By Randall Osborne
West Coast Editor
Aiming for pivotal studies with its cholera vaccine in the first half of next year, Avant Therapeutics Inc. said Phase IIb results with the oral Peru-15 product showed 100 percent protection against moderate to severe diarrhea associated with the disease.
The study was conducted in 59 volunteers to whom live Vibrio cholerae bacteria were administered. Ninety-three percent of subjects had no diarrhea at all, and the only noted side effects were mild headaches and abdominal cramps.
¿There¿s no need to sit here arguing about endpoints,¿ said Una Ryan, president and CEO of Needham, Mass.-based Avant. ¿You either have cholera or you don¿t. I¿m kind of glad I wasn¿t one of the volunteers,¿ she added.
In the study¿s first part, 40 volunteers got Peru-15 and the remainder got placebo. All but one of the treated subjects achieved the protocol definition of seroconversion for Inaba vibriocidal antibodies. The one who didn¿t had an atypically high baseline antibody titer. None of the placebo recipients achieved seroconversion.
In the second part, 36 volunteers agreed to return for a dose of live bacteria. Of these, 24 got vaccine and 12 got placebo. It was among these subjects that the favorable results against diarrhea were shown, along with favorable other parameters for vaccine efficacy. The number of diarrheal stools went down in vaccinated subjects, as did stool weight, fever and peak stool V. cholerae excretion, with no serious adverse events.
¿The amazing thing is that people had the confidence to come back and be challenged,¿ Ryan told BioWorld Today. ¿There isn¿t a good cholera vaccine, so the [Centers for Disease Control] doesn¿t even recommend vaccination to travelers.¿
Diarrhea of any severity was reported by one subject in the trials who received vaccine, and seven placebo recipients, hence about 93 percent protection with the Avant product.
Peru-15, developed using technology licensed from Harvard Medical School, deploys a live, attenuated mutant of V. cholerae O1 biotype El Tor, created through genetic engineering techniques to delete genes that encode cholera toxin. The nontoxic cholera toxin B-subunit gene was reintroduced into the bacterium, after which researchers screened for non-motile mutants of the engineered V. cholerae.
While Peru-15 targets the common O1 strain of V. cholerae, Avant also has developed a vaccine against the O139 strain, incidence of which is increasing.
¿If that should become a global pandemic ¿ and these things do sweep across the world ¿ we¿re ready with that one in the wings, but we haven¿t put it into manufacturing,¿ Ryan said.
Though rare in the U.S., cholera is becoming endemic in many countries in Latin America, Asia and Africa, and the current cholera pandemic, which started 40 years ago, is caused by the strain against which Peru-15 is engineered. Currently marketed vaccines, by comparison, provide only 65 percent to 80 percent protection.
¿I don¿t know what the FDA will require us to do as a size of [pivotal] study, but the vaccine is for travelers, healthy American and European travelers going to areas where cholera is endemic, so we believe efficacy could be shown with a similar study,¿ Ryan said. ¿We¿re ready to do the same thing again this time next year.¿
Peru-15¿s main benefits are that it¿s oral, uses live attenuated virus, and has a quick mode of action, Ryan said.
¿Most everybody would rather take something than bare themselves for a series of shots,¿ Ryan said. ¿You jump on your plane, take a swig of your vaccine, and you¿re on your way.¿ Tests have shown efficacy at seven to 10 days, she said, ¿but it¿s probably fair to say there¿s some protection at five days. There¿s a very nice high-end market we could access through travel clinics,¿ she added, noting that the market for treating bacterially caused diarrhea is expected to reach $1 billion by 2005.
Avant also has a typhoid vaccine, Ty800, which has completed Phase I/II trials. In preclinical study is a Shigella sonnei vaccine, aimed at the strain of Shigella most often suffered by travelers.
The company also said late Monday it has entered into a manufacturing deal with Bio Sidus SA, of Buenos Aires, Argentina, for production of Peru-15. Terms were not disclosed.
¿We¿ve really got all our ducks in a row,¿ Ryan said.
News of the cholera trial results was released after the market closed Monday. The company¿s stock (NASDAQ:AVAN) ended Monday at $5, up 33 cents.