2017 Chronic Hepatitis Drug Pipeline

January 19, 2017

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In 2017, 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.

Hepatitis B

According to 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.” The currently approved oral antivirals for Hepatitis B do a good job of suppressing viral DNA levels, but none of them reliably achieve a functional cure – which is a sustained reduction in virus and other disease markers in the blood even after a drug is stopped. As such, there is still a need to develop new drugs that attack different pathways of the Hepatitis B life cycle to eventually achieve a cure.

There are more than 30 new Hepatitis B drugs being developed that differ from the currently approved therapies [interferons and nucleos(t)ides]. In general, the new Hepatitis B drugs are either:

• Direct-acting that target the virus
• Indirect-acting that target the human host

Direct-Acting Hepatitis B Drugs in Development

siRNA = Short for “silencing” RNA, these are nucleotide drugs that interfere with and cause the destruction of the viral RNA.

• ARB-1467 is currently in phase II development*
• ALN-HBV is currently in preclinical trials
• Hepbarna (BB-HB-331) is currently in preclinical trials
• ARB-1740 is currently in preclinical trials
• Lunar-HBV is currently in preclinical trials

*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. Learn more about clinical research and FDA-approval.

TDF Pro Drugs = A modified tenofovir drug that can get into liver cells more easily.

• CMX 157 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.

• Myrcludex B 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.

• Morphothiadin (GLS4) is currently in phase II development
• NVR 3-778 is currently in phase II development
• AIC 649 is currently in phase I development
• JNJ56136379 is currently in phase I development
• HBV CpAM is in preclinical trials
• AB-423 is in preclinical trials

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.

• Rep 2139 is currently in phase II development
• Rep 2165 is currently in phase II development
• RO7020322 (RG7834) is currently in phase I development

Antisense Molecules = Binds to the viral mRNA to prevent it from turning into a viral protein

• IONIS-HBVRx (GSK3228836) is currently in phase I development
• IONIS-HBVLRx (GSK33389404) is currently in phase I development

Indirect-Acting Hepatitis B Drugs in Development

Therapeutic Vaccines = These drugs use vaccine technology to stimulate immunity as a potential therapy.

• GS 4774 is currently in phase II development
• INO-1800 is currently in phase I development
• HB-110 is currently in phase I development
• TG1050 is currently in phase I development
• HepTcell is currently in phase I development
• TomegaVax HBV is in preclinical trials

Innate Immune Defense Pathway = Compounds that activate the innate immune system.

• GS 9620 is currently in Phase II development
• RO6864018 (RG7795, ANA773) is currently in phase II development
• SB9200 is currently in phase II development

Host Acting Pathway = Compounds that induce programmed cell death

• EYP001 is currently in phase 1 development
• CRV 431 (CPI 431-32) is currently in preclinical trials

Hepatitis C

2016 was an amazing year for Hepatitis C drug progress. In 2016, Harvoni and Viekira Pak were the most likely prescribed Hepatitis C medications. In addition, Zepatier, Viekira XR, Technivie and Epclusa were approved by the FDA to treat Hepatitis C. Used for different Hepatitis C genotypes, these medications boast a very high success rate, eliminating the Hepatitis C virus in 95 to 100 percent of patients.

However, there is always room for improvement. The following pharmaceutical companies are leading the way:

Gilead

This combination consists of sofosbuvir, velpatasvir and voxilaprevir to treat people who had failed previous therapies and to provide 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).

The investment in finding better therapeutic solutions for chronic Hepatitis B and Hepatitis C is immense. The complexity in combining drugs is increasing in the effort to find cures for these viral menaces. Our hopes are high as the race heats up to find both direct and indirect-acting antivirals for Hepatitis B and better, safer, less expensive, pan-genotypic solutions for Hepatitis C.