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.
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.
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:
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?
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?
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?
These are good questions and I am happy to provide some answers.
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.
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.
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.
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.
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
We can look at how siRNA or siRNA + PD1 or siRNA + pegIFN have fared in trials run by other companies. All the current siRNAs have identical functionality and so predict success or failure of siRNA based therapies universally. In this context is also important to be aware of the enrollment of unicorn patients in all of these recent clinical trials. These patients have baseline HBsAg < 1000 IU/mL, only represent 5% of the patient population and are much easier to achieve functional cure in than typical patients with chronic HBV (the average HBsAg is ~10,000 IU/mL). Data from these kinds of patients provides no real information on therapeutic potential in the 95% of patients who are not unicorn patients.
VIR: initial 30% HBsAg loss at end of therapy with siRNA + pegIFN but most were unicorn patients (pegIFN achieves this rate of HBsAg loss alone in these patients). Rebound of HBsAg after 24 weeks of follow-up was recently shown to occur in most patients.
JNJ: no HBsAg loss at EOT with siRNA + pegIFN and delayed but universal rebound in HBsAg in all patients. Longer rebound delays were in unicorn patients.
Arbutus: the few patients with HBsAg loss on therapy (only 4) are unicorn patients and are already showing signs of impending HBsAg rebound (including rapid loss of anti-HBs).
In the most recent trial with siRNA + PD1, PD1 therapy had to be removed early from the trial for toxicity reasons (it was causing autoimmune hepatitis). This is an expected consequence of PD1 antagonists. In general PD-1 antagonism has only showed some interesting declines during therapy in clinical trials in unicorn patients. These toxicity concerns will very likely halt the development of any approach which blocks PD1 function. Remember PD1 also regulates good and bad endogenous immune responses (including autoimmunity).
In chronic HBV, animal model data with all siRNA, therapeutic vaccines, TLR agonists or PD1 antagonists have never predicted effects in the clinic to data. It is not worth assessing therapeutic potential from any model data with the current models in hand.
Note that unicorn patients are always included from NAP trials. Our data is the only clinical data applicable to the entire patient population worldwide.
While looking at the Replicors current clinical pipeline, i noticed that there are two other planned clinical phases, indicating for an ongoing enrollment Q1 2024.
What is the current status of these two phases? Are they still enrolling people?
Q1 is over already.
I have read in the forum that new approaches lack achieving a functional cure due to highly diverse quasispecies, please correct me if I am wrong.
Question 2.1: How come these scientists/researchers and their teams behind all this amount of research and pre-clinical trials are not aware of this composition of HBV-DNA and they continue building semi-functional cures? Question 2.2: If they are not aware of such composition, is there not any kind of exchange in the community to delve deeper into this knowledge and focus all energy and resources in a complete cure? I mean scientists learning from each other and exchange ideas. Is there not such a thing?
These trials are delayed as we are working on some improvements to the drug product to ensure the best antiviral response possible in all patients.
Regarding question 2:
We should call quasispecies genetic variants. The term “quasispecies” indicates some linkage between the mutations, which is not the case. In HBV these are random mutations caused by the lack of proofreading functionality in the HBV enzyme that converts the immature RNA genome inside the capsid into its mature (and infectious) partially double stranded DNA form. In our body, enzymes that are involved in replicating our genetic information have a highly accurate proofreading function to ensure the fidelity of DNA replication. In HBV (and other viruses) this proofreading functionality in the viral enzyme is far less accurate.
This is very old knowledge and the failure of siRNA / antisense to target mRNA degradation has long been demonstrated in the clinic for other viruses (i.e. influenza) and well demonstrated in early in vitro, pre-clinical (DHBV infected ducks) and clinical studies (ARB-1467).
Unfortunately, while presented publicly at meetings, much of this data was prevented from being published (this does not benefit the scientific community). Also, there appears to be a fundamental lack of understanding of how these compounds work and their off target functions (also very well characterized). These off target immunological functions can provide some measure of antiviral response in HBV and other viral infections, which has been entirely misinterpreted as being driven by mRNA degradation. There are many more technical aspects to this discussion which can be read in the oligonucleotide primer I had published for the field here.
Open communication and objective analysis of all data is indeed the mainstay of proper drug development but this seems to be curiously lacking in the HBV space. As the patient community well knows, there have been a lot of broken promises over the past several years (this is quite unfortunate).
How extremely frustrating for yourself and people with HBV
Long shot, and maybe not what you were aiming for, but this is the only place I know of legally doing medical stuff that is outside of the purview of the FDA. It’s a sovereign startup city with its own laws, where people are going for gene therapy: https://youtu.be/bax8to_s07Q?si=_Udj2sMMbwo1bANk
Among other medical treatments
Providing a cure here and getting it recognized this way might be a path to getting the recognition deserved