Tibotec: Safety Warning Highlights Limitation of Protease Inhibitors

Following 15 cases of liver damage and several deaths in Prezista trial patients, the FDA and Tibotec have issued a safety warning. Although Datamonitor believes that this will have a limited impact on the drug’s future performance, the safety warning highlights the overall need for protease inhibitors with a better toxicity and tolerability profile.

Protease inhibitors (PIs) have become a cornerstone in antiretroviral therapy, achieving total sales in 2007 of $3 billion across the US and EU5 (France, Germany, Italy, Spain, and the UK), according to IMS. The market leaders in this class are Abbott’s Kaletra (lopinavir/ritonavir) and Bristol-Myers Squibb’s Reyataz (atazanavir) with each drug accounting for almost one third of total class sales in 2007. Factors contributing to the large success of Kaletra include once-daily dosing formulation, potent antiviral efficacy and a good resistance profile, while Reyataz is credited with a very good cardiovascular and GI safety profile.

Tibotec’s PI Prezista (darunavir) was approved in 2006 for use in highly treatment-experienced HIV patients. Prezista is in competition with Boehringer Ingelheim’s Aptivus (tipranavir) in this patient subgroup, and, because of this, Tibotec is aiming to achieve approval for the drug in earlier lines of HIV treatment in order to increase the market opportunity. In a head-to-head trial of once daily Prezista against Kaletra in treatment naive patients (ARTEMIS study), Prezista demonstrated non-inferiority and had a slightly better side effect profile. These results support an approval for first line use, which is likely to be granted in 2008.

However, after fifteen cases of liver problems and several deaths occurred in Prezista patients during clinical trials, the FDA and Tibotec have now published warnings of potentially fatal liver damage in patients taking Prezista. Despite this, Datamonitor believes that the impact on Prezista’s overall future performance will be limited: the hepatic adverse events were mostly observed in treatment-experienced patients with co-existing liver disease and could not be clearly linked to Prezista, since patients received multiple drugs at a time. Furthermore, since Prezista will be used in a lower dose in treatment-naive patients than in the currently approved indication, its competitiveness versus Reyataz in first line use should be unaffected.

However, the warning issued by Tibotec and the FDA has highlighted a significant issue with all PIs: their suboptimal tolerability profiles. Indeed, toxicity is a general problem associated with the PI class: Prezista’s direct competitor Aptivus carries a boxed warning for hepatotoxicity and intracranial hemorrhage, while Kaletra is associated with dyslipidemias, gastrointestinal adverse effects and hyperbilirubinemia. Despite the drug class’s position as a ‘cornerstone’ in HIV treatment, the fact remains that PIs suffer a crucial limitation in their application to antiretroviral therapy.