Shares of ConjuChem Inc. plunged more than 50 percent after the company said it was temporarily stopping development of its DAC:GLP-1 compound in favor of a preclinical candidate that promises longer-term dosing to stabilize glucose levels in Type II diabetics.

The move followed reports of toxicity issues related to a new diluent used in the administration of DAC:GLP-1, as well as the recent availability of recombinant albumin for the company's PC-DAC platform technology. The first product developed under that platform, PC-DAC:Exendin-4, is expected to enter Phase I trials during the first half of 2006.

ConjuChem's stock, (TSE:CJC) fell C$1.04 (US$0.90), or 57.1 percent, Friday to close at C$0.78.

Jacque Lapointe, president and CEO of the Montreal-based company, assured that both the DAC (Drug Affinity Complex) and the PC-DAC (Pre-formed Conjugate-Drug Affinity Complex) programs are "very much alive and well." He added, "We just do not plan to spend more money on the original DAC:GLP-1 until we see what we have with the PC-DAC program."

It isn't the first snag the DC:GLP-1 product has hit. The product, a form of glucagen-like peptide-1 but with an extended half-life, hit its primary endpoint in a Phase II trial last year at once-weekly administration. However, more than half of the patients enrolled in the trial experienced mild to moderate nausea and vomiting. While those are common side effects with the GLP-1 class of compounds, they limited the product in terms of dose level. (See BioWorld Today, July 19, 2004.)

Following those Phase II results, the company put in motion a three-pronged strategy. The first involved "an easier titration and lower dose" of the drug, Lapointe said, which so far has generated good results as a once-daily formulation and would be "comparable to the market leader, with advantages since that is given twice a day."

Lapointe was referring to Byetta (exenatide), which was launched in June as an adjunct treatment for Type II diabetes patients who failed to achieve adequate blood sugar control using metformin or sulfonylurea, or a combination of both. A long-acting formulation of the drug now is in Phase II studies by partners San Diego-based Amylin Pharmaceuticals Inc. and Indianapolis-based Eli Lilly and Co.

In another effort to reconfigure DAC:GLP-1, ConjuChem tried out a new diluent, hoping to get to the desired long-acting doses.

"And we did," Lapointe told BioWorld Today. "Unfortunately, as sometimes happens in drug development, we saw some toxicity in the toxicity trials that basically precluded us from using that diluent."

ConjuChem's third option was to explore the use of PC-DAC, a platform that "only recently was made possible with the availability of high-quality recombinant albumin," he said.

PC-DAC involves the conjugation of a DAC peptide ex vivo with the recombinant albumin. The preformed conjugate is designed to provide the same efficacy seen in the DAC compound, but without the side effects.

"One of the known factors of the DAC technology was that not all of the peptide bound to the cysteine 34 albumin," Lapointe said, adding that the remaining free-floating part of the product was able to cross the blood-brain barrier and was the primary cause of the nausea and vomiting.

In August, the company signed a supply deal with recombinant protein manufacturing company Delta Biotechnologies Ltd. for Recombumin, a recombinant human albumin produced in the yeast Saccharomyces cerevisiae. Delta, based in Nottingham, UK, is a wholly owned subsidiary of Sanofi-Aventis Group, of Paris.

Preclinical work so far has shown that PC-DAC:Exendin-4 "outdoes just about everything that has ever been seen, including exendin-4 and DAC:GLP-1," Lapointe said. "So it's very promising."

If ConjuChem is successful at developing PC-DAC:Exendin-4, "we would have one of the very few products that would have the potential of dosing once a week," he added. "That would knock much of the competition out. It's sort of the Holy Grail of GLP-1 to get an injection that lasts a whole week."

Even though DAC:GLP-1 has been sidelined, Lapointe said the plan eventually is to partner both that and the PC-DAC program as a unit.

The rest of ConjuChem's pipeline has not been affected, though the company intends to switch its early stage programs from DAC to PC-DAC. Those programs focus on antivirals and drugs for congestive heart failure.

The company continues to move forward with its growth hormone product, DAC:GRF, which has demonstrated in early trials the ability to provide adequate dosing when given once a week. A Phase II study is expected to begin next quarter in HIV lipodystrophy and visceral obesity with metabolic syndrome.

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