Fighting the Doom and Gloom: Prevention Works!

laos_mother_and_child

Hepatitis B vaccination event in Laos.

In recognition of Liver Cancer Awareness Month, Liver Cancer Connect is highlighting some of the advances in prevention, screening, and treatment that are leading to increased survival among people with liver cancer. Continue reading

Arrowhead’s HBV Candidate Requires Further Dose Escalation

It should be noted while numerically the improvement in knockdown from 1mg/kg to 2mg/kg was only 12%, this is likely the result of the apparent high variability at the lower dose level with the increased tightness of the knockdown range at 2mg/kg indicating that the RNAi mechanism is starting to be solidly engaged with the expectation of a steepening dose response going forward.

It should be noted while numerically the improvement in knockdown from 1mg/kg to 2mg/kg was only 12%, this is likely the result of the apparent high variability at the lower dose level with the increased tightness of the knockdown range at 2mg/kg indicating that the RNAi mechanism is starting to be solidly engaged with the expectation of a steepening dose response going forward.

Sadly, we read that Phase 2a data presented by Arrowhead fell short of expectations for their ARC-520 drug to treat chronic hepatitis B. Hopefully dose escalation to 4mg/kg will result in both effective and safe results. However, there are others in the race for the cure, and may the most effective and safe drug soon result in a functional cure for chronic HBV.
~ hepbtalk

 

Harnessing the Power of RNAi Gene Silencing in Quest of a Cure for Chronic Hepatitis B, and the HBV KnockDown blog written by Dirk Haussecker, who believes it’s about time everyone got serious about a functional cure for hepatitis B.  Be sure to visit Dirk Haussecker’s blog !  

Today, we learned about some hard HBsAg knockdown numbers from the phase IIa Hong Kong study of ARC520 in chronically infected HBV patients.  The data relate to the first 2 cohorts in this ongoing dose escalation trial.  Accordingly, the mean HBsAg knockdown at nadir for the starting dose of 1mg/kg was 39% within a range of 22-57%(n=6) while it was 51% within a range of 46-59% for the 2mg/kg cohort (n=6).

ARC520 was given as a single dose to patients already stably on polymerase inhibitor entecavir.

While clearly missing the company’s own guidance of a 1 log reduction at 2mg/kg, the good safety profile-no SAEs at all in the study with all AEs rated to be unrelated to ARC520- in addition to the steepening dose-response curve following 2mg/kg means that ARC520 is far from being out of the HBV knockdown race.  Still, the stock market over-reacted, punishing ARWR stock with a percent decrease that matched the reported knockdowns.

Although even I ended up willing myself into believing that a 70-80% knockdown was possible following a single ARC520 dose of 2mg/kg, revisiting the chimp study which involved 2 doses of ARC520 (first one at 2mg/kg then one at 3mg/kg), it should be noted that at the time the 3mg/kg dose was administered, the HBsAg levels had only declined by 50%…about the same as achieved in the phase IIa study.  It is thus possible that Arrowhead gave the 2nd dose just as HBsAg levels were about to go up again, consistent with the already rebounding levels of HBV DNA and HBeAg in that study.

As a result, my expectations for the single 3mg/kg dose are now 70-75% based on the ~75-80% peak HBsAg knockdown in the chimp study following the 2mg/kg and 3mg/kg doses.  This also means that in order to reach that 1log knockdown goal the company had set for itself, 4mg/kg will most likely be needed.  Importantly, in the concurrent phase I dose-escalating study in healthy volunteers, this quite large amount of drug seemed to be well tolerated and the company is awaiting approval to adopt this dose in the Hong Kong study.

This projection is not much off the 90% knockdown achieved in the ARC-AAT program at 3mg/kg in non-human primates.  The improvement of this 2nd DPC-based candidate about to enter the clinic is possibly explained by progress in the potency of 2-molecule DPC delivery technology.  I add this as today many were confused about what the interim phase IIa results meant for the platform and the value of the company.

Overall, as long as 4mg/kg is an acceptable dose from a tox point-of-view, ARC520 is still in the game to be first-in-class in HBV knockdown.  It would have been much worse if say a 70% knockdown had been reported, but worrisome safety signals emerged.  On the other hand, the continued need for a dose escalation would seem to delay Arrowhead’s broad-based phase IIb study plans, meaning that the competition, in particular Tekmira’s TKM-HBV is coming closer.

At a market cap of ~$400M, the market has almost fully discounted the potential of ARC520 given the $150M+ in cash as well as the IND-ready, first-in-class ARC-AAT for which we can expect solid knockdowns in the clinic.  Interestingly, data for this candidate were selected for an oral presentation at AASLD while the ARC520 data will be in less prestigious poster form. Finally, should the single-molecule DPC which got me excited about the Arrowhead RNAi platform in the first place finally reach the clinic, it would necessitate an upward revision of the value of the company.
Disclosure: Long ARWR.  I sold most of my holdings at $11 and change given the underwhelming results and increasingly negative market reaction, but got back in below $6 when I considered the sell-off to be a gross over-reaction and imminent 3mg/kg data having the potential to surprise the market to the upside from now much lowered expectations.  Add to this ARC-AAT, the platform…

HBV Journal Review – October 2014

ChrisKHBF is pleased to connect our blog readers to Christine Kukka’s monthly HBV Journal Review that she writes for the HBV Advocate. The journal presents the
 latest in hepatitis B research, treatment, and prevention from recent academic and medical journals. This month, the following topics are explored:

  • Chronic Hepatitis B Remains Public Health Challenge in U.S.
  • Epidemiologists Become Molecular Detectives to Investigate HBV Outbreaks
  • Telbivudine Effectively Prevents Infection of Newborns Born to Infected Mothers
  • GGT Blood Test Reveals Fibrosis and Cirrhosis in Hepatitis B Patients
  • Early Research Combining Antivirals with a Protein “De-activator” Shows Promise
  • Diabetes Dramatically Increases Liver Cancer Risk in Cirrhotic Patients
  • Tenofovir Linked to Higher Rates of Bone Loss than Entecavir
  • Tenofovir Equally Effective against Hepatitis B in Asians and Non-Asians
  • Liver Cancer Risk Factors Do Vary Between Racial Groups
  • Even Liver Specialists Fail to Screen Chemotherapy Patients for Hepatitis B
  • European Study Confirms Coffee Dramatically Lowers Liver Cancer Risk

HBV Journal Review

October 1, 2014
Volume 11, Issue 10
by Christine M. Kukka

Chronic Hepatitis B Remains Public Health Challenge in U.S.

A new U.S. Centers for Disease Control and Prevention report on hepatitis B prevalence finds that while new infections have declined markedly, treating chronic hepatitis B infection remains a public health challenge.

New hepatitis B virus (HBV) infections have plummeted since 1990 due to comprehensive immunizations. The CDC report estimates only 18,760 people were infected with HBV in 2012.

In 2012, the highest rates of new infections were among those aged 30–39 years (2.17 cases per 100,000 population), and the lowest were among children under age 19 who had been immunized at birth.

Many of the new infections were transmitted sexually or through injecting drug use.

However, an estimated 700,000 to 1.4 million U.S. residents are chronically infected. According to the report, Viral Hepatitis Surveillance United States, 2012, about half of those chronically infected were either born in Asia or were born to HBV-infected mothers in the United States.

In 2011, the death rate from chronic hepatitis B was 0.5 deaths per 100,000 population. The highest mortality rates were among people aged 55–64 years, Asian and Pacific Islander, and male.

“Identifying these chronically infected persons and linking them to care remains a challenge,” the authors reported.

Source: www.cdc.gov/hepatitis/Statistics/
2012Surveillance/

Epidemiologists Become Molecular Detectives to Investigate HBV Outbreaks

While new HBV infections have declined dramatically since the early 1990s due to effective immunizations, public health officials continue to examine where new infections are coming from and who is getting infected.

Read the HBV Journal Review in its entirety here. 

 

Hepatitis B Positive Speakers Discuss HepB with Geraldine Doogue

Heartfelt discussion with the “Hepatitis B Positive Speakers Group”, led by Australia’s Geraldine Doogue, ABC TV and Radio. Join Yvonne, David, Trevor, Linh and “Tina”, as they discuss their personal hepatitis B experiences -living with the stigma, and discrimination you can both see and “not quite put your finger on”, and their willingness to give back, and to increase community awareness.

If you’re on the Hepatitis B Information and Support Listserve, you may recognize Yvonne, one of the list moderators who mentions the emotional support she gets from her her cyber friends. 

Thank you Hepatitis Australia for sharing this discussion! 

 

HBV Journal Review – September 2014

ChrisKHBF is pleased to connect our blog readers to Christine Kukka’s monthly HBV Journal Review that she writes for the HBV Advocate. The journal presents the
 latest in hepatitis B research, treatment, and prevention from recent academic and medical journals. This month, the following topics are explored:

  • New Study Finds HBV Genotype E Responds Poorly to Entecavir
  • HBV Genotypes Help Tell the Human Story of Slavery in the Americas
  • Researchers Find Tenofovir Increases Hip Bone Loss in Older Patients
  • Decline in HBV RNA Indicates Who Loses HBeAg During Antiviral Treatment
  •  Shortened Vaccination Schedule May Get More Drug Users Immunized
  • Primary Care Doctors Rarely Screen Patients for Cirrhosis
  • Tenofovir or Telbivudine Recommended for Pregnant Women with High Viral Loads
  • Access to Healthy Food Vital for HBV Patients, but Many Live in Food “Deserts”
  • Scientists Create Viable Liver Cells in a Lab for HBV Research
  • Nerve Damage Prompts Warning Against Telbivudine-Interferon Combo Treatment

HBV Journal Review

September 1, 2014
Volume 11, Issue 9
by Christine M. Kukka

New Study Finds HBV Genotype E Responds Poorly to Entecavir
Experts know some hepatitis B virus (HBV) strains called genotypes respond better to interferon treatment than others, but now scientists are discovering that genotypes respond differently to antiviral treatment too.

HBV genotypes are found in different regions of the world and each evolved over centuries to have slightly different molecular make-ups with unique traits. Some carry a higher risk of liver damage and cancer, while other genotypes are less virulent.

In a recent study, Italian researchers compared how well patients with genotypes A, D and E fared after three years of treatment with the antiviral entecavir (Baraclude). All of the patients tested negative for the hepatitis B “e” antigen (HBeAg-negative). The scientists measured hepatitis B surface antigen (HBsAg) levels and HBV DNA (viral load) every three months during the first year of treatment and then every six months over the study period.

They found the rates of HBsAg declines resulting from antiviral treatment varied markedly between genotypes. They extrapolated how many years of entecavir treatment each genotype required before a patient would clear HBsAg and achieve undetectable viral load.

HBV genotype A: It would take on average 15.6 years of entecavir treatment for an HBeAg-negative patient with HBV genotype A to lose HBsAg. This genotype is found in northern Europe, North America, India and southern Africa.

HBV genotype D: It would take 17 years for genotype D patients to lose HBsAg. This strain is found primarily in Russia, the Middle East, the Mediterranean region, and India.

HBV genotype E: This genotype, found in Central Africa, responded the most poorly to entecavir. Scientists estimated it would take 24.6 years for these patients to lose HBsAg, according to the report published in the August issue of the Journal of Medical Virology.

Source: www.ncbi.nlm.nih.gov/pubmed/25131947

HBV Genotypes Help Tell the Human Story of Slavery in the Americas
Because HBV genotypes develop in specific regions around the world, their distribution around the world today can help tell the story of mass human migrations, including the enslavement and forced migration of millions of Africans to Brazil since the 1500s.

Read the HBV Journal Review in its entirety here.