Advancis Pharmaceutical Corp.'s stock lost more than half its value after top-line results of its Phase III trial showed that Amoxicillin Pulsys missed its primary endpoint in strep throat.
Results failed to demonstrate statistical non-inferiority in bacterial eradication between once-daily doses of 775-mg tablets of Amoxicillin Pulsys for seven days vs. 250-mg doses of penicillin administered four times a day for 10 days. Throat cultures taken at the end of the treatment period showed bacterial eradication in 76.6 percent (131 of 171) of the adult and adolescent patients receiving Advancis' product and 88.5 percent (161 of 182) of those in the penicillin-treated group.
Shares of Advancis (NASDAQ:AVNC) fell 59.3 percent Thursday, or $2.96, to close at $2.03.
"We were very surprised at the results," said Bob Bannon, senior director of investor relations at the Germantown, Md.-based company. "Going into this we had a high degree of confidence that the trial was going to be successful for a number of reasons."
He said researchers previously had looked at measurements, such as the minimum inhibitory threshold - marked by the minimum levels of antibody in blood plasma needed to prevent the bacteria from growing - and believed Amoxicillin Pulsys would prove to be comparable to existing antibiotics in treating pharyngitis/tonsillitis due to Group A streptococcal infections.
The Phase III data were startling, "not only in terms of the eradication rate for our product," Bannon told BioWorld Today, but also for the comparator therapy. "For penicillin to have 88 percent is particularly high."
Regardless, Amoxicillin Pulsys fell below the 85 percent eradication rate needed for FDA approval as a front-line therapy, and it failed to hit expectations at other clinical endpoints that measured patients' symptoms and recurrence of infection at 30 days following treatment.
Results appear to be consistent at all endpoints and across all patient groups. On the plus side, that "indicates the trial is well done," Bannon said, but it also shows "we're consistently below the level where we needed to be."
He said it's too early to speculate on why the drug failed, though Advancis will continue analyzing data over the next few weeks. The company also expects top-line results from a pediatric trial of Amoxicillin Pulsys during the last half of July. Structured in much the same way as the Phase III trial in adults and adolescents, the pediatric study is evaluating the same product administered in a "sprinkle" form that can be added to food. Dosage levels were set at either 475 mg or 775 mg, depending on the patients' ages.
"The results of the pediatric [trial] will definitely be pivotal for us," Bannon said, "as far as making a decision as to whether we want to proceed with further Amoxicillin Pulsys trials, or even with other Pulsys products entirely."
The amoxicillin formulation is the company's lead product candidate using Pulsys, its once-a-day pulsatile delivery technology developed based on findings that indicate bacteria are killed more efficiently by antibiotics released in front-loaded staccato bursts. The Pulsys system is designed to enhance existing antibiotics by reducing dose and treatment duration and by inhibiting bacterial resistance while improving the side effect profile and patient compliance. In addition to amoxicillin, the company is preparing to produce a Pulsys version of Keflex, acquired from Indianapolis-based Eli Lilly and Co., and is scheduled to begin a Phase I/II trial in the second half of the year. Advancis also is looking to apply its technology to Augmentin, a combination of amoxicillin and potassium clavulanate, expected to enter Phase I development later this year.
"Clearly, we would re-evaluate that," Bannon said, "if the pediatric trial [of Amoxicillin Pulsys] was not successful."
At best, a potential new drug application submission would be delayed for at least a year to allow Advancis to conduct another Phase III study in adults and adolescents. But Bannon said the firm has a cash position of about $45 million, and likely will not need to raise more funds to support a future trial.
Advancis completed a $27 million private placement in April. It expected to use those funds to finish up the trials of Amoxicillin Pulsys and prepare for commercial launch, which had been anticipated for 2006. (See BioWorld Today, April 27, 2005.)
The recently completed Phase III study cost between $6 million and $7 million to run, and development funding is coming from Advancis' partner, Spring Valley, N.Y.-based Par Pharmaceutical Companies Inc. The companies have a joint marketing agreement and would split any profits from the product on a 50-50 basis.