people affected by rare diseases through the development of potentially curative gene therapies. Its ex vivo autologous hematopoietic stem cell, or HSC, gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. The company seeks to achieve this outcome by utilizing a lentiviral vector to introduce a functional copy of a missing or faulty gene into the patient’s own, or autologous, HSCs through an ex vivo process, resulting in a gene-modified cellular drug product that can then be administered to the patient at the bedside.
The company is focusing its ex vivo autologous HSC gene therapy approach on severe neurometabolic diseases and early research programs. The company’s lead program is OTL-200, which was approved in the European Union, the United Kingdom, Iceland, Liechtenstein and Norway under the brand name Libmeldy for eligible patients with early-onset metachromatic leukodystrophy, or MLD. Pending the outcome of the multidisciplinary pre-BLA meeting scheduled for the second quarter of 2023, the company anticipates a potential BLA submission in mid-2023.
The company’s portfolio includes a commercial-stage product and research and development-stage product candidates. The company’s approach of using lentiviral vectors to genetically modify HSCs has wide-ranging applicability to a large number of indications. The ability of HSCs to differentiate into multiple cell types allows the company to deliver gene-modified cells to multiple physiological systems, including the central nervous system, immune system and red blood cell and platelet lineage, thereby potentially enabling the correction of a wide range of diseases. By leveraging the innate self-renewing capability of HSCs that are engrafted in the bone marrow, as well as the ability of lentiviral vectors to achieve stable integration of a modified gene into the chromosomes of HSCs, the company’s gene therapies have the potential to provide a durable effect following a single administration.
The diseases the company targets affect patients around the world, requiring an infrastructure to deliver gene therapies globally. In order to meet anticipated demand for the company’s pipeline of approved products and product candidates still in development, the company is utilizing its existing network of contract development and manufacturing organizations, or CDMOs, to manufacture lentiviral vectors and drug product. In addition, the company has established process development capabilities in London, the U.K.; and is leveraging technologies that will allow the company to deliver the company’s gene therapies globally.
Cryopreservation of the company’s gene-modified HSCs is a key component of the company’s commercialization strategy to deliver potentially curative gene therapies to patients worldwide, facilitating both local treatment and local or cross-border product reimbursement. The company developed a cryopreserved formulation of Libmeldy (OTL-200) and is collecting supportive clinical data from patients treated with cryopreserved formulations to support the analytical comparability to the fresh cell formulations used in the company’s registrational clinical trials. The registrational trials for all the company’s earlier stage product candidates are expected to be conducted using a cryopreserved formulation.
With the exception of OTL-105, the company’s product candidate for the potential treatment of hereditary angioedema, or HAE, which the company is pursuing in partnership with Pharming Group N.V., the company has global commercial rights to all the company’s clinical product candidates and plan to commercialize the company’s gene therapies in key markets worldwide, including in Europe and the U.S. initially, subject to obtaining the necessary marketing approvals for these jurisdictions. The company focuses on deploying a commercial infrastructure to deliver Libmeldy and the company’s product candidates, if approved, to patients and are focused on working closely with all relevant stakeholders, including patients, caregivers, specialist physicians and payors, to ensure the widest possible post-approval access for the company’s product candidates. In addition, the company may rely on third parties to assist with regulatory submissions, disease awareness, patient identification and reimbursement in countries where local expertise is required or where the company does not have a direct presence.
The company’s management team has extensive experience in rare diseases and in the manufacturing, pre-clinical and clinical development and commercialization of gene and cell therapies. In addition, the company partners with leading academic institutions around the world, which are pioneers in ex vivo autologous HSC-based gene therapy. The company plans to leverage its internal expertise combined with the company’s relationships with leading academic institutions to transition the company’s lead clinical-stage product candidates to commercialization and continue to expand the company’s portfolio of ex vivo autologous HSC gene therapy products.
Strategy
The company is building a leading, global, fully-integrated gene therapy company focused on transforming the lives of people affected by severe diseases. To achieve this, the company is pursuing the following strategies:
Continue the company’s commercialization efforts for Libmeldy (OTL-200) for the treatment of eligible patients with early-onset MLD in Europe and expand geographically into new markets as regulatory approvals are obtained.
Advance the company’s clinical-stage product candidates towards marketing approvals, including a potential BLA submission for OTL-200 in the U.S. in mid-2023.
Leverage the power of the company’s therapeutic approach to investigate the potential of HSC gene therapy in larger indications.
Invest in new technologies and innovations to continue to improve the company’s manufacturing processes for lentiviral vector and drug product and reduce costs of goods manufactured.
Establish end-to-end process development, manufacturing and supply chain capabilities, initially through third parties and internally over time.
Establish a patient-centric, global commercial infrastructure, including with third parties in certain regions where the company do not have a direct presence.
Execute a business development strategy to leverage the company’s HSC gene therapy approach, expand geographically, accelerate time-to-market or attract disease-area expertise to optimize the value of the company’s portfolio of product candidates or expand into new indications.
Pipeline
The company’s programs focused on neurodegenerative disorders consist of the company’s commercial program approved in Europe, Libmeldy (OTL-200) for MLD, two clinical proof of concept-stage programs, OTL-203 for MPS-I and OTL-201 for mucopolysaccharidosis type IIIA, or MPS-IIIA, and one pre-clinical program, OTL-204 for frontotemporal dementia with progranulin mutations, or GRN-FTD.
The company’s programs in immunological disorders consist of two pre-clinical programs, OTL-104 for Crohn’s disease with mutations in the nucleotide-binding oligomerization domain-containing protein 2, or NOD2-CD, and OTL-105 for HAE.
In July 2021, the company entered into a collaboration with Pharming Group N.V., or Pharming, pursuant to which the company granted Pharming worldwide rights to OTL-105. Under the company’s agreement with Pharming, the company will lead the completion of IND-enabling activities of OTL-105 and oversee its manufacturing during pre-clinical and clinical development, which will be funded by Pharming. Pharming will be responsible for clinical development, regulatory filings and commercialization of OTL-105, if approved, including associated costs.
The company also has a commercial product approved in Europe, Strimvelis for ADA-SCID, an advanced registrational clinical program, OTL-103 for Wiskott Aldrich syndrome, or WAS, and one clinical proof of concept-stage program, OTL-102 for X-linked chronic granulomatous disease, or X-CGD. However, in March 2022, the company announced that the company would discontinue the company’s investment in and seek alternatives for these programs.
Libmeldy (OTL-200) for the treatment of MLD
OTL-200 is designed as a one-time therapy that aims to correct the underlying genetic cause of MLD, offering eligible patients the potential for long-term positive effects on cognitive development and maintenance of motor function at ages at which untreated patients show severe motor and cognitive impairments. With OTL-200, a patient’s own HSCs are selected, and functional copies of the ARSA gene are inserted into the genome of the HSCs using a lentiviral vector before these genetically modified cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate across the blood-brain barrier into the brain, engraft, and express the functional enzyme has the potential to persistently correct the underlying disease with a single treatment.
The company obtained worldwide rights to this program through the company’s asset purchase and license agreement with Glaxo Group Limited and GlaxoSmithKline Intellectual Property Development LTD, or, together, GSK. The clinical trials for this program have been conducted under a GSK-sponsored clinical trial authorization, which was transferred to the company during the third quarter of 2018.
Libmeldy approval in Europe as Orphan Drug
In December 2020, the European Commission granted full, or standard, marketing authorization for Libmeldy (OTL-200) (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene) for the treatment of early-onset MLD characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with (i) late infantile or early juvenile forms, without clinical manifestations of the disease, or (ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline.
Libmeldy has received orphan drug designation from the EMA for the treatment of MLD and orphan drug status was maintained at the time of approval. The company is continuing to follow patients in the clinical development program for up to 15 years as a post-marketing commitment, and data will be presented to regulators at agreed time points in order to further characterize the long-term efficacy and safety of Libmeldy, particularly in the early symptomatic early juvenile population.
OTL-200 development in the U.S.
OTL-200 has received orphan drug designation for the treatment of MLD, as well as Rare Pediatric Disease designation. In late 2020, the FDA cleared the company’s IND application for OTL-200 in the U.S., and in January 2021, FDA granted regenerative medicine advanced therapy, or RMAT, designation for OTL-200. Based on feedback received from the FDA, the company is preparing for a BLA filing for OTL-200 in pre-symptomatic, early-onset MLD patients, expected in mid-2023, using data from existing OTL-200 patients. This approach and timeline are subject to the successful completion of activities remaining in advance of a pre-BLA meeting with the FDA, scheduled for the second quarter of 2023.
OTL-203 for the treatment of MPS-IH
OTL-203 is a single administration, gene therapy product candidate consisting of autologous CD34+ enriched HSPCs, derived from mobilized peripheral blood, genetically modified ex vivo with the lentiviral vector encoding for the IDUA complementary DNA, or cDNA. It is being developed as a cryopreserved formulation. Ex vivo autologous gene therapies, such as OTL-203, are designed to correct the genetic defect in patients’ own HSCs and their progeny by addition of functional cDNA. The OTL-203 mechanism of action, or MOA, addresses the disease pathophysiology by restoring enzymatic IDUA expression in peripheral and central body compartments as well as restoring microglia homeostasis in the central nervous system, or CNS, to confer neuroprotective effects against the neurotoxic effects of glycosaminoglycan, or GAG, accumulation in affected cells.
In addition, OTL-203 has the potential to overcome safety issues associated with the current standard of care. Compared to allogeneic transplantation, which is the current standard of care for MPS-IH treatment, the autologous nature of OTL-203 is associated with a significantly reduced transplant-related morbidity and mortality and avoidance of graft versus host (both acute and chronic) and immune mediated graft rejection.
The company has obtained worldwide development and commercialization rights to OTL-203 from Telethon Foundation and San Raffaele Hospital.
OTL-203 has received orphan drug and PRIME designation from the EMA, as well as orphan drug designation and rare pediatric disease designation from the FDA for the treatment of MPS-I.
Ongoing Clinical Trials
OTL-203 is being investigated in an ongoing, academic-sponsored clinical trial at the San Raffaele Hospital in Milan, Italy to establish proof of concept. The study is a prospective, single dose, single center, non-randomized, open label study involving a single administration of OTL-203 in eight patients with a confirmed diagnosis of MPS-IH. The study is fully enrolled using a cryopreserved formulation of OTL-203.
The patients evaluated in this trial include pediatric MPS-IH patients from 14 to 34 months of age at the time of treatment and will be followed for at least five years post-treatment in the context of the proof of concept study and then continue to be evaluated in a long-term follow-up study.
In September 2022, the company announced the presentation of the interim clinical results from the ongoing academic-sponsored clinical trial at the San Raffaele Hospital. For this presentation’s last follow up of all patients (range: 24 and 36 months), interim data supporting clinical proof-of-concept illustrated that treatment with OTL-203 was generally well-tolerated with a safety profile consistent with the selected conditioning regimen. IDUA antibodies present prior to gene therapy as a result of ERT were not seen in any patient within three months following treatment. In addition, ERT was discontinued at least three weeks prior to any patient receiving gene therapy treatment, and no patients had re-started ERT post-treatment.
In December 2022 the company received IND clearance of OTL-203 from the FDA, which allows the company to initiate a global registrational study in MPS-IH. The company plans to initiate the study, which will include centers across the U.S. and Europe, in the second half of 2023.
The study will be a multi-center, randomized, active controlled clinical trial designed to evaluate the efficacy and safety of OTL-203 in patients with MPS-IH compared to standard of care with allogeneic hematopoietic stem cell transplant. A total of 40 patients with a confirmed diagnosis of MPS-IH who meet the study inclusion criteria will be randomized 1:1 to receive either OTL-203 or allogeneic HSCT. The study is powered to demonstrate superiority of OTL-203 over allo-HSCT.
OTL-201 for the treatment of MPS-IIIA
The company is developing OTL-201 as an ex vivo autologous HSC gene therapy for the treatment of patients with MPS-IIIA. Pre-clinical studies in mice have shown that ex vivo autologous gene therapy has the potential to address the neurological manifestations of MPS-IIIA. The company has obtained worldwide development and commercialization rights to OTL-201 from The University of Manchester.
OTL-201 has received orphan drug designation from the EMA and FDA for the treatment of MPS-IIIA and has received rare pediatric disease designation from the FDA.
Proof of concept trial in MPS-IIIA
The company is supporting a proof-of-concept trial for the treatment of MPS-IIIA, which started enrollment in January 2020. The trial, which is being conducted by the Royal Manchester Children’s Hospital and sponsored by the Manchester University NHS Foundation Trust, completed enrollment in 2021 with the fifth patient treated in September 2021.
Early clinical findings, including the first neurocognitive results, from the proof-of-concept trial were presented at the American Society of Hematology (ASH) Annual Meeting in December 2022 and at the WORLD Symposium in February 2023. The data, which encompassed follow-up ranging from 9 to 24 months, showed robust, prompt, sustained, multi-lineage engraftment of genetically modified cells. Supraphysiological levels of SGSH enzyme were seen in leukocytes, plasma and CSF and rapid and reduction of substrate (glycosaminoglycans, GAGs) observed in all compartments.
Early neurocognitive outcomes also indicated that since receiving OTL-201, four out of five patients showed gain of cognitive skills in line with development in healthy children. The oldest patient at last follow up has maintained this normal cognitive development since treatment, despite reaching a chronological age where cognition is observed to decline in natural history patients, showing improvement from this comparator. Three additional patients are within the normal development quotient (DQ) range at 9 to 18 months post-treatment but require longer follow-up to assess outcomes.
Treatment with OTL-201 was generally well-tolerated in the initial study population. Of the six serious adverse events (SAEs) reported to date, four were determined to be due to conditioning or leukapheresis and one was related to background disease. One patient had delayed platelet engraftment until day 52 post-treatment, likely due to Cytomegalovirus infection around the time of infusion.
OTL-204 for the treatment of FTD
OTL-204 is an ex vivo autologous HSC gene therapy being developed to replace the defective microglia cells in the brain of GRN-FTD patients with genetically modified microglia cells that produce and secrete a corrective amount of GRN. These cells develop naturally from HSCs, which are collected from the patient and modified by using a viral vector that brings a functional copy of the GRN gene. When they are infused in the patient, the genetically modified HSCs naturally reach the brain and become resident microglia cells. OTL-204 is being developed in partnership with Professor Alessandra Biffi at the University of Padua in Italy. As part of the collaboration, the company initiated a sponsored research agreement with the University of Padua and obtained an exclusive option with Boston Children’s Hospital to develop and exclusively license the program.
Pre-clinical development of OTL-204
Preliminary in vitro data obtained in 2020 have demonstrated that human cell lines and mouse HSCs can be efficiently transduced to produce GRN. GRN is then secreted in the culture medium and can be taken up by other types of cells that do not produce GRN themselves.
Preliminary in vivo data from the pre-clinical proof-of-concept study showed that murine GRN-/- HSPCs, transduced with an LV expressing progranulin under the control of a novel promoter, are able to engraft and repopulate the brain myeloid compartment of FTD mice and to locally deliver the GRN enzyme.
Immunological Disorders
solution, OTL-104 for the treatment of NOD2-CD
The company is developing OTL-104 to evaluate its therapeutic efficacy as an ex vivo autologous HSC gene therapy to treat patients with NOD2-CD through a single administration. As the pathogenesis of NOD2-CD is associated with the function of cells of the hematopoietic system, ex vivo autologous HSC gene therapy may therefore be used to restore NOD2 function to immune cells, such as tissue resident macrophages within the gastrointestinal tract. The company’s OTL-104 program is being designed to introduce the NOD2 gene into cells of the hematopoietic system by lentiviral transduction of a patient’s own blood or bone marrow derived HSCs, and the gene-modified cells can then be infused back into the patient. Clinical observations in the allogeneic transplant setting, where HSCT has resulted in the clinical reversion of Crohn’s Disease and other monogenic forms of IBD, supports the scientific rationale and mode of action of OTL-104. The company owns patent applications in the United States and other jurisdictions and all other intellectual property rights associated with the OTL-104 program.
Pre-clinical development of OTL-104
OTL-104 pre-clinical work has shown that restoration of NOD2 gene expression in murine and human stem cells can rescue a defective myeloid immune response to MDP. NOD2 defective inflammatory functions in primary human myeloid cells can be restored by both lentiviral and gene editing approaches. The OTL-104 lentiviral vector is designed to express NOD2 under the chimeric CathepsinG/cFES promoter to deliver myeloid directed transgene expression. Pre-clinical studies to evaluate the safety of this approach show that NOD2-LV gene modification of human CD34+stem cells and murine lineage negative stem cells does not affect HSC engraftment or immune subset development and differentiation following transplantation into NSG or NOD2-KO mice, respectively. Transplantation of NOD2-LV gene modified murine stem cells further demonstrates that HSC derived cells can efficiently migrate and reconstitute the myeloid cell compartments of intestinal tissue, restoring a normal biodistribution of NOD2 expression within the gut.
Pre-clinical proof-of-concept studies include in vivo colitis disease modeling and a non-interventional clinical research study using NOD2-genetically defined patients with Crohn’s Disease. The company has generated in vivo evidence that defective monocyte functions in NOD2-KO mice can be corrected by OTL-104 gene therapy, restoring NOD2-dependent systemic cytokine responses and innate immune cell mobilization. In vitro, myeloid cells differentiated from CD34+ cells obtained from peripheral blood of genetically characterized NOD2 deficient CD patients, are refractory to MDP stimulation and unable to generate a normal cytokine response profile. LV transduction of NOD2-deficient patient cells restores MDP-induced cytokine responses to levels comparable to those observed in monocytes derived from CD34+ cells from healthy donors, correcting a NOD2-defective phenotype. Orchard’s OTL-104 program is under development towards IND-/ CTA- enabling toxicology / biodistribution studies.
Other Programs
In March 2022, the company announced that the company would discontinue the company’s investment in and seek alternatives for Strimvelis, OTL-103 for the treatment of WAS and OTL-102 for the treatment of X-CGD.
Manufacturing
The company partners with a network of experienced CDMOs, including AGC Biologics S.p.A. (formerly MolMed S.p.A.) and Oxford BioMedica, for the supply of the company’s vectors and drug products, including Libmeldy. The company has established relationships with commercial CDMO partners with the resources and capacity to meet the company’s clinical and existing and expected initial commercial needs. The company’s CDMO partners also provide the company with access to their manufacturing technologies.
The company has licensed lentiviral vector stable cell line technologies from GSK, completed transduction enhancer screening processes, established a vector process development lab at a Catapult Network facility in the U.K., and are in the process of building cell therapy and analytical development capabilities at the company’s London, the U.K. global headquarters.
Commercial operations
The company has launched Libmeldy (OTL-200) for the treatment of early-onset MLD following receipt of full, or standard, marketing approval from the European Commission in December 2020.
Oxford BioMedica license and development agreement
In November 2016, the company entered into a license and development agreement, or the Oxford Development Agreement, with Oxford BioMedica (UK) Limited, or Oxford BioMedica, for the development of gene therapies for ADA-SCID, MPS-IIIA and certain other diseases that the company may request be included under the Oxford Development Agreement, such other diseases referred to as Subsequent Indications. The Oxford Development Agreement was amended on multiple occasions and most recently in April 2020.
Pursuant to the Oxford Development Agreement, Oxford BioMedica granted the company an exclusive, worldwide license under certain intellectual property rights for the purposes of research, development and commercialization of ex vivo gene therapy products for the treatment of ADA-SCID, MPS-IIIA and Subsequent Indications, except that such license is non-exclusive to the extent the treatment of a Subsequent Indication is the subject of a certain previous license granted by Oxford BioMedica. Oxford BioMedica also granted the company a non-exclusive, worldwide license under certain intellectual property rights for the purposes of research, development, commercialization and manufacture of ex vivo gene therapy products for the treatment of certain diseases other than ADA-SCID, MPS-IIIA and Subsequent Indications. Under the Oxford Development Agreement, Oxford BioMedica is required to use commercially reasonable efforts to perform the activities set forth in a collaboration plan approved by a joint steering committee, and the company is responsible for certain costs of the activities set forth in such collaboration plan.
Telethon-OSR license agreement
In May 2019, the company entered into a license agreement with Telethon-OSR under which Telethon-OSR granted the company an exclusive worldwide license for the research, development, manufacture and commercialization of ex vivo autologous HSC lentiviral based gene therapy products for the treatment of MPS-I, including MPS IH. Under the terms of the agreement, Telethon-OSR is entitled to receive an upfront payment, and the company may be required to make milestone payments if certain development, regulatory and commercial milestones are achieved. Additionally, the company will be required to pay Telethon-OSR a tiered mid-single to low-double digit royalty percentage on annual net sales of licensed products.
Government Regulation
The company must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as ‘off-label use’), industry-sponsored scientific and educational activities, and promotional activities involving the internet.
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, affect the company’s business.
The U.S. Foreign Corrupt Practices Act, to which the company is subject, prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
In the United States, the company’s operations are subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services, or HHS (such as the Office of Inspector General, Office for Civil Rights and the Health Resources and Service Administration), the U.S. Department of Justice, or DOJ, and individual U.S. Attorney offices within the DOJ, and state and local governments.
History
The company was founded in 2015. It was incorporated under the laws of England and Wales in August 2018. The company was formerly known as Orchard Rx Limited and changed its name to Orchard Therapeutics plc in October 2018.
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