NADPH oxidase gene therapy


New Medicines

X-linked chronic granulomatous disease (CGD)


New molecular entity
Orchard Therapeutics
Orchard Therapeutics

Development and Regulatory status

Phase II Clinical Trials
Phase II Clinical Trials
Phase II Clinical Trials
Feb 20Orchard is planning a further clinical trial of OTL-102 for X-CGD [7].
Feb 20Has orphan drug status in US [7].
Apr 19According to company pipeline, OTL-102 is still at proof-of-concept stage [5].
Apr 19Has orphan drug status in EU [3].
Dec 18Orchard plans to discuss clinical development of the OTL-102 program in patients with X-CGD with regulatory authorities in 2019 [3].
Dec 17Orchard enters into a licensing deal with Genethon to develop gene therapy for X-CGD. Under the terms of the agreement, Orchard has obtained an exclusive option to license Généthon’s rights and know-how related to the G1XCGD lentiviral vector, including rights to the data generated under ongoing clinical trials supported by Généthon in the US and in Europe to assess the safety and efficacy of CD34+ autologous stem cells transduced with G1XCGD for the treatment of X-CGD [3].


Autologous CD34+ cells transduced with lentiviral vector containing XCGD gene
CGD is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is rare (prevalence approximately 1 in 250,000). CGD is caused by pathogenic variants in one of five genes that encode the subunits of phagocyte NADPH oxidase: biallelic pathogenic variants in CYBA, NCF1, NCF2 and NCF4 cause autosomal recessive CGD (AR-CGD), and mutation of CYBB causes X-linked CGD [1]
X-linked chronic granulomatous disease (CGD)
Intravenous infusion

Trial or other data

Mar 20PI/II trial (NCT01855685) has finished recruiting. Collection of primary outcome data now due to finish Sep 22 [9].
Feb 20Orchard reports that OTL-102 is currently being investigated in two ongoing investigator-sponsored proof of concept clinical trials in the US and Europe, with target enrolment of 10 patients in a clinical trial sponsored by UCLA in the US and target enrolment of five patients in a clinical trial conducted by GOSH in Europe. The clinical trial sites include Boston Childrens Hospital, the NIH, and UCLA in the United States, and GOSH and The Royal Free Hospital in London. Manufacture of the drug product occurred at each of these sites using the same vector. As of July 2019, nine patients have been treated in the clinical trial in the US, five of which were treated with a fresh product formulation and four of which were treated with a cryopreserved formulation. Further, three patients have been treated in the clinical trial in Europe, one of which was treated with a fresh product formulation and two of which were treated with a cryopreserved product formulation. One patient has been treated in a compassionate use program in Europe with a cryopreserved product formulation. In the future, we expect to treat additional patients in this trial with a cryopreserved formulation of OTL-102. Patients enrolled in these trials have advanced and severe stages of X-CGD [7].
Dec 19NCT01855685 - UK trial sites: UCL, Royal Free, Great Ormond Street [6]
Apr 19PI/II trial (NCT01855685) is recruiting & is due to complete collection of primary outcome data in Mar 20 [2].
Dec 18Orchard presents clinical proof-of-concept data from an ongoing academic clinical trial evaluating OTL-102 at ASH 2018. The data are from seven patients (ages 2-27) severely affected by X-CGD. Six of the seven evaluable patients showed persistence of 16-46% (mean 30.2%) functioning neutrophils 12 or more months after treatment, which prior publicly available data suggests is above the 10% minimum threshold necessary to show potential clinical benefit and restoration of both biochemical function and immunity. Two additional patients were treated but died within three months of treatment from complications deemed by the investigator to be related to pre-existing disease-associated comorbidities due to advanced disease progression. These results are the first demonstration that ex vivo autologous hematopoietic stem cell gene therapy has the potential to produce sustained corrected neutrophil function for 12 months or more in severely affected X-CGD patients [4].
Feb 18PI/II trial (G1XCGD; NCT02234934) re-starts. The trial suspended for participant recruitment in Oct 17, as it was under review for a serious adverse event [3].
Jan 15PI/II proof of concept trial to evaluate the safety, feasibility and efficacy of NADPH-oxidase gene therapy in patients with X-linked chronic granulomatous disease starts (G1XCGD; NCT02234934). It will enrol 10 patients, aged 23 months and older, in the US [2].
Feb 13PI/II trial to investigate the NADPH oxidase gene therapy in patients with X-CGD starts (G1XCGD.01; NCT01855685). It will enrol approximately 5 patients in the UK, France, Germany & Switzerland. The trial has been withdrawn in Germany and Switzerland, where it was previously ongoing. The trial was being conducted in collaboration with the Great Ormond Hospital in London, the Necker Hospital for Sick Children in Paris, the University Hospital in Frankfurt and the Children´s Hospital of Zurich. This collaboration, referred to as Net4CGD, is funded by the European Commission under a programme coordinated by Genethon [2,3].