Important from The PBC Foundation....

[DonnaBoll]

We are asking for your help.

4/6/2024

Very directly. Very succinctly. We need your help.

This is the most important thing the Foundation has ever worked on: more important than the surveys, more important than the helpline, more important than the name change.

We are writing a letter which we would like to share with regulators about the patients’ collective views on PBC treatments and about clinical trials in PBC. We need you to sign this letter and to share this letter for others to sign. We need your voice so that we can all be heard.

As I am writing this, I am fighting back the tears because I know in my very core how vital it is that we, together, drive these changes for PBC patients around the world, for generations to come. This isn’t just about you or I, or now. This is about the thousands of PBC patients in the next generations who need the best possible care in their journey.

We are emphasising two things in this letter: 1) That Obeticholic Acid, aka OCA or Ocaliva continues to have a license, even if it is still conditional, as a treatment for PBC. There is a risk, and we are not entirely sure how big or how small, that the license may be under threat and we need to ensure the regulators know that PBC needs OCA to be part of the toolkit 2) that placebo arm trials stop in the later phases (iii and iv) of drug development for PBC disease management. Regulators still have a belief that placebo arm trials are the best and safest way to conduct these trials, and it is our strong belief that they are not.

1. OCA

There is a lot of real world evidence (i.e. from clinics working in PBC) that OCA makes a difference to those who need it. It is a small percentage of people with PBC, but a significant number who need OCA to improve their chances of a normal life expectancy. As with Urso, some people respond, some not: however, it is a vitally important part of a clinician’s toolkit in treating PBC. (it may actually be used in triple therapy for those difficult to treat cases, which also seems to be the case in the real world, currently)

OCA is not the answer for everyone. Indeed, some patients cannot take OCA because of side effects, or because it is not available in their country. It is clear, however, that OCA is an answer for many patients.

The challenge to OCA is that it was unable to prove in a confirmatory study that it works. Why? Patients who found out they were on placebo (their liver tests were not improving) and obtained OCA from their clinicians. Do bear in mind, OCA was available to PBC patients in a number of countries, but not to those patients in the placebo arm of this trial. So, patients were benefitting from a new drug, showing the drug worked. So much so, that patients not on the drug (in placebo) got access to the drug and had their liver results improve, showing the drug worked. This meant the placebo arm on the trial managed to miraculously improve their liver tests. Oh, and patients also dropped out the trial. The drug worked to the point where the company were not able to prove that the drug worked.

Confused?? Yep. We are too…

This is why this letter is so important.

2. Placebo

In short, the traditional way to have a clinical trial is for some patients to be given the new treatment, and some patients don’t. The patients usually do not know what they have been given. Results come from who benefitted, by how much, and who didn’t. It is a proven scientific method used for many years and has yielded many good results and some amazing therapies.

However, in PBC disease management trials the people taking part are the exact people who should be on a working therapy. These are the people at the greatest risk of disease progression. As PBC progresses, we know it is more difficult to treat. As biochemistry rises higher and higher, we know it is more difficult to normalise. Not impossible: but more difficult.

Yet, knowing this, regulators ask patients in the high risk group to volunteer to not take any working medicine, adding to their risk of not responding in the future when they do finally take a treatment. We have an enormous wealth of data from groups such as UK-PBC and the Global PBC Group that can tell us what happens to patients who are not on treatment for years. We no longer need to have any single PBC patient not on a treatment that works.

And so we are calling for change. We need you to sign this letter. We need to come together: the newly diagnosed, the lived with PBC forever, families, friends, clinicians, industry partners, but mostly you. There is so much more we can add, but we would invite you to contact us directly if you have any thoughts or questions, and chat with us the issues at hand.

So, we beseech you with everything we are: can you go to this link change.org/Caring_for_PBC and sign?

[CeeJay56]

No. I believe in the scientific method and believe it has served me and our society very well. So, I am sorry I cannot support your petition

Not everyone responds well to OCA, there are serious risks and such risks are discovered using controlled, standardized, clinical trials. I believe those clinicians and patients who participate in a clinical trial help all those who suffer from the disease and the potential treatment being studied. While the vast majority of treatments may not prove efficacious, it is still important to maintain controlled studies using time-tested research methodology until we discover a better alternative.

I appreciate all you do for the PBCers and understand we have a different point of view on this matter.

With my best regards.

CJ Lambert

[PBCRobert Partner in reply to CeeJay56]

Thank you for your input.There are times placebo arms are appropriate, there are times when they are not.

Maja Angelou said something like we do the best we can till we know better; once we know better, we do better. There are a number of drugs now that have been approved using synthetic control arms, or retrospective data. These methods are just as scientific and don't rely on patients with a progressive disease getting no treatment. We are not asking to drop all placebo arm trials- just the ones that put patients at risk.

COBALT failed as a trial. It js cited often as the scientific community asking the wrong question. And clearly finding the wrong answer. Real World Evidence shows the answer. There have been multiple presentations at EASL this week- the scientific bit- telling us OCA works for many, improves liver stiffness, etc all with Real World Wxidenxe.

The data tells us very plainly that time spent above the ULN in ALP takes time off a PBC patients potential lifespan.

The open letter was co-written by clinicians from our MAB. Also, they wrote a more scientific piece, collectively, saying some of the same thing recently in the AASLD journal. I trust them. Probably because now they know better, they are trying to do better.

Not many of us remember when leeches were the Gold standard, but once upon a time they were. I remember when biopsy was the Gold standard for staging. It no longer is.

We learn. We progress. We do better.

Please help us to do better.

As an addition, we are currently at EASL congress where the very latest science is being shared and there is cross stakeholder agreement that the letter highlights the issues and drives for improvements that can be made.

Synthetic control substitutes one set of imperfections for another. However, these imperfections are less risky than current systems and long-term sugar pills.

[butterflyEi in reply to PBCRobert]

Good morning Robert, I have no doubt that this matter has been discussed by your medical board and some very senior specialists and with well over 100 years of medical investigations there has been much learned. There are a good deal of research papers published on retrospective data. I agree we learn, we progress. we do better.

I will complete the form after my holiday, at the moment when I clicked the link it came up in the language of the country😅. I have shared this in a PBC Facebook group.

kind regards

[PBCRobert Partner in reply to butterflyEi]

Can you go to multiple countries and sign in multiple languages??? 🤣🤣🤣Awesome, thank you.

Already, we are close to 600 signatories and we have only just publicised it for a couple of days.

[butterflyEi in reply to PBCRobert]

Marvellous. Country hopping sounds like a great idea🤣🤣

[Turquoise2075]

Thank you, I have signed the petition. Ocaliva has given me my life back. Before I was on it I was barely functional with no quality of life with severe cognitive dysfunction and fatigue. I was incapacitated everyday, barely able to get up and do anything. It was a huge effort simply to make a meal and my cognition deteriorated so badly I had trouble making a cup of tea. After 3 weeks on Ocaliva I began to be able to think, function and move again. It is believed it restores the blood-brain barrier, protecting the brain from the substances released as the bile ducts are damaged. If it is removed from being available I’m in trouble. I was a non-responder to Urso and made very ill with Fenofibrate, so Ocaliva is the only med left available to me. Currently my liver readings are good and I am a much more functional human being. I have been willing to trial Ocaliva so I have some quality of life. I think that flexibility needs to be in the system for a condition such as PBC where there are limited treatment options available.

[DonnaBoll Administrator in reply to Turquoise2075]

I am so glad for you! Thank you for such a positive post about Ocaliva. I know for many that isn't the case. It surely has been a life changing drug for you. I believe that the intent to drop the 'blind study' in clinical trials for PBC patients is that many who are participating in the trials have not gotten any results from Urso or Ocaliva. They have become very sick having no other options but a drug in a clinical trial. These people don't have those years or even months to wait to see if they are on the drug or the placebo. This is the thinking behind eliminating the blind study for them. Time is of the essence for them. Thank you again for sharing such a positive post. I'm so glad you have your quality of life back.

[Turquoise2075 in reply to DonnaBoll]

Hi Donna, yes I understand about time being of the essence. I understand the importance of rigour in clinical trials, but I also see human beings who may be facing potentially serious outcomes if they are on placebo but don't know and may be losing valuable time. I have been very fortunate on Ocaliva so far with the only side effect a very temporary increase in itching that soon subsided. It is certainly very different with different people for all the three kinds of meds for PBC.

[Turquoise2075 in reply to Turquoise2075]

P.S. I should add that my liver readings actually normalised as a result of supplements tailored to my body based on the results of advanced microbiome testing. This also temporarily cleared the cognitive and fatigue issues and was before I started Ocaliva. But then the cognitive dysfunction and fatigue came back strongly after a few months while the liver readings remained stable. My liver specialist decided to try Ocaliva on the basis of restoring the blood-brain barrier and it was very successful and it has kept the cognitive and fatigue issues at bay for a year now. As my liver readings were already stabilised I don't know how much of a role Ocaliva played in that if at all, but it did seem to have a decisive effect on cognition and fatigue which is what has improved my quality of life greatly. I just thought I should clarify those details.

[DonnaBoll Administrator in reply to Turquoise2075]

Thank you for all that positive input. It gives lots of others hope that their lives can be better. I'm so glad the brain fog and fatigue was helped... that has such an impact on our whole lives.

[DonnaBoll Administrator in reply to Turquoise2075]

Absolutely right about so many on the trials 'time is of the essence' just for their actual survival. Taking a placebo for months or even years can be catastrophic for them.

[Turquoise2075 in reply to DonnaBoll]

Yes, it is a different thing all together when your health is deteriorating rapidly. I am concerned what will happen to me if Ocaliva is no longer licensed. I was in a very bad way before I went on it. I read that there have been some bad side effects for some people but I was willing to take the risk of trying it. So there are risks as is true for all medications, but I read up thoroughly on all the latest research myself and made an informed decision. I think we need to empower people with chronic conditions to be able to make such informed decisions where their quality of life has disappeared and they are very ill. I feel I have a future now.

[DonnaBoll Administrator in reply to Turquoise2075]

Thank you such an insightful and powerful post. You are so right! We depend on medications for our very existence with this disease. We have a responsibility to ourselves and our loved ones to learn as much as we can about the disease as well as the drugs we can choose from. The 2 drugs on the market have given many their 'future' as you wrote. We have to keep hopeful about the drugs now coming to our list as well - Seladelpar should be available soon. We do often have to make the decision to take the drug in spite of side effects that can happen.