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Switzerland ’s Actelion has seen some leaks from its pipeline over the past two years. But
in recent months, the tide has turned and the company claims it is within reach
of its goal of becoming one of the world’s 10 largest biopharmaceutical firms.
Back in November 2004, the
company had a bitter disappointment with the abandonment of a 1,800-patient
trial of its intravenous dual endothelin receptor antagonist Veletri (tezosentan)
for acute heart failure. Then in May 2005, its urotensin-II receptor antagonist
palosuran failed a proof-of-concept study for diabetic nephropathy, while in
November 2005 its lead product Tracleer (bosentan) failed in Phase III trials
for patients with pulmonary fibrosis.
It suffered a fourth setback in
June of this year when a Phase III trial showed that another of its most
promising products, clazosentan, produced no clinical benefit in patients with
subarachnoidal hemorrhages, a form of stroke.
Palosuran was soon airbrushed
out of the company’s plans, while Veletri is “not out of the pipeline but
not in it either until we know what to do with it,” CEO Jean-Paul Clozel told
investment analysts in July. Clazosentan appears to be in a similar limbo.
So Actelion’s pipeline was
beginning to look distinctly shaky, with a heavy attrition rate on the
later-stage compounds, nothing in Phase I trials, and — it seemed — no good
news from preclinical.
Then suddenly, in July, came
two breakthroughs. First was the announcement of first-in-man trials for a renin
inhibitor that the company is developing in cooperation with Merck, triggering a
$7 million milestone payment from Merck. Renin inhibitors are a new class of
antihypertensives that block the enzyme renin, a precursor of angiotensin.
Second, Actelion announced it
had signed a massive joint development deal with
Switzerland
’s Roche, under which the two firms will commercialize Actelion’s selective
S1P1 receptor agonist for multiple autoimmune disorders. S1P1 agonists bind to
the sphingosine 1-phosphate receptor-1 on T-lymphocytes, causing them to be
captured by lymph nodes. This reduces the number of activated T-cells
circulating in the body, thus reducing inflammatory damage and myelin damage in
the brain and spinal cord. Multiple sclerosis is likely to be a high-priority
target.
Proof of Value
The S1P1 agonist and the renin
inhibitor products are still only in Phase I trials. But Sally Bennett, senior
research analyst at investment bank Piper Jaffray in
London, notes that both can demonstrate value from proof-of-concept studies of
related Novartis compounds. Novartis has an S1P1 inhibitor FTY720 (fingolimod)
in Phase III trials for multiple sclerosis, and its oral direct renin inhibitor
Rasilez (aliskiren) awaits
U.S.
approval for hypertension.
The Roche agreement brings
Actelion an immediate $75 million down payment, with the possibility of
collecting a further $555 million in milestone payments for all the indications
targeted by the agreement.
The company is pursuing a
scattergun strategy on S1P1’s development. According to Clozel, the best way
to maximize the value of Actelion’s work on selective S1P1 agonists is “to
develop the principle in all possible autoimmune disorders as rapidly as we can
by performing the clinical trials in parallel.” Hence the choice of Roche,
with its massive development resources, as partner.
But Actelion itself is also
generating strong cash flow, mainly from its lead drug Tracleer (bosentan), a
dual endothelin receptor antagonist approved for pulmonary arterial
hypertension. The firm is now sitting on a cash pile exceeding CHF400 million
(approximately $325 million) — and the new Roche agreement will boost that
further.
Will the company spend to plug
the gaps in its pipeline, knowing that its existing programs might consume
mountains of cash before reaching fruition?
This year alone could prove
expensive: Peter Walford of Lehman Brothers notes that the company is expecting
“a big uptick” in R&D spend for the second half of 2006.
Actelion CFO Andrew Oakley says
the increase was needed to underwrite development of S1P1; an orexin receptor
antagonist about to enter Phase II trials for insomnia; and the launch of a
Phase III study for Tracleer in a new indication.
It also needs to solve a puzzle
arising from the clazosentan trial, which failed to reduce mortality even though
it produced “highly significant” reductions in cerebral vasospasm —
generally taken as a key indicator of fatal subarachnoidal hemorrhage. Clozel
described the finding as “defying medical logic.”
With this uncertainty, it is no
wonder Actelion plans to be “very selective” about buying products or
companies. “We really do not want to add risk or potential problems to our
pipeline,” said Clozel.
click to
enlarge
AUTOIMMUNE ACTOR: S1P1
modulators inhibit lymphocyte release and recirculation from lymph nodes, a key
autoimmune response.
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