Clinical trial of gene therapy for hemophilia B AMT-061

A few days ago, UniQure announced that the FDA has lifted the suspension of clinical trials of the gene therapy AMT-061 for hemophilia B.

In December 2020, after a patient treated with the research gene therapy AMT-061 was diagnosed with hepatocellular carcinoma (HCC), the FDA asked UniQure to temporarily shelve the HOPE-B clinical trial to further investigate whether the AAV virus itself caused it. The patient developed cancer and the company was asked to provide sufficient evidence to convince the FDA that the trial can continue. The company currently said that after the FDA's evaluation, it believes that the current trial data can resolve all doubts and questions related to the patient.

Last month, UniQure announced the results of its investigation into the HCC incident. The report showed that the relationship between the gene therapy and the patient's cancer was not clear. Studies have shown that the integration of AAV vectors produced by AMT-061 treatment into patient tissue samples is extremely rare, accounting for only 0.027% of the sample cells. The AAV vector is evenly distributed in the patient's genome, and "there is no evidence that clonal expansion or any dominant integration has occurred in the patient."

In addition, the aforementioned AMT-061 subjects with liver cancer have a variety of risk factors related to HCC, including a 25-year history of hepatitis C and hepatitis B. Relevant evidence shows that chronic infections of hepatitis B and C are associated with approximately 80% of cases of hepatocellular carcinoma. In addition, the genome sequencing of the patient's tumor also reached a supporting conclusion that the patient originally had a number of common gene mutations highly associated with HCC and was not related to the integration of the AAV vector involved in gene therapy AMT-061.

The report also showed that "analysis of tumor gene expression and adjacent tissues showed that the subject's tumor is in a precancerous state, which is consistent with the conclusion that the patient has risk factors for HCC."

UniQure's gene therapy candidate drug AMT-061 is a gene therapy based on adeno-associated virus 5 (AAV-5). Prior to this, AMT-061 was granted Breakthrough Drug Designation (BTD) by the US FDA and Priority Drug Designation (PRIME) by the European Union EMA. The vector contains a gene cassette with a patented Padua IX variant (FIX-Padua).

HOPE-B is an open-label, single-dose, single-arm, global clinical trial. The subjects are mainly adult male patients with moderate or severe hemophilia. All patients need to undergo preventive conventional FIX replacement therapy before entering clinical trials, and patients with neutralizing antibodies (NAb) to AAV5 are not excluded from the trial.

Previous trial data showed that AMT-061 promoted the production of FIX in patients in almost all trial participants. The need for FIX replacement therapy in all patients was reduced by 96%. Past clinical evidence shows that AMT-061 has the potential to achieve the results of functional therapy, as well as the hope that gene therapy will be "once and forever".

Huntington's disease gene therapy VY-HTT01 clinical trial

After lifting the clinical trial suspension of uniQure's type B gene therapy, the FDA also lifted the clinical suspension of Voyager Therapeutics's Huntington's disease (HD) gene therapy VY-HTT01.

The suspension of the VY-HTT01 clinical trial project was due to chemistry, manufacturing and control (CMC) issues. One year after Sanofi's Genzyme withdrew from the cooperation, the FDA's clinical suspension marked a miserable period for the project.

But now, the FDA has lifted the restrictions on VY-HTT01. According to a statement from Voyager Therapeutics, the company may continue the planned Phase 1/2 VYTAL clinical trial, which will begin testing in early-stage HD patients this year. The FDA's decision is based on Voyager Therapeutics' clarification of the CMC issue. The company said, "This decision was made after a comprehensive review of the CMC information previously submitted to the FDA."

Huntington's disease is a progressive brain disease caused by defective genes, usually fatal after about 20 years. The disease usually starts in young to middle-aged people. The main cause of HD is a mutation in the huntingtin gene, which produces a toxic mutant huntingtin protein (mHTT). Currently, there is no disease-modifying therapy for HD.

Just last month, a once promising HD project from Singapore genetic medicine company Wave Life Sciences was abandoned. The project used a different method, namely antisense oligonucleotides, to prevent the production of mHTT. Data from two phase 1/2 clinical trials show that there is no evidence that the two drugs in this project (WVE-120102, WVE-120101) have a dose response at the tested dose level, and pharmacokinetics (PK) The model shows that the additional dose increase is unlikely to reach the drug concentration required for mHTT knockout, which is considered to be unable to bring therapeutic benefits to HD patients.

A few days ago, Roche and Ionis also stopped the research work of tominersen (also known as IONIS-HTTRx, RG6042), which is an antisense RNA drug designed to reduce the production of all types of huntingtin proteins (HTT, including mHTT). However, the low efficacy hindered the further development of the project.

Reference source: 1. FDA Officially Lifts Hold on UniQure’s Promising Hemophilia B Therapy 2. FDA says Voyager can trek on as it removes trial hold for Huntington's gene therapy test