First and Second Generation Recombinant Factor VIII Concentrates in Previously Untreated Patients: Recovery, Safety, Efficacy, and Inhibitor Development

ABSTRACT The first of the prospective multicenter studies in previously untreated patients (PUPs) with a recombinant factor VIII (FVIII) concentrate began in January 1989. Over the past 11 years, PUP studies have amassed a great deal of information concerning safety, efficacy, and inhibitor development of the two ``first-generation'' recombinant (r) FVIII concentrates (Kogenate℗ and Recombinate℗) and of two ``second-generation'' products (ReFacto℗ and Kogenate FS℗, which is formulated with sucrose rather than with albumin). Each of these products has proved to be safe, effective, and well-tolerated. Side effects have been rare and mild in nature. There have been no clinical reactions to hamster or murine proteins. During the course of the multinational PUP trials with Kogenate, Recombinate, and ReFacto, inhibitors developed in 29.7, 31, and 33%, respectively, of severely affected PUPs. Half of these were high titer and half were low titer. In each of these trials, several inhibitors were transient. PUPs and minimally treated patients (MTPs) in the Kogenate SF trial have not been followed long enough to determine the incidence of inhibitor development; however, the product appears to be safe and effective. Following demonstration of safety and efficacy with each rFVIII concentrate in previously treated patients with hemophilia A, studies in PUPs began. In general, the prospective trials in PUPs with each recombinant product were conducted similarly, allowing comparison of data. This article is intended to provide a review of the experience with both first- and second-generation rFVIII products in the prospective clinical trials in PUPs.