Lexiva Launch: Glaxo Makes Aggressive Push Into Protease Market With New and Improved Amprenavir

Glaxo Makes Aggressive Push Into Protease Market With New and Improved Amprenavir

By Rob Camp and Heidi Nass

Fall Harvest: Bumper Crop of New Drug Approvals in 2003
Drug	Novel Mechanism?
T-20	Yes
atazanavir	No
FTC (emtricitabine)	No
fosamprenavir	No

Post-Marketing Oblivion

The U.S. FDA granted accelerated approval to amprenavir (Agenerase) in April 1999. In the intervening four years, clinical management questions have not been studied by the sponsors, and the drug has languished at around the 5% mark of the total protease inhibitor market share. This may have to do with unresolved uncertainties about how best to integrate amprenavir into clinical practice — what with its menacing pill burden (16 pills per day), less than ideal side effects (primarily GI and rash), unelucidated interactions with other commonly used agents and its less than overwhelming efficacy profile.

The only two important interaction studies completed since amprenavir’s 1999 licensure (both of which took more than two years to complete) are for methadone and oral contraceptives.

Now a reformulated, “fos” amprenavir, arrives on the scene. Known among wonkish types by bits of its Vertex code name, “908,” the less messy PI gives GlaxoSmithKline what it sees as a fighting chance to whittle away some of the protease market share from the likes of Abbott, Agouron and Merck. Not unlike the hasty development and approval of its predecessor, the clinical research on fosamprenavir (Lexiva, as it will be marketed) is similarly lacking — at least according to the authors of TAG’s official tract on this the 19th antiretroviral, expected to be waved in to home by the time we hit the newsstand. For Rob Camp and Heidi Nass, the new drug begs the usual questions.

How Should Fosamprenavir Be Used?

In the July 2003 Public Health Service Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents, amprenavir is recommended (and only when boosted with ritonavir) as only an alternative protease inhibitor-based regimen.

Two of the three open-label studies done — Solo and Context — have clearly demonstrated that fosamprenavir, like amprenavir itself, is more potent when boosted with ritonavir. We see no reason to approve another mediocre protease inhibitor without the requirement for co-administered ritonavir.

Is Fosamprenavir Effective?

In all studies to date, this drug has been seen as a mediocre protease inhibitor. In the language of the trial design, it has been seen as non-inferior to (as potent as?) nelfinavir in the Neat study, although not non-inferior (inferior?) to lopinavir/ritonavir in the Context study. The sponsor’s development strategy utilized non-inferiority designs, with an AAUCMB statistical analysis [biostat-ese for “Average Area Under the Curve Minus Baseline”: see your bio-stat wonk manual, v 6.0].

Does the AAUCMB Analysis “Forgive” a Large Dropout Rate?

All studies had significant rates of drop-outs (approximately 30% in the better arms).

Fosamprenavir has been analyzed in an advanced yet naive 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 of any type.

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

What Are the Benefits of Fosamprenavir?

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

The pill burden for fosamprenavir (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 protease inhibitors. (One mustn’t forget the one extra pill — ritonavir — with each administration!)

What Are the Risks of Fosamprenavir?

• The absence of an expanded access program for fosamprenavir may leave the community at a disadvantage in assessing the product in real life. The lack of data comparing fosamprenavir to amprenavir raises many questions regarding bio-equivalence, not least in the panoply of drug-drug interactions.
• The community is greatly concerned that as a sulfa drug, the use of fosamprenavir needs to be monitored when administered with other sulfa drugs and is contraindicated in people with sulfa allergies.
• Depression and “mood problems” hover around 5% and are of particular concern. Headache and sleep disorders are also higher than with amprenavir.

Who Will Benefit From Fosamprenavir?

There are many ill-defined aspects of this drug, including interactions, side effects and resistance, all of which would have been helped through an expanded access program. The generous expanded access programs for amprenavir, which tried to look at questions of lipodystrophy and double PIs, were abandoned in the fosamprenavir development program.

We urge GSK and Vertex to price fosamprenavir cost neutral with Kaletra (lopinavir/r) to afford the greatest number of people the option of using the drug.

What Is Unknown About (or Missing From) the Fosamprenavir Application?

• Influence of gender on efficacy, side effects and toxicities
• Influence of race on efficacy, side effects and toxicities
• Pediatric dosing
• Liquid formulation
• The clinical relevance of the I50V/L mutation
• Once daily vs. twice daily dosing

Resistance

The protease I50V mutation and others at positions 10, 20, 36, 73, 82, 90 were individually associated with a poor virological response to amprenavir, in a univariate analysis. The 459 insertion mutation was significantly associated with a decreased virological response and was more frequent when the V82 mutation was present. In a multivariate analysis, the impact of the 459 insertion mutation remained significant (after adjustment for predictive factors of the virological response) in NARVAL, a French study, and on the protease mutations linked with response.

These results suggest that insertions in the p6 region of HIV-1 gag gene can affect the virological response in highly pre-treated patients receiving an unboosted amprenavir-containing regimen.

In the Neat and Solo studies, emergence of resistance was examined by ViroLogics via genotypic and phenotypic analyses of virus from all individuals with HIV RNA >1,000 copies/mL at two consecutive visits between weeks 12 and the end of study.

In the Neat study, mutations characteristic of development of fosamprenavir resistance were detected in virus from 5/29 (17%) fosamprenavir treated individuals analyzed and included I54L/M, V32I + I47V and M46I. Mutations observed with other protease inhibitors (D30N, I54V, V82, L90M) were not observed with fosamprenavir. Nelfinavir-selected mutations (D30N, N88D/S, or L90M) were detected in 6/26 (23%) nelfinavir-treated individuals analyzed.

In the Solo study, no selection of protease inhibitor resistance by fosamprenavir/r was observed in virus from 31 individuals analyzed. Emergence of resistance with nelfinavir was significantly greater, with D30N and/or L90M detected in 20/55 (36%) nelfinavir-treated individuals analyzed. The absence of resistance selection at 48 weeks in the group treated with fosamprenavir in combination with ritonavir contrasts strikingly with the resistance picture when fosamprenavir is used as a single protease (as in the Solo study). Clearly, this is another reason to recommend its use only when boosted with ritonavir.

Cross Resistance

A poster from the 2003 Retrovirus conference (poster 598) suggests that fosamprenavir virologic failures are still susceptible to the gamut of protease inhibitors (i.e., no cross-resistance). Experience tells us that no matter how good the in vitro data, real life can’t be beat. We do not know what fosamprenavir users switch to — and how well the subsequent therapy works — if they are one of the approximately 30% of people in whom it fails.

Novel early mutations to amprenavir may not initially confer cross-resistance to other PIs, but the subsequent accumulation of additional mutations confers broad cross-resistance to the entire protease inhibitor class.

Fosamprenavir-resistant isolates of HIV have been selected in vitro. Genotypic analysis of these isolates do not show much although the drug has been around for four years! This is simply unacceptable.

What’s Unknown?

1. Amprenavir is defined as a Class C antiretroviral for pregnancy; that is, it has unknown placental passage. A full four years after approval, GSK has not even completed long-term animal carcinogenicity studies on amprenavir — let alone fosamprenavir. (Results of animal teratogen studies were negative, but deficient ossification and thymic elongation were observed in rats and rabbits). We firmly believe that fosamprenavir should be studied and categorized for use in pregnant women.
2. Three ACTG studies were in place at the time of amprenavir’s accelerated approval. One of those had to close because of important interaction issues, while another could not recruit sufficient numbers of study volunteers. Results of the third one have never been fully published. The community hopes that transparency and better definition will be the hallmarks of all subsequent Phase IV studies — both those already begun as well as those requested in our full report.
3. The pediatric formulations need to be devised and studied in newborns and infants.
4. Fosamprenavir/r vs. atazanavir/r (QD) in different populations to help better define the use of fosamprenavir/r in the real world.
5. Another study in advanced patients — fosamprenavir/r vs. tipranavir/r vs. lopinavir/r (all BID) — would be very useful.
6. A pharmacokinetic (PK) assessment in people with different stages of hepatic impairment should be done.
7. What is the significance of the I50L and hypersusceptibility?
8. ACTG studies 5015 (accelerated disease and aging) and 5073 (a DOT study) are fully enrolled and should be reporting results soon.

We cannot say if fosamprenavir is effective in specific populations because the stratified data have not been made available. Fosamprenavir has not been looked at head-to-head with amprenavir, nor has there been an expanded access program. FDA oversight of Phase IV, as previously implied, is a toothless tiger. 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. Fosamprenavir 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?