Nucleic acid polymers (NAPs): targeting subviral particles to acheive HBV functional cure

Hi Suresh,

My suggestion is that you refer to the Replicor website for these kinds of details.

Best regards,

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NAPs

Interesting to read. I have also visited the website hoping to see if someone based in East Africa can enroll for the ongoing trial but didn’t find info. Let me know if you have any relevant link or info.

Also, do you know of any other drug that has potential to seek approval earlier that the NAP you talk of in your post (i.e 3 to 4 yrs).

As also if 39 % get functional cure and another 39% get partial cure why has the drug not been approved? 39 is too good rate

Hi CNN,

This these are very good questions.

Unfortunately, the latest phase II study data from J&J and Assembly tell us that even combination therapy with NUCs + RNAi + current CAMs cannot achieve functional cure. This has been acknowledged by the folks at J&J and Assembly. As you point out, the only approach able to accomplish this right now is NAP-based combination therapy.

NAPs have taken longer than usual to move through clinical development for following reasons:

  1. The HBsAg response to NAPs in patients was first disclosed in 2009. The speed with which HBsAg loss occurred was unprecedented and the biochemistry of NAPs was difficult to grasp by most experienced scientists and doctors in the field. As a result there was a lot of skepticism about the antiviral effects of NAPs.

  2. NAP based therapy is accompanied by transaminase flares. Although these flares signal the removal of infected hepatocytes and are an important event in functional cure with other therapies, there were concerns that somehow these flares were a sign of toxicity with NAPs. Again this reflected the difficult to understand nature of NAP biochemistry and not any real toxicity with NAPs.

  3. The initial route of administration of NAPs was by weekly IV infusion and this is not a convenient approach for therapy.

  4. Effective therapy of chronic HBV will require 48 weeks and determining functional cure requires 6-12 months after therapy to verify. Replicor is the only company where all of its trials have incorporated a 48 week therapy with a minimum of 1 year of follow-up (for some trials 3.5-5 years follow-up). This slows down the pace of clinical development.

Because of these unique challenges , we have had to work harder than most companies to accomplish the following:

  1. Prove the validity, reproducibility and reliability of the NAP effect.
  2. Fully elucidate the molecular mechanism of NAPs and educate the field on the biochemistry of NAPs.
  3. Establish a NAP-based combination therapy which optimized functional cure.
  4. Demonstrate the safe, essential and beneficial effect of transaminase flares in the high cure rates seen only with NAP-based therapy.
  5. Develop a optimized NAP and NAP formulation (REP 2139-Mg) which is now well tolerated and highly effective when given as a self-administered weekly subcutaneous injection (this took 4 clinical trials to accomplish).
  6. Demonstrate the safety and efficacy of REP 2139-Mg and transaminase flares in the sickest of patients with the most advanced liver disease.

We are now at the last step of this process and plan to move NAPs into the larger trials required for approval at the earliest opportunity. We are highly dedicated to bringing this therapy to all patients worldwide.

Best regards,

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That’s a compressive explanation. Already feeling like a ‘scientist’. I now appreciate why you said 3 to 4 years. I hope you get more funding and are able to roll out on less than 2 yrs. Cheers and all the best.

CNN,

Yes I think that at this point the community deserves to understand why NAPs are taking so long. Disruptive technologies are always the most difficult to move forward.

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as there is currently no cure available for HDV, so i think it will be good idea to apply NAPs approval for HDV. there is a good chance to get quick approval as currently there is no cure available in market.

Thanks Suresh, we agree!

Both …I would say apply to both HDV and HBV

Thanks CNN, we agree. Suresh is correct however in that HDV approval is a gateway for HBV approval for NAPs as they are effective against both infections. Both are a high priority.

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dear availlant,

how much is the efficacy of the NAPs without pegINF for HBV and HDV

NAPs do not need pegIFN to clear HBsAg or HDV RNA.

However, pegIFN is required to stimulate the T-cell function needed to eliminate integrated HBV DNA from the liver. This is not required for “cure” of HDV but is required for high rates of functional cure of HBV.

Becuase HBsAg normally interferes with the action of pegIFN, using pegIFN with NAPs gives a greatly improved immune stimulation with pegIFN.

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dear availlant,

I am already on pegINF, send me NAPs so i can combine :slight_smile:

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@availlant I keep on the reading this trail with intrest and hope. At times hope keeps us going. Allow me to ask, are you the only guys working on NAPs for HBV?

Also, are there other drugs already approved that use a NAP type of technology?..even if for different diseases?

Last, is TherVacB based on a NAP technology? If not, would you know the significant difference btn NAPs and the technology being applied by ThervacB? Based on what is publicly available or at your disposal?. Have tried digging in vain. Not sure if they have even started the human trials. Would you or any other person in this community of ours know?

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Hi CNN,

Yes NAPs are wholly owned by Replicor Inc. We are the only company developing this technology.

Yes NAPs do have activity against other diseases but the current focus on development is HBV and HDV.

TherVacB is a therapeutic vaccine based approach that will attempt to stimulate an antiviral T-cell response to help in the treatment of HBV infection. The difference between NAPs and therapeutic vaccines is that NAPs target the bulk of HBsAg (> 99.99%) whereas trials with previous therapeutic vaccines have had little or no effect on HBsAg.

I look forward to seeing how the TherVacB approach will work. It might be useful to have a different form of immunotherapy to add to NAP-based combination approaches.

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Wow,
Availlant, I am very impressed with your clear explanation of such a confused topic about CHB in today’s 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.

Thanks for the feedback and sharing the real facts;
We all agreed that the future looks good by 2030 for the majority of us:

However; I though there will be some medicine that will cure 40%~60% of patients in 3-4 yrs…Like Replicor Rep2139 and others that are now in phase 2 trails…

By the way, I wonder if Replicor phase 3 trail started and when their data is expected??
I am very interested in participating their phase 3 clinical trials… not much info available on their website.

Thanks

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@Nass I think maybe @availlant could comment on this…I have read a number of useful updates from him about Replicor. Not sure if phase three you refer is REP 2139-Mg or weather they have more up their sleeves…

Hi Nass and CNN,

REP 2139-Mg is the final version of NAPs which will be taken through to commercialization.

Mature phase II trials for combination therapy with NUCs, RNAi and CAMs have proven that combination approaches with these agents cannot establish functional cure.

Current phase II data with REP 2139-Mg based combination therapy shows this approach delivers 78% immune control (no further therapy required) with 39% functional cure. These are in the most difficult to treat HBV genotype (D) where pegIFN very rarely achieves functional cure.

There is an ongoing compassionate use program with REP 2139-Mg in patients with HBV/HDV co-infection with compensated and decompensated cirrhosis who have either failed on bulevirtide or are not eligible for it. See here http://replicor.com/wp-content/uploads/2022/10/SC-REP-2139-Mg-HDV-DeltaCure-2022-Poster-27.pdf.

This approach is allowing us to confirm the safety and efficacy of a once weekly SC injection of REP 2139-Mg in patients with the most advanced liver disease. This will allow us to open enrollment of our next clinical trials to a much wider population of patients with a very convenient dosing strategy.

Hope this helps.

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Thanks Availlant
And thanks for your tireless research and dedication for a cure!
This is a very promising and probably will be one of the best treatment to come in few years. Please keep us updated when the clinical trials enrollment begin.
I guess next clinical trails are phase 2b or 3?
Thanks!
Nass

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The best way to keep abreast of clinical development details is to ask to join our mailing list for press releases at info@replicor.com.

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