WUPPERTAL, Germany—German drug discovery and development company AiCuris Anti-infective Cures GmbH announced in January the promising results of a preclinical study involving its proprietary immune modulator AIC649 in animal models for chronic hepatitis B, which not only showed the antiviral efficacy of the compound but also indicated its potential to induce a functional cure for the disease.
The AIC649 compound is derived from inactivated parapoxvirus particles—elements of parapoxviruses belonging to a family of large, double-stranded DNA viruses that mainly infect hoofed animals such as sheep, goats and cattle. The particles used in the preclinical study come from naturally occurring strains that have been inactivated to allow for safe administration. Although inactive, these particles induce a natural immune response capable of attacking other, unrelated viruses in an organism.
“In patients chronically infected with hepatitis B virus (HBV), the immune system has been instructed to ‘tolerate’ the presence of the virus,” says Dr. Holger Zimmermann, CEO of AiCuris. “Such patients are incapable of generating productive immune responses that help control the disease. Treatment of these patients with inactivated parapoxvirus particles initiates an antiviral immune response, enhancing the body’s own response against HBV.”
AiCuris tested the antiviral effectiveness of AIC649 in a study of hepatitis B transgenic mice. Over a 29-day period, investigators administered the mice either twice-weekly treatments of AIC649 or twice-daily doses of Tenofovir, which is considered the gold standard of current hepatitis B treatment regimens. Both treatment regimens showed a significant reduction of HBV concentrations compared to the control group, and the twice-weekly AIC649 treatment showed an antiviral effect similar to twice-daily treatment with Tenofovir.
“AIC649 is conceived as part of a combination therapy including current nucleotide/nucleoside standard-of-care treatments,” says Zimmermann.
The company used a separate, longer-term test in woodchucks infected with woodchuck hepatitis virus (WHV)—analogous to the human version of the virus—to test AIC649’s potential to induce a functional cure. The study showed a two-phase response, with WHV antigen levels peaking at two to four weeks into treatment, followed by the levels of the virus present in the blood declining significantly between 16 and 20 weeks and remaining lower through the end of the study. These results are consistent with a reconstituted immune response against the virus.
“The woodchuck model is regarded as the best model in terms of pathogenesis (disease course) and the immunological parameters associated to the infection’s control,” says Zimmermann. “The model has been validated with marketed drugs … and shown to mimic the responses of chronically HBV-infected patients. Therefore, we are quite confident that the results shown for AIC649 in WHV-infected woodchucks will translate into the human situation, leading to induction of functional cure of chronically HBV-infected patients.”
As a follow-up to the promising preclinical data, AiCuris has initiated the clinical development of AIC649 in human patients infected with chronic hepatitis B. The study is designed to provide an evaluation of the safety of AIC649, and will also assess its ability to activate the immune system in human patients. A multiple-dose clinical study is planned thereafter.
The results from the first-in-human clinical study are expected in the second half of 2016. The clinical development and its timeline, however, also may depend on AiCuris’ ability to secure a partner in the pharmaceutical industry.
“It is AiCuris’ aim to bring AIC649 to HBV patients and contribute to the cure of this severe disease,” says Zimmermann. “As a clinical proof-of-concept company, AiCuris’ goal is to partner further development of AIC649. The promising results published in this study already raised interest.”
Hepatitis B, a potentially life-threatening liver infection caused by the hepatitis B virus, represents a major global health problem, with an estimated 240 million people chronically infected worldwide, according to a World Health Organization estimate published in July 2015. More than 780,000 people die each year due to complications of the disease such as liver cancer and cirrhosis. The virus represents a significant occupational hazard, especially for healthcare workers, wherever contact with blood or bodily fluids containing blood is possible. Current therapies provide a functional cure of the disease only in a small percentage of patients, but more commonly serve to suppress the virus. Market experts estimate the HBV market will reach $3.9 billion in 2016, according to a January media release issued by AiCuris.
“We very much look forward to speeding up the clinical development of this promising candidate to provide patients suffering from this life-threatening liver infection with a new treatment option as soon as possible and are open for partnering opportunities,” says Zimmermann.