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

Networking and learning resources Scientific Studies
61

Do NAPs work for both HBeAg-negative and positive?

2 Likes
62

Hi Will,

NAPs work in any patient with HBV infection, regardless of phase of infection, HBeAg status or the presence of other co-infections.

Best regards,

3 Likes
63

Hi Mr. Availant,

We wish Replicor the best and hope it is available to everyone across the globe 2-3 years time.

In Replicor’s pipeline, Phase 2 clinical trials are in planning stage in Asia. When are the trials likely to start in India ? How should one participate in this ?

Also i think the trials here would have Themosyn alpha 1 along with magical REP 2139. I guess Themosin alpha is approved here and has very mild side effects vis a vis PegIfn.

Also, I assume there won’t be any difference in functional cure rates with the same ?

Regards,

64

Welcome to the forum @rjktgj

While I cannot comment publicly on where and when clinical trials will happen, I would offer the following comments:

  1. We have tested thymosin alpha 1 or pegIFN in combination with REP 2139-Mg in patients with HBeAg positive chronic HBV infection (see here). Antiviral responses during therapy and outcomes after therapy were better with thymosin alpha 1 than with pegIFN. It would be interesting to see if this would hold in other patient populations.

  2. In combination with REP 2139, both thymosin alpha 1 and pegIFN have mild side effects. There are mild to moderate reductions in white blood cells and platelets unique to pegIFN which do not cause symptoms.

  3. In countries where thymosin alpha 1 is approved for the treatment of HBV infection (India and China), it would be interesting to test these immunotherapies head to head in HBeAg negative, NUC suppressed patients.

Best regards,

1 Like
65

Hi Mr. Avvailant,

Does this study tell that 8 out of 9 people with combination therapy (NAPs +Themosin or PegIF) achieved Hbsag loss for Hbeag+ people.

Would it have similar effect on Hbeag - population as well.

Somewhere in the above thread it was mentioned that 40% of the population has achieved functional cure and around 40% patial cure (no need of further treatment) in trails.

Hope someone who has had one stent (angioplasty), relatively young (42-47 yrs) and otherwise healthy would be able to take this combination therapy when made available.

Regards

66

Dear @rjktgj

HBsAg loss with NAPs in easily achieved in both HBeAg+ and HBeAg- infection.

Persons with the kinds of complications you have would not be excluded from NAP therapy.

Best regards,

4 Likes
67

Dear @availlant ,
Hope you are doing great. I would like to know if there is any plan for a clinical trial to take part in Europe?

I had sent an email to be connected and receive information about future pipeline, but there was no answer. Maybe I did not do it correctly. May I ask you to help, by your suggestions?

Thank you in advance.

68

Dear @IWillBeCured

We cannot reply to individual requests. However, we do add the email address from all of these inquiries to our mailing list. This mailing list is used when we publish updates on development activities at Replicor.

Best regards,

2 Likes
69

Dear Mr.@availlant

this is stefano (stef2011) from medhelp hbv community, i am very glad this community is very active…just an idea:
i remember private clinics in germany have very permissive laws for experimental treatments, would it be possible to get NAPs +Thymosin+tdf/taf or etv treatment there if the patient pays all the expenses?HDV has no cure but also HBV has no cure (we can just manage damage) and TDF/TAF are not totally free from side effects for all patients longterm (10-20 years of treatment can damage kidneys/bones and mitochondria)…i mean we cannot take tdf/taf for life.what do you think?after we see naps are very safe on decompendated cirrhosis maybe we can open a door for hbv infected patients that want to stop nucs but avoid relapse/fulminant hepatitis
thank you

2 Likes
70

Dear @stef2011,

We have made public the compassionate use program for REP 2139-Mg both on our website here and on Clinicaltrials.gov here.

It is important for the community to be aware that this program can only be investigator initiated and is for patients with URGENT medical condition only. This is essential both for proper observation and patient safety.

This compassionate use program is NOT a substitute for phase II trials (which are to come) and regulatory approval for use. Mainstream access for patients will unfortunately have to wait for these events. Replicor is working to make this happen as quickly as possible.

Best regards,

2 Likes
71

Dear Mr.@availlant
I have a question for you. Generally, one HBV test drug test takes at least 2 to 3 years. It seems that rep2139-Mg needs two more tests (phase 2b and phase 3), which may take at least 5 years. I want to know whether the replicator has measures to optimize this process and speed up the time of drug marketing.

1 Like
72

Dear @Tamron , welcome to the community.

Phase II / III trials for HBV typically take 4 years to complete (1 year for treatment and 3 years of treatment free follow-up to ensure functional cure is maintained).

REP 2139-Mg will have to have two more phase IIA trials as a subcutaneous drug (one for HBV and one for HBV / HDV).

We expect that phase II B studies will start long before the phase IIA study is complete (with as little as 24 weeks of data).

Like other drugs with breakthrough impact (e.g. bulevirtide for HDV), it is possible that REP 2139-Mg may receive conditional marketing approval with phase IIB data.

Best regards,

2 Likes
73

If all was to go per your plans, when do you anticipate to finalize Phase II B REP 2139-Mg

74

Dear @CNN ,

This is a very fair question. Hopefully you will understand that I really cannot comment on clinical timelines like this publicly. The best I can do is refer you to my previous post and our pipeline page here.

Best regards,

1 Like
75

Dear Mr Avvailant

When are the trials in India planned ?
Also trials for other markets are in Q1 24 as per
Can the trails not start in Q1/Q2 23 across the globe so that in two years’ time (by 2024 end), conditional approval is received for marketing.
Covid vaccines were approved in record two years time.

Any possibility of the above to end sufferings of the patients.

Regards,

1 Like
76

Dear @rjktgj,

Your comments are appreciated and we are certainly aware of the need for a therapy which can achieve functional cure and of the urgent medical needs of patients worldwide. This is one of the reasons we have allocated a significant amount of drug to treating the very sickest of patients right now.

As I have mentioned in my previous posts, please check our website (see posts above) for available details on planned clinical development activity.

Best regards,

2 Likes
77

Dear Mr Avvailant

Thank you for your reply. I checked the previous research records of REP 2139-Mg and found that this drug has been studied for 10 years. So many people around me who had heard of this drug 10 years ago seem to be disappointed that REP 2139-Mg is still in the phase II experiment. Because they had great expectations, they now pay more attention to Bepirovirsen. I said these words without malice, I have great respect for scientific researchers like you who have made contributions to human health. But I hope that REP 2139-Mg can show more progress. I wonder if your company can try to simplify the R&D process or seek external cooperation to accelerate the R&D progress of REP 2139-Mg.

Best regards,

78

Dear @Tamron,

First it is important that everyone in the community has the freedom to speak plainly so your post is greatly appreciated and encouraged! You raise some important questions which I think are important to answer for the community.

You are correct, NAPs (first REP 2055 and then its progenitor REP 2139) have been in the clinical space since 2009 actually. Some of the challenges we have since that time are:

  1. When NAPs emerged onto the seen, HBsAg was thought to just be a marker for functional cure. The role of HBsAg and more precisely subviral particles in preventing functional cure was not widely accepted (it now is, in no small part because of our clinical data).

  2. The importance of liver enzyme flares and the removal of integrated HBV DNA in achieving functional cure was not recognized at the time (although it was well entrenched in the literature for 20 years or more). This is much more widely accepted now.

  3. In 2014, there was an explosion of alternative antiviral technologies on the scene, including ASOs, siRNA and CAMs. There were a lot of high expectations for these technologies but in 2022 all of these approaches were shown to be futile for achieving functional cure. This is why J&J very recently abandoned these technologies and other companies like Aligos have signaled the same for their siRNA and CAM approaches.

  4. In 2019, Aligos emerged onto the scene with what was ultimately revealed to be a NAP we had abandoned 15 years ago (ALG-010133) with good reason. Despite promising 100x better activity than REP 2139 and getting intense buy in from the investor community, this NAP failed utterly in clinical studies, with very poor administration tolerably and no effect on HBsAg. We told the community this would happen before dosing began in infected patients.

Developing a drug is a financially intensive process and as you can see, Replicor has had to contend with a lot of competition for funding for technologies which appeared to have potential but ultimately failed to achieve functional cure. This has had a predictably negative impact on the pace of clinical development for REP 2139-Mg for many years and is the only reason why the progression of development of REP 2139-Mg has taken so long. We expect this will improve now that these competing technologies are largely disappearing from the development space.

The case of bepirovirsen is another case of confusion about what is really happening. This oligo is not acting as an ASO but as simulator of innate immunity (which GSK has acknowledged). As a result, the HBsAg loss is obtained mainly in a fraction of patients with HBsAg < 1000 IU/mL (where stimulation of innate immunity can have a stronger effect). Unfortunately, patients with this low level of HBsAg comprise < 10% of the patient population as a whole. While 30% of patients achieved HBsAg loss during therapy in the latest phase IIB study, by 24 weeks off therapy only 9 % of patients had maintained HBsAg loss and this will almost certainly drop significantly again when we see the 48 week follow-up. There is little cause to be excited about this current clinical data (it is possible that new clinical data could show us otherwise).

Best regards,

1 Like
79

Dear Mr Avvailant,

Thank you for your reply. I have a general understanding. However, in the face of the capital market, such as the partnership between GSK and lonis, or the partnership between J&J and ArrowHead, whether your company intends to cooperate with some large medical companies, because they have sufficient funds and resources (my friends around me claim to have seen the donation website of Replicor), which can greatly help Rep2139-Mg, Because someone around me raised a question that if the experimental data of Rep2139-Mg were good, the capital market would be the first to perceive it, so it would produce a series of capital operations such as cooperative development or acquisition to expand Rep2139-Mg’s influence and reputation.

Best regards,

2 Likes
80

Dear @Tamron ,

There are two incorrect statements in your last post .

Firstly, there is no donation website for Replicor. None has ever existed.

Secondly, developmental delays with REP 2139-Mg are not driven by any problems with the data but by misunderstandings by capitol markets on how to achieve functional cure which was only very recently proven out by failures of competing technologies which I have detailed in my previous post. These misundertandings were unfortunately influenced by the large capital expenditures of J&J and GSK on ASO / RNAi and CAM approaches starting in 2017 which have only been recently abandoned. This dynamic is the underlying explanation of how capital markets have behaved with respect to allocation of funding for HBV cure since 2014. There has been almost an exclusive focus on CAMs / siRNA / ASOs during this time by all players in the space and most spectacularly in the recently failed NAP (ALG-010133) which drove the market evaluation of Aligos to 1.2 billion at one point (now at 72 million with its failure).

On our website, you will find here very recent clinical data from well recognized and independent investigators in France replicating all of findings in our previous clinical data with REP 2139. This being done in patients with very advanced liver disease where all other treatments are contraindicated and with approval of the French regulatory authority. In encourage you to follow developments on this rapidly expanding dataset in the months to come.

Importantly, Replicor’s previous clinical studies have been published in the highest ranking peer reviewed journals here and here. Additionally, these previous clinical results have been corroborated in series of peer reviewed studies performed in collaboration with the scientific leadership at Abbott Diagnostics here, here and here.

Best regards,

2 Likes