New Medicines

Adenosine deaminase deficiency (ADA) in patients with severe combined immunodeficiency due to ADA


New molecular entity

Development and Regulatory status

Compassionate use
Compassionate use
Compassionate use
Jun 21Despite positive outcome data, Orchard have officially abandoned development of OTL-101, terminating its license from the University of California Los Angeles and the University College London. They had encountered technical issues in manufacturing a commercial-grade product and couldn´t find a "viable path forward after considering possible solutions and seeking new partners." Orchard have returned OTL-101 to academic partners (including University College London) and will help facilitate compassionate use, making data and other resources available. [11]
May 20Orchard announces several key changes to its operations intended to support its new strategic plan including reducing investment in ADA-SCID (OTL-101). Collectively, all of the actions announced are expected to achieve cash savings of approximately $125 million through the end of 2021, extending their existing cash runway into 2022. OTL-101 is still listed in its pipeline, but it seems unlikely Orchard will be seeking a licence at this time [7].
May 19Company expects US licence submission (BLA) in 2020, followed by EU MAA [5].
Feb 19Granted orphan drug status in EU [4].
Aug 17Granted Promising Innovative Medicine designation by the MHRA for treatment of ADA-SCID. This designation is the first step of a two-step process under which ADA SCID gene therapy could benefit from the Early Access to Medicine Scheme (EAMS) [4].
Jul 17Granted rare paediatric disease designation by the US FDA, and also has breakthrough therapy status [4].
Oct 14Granted orphan drug status in US [4].


ADA SCID ex-vivo lentiviral gene therapy, uses stem cells from the patients and corrects them genetically outside the body (ex-vivo) with a lentiviral vector carrying a functioning copy of the missing or faulty gene. Single dose infusion.
ADA deficiency is very rare and is estimated to occur in approximately 1 in 200,000 to 1,000,000 newborns worldwide. Most individuals are diagnosed in the first 6 months of life. Without treatment, they do not usually survive past age 2 years. In 10 to 15% of cases, onset of immune deficiency occurs between 6 and 24 months of age (delayed onset) or in adulthood (late onset) [1].
Adenosine deaminase deficiency (ADA) in patients with severe combined immunodeficiency due to ADA
Intravenous infusion

Trial or other data

Apr 22A PIII long-term observational study to collect safety and efficacy data from ADA-SCID patients previously treated with autologous ex vivo gene therapy products based on the EFS-ADA LV encoding for human adenosine deaminase (ADA) gene (EFS-ADA LV), as part of the OTL-101 clinical development program, is enrolling 70 patients by invitation at Mattel Children´s Hospital UCLA/Ronald Reagan UCLA Medical Center in Los Angeles and UCL Great Ormond Street Institute of Child Health in London. The study is due to complete Aug 35 [13].
Nov 21Orchard Therapeutics terminates the PII/III trial (OTL-101-7; NCT04140539) [12].
May 21Results of NCT01852071; NCT02999984 and NCT01380990 published in the NEJM. In 50 patients with ADA-SCID overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in absence of reinitiation of enzyme-replacement therapy or rescue allogenic HSCT was 97% (US studies) and 100% (UK studies) at 12 months; 97% and 95%, respectively at 24 months and 95% (UK) at 36 months [9,10].
Jul 20PII/III study (NCT04140539) has been suspended, with recruitment on hold for business reasons. The safety and efficacy of OTL-101 for the treatment of patients with ADA- SCID have been established in previous clinical trials. The purpose of the current study is to treat at least 3 ADA-SCID patients with OTL-101 prepared by the commercial manufacturing process in order to facilitate collection of data necessary for final manufacturing [8].
Apr 20No updates available for PII study (NCT03765632) [6].
Jan 19PII prospective, non-randomised, single-cohort, longitudinal clinical study designed to assess the efficacy and safety of OTL-101 cryopreserved formulation administered in ADA-SCID subjects aged ≥30 days to <18 years of age, who are not eligible for a human leukocyte antigen (HLA)-matched sibling/family donor and meet the inclusion/exclusion criteria starts. This study aims to enrol 10 subjects in the UK. It is due to complete Q4 20 [2].
Jan 19PII trial is NCT03765632; OTL-101-5(17IC04); 2017-001275-23 [6].
Aug 18PI/II study (NCT01852071) completes. 20 infants and children diagnosed with ADA-deficient SCID who do not have a medically eligible, HLA-identical sibling donor for bone marrow transplantation were enrolled. The EFS-ADA lentiviral vector with the human ADA cDNA was used to transduce autologous CD34+ cells from the bone marrow of these subjects. The subjects receivde 4 mg/kg busulfan prior to re-infusion of their gene-modified cells. Safety was the primary endpoint. During the follow-up phase, the investigators will determine whether the cells can engraft and produce mature cells that contain and express the corrected ADA gene in the absence of PEG-ADA enzyme replacement therapy (ERT), which will be withheld at Day +30 following transplant [3].
Dec 16PI/II trial to assess the efficacy and safety of ADA SCID gene therapy in patients (aged 30 days to 17 years) with ADA-SCID starts (NCT02999984). The non-randomised, open-label, single-group trial is recruiting 10 patients in the US. Primary outcomes include evaluation of therapy success for each subject & overall survival and event free survival 12 months post OTL-101 infusion. The study is due to complete Q4 19 [2,4].
Sep 16Orchard releases results from an ongoing registrational non-randomised clinical study which evaluated the safety and efficacy of treatment. Main endpoints include overall survival, event-free survival, immune system reconstitution, ADA enzyme activity and safety parameters. A total of 46 patients with ADA-SCID have been treated at Great Ormond Street Hospital and University of California at Los Angeles, with a follow-up of 1–55 months. Early results from the trial showed a 100% overall survival and 31 out of 32 patients showed immune reconstitution, with a favourable safety profile [4].
Nov 12Great Ormond Street Hospital for Children NHS Foundation Trust initiates a PI/II trial to assess the safety and efficacy of EF1αS-ADA lentiviral vector mediated gene modification of autologous CD34+ cells from ADA-deficient individuals (NCT01380990). The trial intends to enroll approximately 10 patients in the UK. Primary outcomes include survival & event free survival at 1 year compared to patients treated with allogeneic HSCT. The study is expected to complete Q2 19 [2,4].

Evidence based evaluations