NEW YORK – Results from Pfizer’s BENEGENE-2 Phase III trial affirm the company’s new gene therapy for hemophilia B leads to fewer bleeds for most patients, though researchers are unsure why some stop responding to the one-time treatment.
In the New England Journal of Medicine last week, researchers published data from the open-label Phase III trial, which have underpinned recent regulatory approvals for Pfizer's Beqvez (fidanacogene elaparvovec) in the US, Canada, and Europe. A single dose of Beqvez was better at reducing bleeds than the typical treatment, according to the published paper.
"The findings of this Phase III study showed that fidanacogene elaparvovec had a favorable benefit-risk profile providing efficacy at one of the lowest doses of AAV-based gene therapy studied for hemophilia B," the study authors wrote of the gene therapy, a one-time treatment for men with moderate to severe forms of hemophilia B.
Investigators enrolled 45 adult men across 13 countries with the condition into the trial, each of whom received a single intravenous infusion of Beqvez. In a lead-in period before treatment, patients also spent at least six months receiving routine prophylactic infusions of factor IX replacement therapy, which is the standard treatment for hemophilia B.
Patients with hemophilia B, a rare and hereditary bleeding disorder, have certain mutations in the F9 gene that result in lack of factor IX, a protein that helps blood to clot. Since it is an X-linked recessive disorder, most hemophilia B patients are male.
Hemophilia B is a good opportunity for gene therapy because it's a monogenic disorder, said Adam Cuker, director of the comprehensive hemophilia and thrombosis program at Penn Medicine, and existing treatments have a high treatment burden and provide only partial protection against bleeding. Cuker was the site lead for the BENEGENE-2 trial at Penn Medicine and the lead author on the NEJM paper.
Hemophilia B is also a serious disease with significant consequences if left untreated, he added.
Beqvez is designed to treat the condition by using an adeno-associated virus (AAV) vector to deliver an F9 transgene that encodes a high-activity variant of factor IX, so that patients can produce the protein themselves.
Cuker and colleagues within the BENEGENE-2 trial analyzed patients' annualized bleeding rate and compared the rate after gene therapy treatment against the rate during the lead-in period.
They found that the average annualized bleeding rate decreased from 4.42 before gene therapy to 1.28 in the period between week 12 through month 15 post-treatment, representing a decrease of 71 percent. The clinical trial's primary endpoint was to show Beqvez was noninferior to typical treatment, but it found the gene therapy proved superior to factor IX replacement therapy.
Twenty-nine of the 45 patients did not have any bleeding episodes through 15 months post-treatment, compared to 13 patients during the lead-in period. The average annualized rate of factor IX infusions dropped by 92.3 percent after the gene therapy, and annualized total factor IX consumption was reduced by 92.4 percent.
As patients continue to be monitored for 15 years post-treatment in a follow-up study, Cuker said he's interested in better understanding the durability of response. "Most participants have had stable factor IX expression to date," he said. "But our goal with this treatment is lifelong response, and we need long-term follow-up to determine whether that goal has been met."
The gene therapy did not work for everyone over the long term, however.
Two years after receiving Beqvez, 82 percent of participants sustained factor IX levels above 5 percent, representing normal levels or mild hemophilia. Seven of those patients had factor IX activity above 40 percent, which researchers said put them at a normal level.
However, six patients resumed factor IX replacement therapy within 15 months of receiving the gene therapy. Five returned to factor IX prophylaxis due to low factor IX activity, while one patient did so due to the frequency of bleeding episodes.
All six of these patients had responded to the gene therapy and initially had factor IX levels higher than at baseline, according to the study authors. Researchers did not identify factors to proactively predict this subset of patients who lost response to the gene therapy.
"All of these individuals initially responded to fidanacogene elaparvovec, but subsequently had a decline in factor IX expression," Cuker said. "More research is needed to identify the mechanism and predictors of loss of response and, most importantly, how to prevent loss of response in future patients."
In terms of safety, there were not any adverse events that led to study discontinuation or death, nor infusion-related serious adverse events.
The most common adverse event associated with Beqvez treatment was an increased level of aminotransferase, which can indicate liver damage and was related to an immune response, which was observed in 53.3 percent of patients. This reaction can result in the gene therapy not working if it's left untreated.
Most of the cases were mild and asymptomatic, according to study authors, and patients were given glucocorticoids to treat the immune reaction. In total, 28 participants received glucocorticoids either because of increased aminotransferase levels or decreased factor IX levels, and six of these patients were those that later resumed prophylaxis.
"Further work is needed to address the range of responses seen in our study and in most hemophilia gene-therapy trials and to examine why some participants resumed prophylaxis," study authors wrote in the paper.
The BENEGENE-2 trial was funded by Pfizer, which licensed Beqvez from Spark Therapeutics in December 2014.
In April, after receiving approval from the US Food and Drug Administration, Pfizer set a wholesale acquisition cost of $3.5 million for Beqvez, which it said takes into account the gene therapy's benefits for "patients, healthcare systems, and society." The company estimated that the annual costs per patient for standard hemophilia B treatment can be as high as $1.1 million, making Beqvez's long-term bleed protection more cost-effective over time. Pfizer also said it would launch a warranty program for payors, under which the company will tie potential refunds to the durability of patients' responses to Beqvez.
Beqvez is the second hemophilia B gene therapy on the market, following CSL Behring's Hemgenix (etranacogene dezaparvovec), which also has a $3.5 million price tag.
When discussing treatment options with patients, there are a host of factors to consider, including effectiveness, safety, convenience, cost, and possible impact on lifestyle, Cuker said. "There are more and better treatment options for hemophilia B than there have ever been before, and the list continues to grow," he added.
In addition to demonstrating gene therapy's ability to reduce bleeds in most patients, data from the BENEGENE-2 trial also suggest an improvement for patients' quality of life, noted Margaret Ragni, director of the Hemophilia Center of Western Pennsylvania, who was not involved in the clinical trial. Patients who no longer have to take factor IX prophylaxis, for example, don't have to worry about coordinating these infusions or the risk of frequent bleeding episodes.
This study "confirms the life-changing impact of gene therapy on hemophilia B," Ragni said. "It's very exciting. We have something that is better than current therapy."
However, she noted that many patients won't be a fit for Beqvez. The product is only indicated for patients who don't have neutralizing antibodies to the AAV serotype Rh74var capsid that is used to deliver the gene therapy, which physicians are encouraged to test for before treating patients, according to the product's FDA label.
Within the BENEGENE-2 study, of 316 men with moderate to severe hemophilia B who were screened for entry into the lead-in study, 59.5 percent were not eligible because they tested positive for these anti-AAV neutralizing antibodies.
The FDA label also specifies that the safety and effectiveness of Beqvez haven't been established for patients with factor IX inhibitors, which can develop in patients who have taken factor IX replacement therapy for a long time and whose bodies no longer accept the factor IX therapy.
Ragni said she would like to see advancements in the field that enable gene therapy to be an option for more patients, as well as research into how to predict which patients will respond well to it and how best to treat, or potentially even avoid, immune reactions. "The hope is that, in the future, we'll have enough options and enough information [to predict] who's going to do well with which gene therapy," she said.