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Arrowhead Begins Phase 1 Trial of RNAi ARC-520 for Treatment of Chronic HBV
Arrowhead Begins Phase 1 Trial of RNAi Therapeutic ARC-520 for Treatment of Chronic Hepatitis B Infection
PASADENA, Calif. - July 23, 2013 - Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced that it has initiated dosing in a Phase 1 clinical trial of ARC-520, the Company's candidate for the treatment of chronic hepatitis B virus infection. Trial initiation followed successful completion of the Clinical Trial Notification (CTN) regulatory process in Australia. The objectives of the study are to characterize the safety profile of ARC-520, determine maximum tolerated dose, and evaluate pharmacokinetics in healthy volunteers. ARC-520 is the first candidate to use Arrowhead's proprietary Dynamic Polyconjugate (DPC) delivery platform and includes two distinct siRNA sequences that have pan-genotypic coverage for 99.6% HBV GenBank sequences.
The Phase 1 trial is a single-center, randomized, double-blind, placebo-controlled, single dose-escalation, first-in-human study of ARC-520 administered intravenously to healthy adult volunteers and is being conducted in Melbourne, Australia. Each dose cohort includes 6 subjects randomized at ratio of 1:2 (placebo: active) to receive a single intravenous injection of either placebo or ARC-520. Arrowhead expects to complete this Phase 1 trial in the fourth quarter of 2013 and begin a Phase 2a trial in chronic HBV patients in 2014.
"This Phase 1 study will establish a safety profile for ARC-520 as well as provide the first human data for our DPC delivery platform. This is an important step forward as we seek to advance ARC-520 into HBV patients and build additional RNAi therapeutics based on what we believe is the most potent delivery system in the industry," said Dr. Christopher Anzalone, President and Chief Executive Officer.
Hepatitis B is the world's most common serious liver infection. It is estimated that 350 million people worldwide are chronically infected with HBV, representing approximately 1 in 20 people on the planet. No currently available treatment methods can reliably achieve meaningful cure rates. ARC-520 is designed to reduce the production of new viral particles and viral proteins. Many experts believe that reducing key viral proteins can revive patients' adaptive immune response and potentially lead to a functional cure of chronic HBV infection with a finite treatment regimen. Arrowhead previously presented data generated in rodent models and in a chimpanzee chronically infected with HBV, showing that ARC-520 induces rapid, deep, and durable knockdown of both circulating HBV DNA and key viral proteins, including hepatitis B s-antigen, e-antigen, and the core protein that forms the capsid.
PASADENA, Calif. - July 23, 2013 - Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced that it has initiated dosing in a Phase 1 clinical trial of ARC-520, the Company's candidate for the treatment of chronic hepatitis B virus infection. Trial initiation followed successful completion of the Clinical Trial Notification (CTN) regulatory process in Australia. The objectives of the study are to characterize the safety profile of ARC-520, determine maximum tolerated dose, and evaluate pharmacokinetics in healthy volunteers. ARC-520 is the first candidate to use Arrowhead's proprietary Dynamic Polyconjugate (DPC) delivery platform and includes two distinct siRNA sequences that have pan-genotypic coverage for 99.6% HBV GenBank sequences.
The Phase 1 trial is a single-center, randomized, double-blind, placebo-controlled, single dose-escalation, first-in-human study of ARC-520 administered intravenously to healthy adult volunteers and is being conducted in Melbourne, Australia. Each dose cohort includes 6 subjects randomized at ratio of 1:2 (placebo: active) to receive a single intravenous injection of either placebo or ARC-520. Arrowhead expects to complete this Phase 1 trial in the fourth quarter of 2013 and begin a Phase 2a trial in chronic HBV patients in 2014.
"This Phase 1 study will establish a safety profile for ARC-520 as well as provide the first human data for our DPC delivery platform. This is an important step forward as we seek to advance ARC-520 into HBV patients and build additional RNAi therapeutics based on what we believe is the most potent delivery system in the industry," said Dr. Christopher Anzalone, President and Chief Executive Officer.
Hepatitis B is the world's most common serious liver infection. It is estimated that 350 million people worldwide are chronically infected with HBV, representing approximately 1 in 20 people on the planet. No currently available treatment methods can reliably achieve meaningful cure rates. ARC-520 is designed to reduce the production of new viral particles and viral proteins. Many experts believe that reducing key viral proteins can revive patients' adaptive immune response and potentially lead to a functional cure of chronic HBV infection with a finite treatment regimen. Arrowhead previously presented data generated in rodent models and in a chimpanzee chronically infected with HBV, showing that ARC-520 induces rapid, deep, and durable knockdown of both circulating HBV DNA and key viral proteins, including hepatitis B s-antigen, e-antigen, and the core protein that forms the capsid.
I agree the half life of 8 days seems too long. This question was never accessible experimentally in patients, since elimination and production are equal at equilibrium.
So for a moment I believed the bloggers report of estimations from acute HBV, where they assumed there was a phase, where de novo production was close to zero and the downwards curve therefore allowed the calculation of the half life of surface antigen particles circulating.
But strangely, we have right now by happenstance a very simple and useful source for the determination of this half life. In the replicor trials, the release of the surface antigen is completely blocked and the resulting downwards curve therefore shows the upper limit for its elimination kinetics and the half life is directly visible from the poster information. It takes four to six weeks to come down from rather high starting values to the detection limit. Ten half lifes reflects about a reduction by a factor of one thousand. Thus we can see that the half life is in the range of three to four days.
This is the same concept that was used to determine virion half lifes once replication blocking antivirals became available.
So for a moment I believed the bloggers report of estimations from acute HBV, where they assumed there was a phase, where de novo production was close to zero and the downwards curve therefore allowed the calculation of the half life of surface antigen particles circulating.
But strangely, we have right now by happenstance a very simple and useful source for the determination of this half life. In the replicor trials, the release of the surface antigen is completely blocked and the resulting downwards curve therefore shows the upper limit for its elimination kinetics and the half life is directly visible from the poster information. It takes four to six weeks to come down from rather high starting values to the detection limit. Ten half lifes reflects about a reduction by a factor of one thousand. Thus we can see that the half life is in the range of three to four days.
This is the same concept that was used to determine virion half lifes once replication blocking antivirals became available.
it should not be taken otherwise. ok dear, nobody here is denying anybodies faith,sometimes it gives strength to fight. but here we are gathered to discuss and care about policies,aspects and treatment options of hep b not the existance or working phiosophy of lord/god. we are with you to disscuss any thing scientific or managerial which is related to hep b future and helpful to you in physical terms/tretment.
we accept psychological/social aspects of hep b are least disscussed here, if you want to discuss them please feel free to discuss as a new thread as they are indifferent part of hep b. still politely very politely please dont argue about gods. offcourse god may put his kindness to all of us and to those who are working for us and our healthy future.
we accept psychological/social aspects of hep b are least disscussed here, if you want to discuss them please feel free to discuss as a new thread as they are indifferent part of hep b. still politely very politely please dont argue about gods. offcourse god may put his kindness to all of us and to those who are working for us and our healthy future.
your statement is totally refused .. Allah is the creator of every things .. to examine our patience ..
sorry but the lord has nothing to do with our community, this is scientific discussion and patient to patient discussion, religion is off topic and does not belong here nor we want to discuss it here
promising treatment. They need a subcutaneous form though. sounds like repeated application may be necessary.
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The chimpanzee HBV data on ARC520 showed that while HBV viral DNA and the HBeAg were greatly reduced almost immediately following onset of gene silencing, HBsAg elimination lagged behind: a 50% reduction following ~8 days and another 50% reduction following 15-20 days. This raised questions in the minds of some readers here about the potency of ARC520 in real patients.
My response was that this most likely reflects a slow HBsAg elimination even in the absence of new HBsAg production. This was also speculated on in the ARC520 analyst day webcast by Arrowhead Research.
Thanks to the patent application by GSK which I discussed here last night, I was finally able to find a good reference on HBV elimination in real patients (not mice and woodchucks). In this paper by Chulanov et al., the kinetics of viral components were followed in patients with acute hepatitis caused by HBV. In this setting, it is assumed that almost no new viral production occurs thus facilitating the determination of half-lives.
Strikingly, the observations were entirely consistent with the chimpanzee data: whereas the HBV DNA and HBeAg half-lives were on the order of 1-2 days, the half-life of HBsAg was ~8 days. What is more, in patients with high viral titers (remember, the chimpanzee had exceptionally high titers) to start with, the half-life increased. This means that even if there was almost complete knockdown of HBsAg with ARC520 in the chimpanzee, HBsAg after 8 days would still be predicted to be ~50% of the starting value…exactly what was observed. The fact that a 75% reduction (i.e. another halving) was observed after 15-20 days suggest that RNAi gene silencing was still near its peak even 2 weeks following ARC520 administration. Thus, the chimpanzee data are entirely consistent with a high potency of ARC520 ‘in the real world’.
The slow HBsAg kinetics, however, have important implications for the dosing regimen and expectations for the outcome of the single-dose phase IIa Hong Kong study. Whereas I had speculated that functional cures may be seen in the results from this study around a year from now, I now have to moderate my expectations. This is because a 8 day half-life predicts that a 90% reduction of HBsAg, which seems to be a benchmark set by the companies, could theoretically be achieved only 3-4 weeks after drug administration. At this point, however, the RNAi activity is expected to wane such that at least 2 or 3 doses every 10 to 14 days would be needed to safely achieve the 90%+ knockdowns in most patients.
As a result, it may be worth for the company to seek an extension for the Hong Kong study. This, however, would likely require a degree flexibility by the Hong Kong authorities since the 9-month chronic tox studies are only beginning. If seeking such an extension would mean delays in the clinical development timelines, I would do just the single-dose as the multi-dose study should begin in the second half of 2014 anyway.
Update: According to information provided by Arrowhead Research yesterday, following just 2 weeks of study initiation, dosing with ARC520 has already been completed for 2 out of the 6 ascending dose cohorts. Accordingly, the company remains on track to report data in Q4 or even by the end of Q3 and initiate the Hong Kong study soon thereafter.