News that Nabi Biopharmaceuticals intends to continue development of its Gram-positive programs - which includes the lead drugs StaphVAX and Altastaph - restored investor hopes Wednesday, as the company’s stock climbed 15.8 percent.
Shares (NASDAQ:NABI) rose 76 cents to close at $5.56, still several dollars shy of the $12.85 closing it had in early November, the day before Nabi halted further development of the program after StaphVAX missed its primary endpoint in a Phase III trial to treat Staphylococcus aureus-caused infections in patients with end-stage renal disease. The stock fell 71.8 percent that day, closing at $3.63. (See BioWorld Today, Nov. 2, 2005.)
But the Boca Raton, Fla.-based company never said it would give up on the program, only that it would conduct a deeper data analysis to figure out what went wrong.
The answer came by way of an outside advisory panel assessment, which reached two important conclusions.
One: "The antibodies generated in patients in the confirmatory Phase III study," said Thomas McLain, Nabi’s chairman, president and CEO, "were inferior in quality to the antibodies generated by other lots of vaccines used in previous and subsequent trials."
And two: The virulence of bacteria and each patient’s immune system played a large role in whether optimal protection could be achieved with the vaccine. In other words, the dialysis patients enrolled in the trial were a difficult population due to underlying factors associated with kidney disease, which compromised their immune system and caused the "vaccine to work as a treatment vs. a true preventive approach," McLain said in a conference call.
Antibody Quality Key To Protection
Results from the confirmatory Phase III trial baffled Nabi management last November when the study failed to show that StaphVAX reduced the incidents of S. aureus types 5 and 8 infections compared to placebo. The trial enrolled 3,600 patients on hemodialysis who received either StaphVAX, a polysaccharide conjugate vaccine or placebo.
The data ran contrary to results of a Phase III study in the same population completed in September 2000 and involving 1,804 patients. That trial demonstrated a 60 percent reduction in infection in those dosed with StaphVAX through 10 months.
The difference between the trials was that the first used a vaccine produced at small scale at Nabi’s own research and development pilot manufacturing facility, whereas the confirmatory study used product made on a large scale by an unnamed contract manufacturer.
The company determined the inferiority through an assay that "was able to distinguish between lots that were good and lots that were suboptimal," said Raafat Fahim, Nabi’s senior vice president of research and technical and production operations. That was confirmed through a series of animal protection model studies; healthy animals dosed with Nabi’s manufactured vaccines or human antibodies generated from the vaccines were 100 percent protected from challenge against Type 8 S. aureus bacteria, whereas only 30 percent to 50 percent of animals dosed with the vaccine from the lot used in the confirmatory Phase III study were protected.
Also of note, a second contract manufacturer, Cambrex Bio Science Baltimore Inc., provided lots for subsequent bridging and immunogenicity studies completed last year. The lots of vaccine produced at Cambrex demonstrated a protection benefit similar to the vaccine produced by Nabi, indicating it was possible to manufacture StaphVAX to the quality required for success in a confirmatory Phase III trial. Nabi had moved production from the first manufacturer to Cambrex because the Cambrex facility was configured to be licensable for Europe.
Through the whole analysis of the trial, Nabi has learned of changes that must be made to the manufacturing process, including alterations in the capsular polysaccharide structure, which is important for producing high-quality and high-affinity antibodies.
The company, basically, is adding two antigens to the product, said Thomas Rathjen, vice president of investor relations at Nabi.
"It’s going to have a different composition, a broader composition," he told BioWorld Today. "The StaphVAX [vaccine] had the Type 5 and 8 antigen targets. We’re adding two additional targets, Type 336 and PS-1 for Staph epidermis."
"It is important to note," McLain said, "that this is new intellectual property that we are moving to protect."
Virulence Of Bacteria Also Played Role
Nabi does not expect to go after the same patient population used in the confirmatory Phase III trial.
"One of the things we found was that the patient population we were dealing with, the dialysis patients - these folks had really a very much compromised immune system," Rathjen said. "And we do not think that is a viable patient population for this next trial."
The company expects to look at a "broader patient population that has a more intact or more viable immune capability," he added, although the exact population has not been decided upon.
Dialysis patients have immune system problems because of kidney disease and the release of higher levels of toxins. They are at constant risk for infection, and S. aureus bacteria often colonize at the dialysis access site. In the first Phase III trial, high levels of optimal antibodies may have compensated for the virulence.
As for the next steps, Nabi anticipates securing a partner for StaphVAX (Staphylococcus aureus polysaccharide conjugate vaccine) and the new Phase III trial, taking its second product, Altastaph (Staphylococcus aureus immune globulin intravenous [human]), through a Phase II proof-of-concept study on its own.
Altastaph is considered "a treatment for patients that are currently suffering from Staph infections," Rathjen said, "as opposed to the vaccine that [is designed] to prevent future Staph infections."
Nabi believes development of a multi-valent antibody will be faster than that of a multi-valent vaccine, and the cost of an Altastaph development program should be less, considering the enrollment of the clinical studies should be "in the hundreds and not in the thousands" of patients, McLain said.
This year, Nabi plans to initiate an immunogenicity study in the second half with StaphVAX. And with a partner, it hopes to start the prevention Phase III study in 2007. A donor stimulation study of next-generation Altastaph will begin in the first half of this year, whereas the Phase II proof-of-concept study, funded by Nabi, is slated to start in the first half of 2007.