Atazanavir approval recommended in US

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with additional reporting by Bob Huff, editor of GMHC Treatment Issues (the monthly treatment newsletter of Gay Men's Health Crisis, New York)

A panel of US HIV experts has voted unanimously in favour of US Food and Drug Administration approval of atazanavir, the new once daily protease inhibitor developed by Bristol Myers Squibb. The FDA is likely to announce its decision by June 20.

Atazanavir approval was recommended for use in combination therapy without specifying whether its use should be restricted to treatment-naïve patients, but the FDA has the latitude to make the final decision on the license.

Glossary

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

lipid

Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

The panel expressed concerns over evidence of efficacy in treatment-experienced patients, particularly where the drug is not boosted by ritonavir, but did not make a firm recommendation against its use in this population.

The decision leaves the door open for the FDA to apply restrictions, but advisory panellists gave a clear steer in favour of across the board approval in discussions at the public hearing.

“We would not be well advised to take the position that it should not be used in treatment-experienced patients because it didn’t perform as well as Kaletra” said Professor Christopher Matthews of University of California San Diego, referring to data from the 043 study, which showed that atazanavir 400mg was inferior to lopinavir/ritonavir after 24 weeks in PI-experienced patients.

Panel chairman Roy Gulick of Cornell University, New York, noted that the data suggesting inferiority of unboosted atazanavir to lopinavir/ritonavir needed to be considered in the light of information on atazanavir resistance presented at the meeting, which would allow clinicians to optimise atazanavir treatment with ritonavir boosting if a resistance test led them to expect a problem with overcoming protease inhibitor resistance.

Richard d`Aquila of Vanderbilt University, Tenessee, said that he expected a phenotypic cut-off of around 2.5-fold loss of susceptibility would prove to be appropriate for atazanavir, with a higher cut-off point when the drug is boosted with ritonavir. He also noted that the greatest potential use of the drug is likely to be after first-line PI failure, rather than later.

Concern about the possibility of a low inhibitory quotient for atazanavir was expressed by Rob Camp of the Treatment Action Group, who reminded the panel that Bristol Myers Squibb had selected the 400mg dose because it caused less hyperbilirubinemia. If it is possible to identify individuals not at risk of hyperbilirubinemia, is dose escalation an option to prevent viral breakthrough, he asked?

Ritonavir boosting of atazanavir

Last year, Bristol Myers Squibb had provided the FDA with 16 week data on 106 patients from its 045 study, which compared atazanavir/ritonavir with atazanavir/saquinavir and lopinavir/ritonavir. At the meeting BMS was able to present full 24 week data on all randomised patient, showing that atazanavir/ritonavir has a similar effect on viral load to lopinavir/ritonavir, whilst improving cholesterol and triglyceride levels substantially in patients with multiple PI experience. (Click here for summary of the data presented yesterday).

FDA reviewers said that they would not have time to review the additional data for safety before the June 20th cut-off date.

The 045 data will be presented in more detail at the International AIDS Society conference in Paris, which takes place July 13-16.

Effect of atazanavir on lipids

The panel concluded that atazanavir offers a significant benefit in terms of its lack of effect on lipids when compared with other agents, although FDA reviewers stressed that the cardiovascular benefit remains undefined.

Prof. Christopher Matthews called on the FDA to avoid product labelling that might overstate the lipid benefits for treatment-experienced patients receiving ritonavir-boosted atazanavir, until further data are available.

Rob Camp of the Treatment Action Group commented that atazanavir labelling should make clear to patients that the drug’s favourable effects on lipids are not proven to extend to lipodystrophy.

Side effects

As mentioned earlier, the 400mg dose of atazanavir was selected because it was associated with a lower incidence of hyperbilirubinemia (elevation of bilirubin, which can lead to jaundice or yellowing of the skin and eyes). The hyperbilirubinemia is not an indicator of liver damage, the panel concluded. Baseline bilirubin levels appear to predict who will develop the greater bilirubin elevations that lead to jaundice, and could be used to screen out people who may experience this unacceptable side-effect before starting treatment. The form of hyperbilirubinemia seen in atazanavir-treated patients (unconjugated) is not sufficiently serious to warrant a dose reduction, advised Kenneth Sherman of the University of Cincinatti, the panel’s expert hepatologist. Dose reduction, given the relatively low inhibitory quotient of atazanavir, might lead to treatment failure, and discontinuation is the preferred option.

There was some disagreement over the implications of cardiac disturbances seen in small numbers of patients (QT prolongation and PR interval). Whilst some panel members felt that ECG monitoring was advisable at baseline, it was concluded that monitoring was only appropriate for people with existing heart conditions or concomitant medication known to affect QT or PR interval), and that atazanavir did not provide any greater concern than other protease inhibitors already licensed.

Dosing and drug interactions

On the critical question of what food atazanavir could be taken with, BMS revealed that taking the drug with a light meal of around 350 calories resulted in higher drug availability, whilst a larger meal of around 900 calories, high in fat, resulted in similar drug availability to taking atazanavir on an empty stomach. As usual, the FDA panel failed to ask questions that could save a lot of confusion amongst patients later on, such as: what is the effect of a meal greater than 900 calories? Is the blunting of absorption mediated by fat, or by food volume? How long after a large meal should patients wait before taking atazanavir for the best results? As with nelfinavir, the food issue is likely to come back and haunt the manufacturer without further data, given the relatively low genetic barrier to resistance for this protease inhibitor. Low drug levels could lead to resistance, especially in patients with a genetic tendency towards lower blood levels of drugs metabolised by the cystochrome p450 3A4 route.

Atazanavir should not be taken with antacids, since a reduction in stomach acidity will reduce drug absorption. They should be taken at least two hours before or after atazanavir.

FDA website

FDA advisory committee webscast and report

Further information on this website

Atazanavir – data from previously presented studies and drug overview