Available ATTR Selective Stabilizers

John L. Berk, MD: So, Dr Hanna, TTR [transthyretin] tetramer stabilizers. The idea is to keep the 4 proteins together and prevent the monomer from being released and misfolded.

There are a couple of agents, tafamidis and diflunisal. Can you take us through the important results of the international trial? We’ll focus on cardiomyopathy with tafamidis.

Mazen Hanna, MD: The ATTR-ACT trial, which is testing tafamidis versus placebo in patients with transthyretin cardiac amyloidosis—and that’s both wild-type and hereditary—basically took 441 patients, and patients were randomized to 3 arms, either in a 2-to-1 ratio. So, either tafamidis 80 mg, tafamidis 20 mg, or placebo.

The trial lasted 30 months. They took the pooled tafamidis group, both those that were in 80 mg and 20 mg, and compared them to the placebo group. And ultimately, the primary end point was a very hard end point. It was all-cause mortality, plus frequency of cardiovascular hospitalizations. And there were secondary end points looking at the Kansas City cardiomyopathy questionnaire, which is a quality-of-life metric, and also at the 6-minute walk distance. Again, it’s 0 and 30 months.

The results were quite striking in that as far as all-cause mortality in and of itself, there was a very significant of 13-1/2 absolute risk reduction and mortality. About 71% of patients at the end of 30 months were alive in those who took the tafamidis and about 57% of patients were alive in those patients who took placebo. So, that was very striking; it was ultimately a 30% relative risk reduction in a mortality.

The same went for hospitalizations; there was a very significant reduction in frequency of hospitalizations. As far as the 6-minute walk, the secondary end point, and the patients, the decline in the 6-minute walk was much less over the 30 months in the tafamidis group than it was in the placebo group. I think there was about a 70-, 80-meter difference by the end of those 30 months.

The same thing goes for the Kansas City cardiomyopathy questionnaire. There was a very substantial difference in that the quality of life declines at a much slower pace in the patients who took tafamidis versus placebo.

So, this was a very positive trial. The number needed to treat to save 1 life was about 1 in 8, which is as good as we have in cardiology. That is, to treat more than 31 patients over 30 months. That’s translated to tafamidis FDA approval in May of 2019 as the only FDA-approved stabilizer or treatment right now for ATTR [transthyretin amyloidosis] cardiomyopathy.

The good news about this trial was the safety was excellent. There were more adverse effects in the placebo group than in the tafamidis arm. There was no signal of a safety issue. So, here we have a very effective drug that’s taken orally once a day, that not only has a mortality benefit, a decrease in hospitalization, a quality-of-life benefit, but it’s also safe.

John L. Berk, MD: Dr Desai, is the placebo the ultimate goal of therapy? Do people truly stabilize or is this just a slowing of their disease?

Akshay S. Desai, MD, MPH: Well, I think that we have the sort of 30-month follow-up in the ATTR-ACT trial that tells us that over that time interval at least we’ve seen improvements in survival as mentioned and also stabilization of the disease. I don’t think we have longer-term data to really tell us whether the disease is truly stalled or the progression is actually simply slowed over time.

My impression is that this is not an indefinite cure for the problem. It’s rather an approach to stabilization of the protein and stalling disease progression. But that’s quite meaningful in a disease with very limited overall survival. I think the other point to make about ATTR-ACT is, to add to Dr Hanna’s point, it’s really the bulk of the benefit was in those patients in the earlier stages of the disease, the class 2 patients. The 3 and 4 patients got a little bit less benefit over the course of the trial, and it may speak to the fact that some patients may be a bit beyond the reach of rescue with tafamidis. I think it’s probably worthwhile considering in the context of the overwhelming cost of the agent to patient, when the drug was released. I think the annualized cost was almost a quarter of a million dollars for patients. Fortunately, with subsidies, many patients can access the drug at far less of a cost. But I think it’s another reason to build on what Dr Witteles said earlier, that these patients really ought to be seen at specialized centers that have the experience of securing the drug for the patients.

John L. Berk, MD: And Dr Hanna, at the end of 30 months, the echocardiographic features of disease were improved or unchanged?

Mazen Hanna, MD: Well, this is something we’re looking at. There’s no published data discussing what’s happened to the echocardiographic features of baseline of 30 months. Ron, I don’t know if you can speak to that.

Ronald Witteles, MD: I’d empathize that patients with transthyretin amyloidosis, their echoes tend not to change that quickly. But far more important than what the echoes show is what happens clinically to the patient. And we know from ATTR-ACT that the average patient worsened on tafamidis, very clearly. You can look at the quality-of-life curves, and you can look at the 6-minute walk time. And clearly, these patients’ disease progresses over the 30 months. It just does so at a markedly slower rate than those on placebo.

So, I’m always very careful when I’m starting a patient on tafamidis to make sure that the patient and their family understands: do not take this thinking you’re going to feel better. In fact, take this with the expectation that you’ll probably feel worse a year from now than you do today. But, that you’re going to be hopefully feeling significantly better a year from now, or 2 years or 3 years than you would have otherwise felt if you were not taking it.

John L. Berk, MD: OK, a very quick question. This is going to be quite controversial. My understanding is the VA [Veterans Affairs] system nationally recommends initiating tafamidis at 20 mg. Your very brief comment about whether this is appropriate or this should be reconsidered, Dr Witteles.

Ronald Witteles, MD: I think yes and yes. It should definitely be reconsidered; 20 mg is not an FDA- approved dose. It is incredible to me that the VA, a federal institution, would prescribe a non-FDA approved dose for patients. Why they’re doing it is because in ATTR-ACT, the 20- and 80-mg groups looked very similar to one another. And so, the idea was given the cost that Dr Desai noted before, if you could give them one-fourth of the dose, maybe you’d save a lot of money.

That’s why not that it’s unreasonable, but they are using a non-FDA approved dose. And I think the jury is still out, particularly with longer-term follow-up as well as with patients with hereditary mutation, if 20 milligrams will be as good.

John L. Berk, MD: Dr Hanna, do you feel any different?

Mazen Hanna, MD: I agree with everything Dr Witteles stated, and there will be analyses looking at 80 mg versus 20 mg, but nothing really that we can discuss at this time.