AVROBIO has cancelled its Fabry disease (FD) gene therapy, AVR-RD-01, which was expected to launch in H2 2022, after reporting disappointing results from a recent Phase II clinical trial. Previously, the company had reported promising results from earlier clinical trials, so these recent results are unexpected and will prove a significant disappointment to physicians and patients hoping for therapy with significant efficacy and curative potential to enter the market.

AVROBIO stated that it has halted the recruitment of patients into a mid-stage study for FD and is deprioritising its FD research programme. However, they will continue to monitor the results for the 14 FD patients who have received the lentiviral therapy so far. The decision comes following new data that showed five of the most recently treated patients had declines in levels of α-galactosidase A (α-Gal A), a critical enzyme that the lentiviral therapy AVR-RD-01 is meant to produce.

FD is a rare inherited lysosomal storage disorder that results from the absence, or markedly deficient activity, of the lysosomal enzyme α-Gal A. Key opinion leaders (KOLs) interviewed by GlobalData expressed positive sentiment for a gene therapy that has curative potential, especially for the severe FD patients for whom enzyme replacement therapy (ERT) often proves insufficient.  With AVROBIO deprioritising its FD programme, this will likely provide an increased market share for its competitors in the FD gene therapy space, including 4D Molecular Therapeutics’ 4D-310 and Freeline Therapeutics’ FLT-190, both in Phase II.

New data demonstrated that five patients in the Phase II trial for AVR-RD-01 may have become resistant to engraftment. AVR-RD-01 was developed to be administered intravenously and consists of autologous CD34+ hematopoietic stem cells genetically modified with lentivirus to express α-Gal A. AVROBIO had initially hoped that the therapy would lead patients to express functional copies of the α-Gal A gene that encode for the α-Gal A protein. Previously, AVROBIO had found durable engraftment from 13 patients across three clinical trials for AVR-RD-01 leading to the therapy being indicated as having curative potential for FD patients. Furthermore, AVROBIO has stated that there are market and regulatory challenges in the rare disease space that have fueled their decision. AVROBIO had planned a registrational trial for mid-2022 comparing AVR-RD-01 with the ERT Fabrazyme, which gained full approval from the FDA following 18 years on the accelerated approval pathway and AVROBIO had planned to use the accelerated pathway for AVR-RD-01, but Fabrazyme’s full approval has led to a change in these plans.

With the halting of the AVR-RD-01 therapy’s development, significant promise for AVROBIO’s lentivral vector platform remains with the development of AVR-RD-03 for Pompe disease, as well as AV-RD-02 for Gaucher disease, which are in preclinical and Phase I/II stages, respectively. In the wider FD market, 4D Molecular Therapeutics’ 4D-310, an adeno-associated virus (AAV) variant, achieved successful Phase I/II results in a proof-of-concept trial that announced positive results in October 2021 and Freeline Therapeutics’ FLT-190 reported the dosing of their second patient in the MARVEL-1 trial for FD in June 2021. GlobalData predicts that the FD market will likely have a successful gene therapy entering the market before 2030, but the level of efficacy for such therapy remains to be determined. In addition, AVROBIO will require good clinical data from its other candidates in the pipeline to remain a leader in the lysosomal storage disease and wider gene therapy market.

Cell & Gene Therapy coverage on Clinical Trials Arena is supported by Cytiva.

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