Important note: Information in this article was accurate in 2001. The state of the art may have changed since the publication date. TAGline - Volume 8 Issue 8 - October 2001
"Neither kinder nor gentler"
Observing the race between Roche and Schering for FDA approval of the two pegylated interferons (interferon as monotherapy as well as interferon in combination with ribavirin)--and a lion's share of the hepatitis C market--makes the race in the mid-1990s for FDA approval of the HIV protease inhibitors look like child's play. There is absolutely no love lost between the hep C clinical and marketing teams of the two companies. It's said that a Roche employee nearly had his lawyers file a cease and desist order against someone on the Schering team who continuously bad mouthed Pegasys at hepatology conferences. Michael Marco brings the laundry out for air.
The competitiveness with which the companies release data is like a carefully orchestrated fencing match. Hoffmann-La Roche filed a new drug application (NDA) with the FDA nineteen months ago for its pegylated interferon (Pegasys). During this time, hep C kingpin and marketing maven Schering-Plough sailed through the FDA approval process with its pegylated interferon (PEG-Intron), with not just a monotherapy indication, but also a recent combination therapy indication for use with its ribavirin. It is unfortunate that the FDA did not grant Roche's NDA a much-deserved "expedited" review (6 vs. 12 months) for use in treating HCV-positive cirrhotics.
Roche beat Schering with publishing its monotherapy study first--and in the New England Journal to boot--while Schering was reduced to Hepatology. But Schering then snuck by Roche with the publication of its combination therapy study in the Lancet--while Roche's data are still in abstract form.
Roche is planning on filing its NDA for Pegasys and ribavirin in the current quarter. The FDA granted Roche's Pegasys/ribavirin combination therapy NDA an "expedited" review. Roche will also be filing a separate NDA for approval of its own manufactured ribavirin. The goal is to have Pegasys and ribavirin available by the first half of 2002. Jesus Leal, Roche's HCV marketing director, said that Pegasys and ribavirin will be sold as separate products and no plans have been made to bundle them. Schering, in its usual arrogant and cagey way, will not commit to not bundling peginterferon and ribavirin (like it did with its standard interferon+ribavirin formulation, Rebetron) or making them individually so costly that one has no choice but to by the bundled product.
Roche has studied its pegylated interferon in over 1,000 HIV/HCV co-infected patients (compared to Schering with <200) and is currently conducting a Phase III trial in this population. Once they receive monotherapy approval, Roche plans to seek a supplemental NDA for the use of Pegasys in treating HIV/HCV co-infected patients.
Combination therapy data from Roche and Schering's Phase III registrational pegylated interferon plus ribavirin studies have recently been presented and published.
Schering conducted a 3-arm 1,500 patient study comparing two doses of peginterferon plus ribavirin against standard interferon+ribavirin for 48 weeks. According to the FDA's analysis--stricter than Schering's and thus differs from the Lancet piece--52% of individuals in the 1.5 mcg/kg arm achieved a sustained viral response compared to 47% and 46% of those in the low-dose peginterferon (0.5 mcg/kg) and interferon+ribavirin arms, respectively. When broken down according to genotype, 41% of the genotype 1 individuals in the high-dose peginterferon arm achieved a sustained viral response compared to 33% of the interferon+ribavirin ones. In genotype 2/3 individuals, there were no differences in response rates between the three arms with all achieving an &#tilde;80% sustained viral response.
As for side effects, in the Schering phase III (PEG-Intron) combination trial (which compared high-dose peginterferon+ribavirin vs. low-dose peginterferon+ribavirin vs. standard interferon+ribavirin) neutropenia occurred in 26% of the high-dose peginterferon+ribavirin study volunteers compared to 14% of those in the standard interferon+ribavirin arm. Anemia occurred in 12% and 17% of the volunteers, respectively. Approximately 60% of all study participants experienced fatigue and/or headaches, and more than 40% in all arms experienced depression of anxiety. Suicidal behavior was recorded in 2% of individuals, with three suicides occurring during the study: two in the high-dose peginterferon arm and one in the standard interferon arm. Virology data from the Roche combination therapy study look similar to that of Schering.
Presented at DDW last May, results from Roche's NV15801 study documented that 30% of the patients in the monotherapy arm achieved a sustained viral response compared to 45% in the interferon+ribavirin arm and 56% in the PEG-interferon+ribavirin arm for all comparisons). In genotype 1 patients, the sustained viral response rates were 21%, 37%, and 46%, respectively. And, in genotype 2/3 patients, the sustained viral response rates for the three arms were 45%, 61%, and 76%, respectively.
Results from the viral kinetics substudy have also become available. The study found that individuals who have either a 2 log drop in HCV RNA or become HCV RNA undetectable by week 12 have a 65% chance of remaining undetectable for 72 weeks (considered cured by some people). Conversely, for individuals who did not achieve a 2 log drop in HCV RNA or become HCV RNA undetectable after 12 weeks of treatment, there is a 97% chance that they never will. These kinetic data are similar to those presented by Schering in its Lancet paper. This indicates that checking one's HCV RNA at 12 weeks may help to determine if therapy should continue for a year or be discontinued.
Pegylated interferon, while markedly more convenient than and equally effective as standard interferon alone, is turning out to be neither kinder nor gentler. Nor is it more effective than standard interferon+ribavirin (Schering's Rebetron) for poor prognostic factor patients, individuals with a baseline HCV viral load >2 million copies/mL and an HCV genotype 1.
This, however, is not public knowledge. It appears nowhere in the Lancet paper. One has to look into the FDA label (page 6, section 2.0) in order to see that the response rates for individuals with poor prognostic factors were virtually indistinguishable between the two treatments: 30% for high-dose peginterferon+ribavirin and 29% for standard interferon+ribavirin in the Schering trial. This crucial piece of evidence means that while peginterferon is more convenient than standard interferon+ribavirin, it is not virologically superior in fully half the people with HCV.
Like Schering, Roche appears to be hush-hush about the comparative results in poor prognostic patients. The data were not presented at DDW and are not scheduled to be presented in a peer-reviewed oral or abstract presentation at the upcoming AASLD meeting. Sources say it's doubtful they will appear in the manuscript.
Officials at Hoffmann-La Roche recently notified the FDA that a serious adverse event (hepatic decompensation) has occurred in seven HCV/HIV co-infected individuals enrolled in its NR15961 study. Five of these cases occurred among study participants in the PEG-Intron+ribavirin study group, and two of the cases occurred in those receiving standard interferon (Intron) plus ribavirin. Five of these study volunteers didn't recover. According to the Roche letter:
All seven of these patients had cirrhosis and were receiving concomitant HAART therapy. 5 of 7 were on stavudine, 4 of these 5 patients were also on didanosine. All seven of these cases of hepatic decompensation occurred during the first 4 months of therapy. In five of the seven cases, the patients subsequently died while off study drug. Among the seven patients, three patients were enrolled by investigators even though they violated the protocol entry criteria; two patients had Child's class B and one had previous splenectomy...All three of these patients who violated entry criteria had further progression of hepatic decompensation and later died. The other four patients fulfilled all protocol entry criteria and had no evidence of pre-existing hepatic decompensation. Two of these patients died.
Roche says that "a thorough evaluation of the safety data from all other on-going trials with patients co-infected with HCV/HIV has not identified any additional cases of hepatic decompensation." The study will continue, but Roche has requested all investigators ensure that:
It will take some time to understand why these patents decompensated so quickly after study entry. It may be a combination of several things, including: 1) the natural history of HIV/HCV co-infection in patients with cirrhosis; 2) HAART hepatotoxicity; and/or 3) interferon-based therapy in late-stage cirrhotics. To determine if this deleterious interaction between HAART and interferon in cirrhotic patients has occurred before, the FDA must gain access to Schering and Amgen's databases of co-infected patients--before Schering's marketing division figures out a way to use this as PR propaganda against Roche.
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