Wiskott Aldrich syndrome
New molecular entity
Development and Regulatory status
Phase III Clinical Trials
Aug 21Orchard Therapeutics annouced plan to submit MAA to EMA in 2022, subject to further dialogue with EMA. According to a press release, this is to allow time for remaining work on potency assay development and validation. 
Jan 21Orchard announces it is proceeding with plans to file a MAA for OTL-103 in WAS by year end 2021 in the EU, followed by BLA filing in 2022 in the US. Plans in the US have been delayed by Covid, caused by restrictions to laboratory access at Orchard and third-party service providers, which is impacting the timeline to develop a specific functional potency assay .
Nov 20Filings on course for submission to the FDA and EMA in 2021 .
Nov 20OTL-103 also has Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA .
Apr 19Orchard plans to file in the EU & US in 2021 .
Aug 18OTL 103 has been assigned Rare Pediatric Disease designation by the US FDA. It also has orphan drug status in EU & US .
Stem and progenitor cells (CD34+ cells) obtained by leukapheresis from the patient’s peripheral blood are modified with a WASp lentiviral vector ex vivo to insert a functional WAS gene, cryopreserved, then infused back into the patient as a single dose
The underlying mutation is in the gene for the Wiskott-Aldrich syndrome protein (WASP) on the X-chromosome at Xp11.22-23. WASP is needed for normal antibody function, T-cell responses and platelet production. The incidence of the classic syndrome is estimated to be between one and ten in one million individuals, although it is likely to be higher .
Wiskott Aldrich syndrome
Topic prioritised for potential TA guidance production
Trial or other data
Sep 21PIII study of cryopreserved formulation (NCT03837483) now due to report primary outcome data in July 2023. 
Mar 21Study of the cryopreserved formulation is now described as a PIII study (previously PI/II) [14,15].
Mar 21Orchard reports that cumulatively, as of Jan 21, a total of 23 subjects from clinical trials and an EAP have been treated with OTL-103. Seventeen of the subjects – eight from clinical trials and nine from the EAP – have been treated with the fresh formulation of OTL-103, and six subjects have been treated with the cryopreserved formulation of OTL-103. From these two trials and the EAP, 18 SAEs were reported in a total of seven subjects during the reporting period. Nine of the 18 events occurred pre-gene therapy in the cryopreserved study of OTL-103. None of these SAEs were considered to be related to OTL-103, no antibodies against WASP were detected, and no allergic reactions related to OTL-103 have been reported in subjects treated with OTL-103. No new safety information has changed the known safety profile of OTL-103 .
Sep 20OTL-103 has been prioritised for a NICE technology appraisal and the topic passed to the scoping team to prepare for a consultation exercise .
Apr 20PI/II trial of the cryopreserved formulation of OTL 103 (OTL-103-4; NCT03837483) has finished recruiting and expects to complete collection of primary outcome data (Number of participants with successful engraftment of OTL-103 after 6 months) in Feb 22 .
Jan 20PI/II TIGET-WAS study (NCT01515462) has completed collection of primary outcome data and is due to finish in Sep 25 .
Dec 19NCT01515462 and NCT03837483 - no UK sites 
Dec 19Poster presentation. Gene Therapy and Transfer: December 8, Results from an integrated analysis of 17 patients, including the complete data set for the eight patients from the registrational study and nine who received OTL-103 as part of an expanded access program (EAP). Participants have been followed for a median of three years. In the eight-patient registrational trial, investigators reported that the study achieved its key primary and secondary endpoints at three years, including the elimination of severe bleeding episodes and a significant reduction in the frequency of moderate bleeding episodes. Successful engraftment was observed within three months, leading to an increase in WAS protein expression and a vector copy number that has been maintained for up to eight years. Nine months post-administration, all patients stopped receiving platelet transfusions, and no severe bleeding events were reported. A significant reduction in the rate of severe infections was also observed and all patients were able to stop immunoglobin replacement therapy (IgRT), suggesting a complete reconstitution of immune function with durability of effect of up to eight years of follow-up post-gene therapy. Similar clinical results were seen in the integrated analysis of 17 patients and overall survival was 94% (16/17). One death occurred among the EAP cohort that was considered by the investigator to be unrelated to OTL-103. Across the original and integrated data sets, there were no adverse events considered to be related to OTL-103, including no evidence of oncogenesis, replication competent lentivirus or abnormal clonal proliferation. Clinical benefit was also attained in patients older than five years of age, a group considered at higher risk when treated with allogeneic hematopoietic stem cell transplantation (HSCT). 
Feb 19PI/II trial for Wiskott Aldrich Syndrome in Italy continues but has completed patient recruitment (NCT01515462) .
Jan 19PI/II trial to investigate the use of a cryopreserved formulation of OTL 103 for the treatment of patients with Wiskott Aldrich syndrome starts (OTL-103-4; NCT03837483). The single arm, open-label study intends to enrol approximately 6 patients in Italy .
Apr 10PI/II TIGET-WAS study to assess the safety and efficacy of autologous CD34+ cells transduced with Wiskott Aldrich syndrome encoding lentiviral vector for the treatment of Wiskott Aldrich syndrome starts (NCT01515462). 8 patients will be recruited in Italy. Patients will receive a conditioning regimen prior to reinfusion of the gene-corrected haematopoietic stem cells .