Recombinant Factor VIII products increase inhibitor development in severe hemophilia A

Issue: February 10, 2016

ORLANDO, Fla. — Recombinant Factor VIII replacement products for severe hemophilia A appeared to increase inhibitor development 1.87-fold compared with products in the plasma-derived class, according to study results presented during the plenary session of the ASH Annual Meeting and Exposition.

Perspective from Donna Dimichele, MD; Beth Boulden Warren, MD, and Brian Branchford, MD

Flora Peyvandi, MD, PhD, associate professor of internal medicine at University of Milan and head of the internal medicine department and of the Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre of Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico in Milan, Italy, and colleagues conducted this multicenter, open-label, randomized study to evaluate whether the rate of inhibitory alloantibody development differed based on the source of Factor VIII replacement — plasma-derived or recombinant — in previously untreated patients with severe hemophilia A.

“One of the most important complications in the management of severe hemophilia A is the development of inhibitors present in almost one-third of the children,” Peyvandi said during her presentation during the plenary session. “That is a major challenge — to identify the risk factor for the development of inhibitors.

“Some of the risk factors, like Factor VIII gene mutation, are well-established,” she added. “However, some other risk factors related to the treatment regarding exposure during the treatment and the intensity of the treatment are still a matter of discussion. [We wanted to look] at the type of Factor VIII concentrate and its relation to the development of inhibitors.”

The researchers enrolled 303 previously untreated patients between 2010 and 2014 who were screened at one of 42 participating centers in 14 countries.

After 39 screening failures and 13 exclusions, researchers evaluated data from 251 patients aged 0 to 81 months (median age, 14 months). From that group, 35 had shortened follow-up due to study dropout or termination

Researchers randomly assigned patients 1:1 to receive one product within the plasma-derived (n = 125) or the recombinant (n = 126) Factor VIII class. The product selected from the class was allocated based on site licensing and availability.

Researchers then monitored patients for inhibitor development, which served as the study’s primary endpoint (≥ 0.4 BU/mL). The development of high-titred inhibitors (peak levels ˃ 5 BU/mL) served as a secondary outcome.

Patients received between one and 50 infusions (median, 22) of Factor VIII concentrates.

Overall, 76 patients developed an inhibitor — 50 of which were high-titred for a cumulative inhibitor incidence of 35.4% (95% CI, 28.9-41.9). Ninety percent of the inhibitors developed within 20 exposure days.

Among patients who did not develop an inhibitor, more than 70% had at least 20 exposure days.

Inhibitors developed in 29 patients in the plasma-derived cohort (20 high-titred) and 47 patients (30 high-titred) in the recombinant cohort. These data equated to a cumulative inhibitor incidence of 26.7% (95% CI, 18.3-35.1) for plasma-derived Factor VIII replacement and 44.5% (95% CI, 34.7-54.3) for recombinant Factor VIII replacement.

The cumulative incidence of only high-titre inhibitors was 18.5% (95% CI, 12.1-26.9) in the plasma-derived cohort and 28.4% (95% CI, 19.6-37.2) in the recombinant cohort.

Results of a univariate analysis indicated recombinant replacement increased inhibitor development 87% compared with plasma-derived products (HR = 1.87; 95% CI, 1.18-2.97). Further, recombinant replacement appeared associated with a 70% increase in high-titre inhibitor development (HR = 1.7; 95% CI, 0.96-2.99).

These rates appeared comparable in adjusted models and analyses of sites that did not randomly assign patients to one of the study arms.

“We can say that patients treated with recombinant factor VIII have an 87% higher risk to develop inhibitors than those treated with plasma-derived containing von Willebrand factor,” Peyvandi said. “This difference remained even when second-generation, full-length recombinant Factor VIII concentrate was excluded from the analysis.

“Finally, these findings are clinically important due to the development of inhibitors, [which is] the major thrombotic complication in hemophilia A and causes a marked increase in morbidity, mortality and treatment cost.” – by Anthony SanFilippo

Reference:

Peyvandi F, et al. Abstract 5. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: This study was funded in part by Grifols, Kedrion and LFB. Peyvandi reports research funding and honoraria from, consultant/advisory roles with, and other financial relationships with Bayer, CSL Behring, Kedrion, LFB, Novo Nordisk, Octapharma and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Donna Dimichele, MD

The protein characteristics that should be brought to attention are the association of Factor VIII with its carrier protein von Willebrand factor and the glycosylation of both von Willebrand factor and the non–B-domain sites of Factor VIII, both of which have the great propensity to alter peptide presentation to T cells and both of which are different in recombinant and plasma-derived products.

The clinical studies have not been clear have been to date. Multiple studies, mostly observational and largely retrospective, have produced RRs, HRs and ORs between 1 and 6 when comparing the risk for inhibitor development in recombinant and plasma-derived products. The most recent of these, and the largest, is a prospective study that demonstrated no difference and replicated the results of a Cochrane analysis 10 years earlier.

This study is the first prospective, randomized comparison of either plasma-derived or recombinant products on neutralizing anti-Factor VIII antibodies in an international cohort of previously untreated or minimally treated children. This study controlled for major significant host treatment-related risk factors enabling it to really study product classes and independent variables.

The study’s influence on future choice of product class on the treatment for the treatment of infants and children with severe hemophilia is unclear because this is a multifactorial decision.

But the significance of this study is that it brings new data to bear on this enigma of Factor VIII immunogenicity. Hopefully it moves us closer to the knowledge that will reduce and prevent all anti-drug antibodies in at-risk individuals with hemophilia A.

Donna Dimichele, MD

National Heart, Lung, and Blood Institute

National Institutes of Health

Disclosures: Dimichele reports no relevant financial disclosures.

Perspective

Beth Boulden Warren, MD, and Brian Branchford, MD

Beth Boulden Warren

Brian Branchford

In the 1970s, lyophilized plasma-derived Factor VIII (FVIII) revolutionized hemophilia care, allowing for home treatment. However, devastating viral contamination in the 1980s spurred development of viral inactivation procedures and recombinant FVIII products. The rise in recombinant factor use correlated with increased anti-FVIII
alloantibody (“inhibitor”) incidence. Traditionally, recombinant factor products do not contain von Willebrand factor and are produced in non-human mammalian cell lines, raising questions about the role of von Willebrand factor and the production process in inhibitor development.
The presentation of the SIPPET trial (Survey of Inhibitors in Plasma-Product Exposed Toddlers) during the plenary session at the ASH Annual Meeting and Exposition addressed these questions. In this investigator-initiated, open-label, multicenter (42 sites in 14 countries), randomized controlled trial, 251 treatment-naive patients with severe hemophilia A were randomly assigned to receive either recombinant FVIII or plasma-derived FVIII/von Willebrand factor, and then followed for 50 factor exposures or 3 years.
The study showed a 1.87-fold higher inhibitor incidence (1.7-fold higher high-titre inhibitors) in the recombinant FVIII group compared with the plasma-derived FVIII group, a difference that remained statistically significant even when excluding second-generation recombinant FVIII concentrates with reported increased inhibitor risk and adjusting for putative confounders such as FVII mutation. The trial demonstrated a higher inhibitor incidence than previously reported, potentially because of enrollment bias toward patients with higher inhibitor development risk.
The SIPPET trial joins two previous randomized controlled trials in shaping pediatric hemophilia treatment. The Joint Outcome Study demonstrated improved joint outcomes in patients who received prophylactic FVIII therapy in childhood compared with those who received on-demand FVIII therapy. The International Immune Tolerance Study showed that daily high-dose FVIII immune tolerance regimens decreased bleeding episodes and time to inhibitor tolerization compared with low-dose regimens.
In the emerging landscape of long-acting recombinant FVIII products, the overall clinical impact of the SIPPET trial is not yet clear, but these provocative results will help shape the future of hemophilia care.

References:

Calvez T, et al. Blood. 2015;doi:10.1182/blood-2014-07-586347.
Gouw SC, et al. Blood. 2013;doi:10.1182/blood-2012-09-457036.
Hay CR, et al. Blood. 2012;119:1335-1344.
Lee CL. Textbook of Hemophilia. Hoboken (NJ): Wiley-Blackwell;2010.
Manco-Johnson MJ, et al. N Engl J Med. 2007;357:535-544.
Wight J, et al. Haemophilia. 2003;9:418-435.

Beth Boulden Warren, MD, and Brian Branchford, MD

University of Colorado Anschutz Medical Center

Disclosures: Branchford and Warren report no relevant financial disclosures.