Hemophilia B Gene Therapy AMT-061 Unlikely to Have Caused Liver Tumor

AMT-061 (etranacogene dezaparvovec), uniQure’s investigational gene therapy for hemophilia B, likely did not cause the case of hepatocellular carcinoma (HCC) — a form of liver cancer — that led to the program’s clinical hold in December 2020, an investigation has found.

The U.S. Food and Drug Administration (FDA) had put the AMT-061 program on hold after the case of HCC was detected in a participant in the Phase 3 HOPE-B trial, which was testing the gene therapy in people with hemophilia B, a rare subtype of the disease.

Now, a comprehensive investigation, conducted by an independent laboratory and reviewed by leading external experts, has concluded that the adeno-associated virus (AAV) vector used in the gene therapy did not lead to that case of liver cell cancer, David Lillicrap, MD, a professor in the department of pathology and molecular medicine at Queen’s University, in Canada, said in a press release.

“The investigations that have been performed have shown no evidence to suggest that the AAV vector delivered in the HOPE-B study has played a [harmful] role in the hepatocellular cancer that has now been diagnosed in the patient,” Lillicrap said.

AAVs are widely used in gene therapy to deliver the gene of interest to patients’ cells.

AMT-061 uses a modified and harmless version of the AAV variant 5 to deliver FIX-Padua, a highly functional copy of the F9 gene, to people with hemophilia B. The F9 gene is mutated in these patients and impairs the production of a clotting protein called factor IX, or FIX.

Ricardo Dolmetsch, PhD, president of research and development at uniQure, noted other study findings that the patient diagnosed with cancer had chromosomal abnormalities “that are commonly associated with HCC.”

“Taken together, the findings from this investigation strongly suggest that [AMT-061] did not contribute to this case of HCC,” Dolmetsch said.

The company has shared these data with the FDA, he said, and is “prepared to have further communications regarding the status of the clinical hold in the second quarter of 2021.”

“Patient safety will always be our top priority,” said Matt Kapusta, uniQure’s CEO.

“As stated previously, we do not anticipate any impact to the HOPE-B pivotal study or our regulatory submission timeline [for AMT-061] as a result of the clinical hold,” Kapusta added.

Dolmetsch said the company expects to present the data at an upcoming industry conference, although the specific one has not yet been determined.

HOPE-B (NCT03569891) is evaluating the five-year safety and effectiveness of a single into-the-vein injection of AMT-061 in 54 men with moderate to severe hemophilia B. The study is expected to finish in March 2025.

The HCC case was detected during an abdominal ultrasound, which was performed as part of the trial’s routine annual assessment one year following treatment. The tumor was still small enough at the time to be surgically removed, and then was processed for a detailed genetic and molecular analysis.

Results from this comprehensive analysis showed that integration of the viral DNA into the liver cells’ DNA — which could inadvertently cause cancer-promoting mutations — was extremely rare, accounting for only 0.027% of the cells in the patient’s liver sample.

In addition, this integration was found to be randomly distributed across the genome of affected cells, suggesting that none of these viral DNA-containing cells gave rise to identical tumor cells. If the AAV vector had triggered a single liver cell to grow out of control, the viral DNA would have shown up in the same DNA regions in many tumor cells.

“The external lab analyzed more than 220,000 cells from the tissue sample and identified 60 cells with random integration events that have no known association with the development of HCC,” Dolmetsch said.

Further analysis confirmed the presence of genetic mutations commonly associated with HCC and cancer in general in tumor cells, and suggested a pre-cancerous state in the surrounding liver tissue, consistent with several risk factors that predisposed the patient to HCC.

Among the patient’s risk factors were a 25-year history of infection with hepatitis C and B viruses, which mainly affect the liver and are linked to about 80% of HCC cases, evidence of non-alcoholic fatty liver disease, and advanced age. The man also had a history of smoking and of cancer in his family.

Besides HOPE-B, AMT-061’s clinical program also includes a Phase 2b trial (NCT03489291), which is assessing the therapy’s long-term safety and effectiveness in three men with severe hemophilia B.

Previous data from both studies showed that AMT-061 was generally safe and increased FIX activity, controlled bleeds, and prevented the need for prophylactic (preventive) treatment.

uniQure’s hemophilia B gene therapy program, which was all placed on hold after the detection of the HHC case, also includes a Phase 1/2 study (NCT02396342) of the company’s first-generation candidate, AMT-060, of which AMT-061 is meant to be an improved version. Up to five years of follow-up data from its 10 participants also have highlighted a favorable safety profile and promising effectiveness.

Enrollment and dosing have been completed in all three trials.

The company said that all patients in these trials have now undergone abdominal ultrasounds at one year post-dosing, and each will continue to be monitored by their care teams.

No other cases of HCC have been reported among the more than 100 patients who received uniQure’s experimental gene therapies during the past 10 years, including some HOPE-B participants who had a history of hepatitis C and/or B infection.