Faced with disappointing Phase IIa results of its lead LSAID, Inflazyme Pharmaceuticals Ltd. said it expects to discontinue further development of IPL512,602 in asthma.
Following the announcement on Friday, Inflazyme's stock (TSE:IZP) lost 71.5 percent of its value, dropping C93 cents (about US68 cents) to close at C37 cents.
The compound - a leukocyte selective anti-inflammatory drug (LSAID) - failed to meet its primary endpoint of improvement in forced expiratory volume in one second (FEV1), which measures the amount of air that comes out of the lung.
"Without an improvement in FEV1, which is the measure the FDA would look at for approval, it would be difficult to take this drug forward," said Ian McBeath, the Vancouver, British Columbia-based company's president and CEO.
Partner Aventis Pharma, of Lyon, France, paid for the trial. Now the parties need to sit down and conduct a thorough analysis to determine what went wrong, and whether the partnership will continue with a different compound. A decision should be made by the end of July, McBeath told BioWorld Today. Inflazyme also needs to determine whether it will move forward with its other LSAID compounds outside the respiratory realm of the Aventis partnership. Those compounds are in Phase I development for various inflammatory indications.
The Phase IIa study of IPL512,602 was a double blind, placebo-controlled study involving 169 evaluable patients, who received either 20 mg of the drug or placebo once a day for three months. The drug-treated patients demonstrated less than a 2 percent improvement in lung function over placebo. Secondary endpoints, such as morning peak expiratory flow, need for rescue medication (albuterol use), asthma exacerbations and airway hyper-reactivity to a chemical challenge, all demonstrated an improvement in asthma symptoms. But Inflazyme really needed the FEV1 improvement to impress the FDA, McBeath said.
Inflazyme began researching LSAIDs in 1994, finding its first active compound, IPL576,092, in 1998. That compound showed an improvement in FEV1 of about 14 percent and blocked hyper-reactivity, but Inflazyme and Aventis decided to go forward with the second compound, IPL512,602, which showed greater potency in animal studies, could be dosed once a day and had a more solid PK profile. McBeath said the two partners could revisit IPL576,092, but it would be more likely for them to move forward with IPL12, which has a different structure but still profiles in animal models the same way that IPL512,602 did. However, McBeath questions the meaningfulness of animal models that sometimes show positive results that don't seem to transfer into humans.
He said the future of the whole LSAID program - the internal and partnered compounds - is unclear.
"We've never known the mechanism of action through LSAIDs," he said. "All we've seen is biological activity. Without the mechanism of action, it's difficult to predict how you can take these forward."
Inflazyme has more than $31 million in cash that will carry it through the end of 2005 or later, allowing the company to reach milestones for its next major focus on complement inhibitors. Inflazyme has three complement inhibitors in development, including APT070, a fragment of complement receptor 1 (CR1), which is in an early Phase I/II trial in rheumatoid arthritis. The results of that trial are expected later this year, and Inflazyme could move the product into a second indication in 2005. Two other complement inhibitors, CD59 and CD55, are being studied in the preclinical stage.
Inflazyme also plans to focus on its Prodaptin technology, which represents a series of molecules that can tether another molecule. One form of Prodaptin has been applied to CR1, constituting part of APT070. Prodaptins also could improve the activity of CD55 and CD59, McBeath said.
Both the complement inhibitor program and the Prodaptin technology came to Inflazyme through its $14.9 million acquisition earlier this year of Cambridge, UK-based Adprotech Ltd. (See BioWorld Today, April 13, 2004.)
Inflazyme hopes to move into the clinic in 2005 with ATH, an activated form of anti-thrombin. The company gained that product last year through its C$12.8 million merger with GlycoDesign Inc., of Toronto. (See BioWorld Today, April 10, 2003.)
"We think that the real indication for that would be protection of the brain during major surgery like cardiac surgery," McBeath said.
Thromboses formed during surgery can travel to the brain where they become lodged. That leads to neurological impairment, such as memory loss and mood changes.
"The preclinical studies look very strong. We are potentially going to be working with a partner in this area," McBeath said, adding that because there is a scarcity of drugs for the indication, it "could be a major opportunity."
Lastly, the company has an ongoing collaboration with Helicon Therapeutics Inc., of New York, for a PDE4 (phosphodiesterase 4) inhibitor as a potential new agent to treat learning and memory disorders. That product could enter the clinic by the end of this year. Inflazyme also has an option to do a 50/50 joint venture with Helicon on the product, which it must exercise by the end of Phase II testing. (See BioWorld Today, Feb. 8, 2001.)
"We've got products. We've got cash. We've got good infrastructure," McBeath said. "We have a track record of moving products from discovery into the clinic. We are still in good shape."
In May, Inflazyme dropped development of an antithrombotic agent, GH9001, when it showed an increase in liver enzymes in a Phase Ib trial. It decided not to move forward because of the expense for doing more studies, and because the product was not in the company's core anti-inflammatory focus. (See BioWorld Today, May 17, 2004.)