Important note: Information in this article was accurate in February 2001. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, February 2001
Emily Bass
The January 22 approval of Peg-Intron, Schering-Plough's new pegylated version of interferon-a, marks a step forward in treatment options for hepatitis C. It also marks a new stage in the debate over pricing and packaging of medications for this chronic disease. Current standard-of-care for hepatitis C is alpha-interferon-ribavirin combination therapy. Schering-Plough also markets these two drugs in a single, "bundled" form called Rebetron. On its own, Peg-Intron is less effective than Rebetron, but available data suggest that a Peg-Intron-ribavirin combination will be the most effective hepatitis C treatment to date.
The new drug is enhanced by "pegylation" - the attachment of a polyethylene glycol (PEG) tail to interferon. The PEG molecule makes the interferon more soluble in water and shields it from degradation by blood enzymes and antibodies. The larger size also retards its passage to extraneous sites in the body, including to the kidneys where it is excreted. As a result, Peg-Intron has a half life in the blood of 37 hours, compared to eight hours for standard interferon. A longer half-life leads to simpler dosing, with more moderate changes in blood levels during the dosing cycle. Peg-Intron requires once-weekly injections, compared to three times a week for standard interferon. In the course of Peg-Intron's weekly cycle, peak interferon-a levels are lower and trough levels higher than those experienced with thrice-weekly standard interferon.
The two drugs have similar side-effects profiles at their recommended doses. But Peg-Intron's more stable blood levels, especially its lower peak levels, allowed increasing the recommended dose, making it more effective: In a comparison study of Peg-Intron and standard interferon monotherapy, Peg-Intron was twice as effective. After 48 weeks of treatment, 25% of over 1,200 individuals on Peg-Intron exhibited sustained virologic suppression (undetectable plasma HCV levels at week 72) and normal liver enzyme levels in the blood. Only 12% of those on standard interferon had such results.
Peg-Intron's efficacy is limited, for the moment, by the fact that it is only available as monotherapy. There has been no direct comparison study of Rebetron versus Peg-Intron monotherapy. Separate studies put Rebetron's efficacy at 40% to 47%.
Schering-Plough has done one study that compares Peg-Intron plus ribavirin dual therapy to Rebetron. The Peg-Intron-ribavirin combo had a slight, but statistically significant edge: 54% of participants had sustained virologic suppression after 72 weeks' treatment for all HCV genotypes, compared to 47% for Rebetron. In a detailed analysis of the data, Peg-Intron plus ribavirin also was significantly more effective against HCV genotype 1 (42% sustained response rate vs. 33% for Rebetron). Genotype 1 is the most common genotype in the United States and the least responsive to interferon-a therapy. There was no significant difference in efficacy in treating genotypes 2 and 3 (sustained response rates of 82% and 79% for Peg-Intron and Rebetron, respectively).
For now, Schering is marketing Peg-Intron as an individual drug for patients who cannot tolerate ribavirin. But this is likely to change. In November, the company applied to the FDA for separate approval of ribavirin. On February 6, Schering submitted a supplemental application to allow Peg-Intron's use in combination with ribavirin.
Schering has been under considerable pressure to sell ribavirin by itself. Activists and treatment advocates, alarmed at the high price and the dosing restrictions of the Rebetron package, have sought "unbundling" since Rebetron's approval in 1998. For the past year, the FDA has indicated to Schering that it would look favorably on an unbundling application.
Schering spokesperson Robert Consalvo says that it has taken the company two years to determine that ribavirin is safe on its own. Treatment advocates argue that the profits to be gained by pairing Peg-Intron with the drug are what finally tipped the scales. Brian Klein, of the Hepatitis Action and Advocacy Coalition has stated publicly, "This has nothing to do with...the community. It has everything to do with what they think will sell their drug."
Separate approval for ribavirin will likely come in the next six months, at which point Schering-Plough hopes that the Peg-Intron-ribavirin combo becomes standard-of-care. Unbundling ribavirin will allow physicians to dose the drug by body weight, a strategy that could increase its efficacy.
Unbundling will also make it easier for patients to use the ribavirin with different brands of interferon-a and could increase the options for obtaining generic ribavirin. Both of these options could cut the price of hepatitis C combination therapy. Rebetron costs approximately $18,000 a year. One U.S. pharmacy already sells ribavirin separately, for roughly a fifth of the cost of the ribavirin in the Rebetron package.
Although unbundling will allow patient savings on ribavirin capsules, Schering-Plough's interferon products will still come with a hefty price tag. The average wholesale price (AWP) for Peg-Intron is $900 to $1100 a month. AWP is the benchmark cost that drug distributors in theory charge retailers. It does not reflect what consumers will pay, says Schering's Consalvo, who adds some patients could pay less and that pharmaceutical companies "cannot control the mark-ups."
Such a detached attitude toward the expense of treatment has angered advocates in the past. While cheaper than Rebetron, Peg-Intron is two to three times the cost of standard interferon. Rebetron's AWP, which was set without consultation with consumer groups, gives Schering a "huge profit margin," Brian Klein has stated.
With Peg-Intron as the front runner, Klein and others are hopeful about Pegasys, a version of pegylated-interferon under development by Hoffmann-La Roche. Its approval is expected this spring. There have been no head-to-head comparisons of the two new products. However, Pegasys has a 90-hour half-life - more than double that of Peg-Intron - which could make it still more effective and better suited to once-weekly dosing.
Pegasys is metabolized primarily by the liver, whereas Peg-Intron is excreted by the kidney. For now, it does not appear that use of different elimination pathways affects drug tolerability and side effects. This is an especially thorny issue for HCV-HIV coinfected individuals. They already face a litany of drug-drug interactions and organ toxicities.
"The only difference that I can see is that some Pegasys patients who have HCV viral loads of less than 1,000 at the end of treatment still have mildly elevated AST," says Dr. Douglas Dieterich, a liver expert from New York University. (AST is a liver enzyme. Elevated quantities escape into the blood if liver tissue is damaged.) "That [AST elevation] goes away when the "peg" stops. That indicates mild liver tox of either IFN or peg. However, it has no effect on the virus, so it does not bother me in the least."
It is too soon to say what Roche's price for the drug, which should be approved in 2001, will be. After a meeting with Roche last November, HAAC's Klein is hopeful that the cost of the next pegylated product will be closer to that of current standard interferons.
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Copyright © 2001 by the American Foundation for AIDS Research (amfAR) and first displayed on amfAR's Treatment Directory web site (http://www.amfar.org/gl). They appear on AEGIS with amfAR's permission. Organizations wishing to reprint or redistribute these materials should request authorization from amfAR's Department of Treatment Information Services (212/806-1600).
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