Long-lasting clotting factors key step in hemophilia treatment

Since the introduction of aggressive hemophilia prophylaxis in Sweden in the 1960s, there has been a dramatic reduction in the number of spontaneous bleeds, sparing many patients from the severe musculoskeletal sequelae associated with hemophilia.

However, the required dosing regimen — typically three times weekly, and up to every other day for some patients — has a tremendous impact on the cost of care and often leads to poor compliance.

By fusion of coagulation factors to other proteins or substances that extend half-life, researchers have been able to demonstrate improved pharmacokinetic profiles. With decreased fusion frequency, some patients with hemophilia may be able to infuse themselves as infrequently as once a week and still maintain excellent bleed protection.

“It is burdensome to do an infusion every other day, which is now the standard to prevent bleeds in hemophilia A or severe disease, which is what the majority of patients with hemophilia have,” Margaret V. Ragni, MD, MPH, professor of medicine in the division of hematology/oncology at the University of Pittsburgh, told HemOnc Today. “[Long-lasting clotting factors] have the potential to dramatically improve quality of life for these patients.”

Extended half-life products are the subject of intense research, with 20 pipeline programs currently under way for the treatment of hemophilia A (Factor VIII), hemophilia B (Factor IX) and hemophilia with inhibitors, according to Steven W. Pipe, MD, director of the division of pediatric hematology and oncology and pediatric medical director of the hemophilia and coagulation disorder program at the University of Michigan.

Clinical trials are under way on six continents. These multicenter trials — with up to 93 sites per study — include up to 172 patients each.

HemOnc Today spoke with several clinicians about how longer-lasting clotting factors could improve patient care, whether their cost could be a barrier to widespread use, and the growing sense of optimism regarding another therapeutic approach under investigation — gene therapy — that could represent a significant step toward a cure for hemophilia.

Three approaches, one basic principle

Researchers primarily have focused on three strategies to extend clotting factor half-life: Fc fusion, albumin fusion and polyethylene glycol conjugation, often called PEGylation. Researchers are investigating products that employ these approaches for both Factor VIII and Factor IX therapeutics.

“For all of these [strategies], the basic principle is to alter the protein in some way so that it is less rapidly cleared from the circulation,” Katherine A. High, MD, William H. Bennett professor of pediatrics in the Perelman School of Medicine at the University of Pennsylvania, director of the Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia and a HemOnc Today Editorial Board member, said in an interview.

The Fc protein is part of the immunoglobulin molecule. Fc protein has a considerably longer half-life compared with Factors VIII and IX — weeks compared with hours — and has been used in other current biotherapeutics, including the rheumatology drug etanercept (Enbrel, Amgen).

“There are a half-dozen molecules that have different proteins that are biologically active fused to the Fc portion of immunoglobulin,” said Jerry S. Powell, MD, director of the Hemophilia and Thrombosis Center at UC Davis Comprehensive Cancer Center in Sacramento, Calif. “Nobody has found any trouble with those during the last 10 years. It is a well-established technology [that has been] proven safe.”

Biogen Idec has two Fc fusion products in clinical trials. Results of the multicenter, phase 3 A-LONG trial demonstrated effective bleed control and prevention with the recombinant Factor VIII Fc fusion protein (rFVIIIFc) administered once or twice weekly.

This agent uses a natural pathway to prolong rFVIIIFc half-life by recycling rFVIIIFc back into the circulation.

The study included 165 males with severe hemophilia A who were previously treated with a Factor VIII product. Participants injected themselves once or twice weekly for prophylaxis, while some continued to treat on-demand, meaning they treated bleeding episodes as they occurred. The median annualized bleed rate was 1.6.

Half-life was extended from 1.5 to 1.7 times, according to Amy D. Shapiro, MD, co-medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis.

“I have one patient who, even on a currently licensed replacement product, continued to experience many breakthrough bleeding episodes,” Shapiro told HemOnc Today. “[It] was difficult to suppress his bleeds on prophylaxis. On the rFVIIIFc, he has done extremely well, and he has had few, if any, breakthrough bleeding episodes.”

Based on these results, the FDA in May accepted the company’s biologic license application for rFVIIIFc.

The results for Biogen’s recombinant Factor IX Fc fusion (rFIXFc) product were similar: Prophylaxis with the Fc fusion product yielded single-digit annualized bleeding rates. The multicenter, phase 3 study included 123 males with severe hemophilia B.

The half-life for this product is at least three times longer than native Factor IX, Shapiro said.

Albumin fusion

Albumin, a natural blood plasma protein, has about a 20-day half-life. Although it is a novel technique, it uses a normal molecule and a normal factor.

“Nobody thinks it’s going to make an immune system response because there’s really no foreign epitopes,” Powell said.

Albumin specifically promotes Factor IX function.

“The nice thing about that technology is the activation of Factor IX from a proenzyme to the enzyme occurs by an activation peptide where a small part is cleaved off,” Powell said. “They’ve done the activation process so that the fusion is cleaved off. What’s present where the clot has to form is native Factor IX. The albumin is gone.”

When linked with Factor IX as a prophylactic treatment for hemophilia B, albumin significantly decreased the required dose frequency, according to a first-in-human trial by Santagostino and colleagues published in Blood in 2012.

The dose-escalation study included 25 previously treated patients with hemophilia B. In the 50-IU/kg group, the mean half-life of the recombinant albumin Factor IX fusion protein (rIX-FP) was 92 hours, which is approximately five times longer than that observed with native Factor IX.

PEGylation

The use of polyethylene glycol (PEG) linked to a target is an established technique to prolong half-life, with a dozen FDA-approved compounds currently in use, according to Powell.

“It just took modifying that technique to add the polyethylene glycol moiety to Factor VIII,” Powell said.

Baxter, Bayer and Novo Nordisk are investigating PEGylated Factor VIII products.

In January, Baxter International Inc. submitted an investigational new drug application to the FDA for its hemophilia A treatment BAX 855, a full-length, longer-acting PEGylated recombinant Factor VIII developed to increase the half-life of Advate, a third-generation full-length recombinant Factor VIII concentrate used in treatment, including prophylaxis, for hemophilia A.

Patient enrollment in the phase 2/3 study is under way.

Results of a phase 1, prospective, open-label study that included 19 previously treated patients with severe hemophilia A showed that the half-life was 1.5 times longer compared with Advate, according to a company press release.

The researchers observed 11 adverse events in eight patients in both treatment arms. However, none were serious, related to treatment or resulted in study withdrawal.

Novo Nordisk recently announced positive results from a phase 3, multicenter, masked study designed to assess its glycoPEGylated recombinant Factor IX product, N9-GP. Patients assigned to the once-weekly prophylaxis dose of 
40 IU/kg had a median annualized bleed rate of one, and those assigned to the once-weekly dose of 10 IU/kg had a median annualized bleed rate of 2.9, according to a company press release.

The company’s glycoPEGylated Factor VIII product, N8-GP, demonstrated similar results in a study conducted by Tiede and colleagues, published in the Journal of Thrombosis and Haemostasis.

The study included 26 patients. A single 75-IU/kg dose was well tolerated and demonstrated a prolonged half-life of 19 hours, a 1.6-fold increase compared with the previously utilized comparator products, according to the researchers.

There is a concern about PEGylation, however: Over time, the repeated doses needed for hemophilia prophylaxis could cause a toxic PEG accumulation.

“Nobody thinks it’s not safe,” Powell said. “We have 20 years of experience with all of these other compounds. The total lifetime dose during 10, 15 or even 20 years is probably a 20th or a 40th of the dose of polyethylene glycol that the already FDA-approved products have exposed children to, and they’ve had no trouble.”

Once-weekly injections

A typical prophylactic regimen for patients with hemophilia A involves every-other-day infusion. With extended half-life products, these patients may be able to shift to twice-weekly infusions with effective prophylaxis, Pipe said.

The greatest effect seems to be seen with the Factor IX products, with which researchers have observed threefold to fivefold half-life extensions.

“You’re now talking about a dosing strategy that looks like about once weekly,” Pipe told HemOnc Today. “It’s entirely possible that some subsets of patients may be able to push that even further, maybe once every 2 weeks.”

Hampered by its dependency on interaction with von Willebrand factor, results have been less robust for Factor VIII, with a half-life extension of about 1.5 to 1.7 times.

The sheer size of Factor VIII has also been a problem.

“Factor VIII is one of the largest coagulation factors,” Powell said. “Any time you change anything about a coagulation factor, you mess up the entire coagulation cascade. It is complicated.”

At roughly one-fifth of the size of Factor VIII, Factor IX has been much easier to work with, Powell said. Unlike Factor VIII, which has complex co-factor interactions, achieving prolonged half-life has been more easily realized with Factor IX.

Potential resolution of treatment issues

The extended half-life products may help solve some of the current problems in hemophilia treatment. For example, patient compliance with frequent infusions required in prophylaxis can prove challenging.

“We’re aggressive with prophylaxis, especially with the pediatric age group,” Pipe said. “We sometimes struggle with compliance issues and adherence in adolescents.”

The hope is that more convenient dosing schedules will improve compliance.

“You’ll see greater adoption of prophylaxis for those who haven’t been on it and maybe a greater adherence in younger patients as they graduate into the adult age group,” Pipe said.

Among the complications seen with traditional replacement therapy, inhibitor formation — an immune system response to exogenously administered clotting factor — is the most serious. About 10% to 15% of patients with hemophilia develop inhibitors, according to the CDC. Incidence is about 30% in patients with severe hemophilia A.

There is hope, based on limited data from small studies of animals, that inhibitor formation may be reduced with these agents, Ragni said.

However, the inhibitor question will remain unanswered until extended half-life products are used in previously untreated patients.

“That’s where it will be exciting to see what happens,” Powell said. “My expectation is that these new extended half-life products will end up with a lower inhibitor rate when we finish those trials in 5 or 6 years. A lot of immunology depends on the area under the curve, and these will markedly increase the area under the curve, which will lead to a lower inhibitor rate.”

Equivalent products

So far, study results indicate that these compounds are equivalent.

“This is only a first approximation, but it looks roughly like if you consider a patient with hemophilia who is assigned to Advate, each of these products will extend the half-life predictably by the same amount,” Powell said. “A 10-hour half-life on Advate will go to 1.6 times that, or a 16-hour half-life.”

Similarly, a 19-hour half-life will extend by 1.6 times, or about 34 hours.

“But there are individuals who don’t exactly multiply that half-life by 1.6,” Powell said.

Individual pharmacokinetic differences require individualized treatment. Currently, hematologists rely on generalized pharmacokinetic information.

“It might actually improve our understanding of what each person might look like with each product,” Ragni said. “Each person might be able to have a personalized pharmacokinetic study or knowledge based on what’s available in their own assays.”

Obstacles to success

Despite the promising data from early clinical trials, some issues remain with extended half-life products.

Current hemophilia prophylaxis is expensive, Charles S. Abrams, MD, professor of medicine and the director of the Penn-CHOP Blood Center for Patient Care and Discovery, said in an interview.

The total annual cost can range from $60,000 to $150,000 per patient, according to the National Hemophilia Foundation.

“These drugs are going to turn out to be the real deal,” Abrams said. “My guess is they’re going to turn out to be safer and easier to administer. What I don’t know is whether they’re going to be priced in a way that’s going to make them appealing.”

Pricing is critical to increasing worldwide access to hemophilia prophylaxis, according to High.

“It’s estimated now that, based on the cost of the clotting factors, about 20% of the world’s hemophilia population has access to an optimal regimen,” she said. “The real question is, will [long-lasting clotting factors] expand access? Much will depend on the pricing.”

Bridge to gene therapy

For some clinicians, gene therapy — at least for Factor IX, which is already in early trials — is the next anticipated breakthrough in the treatment of hemophilia. However, extended half-life clotting factors may represent the next step in the pursuit of a hemophilia cure, improving clinical care and patient quality of life until gene therapy is ready for use.

“Gene therapy is still on everybody’s mind, if not as the ultimate cure, then at least as a significant milestone to convert the majority of patients from the severe phenotype to a milder phenotype, where they will be liberated from the risk for recurrent joint bleeding,” Pipe said.

A study by Nathwani and colleagues, published in 2011 in The New England Journal of Medicine, demonstrated durable improvements in plasma levels with gene therapy.

The trial included six men with severe hemophilia B who were infused with a single dose of adeno-associated virus vector that delivered a Factor IX gene construct. More than 2 years after treatment, the men at the highest dosing cohort have maintained meaningful plasma levels that have altered their clinical phenotype, Pipe said.

As a result of these findings, several other clinical trials for both hemophilia A and B are moving forward.

“Maybe these novel clotting factors are filling a gap while we wait to see how the protocols and the technology roll out for gene therapy,” Pipe said. “It’s an exciting time. We are hopeful that, in the next 5 to 10 years, we’re going to see some gene therapy products that are actually commercialized for use.” – by Colleen Owens

References:

CDC. Hemophilia fact sheet. Available at www.cdc.gov/ncbddd/hemophilia/facts.html. Accessed July 23, 2013.

Nathwani AC. N Engl J Med. 2011;365:2357-2365.

National Hemophilia Foundation. Financial and Insurance Issues. Available at www.hemophilia.org/nhfweb/mainpgs/mainnhf.aspx?menuid=34&contentid=24. Accessed on June 20, 2013.

Ragni M. Factor VII, VIII and IX: Making a Long-Lasting Impression. The Hematologist. Available at: www.hematology.org/publications/hematologist/issues/10494.aspx. Accessed on July 23, 2013.

Santagostino E. Blood. 2012;120:2405-2411.

Tiede A. J Thromb Haemost. 2013;11:670-678.

For more information:

Charles S. Abrams, MD, can be reached at the Hospital of the University of Pennsylvania, 3 Dulles, 3400 Spruce St., Philadelphia, PA 19104; email: abrams@mail.med.upenn.edu.

Katherine A. High, MD, can be reached at The Children’s Hospital of Philadelphia, 5060 CTRB, 3501 Civic Center Blvd., Philadelphia, PA 19104; email: high@email.chop.edu.

Steven W. Pipe, MD, can be reached at University of Michigan Pediatric Hematology and Oncology, CS Mott Children’s Hospital, MPB D4202, 15040 E. Medical Center Drive, Ann Arbor, MI 48109; email: ummdswp@med.umich.edu.

Jerry S. Powell, MD, can be reached at UC Davis Comprehensive Cancer Center, 4501 X St., Suite 3016, Sacramento, CA 95817; email: jspowell@ucdavis.edu.

Margaret V. Ragni, MD, MPH, can be reached at University of Pittsburgh, 3636 Boulevard of the Allies, Second floor, Pittsburgh, PA 15213; email: ragni@pitt.edu.

Amy D. Shapiro, MD, can be reached at Indiana Hemophilia and Thrombosis Center, 8402 Harcourt Road, Indianapolis, IN 46260; email: ashapiro@ihtc.org.

Disclosure: Abrams, High, Pipe, Powell, Ragni and Shapiro report no relevant financial disclosures.

 

Should hemophilia prophylaxis be lifelong?

The answer is an unqualified yes.

It would seem intuitive that the adequate replacement of factor in moderate-to-severe hemophilia patients should occur throughout their lives. The benefits of prophylaxis — at least in terms of joint health — in children have been borne out. Prophylaxis rates in children are on average 80%, compared with a miserable 30% in adults.

Why the discrepancy between children and adult patients?

Is it due to lack of data? Are data from a double blind, placebo-controlled, randomized trial required to prove this point? An ongoing trial, SPINART, is looking at joint health in adult patients on prophylaxis compared with on-demand patients for a 3-year period. Although bleeding on prophylaxis was significantly reduced, evaluation on joint effects is forthcoming. Whether a 3-year follow-up period is sufficient time to evaluate joint disease remains a question.

Is it cost? One can argue that the cost of adult prophylaxis — $100,000 to $300,000 per year, depending on weight and individual factor turnover — prohibits its use. Yet, in our experience, most third-party payers understand that when patients take factor they do not suffer the terrible joint-crippling consequences and can live reasonably normal lives.

Is it the risk of inhibitor formation during prophylaxis? Currently, the No. 1 scourge in the field is the development of autoantibody inhibitors. The “fear” is that patients will be at greater risk for inhibitors. Data refute this and, in fact, suggest the opposite: Patients on prophylaxis either have no greater risk or perhaps a lower inhibitor rate.

Is it that some patients do not need prophylaxis? Certainly, we see patients who have classic <1% factor levels, yet present with a milder-than-expected bleeding history. These patients are difficult to persuade to take regular doses of factor because they feel it will not significantly change their outcome. This group clearly must have their own preventive bleeding mechanism(s) that the majority of patients do not have. Regardless of the mechanism, this subset of patients further argues that prophylaxis benefits patients. Some argue that older patients do not bleed as much as children and, therefore, do not need factor. The development of new target joints is a clinical observation seen all too often in aging patients not on prophylaxis.

Preventive measures such as factor prophylaxis should be instituted for patients lifelong. Although a poor analogy, one could view this in the same fashion as reducing greenhouse gases that affect climate. Aggressive intervention taken now will have a tremendous effect on our patients in the years ahead.

References:

Gouw SC. Blood. 2013;121:4046-4055.

Manco-Johnson MJ. N Engl J Med. 2007;357:535-544.

Manco-Johnson MJ. J Thromb Haemost. 2013;11:1119-1127.

Nilsson I. J Intern Med. 1992;232:25-32.

Zappa S. Haemophilia. 2012;18:e140-153.

Christopher Walsh, MD, directs the hemophilia program in the division of hematology and medical oncology at Mount Sinai School of Medicine. He can be reached at Department of Medicine — Hematology, 5 E. 98th St., 12th floor, New York, NY 10029. Disclosure: Walsh reports no relevant financial disclosures.

The decision to continue prophylaxis is personal.

The ability of prophylaxis to reduce joint and other serious bleeding events in children and adults with severe hemophilia A has been conclusively demonstrated in multiple prospective clinical studies. The duration of the prophylaxis remains a matter of debate, and some have suggested that up to one-third of young adults with severe hemophilia who have received prophylaxis during childhood may discontinue their regular treatments without an increase in bleeding frequency or the development of arthropathy.

This issue raises concerns on the part of patients, physicians and payers because no data are available to assess the impact of prophylaxis in adults on their quality of life and the pharmacoeconomic impact.

What is clear is that prophylaxis does reduce the overall and joint bleeding frequency of adults. This may translate into a slowing of the progression of existing joint disease and abrogation of new joint disease, as well as a reduction in life-threatening bleeding events.

Given the current state of knowledge, no firm recommendations can be made; however, one would presume that prevention of bleeding and the negative consequences that follow is beneficial. Until there are data to shed light upon the impact of prophylaxis in adults on quality of life and pharmacoeconomics, the decision is personal.

Hemophilia treatment is moving toward a personalized approach, taking into consideration the patient’s prior bleeding pattern, joint status, level of physical activity, body habitus, pharmacokinetics and probably other factors yet to be discovered. The option of continuing prophylaxis into adulthood or first initiating prophylaxis in adults should be available for patients to consider with their caregivers, with an individualized approach taken to decision making.

References:

Aledort LM. J Intern Med. 1994;236:391-399.

Gringeri A. J Thromb Haemost. 2011;9:700-710.

Manco-Johnson MJ. N Engl J Med. 2007;357:535-544.

Manco-Johnson MJ. J Thromb Haemost. 2013;11:1119-1127.

Valentino LA. J Thromb Haemost. 2012;10:359-367.

Leonard A. Valentino, MD, ABP, is director of the Rush Hemophilia and Thrombophilia Center and section of pediatric hematology/oncology at Rush University in Chicago. He can be reached at 1653 W. Congress Parkway, Jelke Building, Suite 1591, Chicago, IL 60612-3833. Disclosure: Valentino reports no relevant financial disclosures.