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.
If you did not appreciate the value the pharmaceutical industry has come to place on the HBsAg knockdown concept for achieving a functional cure for chronic Hepatitis B (HBV) infection, the last two days will have woken you up.
Yesterday, ISIS Pharmaceuticals reported that it had received a $7M milestone payment related to the development of an antiviral RNaseH development candidate (ISIS-GSK3Rx, aka ISIS-HBVRx) which, although undisclosed for competitive reasons, has got to be for HBV. And today, Tekmira publicly announced that they will file an IND for an HBV-RNAi candidate in 2014 while hinting at the partnering potential of such a treatment candidate.
Arrowhead Research is thus not alone in their efforts any more. Coincidentally, Arrowhead reported today the completion of their enrollment of the phase I single-dose, healthy volunteer study with ARC520, their DPC-delivered candidate for chronic HBV. Accordingly, the dose escalation was able to run through all the pre-planned 6 dose cohorts up to the top dose of 2.0mg/kg.
Apparently, there were no signs of significant dose-related toxicities. The only finding of concern among the 36 volunteers, 24 of which received drug, was 2 cases of lightheadedness of uncertain clinical relevance. As these occurred at the highest dose, it seems that the company suspects that it could have been drug-related although the study remains blinded for follow-up.
A dose of 2mg/kg without any serious adverse events or dose-limiting toxicities is a great start for DPC delivery technology. This is especially the case when one considers that the single-molecule subQ version of DPC that I hope will form the basis for the upcoming pipeline candidates, except for the next one perhaps, will be much more potent than the two-molecule version of intravenously delivered ARC520 based on the non-human primate data presented at last year’s OTS meeting.
With 2mg/kg of ARC520, I further believe that HBsAg knockdowns of over 90% are likely. The biggest challenge going forward with this program will be setting a knockdown goal and getting the dose and dose frequency right.
Direct from the Department of Justice (see below), the first DOJ settlement of an American with Disabilities Act (ADA) case involving people with hepatitis B was announced. The Hepatitis B Foundation is proud to have played a critical role in successfully advocating for these students who suffered from discrimination as a result of chronic hepatitis B infection.
July 2011, a meeting was convened by the CDC, with the HBF and others, resulting in the July 2012 CDC update “Recommendations for the Management of Hepatitis B virus-Infected Health Care Providers and Students. ”These recommendations were cited in the DOJ statement and clearly contributed to the DOJ settlement on behalf of people living with chronic HBV eliminating them from being excluded or discriminated against due to health issues. Since all applicants are from the Asian American Pacific Islander (AAPI) community, which accounts for more than 50% of Americans living with chronic HBV, The DOJ assures that the Civil Rights Division is committed to ensuring discrimination does not occur in this community as a result of this disability. On behalf of those living with HBV, the HBF applauds this decision by the DOJ.
The Justice Department announced today that it has reached a settlement with the University of Medicine and Dentistry of New Jersey School (UMDNJ) under the Americans with Disabilities Act (ADA). The settlement resolves complaints that the UMDNJ School of Medicine and the UMDNJ School of Osteopathic Medicine unlawfully excluded applicants because they have hepatitis B. This is the first ADA settlement ever reached by the Justice Department on behalf of people with hepatitis B.In 2011, the two applicants in this matter applied and were accepted to the UMDNJ School of Osteopathic Medicine, and one of them was also accepted to the UMDNJ School of Medicine. The schools later revoked the acceptances when the schools learned that the applicants have hepatitis B. The Justice Department determined that the schools had no lawful basis for excluding the applicants, especially because students at the schools are not even required to perform invasive surgical procedures, and that the exclusion of the applicants contradicts the Centers for Disease Control and Prevention’s (CDC) updated guidance on this issue.
According to the CDC’s July 2012 “Updated Recommendations for Preventing Transmission and Medical Management of Hepatitis B Virus (HBV) – Infected Health Care Workers and Students,” no transmission of Hepatitis B has been reported in the United States from primary care providers, clinicians, medical or dental students, residents, nurses, or other health care providers to patients since 1991.
“Excluding people with disabilities from higher education based on unfounded fears or incorrect scientific information is unacceptable,” said Thomas E. Perez, Assistant Attorney General for the Civil Rights Division. “We applaud the UMDNJ for working cooperatively with the Justice Department to resolve these matters in a fair manner.”
“It is especially important that a public institution of higher learning – especially one with a mission to prepare future generations of medical professionals – strictly follow the laws Congress has enacted to protect from discrimination those people who have health issues,” said U.S. Attorney for the District of New Jersey Paul Fishman. “The remedies to which the school has agreed should ensure this does not happen again.”
Under the settlement agreement, the UMDNJ must adopta disability rights policy that is based on the CDC’s Hepatitis B recommendations, permit the applicants to enroll in the schools, provide ADA training to their employees and provide the applicants a total of $75,000 in compensation and tuition credits.
Both of the applicants in this matter come from the Asian American Pacific Islander community. The CDC reports that Asian American Pacific Islanders (AAPIs) make up less than 5 percent of the total population in the United States, but account for more than 50 percent of Americans living with chronic Hepatitis B. Nearly 70 percent of AAPIs living in the United States were born, or have parents who were born, in countries where hepatitis B is common. Most AAPIs with Hepatitis B contracted Hepatitis B during childbirth . The Civil Rights Division is committed to ensuring that this community is not subjected to discrimination because of disability.
Title II of the ADA prohibits state and local government entities, like the UMDNJ, from discriminating against individuals with disabilities in programs, services, and activities. State and local governments must also make reasonable modifications in policies, practices, and procedures when the modifications are necessary to avoid discrimination on the basis of disability, unless those modifications would result in a fundamental alteration.
More information about the Civil Rights Division and the laws it enforces is available at the website www.justice.gov/crt. More information about the ADA and today’s agreement with UMDNJ can be accessed at the ADA website at www.ada.gov or by calling the toll-free ADA information line at 800-514-0301 or 800-514-0383 (TTY).
HBF welcomes special guest bloggers, Vikrant V. Sahasrabuddhe, M.B.B.S., M.P.H., Dr.P.H and Katherine A. McGlynn, Ph.D, M.P.H. both researchers at the National Cancer Institute of the NIH, and study authors of the recent Journal of the National Cancer Institute publication.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. New cases of HCC and deaths related to HCC have been increasing in the United States since the 1980s. Most cases of HCC occur in individuals with chronic liver disease (CLD). CLD is caused by chronic inflammation related to viral infection, excess alcohol consumption or other causes. While HCC is relatively rare in the U.S., occurring in fewer than 10 per 100,000 persons per year, CLD is more common. Unfortunately, CLD is among the top 10 causes of death in adults between the ages of 45 and 75 years.
In a new study from the National Cancer Institute, researchers investigated whether reduction of inflammation, through the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, could reduce the risk of developing HCC or death due to CLD. The study was published in the Journal of the National Cancer Institute on November 28, 2012.
The researchers studied a cohort of over 300,000 men and women between the ages of 50 and 71 years who were enrolled in the NIH-AARP Diet and Health Study. Aspirin and non-aspirin NSAID (for example Advil, Motrin) use was compared among persons who developed HCC or died from CLD and those who did not develop these outcomes. In all, 250 study participants developed HCC and 428 died from CLD. Almost three-fourths of the participants reported using aspirin and approximately one-half reported using non-aspirin NSAIDs.
The study found that participants who reported taking aspirin were 41% less likely to develop HCC, and 45% less likely to die from CLD than those who did not take aspirin. Use of non-aspirin NSAIDS did not reduce the risk of developing HCC, but did reduce the risk of dying from CLD by 26%. The researchers note that additional studies will be required to confirm these findings.
While this study will not lead to any immediate changes in clinical practice, it raises interesting new questions on the role of inflammation in risk for HCC. Although the researchers took into consideration the effect of alcohol intake (a major risk factor for HCC) as well as smoking and body mass index, the study had no information on hepatitis B virus (HBV) or hepatitis C virus (HCV) status of the study participants. In addition, NSAID use was only measured for the past 12 months, and the study had no information on the indication, duration or dose. To partially overcome such limitations, results were analyzed after excluding participants who reported hypertension or cardiovascular disease at the beginning of the study. Those individuals might be taking a low-dose aspirin for a longer duration for the prevention of cardiovascular disease. The results were similar after excluding these participants, which suggests that the main results are likely valid regardless of the indication, duration or dose of aspirin.
The study is the largest population-based study to date to assess development of HCC and risk of death due to CLD in relation to NSAID use. HCC and CLD involve chronic, long-term inflammatory changes in liver cells, which are caused by enzymes such as cyclooxygenases (COX). One of the primary ways that NSAIDs modulate the risk of chronic inflammation is by stopping or inhibiting the action of COX enzymes; thus inflammatory changes that contribute to the development of CLD and HCC are reduced. It is also speculated that aspirin may have other anti-inflammatory mechanisms. NCI researchers are investigating these hypotheses through basic and translational research studies, as well as assessing the risk of developing HCC and dying of CLD in association with NSAID intake in other epidemiologic studies.
Editorial Comments by W. Thomas London, HBF Senior Medical Advisor
In previous blogs I reported that several drugs commonly used to treat or prevent diseases or conditions other than liver cancer or chronic liver disease may also prevent these serious liver diseases. These included propranolol used to reduce pressure in the portal vein; metformin used to treat diabetes; and statins for the lowering of cholesterol and reducing the risk of heart disease.
The above report adds aspirin to this list, but people with chronic hepatitis B or C should not begin taking aspirin immediately. Aspirin may cause serious bleeding that is sometimes fatal. In order for blood to clot, platelets (cell fragments in blood) must clump. One of aspirin’s actions is to prevent platelets from aggregating (clumping). This action may be the main reason that regular aspirin may prevent heart attacks. Patients with CLD are already at risk of developing serious bleeding. The take home message is that patients with chronic hepatitis B or C should consult their doctor before taking aspirin or any other drug.
I was fortunate to have the opportunity to represent the Hepatitis B Foundation at yesterday’s FDA vaccine advisory panel review of Dynavax’s new HEPLISAV vaccine for hepatitis B. I was there for the public comment period on the second day of the meeting with my prepared statement. I was surprised to find I was the only one there for public comment. Since I’ve never been to anything like this, I don’t know if that is typical or not. I think my personal story with HBV, and the message from the HBF was important for the FDA panel to hear, so they were sure to be reminded that there are real people affected by chronic hepatitis B.
There has been a great deal of good press about the new Dynavax vaccine. In studies it has superior immunogenicity when compared to the currently available vaccines. Immunity is generated in 2 doses given one month apart, versus the currently available vaccines where it is a three shot series over 6 months. This is particularly important to subpopulations such as those undergoing dialysis, and diabetic adults who are encouraged to be vaccinated against hepatitis B – a new recommendation by the CDC this year. It is also important to the general adult population, where it is found that 30-50% of adults may not complete the 3 shot HBV vaccine series making them vulnerable to infection. This need for HBV prevention via a more effective vaccine, particularly in needy subpopulations was what was stressed in HBF’s public statement.
I do believe the panel was well aware of the importance of HBV prevention and one doctor made mention of the importance based on “the public comment”, so they were listening. Another doctor mentioned the burden of the disease not only globally, but also in the US. That is often understated.
The FDA panel met both Wednesday and Thursday. The public comment period was Thursday, and I remained there for the vote on two vital questions. The first question was about whether the immunogenicity data was adequate to support the effectiveness of HEPLISAV for the prevention of hepatitis B infection in adults 18 through 70 years of age? The vote cast showed unanimous agreement in the efficacy of the vaccine.
The other question was about whether the data was adequate to support the safety of HEPLISAV when administered to adults 18 through 70 years. Five members said “yes”, 1 abstained and 8 voted “no”.
Prior to both votes there was a great deal of discussion amongst the panelists, and the representative from Dynavax who responded directly to questions.
Ultimately it came down to a few key points. It was clear that the panel was impressed with efficacy or level of immunity generated by this new, 2 shot series. This vaccine uses a unique adjuvant. An adjuvant is a substance that is added to the vaccine in order to increase the body’s immune response to the vaccine. In this case it was a nucleic acid versus a lipid – details of which I do not even pretend to understand. Although this new adjuvant was exciting based on the great immunogenicity data presented by Dynavax, it was also a source of concern because the panel was not sure if there was enough study data that represented all demographics. In other words, this vaccine performed really well, but they weren’t sure if it had been proven safe in different ethnic groups such as African Americans, Asian-Americans, and Hispanics. Since the US is a melting pot, this is important.
The other concern was that the vaccine had not been administered along with other vaccines. Because this vaccine is to be given to adults, they felt it was important that it could be given when an adult came in for their annual flu shot, or another immunization. Adults just don’t get to the doctor’s office that often! Although this was clearly of interest, it was not a deal breaker like the lack of safety data among all demographics. There was the suggestion to introduce the vaccine into the current sub-populations that were in particular need, but not much discussion beyond.
The votes were cast and the panel and the audience dispersed. Looks like Dynavax will need to complete further studies before the vaccine is once again reviewed by the FDA panel for approval. Personally, I believe there’s a real need and a place for this vaccine, but of course safety always comes first.
The Hepatitis B Foundation mourns the loss of a great hepatitis B champion. Dr. R. Palmer Beasley. The Hepatitis B Foundation was proud to have honored Dr. Beasley with the Distinguished Scientist Award 2010, at HBF’s annual Crystal Ball. Dr. Beasley’s groundbreaking research discoveries in Taiwan included identifying mother-to-infant hepatitis B transmission, and the fatal link between hepatitis B and hepatocellular carcinoma (primary liver cancer). Additionally, Dr. Beasley’s initiation of a national hepatitis B immunization program has protected a generation of people in Taiwan against hepatitis B and liver cancer.
Dr. Timothy Block, President and Co-Founder of the Hepatitis B Foundation wrote: “Our cause has lost another great one with the passing of Palmer Beasley. He was passionate and visionary in working to advance hepatitis B awareness and research. His work with the HBV vaccine, particularly in Taiwan, is considered definitive and as having set the stage for saving millions of people. The HBF recognized him as our honoree in 2010, and for that, I am glad.”
Adventurous, meticulous and intensely curious about the world and its people, Dr. R. Palmer Beasley, epidemiologist and infectious-disease expert, used those skills to discover the link between the hepatitis B virus and liver cancer — proof that a virus could cause a human cancer, and a finding that ultimately led to vaccinations that saved hundreds of thousands of lives.
Dr. Beasley, a former University of Washington faculty member and dean of the University of Texas School of Public Health, died Aug. 25 at his home in Houston. He was 76. His death, from pancreatic cancer, was confirmed by his wife Lu-Yu Hwang.
Measles, plague, HIV — they all intrigued Dr. Beasley, who had decided as a student at Harvard Medical School that he wanted to be an epidemiologist, studying infectious diseases. In the early 1970s, as a fellow at what later became the University of Washington School of Public Health, he jumped at the chance to go to Taiwan to research rubella (German measles). There, he became determined to delve into the mysteries of hepatitis B, which he considered the least understood unconquered virus of the time.
“He took an approach like Albert Schweitzer,” said Herbert DuPont, director of the Center for Infectious Diseases at the University of Texas. “He lived in the field, he worked with patients, with the people. He didn’t go back to Seattle and sit in an office at the University of Washington and contact people in Taiwan.”
J. Thomas Grayston, then Dr. Beasley’s supervisor at the University of Washington, recalls a bit of friction in that regard. “We talked to him about coming back, and he wasn’t going to do that,” he said.
Dr. Beasley arranged independent funding for his research project, married a co-researcher and settled down in Taiwan, where he would spend the next 14 years. But he kept his affiliation with the University of Washington, which lasted nearly two decades.
With exacting attention to detail, Dr. Beasley and his colleagues designed long-term studies that would follow more than 22,000 Taiwanese government workers for decades, in the process proving that the hepatitis B virus is a main cause of liver cancer — at the time a controversial theory — and that childbirth can transmit the virus from a mother to her baby, who becomes a carrier and much more likely to develop liver cancer.
Dr. Beasley found that a shot of immune globulin at birth protected babies; later, his work helped push the World Health Organization to include the hepatitis B vaccine in routine vaccination programs.
For his work, Dr. Beasley was awarded the King Faisal International Prize in Medicine, the Charles S. Mott Prize, the Maxwell Finland Award for Scientific Achievement and the 2010 Distinguished Scientist Award by the Hepatitis B Foundation.
“There are at least a million people alive today who otherwise would not be here if not for Dr. Beasley’s pioneering research in hepatitis B,” Nobel laureate Baruch Blumberg said at the award ceremony, according to the foundation.
Robert Palmer Beasley was born in Glendale, Calif. He received a degree in philosophy from Dartmouth College in 1958, a medical degree from Harvard University in 1962 and a master’s degree in preventive medicine from the University of Washington in 1969.
Early in his career, he worked as an epidemic investigator for what is now the Centers for Disease Control and Prevention in Atlanta from 1963 to 1965, including an assignment to find a sample of plague in Bolivia.
Riding in trucks and on burros, he and his colleague James Gale tracked down plague in a tiny village on the east side of the Andes, said Gale, now an emeritus professor of epidemiology at the University of Washington. Because the disease had killed nearly all those in the village, they had to exhume a body, cut off a finger and get it back to the capital city, where the material containing the plague was injected into a guinea pig, which promptly died.
Assured that the pathogen was still viable, the two doctors packed it up in dry ice for shipment to a secure lab in Maryland.
From 1987 to 2005, Dr. Beasley was dean of the University of Texas School of Public Health.
His first marriage, to Sonia Garon, ended in divorce. Survivors include his wife of 32 years, Dr. Lu-Yu Hwang of Houston, an epidemiologist who collaborated with him on his research; two children from his first marriage, Monica Payson of Seattle and Fletcher Beasley of Los Angeles; a daughter from his second marriage, Bernice Hwang Beasley of Seattle; a brother; and two grandchildren.
Hepatitis Awareness Month has come to a close, and it has been one exciting, busy month for those of us at HBF and Hep B United Philadelphia. In the course of 6 weeks, we have had many of our major events of the year – nearly all featured during Hepatitis Awareness Month or on Hepatitis Testing Day. Have a look at what we’ve been up to this past month…
On May 15th, AAPCHO and HBF, with the support of the U.S. Department of Health and Human Services’ Office of Minority Health, launched the Hep B United national campaign. This unique partnering and collaborative effort will bring attention and action to end hepatitis B – especially among high-risk Asian Americans and Pacific Islanders (AAPIs) in the U.S. You’re going to see a lot of activity out of Hep B United...
HBF’s Director of Public Policy & Affairs set off to Washington D.C. to attend the Congressional Briefing on Chronic Viral Hepatitis and Liver Cancer hosted by our champions in Congress. Keeping Hepatitis in the hearts and minds of our elected Representatives is paramount in supporting viral hepatitis efforts in our country.
Hep B United Philadelphia wrapped up its awesome “B A Hero” PSA video contest and finalists and winners were announced. Check out these great PSAs!
Hepatitis Testing Day and the days leading up to the event were extremely busy for the Hepatitis B Foundation, Hep B United Philadelphia, and Partners. We kicked off testing day with our awareness-raising Flash Mob Event in Love Park in Philadelphia. This fantastic event included special guests Mayor Nutter, and Councilman David Oh, and plenty of other notable Hep B Heroes in attendance. It was an honor to receive a City Proclamation by Councilman Oh, supporting efforts to eradicate hepatitis B in the city of Philadelphia. And of course the students put their spin on the event with a “B A Hero” Rap. You have to listen to this...
Saturday, Hepatitis Testing Day, Hep B United Heroes donned their hero capes for the Hepatitis Testing Day Event held at the Asian Pacific Heritage Festival in Philadelphia. It was a successful event with 112 screened. Those screened and in need of vaccination will be provided with the HBV vaccination series, free of charge, from the Philadelphia Department of Health.
That same day, Hepatitis B Foundation heroes hosted HBF’s B Informed Conference. This year’s conference was specifically directed to parents of children with hepatitis B. This was an incredible full-day conference. Expert specialists in the field addressed both the medical issues and personal challenges of parenting a child with hepatitis B. It was a wonderful opportunities for parents to meet and discuss, face-to-face, with families facing like challenges. Lasting bonds were created that day. You’ll want to check back at a later time to read a reflection on the day, and access information presented by our expert speakers.
And finally we end this month’s awareness efforts this weekend by participating in the Philadelphia Independence Dragon Boat Regatta. Team Philadelphia Hep B Heroes will (hopefully) row their boat to victory, but even if they don’t win, they are winners at heart. The team is composed not of an expert crew, but rather Hep B United Philly community partners, student partners and staff. If you’re in Philly, stop by and cheer the team to victory. Plenty of team members will be at the event to raise HBV awareness and discuss hepatitis B testing, prevention and treatment.
There were a lot of Hep B Heroes out there this month. Feel free to share the events of your organization this month!
For those living with HBV, this dilemma is especially disheartening. With organ donation highly unlikely due to their HBV status, those living with HBV also face the possibility of requiring a liver transplant due to end-stage liver disease or HCC.
Organs for donation don’t come easily. These proposed guidelines are limiting. The question is, are these guidelines even realistic? Dr. Harry Dorn-Arias, a transplant surgeon at the Univeristy of Virginia told MSNBC, said it best: “With the new guidelines, every college student in America will be high-risk”. Perfectly healthy, young candidates may choose to waive their decision to donate their organs because the guidelines seem so… judgmental. They might not even consider the act of donation.
And who will be out there to ensure that the now smaller subset of potential donors isn’t lying, and who will update the information annually? Will the Department of Motor Vehicles (DMV) be quizzing you on your sexual activities when you choose one way or the other to check the organ donor box for your license? If you’re sixteen and standing there with your mom at the DMV, are you going to take a stand and not be an organ donor because you have multiple sex partners, and mom doesn’t even know you’re having sex? (Just went through the whole DMV process, so it’s fresh in my mind). What if you are completely monogamous, but your partner is not? Do you have high-risk organs due to association? And what if you are considering a life-saving, living related donation for your wife, but you’re afraid to tell her you’ve had multiple sexual partners for the last 10 years of the marriage? If you’ve been lying the last 10 years, why stop now? What if you had a very active sex life, but settled into a happy monogamous relationship, but forgot to update your organ donor card? Although there’s a little levity thrown in here, these scenarios are not that far-fetched.
When you are in need of an organ, and you are fortunate to find a match, you have to assume there will be risks involved in the process. Naturally you want the safest organ available, but there is not the time or the medical testing available to screen for every medical conceivable complication that might result in a failed transplant. At some point there has to be a leap of faith. Personally I would choose the “high-risk” organ from a healthy 20 year-old with 5 sex partners last-year, over no organ at all.
It’s all about risks vs. benefits. Slashing the pool of potential donors based on the number of sexual partners is riskier than having no choice from a much smaller, reduced pool filled with many of the same unknown variables. The donor pool isn’t necessarily safer, it’s just smaller.
Organ donation truly is a gift. If you are living a life style that you know to be high-risk, or if you knowingly have a disease that will put a recipient at risk, then do not donate. Otherwise, carry your organ donor card with pride and check the box “yes” next time you’re at the DMV.