Gene therapy for the blood disorder hemophilia A offers a lot of promise for patients (not to mention a lot of cash for pharma companies). But new findings on the way liver cancer is formed have researchers concerned about potential side effects from the treatment.
In a study published Dec. 7 in Molecular Therapy after running online in mid-October, scientists from Sanford Burnham Presbys in La Jolla, California, described how they found a direct link between misfolded proteins that may be produced by hemophilia A gene therapy and liver cancer.
“When misfolded proteins accumulate, it puts a lot of stress on cells, and this is at the core of many diseases including cancer,” Randal Kaufman, Ph.D., the study’s corresponding author, said in a press release. “Gene therapy for hemophilia could transform the way we care for people with this disease, but the effects of protein misfolding on [liver cells] need to be considered to ensure the safety and durability of these treatments over time.”
Patients with hemophilia A don’t make enough clotting factor VIII due to an inherited genetic mutation. Gene therapies like BioMarin Therapeutics’ Roctavian replicate that process by inserting a gene called B domain-deleted factor VIII, or BDD-FVIII, into liver cells to induce factor VIII expression.
Gene therapy is meant to negate the need for protein replacement therapy, a lifelong treatment of infusions of the missing protein. The inefficiency and expense of that treatment was enough to justify Roctavian’s $1.9 million price tag in the eyes of the cost watchdog Institute for Clinical and Economic Review.
But while the treatment’s cost may be warranted, it’s not without drawbacks. Inserting the BDD-FVIII gene causes stress in the cell, increasing the risk that the factor VIII protein it expresses will wind up misfolded, according to previous work by the Sanford Burnham Presbys researchers. In their new study, they found that levels of misfolded factor VIII corresponded to liver cancer development in mice, specifically those who were fed a high-fat diet.
The researchers split the mice into different groups and injected their tail veins with a plasmid containing DNA for either BDD-FVIII—the same gene that’s used in hemophilia A gene therapies—or N6-FVIII, a different factor VIII-producing gene that misfolds less frequently. A control group was injected with DHFR, a protein that doesn’t tend to misfold.
One week later, the scientists started all the mice on a high-fat diet, continuing the experiment for 65 weeks. At the end of the study period, all 10 mice in the BDD-FVIII group developed liver tumors, compared with just over half of the 12 mice that received N6-FVIII DNA. None of the controls got cancer.
Other studies on the risks of gene therapy and cancer have focused on the viral vector that’s used to carry the gene to the cell. In this case, the scientists used DNA plasmids, eliminating the vector as a possible factor.“Hence, protein misfolding contributes to risks related to gene therapy independent of the viral vector,” the researchers said in a video abstract accompanying the paper.
Cancer has popped up in clinical trials for gene therapies treating hemophilia A, albeit not liver cancer specifically. In September, BioMarin reported that a patient in a phase 3 Roctavian study developed leukemia, though it said the cancer was “consistent with expected rates” of cancer in hemophilia patients and determined that it was unrelated to the therapy. The company also saw a case of salivary gland cancer in November 2021 during their phase 1/2 trial. This cancer wasn’t related to the therapy either, according to BioMarin.
Roctavian has been cleared for sale in Europe. BioMarin is hoping for an FDA greenlight in March 2023, though the agency has pushed back its approval timeline already and may do so again after requesting a look at the company’s manufacturing site and long-term phase 3 data.
In addition, Pfizer and Roche’s Spark Therapeutics unit are developing hemophilia A gene therapies. Spark’s drug, SPK-8011, is in phase 2 trials, while Pfizer’s asset—a collaboration with Sangamo Therapeutics—is in phase 3.
Neither Pfizer nor Spark has reported cancer among trial participants, and again, the only cancers that came up in the Roctavian trials were deemed unrelated. There were no liver cancer reports in the animal studies the companies conducted, either, including those in non-human primates.
But as Glenn Pierce, M.D., Ph.D., and Aras Mattis, M.D., Ph.D., explained in a commentary that ran in Molecular Therapy alongside the Sanford Burnham study, that could have something to do with the way the companies’ studies were designed. They were carried out on small populations, and it hasn’t been long enough since the therapy was infused to tell whether there will be long-term side effects.
There were also no controls for diet, which is key to liver cancer development.
“Non-human primate studies have all been negative for hepatocellular carcinoma but are relatively short-term and do not take into account the substantial rates of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in individuals consuming Western diets, which are independent risk factors for (liver cancer),” Pierce and Mattis wrote.
Ultimately, the Sanford Burnham researchers’ goal is to develop safer gene therapies for hemophilia A, they said, as well as to encourage companies to monitor patients for side effects.
Fierce Biotech Research reached out to the FDA about the relevance of the Sanford Burnham team’s latest research, and the agency noted that it does not comment on specific studies but that it does review peer-reviewed journals for important information. When Fierce Biotech Research contacted Pfizer and Sangamo for comment, Pfizer noted that it cannot comment on the data, since it is an independent study.
Spark was not able to respond to a request for comment by press time, while BioMarin did not respond.