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Special Report: The Frontier of Bleeding Disorders Treatment

14th Workshop on Novel Technologies and Gene Transfer for Hemophilia highlights tremendous progress and the challenges ahead
Author: Sharon Reynolds

On February 23 and 24, an international group of researchers from universities, industry and government gathered in Washington, DC, for the National Hemophilia Foundation’s (NHF’s) 14th Workshop on Novel Technologies and Gene Transfer for Hemophilia.

This year’s workshop was the longest since the gatherings began in 1996, reflecting both the groundbreaking progress in hemophilia treatments made in the last several years and the need for collaboration to address barriers to bringing potentially curative treatments to the clinic.

“The workshop’s ability to merge diverse disciplines that don’t normally talk to each other has been very effective over these last 22 years,” says Glenn Pierce, MD, PhD, a consultant and member of NHF’s Medical and Scientific Advisory Council (MASAC) who co-chaired the conference along with David Lillicrap, MD, of Queen’s University in Ontario, Canada. Pierce says such collaboration has helped speed the development of promising new technologies.

Gene therapy for hemophilia A

One highlight of this year’s workshop was a report of updated results from an early clinical trial of the first gene therapy for hemophilia A.

Previous research has shown gene therapy’s ability to boost clotting factor levels close to a normal range for patients with hemophilia B. But until recently, hemophilia A had proved trickier to tackle.

One reason is the relatively large size of the factor VIII (FVIII) gene that is defective in hemophilia A, which makes it difficult to pack inside the modified viruses used to deliver gene therapy. Researchers have thus identified and cut out unnecessary parts of the FVIII gene sequence, enabling it to be squeezed inside the delivery virus.

A beneficial side effect of this tweaking is that scientists can actually improve the FVIII gene to make it better than the natural version at producing clotting factor, explained Andrew Davidoff, MD, of St. Jude Children’s Research Hospital, in a presentation at the workshop.

At the previous workshop, in 2016, an FVIII gene therapy developed by BioMarin Pharmaceuticals, called BMN-270, had shown promising short-term follow-up results in nine volunteers. This year, BioMarin presented updated results from 13 participants. Seven received a high dose of the gene therapy and saw factor levels rise to an average within the normal range—over 50%—between five and 16 months after treatment. Six participants receiving a lower dose saw factor levels rise more slowly, but levels were approaching normal range by the time of the workshop.

Both doses eliminated the occurrence of spontaneous and traumatic bleeds once FVIII activity levels rose above 5%, and all participants discontinued prophylactic FVIII use. “We’re really excited about seeing this,” said Benjamin Kim, MD, senior medical director at BioMarin, who presented the results.

Also at this year’s workshop, Spark Therapeutics presented information from a trial of its FVIII gene therapy, called SPK-8011. Spark is still recruiting participants, but the first four people who received the treatment showed FVIII levels between 9% and 13% of normal, which eliminated spontaneous bleeding even in the absence of prophylaxis. The trial is continuing, with participants receiving higher doses of the gene therapy to further increase factor expression.

A third hemophilia A gene therapy trial, developed by St. Jude Children’s Research Hospital and University College London, has just begun, with one participant having received the first of three planned dose levels at the time of the workshop.

No patient in any of the three trials presented had developed inhibitors, antibodies produced by the body that misidentify factor replacement products as harmful invaders and destroy them before they can work.

Despite the fact that other studies have not yet matched the BioMarin results for hemophilia A, “at the 2016 workshop, only one group was in the clinic with factor VIII, and now we’ve got four clinical trials,” including one that was not presented at the workshop, says Pierce.

“So that’s very encouraging.”

Sustained factor IX expression

Ongoing gene therapy trials for hemophilia B brought encouraging longer-term data to the 2018 workshop. Most promising was one-year follow-up results from Spark Therapeutics’ SPK-9001, in which 10 out of 11 men who received the treatment maintained factor IX (FIX) levels within a range that would be considered curative, and all 11 discontinued prophylactic treatment.

The Spark gene therapy incorporates a naturally occurring mutant form of the FIX gene, which produces about seven times the normal activity of clotting factor. Other companies at the workshop expressed interest in changing FIX therapies under development to use this “hyperactive” version of the gene.

Another FIX gene therapy from St. Jude Children’s Research Hospital and University College London was the first to show successful FIX expression, although factor levels in that trial were not high enough to be considered curative. However, at the 2018 workshop, the research team reported sustained expression of low levels of FIX for up to eight years after administration. This is encouraging for the potential durability of gene therapy, says Pierce.

Researchers from two other hemophilia B gene therapy trials shared their experiences of relative failure. In one of these trials, immune responses destroyed the cells containing the gene after it was delivered to the liver, despite the administration of steroids. In the second trial, all but one participant lost promising factor expression over time, again after inflammation in the liver.

During discussions at the workshop, researchers put their heads together to figure out why this might have happened in some trials but not in others, and how to prevent the same problems from occurring again.

If pharmaceutical companies would be willing to share with other companies and with academic researchers some of the information regarding how their treatments are constructed, that might help developers avoid “barking up the wrong tree,” when looking for a solution, said John Chapin, MD, medical director at Shire PLC, who presented one of the unsuccessful trials.

Hope and expectations

BioMarin has launched a phase III clinical trial of its FVIII gene therapy. Spark, which has partnered with Pfizer to bring its FIX gene therapy to the clinic, hopes to follow within a year, says Pierce. Phase III trials are the last step before applying to the Food and Drug Administration (FDA) for approval to market a treatment in the United States.

“If the phase III trials confirm results from the early trials, we could potentially see a gene therapy product approved by 2022. But it’s important to say if,” cautions Pierce. “With a new technology that is very different from everything else that’s been done before, it will take some time to work out the variables.”

Among those variables are issues of cost, and how payers will calculate the relative benefit of gene therapy compared with other factor replacement products. Mark Skinner, JD, a MASAC member, presented an overview of the ongoing coreHEM initiative, which is working with researchers, patient advocates and industry partners to develop a core set of outcomes that can be used in the future to compare the results from gene therapy trials with each other and with older, established therapies.

Regardless of cost issues, an approved gene therapy will not immediately be available to everyone with hemophilia A or B, adds Pierce. None of the current trials have tested the treatments in adolescents or children, for example, whose rapidly growing livers may pose an additional hurdle. Questions about how to manage the immune system’s variable response to some gene therapies also remain unanswered.

Immunity and tolerance

One challenge to using gene therapy in diverse groups of people with hemophilia is the virus currently used to deliver the treatments. Many strains of this virus, called adeno-associated virus (AAV), exist naturally in the wild. It does not cause illness, but many people have already been exposed to it during their lifetime.

Exposure to AAV causes the body to produce antibodies, which could then recognize and attack the modified form of the virus that’s used to deliver gene therapy, making the treatment ineffective. The clinical trials presented at the workshop had to exclude many interested volunteers because they had existing antibodies to AAV, and this exclusion will extend to future patients.

In addition, even if a person does not have pre-existing antibodies to AAV, they will develop them after gene therapy. Therefore, at this time, administration is a one-shot chance. While the effects of gene therapy appear to be long-lasting, research done to date cannot tell whether the effects will last for a lifetime. If re-administration does turn out to be required, it cannot be done using the same delivery system.

“Right now we have several examples of how gene therapy for hemophilia can not only work but deliver meaningful results. So now, how can we deliver these results consistently in patients?” asked Federico Mingozzi, PhD, chief scientific officer at Spark Therapeutics, during one of his several talks on immunity.

New research presented this year looked at ways to circumvent limitations posed by the immune system. Some of these—such as engineering a different type of virus called a lentivirus, which very few people have prior exposure to—to carry gene therapy are getting close to the first human trials. Others are intriguing but will require more laboratory work before first-in-human testing, commented Mingozzi, including several nonvirus-based gene delivery systems.

Researchers are also looking at engineering AAV so it can hide from circulating immune cells. Similar methods for tricking or manipulating the immune system are being examined to address the problem of inhibitor development, including ways to train immune cells to ignore recombinant clotting factors.

Novel therapies poised to make significant impact

Gene therapy isn’t the only technology poised to change hemophilia treatment in the coming years. Many therapies presented at the workshop, for example, are targeting methods other than factor replacement. Such treatments are especially important for patients who develop inhibitors to factor replacement products.

One novel treatment, emicizumab (now on the market as HEMLIBRA®) from Genentech, has progressed from a small clinical trial in Japan presented at the 2016 workshop to large ongoing and completed phase III trials enrolling more than 300 adults and children. In November, the FDA approved HEMLIBRA for prophylactic use in the United States in patients with hemophilia A and inhibitors to recombinant FVIII.

Emicizumab replaces the function of FVIII in the clotting cascade, but its structure does not resemble that of the factor, so it is not recognized by inhibitors. Added benefits for patients are that emicizumab only needs to be taken once a week, or even less often, and it’s given subcutaneously—under the skin—and not by infusion into a vein.

In data from the ongoing trials presented at the workshop, reductions in bleeding of around 90% were seen. Newer trials of the drug are now testing whether the time between injections can be extended even further, out to even once a month, and how well the drug works in patients without inhibitors. If approval is extended to more groups of patients, “that’s a drug that is going to make a significant impact in hemophilia A,” says Pierce.

Another novel subcutaneous therapy presented at the 2016 workshop was fitusiran. Developed by Alnylam Pharmaceuticals, it has also progressed to larger clinical studies. In 2017, one trial was stopped temporarily because of the death of a patient. Since then, to reduce the likelihood of dangerous clotting events, Alnylam has developed guidelines for on-demand bleed management when using fitusiran, said Kate Madigan, MD, senior medical director of clinical research at Alnylam, at the workshop. (Fitusiran causes the expression of more thrombin, a protein in the clotting cascade, independent of both FVIII and FIX.) The large, randomized trials of fitusiran that could eventually lead to FDA approval for both hemophilia A and B are currently enrolling participants.

Another new class of drug in early human trials is designed to block a protein in the clotting cascade called TFPI. Like fitusiran, such drugs could potentially work across multiple types of hemophilia. Other research presented at the workshop showcased technology in development that extends the life of FVIII replacements to a week or more. These new products bind protective molecules to recombinant FVIII, which prevent the body from breaking the factor down and allow it to circulate longer in the bloodstream.

Holding out for a cure

As the workshop drew to a close, researchers and doctors had the opportunity to hear from two members of the hemophilia community about what they need and want from novel therapies.

One perspective was provided by Brendan Hayes, a mother of two adult sons with severe hemophilia A. The other point of view came from Radoslaw (Radek) Kaczmarek, PhD, a young hemophilia researcher from Warsaw, Poland, who has severe hemophilia A.

Patients tend to have an “if it’s not broken why should I fix it?” perspective on switching therapies, commented Hayes, a government relations specialist at NHF. Her sons are able to live the active lives they want on standard prophylactic factor treatment—even running a marathon or participating in high-intensity CrossFit training—and thus they would be reluctant to switch to a new therapy just for the sake of switching, she said during the session.

Kaczmarek said that while longer-lasting treatments might have appeal for some, he would be more interested in future treatments that would provide less of a drop-off—a trough—in factor levels over time. Hayes pointed out that a parent’s perspective might differ: “When my children were younger, if I only had to do infusions twice a week on each as opposed to three times a week, that’s something I would have been really interested in,” she said.

Both Hayes and Kaczmarek acknowledged that the relative reliability of current treatments makes the bar for considering gene therapy rather high. Nothing less than a cure would tempt Kaczmarek or Hayes’ sons. “It would have to provide a factor level that would allow me to go on living without any replacement therapy needed whatsoever,” said Kaczmarek.

Hayes also thinks questions about the durability and long-term safety of gene therapy still need to be answered. “If a patient did a first round, would they be eligible for another gene therapy in the future if they didn’t get the results they’d hoped for? If they have to reintroduce factor later, would they be at higher risk of developing inhibitors?” she asked.

But despite the cautions expressed, “we are no less enthusiastic than you are,” about new advances in the field, said Kaczmarek. “The patient community really appreciates all the developments and all the effort put into the development of these new therapies. And the last thing I would say is: Don’t curb your enthusiasm.”