Arbutus’ Imdusiran with Short Course Interferon Achieves Sustained Undetectable HBsAg

Dear @3kids4me ,

We had several presentations at the EASL 2024 meeting. Please see here:

These are the final proof of concept of the safety of NAPs (and the ALT flares which accompany HBsAg clearance) in patients with very advanced disease. Most of these patients failed on prior HDV therapy and have cirrhosis or de-compensated cirrhosis and were awaiting liver transplant. The goal of these studies were to validate the safety and efficacy of weekly subcutaneous administration (we have a small formulation improvement to optimize the efficacy via subcutaneous administration).

Recall that NAPs are the only bifunctional agent capable of simultaneously targeting subviral particles and blocking the replication of HDV. We expect that this improved formulation will result in high rates of HBV functional cure in HBV and HBV / HDV co-infection as well has high rates of HDV cure.

You may wish to see our 5-7 year follow-up evaluation from our previous clinical studies here presented at the Global Hepatitis summit last year. These showed high rates of HBV functional cure stable at 5 years follow-up (in HBV monoinfection) as well as high rates of HDV cure at 7 years follow-up (in HBV / HDV mono-infection).



Thank you and impressive! Any word on when Phase 3 trials for HBV only? Replicor has stood out to us with HBV for many, many years. Understandably, compassionate care needs to be addressed before the rest of us that are “healthy” living with HBV, but it sure would be amazing if Replicor can progress to Phase 3 and further in the near future.

Dear @3kids4me,

The current clinical work was addressing many important interim steps before we begin the final push towards final phase IIA, B and phase III trials. These were: establishing the safety envelope for REP 2139-Mg in patients we had not yet examined (advanced liver disease) and if the SC formulation we used (this was actually the same REP 2139-Mg drug product we used for IV infusion more than 7 years ago in the REP 401 study) was ready for prime time.

As I mentioned, these current studies have been very useful in helping us perform the final tweaks to the drug product so that we can see rapid antiviral responses in all patients, regardless of liver disease status.

Our goal is to ensure that all patients worldwide have access to REP 2139-Mg as soon as possible.



Wonderful, thank you again!

Dear @availlant,

thank you for your valuable insights!

A couple of questions arised concerning NAPs. So far the success rate is 78% in restoring imune control in HBV patients and 74% of eliminating HDV infection, which its amazing.

My questions are the following, and sorry if some questions might sound basic or repetitive but im new to this community, diagnosed 1,5 months ago, and I am not yet very much familiar with many terms and medicines available:

  1. Why did NAPs not achieve 100% success rate? Why the treatment was not successful in 22% of cHBV patients? Are you currently working towards filling this gap?

  2. When there is such a great success rate with NAPs how come the other companies around do not show some and the same interest in such technology and work together with you towards bringing the cure faster to the market, but instead they invest great amount of resources, time and energy in other techs whose success rate is 10% or lower?

  3. Will REP 2139-Mg still aim to play a pivotal role in achieving WHOs goal of eliminating viral hepatitis by 2030? Is this still the goal and what might stop it from achieving this?

Thank you very much in advance for your feedback!

Best regards,

Hi @Eddy,

These are good questions and I am happy to provide some answers.

  1. Treatment was not successful in 22% of patients with HBV monoinfeciton becuase of the variability between different patients in how efficiently NAPs get taken up by hepatocytes after they are administered into the blood. This is likely due to genetic differences between patients. Instead of spending a large amount of time and resources in figuring out who these people are from a genetic standpoint, we are instead modifying the drug product to overcome this issue so that it will work properly for everyone. There is never a guarantee that is will become 100% effective but we hope to improve significantly on the rate of patients that respond well.

  2. At Replicor, we have a very deep understanding of oligonucleotides, how they have worked in clinical studies over the past two decades and their limitations. We have for a long time been confident that all oligonucleotide approaches (antisense, siRNA and CRISPR) would fail to achieve functional cure in HBV. We also know that eliminating circulating HBsAg is a critical first step in this process. I cannot comment on why so many companies have spent so much money only to come to the same conclusion. This has of course added a lot of confusion to the field. Fruther to your comment to other techs with a sucess rate of 10% or lower; this is an obvious reference to beiprovirsen, a molecule that GSK has acknowledged to act via an immunostimulatory mechanism. It is important that the rate of HBsAg loss declined from 25% at end of treatment to 9% at 24 weeks post-therapy. It is very likely that the HBsAg loss rate at 48 weeks was much lower. For some reason we have not yet seen this data.

  3. REP 2139-Mg will play a pivotal role in eliminating viral hepatitis. At Replicor, we are committed to eliminating HBV and HDV in every patients. The pace of NAP development has slowed while we wait for all of these other technologies to fail so we expect to be able to proceed at a faster pace in the future.



Thanks again for your detailed and imformative responses. I hope Replicor can soon start up and deliver FC.

I do have a question in regards to another method some bios are going about in their trials. What do you think of the PD-L1 approach that is being tested? Is there a chance that targeting PD-L1 will be able to bring durable FC? I saw an abstract from EASL (of course a mouse model so it most likely wont apply similarly to humans) that sirna pd-l1 cleared hbv. Article titled “SA-012 alone or in combination clears HBsAg in murine model”

Also Ascletis had some success targeting pd-l1 and of course Arbutus thinks their oral PD-L1 might be effective.

Any thoughts?

Hi @Mike2,

In short, no. We already have some clinical data from combining PD1 antagonists in the chronic HBV setting. Moderate HBsAg declines are restricted to unicorn patients again and we have the additonal problem of the development of fulminant (=severe) autoimmune hepatitis in these patients. Unfortunately, PD1 is responsible for regulating many immune functions in the liver (including those that are potentially dangerous). Preventing PD1 from doing its job will have some effect on allowing better HBV-directed immune responses but will also allow autoimmune (= inflammatory) responses to become inappropriately activated.


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How would you objectively rate the chances of Arbutus’ latest therapy at having a shot at being overall effective in terms of a potential cure @availlant?
Between reasonably likely and a snowballs chance in hell

One other question: you mentioned that tweaking the final product of Rep2139mg being an ongoing process. After you make tweaks do you still refer to it as Rep2139mg or do you change the name after that?
Also do you publish the manufacturing instructions etc to allow people to do independent research / third party validation etc?
Wondering why it appears to be the best candidate for a cure for many years now but also doesn’t appear to be getting acceptance or enough traction in the scientific community at present. Is there anything that could be done to help with this, such as supplying samples to researchers etc?
The ALT flares appear to me to be the most bullish signal for its effectiveness even if that seems to scare some researchers. But since cures seem to be nearly always be associated with ALT flares it looks more like we should be welcoming them in some cases