♦ Battleground: Schering and Roche Duke It Out Over the
Huge Hepatitis C Market As Concerns Arise for Some Patients
TAGline - Volume 8 Issue 8 - October 2001
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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:
Study personnel should be educated on the importance of careful assessment for
evidence of hepatic decompensation in co-infected patients with cirrhosis who
are being treated with antiretroviral therapy, especially at baseline, but also
throughout therapy, particularly within the first 16 weeks.
Patients with evidence of hepatic decompensation should be withdrawn from
therapy immediately and carefully followed until they recover completely.
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.
http://www.aegis.com/pubs/tag/2001/TG011002.html
011010
TG011002
PEG-Intron Pen Introduced in Europe
Schering-Plough has introduced an injector pen in Europe that is pre-filled with
PEG-Intron for the treatment of hepatitis C.
Each pre-filled pen will contain PEG-Intron at one of five different dosing
strengths for a single use. The maximum injection volume is 0.5 ml delivered
through a very fine needle specifically designed to reduce patient discomfort.
Roch Doliveux, president Schering-Plough International, said the pen offers a
convenient method for administering PEG-Intron that may help patients adhere to
their treatment regimens.
Other sources: Schering-Plough
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