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Hep C pill race report 2012: Gilead, others rush toward pharma gold
Vertex Pharmaceuticals ($VRTX) radically improved the treatment of hepatitis C with its protease inhibitor Incivek, which fast became a blockbuster success after the FDA
stamped an approval on the drug in May 2011. Investors and physicians cheered, thousands of patients embraced the treatment, and Vertex's sales skyrocketed.
Temporarily. Early this month, Cambridge, MA-based Vertex reported financial results that showed a steep decline in sales of Incivek, down from $419.6 million in the third quarter of 2011 to $254.3 million in the same period this year. Blame much of the 39% drop in sales of the drug on at least a couple of related factors. Firstly, Incivek is approved only for use with injected interferon, which causes a range of nasty and flulike side effects. Secondly, physicians and patients appear to be waiting for a new generation of oral antivirals that offer the promise of wiping out the virus relatively quickly without requiring interferon
injections。
This wasn't news to Vertex. Along with a bevy of competitors, the pharma company has hurried to advance interferon-sparing treatments for a while. If the all-oral therapies now in development hit the market as expected within the next couple of years, sales of interferon-based treatments are in big trouble. Vertex knows this. Merck ($MRK), which markets the rival hep C drug Victrelis, knows this. Both companies are hustling to develop all-oral approaches to fighting the disease.
"Obviously, we're moving as fast as we possibly can," Dr. Robert Kauffman,
Vertex's chief medical officer, said in an interview with FierceBiotech. He also
noted: "The news is that the field is changing rapidly; all-oral regimens look to be
on the horizon."
The evolution of hepatitis C treatment threatens to leave today's dominant
companies with fossilized offerings. Vertex and Merck have the state-of-the-art
approved drugs against the virus, but both companies are chasing after Gilead
Sciences ($GILD), Abbott Laboratories ($ABT) and others with programs that
could be the first to win market approval with pill-only options.
There's no cozy position in the hep C race, however. The all-oral cocktails are
largely unproven and in need of confirmation in fully baked pivotal studies, and
that keeps the contest wide open for a number of contenders, Vertex included.
Oral hep C nucs: Virus assassins or toxic agents?
Bristol-Myers Squibb ($BMY) killed development of its once-promising
nucleotide polymerase inhibitor in August after a patient who took the
experimental compound, known as BMS-986094, died of heart failure. The
death sounded the safety alerts at the FDA, which hit the brakes on studies of
the "nuc" drug in August. And by the time Bristol put the kibosh on further
development of the compound on Aug. 23, a total of 9 patients had been
hospitalized, including the person who had died.
The "094" disaster was felt across the industry. The FDA quickly called for a hold
on development of two hep C pills from Idenix Pharmaceuticals ($IDIX). The
first, called IDX184, is in midstage development and was placed on partial
clinical hold, and the second, IDX19368, is a preclinical compound from the
same drug class. Both experimental pills share similarities with Bristol's doomed
nuc.
Idenix has to prove that its clinical-stage drug isn't another toxic dud before
further trials in patients can resume. Hopeful to resume testing of IDX184, Idenix
made clear at the American Association for the Study of Liver Diseases annual
meeting that there's been no evidence of severe heart side effects in patients on
the pill.
Bristol managed to let its 094 program die while maintaining that the cause of
the death and hospitalizations among patients who took the drug was uncertain.
Nevertheless, toxicity concerns hang like a dark cloud over the enterprise of
advancing new nucs against hepatitis C virus.
Idenix's and Bristol's woes have made news recently, but safety problems have
plagued a number of previous oral compounds against the liver-damaging virus.
NM-283, a nucleoside polymerase inhibitor from Idenix developed in partnership
with Novartis ($NVS), fell from grace years ago after investigators found
gastrointestinal side effects. Roche's ($RHHBY) polymerase inhibitor, R1626,
was axed after doctors saw evidence of bone marrow suppression.
"Anytime we study a new 'nuc,' we're on alert for those kinds of side effects,"
said Dr. Paul Pockros, head of the division of gastroenterology/hepatology at the
Scripps Clinic's Liver Disease Center, in an interview with FierceBiotech.
Pockros, who was involved in the ill-fated study of Bristol's 094, said that the
death of the patient from heart failure has heightened concerns about potential
cardiovascular side effects of nucs in hep C studies.
Hep C bigger than HIV
Intravenous drug use, dirty tattoo parlors, tainted blood transfusions and carriers
infecting offspring are several of the many ways an estimated 170 million people
around the world have contracted hepatitis C. In the U.S., estimates place the
total number of cases at 4 million, making the disease far more prevalent than
headline-grabbing HIV in the country.
The good news for hep C-infected patients: Current therapies offer viral cures,
and others in development could wipe out the illness faster than today's drugs.
The bad news: Most people with the chronic disease are unaware of their
illness, according to the Centers for Disease Control and Prevention (CDC).
Many of them are from the baby-boomer generation.
Hepatitis C damages liver tissue and results in scarring known as cirrhosis.
Once a patient has cirrhosis, he's got a greater risk of developing liver cancer,
liver failure and dying. In fact, the virus is responsible for driving up rates of liver
cancer, liver transplants and liver failure.
It takes decades before the virus significantly damages the liver. With the
disease killing higher numbers of aging boomers, the CDC made new guidelines
this year for physicians to screen all their patients born between 1945 and 1965
for the virus. But the jury is out on how well the guidelines will be followed.
For developers of hep C drugs, the HCV testing could benefit sales of meds
against the disease. Yet unless a patient's hep C has made him sick, doctors
might keep him on the sidelines in anticipation of the all-oral therapies hitting the
market in 2014.
"If you already have cirrhosis, and you're scared that you may be
decompensated and could develop cancer, you may want to take what's
available," Dr. Guadalupe Garcia-Tsao, president of the American Association
for the Study of Liver Diseases, told reporters last week in Boston. Otherwise,
she said, hep C patients might want to wait for next-generation therapies.
A pharma gold rush
There are plenty of arms races in the pharma industry, with companies sprinting
to advance rival therapies to market. Yet few move as quickly as the hep C race,
and the lucrative market and clinical development dynamics are incentives to
work fast.
"If you go away for a couple hours, things change in HCV," laughed Joseph
Truitt, head of business development for Achillion Pharmaceuticals ($ACHN), a
developer of three clinical-stage drugs against hep C.
The hep C drug market saw explosive growth in 2011 with the introduction of
Merck's ($MRK) and Vertex's ($VRTX) then newly approved protease inhibitors,
which boosted sales in the category by about $1 billion last year to $2.6 billion,
according to market research from GBI Research. With patients waiting for alloral
options, no such growth is in the offing for 2012.
The interferon-free cocktails could trigger tremendous growth in a few years,
many say by 2015, when multiple all-oral regimens could be on the market. The
market could grow to nearly $15 billion by 2018, with Gilead ($GILD) and Abbott
($ABT) controlling the largest two pieces of the pie, respectively, according to
GBI. Bloomberg says $20 billion by 2020. These are irresistible numbers for
many pharma outfits.
Gilead famously forked over $11 billion for Pharmasset this year, spending an
enormous sum to gain its lead nuc drug, GS-7977, and arguably the leading
position in the all-oral-regimen race. And if the company's late-stage studies pan
out as well as hoped, the multibillion-dollar gamble will become money well
spent.
Nuc or no nuc
Credit or blame Pharmasset for much of the fervor over nucs. Last year the
company wowed industry watchers with midstage study data of interferon-free
regimens built around GS-7977, which appears to crush the ability of hep C virus
to build resistance to treatment. Then the theory went: If you want take interferon
out of the hep C cocktail, you might need a nuc.
Last week Gilead ($GILD) reaffirmed why Pharmasset might be worth the
fortune it paid for the precommercial outfit. Gilead unveiled impressive data
during the American Association for the Study of Liver Diseases meeting
(AASLD) meeting that showed there were no detectable signs of HCV four
weeks after treatment in 100% of 25 genotype 1 patients who took a 12-week
course of 7977; the company's NS5A pill, GS-5885; and ribavirin. These were
patients who had never taken interferon-based treatments.
Bristol ($BMY), conversely, lost big on a $2.5 billion bet on Inhibitex early this
year after the 094 nuc compound from the developer flamed out in Phase II and
a study patient died this summer.
"094 we thought was a reasonable bet, a reasonable hedge should the science
tilt toward the you-must-have-a-nuc" theory, Dr. Doug Manion, senior vice
president of development for virology at BMS, said in an interview. "But since
then the science has evolved that we now know from the Abbott data and our
own data that a nuc isn't quite as important as everyone thought."
In October and in detailed data presented during the AASLD meeting, Abbott
impressed with an all-oral combination of 5 drugs, none of which are nucs, in a
Phase IIb study. Tests showed no signs of the virus 12 weeks after treatment in
97.5% of treatment-naive patients with the most common type of hepatitis C,
genotype 1, on Abbott's ($ABT) ABT-450/r (a protease inhibitor boosted with the
HIV drug ritonavir), ABT-267 (a polymerase inhibitor), ABT-333 (an NS5A
inhibitor) and ribavirin. Its Phase III program for the regimen is enrolling
patients.
Bristol, which got into the hep C game long before it bought Inhibitex, has tested
multiple all-oral combos sans nucs with upbeat results. For instance, this week
the company highlighted data from a midstage study, with measures showing no
viral activity in 94% of genotype 1 patients on a 12-week course of three
experimental compounds: daclatasvir (an NS5A inhibitor), asunaprevir (an NS3
protease inhibitor) and BMS-791325 (NS5B non-nucleoside polymerase
inhibitor). The company plans to start Phase III studies of the three-drug combo
in 2014.
Japan cases abound
Talk to the proud contenders in the hep C arena, and you'll learn that each one
sees his advantage over rivals. With Gilead's ($GILD) annihilation of the virus in
a Phase II study that it's taken to Phase III development, analysts see the drug
giant as the leader in advancing simple, all-oral regimens to the U.S. market.
However, hep C afflicts patients around the world, has 6 different genotypes and
brings a bevy of other variables into the treatment equation, according to Dr.
Doug Manion, senior vice president of development for virology at Bristol-Myers
Squibb ($BMY). The mixed bag brings opportunities. Take Japan, where Manion
believes Bristol could be the first to market with an all-oral regimen, with plans to
file for approval of a dual combo of daclatasvir and asunaprevir by end of 2013.
To hear Manion tell it, the Japanese market for hep C drugs is nothing to sneeze
at. Japan, where an estimated 2 million people have hep C, has an infected
population composed of many elderly patients and mostly genotype 1b cases.
The virus spread in large part because of contaminated blood supplies in
country.
"These are elderly patients. They are very sensitive to the adverse events of
interferon," said Manion, who leads Bristol's development in Japan. "A lot of
them have been unwilling to even try a curative regimen that contains interferon.
So that's why [the government] is so keen on getting an all-oral regimen there."
Enter Bristol and its all-oral cocktail. If approved in Japan, Bristol's combo could
quickly seize market share as those who have forgone interferon-based
therapies come off the sidelines to be treated.
Still, many contenders have an argument that buttresses their case for success
in the hep C field.
Vertex finds strength in numbers
At Vertex ($VRTX), there are multiple all-oral options on the table, even though
none of those options yet involves a Phase III study, which could come in 2014.
The Cambridge, MA-based company has been wheeling and dealing since last
June, when it struck an exclusive licensing deal with Alios BioPharma that
featured a nucleotide polymerase inhibitor called VX-135 (formerly ALS-2200).
Vertex now plans to study VX-135 in four Phase II studies, including one that
combines the drug with its fading blockbuster Incivek and another with ribavirin.
Two more Phase II studies hit Vertex's drawing board this month when the
company revealed two separate agreements with GlaxoSmithKline ($GSK) and
Johnson & Johnson's ($JNJ) Janssen to test 135 in combination with GSK's
NS5A inhibitor GSK2336805 in one midstage trial and in a dual combo with
Janssen's protease inhibitor simeprevir (TMC435) from its partner Medivir.
"Because the efficacy we have no doubt about, the antiviral activity we have no
doubt about, it's really generating the safety data to let the [VX-135] program go
forward," Dr. Robert Kauffman, Vertex's chief medical officer, said in an
interview. The four midstage studies should provide more of that key safety data
as well as results on which patient populations respond best to which combos.
Achillion, the lone warrior
Unlike Vertex ($VRTX), Achillion thinks that it could have all the ingredients for a
potent all-oral combo for hepatitis C with the three antivirals it's studying in
clinical trials.
That's not to say Joseph Truitt, head of business development for Achillion
Pharmaceuticals, isn't open to collaborations with other hep C developers,
because he says he definitely is. But the New Haven, CT-based company,
despite lots of rumors earlier this year that it was buyout bait, could advance an
interferon-free cocktail to market alone.
Add to the mix Roche ($RHHBY) and Boehringer Ingelheim, two more of the 20
largest drugmakers in the world that want a piece of the action in hep C.
Boehringer is planning to begin a Phase III trial of an all-oral combo for the U.S.
market. The herd is large and running fast.
For Vertex, this doesn't leave much time to remain the top act in the industry
with Incivek. Many blockbusters generate billions of dollars in annual revenue for
a decade or more. But Vertex is already seeing sales of Incivek fade after a year
and half on the market.
"Not just crowded, but the speed of change is I think very unique," Dr. Robert
Kauffman, Vertex's chief medical officer, said. "It is really quite remarkable and
we are very happy to have been at the forefront of this. [Incivek] paved the way
for direct-acting antivirals."
