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Breakthroughs in Gene Therapy for Hemophilia

December 30, 2021

Gene therapy for hemophilia is here – and it's working. The field is advancing at a steady clip: Results from recent trials of this revolutionary approach have restored patients' anticoagulant factor activity levels to normal or near-normal levels and reduced patients' annualized bleeding rates by nearly 90 percent.

A handful of candidate products are being evaluated in phase III studies of patients with hemophilia, and several more are in early development, but questions about their long-term safety and efficacy remain.

"With gene therapy, the goal is to provide a single intervention that will have a long-lasting effect and free people from the need for chronic administration of medicine," according to Katherine A. High, MD, a hematologist and president and head of research and development at Spark Therapeutics, a Philadelphia-based biomedical company that focuses on gene therapy products for inherited disorders like hemophilia.

ASH Clinical News spoke with Dr. High and other hemophilia specialists to better understand the details of this revolutionary new treatment and to get an update on the race to a "cure" for hemophilia.

A One-and-Done Treatment? 

The typical treatment of hemophilia entails frequent intravenous infusions of the missing coagulation protein to either treat or prevent bleeding episodes. The need for weekly (or more frequent) administration of recombinant factor VIII (FVIII) or factor IX (FIX) replacement is costly, burdensome, and complicated. And, with only about 25 to 30 percent of the world's hemophilia population having full access to factor replacement, the promise of a gene therapy solution for hemophilia offers hope for more global access to treatment.

Gene therapy is designed to provide long-term expression of the missing or abnormal coagulation factor at sufficient and steady enough levels to reduce – or even eliminate – the need for exogenous factor replacement. A number of different gene delivery vehicles have been tested, but all the therapies now in advanced development use a recombinant adeno-associated virus (rAAV) vector to deliver the coagulation factor gene to a patient's liver.

AAV is a versatile viral vector technology discovered more than 50 years ago that can be engineered for very specific functionality in gene therapy applications.1 The rAAV vectors lack viral DNA and essentially are protein-based nanoparticles engineered to traverse the cell membrane and deliver their gene of interest into the cell nucleus.

As Dr. High explained, gene therapies are designed to be single-dose treatments with potentially curative results. As far as whether gene therapy will really offer a "cure," John Pasi, MBChB, PhD, Hemophilia Centre Director at Barts and The London School of Medicine and Dentistry, is hesitant to use that word.

"Cure is a word we use with considerable caution," said Dr. Pasi, who is the principal investigator on trials evaluating valoctocogene roxaparvovec, BioMarin Pharmaceutical's gene therapy product for hemophilia A. "We don't know how long gene therapy will last yet, but we may be looking at a treatment that can massively reduce the treatment burden and substantially improve quality-of-life for men with severe hemophilia," he added.

Also, this treatment only affects the patient living with hemophilia; since the genetic mutation remains, hemophiliacs can still pass the disorder to their offspring.

Lindsey A. George, MD, another gene therapy researcher and an attending hematologist at Children's Hospital of Philadelphia, is also reluctant to call gene therapy a cure, but said the clinical trial results are often profound and life-changing for participants.

"What we can say is that these patients are not requiring factor replacement for extended periods of time, they're not having breakthrough bleeds, and their lives are no longer dictated by hemophilia – all of which is consistent with a cure," Dr. George said.

Indeed, many of her patients have expressed a newfound sense of freedom after receiving gene therapy, including a noticeable uptick in their activity levels.

The Race Is On!

Hemophilia B, despite being far less common than hemophilia A, was initially a more attractive target for gene therapy from a molecular perspective.

"Typically, the diseases are identical and, in both, only a modest amount of expression is required to produce a big benefit for the patient," Dr. George explained. "But, the FVIII gene is much bigger than the FIX gene and the packaging capacity of an AAV vector (in other words, how much DNA can be fit in) is smaller than the FVIII gene itself." Researchers needed extra years, even decades, to figure out how to package the FVIII gene into an AAV vector, which involved bioengineering smaller promoters and coding for a truncated (B domain deleted) factor VIII protein that maintains function.

As more pharmaceutical companies develop their own gene transfer products for the treatment of hemophilia, the field is starting to get crowded. Dozens of gene transfer protocols have been approved by the U.S. Food and Drug Administration (FDA) over the years, more than a dozen experimental treatments are in phase I and II study, and four products have entered late-stage development in just the last few months.

"My experience is that when you start to see many people working along the same lines, it usually means things are working," said Dr. High.

At present, BioMarin Pharmaceuticals, Spark Therapeutics, Pfizer, and UniQure all have gene therapy products being evaluated in phase III studies. The BioMarin and Spark products are FVIII gene transfer products and the Pfizer and UniQure products target FIX (see TABLE). Each of these companies have reported factor activity levels returning to the normal range in patients with mild hemophilia in phase I and II trials, although not all these data have been published in peer-reviewed journals.2,3

In results from the Spark/Pfizer trial of gene therapy for hemophilia B treatment with SPK-9001 resulted in a mean steadystate FIX coagulant activity of about 33 percent of normal two years after treatment.4 Before treatment, FIX activity level was ≤2 percent of normal in the 10 men treated. (Note: Pfizer and Spark Therapeutics entered into a License Agreement in December 2014 for the hemophilia B gene therapy program. In July 2018, Pfizer assumed sole responsibility for all pivotal studies, regulatory activities, and manufacturing and global commercialization of any products resulting from the program.)

"At the 33-percent level of expression, most people do not bleed, and, indeed, the trial showed that the annualized bleeding rate was reduced by close to 98 percent – even in people who were already on standard-of-care management," said Dr. High, senior author on that paper.

In the early-phase trial of BioMarin's gene therapy candidate for hemophilia A, patients have maintained FVIII levels of 50 percent two years after infusion.5

Dr. High suggested that it would likely take at least two years from the point a product entered phase III testing before a company could expect its candidate to be approved, "with an upper bound of ‘who knows.'" For example, Spark's voretigene neparvovec-rzyl (indicated for the treatment of an inherited retinal disease) became the first gene therapy approved by the FDA in December 2017 – a full five years after it entered phase III testing.6

"It's expected that the very first approval of a new class of therapeutics will take longer," she said, adding that, in hemophilia, the endpoints for clinical trials are well known, while with voretigene neparvovec-rzyl, "we had to develop and validate [the endpoints]" during the clinical study process.

The Unknowns of Gene Therapy

"The big question for all gene therapy approaches for hemophilia will always be durability," Dr. Pasi said. "The only way to answer that question is to observe all of our patient cohorts over time."

In human trials, the longest follow-up has been reported in patients with hemophilia B, and durability appears to be good at up to eight years. In dog studies, long-term gene expression has been noted for up to 10 years, "which is pretty much the lifespan of the dog, so it's hard to have information beyond that," Dr. George said.

Any hints of issues in durability or therapy-related adverse events can cause precipitous stock declines for companies developing late-phase products. For example, BioMarin's stock price slumped in May 2018, when new data on its candidate product were released at the 2018 World Federation of Hemophilia World Congress.7

The data suggest a loss of effectiveness over time, which Dr. George notes has not been observed in any clinical trials of AAV in hemophilia B or large-animal preclinical studies of hemophilia A or B. However, Dr. Pasi, the primary investigator on this trial, explained that the "gene-expression levels are stabilizing and following a pattern of expression typically seen in many AAV systems."

Other questions that are still missing clear answers include the potential liver toxicity of these products, and the potential for vector shedding. Also, approximately half of individuals with hemophilia have pre-existing AAV neutralizing antibodies (NAb), making them ineligible for gene therapy. Patients may even develop AAV NAb after gene therapy.

"The development of AAV NAb after vector infusion is particularly important when considering extending this therapy to pediatric patients, who may require repeat infusion to accommodate hepatic growth and expanded plasma volume," said Dr. George. But, at this point, there is no clear solution to this issue.

A Therapy for All?

"Obviously, I am biased, and I think very optimistically about gene therapy," said Dr. George, "but if we can achieve predictable and durable expression, then, theoretically, this approach could help everyone." However, there are some noteworthy barriers to achieving that goal – including that not all patients are eligible for trials.

An estimated 20,000 individuals in the U.S. have hemophilia, with hemophilia A being about four times more common than hemophilia B. The worldwide incidence of hemophilia is unknown but is estimated at more than 400,000 people.8

Because hemophilia is an X-linked disorder, it is rare in women and, typically, they are excluded from trials because "all of the pharmacology, toxicology, and vertical transmission TABLE. Ongoing or Announced Phase III rAAV-Mediated Gene Therapy Trials for Hemophilia A and B Sponsor Therapy Coagulation Factor BioMarin Pharmaceuticals Valoctocogene roxaparvovec ("val-rox", formerly BMN-270) Factor VIII Spark Therapeutics SPK-8011 Factor VIII Pfizer Fidanacogene elaparvovec (formerly SPK-9001) Factor IX UniQure AMT-061 Factor IX FEATURE 18 Focus on Classical Hematology studies were performed in men," Dr. George explained. "However, AAV vectors are being used to treat other conditions in women, so I think it's feasible that it could be extended to female patients in the future."

Dr. High suggested the possibility of identifying which patients are most likely to "buy into" the promise of gene therapy by looking at those who have opted to enroll in the trials. These include older individuals who have developed other medical problems and don't want to have to worry about their hemophilia anymore. "We have also seen many younger people volunteer for trials," she added. "These are people who resent the so-called ‘brutal discipline of prophylaxis.' They want to live their lives without being reminded several times a week that they're different."

While some "early adopters" will likely jump on board for gene therapy, Dr. Pasi said, others will take the "wait-and-see" approach as researchers learn more about the products' longterm safety and durability. "The history of hemophilia makes for a very conservative population," he noted.

He also said that gene therapy is being explored in developing countries. "We currently are looking at gene therapy through the prism of use in the developed world, but those with arguably the most to gain from a one-off treatment are those who cannot access standard treatments or who live in places where factor replacement regimens are impractical for various reasons," he explained. —By Debra L. Beck


  1. Naso MF, Tomkowicz B, Perry WL, Strohl WR. Adeno-associated virus (AV) as a vector for gene therapy. BioDrugs. 2017;31:317-34.
  2. Meisbach W, Meijer K, Coppens M, et al. Gene therapy with adeno-associated viral vector 5-human factor IX in adults with hemophilia B. Blood. 2018;131:1022-31.
  3. Sullivan SK, George LA, Ragni MV, et al. SPK-8011: preliminary results from a phase 1/2 trial of investigational gene therapy for hemophilia confirm transgene derived increases in FVIII activity that are persistent and stable beyond eight months. Mol Ther. 2018;26(suppl):350.
  4. George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a highspecific- activity factor IX variant. N Engl J Med. 2017;377:2215-27.
  5. Rangarajan S, Walsh L, Lester W, et al. N Engl J Med. 2017;377:2519-30.
  6. U.S. Food and Drug Administration. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. Accessed September 6, 2018, from https://
  7. BioMarin Pharmaceuticals press release. Accessed September 6, 2018, from http:// 6e13-vg-kg-Dose-from-Ongoing-Phase-1-2-Study-in-Valoctocogene-Roxaparvovec- Gene-Therapy-for-Severe-Hemophilia-A-at-World-Federation-of-Hemophilia-2018- World-Congress.
  8. National Hemophilia Foundation. Fast facts about bleeding disorders. Accessed September 6, 2018, from

Manufacturers have yet to offer clear intentions on pricing, but even at seven figures, gene therapy may be a bargain if it can offset years of costly prophylaxis. Although none of the experts who spoke with ASH Clinical News could offer any solid information on pricing, the talk among analysts is that these products could top $1 million for a single infusion.

The cost of a year's worth of recombinant product can run as high as $300,000 per year, not accounting for potential complications.1 On top of that, the disease incurs tremendous indirect and intangible costs from diminished work productivity, absenteeism, and reduced quality of life.

"Even if [manufacturers] charge $1 million, that would be a great deal," said Express Scripts Chief Medical Officer Steve Miller, MD, in a recent interview with Reuters. "So, there are going to be some gene therapies where it is very clear that everyone who has that disease should get it."2

In a recent economic analysis published in Blood Advances, researchers indicated that gene therapy for severe hemophilia A would still be cost-effective at a price of $1 million, compared with standard factor VIII prophylaxis. They estimated that, with gene therapy, patients would gain 8.33 quality-adjusted life years (QALYs) over a 10-year horizon, compared with 6.62 QALYs for standard therapy.3

The model also assumed a success rate of 90 percent with gene therapy, which is lower than what has been reported in phase I and II trials. "I think this paper is a nice summary, albeit from a developed world perspective and with the financial caveats that that would entail," John Pasi, MBChB, PhD, commented.


  1. Chen SL. Economic costs of hemophilia and the impact of prophylactic treatment on patient management. Am J Manag Care. 2016;22 (5 Suppl):s126-33.
  2. Reuters. Express scripts staking out million-dollar gene therapies. Accessed September 6, 2018, from express-scripts-staking-out-million-dollar-gene-therapiesidUSKBN1L00EE.
  3. Machin N, Ragni MV, Smith KJ. Gene therapy in hemophilia A: a cost-effectiveness analysis. Blood Adv. 2018;2:1792-98.

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