Bulivertide is a peptide drug derived from a portion of the HBsAg protein involved in the entry of HBV (and HDV) via a specific receptor on liver cells (called the NTCP receptor). This drug provides a very efficient barrier to this entry mechanism in all hepatocytes but must be taken every day by subcutaneous injection. Unfortunately, in most patients there still remains a portion of HDV which is not impacted by this drug.
REP 2139-Mg is a drug polymer built from the building blocks of found in DNA (so very well tolerated and easily manged by patients). This drug has multiple actions:
Binds to the host protein involved in the formation of HBV subviral particles (which is also used to envelop HDV virions during their formation).
Binds to the hepatitis delta antigen protein involved in the replication of HDV prior to envelopment.
REP 2139-based combination therapy achieves universal HDV RNA loss during therapy and high rates of functional cure of HBV and HDV infections (no viral rebound when therapy is removed). The ease and convenience of a once weekly subcutaneous therapy of REP 2139-Mg for 48 weeks is now being confirmed in an ongoing international compassionate use access program.
Wow,
Availlant, I am very impressed with your clear explanation of such a confused topic about CHB in todayâs world.
Truly your knowledge and understanding of the subject is outstanding. I certainly will read more about the latest science, and I will follow you on this network very closely. Thanks again for your help and great contribution to this Community of people in needs.
We are waiting for replicors NAP since it is only one therapy which has shown to reduce HBsAg and induce ALT flares.
My question is does it take into consideration highly mutating nature of Hep B or just targeted towards HbeAg + CHB?
Also eagerly waiting for replicors progress on NAP trials any update on timeline when is next trials starting and would there be one in US?. The results published are really promising and can work wonders as mono or combination therapy.
I really appreciate for all people working towards cure.
Nucleic acid polymers target a host protein in liver cells which is critical for the assembly of HBV subviral particles. These subviral particles are a critically important target since they represent > 99.99% of circulating HBsAg.
Because NAPs target a host protein, their antiviral effect will be the same regardless of HBsAg baseline (even > 125,000 IU/mL), HBeAg status, HBV genotype, the presence of HBV mutants or the presence of co-infections like HDV, HIV or HCV. This universal response has already been demonstrated in the 5 clinical trials that have performed to date with NAPs. Aside from the unique ability of NAPs to target subviral particles, one of reasons why NAPs are still the only agents to achieve high rates of HBsAg loss is that they act independently of any viral protein.
You are correct that the highly mutable nature of HBV is a considerable problem with many agents in development. It is one of the reasons why technologies which are critically dependent on the absence of mutations (like ASO and siRNA and CRISPR and others) have not succeed in clinical trials to achieve functional cure.
Some of the clinical data to date suggests that NAPs can eliminate HDV infection in monotherapy but this question has not yet been properly addressed and we need more data to understand this issue.
In the case of HBV infection, it is important to realize that functional cure is a two step process:
Clear subviral particles so that immune responsiveness can be restored.
Reawaken the immune system with therapies like pegIFN to restore immune control.
It is important to understand that while NAPs are very effective in achieving HBsAg loss, the currently available clinical data indicate that high rates of functional cure of HBV require combining NAPs with immunotherapy. Of course more clinical data is required to address this question.
There are two ways to keep apprised of developments at Replicor:
Contact Replicor at info@replicor.com and ask to be part of our mailing list when we issue formal press releases.
Follow Replicor on Linked In here where periodic interim updates are posted.
Thanks for the explanation Andrew! Really appreciate it. I know you are also up to date with TherVacB approach. Are they using siRNA as well for priming and reducing HBsAg or is that something else?
I know the vaccine will only work in absence of HBsAg so the critical question would be would the vaccine even work in Hbe negative CHB where usually HbsAg is high and not sure if mutants produce siRNA?
The ThervacB vaccine is an interesting approach to try to induce the production of immune responses which will target infected cells in the liver. It is a two staged approach which involves an initial immunization specific to HBV (with HBsAg and HBcAg) (the âPrimeâ) followed by a boost using an unrelated virus to further stimulate the immune responses engendered (the âboostâ).
The clinical trial which will begin next summer will address the safety and immunogenicity of this vaccine approach. The design of later trials may try this approach in patients with HBV infection where HBsAg has been reduced using siRNA.
As you have rightly guessed, there are two important hurdles in this approach to succeed in functional cure:
Overcoming existing HBsAg burden.
Stimulating immune responses which act broadly enough to efficiently target the numerous âquasispeciesâ of HBsAg which exist in all patients.
In the pre-clinical assessments of ThervacB, the animal model employed (AAV-HBV) has no genetic diversity or quasispecies so the efficacy data here cannot really be translated to potential effects in humans.
Other therapeutic vaccines (i.e. VBI-2601 aka BRI-179) have succeeded in developing HBsAg specific immune responses and even the production of antibodies to HBsAg but with no effect on HBsAg (becuase the immune responses (and anti-HBs) engendered to not target the circulating HBsAg). See here. This is the fundamental issue with therapeutic vaccines for HBV.
A fairly exhaustive clinical assessment of a variety of siRNA has revealed that a significant pool of HBsAg is not targeted by this class of compounds so we will have to see if this approach will be good enough. Clinical data showing that siRNA only mildly potentiates the effects of interferon is not an encouraging sign - see here. Unfortunately, patients with very low baseline HBsAg are included in this trial and it is missing the critically important pegIFN monotherapy control arm.
Thanks for the explanation Andrew. Since we know from trials only NAP technology has some effect on HBsAg will have to wait for NAP to be released and then used in combination with immune therapy like VBI-2601. Hope that is within 5 years.
Of course all options are being considered with NAPs. However, we still only have two agents which we know can âwake upâ the broad spectrum HBsAg response that lies sleeping in patients with chronic HBV. These are pegIFN and thymosin alpha 1.
For therapeutic vaccines to be an effective immunotherapy they will most likely have to contain multiple different HBsAg species.
Been keenly following. @availlant you posted this early this year.
What work needs to be completed before NAPs will be available?
REP 2139-Mg is currently in phase IIa trials. Larger phase IIB and phase III trials will be required before regulatory approval can be sought. This process can take anywhere from 3-4 years.
Questions if able.to.respond:
Is phase IIB over?
What are the current timelines i.e If all goes well, are we looking at a cure in 2026 or earlier?
Also, has any of the patients under compassionate treatment using NAPs gotten a functional cure? If yes, the longest has sustained the functional cure for how long? Last,
Whatâs the current (based on your data) percentage for functional cure for those on trials?
REP 2139-Mg is currently in phase IIA of development.
We are currently focused on our compassionate use program which has the following goals:
Demonstrate that REP 2139-Mg as a once weekly subcutaneous injection is well tolerated, convenient and potently active.
Demonstrate that REP 2139-Mg is safe in the most difficult to treat patients which currently include:
Patients with HDV co-infection who have failed on bulevirtide or lonafarnib.
Patients with cirrhosis.
Patients with decompensated cirrhosis.
Patients with decompensated cirrhosis awaiting liver transplant.
Allow many investigators around the world to have experience with REP 2139-Mg so that the medical community can see first hand how well the compound is working.
The latest public results from the first 5 patients in this program in France can be found here and here and show we are achieving these three goals with very encouraging results.
The first patient to have completed therapy in this program has maintained HBsAg loss and seroconversion and HDV RNA loss for 5 months after removal of REP 2139-Mg and pegIFN (a good sign). TDF has only recently been removed from this patient so we will await these data which will formally demonstrate functional cure of HBV and HDV.
Unfortunately, I cannot comment on timelines (much as I am aware of the interest in this in the community). What I can say is that the compassionate use program is rapidly expanding in France and other countries and will allow us to transition a final phase IIA trial to subcutaneous administration in preparation for phase IIB.
I would look to the conditional approval of bulevirtide in the EU for HDV infection, which was only done with phase IIB data. REP 2139-Mg fits this approach very well.
It may be that many people in the community will be very interested in the compassionate use program for REP 2139-Mg as a potential means to access this therapy early (which is very understandable). It is important to understand that this is not a clinical trial. Compassionate access is only available for patients who have exhausted all other antiviral options and have both failed these approaches and have advanced liver disease. Patients are given compassionate access to REP 2139-Mg only through selected investigators we identify who have significant expertise not only in treating HBV and HDV but also in the management of advanced liver disease.
Our current clinical data suggests that very high percentages of patients that receive REP 2139-Mg as part of a combination regimen with TDF and pegIFN (> 80%) will not require further treatment (either establishing inactive HBV or functional cure of HBV). A majority of these will have functional cure.
I am really rooting for NAP to become the backbone of treatment regime we all need here. I had a question on NAP technology. Since NAP is based off of host protein why isnt the efficiency 100%?
Is there any specific criteria of people in NAP trials who are not responding to it? Was any discovery done on that end?
I saw NAP lead to reduction of HBsAG in 24/40 people so just curious what happened with the remaining 16? Did they never responded to it?
All oligonucleotide based medicines come with significant administration issues with subcutaneous administration. These injection site reactions (ISR) can include significant pain, swelling and tissue necrosis / scarring which can last for some time. This issue effects all oligonucleotide based medicines which approved for use (in up to 70% of patients). You will see these ISRs reported for all siRNA and ASO in development for HBV.
In all of our previous clinical trials, Replicor has used IV infusion of its oligonucleotide based medicine (NAPs) while we worked through understanding the basis for these ISRs and how to control them. You will see in the clinical history we have moved from REP 2055 to REP 2139-Ca to REP 2139-Mg. These optimizations represent our working through modification of NAPs and their formulation in order to prevent ISRs. This was proven in the REP 401 study but not implemented with SC administration until our compassionate use program.
The problem with IV infusion is that it is not as efficient in delivering oligonucleotide to hepatocytes in the liver (the source of HBsAg production).
If you look back at the REP 401 study, HBsAg reduction actually occurred in 100% of patients.
90% were > 1 log reduction from baseline (anything less has no clinical impact)
82.5% were < 100 IU/mL
70% were < 1 IU/mL
60% (24/40) had no detectable HBsAg (< 0.005 IU/mL)
This spread of HBsAg impact is most likely a function of the IV administration and perhaps some genetic variability in the way cholesterol is metabolized by patients (this is involved in hepatocyte uptake of NAPs and ASOs). HBsAg response to REP 2139 is independent of baseline HBsAg or HBV genotype or HBeAg status or the presence of other co-infections like HDV.
In our compassionate use program, we are now seeing that SC administration of REP 2139-Mg is very well tolerated with no classic oligonucleotide ISRs. Also SC administration leads to more efficient uptake of REP 2139 into hepatocytes in the liver and we are seeing stronger antiviral effects with this route of administration (including HBsAg reduction and loss). We will need more clinical data to fully assess the impact of SC administration on HBsAg response but the data so far from our compassionate use indicate higher rates of HBsAg loss with SC administration.
@availlant thanks again for brief explanation. I really did not want to be those unlucky people where NAP dont work. Really rooting for NAP and want to see it approved soon. Thanks for all your hardwork and taking the time to respond to every query we have regarding this thing.