How far are we from finding a cure for hepatitis B? We are close, said Timothy Block, PhD, president and co-founder of the Hepatitis B Foundation and its research arm, the Baruch S. Blumberg Institute. He points out that hepatitis C, once thought to be incurable, is today cured with new combination treatments.
Experts believe a cure for hepatitis B will also soon be developed. And the need for a cure has never been greater, with more than 240 million people worldwide living with chronic hepatitis B, causing 1 million deaths per year from related liver failure and liver cancer.
“Treatments are available,” explained Block, “but we have become a little too comfortable with the medications that are currently approved for use.” While these drugs are effective, interferon has many side effects and daily antivirals require lifelong use. These drugs work in only half of the infected population and reduce death rates by only about 40 to 70 percent.
What will a cure look like?
The available antivirals are similar and combining them offers no advantage. They have limited effectiveness against cccDNA, the seemingly indestructible “mini-chromosome” of the hepatitis B virus that continues to produce virus particles in infected liver cells, even in people being treated. A cure, therefore, would have to destroy or silence cccDNA and provide long-term immunity. Because one-drug treatments can lead to drug resistance, a cure would almost certainly involve combination therapy, similar to hepatitis C. Continue reading "Is a Cure for Hepatitis B Coming? Experts Say Yes"→
For years, people with pre-existing conditions like chronic hepatitis B struggled to get health insurance. News stories and Michael Moore’s documentary Sicko highlighted insurance companies’ refusal to cover pre-existing conditions and their practice of inflating premium prices if consumers had chronic health problems.
Outraged by industry efforts to cover only low-cost, “healthy” consumers, lawmakers banned discrimination against pre-existing conditions in the Affordable Care Act (ACA – Obamacare). The ACA’s Healthcare Marketplace website promises, “Your insurance company can’t turn you down or charge you more because of your pre-existing health or medical condition like asthma, back pain, diabetes, or cancer.”
For decades, people living with chronic hepatitis B were told they would be “cured” only when they lost the hepatitis B surface antigen (HBsAg) and developed surface antibodies. It represented the holy grail of recovery that everyone hoped for, but very few achieved.
Today, experts are redefining what constitutes a “functional cure” from chronic hepatitis B and taking the surface antibody out of the equation.
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.
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…
Truly historic news! Those living with chronic hepatitis B will be identified sooner and learn more about their HBV infection. They can live full lives by improving their health through regular monitoring, treatment when necessary, and adopting healthy lifestyles that benefit the liver. Symptoms may not occur for decades so many are completely unaware of their infection. If you believe you are at risk, please talk to your doctor about being screened for hepatitis B.
On Monday, May 26th, the U.S. Preventive Services Task Force (Task Force) published its final recommendation statement on screening for hepatitis B virus (HBV) infection in individuals at high risk. This recommendation includes adults and adolescents who are not pregnant and who have not been vaccinated, as well as other individuals at high risk for infection.
After reviewing the evidence, the Task Force recommends screening people who have the following risk factors for HBV infection:
People born in countries and regions with a high prevalence of HBV infection, such as Africa, Southeast Asia, Pacific Islands, China, Middle East, Eastern Europe, and the northern countries in South America;
U.S.-born persons not vaccinated as infants whose parents were born in countries or regions with a high prevalence of HBV infection;
HIV-positive people, injection drug users, men who have sex with men, and those living with or having sex with someone with HBV infection; or
Patients with weakened immune systems or undergoing treatment for kidney failure (hemodialysis).
There are still as many as 2.2 million people in the United States chronically infected with hepatitis B and 15 to 25 percent of those individuals die from liver disease including liver cancer. “Screening can identify people who have chronic HBV infection, and the good news is that treatment can help prevent liver cancer in these people,” says Task Force member Dr. Douglas K. Owens of Stanford University.
“The Task Force’s new Grade B recommendation in favor of HBV screening for persons at high risk for infection – people who are more likely to get infected or to pass on the infection – provides us with another important tool to use as we pursue the goals of the Action Plan for the Prevention, Care and Treatment of Viral Hepatitis,” observed Ms. Corinna Dan, Viral Hepatitis Policy Advisor at the HHS Office of HIV/AIDS and Infectious Disease Policy. “In the weeks and months ahead, federal and nonfederal stakeholders alike will incorporate this recommendation into efforts detailed in the Action Plan to improve viral hepatitis testing, care and treatment to prevent liver disease and cancer.”
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.
Following cryptic remarks during a conference call earlier this year, Alnylam today officially announced its entry into the cure-HBV race. In impressive data presented at the ongoing TIDES meeting, the company showed that up to 0.5mg/kg SNALP-siRNA was able to knock down HBsAg by ~2 log (99% knockdown) in infected chimpanzees. The data had been generated by Merck from which Alnylam acquired the RNAi assets in January. The goal is now to apply some of the learnings generated with Merck’s research-grade SNALP LNP technology and come up with a new candidate based on Alnylam’s GalNAc delivery platform (IND to be filed end of 2015).
In addition to the impressive HBsAg knockdowns, 3-4log knockdowns of viral DNA in serum were seen in the 4 chimpanzees. In the most viremic chimp, the 4log lowering of viral load was able to normalize liver enzyme (ALT) levels that had been elevated by ~5x ULN. Intriguingly, in 2 chimps with normal ALTs at the time of treatment, liver enzymes started to increase after dosing had finished (ruling out SNALP LNP as the culprit) and in 1 case also well after viral DNA had started to recover following cessation of RNAi dosing.
Intriguingly, while viral DNA recovered in this short study involving the administration of 3 doses (for every chimp 0.125mg/kg, then 0.25mg/kg, then 0.5mg/kg) over a span of 40 days, there were indications of a desired immunological response similar to that seen withARC520 in the chimp study, most notably an elevation of interferon gamma accompanied by ~2x increases in ALT in 2 of the chimps.
With Tekmira, ISIS/GSK and now Alnylam (and possibly more to come) following on the heels of Arrowhead Research and ARC520, the competitive landscape is starting to look quite complex. How it will play out will likely depend on the degree of HBsAg knockdown required (in relative and absolute terms) and who will run the right combination studies with other HBV agents, especially immune boosters such as interferon and possibly RT inhibitors (note: Alnylam speculates that RT inhibitor co-treatment will be beneficial and thereby justified its use of a single RNAi trigger).
If a deep multi-log HBsAg knockdown were required, it would favor Tekmira’s candidate which will be based on a 3rd gen SNALP LNP which can be considered superior to what came out of Merck’s copy-cat efforts subject of today’s presentation. If lesser knockdowns were able to achieve comparable cure rates, then the power would shift to the subcutaneous versions by Alnylam and ISIS/GSK (esp. the likely GalNAc-based follow-up version).
For ARC520, especially at 2mg/kg and Tekmira probably just 6 months behind, the competition may prove too much, not least because in the 2-dose study in the chimpanzee, the HBsAg knockdown was less than a log (80%). Granted it was an extremely viremic chimp and one of the RNAi triggers was a mismatch, but still. If Arrowhead and/or Tekmira demonstrate increased cure rates in 2015, Arrowhead should waste no time and push a single-molecule DPC into development to potentially once again take the lead.
The big question is how far along the way to clinical translation is single-molecule DPC? Tomorrow may provide an answer.
Three new studies presented today at the International Liver Congress 2014 have helped clarify the optimal use of combination therapy with peginterferon and nucleoside analogues (NUCs) to achieve the best treatment outcomes in patients with chronic hepatitis B (CHB).
“Together these ground-breaking data will go a long way to influencing future CHB treatment guidelines,” said EASL’s Educational Councillor Professor Cihan Yurdaydin from the Department of Gastroenterology, University of Ankara, Turkey.
In the first study , CHB patients who had failed on prior long-term exposure to one of the nucleoside analogue (NUC) antivirals demonstrated high rates of complete response and HBsAg loss when prescribed a sequential combination of peginterferon and NUC.
In the second study , adding peginterferon to the nucleoside analogue entecavir was shown to enhance response rates and viral decline in HBeAg-positive CHB patients with compensated liver-disease, was generally safe and well tolerated, and may facilitate the discontinuation of entecavir.
Finally, data from a third study suggested that adding on a NUC for six weeks to PegIFNalfa-2a does not enhance treatment response, with no increase in HBeAg seroconversion rates beyond that achieved by PegIFNα-2a alone after 24 weeks follow-up.
HBF 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: Continue reading "HBV Journal Review – December 2013"→
HBF 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:
Patients Who Clear Hepatitis B During Antiviral Treatment Do Well Long-Term
However, the Prognosis is Poor for Most Who Stop Antiviral Treatment
How Effective Are Antivirals in Reducing Cirrhosis and Preventing Liver Cancer?
New Antiviral Besifovir Hampered by Carnitine Deficiency in Early Clinical Trial
Liver Cancer Remains Major Health Threat, with Few Treatment Options
Scientists Develop a Better Mouse for Hepatitis B and C Research
HBV-Infected People Have a Higher Risk of Rheumatoid Arthritis
Ear Wax May Transmit Hepatitis B
Children with Frequent Ear Infections Do Not Respond as Well to Vaccines