GSK/Vertex Lexiva Clears FDA With Food-Free Dosing, Broad Indication

GlaxoSmithKline will likely focus on the dosing flexibility of Lexiva (fosamprenavir), including the option to take with or without food, in its marketing of the protease inhibitor.

Lexiva, co-developed with Vertex, was approved Oct. 20. Announcement of the approval touted fosamprenavir, the prodrug of GSK/Vertex' Agenerase (amprenavir), as the first protease inhibitor approved without food or water restrictions.

"Lexiva in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared to the fasted state was associated with no significant changes in amprenavir Cmax, Tmax, or AUC," labeling states.

Agenerase labeling notes it "may be taken with or without food; however, a high-fat meal decreases the absorption of amprenavir and should be avoided."

Lexiva also appears to have a more favorable GI profile. Agenerase's indication includes the bolded "point to consider": that "mild to moderate gastrointestinal adverse events led to discontinuation."

¹ Lexiva labeling presents three possible dosing regimens for therapy-naïve patients: 1,400 mg of Lexiva twice daily monotherapy; 1,400 mg Lexiva once daily plus 200 mg ritonavir (Abbott's Norvir ); once daily; and 700 mg Lexiva twice-daily plus ritonavir 100 mg twice daily.

For protease inhibitor-experienced patients, labeling recommends Lexiva 700 mg plus ritonavir 100 mg twice daily. The once-daily dose of Lexiva plus ritonavir is not recommended.

Other protease inhibitors do not differentiate dosing regimens between treatment-naïve and treatment-experienced patients.

Lexiva's once-daily combination option should allow GSK to argue that the product has the same dosing convenience as Bristol-Myers Squibb's Reyataz (atazanavir).

Reyataz, approved June 20 as the first once-daily protease inhibitor, captured 10% of the protease inhibitor market in its first two weeks. Abbott's Kaletra (lopinavir/ritonavir) is the market leader, with 37.4% (² (Also see "HIV Treatment Guidelines Give Kaletra Timely Boost As Reyataz Launches" - Pink Sheet, 21 Jul, 2003.), p. 22).

As with Reyataz, Lexiva was approved with a broad indication for both treatment-naïve and -experienced patients, although both Reyataz and Lexiva failed to show non-inferiority to other drugs in treatment-experienced patients, labeling says.

The 48-week CONTEXT study compared Lexiva once- and twice-daily plus ritonavir to lopinavir/ritonavir twice-daily in 315 treatment-experienced patients.

The mean time-averaged change from viral load at baseline (log10 copies/mL) was -1.4 for twice-daily Lexiva and -1.67 for lopinavir/ritonavir, which was not statistically significant.

Lexiva did show non-inferiority to its comparator on a secondary endpoint, the proportion of patients achieving HIV-1 RNA <400 c/mL. The results were 58% for twice-daily Lexiva plus ritonavir vs. 61% for lopinavir/ritonavir.

Two studies in treatment-naïve patients compared Lexiva with or without ritonavir to nelfinavir (Pfizer/Agouron's Viracept ). Lexiva showed comparable or superior results in both trials.

GSK expects to have Lexiva on pharmacy shelves in November, with a wholesale acquisition cost of $480 for sixty 700 mg tablets, a price the company calls "competitive" to Reyataz and Kaletra.

GSK will perform a postmarketing study to assess the interaction of Lexiva with a proton pump inhibitor. FDA requests such studies on a case-by-case basis based on preliminary observations of the effects of stomach acid on the product. Reyataz has a precaution against co-administration with PPIs.

The other Phase IV commitments include further in vitro testing of combination activity relationships with efavirenz (Bristol's Sustiva ) and delavirdine (Pfizer's Rescriptor ), animal toxicity and carcinogenicity studies, interaction studies with atazanavir, and dosing studies for patients with hepatic impairment.

FDA received the NDA (21-548) on Dec. 20, 2002; the product received standard review and approval.