Orchard Therapeutics Submits BLA for HSC Gene Therapy Libmeldy (OTL-200) with FDA Priority Review Granted; Founded by Ex-GSK Executives and Backed by GSK’s Rare Disease Portfolio

OTL-200 is a lentiviral vector-based, autologous hematopoietic stem cell gene therapy., using a lentiviral vector containing the human arylsulfatase A (ARSA) gene to transfect autologous differentiated CD34+ cells, enabling the cells to express arylsulfatase A.The therapy was approved in the EU in 2020., used to treat MLD patients characterized by reduced ARSA enzyme activity in children due to biallelic mutations in the ARSA gene. This is also the firstThe First Approved Gene-Edited Hematopoietic Stem Cell Therapy for MLDPreviously, OTL-200 had received the FDA's Rare Pediatric Disease (RPD) and Regenerative Medicine Advanced Therapy (RMAT) designations.

The BLA for OTL-200 is based on data from 39 pediatric patients with early-onset MLD who participated in two prospective non-randomized clinical studies (n=30) or received treatment under an expanded access framework (n=9). These patients were compared with natural history data from 49 untreated patients after receiving OTL-200 treatment. Over a follow-up period of up to 12 years (median 6.76 years), compared with the natural history of the disease,OTL-200 treatment preserves motor function and cognitive development in the majority of patients.In terms of safety, OTL-200 treatment was generally well-tolerated, with no serious adverse events or deaths related to the treatment. Most adverse events were associated with busulfan preconditioning or underlying diseases.

Orchard Therapeutics’ co-founder and CEO, Dr. Bobby Gaspar, stated: “We look forward to collaborating with the FDA throughout the review and evaluation of our application, while preparing for a potential approval in 2024 to ensure OTL-200 is made available to U.S. patients as soon as possible.”

As the company that launched the first gene-edited hematopoietic stem cell therapy for MLD, Orchard Therapeutics owes part of its success to GSK's "contributions." This company, which focuses on gene-edited hematopoietic stem cell therapies,It was founded by Andrea Spezzi, a former employee of GSK, as a co-founder.Dr. Andrea served as the Vice President of GSK's Rare Disease Division and the head of pharmaceutical R&D, playing a key role in the successful launch of Strimvelis, the second gene therapy approved by the EU.

In May 2016, Orchard Therapeutics received a Series A investment of £21 million (approximately $33.4 million) led by F-Prime Capital, followed by a Series B financing of $110 million in December 2017.In April 2018, Orchard Therapeutics successfully acquired the rare disease gene therapies (including OTL-200 and OTL-103) developed by GSK, while GSK obtained a 19.9% stake in Orchard Therapeutics as well as a seat on the company's board of directors.. This deal is a win-win for both parties.

In just the past four months, Orchard Therapeutics announced the completion of a $150 million Series C financing round, which was oversubscribed. The funds will be used to advance the portfolio of rare disease gene therapies acquired from GSK, as well as its proprietary multiple clinical and preclinical programs. Just two months later, Orchard successfully went public on NASDAQ, completing an initial public offering that raised a total of $225 million. The proceeds will primarily be used for the development of rare disease gene therapies, the design, construction, and operation of its own manufacturing facility, and the commercial promotion of the gene therapy Strimvelis in the EU region.

Looking back at Orchard Therapeutics' establishment and product advancement, it did not lack investors in terms of financing and successfully went public in just three years. The acquired pipeline successfully gained approval and reached the market, with the backing of GSK, making the overall journey very smooth.

In addition to OTL-200, Orchard's other R&D pipelines are also advancing comprehensively.

OTL-201 is an experimental hematopoietic stem cell (HSC) gene therapy.Lentiviral vectors were used to insert functional copies of the human SGSH gene into patients' hematopoietic stem cells for the treatment of Mucopolysaccharidosis IIIA (MPS-IIIA). Six months after receiving OTL-201 therapy, N-sulfoglucosamine sulfohydrolase (SGSH) levels in the cerebrospinal fluid (CSF) of five patients returned to normal. The drug was well-tolerated, and to date, there is no evidence of insertional oncogenesis in the analyzed samples.

OTL-203 involves inserting a functional copy of the IDUA gene into patients' hematopoietic stem cells using a modified virus., which has been developed for the treatment of Type I Mucopolysaccharidosis (MPS-I). In May 2023, Orchard Therapeutics plc. announced the latest aggregated data from patients treated with OTL-203, with a median follow-up time of 3.78 years. All eight patients achieved the primary endpoint of IDUA activity. Treatment with OTL-203 was generally well-tolerated and demonstrated broad metabolic correction sustained over four years post-treatment. All patients showed persistent engraftment of gene-corrected cells, with blood IDUA activity reaching supraphysiological levels post-treatment and maintaining normal or near-normal substrate levels at their last follow-up. All patients were able to discontinue enzyme replacement therapy.

OTL-103 is also a gene-modified HSC therapy utilizing modified virus transduction., for the treatment of Wiskott-Aldrich Syndrome (WAS). This pipeline is currently in the preclinical development stage. In addition, for the treatment of Frontotemporal Dementia (FTD)OTL-204, co-developed with Pharming Group NV for the treatment of hereditary angioedemaOTL-105All are in the preclinical development stage.

OTL-200 has been successfully approved in the European Union, and clinical data also supports the efficacy and safety of this candidate drug. Although the U.S. FDA has its own review standards, the likelihood of this drug ultimately being approved is still relatively high. Patients with MLD will have more treatment options, and once OTL-200 is launched in the United States and begins to generate profits, it will be more beneficial for the company to continue advancing other hematopoietic stem cell gene therapies.

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