Alpha-1 Antitrypsin Deficiency: Bridging Care
Transcript: The evolving landscape of AATD treatment
Gerry McElvaney, MBBCh, FRCPI, DSc
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
- This question addresses a really important issue in Alpha-1 antitrypsin deficiency about managing the liver disease and the lung disease, which often go hand in hand. In the past we used to think that if you had liver disease you wouldn't get lung disease and vice versa, but now we know that they are intimately linked. So with regards the liver disease, we arrange that we view all our patients on a regular basis, number one, and we look at people with all different forms of Alpha-1 antitrypsin deficiency. So we don't confine ourselves to those with the homozygous ZZ form, we also look at those with MZ, SZ and other forms of Alpha-1 antitrypsin deficiency. And in the average clinic we see our patients at least once a year, sometimes more frequently if they're unwell. In the liver disease area, we do specific blood tests and we're looking at, FIB-4 scores and APRI scores, and we also do fiber scans on a regular basis.
We usually do an ultrasound at the start. We follow up fatty deposition and fibrosis scores with the fiber scan, and if there are abnormalities, we repeat the ultrasound at various times. We also have to be aware that people with Alpha-1 antitrypsin deficiency have an increased risk for liver cancer, so we intermittently screen for that as well. So we always see our liver patients in the same clinic as our lung patients, but in addition to that, if we feel there's a liver problem which is becoming more obvious or more worrisome, we always have a policy whereby we refer our patients to liver specialists as well. Yeah, so there are a number of therapies which in fact started out as looking at the lung disease, but which will also look at the liver disease as well. So the classic therapy aimed at purely the liver disease is silencing RNA or RNA interference therapies. And the issue behind this is that in the ZZ form of Alpha-1, the commonest severe deficiency, the problem arises in the liver because the Z Alpha-1 antitrypsin protein polymerizes in the liver and gums up, sticks up in the endoplasmic reticulum, causing ER stress, which would lead to inflammation and then liver damage. So in addition to causing liver damage, that protein fails to get out of the liver in sufficient quantities to protect the lung. And if it forms polymers in the lung, the Alpha-1 antitrypsin is ineffective at protecting the lung. So the liver disease and lung disease go hand in hand, but in the liver there's too much Alpha-1 in the wrong place, in the lung, there's too little Alpha-1 in the right place.
So in the liver disease, the classical silencing RNA approach will knock off all the liver Alpha-1 that's been produced. It'll stop the liver producing Alpha-1 antitrypsin and that will decrease polymerization in the liver and therefore decrease liver inflammation and fibrosis. Now, that's the good thing. The slight caveat or worry would be that you'll now convert a Z individual to a null individual and they'll have even less Alpha-1 coming out to protect the lung. And that has been one of the concerns about this form of therapy. In other words, does in fact making a person liver free or liver well also make them more susceptible to lung disease? Now, the data does not suggest that's a major problem at the moment. The data would suggest that even decreasing polymers in the liver may also have a good effect on polymers in the lung, which is a good thing. So at the moment we're just keeping a careful eye on whether decreasing the Alpha-1 in the liver, the polymerized Alpha-1 in the liver, which has been shown to have some beneficial effects early on in liver disease, will not make the lung disease any worse. So that's the big state of play there with silencing RNA.
Now, there are other attempts to treat the lung disease which will also be beneficial to the liver disease. And those are, for example, DNA or mRNA BS editing. So here, the recognition is that the Alpha-1 mutation causing a Z mutation is a base mutation, single base mutation. And if you can change that by editing their DNA or their RNA, you can change the Z protein, Z gene, to produce M protein. So instead of being a ZZ, now become an MZ or an MM. And the idea is that if you produce M protein in the liver from a previous Z gene, you now have M protein which can be secreted from the liver into the bloodstream and from there into the lung and protect the lung more efficiently than Z Alpha-1 will but in addition to that, you'll defibrose the liver because you've decreased the amount of Z liver being produced, you've decreased the amount of Z Alpha-1 being polymerized and held up in endoplastic reticulum. So you're almost treating the liver disease and the lung disease in one go, either with DNA editing or RNA editing.
Theoretically DNA editing is one and done. You give it once and it works forever. That may not be the case. RNA editing would require repeat administration, but the concept is still the same. The base abnormality in the Z mutation is an adenosine. The basic concept here is you use an adenosine deaminase to change the adenosine to the proper base, changing a Z to an M gene, and this M gene will now produce M protein, defibrose the liver and protect the lung. So those are the three big, I suppose, advances in Alpha-1 therapies in the liver and lung disease. There are other approaches which have been discussed as well. And those approaches, they're considering protein refolding. In other words, can you refold the Z protein in the cell so now it becomes more like an M protein and it can actually get out of the cell more easily and then also defibrose the liver and protect the lung? The real problem in Alpha-1 antitrypsin deficiency in the past has been case finding. So people are referred when they have lung disease or when they have liver disease. And obviously that's problematic because in many cases the liver and the lung disease may then be irretrievable. You may not be able to reverse the damage that's been done. So theoretically we would like to identify people early before they have significant lung or liver disease and start these therapies as soon as possible. And that goes for all forms of therapy for Alpha-1 antitrypsin deficiency. I believe that early institutional therapy will not reverse the lung or liver disease, but will stop its progression.
So obviously the earlier you get the people, the better. But at this moment in time, most of the therapies are being targeted at people who have already developed lung or liver disease. So theoretically with these conditions, you have a chance Sorry, these therapies, you have a chance of curing the condition as opposed to just ameliorating the condition if you get in early enough. So the analogy here would be a bit like the new cystic fibrosis drugs where you get in early before damage is done and you help the patients. So in the lung disease, I would like to see it as early as possible. I'd like to see it before overt lung damage is present, and I'd like to see it before overt liver damage is present.
The difficulty for us is we're still not that good at predicting who's going to get significant lung or liver disease without Alpha-1 antitrypsin deficiency. So we are falling back on looking at people who have early signs of lung and liver disease who we know will progress. But I do think for the first time in a long time we have a chance of actually dealing with the basic pathogenic mechanisms of Alpha-1 antitrypsin deficiency in the liver and the lung and a really good opportunity to make an impactful intervention which will, I wouldn't say necessarily cure it, but come close enough to cure. And one final point is that with some of the newer therapies, you'll be doing two things. You'd be increasing the level of Alpha-1 antitrypsin in the circulation and in the lung, you'll be decreasing the amount of polymers in the liver and in the circulation, and those two things together are vitally important because it's not all about the levels of Alpha-1, it's about the levels of polymer in the blood as well and in the liver. So if you can increase the levels of Alpha-1 in the blood and in the lung and decrease the polymer levels in the blood and also in the liver, I think you've done a great, great job. You mentioned one of the hurdles to getting new therapies on board, and the answer is there are three major obstacles.
Number one, we have to prove that they work and we have to prove that they work to regulatory authorities who often have a very high bar and a difficult bar for treatments such as this, because bear in mind that although we think Alpha-1 antitrypsin deficiency is a relatively, it's much more common than people think, it's still relatively poorly discovered. We don't have a good idea how many people have the condition and a lot of people are underdiagnosed or misdiagnosed. So with regards to that we have to convince the FDA and the EMA that we could do studies with relatively small numbers of people and the endpoints have to reflect that. So if you're gonna ask to do a study of thousands of Alpha-1 patients over 10 years, that's not going to happen. So they have to realize it's a relatively rare condition, that the people who will benefit from these type of therapies will not be everyone with Alpha-1 antitrypsin deficiency and that has to be reflected in the study design and also in the demands made by the regulatory authorities for these designs. So that's the first thing. Secondly, you have to convince patients that it may be in their interests.
Now, genetic therapy is a big step into the dark for a lot of people. And people are always concerned about, could there be side effects with gene therapy that may not be there with more common therapies such as offsite gene changes and things like that. So you have to get very robust preclinical data, robust head to control data, and then you must then talk to the patients about what the pros and cons of these things are, what they might expect, and then how it may impact upon their lives. And then the third thing is we have to be confident in ourselves that what we're doing is in keeping with all the knowledge we have on Alpha-1 antitrypsin deficiency. So we believe that the levels are important in the blood and in the lung. That's important that we increase the levels. But we're not really sure how high you have to increase the levels to. Secondly, if we think that polymers are important in the liver and in the blood and the lung, we have to decrease the amount of polymers. And again, we have the robust ways of showing these biochemically, but in addition to that, we also have to show them, I think clinically. Now, we've been very fortunate, I think, with the massive progress within the last number of years in the use of the fiber scanning utility in Alpha-1 antitrypsin deficiency. It's now getting widespread acceptance. It's a relatively non-invasive way of following up liver disease. We are quite good at ultrasounds, but we still have to do liver biopsies, usually early in the early stages of these studies. The problem with that is patients are a little bit weary or wary of doing liver biopsies. So we have to make them safe, easy to do and effective. So that's the early parts of the studies, the follow up with fiber scans, ultrasounds, blood tests, et cetera, are reasonably easy but very time consuming for patients and we have to build that into the studies. And then finally in the lung we have to show levels of Alpha-1 normalizing in the blood but also in the lung itself. And that requires bronchoalveolar lavage, which again, a bit like liver biopsy, turns some patients off the studies, but again, may be vital, at least in the early phases of the studies to show that not only are you raising the levels of M Alpha-1 antitrypsin in blood, but you're also increasing it in the lung as well.
So there are a lot of obstacles to these studies, but the obstacles occur at different time points in the studies themselves. So in the early studies you're gonna have to do liver biopsy, perhaps, and also bronchoalveolar lavage. In the later studies, frequent testing with low dose radiation CT scans, fiber scans, blood tests, pulmonary function tests, that sort of thing, and then you're gonna have to produce a cohesive and coherent strategy to funders and the regulatory authorities to say that you basically normalize the condition. The Alpha-1 levels are now in a reasonably good range, there are no polymers or decreased polymers, the liver disease is quiescent now it's been stabilized or maybe in some cases reversed a little bit, the lung disease is now stabilized. And if you can show that, then you should be given an opportunity to proceed. But that's a lot of ifs and buts there. A lot of people would say, you're not treating a fiber scan and you're not treating a CT scan of the lung, you're treating an individual. And there's always a placebo effect in all these things as well. But we have quality of life questionnaires and they're reasonably robust. They're not as good as we'd like, but they're reasonably robust, but we need to improve on those. So if you were to talk to a person about liver disease and we could show that their liver is now less inflamed, that they have less liver symptoms, like maybe less nausea, less fatigue, et cetera, less pruritus, if you can show that that's a big plus. In the lung, if you can show there are less exacerbations, less infections, et cetera, that'll be impressive. And if again, they can walk around more easily and are able to do their daily living, that's important. So the quality of life will take in all those things, but it will also take in other things as well. So for example, are they still able to do their work? They do not retire earlier than they did before? Are they able to do your past times? Are they getting less problems with general fatigue and unwellness?
Now, those are difficult symptoms to capture, but if we have found that in the lung disease end, we find the best way to capture those type of symptoms, is to call the patients on a very regular basis and see how many infections they've got, how many antibiotics they require, et cetera, et cetera. In the liver disease, it's quite similar. You have to talk to people on a regular basis. Very labor intensive, but you get a feel for the symptom burden initially and how that symptom burden is ameliorated by these therapies. Bearing in mind that people in active therapy always feel better because of the placebo effect. I should say also that you can expect in an effective therapy, a prolongation of life with these therapies. We have even shown that in the presently available intravenous augmentation therapy studies with plasma purified Alpha-1 antitrypsin, we have shown that you get an extra five to seven years of life with augmentation therapy.
I would expect that these newer therapies may even deliver more than that, if successful. Once a potentially effective therapy has been shown, it would encourage people to get tested for Alpha-1 antitrypsin deficiency. And secondly, it'll encourage doctors and physicians to consider referring people for therapies for Alpha-1 antitrypsin deficiency. In the past there has been a nihilistic attitude towards Alpha-1 because firstly, people weren't being tested for it, and if they were found to be positive for Alpha-1 antitrypsin deficiency, you would find that the doctors who saw them were quite nihilistic because they felt there's no really effective therapies. Now, for the last 20 years, intravenous augmentation therapy with plasma purified Alpha-1 has been shown to be clinically effective. But the new therapies will also offer you a chance to treat the liver disease and the lung disease. And again, once you've got an effective therapy, you get more case finding, you get more detection and get more referrals to specialized centers. And you'll then find that we'll be picking up people earlier with the condition and with a chance for more effective interventions.
So that's my hope for the next five years. This is an enormously eventful time in Alpha-1 antitrypsin deficiency. We're now moving into new therapies. Inevitably some will work, some will not, but the point is that we need to enthuse our patient population and we need to enthuse reimbursement authorities and regulatory authorities that we have a chance to cure a condition which is not necessarily that uncommon, but one which was uncommonly detected. So we need to push that out there and ensure that our patients get access to these therapies.
And finally, I think we have to make sure that once these therapies are available, that the costs are not too prohibitive, that they leave people out from poorer countries.
Developed independently by EPG Health, which received educational funding from Takeda, awarded to EPG Health to help provide its healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content.
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