Orchard Therapeutics has signed an exclusive global license with Fondazione Telethon and Ospedale San Raffaele in Milan, Italy, for what will be the company’s sixth clinical stage ex vivo autologous hematopoietic stem cell (HSC) gene therapy program—a treatment for Mucopolysaccharidosis Type I (MPS-I) that has shown promising early clinical data in an ongoing Phase I/II proof of concept study.
The value of the license was not disclosed. Orchard agreed to research, develop, manufacture, and commercialize the treatment, which the company will label OTL-203. The treatment has been developed by the San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET) in Milan. Orchard did say, however, that it agreed to pay Fondazione Telethon and Ospedale San Raffaele an upfront payment; additional payments tied to achieving future development, regulatory and sales milestones; as well as royalty payments on net sales.
Orchard presented the promising data from the Phase I/II study (NCT03488394) at the American Society of Gene and Cell Therapy (ASGCT) 22nd Annual Meeting, held April 29–May 2 in Washington, DC. Researchers from SR-TIGET reported that promising signs of disease correction were seen in the most severe subtype of MPS-1, Hurler syndrome (MPSI-H), following treatment with frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase (IDUA) cDNA, in their final formulation medium.
Two patients (14 and 24 months of age) had been treated as of January 15, 2019, as of the date of presentation, with engraftment and high IDUA expression seen in both.
In the 14-month-old patient, the “his hematologic recovery after Flu/Bu-based myeloablative conditioning was fast (ANC<100/mcl: 5 days; last transfusion on day+10) and uneventful,” the SR-TIGET researchers reported in an abstract of their presentation, “2-Ex-Vivo Gene Therapy for Hurler Disease: Initial Results from a Phase I/II Clinical Study.”
“Importantly, the patient reached normal blood IDUA activity by day+11 and supra-normal activity by day+14 that stabilized around 5-fold above the upper limit of normal, along with an in vivo vector copy number around 2 that was sustained in multiple hematopoietic lineages. IDUA activity was also demonstrated in the cerebrospinal fluid, and urinary GAGs were strongly reduced to near-normal levels early after gene therapy (d+90),” the researchers observed. “These initial clinical results strongly support benchmarking of our autologous ex vivo gene therapy approach against allogeneic transplantation, the current standard of care for MPSI-H patients.”
To date, Orchard said, four patients have been enrolled in the trial with up to nine months of follow-up. The trial is expected to enroll up to eight patients by the first half of 2020, with preliminary findings after one year of follow-up.
“The potential to overcome”
“Developing safe and effective treatments for neurometabolic diseases has been a challenge that we believe ex vivo autologous HSC gene therapy has the potential to overcome,” Luigi Naldini, director of SR-TIGET and head of the Gene Transfer Technologies and New Gene Therapy Strategies Unit, said in a statement. “We are pleased to continue our partnership with Orchard as we work together to develop potential ex vivo HSC gene therapies to treat MPS-I and other devastating rare diseases.”
Orchard announced the license for OTL-203 along with first quarter 2019 results. The addition of OTL-203 brings to nine the company’s number of programs from late preclinical to commercial stage.
The company offered additional updates on its gene therapy candidates:
For OTL-200, Orchard has advanced its timeline for submitting a Marketing Authorization Application (MAA) in Europe for the Metachromatic Leukodystrophy (MLD) candidate to the first half of 2020 following a “positive” pre-submission meeting with the European Medicines Agency (EMA) in early May. The company added that it plans to file a Biologics License Application (BLA) in the U.S. approximately one year after the MAA submission.
During the first quarter, Orchard presented two- and three-year follow-up data on 20 patients from the OTL-200 registrational trial for MLD, using the fresh product formulation, at the 45th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT). In the study, late infantile MLD patients achieved gross motor function scores of 65 and 72 percentage points higher at two and three years following gene therapy than MLD patients in a natural history patient cohort who did not receive gene therapy.
For OTL-201, Orchard plans to begin enrolling patients later this year in an upcoming proof-of-concept clinical trial assessing the Sanfilippo Syndrome Type A (MPS-IIIA) candidate. The trial will use the same technology and procedures that were used by the Royal Manchester Children’s Hospital (RMCH) to treat the first MPS-IIIA patient in the world with the ex vivo HSC gene therapy, as disclosed last week by the Manchester University NHS Foundation Trust.
That study was conducted under a “Specials” license, granted by the U.K. government for the use of an unlicensed pharmaceutical product in situations of high unmet need when there is no other treatment option available.
For OTL-103, Orchard said it dosed the first patient in a clinical trial using the cryopreserved formulation of OTL-103 for patients with Wiskott-Aldrich syndrome (WAS; NCT03837483). Orchard says the program remains on track for BLA and MAA filings in 2021—as Orchard president and CEO Mark Rothera told GEN earlier this year.
And for OTL-300, Orchard said the transfusion-dependent beta-thalassemia (TDT) treatment achieved clinical proof-of-concept in a Phase I/II study (NCT03275051), citing data presented at ASGCT in April 2019. Orchard reported that eight of nine patients had a reduced or eliminated need for transfusions 12 months following treatment, with four of six pediatric patients achieving transfusion independence.
In today’s company statement, Rothera said the company aims to have three more approved therapies for pediatric rare diseases in the next three years—in addition to Strimvelis™ (autologous CD34+ cells transduced to express adenosine deaminase, or ADA), an autologous ex vivo gammaretroviral gene therapy approved in Europe following its development by GlaxoSmithKline (GSK).
Strimvelis received European Commission approval in 2016 as the first autologous ex vivo gene therapy for children with adenosine deaminase severe combined immune deficiency (ADA-SCID). Two years later, GSK handed off Strimvelis and the rest of its rare disease gene therapy portfolio—including OTL-200 and OTL-103—to Orchard.