Autologous lentiviral WAS stem cell therapy

Unassigned

New Medicines

Wiskott Aldrich syndrome

Information

New molecular entity
Orchard Therapeutics
Orchard Therapeutics

Development and Regulatory status

None
Phase II Clinical Trials
None
Yes
Yes
Nov 20Filings on course for submission to the FDA and EMA in 2021 [11].
Nov 20OTL-103 also has Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA [9].
Apr 19Orchard plans to file in the EU & US in 2021 [4].
Aug 18OTL 103 has been assigned Rare Pediatric Disease designation by the US FDA. It also has orphan drug status in EU & US [3].

Category

An ex vivo stem cell therapy that uses lentiviral vector to transfer functional WAS genes into autologous haematopoietic stem cells
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 [1].
Wiskott Aldrich syndrome
Intravenous infusion

Trial or other data

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 [10].
Jan 20PI/II TIGET-WAS study (NCT01515462) has completed collection of primary outcome data and is due to finish in Sep 25 [10].
Dec 19NCT01515462 and NCT03837483 - no UK sites [8]
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). [7]
Feb 19PI/II trial for Wiskott Aldrich Syndrome in Italy continues but has completed patient recruitment (NCT01515462) [2].
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 [2].
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 [2].

Evidence based evaluations

Wiskott Aldrich syndrome

Information

New molecular entity
Genethon
Genethon

Development and Regulatory status

Phase II Clinical Trials
Phase II Clinical Trials
Phase II Clinical Trials
Yes
Nov 20No longer mentioned on Genethon website; unclear whether Genethon is still progressing this [10].
Jun 20The company has not released any information on licensing plans or results since completion of the PI/II trial (NCT01347242); development plans unknown [9].
Oct 13Genethon obtains orphan drug status for this product from the European Medicines Agency (EU/3/13/1196) [4].

Category

WAS gene therapy based on ex vivo gene transfer, where a lentiviral vector carring the therapeutic gene is inserted into the haematopoietic stem cellsof the patient (autologous CD34+ cells)
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 [1].
Wiskott Aldrich syndrome
Intravenous infusion

Trial or other data

Nov 20No update for PI/II trial (NCT01347242) on trial registry website; no results posted. PI/II (NCT02333760) entry not updated since Aug 19, when it was recruiting. PI/II trial (NCT01410825) last updated Jan 20 when it was active but no longer recruiting [11].
Dec 19UK trial sites: NCT02333760- UCL; NCT01347242 - Great Ormond Street, Royal Free [7]
Nov 19NCT01347242 trial completed. This non-randomised, open-label trial was initiated in March 2011 with six patients in the UK [8]
Apr 19Genethon predicts that the last patient will complete the trials in Q3 19. Following treatment, patients are followed for 10 years: 2 years in the main clinical trial and then 8 years in a tolerance monitoring trial [4]. 20/04/2019 21:02:21
Sep 14Genethon initiates a long-term safety follow up study (NCT02333760) of the patients enrolled in thePI/II trials (NCT01347346; NCT01347242). The trial is ongoing in the UK and France [3].
Jun 11Three PI/II trials of the WAS gene therapy product start. The trials aim to investigate WASp gene therapy in patients with Wiskott Aldrich syndrome protein gene, with funding provided by the Gene Therapy Resource Program of the US National Heart, Lung and Blood Institute (Boston site) and the French Muscular Dystrophy Association (AFM; Paris and London sites). One trial is taking place at the Great Ormond Street Hospital in the UK (NCT01347242), the Hôpital Necker-Enfants Malades in France (NCT01347346), and the Childrens Hospital Boston in the US (NCT01410825). A total of 20 patients (n=5 5 at each site respectively) are to be treated in these trials. Collection of primary outcome data is expected to complete in Dec 19, Jan 16 and Jan 18 [2,3].