SAN DIEGO – Infectious diseases have a hard time getting any love from the biopharma community. And historically, antifungals have had a hard time getting any love from the infectious disease community.
"It's this sleepy little corner of infectious disease," Jeff Stein, CEO of Cidara Therapeutics Inc., told BioWorld Insight. "There are only three classes of antifungals" – the azoles, the echinocandins, and amphotericin B.
In contrast, antibacterial drug classes number more than a dozen.
But that sleepy corner is slowly waking up.
At a lively session on new antifungals in the pipeline at the 2015 annual meeting of the International Conference on Antimicrobials and Chemotherapy and the International Congress of Chemotherapy (ICAAC/ICC), convener Oliver Cornely, professor at the University of Cologne, told the audience that "this year there's a lot more to speak about, as opposed to other years, where there just wasn't much happening" in antifungal development.
There are several reasons antifungals have gotten less attention than antibacterials.
One is that overall, there are fewer fungal than bacterial infections. Collectively, though, fungal infections kill almost 100,000 people annually in the U.S. and an estimated 1.5 million to 2 million people globally. That death toll encompasses a variety of different pathogens, but it also surpasses that due to either malaria or tuberculosis.
Fungal infections also tend to kill patients who are already quite sick. "These are complicated patients," Stein said. "They are in the hospital for something else, and that 'something else' gets a lot of attention . . . but many of them ultimately will die due to the underlying fungal infections."
Then, finding good targets is tougher. Unlike bacteria and like humans, fungi are eukaryotes – they have a membrane-enclosed nucleus and organelles. In practice, this means that many proteins that could be targeted therapeutically will have counterparts in humans.
Still, momentum in the antifungal space is growing. At the antifungals in development session, speaker John Perfect, professor at Duke University, took his audience through a tour de force of 10 new compounds in about 25 minutes.
Some of those compounds are members of the currently available classes of drugs. At the symposium on the antifungal pipeline, one presentation was devoted to new echinocandins. Furthest along is Scynexis Inc.'s SCY-078, which has received fast-track designation from the FDA for the treatment of invasive fungal infections and is being developed both as an oral formulation, where it is in phase II trials, and as an IV formulation, a program that is not yet in the clinic. The company presented animal data on SCY-078 at the ICAAC/ICC meeting.
Echinocandins still in preclinical development are ASP9726 (Astellas Pharma Inc.) and Cidara's biafungin (CD101). Stein said the company has completed a phase I trial using a single dose, is currently conducting a multiple-dose trial and expects to announce data from those trials by the end of the year.
But there are also half a dozen agents that target novel mechanisms.
A few of those agents are in the clinic, such as Nikkomycin Z, which targets chitin synthesis and is in phase I trials for Valley fever.
Arno Therapeutics' AR-12 is in preclinical development for fungal as well as viral infections, but there is phase I data on the compound from its previous life as an anticancer agent.
Most of the novel agents, though, are still in preclinical development, such as T2307 (Toyama Chemical Co. Ltd.), which Perfect noted for its "unbelieveably potent and broad-spectrum activity" against both molds and yeast. The compound targets mitochondria, which is a tricky business, as humans as well as fungi rely rather heavily on their mitochondria. But T2307 is selectively transported into fungal cells.
Cidara has developed Cloudbreak, a platform technology that can harness the immune system against fungal infections.
The basic idea of Cloudbreak, Stein said, was inspired by the bispecific antibody Blincyto (blinatumomab, Amgen Inc.), although the first generation of the technology (there are two) does not use antibodies. Instead, the molecule consists of an antifungal drug and a peptide that is derived from bacterial cell walls.
The roles of both molecules are the opposite of what one might expect. Therapeutic efficacy does not come from the antifungal drug; it provides a way to target the entire molecule to fungi. The therapeutic effect comes from the bacterial protein, which alerts immune cells that there is work to be done.
"Fungi . . . are very stealthy," Stein explained. "Some of our most effective immunosuppressants come from fungi. They can make things that mask them from the immune system."
In contrast, the immune system is quite good at recognizing bacteria. By attaching bacterial peptides to the fungus via the antifungal drug, the net effect is to "paint those fungi with a very loud signal and turn them into big bacteria . . . from the perspective of the immune system."
One strength of the approach, Stein pointed out, is that it has the potential to bridge conflicting goals in the patient's treatment.
Fungal infections are often due to a compromised immune system that is itself the result of other medical interventions such as chemotherapy or anti-rejection drugs. Those other medical interventions are both necessary for the patient's survival – and may kill them when such a patient develops an invasive fungal infection.
Cloudbreak, Stein said, is "a way to bridge" the patients' conflicting needs, because it focuses the immune system rather than strengthening or weakening it overall.