Let me remind each one of you all of freedom of speech.
A cured patient means losing a customer for the medicines. They dont care about you or me they care about youre wallet.
Past 15 years theyve been yapping about a cure (yh right) and no progress is made.
I mean past 2 years they send 100+ billion $ to ukraine, but hey no funds for a total cure? Hey man again they dont care lol. I lost my mind my life is ruined and doctors simply dont CARE. Im born in west europe been to hospitals and they are all clueless you know what they say? Shut up and take ur meds daily and get the **** out.
They give you a tiny bit hope for a “functional cure” in other words the virus is still present in your liver instead of doing slow damage…its gonna do ultra low damage untill your liver stops working.
I respect your viewpoint and feel your frustration as well. I want to offer my perspective from being in the room where cures are discussed and the science around it is being developed for the last ~15 years, and also as a person with Hep B myself.
I have never seen anything untoward in terms of suppressing a cure or anything seeking profit over patients in any of my interactions with the scientific or medical community. None of us have come into the field seeking fortune (there are much much less frustrating ways to make money for the amount of training it takes compared to research). Both scientists and industry have poured a lot of effort, time, and money into trying to develop a cure (equivalent to hundreds of millions of dollars).
Just like every other research for treatments, we have found many ways that won’t cure Hep B during this time. But it’s untrue that no progress has been made. For example, we now have one of the first Hep B specific treatments getting out into phase 3 trials.
I wholeheartedly agree with you that there is not enough funds placed into the field relative to its impact. However, this has been an issue of governmental policy, rather than doctors (who are trying to address the health impacts directly on the ground).
I also agree that not every doctor is an expert in Hep B, particularly in Western Europe where Hep B is not common (compared to say South East Asia). Just like everyone else, doctors are trained and most comfortable working with issues that they see more often, and will often fallback to simply following the guidelines for conditions that are less common.
Finally, the existing antivirals do not make a huge profit for the companies who developed them, now that they are able to made as generics. The doctors also get no funding from prescribing these.
I’ve shifted this thread into “Get Involved” because I would like to see such frustration and anger being directed toward productive means. To some extent, there is a need to being upset about injustices and drive awareness of this issue to those controlling the resources.
It’s not about freedom of speech, no one bans negative thoughts. But what was the reason of your post ? If you live in western world you’ve got better treatment and overall live conditions
than 90% of all people around the world. Appreciate it.
Hi @H020,
While I understand your frustration and anger, please let us leave Ukraine out of this. Ukraine is not the reason why there has not been a cure for HBV. Besides, the majority of the funding announced for Ukraine actually doesn’t go to Ukraine. They are military aid and the money is used to replace the weapons we don’t need because they are old and ineffective that are given to Ukraine. The majority of this funding is used to rebuild those supplies. The military manufacturing complex are the ones getting the largest chunk of all those monies and not Ukraine.
Let’s not drag a country that is fighting daily for its survival, existence, and culture into why there is no cure for HBV. Maybe we should blame the people we continue to vote for or elect who don’t seem to care about us. They only care about staying in power and the next election.
Freedom of speech does not mean being inaccurate with facts or falsely accusing others. We can all do better. Best, Bansah1
Thing about all the people that had HCV prior to 2013. They probably felt the same way. But alas, Pharmasset developed a cure for it. The same thing may happen. Theres a ton of trials out there going on right now using different modalities. It takes a while for these and things get discovered along the way. They thought SiRNA was the answer until they found out that SIRNA by itself isnt enough and they would need to combine it with other methods. And I do remember reading from a medical journal that finding a “functional cure” actually puts your chances of developing anything adverse very close to someone whos never been infected.
On another note to the experts, how do you feel about the Arbutus Biopharma SIRNA in combination with the VTP-300 therapeutic vaccine? They had preliminary results at EASL conference and it looks a little promising to me and im hopeful that at the AASLD conference they will have positive results from that trial in combination with Nivolumab. @sunnyban was talking about screening for that trial here last year. Hope hes doing great. Also how does the VTP-300 vaccine differ from the ThervacB vaccine that got a lot of chatter?
It is important to realize the chronic HBV infection is the largest viral infection worldwide for which there is still a significant unmet medical need. Even with the current estimates of ~260million people worldwide, millions of new infections occur each year and only about 5% of people with this infection even know they have and are receiving treatment.
There is AMPLE motivation in the industry to provide a curative therapy for HBV as this is the only step moving forward since we know this is the only way to prevent deaths due to HCC (death rates from HBV are unfortunately rising). The only way to meet the WHO goal of elimination of viral hepatitis B is to have a drug which can achieve functional cure. This happens to ~80% of patients who had acute HBV and self-resolved their infection.
Also, current medications (ETV and TDF) are generic and thus very cheap and are safe and effective in controlling viral replication. The issue with these “stopgap” medications is not their price but instead governmental resistance to providing this care to all patients who need it, especially in jurisdictions where funding is less easily obtained for such measures.
I do believe that the industry in general has made far too many promises to the public regarding the potential for HBV cure but this is the nature of market economies. The appearance of or promise of success by these companies influences stock price or investment in these companies. There is also not enough attention paid to the details of the data generated for one particular member of a family of compounds (i.e. CAMs and siRNA) without understanding what these data say about the potential for other members of these families of compounds.
Finally, most technologies which have failed to achieve functional cure are now turning running trials in unicorn patients: these patients have HBsAg < 1000 IU/mL and respond much better to immunotherapies like pegIFN yet represent only ~5% of patients world wide. All of the recent data from siRNA and immunotherapies like bepirovirsen show that effects are limited to these patients but even so disappear during follow-up. We also have curious trial designs where trials with these kinds of patients omit a pegIFN control group, why? Even the currently enrolling phase III trial for bepirovirsen is designed to greatly enrich the enrolled patient population with unicorn patients. What does this say for all patients in general? Why do none of these companies qualify results with unicorn patients appropriately? They will not be solutions for the patient population in general.
In this regard, patients should take the time to study these issues to they can hold companies to account for the way they design clinical trials and the assumptions they make from the data generated.
Thanks you Dr. @availlant for your honesty.
in some ways I do understand @H020 frustration with it all…
I find it very cruel that the industry makes too many promises for potential cure just to influence stock prices and investment… do they realize they play with real people feelings and mental health? not just numbers?
we are human, suffering physically, emotionally and psychologically.
just wondering how can we as patients hold companies to account for how they design clinical trials? we are at the receiving end of it… unfortunately we are normal human against titans…
best Gregory.
If I’m not mistaken - some siRNA and immunotherapies show both HBV DNA and HBsAg loss - which rebound after discontinuation of the therapy.
Isn’t it already better (both HBV DNA and HBsAg loss) than Entecavir / Tenofovir, which only result in HBV DNA loss (and patients also rebound when the therapy is discontinued)?
We have discussed on this forum about the need for functional cure, where immune control of HBV infection can be maintained by the individual without therapy. This is because this is the only outcome where patients can live a life free from antiviral therapy and also have the lowest possible risk of liver cancer.
In this endeavor, the ability of the liver to produce HBsAg (or rather its elimination) is the goal. This is not important because HBsAg is produced in cells also producing virus but because HBsAg (as non-infectious subviral particles) is produced without the production of virus from integrated HBV DNA (which causes liver cancer). Integrated HBV DNA is also the source of the bulk of HBsAg produced in patients with chronic HBV infection which in turn blocks immune control.
So HBsAg loss during therapy, while an important step in achieving functional cure, does not guarantee functional cure (as we have seen from all recent clinical trials with a variety of agents). When HBsAg in the blood rebounds after removal of therapy, it means that nothing has been done to remove those liver cells with integrated HBV DNA which are producing HBsAg and thus done nothing to actually achieve functional cure. So this result is really no better than NUC therapy.
It is important for the community to pay attention to all compounds which are GalNAc-siRNA. These include:
All of these compounds have a very long residence time in the liver (more than a year) - this is something which the siRNA industry has known for almost 10 years but which for some reason is not acknowleged in any current studies. HBV studies which report outcomes after stopping siRNA therapy are not really off therapy until more than 1.5 years of follow-up have been completed. This is why we see the slow rates of HBsAg rebound over time with these compounds. Results at 24 and 48 weeks of follow-up should not be reported as off-therapy.
Are there any studies which try to evaluate longer time periods?
Say, 5 or 10 year NUC vs GalNAc-siRNA:
with NUC, we already know that functional cure rate is very low also when taken for 5-10 years and longer
how about GalNAc-siRNA? It seems that most of the studies focused on 1 year therapy (with perhaps some followup off-medicine later)? What happens beyond year 1, 2, 5 and later?
The longest publicly disclosed follow-up from a GalNAc-siRNA in for JNJ-3989 and RG6346 (48 weeks after stopping siRNA). In these studies we can see clear and steady rebound from end of therapy through 24 and 48 weeks.
Curiously, we have not seen longer follow-up beyond this point for any GalNAc-siRNA or antisense/immunotherapy.
For NAPs we have done 5 and 7 year follow-ups with stable or increasing rates of functional cure. This is the standard we should expect from all clinical trials (minimum three year follow-up).
I would prefer to see this still as progress and to bring some hope out of it. Even if we see this not as a functional cure, I think being HBsAg-negative on a >1 year-time scale without treatments in between is still an achievement.
Some people may prefer this over daily pills to stay HBV DNA negative, and having greater numbers of modalities to suit people’s preference holds potential benefit.
I appreciate your comments and of course we really want to give patients every hope for the future. However, from my perspective this this not really a step forward since HBsAg loss only occurs with some of these therapies in a faction of the unicorn patients in these trials and unicorn patients themselves only represent a tiny fraction of the patient population. Even in these very limited cases, integrated HBV DNA is still unaffected by these treatments. We know this because HBsAg rebounds back to baseline almost universally. There may be no drug administration in these cases after dosing is stopped but these patients are still under therapy. A good analogy would be if patients could take a depot NUC therapy which would slowly release NUC therapy over 6 months. They only might have to get dosed once or twice a year but therapy would still be life long and if started too late, largely ineffective against HCC.
The true benefit of functional cure is efficient removal of a large fraction of integrated HBV DNA which is why functional cure means no therapy is needed anymore and also has the lowest rates of HCC amongst people infected with HBV.
For sure a therapy which only has to be given once or twice a year is better than NUC therapy but this is not the curative response which patients have been promised since 2016. The path to approval for such a therapy is not clear since all major regulatory agencies are still demanding functional cure for approval.
As an update on this issue, patients should be aware that Roche has halted development of its entire HBV portfolio see here. This includes its GalNAC-siRNA (RG6346 aka xalnesiran), its PD1 GalNAc LNA siRNA (RG6084), its TLR agonist (RG7854 aka ruzotolimod) and its HBsAg antibody (RG6449).
This is what I was getting at in terms of progress. Yes, agree that in itself or in combination with existing treatments that these may not be curative approaches, but it broadens the number of modalities we have at hand to treat HBV (at least from a theoretical standpoint), some of which may be beneficial to some people in some situations.
The continued development, regulatory approval, and implementation is another thing, but at least the community should be made aware of what is possible and inform them on what they could advocate for to be available to them.
Thomas I totally agree. However, we need to temper this hope with a real understanding and dissection of what is actually being achieved in clinical trials and what this means for potential use in the clinic.
The problems are:
None of these agents (siRNA, antisense, therapeutic antibodies) are being evaluated in the absence of NUC backbone therapy.
Early monotherapy results with these agents have shown that they do not perform as well in the absence of NUC therapy (which is not surprising).
None of the tiny fraction of transient HBsAg loss or retarded HBsAg rebound in unicorn patients with siRNA or bepirovirsen is occurring without pegIFN being present (which is not an option for chronic therapy). I am not aware of any trial enrolling or planned with these agents which is not using pegIFN and NUCs.
So currently there is no evidence (as far as I am aware) suggesting the possibility of replacing daily NUC therapy with another chronic therapy, only adding another therapy with a lower dosing frequency on top of existing NUC with no evidence of increased clinical benefit. The chances of such a therapy being approved in this context are virtually NIL from a regulatory and financial perspective. This is important for patients to understand, especially those in more resource challenged environments.
However is maybe possible that GalNAc-siRNA could supplant NUC therapy. We would just would have to get those companies involved with the development of those therapies (GSK, VIR and Arbutus) to consider a different approach with these compounds instead of functional cure. It would be interesting to see how well any GalNAc-siRNA performs with subcutaneous dosing every 3 or 6 months (every month will lead to uncontrolled accumulation in the liver) in the absence of NUC therapy. If such an approach could lead to HBV DNA < LLOQ (or even very low HBV DNA) with persistently normal ALT, I would then suggest that such an approach could replace NUC therapy with similar clinical benefit. The safety issues with such an approach will be far less than with any current NUCs. Also GalNAc-siRNA drug products have good thermal stability in liquid form between 15-25°C so we could envisage deployment even in resource challenged areas. We would still have the HCC issue of course.
I think this video hit the nail on the head. Why would any pharmaceutical company sell you a cure when they can sell you anti-viral drugs for years instead? It simply doesn’t make financial sense.
I’ve seen posts on this website where experts reply to the question “when will there be a cure” by saying “possibly in the next 5-10 years”. With all due respect to the experts who devote their personal time to answering our questions for free, that is the exact same reply my gastroenterologist gave me back in 2007, almost word for word.
I now believe if we’re ever going to get a complete or sterilising cure for CHB, it can only be achieved through technological advancements such as democratised, decentralised drug discovery and synthesis. But then, big pharma will no doubt do everything they can to kill off such technologies.
Finally, I want to apologise if I came off as unnecessarily confrontational or if I offended anyone here. My anger is towards the pharmaceutical industry, not any individual. Both my father and his father died from liver cancer as a result of CHB, and there is a chance I might follow in their footsteps. So it’s a little personal for me.
I agree with you 100% and I asked a similar question on this forum a while back. The pharmaceutical industry has a financial interest in as many people as possible taking as many drugs and vaccines as possible. Covid is a fine example of this. Covid was a disease that primarily killed older people yet, for some reason (i.e. pharmaceutical profits), even children and young people were vaccinated against it. And the vaccine didn’t even work, as the vaccinated still got infected! The older I get, I view the pharmaceutical industry with skepticism.
