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Close to the Vest

tagline 1997

Eluding Public Scrutiny, Nelfinavir Becomes the Fourth Protease Inhibitor to Hit the Pharmacy Shelves

Resistance enigma

The US Food & Drug Administration (FDA), which will soon be under the control of Acting Commissioner Dr. Michael Friedman when Commissioner Dr. David Kessler leaves to run the Medical School at Yale University, is facing a controversy over approval of a promising new anti-HIV drug. On Friday, March 14th the US Food and Drug Administration approved Agouron Pharmaceuticals' Viracept brand nelfinavir, a new HIV protease inhibitor, without a public hearing of its Antiviral Drugs Advisory Committee.

AIDS activists are concerned that, without a hearing, there will be no publicly available objective review of Agouron's data set. In the past, such review has turned up discrepancies between data that were presented to FDA, and data that had been presented in earlier community meetings. For instance, in presentations to AIDS activists, Serano Laboratories which manufactures recombinant Human Growth Hormone for treatment of AIDS-related wasting, claimed a survival advantage. However, as FDA pointed out, no such advantage could be shown based on the company's data. Activists emphasize that the concern is a procedural one, and is not related to the particular drug. Early studies have suggested that nelfinavir is a relatively safe and potent new anti-HIV therapy.

In three early studies, more than 700 patients were treated with nelfinavir alone or in combination with either d4T or AZT+3TC. Subjects included both both antiretroviral-naïve and antiretroviral-experienced patients. Average CD4+ cell counts at baseline ranged from 200 to 300 cells/mm3, and average HIV RNA levels were just below 100,000 copies/mL. Patients taking nelfinavir in combination with AZT+3TC had an average reduction in HIV RNA levels of about 2.5 logs (using an assay with a sensitivity of 100 copies/ml). Sixty-five to 81% of these patients had reductions in viral load to < 500 copies/ml when the Chiron second generation bDNA assay was used. By comparison, patients treated with AZT+3TC experienced an average viral load drop of about 1.5 logs. In a study of patients taking nelfinavir in combination with d4T, the average viral load drop was also about 2.5 logs when the more sensitive assay was used and about 1.5 logs when a cut-off of 1,200 copies was used. 76% of patients in the d4T+NFV group had plasma viral load reductions to levels < 500 copies/ml. By contrast, patients receiving only d4T monotherapy experienced about a .5 log reduction in viral load on both assays.

In general, nelfinavir has an acceptable safety profile: the main side effect is diarrhea, which the company describes as loose stools, "like what you'd get after eating a Mexican meal." Overall, about eleven percent of study participants discontinued treatment due to side effects. More common, it seems, per reports from several nelfinavir pioneers is a nasty case of ozone-withering flatulence, which may abate after the first couple of weeks but often returns -- uncontrollably so -- with little notice.

Nelfinavir, like other marketed protease inhibitors, is processed through a pathway in the liver known as CYP3A. Many drugs are processed in this way, and these drugs may interact with nelfinavir. In particular, rifabutin levels in the blood are increased two-fold by nelfinavir, and therefore rifabutin doses should be reduced by one half when used in combination with nelfinavir. Several other commonly prescribed drugs, terfenadine (Seldane), astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion) and midazolam (Versed), should not be used when taking nelfinavir because competition for CYPA3 by nelfinavir could result in "serious or life-threatening cardiac arrhythmias or prolonged sedation." Rifampin decreases nelfinavir levels by 82%, so the drugs should probably not be combined. Nelfinavir reduces levels of ethinyl estradiol, a common birth control pill, by almost one-half.

On the flip side, nelfinavir interacts with other protease inhibitors in ways that are potentially useful: in combination with indinavir, nelfinavir levels rise by 83% and indinavir levels rise by 51%. In combination with ritonavir, nelfinavir levels rise by 152% and ritonavir levels are unchanged. Some dose adjustments may be called for when combining these drugs. There are no data on the interaction between nelfinavir and Invirase (the currently available formulation of saquinavir), but in a small study of nelfinavir in combination with the new soft-gel formulation of saquinavir, levels of saquinavir were increased by nearly 4-fold with little effect on nelfinavir levels. Unfortunately, the soft-gel capsule formulation of saquinavir is still experimental and unavailable.

There are at present no data on interactions between nelfinavir and approved non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine and delavirdine. But in a combination study with DMP-266, an experimental NNRTI, researchers are raising the dose of indinavir from 800mg to 1,000mg q8h -- because of DMP-266's ability to speed up the rate at which indinavir is processed and cleared by the liver. In general, because the NNRTIs are also processed by the CYP3A pathway, interactions with the nelfinavir are expected.

As for resistance (and cross-resistance), Agouron claims that use of nelfinavir will not produce cross-resistance to the other protease inhibitors, but that use of the other protease inhibitors will produce cross-resistance to nelfinavir. In other words, "Use ours first." This convenient assertion is based on the fact that the major amino acid substitution conferring reduced sensitivity to nelfinavir is a D30N mutation. But D30N is only the first mutation to develop in the presence of nelfinavir, and is quickly followed by amino acid substitutions at the more familiar codons: 84, 46, 36 and 71 -- all of which would be expected to reduce sensitivity to the other protease inhibitors. Agouron's self-serving admonitions could still prove warranted, but without any clinical data to go on it is premature at best to make such claims publicly. Since day one, Roche has heavily promoted a similar scenario with saquinavir based on less-than-convincing evidence. Predictably, competing manufacturers of other anti-protease drugs (Merck in particular) have vociferously disputed this. Recent clinical findings (see "Sweating the Switch," in this issue) suggest that, in this particular case, Merck might just be right.