Intron A (interferon alfa-2b): clinical overview and future directions.

The clinical development of the recombinant alpha interferons represents a prototype for the clinical development of biological compounds. Their testing raises fundamental questions concerning phase I objectives and strategies for biologicals, eg, study design in an immune model v a cytotoxic model. However, with over 5,000 patients treated with these compounds, some general principles have emerged. There is a suggestion of dose-response relationships, and a clearer picture of schedule dependence. The extent of tumor burden and identification of sensitive subtypes of patients also appear to be critical factors in evaluating the true potential activity of biological compounds. The toxicity profile of the alpha interferons is unusual. Fever and flu-like symptoms occur almost universally in all doses and schedules, and are usually dose-limiting. Somnolence and other CNS effects occur in a small percentage of patients. Hematologic toxicity occurs but is minimal at lower doses and is noncumulative and rapidly reversible at all doses. Gastrointestinal toxicity is mild. No other unusual or unexpected toxicities have been reported, and early reports of cardiovascular toxicity have not been confirmed in large trials. The use of these pioneer recombinant DNA products raised concerns about the potential production of antibodies and serum-neutralizing factors. Reports with small patient numbers confirmed the occasional development of serum-neutralizing activity to some alpha interferons, which may coincide with a loss of detectable serum interferon and loss of clinical activity. A large study with interferon alfa-2b (Intron A) has reported a low overall incidence of neutralizing activity (2.5%) and no association with loss of clinical activity. The significance of the neutralizing activity and the reasons for an apparently higher incidence of this phenomenon with other alpha interferon preparations remain to be determined. The full role of alpha interferon by itself or in combination with other available therapies will be resolved in coming years. Efficacy data available to date and phase I combination studies are reviewed.