Closely held Ciclofilin Pharmaceuticals is developing what, it hopes, will be the first clinically effective treatment for hepatitis C virus (HCV)/HIV-1 co-infection, with specific antiviral activity directed against both viruses.
“Other companies are working on one or the other virus, so we would like to position ourselves as the company working on co-infection, where our single drug can treat both viruses simultaneously,” Robert Foster, CEO and a co-founder of the company, says in an interview with BioTuesdays.com. “The number of people infected with both viruses is not insignificant.”
In the U.S. alone, there are 1.4 million patients infected with HIV. Approximately 25% of these patients are co-infected with HCV, which could be explained by the similar mode of transmission of these two viruses.
Dr. Cosme Ordonez, president and a co-founder (along with Dr. Foster), explains that due to the severe immunosuppression caused by HIV-1 and HCV, most co-infected patients do not respond to existing therapies.
“At Ciclofilin, we believe that we have a candidate medicine that could become the preferred treatment for this patient population,” Dr. Ordonez says. “This is an important indication, as liver disease is the main cause of death and hospitalization for HIV patients.”
HCV/HIV-1 co-infected patients have higher viral loads than patients infected with HCV alone, or mono-infected patients. Virus persistence after treatment is a common event for co-infected patients, who develop liver fibrosis, cirrhosis, end-stage liver disease and liver cancer more frequently than mono-infected patients.
Although San Diego-based Ciclofilin is primarily targeting HCV/HIV-1 co-infected patients, Dr. Foster believes that the company’s candidate medicines could potentially be used for the treatment of other difficult-to-treat HCV patients, including those infected with HCV genotype 3 and also suffering from advanced liver disease; and those co-infected with hepatitis B virus.
Ciclofilin’s lead drug, CPI-431-32, inhibits a cellular enzyme known as cyclophilin A (CyPA), which is responsible for activation of viral proteins critical for the replication of both HCV/HIV-1 viruses.
Dr. Foster explains that by targeting a host protein, such as CyPA, rather than the virus, the company’s lead drug has potential advantages over existing medicines.
He contends that CyPA is required for replication of HCV and HIV and that, without CyPA, cells are resistant to infection by both HCV and HIV. “By knocking down CyPA, studies have shown that cells become resistant to viral infections, despite various viral mutations.”
According to Dr. Foster, most commercially available drugs for the treatment of HCV are direct acting antiviral agents (DAAs), which target the virus. Due to mutations of HCV, resistance to DAAs can arise easily, accelerating disease progression and causing treatment failure.
“We don’t have a problem of emerging viral resistance, because our lead drug targets the host, by targeting CyPA, not the virus,”he adds.
In collaboration with Dr. Philippe Gallay of Scripps Research Institute at La Jolla, CA, and the National Institutes of Health, Ciclofilin has demonstrated that its lead drug, CPI-431-32, is efficacious and represents a potential treatment for HCV infection and HIV-1 infection and, perhaps more importantly, for HCV patients co-infected with HIV-1.
Dr. Gallay plans to present these results at the upcoming American Association for the Study of Liver Disease (AASLD) meeting to be held in Boston in the fall. “The AASLD meeting is the most important medical conference in the area,” Dr. Foster says.
“Our compounds have unique chemical properties, have shown potential pharmacokinetic and pharmacodynamic advantages, are relatively easy to manufacture, have a high barrier to resistance, are truly pangenotypic, or effective against all genotypes or variants of HCV, and could become the preferred therapeutic option for difficult-to-treat patients, including those co-infected with HCV and HIV-1,”Dr. Foster contends.
Hepatitis C has become one of the hottest categories in drug research as companies race to develop cost-effective oral combination therapies, free of debilitating side effects.
Dr. Foster points out that Gilead Sciences’ (NASDAQ:GILD)blockbuster Sovaldi is the latest blockbuster drug for the treatment of HCV. While Sovaldi is effective against HCV, it has no effect against HIV. Approved in December for HCV, Sovaldi chalked up more than $2-billion in sales during its first three months on the market, making it potentially the best drug launch in history.
Despite Sovaldi’s initial success, he notes that Gilead is under heavy criticism for the cost of the drug, which runs to $84,000 for a 12-week treatment, or about $1,000 a pill. In certain difficult-to-treat patients, treatment must be extended to 24 weeks, bumping up the cost to $168,000.
There are six distinct genotypes, or subgroups of HCV, and Gilead has suggested that patients with genotype 3 require extended treatment with Sovaldi.
Earlier this month, Merck (NYSE:MRK) agreed to pay $3.85-billion to acquire Idenix Pharmaceuticals (NASDAQ:IDIX), which has three HCV medicines in early-stage development. Idenix’s drugs are a new class called NS5A inhibitors, which disrupt the HCV virus’ life cycle at various stages.
According to Dr. Ordonez, CyPA binds to and activates the NS5A protein of HCV. CyPA also stabilizes a specific protein conformation of NS5A critical for viral replication.
“Our CyPA inhibitors block NS5A-CyPA interaction, inhibiting viral replication and potentially reducing NS5A-driven inflammation, which is the main culprit responsible for the long-term damaging complications of hepatitis,” he adds.
Dr. Foster suggests that Merck would not be spending $3.85-billion for Idenix if Gilead or other companies in the space had all the cost-effective answers and HCV was essentially cured for all genotypes, across all patients. “And, given the history of evolution of resistance to anti-infective agents, whether for viruses or bacteria, it appears that the hunt for novel medicines must continue.”
Conservatively speaking, Ciclofilin could potentially treat 150,000 patients infected with both HCV and HIV in the U.S. Dr. Ordonez figures the U.S. market potential for Ciclofilin’s products to treat HCV/HIV co-infection could be $6.3-billion, assuming a selling price that is about one-half of Sovaldi’s price of $84,000 per patient.
Ciclofilin’s technology platform was developed by Dr. Foster and his team while at Isotechnika Pharma, a company he founded in 1993. Isotechnika, which is best known for its immunosuppressant, voclosporin, acquired Aurinia Pharmaceuticals (TSX:AUP) in 2013, and changed its name following the acquisition of the company.
“I left Aurinia at the beginning of the year to join forces with Dr. Ordonez, who left Difference Capital at the same time. We decided to focus all our efforts on building a new company around the cyclophilin inhibitors technology our team had developed,” he recalls. “After I left Isotechnika, I acquired all these early-stage assets because their potential is truly amazing.”
Dr. Ordonez believes that the cyclophilin enzyme represents a master molecular target, the potential of which is just now becoming more recognized in a wide array of medical applications, including significant markets such as pulmonary arterial hypertension, atherosclerosis and cancer.
So far, Dr. Foster and Dr. Ordonez have built a five-member board at Ciclofilin which, they say, is a “top-notch, highly functional group.” In addition to the two co-founders, the board includes:
Dr. Peter Wijingaard, VP, innovation leader R&D for The Medicines Company (Schweiz) GmbH, and a former transplantation executive with Hoffmann-La Roche in Switzerland.
Martin Hubbes, former chief investment officer and a portfolio manager with AGF Investments.
Jamie Brown, managing partner with Difference Capital and a former vice chairman and president of Canaccord Genuity’s U.S. division.
Ciclofilin is now in the process of raising $2-million, ahead of a series A venture capital round of $5-million to $10-million to get Phase 1 data from clinical testing. The company plans to file an IND in 2016.
Over the next two years, Ciclofilin plans to conduct detailed toxicology and preclinical studies, as well as optimize the medicinal chemistry of its lead compound.
Another advantage of Ciclofilin’s candidate medicines, Dr. Foster points out, is the fact that they are derived by medicinal chemistry through modifications to cyclosporin A, which was introduced in the 1980s for the treatment of organ transplantation.
Isotechnika previously treated more than 2,600 patients in clinical trials with voclosporin, a cyclosporine analog, proving that the drug was safe and effective.
“Given the fact that we’ve been working with cyclosporin and its analogs for 25 years, and we have a great deal of experience with chemistry, manufacturing, clinical and non-clinical programs, we don’t envision any unexpected toxicology results with CPI-431-32,” Dr. Foster says. “Our ability to enter clinical testing should be straight and narrow.”