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Policy Report on Application for Ageneras Approval

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February 19, 1999

Introduction


If one should hear yawns emanating from the consecrated halls of the Food and Drug Administration (FDA), it's possible that the team evaluating the New Drug Application (NDA) for Agenerase™ brand amprenavir is responsible. The HIV treatment community seems equally detached as it looks ahead to the seemingly more potent ABT-378 and a couple of early stage compounds with wished-for efficacy against protease mutated virus. Regardless, amprenavir is likely to become the youngest member of the protease party of five since preliminary data suggests that its strength and safety are comparable to its approved forerunners. Though ordinary in many ways, amprenavir offers the expedience of twice per day dosing without dietary restriction. 

Amprenavir, formerly known as 141W94 and VX-478, belongs to the class of anti-HIV drugs known as protease inhibitors. In combination with two nucleoside analogue reverse transcriptase inhibitors, protease inhibitors are associated with lower mortality and improved clinical outcomes in the management of HIV. In various combinations, amprenavir has demonstrated potent activity in treatment naïve patients though it has not shown much performance in protease inhibitor experienced patients. Thankfully, a number of more finely tuned studies in PI-experienced populations are in progress.

On October 15, 1998, Glaxo-Wellcome submitted a regulatory application to market Agenerase™ in the United States with similar applications following quickly in Canada and the European Union. The FDA put Agenerase™ on fast track review and is expected to approve the application without the customary committee hearing during the early part of 1999. A pediatric formulation of Agenerase™ is reportedly included in the petition for each territory.

Policy Position: Based on our review of publicly available data, TAG supports accelerated approval of Agenerase for use by adults in combination with other antiretrovirals for the treatment of HIV. In lieu of a committee hearing, the FDA should post a summary of its data set analyses on its internet site within a week of sponsor notification. 

Data Summary


In a Phase III randomized placebo-controlled international study, the combination of amprenavir/AZT/3TC was superior to AZT/3TC alone in reducing viral load in treatment naïve patients. In an intent to treat analysis using an assay with a 50 copies/ml lower limit of detection, 67% (56/83) of those receiving triple therapy achieved undetectable viral load versus 17% (16/93) in the AZT/3TC arm. The median CD4 count increase was about 110 cells/mm3 for the amprenavir combination arm versus about 70 cells/mm3 for AZT/3TC. (Goodgame et.al. poster 76 from the 4th International Congress on Drug Therapy in HIV Infection 1998).

Policy Position: TAG deplores the antiquated, unethical AZT/3TC control arm in Glaxo's phase III study comparing AZT/3TC to AZT/3TC/amprenavir and urges it and other sponsors to abandon control arms that utilize sub-optimal treatment regimens unlikely to lead to maximal viral suppression.

Two small studies of amprenavir in combination with Ziagen™ brand abacavir indicated potent activity in treatment naïve patients. In the first study, 8/9 patients maintained viral load below 50 copies through week 48. The average increase in
CD4 cells was 200 cells/mm3. In the second study, sixty percent of patients had HIV RNA levels fall to below 50 copies/ml at week 16 (Bart et.al. abstract 12204, Kelleher et.al. abstract 12210 from 12th World AIDS Conference, Geneva 1998). 

In an open label study of all four of Glaxo's antivirals (AZT/3TC formulated as Combivir, abacavir and amprenavir) in patients that were naïve to protease inhibitors and 3TC, 75% of patients registered viral loads below the 100 copies/mL limit of detection at week 20. All 19 patients reaching the 52-week point had viral loads sustained below 50 copies mL (Kost et al. Abstract 639 from 6th Conference on Retroviruses and Opportunistic Infections 1999).

In a randomized but open label multicenter trial of amprenavir in combination with either indinavir, nelfinavir, saquinavir (soft gel capsule) without NRTI's versus amprenavir/AZT/3TC in 33 PI naïve patients, viral load reductions exceeded 1.5 logs in all arms after 48 weeks. Reductions were greater than 2 logs in the indinavir and nelfinavir arms (Eron et.al. poster 84 from the 4th International Congress on Drug Therapy in HIV Infection 1998). As patients and their doctors begin experimenting with "class sparring" treatment strategies, the availability of amprenavir will expand the range of viable multi-PI drug cocktails.

Resistance Data


In vitro studies have shown that mutations conferring cross-resistance to other PI's develop after sustained exposure to amprenavir. However, as with other anti-HIV drugs, amprenavir resistance develops sequentially, and virus having the most common initial amprenavir mutations at residues 50, 46, and 47 is reportedly sensitive to saquinavir, indinavir and to a lesser extent nelfinavir (Glaxo provided data). This prompted researchers to study whether patients failing amprenavir could benefit if quickly switched to a potent alternative therapy.

In an ACTG-sponsored "roll-over" study - in which investigators monitored the subsequent treatment of patients who had "failed" amprenavir therapy in the initial trial - 70% of patients achieved (or maintained) viral loads below 500 copies/mL at week 8, generally using a four drug regimen of indinavir, nevirapine, d4t, and 3TC. Subjects who rolled over from the trial's monotherapy arm fared the best since they were RTI naïve (Gulick et.al. abstract from the 4th International Congress on Drug Therapy in HIV Infection 1998). Caution is advised in interpreting these results since patients were treated in a controlled clinical trial setting not necessarily reflecting real world conditions. It is important to note that some of the treatment "failures" had not reached a virologic endpoint in the previous trial either because they dropped out from toxicity or were simply part of the discontinued monotherapy arm. Longer-term analysis of this data is warranted.

Salvage Study


In a single arm salvage study, heavily pretreated patients were given a cocktail containing efavirenz, abacavir, and amprenavir. At week 16, only 39% experienced a 0.5 log or greater reduction in viral RNA to this potent regimen. NNRTI naïve patients fared the best, suggesting that amprenavir's role in treatment effect was secondary. As all three drugs cause rash, one-half of patients developed a rash during study. Notably, the incidence of abacavir-associated hypersensitivity syndrome was higher than what has typically been seen in other studies. (Falloon et.al. poster 396: 36th Annual Meeting of the Infectious Diseases Society of America 1998). Data from salvage studies employing amprenavir in combination with other protease inhibitors is urgently needed.

Policy Recommendation: Longer-term safety and efficacy data for multi-protease drug cocktails are needed. Studies should seek to determine whether any synergistic or cross-resensitization effects exist among approved and late-stage development protease inhibitors.

Ongoing Trials

A number of clinical trials involving amprenavir are ongoing.

  • Phase III trial comparing amprenavir to indinavir as part of a standard of care HAART regimen in 460 protease naïve patients. 
  • Phase III pediatric trial. 
  • ACTG 388: in which patients failing indinavir or nelfinavir HAART are being treated with a four-drug salvage regimen including amprenavir. 
  • ACTG 398: a study of amprenavir along with abacavir efavirenz, adefovir plus either indinavir, saquinavir or nelfinavir in 400 patients that failed HAART. 
  • ACTG 400: a randomized study of various salvage regimens in 300 nelfinavir failures. Each arm incorporates efavirenz along with two NRTI's plus either amprenavir, indinavir, saquinavir/ritonavir, or amprenavir/indinavir. 


Safety and Tolerance

Amprenavir appears to be relatively safe and well tolerated though its side effects appear no less troublesome than the approved PI's. According to data from Glaxo Wellcome's safety database, 28% of patients developed rash, 25% felt numbness around the mouth, and more than half suffered some mixture of nausea, vomiting, and diarrhea (Pedneault et.al. abstract 386 from the 6th Retrovirus Conference 1999). Most adverse events, including the rash, are mild to moderate in severity, transient, and require no or only temporary interruption of treatment. One case of Stevens Johnson syndrome was seen but it was attributed to other drugs taken by the patient. 

Policy Recommendation: The sponsors of all rash causing anti-HIV drugs should jointly issue guidance to help doctors differentiate and manage the various rashes.

There are not yet enough data to know whether amprenavir will cause elevated glucose, triglycerides or cholesterol though these conditions have been seen, albeit infrequently, in clinical trials. Research recently presented by Glaxo Wellcome suggests that amprenavir's unique chemical structure may make it less likely than other protease inhibitors to disrupt lipid synthesis and hydrolysis (Lenhard et.al. posters 665, 666 from 6th Conference on Retroviruses and Opportunistic Infections).

Policy Recommendation: We encourage Glaxo Wellcome to continue its research into the causes of lipodystrophy and applaud its implementation of Expanded Access Protocol 30012 which seeks to determine whether switching patients from their current PI to amprenavir can alleviate lipodystrophy symptoms.

Pharmacokinetics

Amprenavir is conveniently dosed twice per day and may be taken with food or on an empty stomach. This makes amprenavir a good confrere for the NRTI's which are generally given twice per day. The recommended 1,200mg BID dose of amprenavir is administered in the form of 8 large soft gelatin pills which may be difficult to swallow, store in pillboxes and transport. An alternative liquid formulation of amprenavir has been developed and is expected to receive FDA approval along with
the oral pill form.

Amprenavir is touted as having a very low molecular weight and favorable solubility characteristics raising hopes that the agent may achieve greater penetration into difficult to reach parts of the body including the brain and testes. Findings released at the 12th World AIDS Conference showed that 8/9 PI naïve patients receiving the triple combination of amprenavir/AZT/3TC achieved CSF viral load levels below 400 copies/mL which was the limit of detection for the assay (8th Annual Neuroscience of HIV Conference 1998). Comparative CSF viral load data was not available for the two drug combination nor was baseline data for the triple therapy patients and so amprenavir's contribution to the viral load reduction is unclear as are the clinical implications of a CSF viral load reduction.

Data were presented at the 6th Retrovirus Conference in February 1999 from a study that monitored the viral load in semen collected from a small group of patients participating in ACTG 347. Fourteen of the 19 men receiving amprenavir monotherapy either maintained or achieved undetectable virus in semen plasma (below 400 copies/mL) at week 8 (Eron et.al. abstract 222 from the 6th Conference on Retroviruses and Opportunistic Infections 1999). The clinical and epidemiological implications of viral load reductions in semen are unclear at this time.

Amprenavir is a substrate and moderately strong inhibitor of p4503A4, a hepatic enzyme that contributes to the metabolism of several other drugs. As a result, clinicians will need to be mindful of amprenavir's potentially serious drug interactions. The anti-tuberculosis drug rifampin should not be co-administered with amprenavir due to accelerated rifampin metabolism, and the dosage of rifabutin (MAC prophylactic) should be decreased when used with amprenavir (Polk et.al. abstract 340 from the Fifth Conference on Retroviruses and Opportunistic Infections1998). Very serious effects can also result from co-administration of a number of other drugs including ergot alkaloids, the contraband Seldane, and sleep inducers Halcion and Versed.

There are similar interactions with other anti-HIV drugs. Sustiva, for example, has been shown to significantly reduce blood levels of amprenavir (AUC -36%) (Sadler et.al. abstract 12389 from the 12th World AIDS Conference 1998). Amprenavir somewhat lowers levels of indinavir and saquinavir, though levels of nelfinavir are increased when it is taken in combination with amprenavir. 

The children's dose is 20 mg per kg of body weight administered twice per day. A smaller 50-mg pill formulation is included in the FDA submission. Data from a partially enrolled open label pediatric trial of amprenavir in combination with 2 NRTI's was presented at the 6th Conference Retroviruses. The treatment was well tolerated with only two children dropping out as the result of adverse events. The overall reduction in HI viremia at week 8 was just 0.8 log though PI naïve patients had a median 1.4 log drop in viral load versus a 0.38 log reduction for those with previous PI usage (Yogev et.al. abstract 430 Sixth Conference on Retroviruses and Opportunistic Infections 1999). No studies have yet looked at amprenavir's effect on reducing the rate of prenatal transmission.

Policy Position:TAG chooses not to express an opinion on the pediatric indication based on the limited amount of data that are publicly available at this time.

Expanded Access

After some unparsimonious haranguing with AIDS Treatment Activists, Glaxo announced an expanded access program for Agenerase™ on September 21, 1998. In an effort to garner useful data from the program, access to the drug is segregated
into three separate protocols:

  • Protocol 30011 - This expanded access protocol is designed to determine whether adding a second protease inhibitor to a regimen containing amprenavir, abacavir and a couple of RTI's improves treatment outcome in heavily pretreated patients. The choice of whether or not to use the second PI (and which second PI to employ) is left to the patient and his/her doctor. The trial is open to adults and adolescents over the age of 13 who have failed at least one PI, have a CD4 count less than 400 and viral load greater than 10,000.
  • Protocol 30012 - This trial was established to determine whether patients suffering the effects of lipodystrophy syndrome and/or hyperlipidemia benefit from switching their current PI to amprenavir. It is open to adults and adolescents > 13 years of age who are not failing their current regimen (defined as viral load < 10,000) but who are experiencing hyperlipidemia (abnormally high fat levels in the blood) with or without lipodystrophy. Concomitant use of another protease inhibitor is not permitted.
  • Protocol 30010 - This arm is similar to a traditional expanded access program. It is open to adults and children age 4 and above who have failed or become intolerant to treatment with at least one protease inhibitor. Patient demand for this protocol has reportedly been strong. 


Marketing Issues:

Should amprenavir be approved, it will be the fifth protease inhibitor to the market. As such, Glaxo would be wise to consider a price for amprenavir that reflects the drug's simpler molecular structure and manufacturing process.

Policy Position: The price for amprenavir should reflect the drug's simpler molecular structure and manufacturing process. Thus, we anticipate that it will be less expensive than the price leaders in its class.

Given the limited data regarding amprenavir's propensity to cause cross-resistance, lipodystrophy symptoms, and its ability to penetrate the CSF and semen, we strongly urge the sponsors to avoid premature claims before the facts are established through well-controlled long-term clinical trials. In particular, we urge Vertex Pharmaceuticals, the original developer of amprenavir, to assume a posture of "under promise and over deliver" and avoid overzealous innuendo in its corporate image ads and press releases.