Pharmaceutical

Clinical Studies

The ability of interferon to stimulate the immune system has been appreciated for decades and IFN-α (high-dose injected systemically) was first approved by the FDA to treat hairy cell leukemia in 1984. High-dose injectable IFN-α has also been used to treat hepatitis B and C. IFN-α has demonstrated anti-viral and anti-proliferative effects in cell cultures, animal studies, and human clinical trials. The main problem with using IFN in humans has been the adverse effects that come with the high doses used.

Researchers have attempted to solve this problem in many creative ways. Pegylated IFN-α is more stable, prolonging its half-life and enabling less frequent injections, but pegylated IFN-α does not solve the problem of serious adverse effects. Recently, a ropeginterferon alpha-2b novel IFNα was found to induce high response rates in polycythemia vera with lower toxicity than previous versions of pegylated IFN-α (Gisslinger 2018). Even this new “lower toxicity” IFN caused adverse events in 88% of the patients with 20% of patients choosing to discontinue the study due to the severity of the side-effects. Some of the 330 drug-related adverse events noted in this study with ropeginterferon alpha-2b included joint pain, headache, diarrhea, flu-like symptoms, nausea, muscle pain, increased sweating, hair loss, leukopenia, and thrombocytopenia. Some labs are now experimenting with IFN-α gene therapy in an effort to stimulate the immune system in cancers (Escobar 2018). In theory, monocyte-mediated IFN-α could have anti-tumor effects by delivering IFN in lower physiologic doses, however gene therapy technology is not without its own challenges and is a long ways from human clinical trials. Another tactic has been to stimulate endogenous production of IFN by using small molecules, viruses, or chemicals that bind to receptors on plasmacytoid dendritic cells (pDCs), the cells that produce the greatest amounts of interferon in the body. These efforts have met with varying levels of success, but often viruses and cancers escape detection by the immune system by down-regulating receptors on pDCs or by secreting viral interferon regulatory proteins that interfere with natural interferon production.

ABI-manufactured low-dose oral IFN-α lozenges could potentially solve all of the above problems. They are not toxic, because the dose is so low adverse events are virtually eliminated. The secret to the efficacy of ABI’s low-dose lozenges is that they act locally in the oral mucosa within minutes, so that a high systemic dose is unnecessary. The action in the oral and nasal-pharyngeal mucosa have a domino signaling effect throughout the body as evidenced by the systemic induction of hundreds of interferon-stimulated genes. Oral administration of murine IFN-α to swiss mice once daily for 4 days before infecting them with encephalomyocarditis virus conferred a significantly greater survival rate and survival time compared to control mice. (Schellekens 2001) Furthermore, oral IFN-α treatment of DBA/2 mice twice daily resulted in 50% survival rate after challenge with 20,000 LD50 Friend Leukemia cells, and greater survival rate after challenge with L1210 lymphoma or EL4 tumor cells. (Tovey 1999). ABI’s low-dose oral IFN-α has been studied in numerous human clinical trials for a multitude of disease states. Its safety has been underscored in every clinical trial to date and its efficacy has been demonstrated in a number of diseases.

The company has conducted 5 trials treating the common cold with various doses (15-150 IU QID) oral IFN-α, resulting in symptom improvement in the IFN groups compared to controls the majority of the time. Sore throat, rhinorrhea, and malaise were significantly reduced in those who took ABI’s low-dose IFN-α lozenges. One trial on influenza resulted in significantly lower flu-like symptoms in the older males who were given IFN compared to the older male controls in the study. Establishing clinical significance in trials of cold and flu is challenging because the symptoms are subjective. ABI has also been involved in hepatitis B studies on three continents. In two 10-month studies in Poland, oral IFN-α (25-200 IU QID) caused seroconversion from HBeAg+ to HBeAg- in over half the subjects taking the IFN and in one study that tested HBV DNA, 100% of the responders were negative for HBV DNA, indicating that these subjects would not relapse in the future as is the case with many hepatitis treatments. ABI’s oral IFN-α has also been studied in hepatitis C with clinically significant reductions in ALT (an indication of liver damage) seen in the majority of subjects given IFN compared to controls. Another trial examined the effects of oral IFN-α on ALT levels in subjects with various liver diseases and over 80% of subjects given IFN saw improvements in their ALT levels, with almost half of those reduced to normal, indicating a healthy liver. And in a trial on colorectal cancer, 2/3 of subjects treated with low dose oral IFN-α as adjuvant therapy (all subjects were taking chemotherapy) saw improvements, with 1/3 of the subjects in the IFN adjuvant therapy group attaining complete cancer remission.

A small trial studying the effects of oral IFN-α on idiopathic pulmonary fibrosis resulted in disease stability in 2/3 of the subjects and improvements in chronic cough and quality of life in over 80% of evaluable subjects. Another small trial showed that low doses of oral IFN-α reduced the need for phlebotomy in the majority of subjects with polycythemia vera. And finally, ABI has been involved with numerous HIV trials with the main significant effect of oral IFN-α being increased CD4+ T-cell counts. Interferon’s ability to stimulate the immune system has been long appreciated, but in recent years with advances in the understanding of tumorigenesis and cancer therapy, interferon has come into the spotlight as an adjuvant to cancer immunotherapy. Boutsikou et al. (2017) examined a group of non-small lung cancer patients who were undergoing PD-1/PDL-1 blockade and found that those patients with higher IFN, TNF, and IL levels had improved treatment response and greater survival at 3 months. The challenge is in delivering the interferon to the tumor without causing intolerable adverse effects. Escobar et al. are experimenting with gene therapy delivery of interferon and Stone et al. are experimenting with epigenetic interferon up-regulation in the tumor microenvironment, but both of these technologies are only testing in cell lines and murine models currently.

ABI’s low-dose oral IFN-α lozenges would be an ideal cancer therapy adjuvant in that it has systemic immune stimulating effects through acting at low doses in the oral mucosa, thus eliminating adverse effects. The company is actively seeking partnerships with other researchers, physicians, and companies to enhance the efficacy of cancer therapy by combining our low-dose oral IFN with PD-1 blockade, CART or other immunotherapies and hematopoietic stem cell transplantation, as well as in combination with chemotherapy. ABI’s low-dose oral IFN-α has been shown to reverse thrombocytopenia, which is one of the more dangerous adverse effects of chemotherapy. The company also plans to move forward in more advanced phase clinical trials on thrombocytopenia, hepatitis, and influenza.

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