News that Protein Design Labs Inc.'s Phase II product ularitide showed positive results in treating acute decompensated heart failure (ADHF) boosted the company's shares Tuesday, and caused one analyst to upgrade the stock.
Ularitide is a synthetic version of a natriuretic peptide produced in the kidney called urodilatin. Phase II data from the SIRIUS II trial showed that ularitide was well tolerated and had dose-dependent favorable effects in treating the symptoms of ADHF without compromising patient kidney function.
The data provide "evidence that ularitide could be better than $400 million Natrecor," said analyst David Webber, of New York-based First Albany Capital, who raised his rating on PDL from "buy" to "strong buy." The company's stock (NASDAQ:PDLI) responded with a $2.99 increase Tuesday, closing out the day at $29.92.
As a result of the data - presented at the annual European Society of Cardiology Congress in Stockholm, Sweden - Fremont, Calif.-based PDL plans to soon initiate new clinical studies in the U.S. and Europe.
Natrecor - the only approved natriuretic peptide - was launched by New Brunswick, N.J.-based Johnson & Johnson in 2001. Its annual sales approached $700 million until concerns surfaced over its potential for kidney damage and increased mortality, causing sales to fall. Ularitide is an atrial natriuretic peptide (ANP), as opposed to Natrecor, which is a brain natriuretic peptide (BNP).
While PDL would need to do a head-to-head comparison of Natrecor vs. ularitide, a preliminary comparison indicates that ularitide, at its two top doses, does a better job of increasing the cardiac index and of lowering wedge pressure.
In a research note, Webber pointed out that Natrecor "has come under fire in the cardiology community" after findings that it could be toxic to the kidneys and might increase mortality. The Cleveland Clinic, a leading heart center, restricted use of the drug as a result, and a panel of experts convened by J&J recommended that use be restricted to hospitalized patients with ADHF.
"As a result, there is likely to be a chance for a second-in-class drug, such as ularitide, to take significant share from Natrecor," Webber said. "PDL hopes that additional studies support its view that urodilatin's source in the kidneys explains its apparent lack of kidney toxicity and may be a key factor differentiating it from nesiritide."
In the randomized, double-blind, placebo-controlled Phase II trial, a total of 221 patients received ularitide 7.5-, 15- or 30-ng/kg/min intravenously over 24 hours or placebo. The drug hit both of its primary endpoints, showing changes in dyspnea score and in pulmonary capillary wedge pressure (PCWP), a measurement of lung vessel pressure, at six hours.
Ularitide was associated with a significantly improved dyspnea (shortness of breath) score in all three dosing groups (p<0.05) compared to placebo. It also demonstrated a significant decrease in pulmonary pressure (p<0.05), and the changes were associated with an increase in cardiac index in the 15- and 30-ng/kg/min groups.
As for the trial's secondary endpoints - serum creatinine levels, length of hospital stay and mortality - ularitide also showed some positive results. Serum creatinine levels were the same in the treatment and placebo groups through 72 hours, suggesting that ularitide does not negatively affect kidney function. The length of hospital stay was lower for those taking the 15- and 30-ng/kg/min doses of ularitide (122 hours and 158 hours, respectively) than it was for those in the placebo and 7.5-ng/kg/min groups (200.5 hours and 192 hours, respectively). And there was no increase in mortality in the ularitide treatment groups compared to placebo. The mortality rate through day 30, however, was higher in the placebo group at 13.2 percent, compared with 3.3 percent, 3.8 percent, and 1.8 percent in the 7.5-, 15- and 30-ng/kg/min groups, respectively.
Ularitide had a higher occurrence than placebo of certain adverse events, though, including hypotension, blood pressure decrease, cardiac failure, sweating increase, dizziness and asthenia.
The peptide was first isolated at Heidelberg University and developed by CardioPep Pharma GmbH, the German company that conducted the Phase II study. PDL gained exclusive development and marketing rights to ularitide for all indications worldwide this year. It plans to file an investigational new drug application to begin its own Phase II trial in Europe and the U.S.
"We're hoping to enroll our first patients in that study at the end of this year or the first quarter of next year," said Steve Benner, PDL's chief medical officer.
ADHF occurs when patients experience a gradual or sudden worsening of congestive heart failure in which the heart is unable to meet the body's demand for oxygen, and congestion or fluid retention occurs in the lungs and other areas throughout the body.
"Most of these patients have a previous diagnosis of congestive heart failure and they are managed on ACE inhibitors and diuretics," Benner said. "At a certain point, their condition worsens and they become acutely short of breath and have to go to the emergency room."
According to the American Heart Association, there are about 5 million heart failure patients in the U.S., and about 1 million people are hospitalized each year for ADHF.
When ularitide is injected into the bloodstream it causes blood vessels - specifically those in the arteries that feed the kidneys, lung and heart - to relax, and stimulates natriuresis and diuresis. If approved, a launch could occur in 2009.
The ularitide data come on the heels of an $800 million deal for PDL with Biogen Idec Inc., of Cambridge, Mass., to develop three Phase II products: daclizumab for multiple sclerosis and indications other than transplant and respiratory illness, volociximab for cancer and fontolizumab for all indications, including autoimmune disorders. (See BioWorld Today, Aug. 4, 2005.)
Earlier this year, PDL acquired Edison, N.J.-based ESP Pharma Inc. for $475 million, to gain marketed products, a 75-person sales force and entry into the cardiac field. (See BioWorld Today, Jan. 26, 2005.)
PDL may choose to use that sales force for ularitide, if it reaches the market, Benner said. But the company hasn't ruled out a marketing partner.
"We haven't made any final decisions on partnering strategy," he told BioWorld Today.