When it comes to gene therapies, nothing tops the price of CSL Behring’s etranacogene dezaparvovec-drlb (Hemgenix®), approved by the US Food and Drug Administration (FDA) in 2022 to treat hemophilia B. It retails for $3.5 million—making it the highest-priced medication in world history.
But the therapy can’t help most people with hemophilia, a disease known since antiquity. That’s because the one-time, adeno-associated virus (AAV) vector-based infusion is aimed specifically at the 10% of males with hemophilia who have hemophilia B, and only those who don’t have inhibitors, or neutralizing antibodies, to their missing clotting factor that would render the medicine ineffective.
This is where GeneVentiv Therapeutics comes in.
“Patients with inhibitors are left behind, and they have no hope of benefitting from gene therapies now in development,” said Damon Race, the company’s president and CEO. “We’re giving all those patients with inhibitors hope.”
Meeting the Needs of More Patients
Race spoke to Rare Disease Advisor from GeneVentiv headquarters in Raleigh, North Carolina. A biotech executive with 25 years of commercial pharmaceutical and investment experience, Race said he launched GeneVentiv after vetting 30-40 promising ideas around which to build a company.
In 2021, the FDA granted Orphan Drug Designation to GeneVentiv for its investigative product, code-named GENV-HEM.
“As I looked through university assets that were ready for technology transfer to a startup, I found this one,” he said. “It’s the first gene therapy that can address the needs of a certain group of hemophilia patients for whom gene therapies in development wouldn’t work.”
Overall, in the developed world—which includes the US, European, Japanese, and Australian markets—some 32,000 of the 150,000 people with hemophilia, either A or B, have inhibitors, Race said. As he explained, the deficient clotting factor in hemophilia A is factor VIII, and people with hemophilia B cannot make factor IX.
“The inhibitor population in hemophilia A is much larger,” he said. “Current gene therapies in development enable the body to produce the clotting factor that the patient doesn’t make. Now, if you have neutralizing antibodies to your missing clotting factor, then your immune system would simply neutralize the very clotting factor that the gene therapy has provided instructions to your body to make. It wouldn’t do any good.”
That’s why patients with neutralizing antibodies are routinely excluded from clinical trials of those products, he said, adding that meanwhile, “hemophilia patients must take extreme care in their daily lives. They must avoid cutting themselves or they may bleed uncontrollably.”
The current standard of care is administration via infusion, several times a week, of their missing clotting factor. What makes GeneVentiv’s approach different is its expression of an activated factor V variant, known as Va.
GENV-HEM is an AAV vector containing a transgene encoding for Va. According to Race, GENV-HEM is the first gene therapy treatment in development to treat both hemophilia A or B in patients with or without inhibitors.
According to the GeneVentiv website, “instructing liver cells to produce additional Factor Va can restore the clotting cascade without the risk of thrombosis.” A one-time infusion for hemophilia that uses the AAV8 vector containing an optimized gene encoding for Factor Va, GENV-HEM improves homeostasis in patients with factor VIII or IX deficiency regardless of the presence of any clotting factor inhibitors, Race said.
“Our therapy allows us to bypass any of the missing factors and any neutralizing antibodies to those factors. That’s what makes us universal,” Race said in explaining the therapy’s mechanism of action. “When we administer the gene therapy, it increases your expression of the active form of factor V. That allows us to convert prothrombin to thrombin, which you need to restore normal clotting.”
No one else is working on an activated factor V in a gene therapy context, according to Race. “That’s one good thing about having a patent,” he said.
Human Trials on the Horizon
In June 2022, GeneVentiv received a $250,000 strategic loan from the North Carolina Biotechnology Center in Research Triangle Park, located just outside Durham. The company is also working closely with the National Bleeding Disorders Foundation, formerly the National Hemophilia Foundation.
At present, GeneVentiv is in the late stages of preclinical studies that could lead to the FDA approving an Investigational New Drug (IND) application to begin human trials.
“We need to raise a Series A round of financing in order to undertake the gene therapy work for IND. That’s a significant barrier to many companies because of the very high cost of manufacturing,” he said. “Hopefully, that cost will continue to come down.”
A phase 1 or phase 2 clinical trial for only 15 patients costs $1 million to $2 million per patient, plus another $12 million or more just to manufacture the material.
“All told, you can very quickly get to $30 million just to complete that phase 1/2 clinical trial and your IND work,” he said. Yet the rewards could be substantial. “Take $3.5 million, and just to make it easier for math’s sake, put it at $3 million for a single infusion and multiply that by just the core niche of inhibitor patients at 32,000.”
Savings for the health care system could also be significant.
“Treating these 15 patients over the course of a lifetime is about $25 million [for current protein replacement therapy],” he said. “At a cost of $3 million for the infusion, you still have an opportunity to not only tremendously improve the lives of the patients, but also to save the healthcare system about $22 million.”
Preventing Irreversible Joint Damage
GeneVentiv is also working on a second gene therapy, this one for hemophilic arthropathy, which causes permanent and irreversible joint damage. The disease affects half of those with hemophilia as a consequence of repeated bleeding into the joints.
“In the Western world, patients have access to their factor replacement therapy they need. In the developing world, not so much. They bleed into the joints, and then the blood has nowhere to go. It accumulates like a rusty sludge or ooze,” Race said. “Gradually, it erodes the lining of the joints, and then it begins to erode into the bones. Their joints become stiff and you get kids with knees and other target joints the size of basketballs. It’s absolutely heartbreaking to see.”
Race said he’d like to be able to get costs down enough to make a gene therapy available that would prevent this kind of damage to joints while patients are still young.
“The space we’re injecting the gene therapy into is so much smaller relative to systemic administration than we need in just a hemophilia patient,” he said. “While we wouldn’t be able to cure their hemophilia—and it would still be cost-prohibitive to do so—we could at least prevent the damage to their joints that limits mobility over their lifetime.”