Dosing Differences Opined for Costly Hemophilia Option

Ingrid Hein

July 12, 2019

More patients with hemophilia A can achieve zero bleeds with tailored exposure to factor VIII (FVIII), according to phase 3 results from the PROPEL trial.

"For the first time, we have the proof that we can reduce bleeds significantly with a higher trough while with others we can do it with a lower one," reported trial investigator Robert Klamroth, MD, PhD, from Vivantes Klinikum in Berlin, Germany.

In standard practice, the aim for prophylactic treatment is a trough level of 1%-3%.

"Forty percent of patients do well with a trough of 1%, but 60% do not," Klamroth pointed out to Medscape Medical News.

One size does not fit all, he added. "I'm convinced there will never be a universal trough level to predict bleeding. It really depends on a patient's pharmacokinetic profiles, FVIII activity levels, and bleeding events."

And cost of treatment factored into the discussion at the International Society on Thrombosis and Haemostasis 2019 Congress in Melbourne, Australia, where the findings were presented July 8.

"If treatment were as cheap as aspirin, I would go for 10% in everyone, but it's an expensive therapy, so we have to find an optimal dose for the patient," Klamroth explained.

While some clinics have been using pharmacokinetic guided dosing for some time, there are complaints that it is difficult to implement.

Adjusting Doses

"If you want to do pharmacokinetic dosing, you have to do blood draws to find the optimal dose," Klamroth noted.

The PROPEL research group enrolled 115 patients with FVIII activity ≤ 1% and an annualized bleed rate of two or more episodes who were either in a previous rurioctocog alfa pegol study or were age 12-65 years old with ≥ 150 exposure days to plasma-derived or recombinant FVIII.

Patients were randomized to pharmacokinetic guided prophylaxis with extended half-life recombinant FVIII rurioctocog alfa pegol (SHP660, BAX 855; Baxalta [part of Shire]) for a period of 12 months targeting either FVIII trough levels of 1%-3% (low) or trough levels of 8%-12% (high). There were 57 patients in the low group, and 58 in the high group.

For the first 6 months of the trial, patients underwent a dose adjustment period to find their optimal dose. In the second 6 months, they stayed on target with their assigned dose. The mean number of weekly injections in the low group was 2.3, and the mean number in the high group was 3.6.

The primary outcome was to get a high percentage of patients down to a total annualized bleed rate of 0 during the second half of the study period. Secondary outcomes included total annualized bleed rate, spontaneous annualized bleed rate, and joint annualized bleed rate.

PROPEL Trial Results

A total of 106 patients completed the study; 56 in the low-trough-level, or reference, group and 50 in the high-trough-level group. Fewer patients in the low group than in the high group achieved the primary end piont of a total annualized bleed rate of 0 (42% vs 62% P = .55).

In addition, fewer patients in the low group than in the high group achieved a spontaneous annualized bleed rate of 0 (60% vs 76%; P = .10) and a spontaneous annualized joint bleed rate of 0 (65% vs 85%; P = .03).

Adverse events were similar in the two groups, indicating a safety profile similar to standard treatment. One patient in the high group (0.9%) experienced a serious adverse event considered to be related to rurioctocog alfa pegol, but that resolved by study end.

At trial completion, patients continued with their personalized treatment. Some receive an injection two or three times weekly, while others continue on a slightly lower dose.

"I think a lot of patients are undertreated," said Klamroth. "Of course, to aim for a higher trough level we need more product, and it's expensive, but for the first time we have a clinical trial saying, yes, you should do it, because it will result in a lower bleeding rate."

More Living, Less Bleeding

"We used to tell patients no soccer, no activities that increase risk of bleeding," Klamroth said, but in the last 10 years, thanks to development of treatments with a longer half-life, the goal is for patients to live normal lives.

For that to happen, "we have to work on reduced bleeding or no bleeding at all," which means appropriate dosing and the development of new treatments are essential, he said.

Extended half-life products are just one of the approaches to treat hemophilia. A bispecific antibody that copies the coagulation activity of FVIII and the development of antibodies for inhibition of anticoagulation proteins such as antithrombin will further escalate the growth of hemophilia treatment market, said analyst Sumant Ugalmugale, MBA, of Sumant has a account, Global Market Insights.

Ongoing research on gene therapy and introduction of nonfactor replacement drugs will provide effective options for hemophilia treatment, he told Medscape Medical News.

In a Hemophilia Treatment Market Outlook report released this month through Global Market Insights, Ugalmugale predicted a growth of 5.3% in the hemophilia A treatment market.

"The increase in prevalence of hemophilia across the globe is due to growing cases of mutation in the gene responsible for producing the clotting factors," he told Medscape Medical News.

There is indeed an increase in people that need to be treated for hemophilia A, said Klamroth, but it's not because more people are being born with the disease.

"For the first time we have a relevant older population with a reduced mortality," he explained. "Before, we infected 50% of our patients with hemophilia with HIV when we gave them blood. A lot of those patients died before treatment, as we have now, was available. Now it's a chronic disease, more or less."

Klamroth has received grants and research support from Bayer, CSL Behring, Biomarin, Novo Nordisk, Octapharma, Pfizer, and Shire and has consulted for Bayer, Biomarin, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire (a Takeda company), and Sobi. Ugalmugale is the senior research manager, Healthcare and Medical Devices, for Global Market Insights.

International Society on Thrombosis and Haemostasis 2019 Congress: Abstract OC 42.1. Presented July 8, 2019.

Editor's note: Data on annualized bleed rates have been updated to reflect final results.

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