And speaking of boosting…

By Rob Camp and Heidi Nass

December 2003

Executive Summary

FDA granted accelerated approval to Agenerase® brand amprenavir (NDA 21-007 and NDA 21-039) in April 1999. 908 allows us an opportunity to get an easier-to-use drug from the same molecule.

In fact, over the last four years, clinical management questions have not been studied by the sponsors, and the drug has languished around the 5% mark of protease inhibitors used. This may have to do with uncertainties about how to best use amprenavir as much as with the high pill burden (16) per day. The only two important interaction studies completed since 1999 (which both took more than two years to complete) are for methadone and oral contraceptives.

How should 908 be used? Two of the three open label studies done – Solo and Context – have clearly demonstrated that 908, like amprenavir itself, is more potent when boosted with ritonavir. We see no reason to approve another mediocre PI (without /r). (See sections 4 &6).

In the July 2003 DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents, amprenavir is recommended only with ritonavir as an alternative PI-based regimen (table 12a). (see Section 3).

Is 908 effective? In all studies to date, this drug has been seen as a mediocre PI. In the language of the trial design, it has been seen as non-inferior to (as potent as?) NFV, although not non-inferior (inferior?) to lopinavir/ritonavir (Kaletra®, LPV/r). The sponsor’s development strategy utilized non-inferiority designs, with an AAUCMB statistical analysis (see Section 3).

Does the AAUCMB analysis “forgive” a large dropout rate? All studies had significant rates of drop-outs (~30% in the better arms).

908 has been analyzed in an advanced yet naïve or less advanced but experienced population, but not in a non-advanced population, nor has there been head-to-head comparison with amprenavir or an expanded access program (EAP) of any type.

Co-administered with ritonavir, it is more potent both clinically and virologically. (In Solo, of the few who failed virologically in the 908/r arms, it was due to NRTI resistance and not PI resistance.)

What are the benefits of 908? Unlike amprenavir, 908 does not have major GI tract side effects, reducing from approximately 70% to 5-9% (grades 2-4). 908 also gets better marks than its predecessor regarding rash, with incidence at 2-7% as compared to ~27% with amprenavir. Lab abnormalities do not reach 2% at 24 weeks.

The pill burden for 908 (one pill BID) is greatly reduced from amprenavir (eight pills BID), because it is more water-soluble and is now in line with the pill count of the majority of PIs. We mustn’t forget the one extra pill (ritonavir) with each administration.

What are the risks of 908? The lack of an expanded access program for 908 may leave the community at a disadvantage in assessing the product in real life. The lack of data comparing 908 to Agenerase® raises many questions regarding bioequivalence, not least in the panoply of drug/drug interactions (see Interactions section and Appendix 1).

The community is greatly concerned that as a sulfa drug, the use of 908 needs to be monitored when administered with other sulfa drugs (see Section 4).

The overall incidence of drug-related adverse events, grades 2-4, is statistically similar between 908/ABC/3TC and NFV/ABC/3TC (30% vs 34% respectively) (Neat) and between 908/r/ABC/3TC and NFV/ABC/3TC (41% vs 39%) (Solo). (see Section 5).

What is unknown about 908?

• Influence of sex/gender on efficacy, side effects and toxicities
• Influence of race/ethnicity on efficacy, side effects and toxicities
• Pediatric dosing · Liquid formulation
• The clinical relevance of the I50V/L mutation
• QD dosing vs BID

We cannot say if 908 is effective in specific populations because the stratified data has not been made available. 908 has not been looked at head-to-head with amprenavir, nor has there been an expanded access program (EAP).

FDA oversight of Phase IV, as previously implied, is a lion without teeth. Companies agree to do trials with FDA, and are reminded ad infinitum that they need to be done; if they are not, FDA can pull a drug from the market. This has never happened in the history of the HIV pandemic. 908 is the 19th anti-HIV drug to be approved. Is it time to start pulling approved HIV drugs off market when Phase IV commitments have not been honored? (see Section 7).

Who will benefit from 908? There are many ill-defined aspects of this drug, including interactions, side effects and resistance, all of which would have been helped through an EAP. The generous EAPs of amprenavir, which tried to look at questions on lipodystrophy and double PIs, were abandoned in the 908 development program (see Appendix 2).

We urge GSK and Vertex to price 908 cost neutral with Kaletra® to afford the greatest number of people the option of using the drug.