Past as Prologue
Expediency, Cost-Cutting Trump Science in Peg-Intron Clinical Development Plan
The Head-to-Head That Wasn'tIn October of 2003, Schering-Plough held a meeting with HCV and HIV/HCV advocates where they announced a "new" Schering -- one that prioritizes earning the trust of community members and advocates for people with hepatitis C and HIV/HCV coinfection. Tracy Swan reports for TAGline.
Schering has had an acrimonious relationship with community members, advocates and activists. In his 2001 testimony to the FDA's Antiviral Advisory Committee, Brian Klein, founder of the Hepatitis Action and Advocacy Coalition, described meetings with Schering as, "the worst in the industry. Schering's community meetings are a window dressing exercise conducted in the hopes that patient advocates will simply rubber stamp what the company has already decided upon."
A major grievance has been Schering's marketing practices. Schering refused to sell its ribavirin (trade name Rebetol) separately; it was only available in a kit (marketed as Rebetron) along with the Schering brand of alfa interferon (Intron-A). This prohibited patients from combining ribavirin with other types of interferon, and forced them to purchase a fixed dose of ribavirin -- whether or not it was the appropriate amount. And Schering's price for ribavirin -- a drug they did not even develop -- was exorbitant. A year's supply of Intron-A cost about $5,000. When ribavirin was added, the total for a year's worth of Rebetron jumped to $18,000! Activists lobbied Congress and the Federal Trade Commission and testified before the FDA (who encouraged Schering to sell its drugs separately but could not mandate this unbundling), but Schering refused to sell Rebetol separately.
Finally, in October of 2001 -- months after the approval of its pegylated interferon (Peg-Intron) -- Schering announced the unbundling of Rebetol. The price of unbundled Rebetol increased by 52% -- to some $1,653 a month -- making it more expensive than even the Rebetron kit (at $1,500 per month) which preceded it.
Peg TalesPegylation -- the attachment of a molecule of polyethylene glycol to interferon -- has increased virologic response rates to hepatitis C treatment. Combination therapy with pegylated interferon and ribavirin is the most effective treatment available for hepatitis C.
The FDA approved Schering's pegylated interferon, Peg-Intron (pegylated interferon alfa-2b), in early 2001, and Roche's Pegasys (pegylated interferon alfa-2a) in late 2002. Since then, Schering has lost more than 40% of its market share to Roche. Convenient dosing has contributed to Pegasys's success: it is premixed and administered at a fixed dose. Peg-Intron is dosed by body weight, and until early 2004, when a premixed injection pen device will be available, it must be reconstituted with sterile water before use. Anecdotal reports of Pegasys's favorable side effect profile have been circulating, but these have not been confirmed by a head-to-head study.
In Europe, Peg-Intron was approved for use in combination with weight-based ribavirin dosing. But because of a lack of prospective data on safety and efficacy of weight-based ribavirin, the U.S. FDA approved Peg-Intron with "flat" (fixed dose, 800 mg/day) ribavirin dosing. They also requested that Schering perform a direct comparison of safety and efficacy of flat vs. weight-based ribavirin. Preliminary safety data from this study (Schering's WIN-R) showed that at week 24 there were no significant differences in serious adverse events or treatment discontinuations by ribavirin dose -- although anemia (a common side effect of ribavirin) occurred more frequently with weight-based dosing. The efficacy data remain blinded, although Schering has submitted it to the FDA. Schering has been unable to tell community members when the data would be available.
Peg-Intron: Still Dose Finding?
The Case for 1.0Little research addresses differences in efficacy between the different Peg-Intron doses. Peg-Intron is currently labeled for use as monotherapy in HCV infection at a dose of 1.0 mg/kg, but the approved dose for use in combination with ribavirin is 1.5 mg/kg.
Lindsay and colleagues studied three doses of Peg-Intron: 0.5, 1.0 and 1.5 mg/kg as monotherapy (that is, without ribavirin). Efficacy, discontinuations and dose reductions were roughly equivalent for the two higher doses, supporting approval of the 1.0 mg/kg dose for use as monotherapy. (Relapse rates, however, especially in genotype 1, were high at both 1.0 and 1.5 µg/kg.)
At this year's Digestive Disease Week Meeting, Flamm and colleagues presented interim data from their HCV treatment trial, which compares response rates to 1.0 mg/kg or 1.5 mg/kg of Peg-Intron plus 800-1,400 mg/day of ribavirin. They reported that virologic responses and discontinuations at week 24 did not differ significantly between the two Peg-Intron doses, but the relative success of the 1.0 µg/kg Peg-Intron dose will ultimately be determined by sustained virologic response rates, which are not yet available.
The Case for 1.5While 1.0 mg/kg of Peg-Intron may be equally effective as and less toxic than 1.5 µg/kg, data from a small pharmacokinetic study suggests that the lower dose may be suboptimal. Formann and colleagues examined the relationship of Peg-Intron levels in the bloodstream and hepatitis C viral load among 20 people with HCV-1. Participants were randomized to receive 1.0 mg/kg of Peg-Intron once or twice weekly. In the twice-weekly dosing group, Peg-Intron was consistently present at detectable levels. In contrast, nine of ten people in the once-weekly group had undetectable levels of Peg-Intron by day seven. Viral kinetics differed by dosing arm: at day 28, four of ten people in the once-weekly group had decreases in HCV RNA>1 log10 vs. nine of ten people in the twice-weekly group.
Peg to PegData from three large trials reflect roughly equivalent efficacy of Peg-Intron and Pegasys, although there were differences in virologic response rates among a subgroup of participants. This subgroup -- those with HCV genotype 1 and high baseline viral loads (>2 million copies/mL or 800,000 IU/mL) -- does not respond to treatment as well as those with non-1 genotypes and low baseline viral loads. Since the majority of people with HCV and HIV/HCV coinfection in the United States have genotype 1 and high baseline viral loads, identifying the optimal treatment regimen is crucial.
A comparison of efficacy using data from different studies has limitations and cannot be considered conclusive. Different dosing schemes-flat dosing vs. weight-based-for ribavirin and pegylated interferon, and different participant characteristics influenced response rates. Yet the data from three studies suggest that a higher dose of ribavirin increases virologic response rates among people with HCV-1 and high viral loads. The relative contribution of Peg-Intron or Pegasys to sustained virologic response is unclear.
Neither Roche nor Schering was initially eager to compare products. A comparison of pegylated interferons is not a burning research priority, since the treatment pipeline for HCV looks robust; new drugs will be entering Phase I studies in early 2003. Nonetheless, the results of a head-to-head comparison will be useful because it is likely that pegylated interferon will remain a mainstay of HCV treatment until effective new combinations become available.
The Problem With IDEALAlthough Schering has been touting the IDEAL (Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy) study as the "first head-to-head study of leading hepatitis C therapies," IDEAL is a mere marketing ploy that will fulfill part of Schering's post-marketing commitments to the FDA.
IDEAL's 2,880 participants will be randomized to:
Schering was asked to study the safety and efficacy of two doses of Peg-Intron (1.0 µg/kg and 1.5 µg/kg) with ribavirin in HCV genotype 1. But because IDEAL combines a dosing study within the overall Peg-Intron vs. Pegasys product comparison, the study does not constitute a head-to-head comparison. Advocates suggested adding a fourth arm to the study (Pegasys with weight-based ribavirin dosing), or changing the ribavirin dosing from fixed to weight-based in the Pegasys arm. Schering refused to consider changes, saying that using the licensed dose of ribavirin with Pegasys was "... the only option."
Before conducting a head-to-head comparison, Schering should identify the optimal dose of Peg-Intron in a separate study. The 1.0 mg/kg dose has been approved for HCV monotherapy, but the dose approved for use with ribavirin is 1.5 mg/kg. Because IDEAL combines a dosing study with the Peg-Intron vs. Pegasys comparison, a higher number of participants will receive low-dose Peg-Intron than would otherwise be required for a stand-alone dosing trial. Greater numbers in each arm are required to reach statistical power, but this may expose a larger than necessary group to a potentially suboptimal dose of Peg-Intron.
Schering was unwilling to consider separate trials, citing expense and competition for participants between the two studies. While participants will be stratified by baseline HCV RNA (<600,000 IU/mL vs. >600,000 IU/mL*), Schering was unable to guarantee that the study would be adequately powered to detect differences in sustained virologic response by baseline HCV RNA levels. Thus, the most important question -- "What is the best regimen for people with HCV-1 and high viral loads?" -- may never be answered by IDEAL. It's a shame that Schering is squandering so many resources -- especially their study volunteers -- on a less-than-ideal study.
This article was provided by Treatment Action Group. It is a part of the publication TAGline.