New Approaches to Hemophilia Treatment: 'Our Cup Runneth Over'

Neil Osterweil

December 22, 2021

ATLANTA, Georgia — It's a problem many clinicians would love to have: a whole variety of new or emerging therapeutic options to use in the care of their patients.

In a session titled "Hemophilia Update: Our Cup Runneth Over," presented here at the 2021 annual meeting of the American Society of Hematology (ASH), experts in the treatment of bleeding disorders discussed the optimal use of factor concentrates in people with hemophilia, new and investigational alternatives to factor concentrates, and the promise of long-time control or even cure with gene therapy.

Factor Concentrates

Prophylaxis — as opposed to episodic treatment — is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.

"Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician," she told the audience.

As the complexity of therapeutic options, including gene therapy, continues to increase "it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes," she added.

Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient's bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.

"The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle," she said.

The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.

The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for Factor VIII concentrates, and every 7 to 14 days for Factor IX concentrates.

"All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues," Lim said.

There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.

The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand Factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.

Factor Mimetic and Rebalancing Therapies

With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, "Is this the beginning of the end of the use of factor?" said Alice Ma, MD, FACP, from the University of North Carolina School of Medicine in Chapel Hill, North Carolina.

Factors that may determine the answer to that question include the convenience of subcutaneous administration of Factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors vs nonfactor products, and safety.

She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the US Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.

Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Ma said. It is unknown, for example whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.

It's also unknown whether the Factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.

Other Factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, US) and NIBX-2101 (Takeda, Japan).

One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting "as a great leap forward" in the treatment of hemophilia.

However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Ma noted.

Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, US) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Ma noted.

"It is really notable that none of the replacements of factor have been free of thrombotic side effects," Ma said. "And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it's not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that."

Considerable Optimism Over Gene Therapy

"There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that's really driving this field," said Lindsey A. George, MD, from the University of Pennsylvania and Children's Hospital of Philadelphia.

She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.

There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.

Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, George said,

"Thankfully, short-term safety in the context of hemophilia has really been quite good," she said.

Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in Factor VIII and Factor IX activity.

In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.

There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.

Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.

"That's obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we're achieving the same phenotypic observations deserves a bit of a deeper dive," she said.

Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.

In canine models for hemophilia A and B, Factor VIII and Factor IX expression have been demonstrated for 8 to 10 years post-vector, and in humans Factor IX expression in patients with hemophilia B has been reported for up to 8 years.

In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.

Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.

Regarding the future of gene therapy, George said that "we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy "will fulfill its promise to alter the paradigm of hemophilia care."

Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Ma disclosed honoraria and research funding from Takeda. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.

63rd American Society of Hematology Annual Meeting & Exposition: Education Session. Presented December 12, 2021.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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