While DAC:GLP-1 hit its primary endpoint as a diabetes monotherapy in a Phase II trial that evaluated it in four doses, the drug's nausea and vomiting side effects sent ConjuChem's stock tumbling.
The Montreal-based company watched its shares (TSE:CJC) drop C$5.45 Thursday, or 53.2 percent, to close at C$4.80 They rose 80 cents Friday to close at C$5.60 (US$4.27).
"There are nervous investors," said Jacques Lapointe, chairman, president and CEO of ConjuChem. "There were some high expectations from the trial. We certainly met and exceeded the efficacy expectations. But we certainly fell short on the nausea expectations."
More than 50 percent of the 206 patients enrolled in the trial experienced mild to moderate nausea and vomiting, which often is associated with the GLP-1 class of compounds. The side effects limited the dose that ConjuChem could use with patients. For instance, those in a once-a-week dosing cohort were able to attain only about 35 percent on average of the target dosing levels.
"We pushed the dosage hard," Lapointe told BioWorld Today. "We wanted to see what the reaction would be, so we had more dropouts."
The trial ended with 94 patients.
However, regarding efficacy the drug did quite well, showing that treated patients experienced a 30 percent lower blood glucose than patients who received no treatment. The glucose levels were tested following a calibrated meal at different time points.
In May, the company moved the product into a Phase II combination trial to test it with Metformin (Bristol-Myers Squibb Co.) at a low dose in which nausea was either non-existent or controllable. Those results are expected in the fourth quarter. ConjuChem still plans to move DAC:GLP-1 into a Phase III trial in the second half of 2005 and hopes to form a global partnership sometime next year. With a Phase III trial taking about two years, ConjuChem could file with regulatory authorities sometime in 2007.
The only reason ConjuChem might not move into the Phase III trial as expected is if the company finds a way to limit the nausea in a once-a-week dosing, instead of a daily dosing. If that occurs, it might conduct another once-weekly dosing Phase II trial, Lapointe said. In the last trial, patients who didn't experience nausea were able to control blood sugar just as well on the once-a-week dose as they were with the once-a-day dose.
Two potential competitors of DAC:GLP-1 are products that are dosed more often. Amylin Pharmaceuticals Inc.'s exenatide is dosed twice a day, while a clinical-stage product from Bagsvaerd, Denmark-based Novo Nordisk A/S would be a once-a-day drug, Lapointe said. Amylin, of San Diego, and partner Eli Lilly and Co., of Indianapolis, filed a new drug application for exenatide in June. (See BioWorld Today, July 1, 2004.)
ConjuChem's Phase II trial, which was conducted at 26 centers in the U.S., Canada and Europe, began in October 2003 and was aimed at showing the drug's impact on a patient's weight, as well as its effectiveness in reducing glucose levels as measured by hemoglobin A1c and other parameters after three months of treatment.
To be included in the study, each patient needed to have an A1c level greater than 7.5 percent. Most of the 206 patients enrolled (69 percent men) were on one or two oral anti-diabetic medications, but the medications were withdrawn up to 15 days prior to the administration of DAC:GLP-1 and during the duration of the trial. The mean age of patients was 56, plus or minus 10 years, while the mean duration of disease was five years, plus or minus 2.9 years.
The trial was broken down into a 28-day titration stage and a 56-day maintenance phase. During the titration stage, patients received daily escalating doses of the drug in order to build the plasma concentration. Then, the patients were randomized into one of five cohorts, in which the drug was administered once a day, three times a week, twice a week, once a week or not at all. During the maintenance phase, patient dosages were adjusted with the objective of maintaining stable plasma concentrations.
Aside from the nausea and vomiting, the tolerability of the product appeared good with no immune or injection site reactions, or blood pressure modifications.
"We're not overly concerned about the nausea," Lapointe said. "At worst, we have a once-a-day product that we know how to control. But the hope for the once-a-week product is very much alive and well."
GLP-1, an insulinotropic hormone, is a naturally occurring 36 amino acid peptide that has been shown to normalize blood glucose levels by stimulating insulin secretion and lowering glucagon secretion. It also delays gastric emptying, induces beta cell proliferation, restores beta cell sensitivity to glucose and increases peripheral sensitivity to insulin. Its half-life, however, is only about five minutes, which can be extended with ConjuChem's Drug Affinity Complex (DAC) technology.
Aside from diabetes, ConjuChem is developing compounds to treat HIV/AIDS, human growth deficiencies and congestive heart failure.