Table of Contents
1. Introduction
2. Hepatitis: Causes and Symptoms
3. Pharmaceutical Industry Advancements
4. Hepatitis B Drugs under Development
• Direct-acting drugs
• siRNA
• TDF Pro Drugs
• Entry Inhibitors
• Capsid Inhibitors
• HBsAg Inhibitors
• Antisense Molecules
• Indirect-Acting drugs
• Therapeutic Vaccines
• Innate Immune Defense Pathway
5. Clinical Trials Phases
6. Conclusion
The word “hepatitis” means inflammation of the liver. Hepatitis is most often caused by one of several viruses, which is why it is often called viral hepatitis. Hepatitis is a contagious viral infection affecting the liver, which may spread on contact with infected blood. It may be a mild condition or may extend over a longer span of time leading to various complications. The characteristic symptoms include abdominal pain, fatigue, fever, jaundice, loss of appetite, nausea and vomiting. The predisposing factors of hepatitis typically include dialysis, organ transplant and blood transfusion and the offspring of an infected mother also has high chances of contracting the disease. With the advent of new technologies, we are getting closer than ever to eliminating the burden of chronic, viral hepatitis. The pharmaceutical industry is continually evolving in this area – creating safer, more effective therapies to get rid of chronic Hepatitis B and chronic Hepatitis C.
According to a report “Hepatitis Drug Development Pipeline Review, 2017” there are a total of 182 products in development for hepatitis B, by 110 companies and 14 academic institutions. Key companies operating in this pipeline space include Arbutus Biopharma, F. Hoffmann-La Roche, Johnson & Johnson, Assembly Biosciences, Gilead Sciences and Instituto Butantan. There are a total of 199 products in development for hepatitis C, by 92 companies and 34 academic institutions. Key companies operating in this pipeline space include Merck & Co, AbbVie, Johnson & Johnson, Gilead Sciences, Cocrystal Pharma, Bristol-Myers Squibb and F. Hoffmann-La Roche.
In the words of Timothy M. Block, PhD, Co-Founder and President of the Hepatitis B Foundation and its Baruch S. Blumberg Institute, excitement and anticipation of a cure for Hepatitis B is growing, partially due to the success of Hepatitis C being “curable.” While the implementation of HBV vaccine has led to a decline in the incidence of new HBV infection, the prevalence of chronic HBV infection still remains high as these therapies also do not lead to a true cure of chronic HBV infection. So, there is still a need to develop new drugs that attack different pathways of the Hepatitis B life cycle to eventually achieve a functional cure.
Hepatitis B drugs under development
There are more than 30 new Hepatitis B drugs being developed and they are different from currently available drugs [interferons and nucleos(t)ides]. The new Hepatitis B drugs which are under development have different mode of action:
- Direct-acting that target the virus
- Indirect-acting that target the human host
*Four phases of clinical research are conducted before a pharmaceutical drug is approved by the FDA. Each phase carries out a different type of research, lasts for a certain time frame, and uses a different amount of people. Phase I tests 20 to 100 people with the disease or condition for safety and dosage. Phase II tests up to several hundred people for efficacy and side effects. Phase III lasts for 1 to 4 years and tests 300 to 3,000 volunteers who have the disease or condition for efficacy and monitors any adverse reactions. In Phase IV, several thousand people with the disease or condition are now monitored for safety and efficacy.
Direct-acting drugs:
- siRNA= Short for “silencing” RNA, these are nucleotide drugs that interfere with and cause the destruction of the viral RNA. Out of 5 drugs under development, four drugs ALN-HBV, Hepbarna (BB-HB-331), ARB-1740, Lunar-HBV are in preclinical stage whereas ARB-1467 has reached to phase II trial.
- TDF Pro Drugs = A modified tenofovir drug CMX 157 that can get into liver cells more easily is currently in phase II development.
- Entry Inhibitors= These interfere with Hepatitis B getting into liver cells via attachment to a specific viral protein called ‘preS1’ and a specific liver cell protein. Drug following this pathway is Myrcludex B and is currently in phase II development.
- Capsid Inhibitors= Interfere with viral capsid formation, which is the protein shield that covers and protects the viral DNA. Out of six drugs under development HBV CpAM and AB-423 are in preclinical trials, AIC 649 and JNJ56136379 are currently in phase I development, Morphothiadin (GLS4) and NVR 3-778 is currently in phase II development.
- HBsAg Inhibitors= Interfere with the production of Hepatitis B surface antigen (HBsAg), which is needed for the virus to enter and exit the liver cell. RO7020322 (RG7834) is currently in phase I development whereas two drugs namely Rep 2139 and Rep 2165 are currently in phase II development
- Antisense Molecules= Binds to the viral mRNA to prevent it from turning into a viral protein. IONIS-HBVRx (GSK3228836) and IONIS-HBVLRx (GSK33389404) are currently in phase I development.
Indirect-Acting drugs:
- Therapeutic Vaccines = These drugs use vaccine technology to stimulate immunity as a potential therapy. Out of 6 drugs under development GS 4774 is currently in phase II development whereas INO-1800, HB-110, TG1050, HepTcell are currently in phase I development and TomegaVax HBV is in preclinical trials.
- Innate Immune Defense Pathway = Compounds that activate the innate immune system. Three drugs being developed currently in phase II are, GS 9620, RO6864018 (RG7795, ANA773) and SB9200.
- Host Acting Pathway = Compounds that induce programmed cell death. Out of 2 drugs under development EYP001 is currently in phase 1 development whereas CRV 431 (CPI 431-32) is currently in preclinical trials.
Hepatitis C drugs under development –
There are several FDA approved drugs to treat Hepatitis C with a high success rate and cures different Hepatitis C genotypes as well. However, there is always room for improvement. The following pharmaceutical companies are leading the way:
Gilead
This company is working on a combination of medicines consisting of sofosbuvir, velpatasvir and voxilaprevir to treat people who had failed previous therapies. Also provides higher cure rates for those who had not been previously treated (genotypes 1 through 6). The cure rates in phase 3 clinical trials were 95 to 98 percent. This led to being granted Breakthrough Therapy designation by the FDA for those with genotype 1 who had failed a previous course of therapy that contained a NS5A inhibitor and being submitted in December 2016 for approval to treat all genotypes.
AbbVie
The combination of glecaprevir (ABT-493) plus pibrentasvir (ABT-530) was used to treat genotypes 1, 3, 4, 5 and 6 for a duration of just eight weeks. This combination was granted Breakthrough Therapy designation by the FDA for those with genotype 1 who had failed a previous course of therapy that contained a NS5A inhibitor. In December 2016 AbbVie applied to the FDA to market and treat all Hepatitis C genotypes with this drug combination.
Janssen
- Samatasvir – currently in phase 1 development for genotypes 1, 2, 3 and 4, and in a phase II study with Olysio (simeprevir) in treatment-naïve patients with genotype 1b or 4.
- AL-335 (odalasvir) – currently in a phase IIa study for genotype 1.
- ACH-3422 and Odalasvir (ACH-3102) and Sovaprevir – currently in phase II studies in for genotype 1.
- Odalasvir plus sofosbuvir is in phase II development for genotype 1.
- Odalasvir, AL-335, and simeprevir in treatment-naive and treatment-experienced patients with and without cirrhosis for genotypes 1 through 6 are in a phase IIb study.
Merck
MK-3682 (polymerase inhibitor), grazoprevir (protease inhibitor) plus ruzasvir (NS5A inhibitor) with and without ribavirin to treat genotypes 1, 2 and 3 is currently in phase II development. This same combination is also being evaluated in an ongoing phase II study to treat people with genotype 1 who had failed a previous course of a direct-acting antiviral therapy (Harvoni or Zepatier).
Future
The present strategy for pharmaceutical companies is to find both direct and indirect-acting antivirals for Hepatitis B and better, safer, less expensive, pan-genotypic solutions for Hepatitis C.