Set My Heart Free: Two AmyloSENS Therapies Targeting Cardiac Amyloid in Clinical Trials

TTR cardiac amyloid contributes to heart failure and appears to limit the lives of the longest-lived humans. One AmyloSENS antibody shows high promise to remove this amyloid and restore function in the aging heart in an early-stage clinical trial. A second such antibody is coming close behind it, and a tiny number of people’s immune systems appear to generate such antibodies on their own.

Short summary: TTR cardiac amyloid contributes to heart failure and appears to limit the lives of the longest-lived humans. One AmyloSENS antibody shows high promise to remove this amyloid and restore function in the aging heart in an early-stage clinical trial. A second such antibody is coming close behind it, and a tiny number of people’s immune systems appear to generate such antibodies on their own.

When it comes to “heart health,” there’s the good news and the bad news — and then some really good news.

The initial good news is that deaths from “heart disease” have fallen precipitously. From their smoking-driven peak in the 1950s until the early 2010s, we cut the rate at which people died from “heart disease” by more than 70%, and have kept them at the same overall low rate since then. Lower smoking rates, lower intake of saturated and trans-fatty acids, statins, and blood pressure medications take the lion’s share of the credit for this remarkable progress.

Deaths from cardiovascular disease (CVD) have been slashed, driven by declines in atherosclerotic cardiovascular disease (ASCVD) in the form of coronary heart disease (CHD) and stroke. Credit: Circ Res 120(2):366-380.

The bad news comes from “heart disease” being a bit of a grab-bag term. When people say “heart disease,” they most often mean atherosclerosis, which is not actually a disease of the heart, but of the blood vessels. It’s only a “heart disease” because atherosclerosis most often kills people by causing a heart attack — which we might rather say is the diseased blood vessel attacking the heart. When a plaque ruptures, the mess trapped under the cap of the lesion spews out, triggering a blood clot that hurtles down the tiny blood vessels that give the heart its blood supply. When the clot gets stuck in the vessel, it chokes off the critical supply of energy and oxygen to the working heart muscle, killing critical heart muscle cells — and, too often, the living human being in whose chest that heart once beat. (When the clot instead blocks off vessels in the brain, the resulting assault is the most common kind of stroke).

But as you can see from the gap between overall cardiovascular disease (CVD) deaths and deaths from atherosclerotic cardiovascular disease (ASCVD — coronary heart disease (CHD) and stroke), we’ve made a lot less progress against “heart diseases” other than ASCVD. The most impactful of these are true degenerative diseases of the heart itself — and that’s where the bad news comes in.

While medical science has prodigiously slashed death from atherosclerosis, very little progress has been made against other kinds of “heart disease.” Deaths from pulmonary heart diseaseheart valve disease, and notably disordered heartbeat (arrhythmia) have remained at the same stubborn levels for decades. Worse yet: after years of making at least incremental progress against heart failure and hypertensive heart disease, the number of people suffering from these degenerative heart conditions is now rising again.

After decades of progress, death from heart failure is rising again. Credit: Circ Res 120(2):366-380.

In the face of this rising threat, the really good news at the center of this post is that the biotech company Neurimmune and their pharma partner AstraZeneca have just run an early-stage trial of a new AmyloSENS therapy that directly removes a malformed protein from patients’ hearts. The study was small, but it found no signal for danger, and the data suggest that the antibody successfully pried its target loose from the patients’ heart tissue — and that their hearts beat more freely as a result.

A Hidden Driver of Heart Failure

Despite what the name suggests, “heart failure” doesn’t mean that the heart has stopped working altogether: that’s cardiac arrest. But it does mean that its ability to pump blood has reached a critically low level, which in most cases is because the heart has become too stiff to relax properly after the squeezing action of a heartbeat. Unable to fully open up, the heart chamber can’t take in a proper heartbeat’s worth of blood — and less blood coming in means less blood pumped out with each subsequent beat of the heart.

To compensate for the fact that the failing heart produces “less juice for the squeeze,” the heart speeds up, sending out a larger number of smaller-volume pumps per minute. Meanwhile, the rest of the body holds onto more fluid. People suffering from heart failure get short of breath when they exercise, with the limits of their endurance slowly closing tighter and tighter around them; their ankles swell with fluid, followed by their arms and legs, lungs, and other parts of the body; their hearts may beat too quickly or with episodes of dangerous erratic beats. Eventually, they die because their heart can’t handle the minimum threshold of function needed to send blood to the brain and other organs, or because a clot forms in the blood that pools in the failing heart’s chambers and triggers a stroke or a deadly clot in the lungs.

One well-studied reason why hearts stiffen up with age is when the heart muscle bulks up in a maladaptive response to the chronic effects of blood pressure. Controlling blood pressure is thus an important and well-understood way to delay some kinds of heart failure. But current medicine is impotent against another cause of heart failure: cardiac amyloid.

Cardiac amyloids are chains of malformed proteins that have twisted out of shape, bound together in chains, and worming its way into the gaps between the heart muscle cells. These deposits then physically impede the heart muscle as it attempts to expand and contract to keep the precious blood of life flowing to our tissues.

Nearly all of the decline in deaths from all forms of cardiovascular disease combined has come from ASCVD (ischemic heart disease). Note the gap in the graph between 25 and 45% of overall deaths. Credit: BMJ 370:m2688.
Left: Autopsy tissue of the heart of a patient with cardiac amyloid, showing two pumping chambers badly distorted by amyloid. Center: Red stain reveals the infiltrating amyloid in the heart muscle. Right: TTR in the heart tissue revealed by staining with an antibody that binds to it. Credit: J Am Coll Cardiol 74 (21) 2638–2651.

The most common kind of amyloid afflicting the aging heart is composed of malformed transthyretin (TTR), which is a protein involved in transporting thyroid hormones and vitamin A. Mutations in the TTR gene cause a tiny fraction of all the cases of life-threatening cardiac amyloid heart disease. But even the standard-issue TTR protein is inherently unstable and occasionally contorts out of its proper conformation, with the result that TTR cardiac amyloid accumulates in all of us progressively with age. The vast majority of cardiac amyloid disease is caused by the accumulation of this molecular aging damage, which impairs the function of our hearts, even in people who are technically below the threshold at which it is diagnosed as a “disease.”

Symptomatic cases of cardiac amyloid are typically first picked up in people’s hearts in their 60s and 70s, but medical researchers using older diagnostic techniques have detected people as young as 47 who have TTR amyloid-related heart problems — and new imaging technology is now enabling doctors to catch the pathology earlier. About a quarter of people over the age of 80 have enough cardiac amyloid to qualify as “disease,” and it appears to be the most important contributor to the deaths of supercentenarians — the currently-privileged few of us who survive past the age of 110.

In addition to stiffening up the heart muscle, TTR amyloid often interferes with the nerves that control the heart’s beating, causing it to spasm at the wrong time. It’s badly underdiagnosed, in part because it’s historically required a dangerous biopsy to confirm the diagnosis, so many people with damaged hearts due to cardiac TTR amyloid have been misdiagnosed with hypertensive heart disease, heart failure with preserved ejection fraction, or hypertrophic cardiomyopathy (heart stiffening due to mutations that thicken the heart). TTR amyloid can also stiffen the valves that regulate the flow of blood out of the heart and into the artery carrying blood to the rest of the body (“aortic stenosis”), and it’s only very recently that scientists have discovered that cardiac amyloid is in part to blame for about one in six cases of aortic stenosis so severe as to require surgical replacement of the aortic valve.

And that’s what makes three recent human studies decidedly good news.

Head of the Pack: NI006

Scientists recently reported the results of an early-stage clinical trial of NI006, an antibody designed to latch on to TTR amyloid and pry it loose from the heart. This is a critical difference between NI006 and other TTR amyloid treatments that are either in use or currently in development. Previous therapies have been designed to merely slow down the rate at which new cardiac amyloid accumulates, either by partially stabilizing the rattletrap TTR protein or by throttling down the body’s ability to produce the protein in the first place. By contrast, NI006 is a true “damage-repair” therapy: if it works, it could prevent and even reverse cardiac amyloid by directly removing existing deposits of mangled TTR from the heart.

In the NI006-101 trial, doctors enrolled patients whose hearts had been insinuated with enough TTR amyloid to impair their heart function. This trial was the first time researchers had ever tested NI006 in humans, so the purpose was mostly just to confirm that the antibody didn’t have any immediate, showstopping safety problems and to get a feel for how much they would have to administer to get an effect. As a result, the researchers only needed 40 volunteers for the trial.

Importantly, 33 out of the 40 patients had wild-type TTR amyloid entrenched in their cardiac muscles: in other words, the kind that develops due to aging processes in people with normal TTR proteins. The results of this trial therefore have implications for every aging person.

For the first four months of the trial, 27 of the volunteers were randomly assigned to receive monthly infusions of NI006, while the remaining 13 people received a saline placebo. Among the patients who got real antibodies, each person started with the lowest dose, but was randomly assigned to escalate up to one of six progressively higher doses ranging from the original 0.3 milligrams of antibody per kilogram of body weight all the way up to 60 mg per kg. Then at the four-month mark, the blinds were taken off, and all the volunteers were eligible to receive NI006 for a further eight months.

In larger trials, scientists ensure that the people who get the experimental therapy begin the trial with a similar disease state and risk factors to those who get the placebo. But that balance was hard to achieve with only 40 people enrolled in the NI006-101 trial, and in the event, the cards were unintentionally stacked against the therapy. The people who were randomly assigned to receive NI006 had more amyloid in their hearts as measured on an imaging test; they had higher levels of blood markers of heart muscle cell injury; and they couldn’t walk as far in six minutes as the people in the placebo group could. 

We can’t fully hang our hats on the results of a study with so few patients — but all the results they did see were encouraging. In just the initial four months of treatment, imaging scans of volunteers who got real NI006 showed that much of the amyloid that had invaded their heart muscles had been cleared out — and the amyloid continued to disappear as they continued to receive NI006 during the eight months of all-comers treatment.

By contrast, the control group suffered the expected further accumulation of amyloid as they were “treated” with salt water for the first four months. But once they got access to the real thing, their cardiac amyloid, too, began to retreat. And across the mix of placebo infusions and differently-dosed antibody treatments that different volunteers received, there appeared to be a “dose-response” effect: the more NI006 a person got, the more amyloid was cleared out of their heart.

NI006 treatment lowers cardiac amyloid, as measured either of two ways — and the more antibody a person cumulatively received, the more cardiac amyloid melted away. Credit: N Engl J Med 389(3):239-250.
Imaging of cardiac amyloid in volunteers’ hearts during treatment with NI006 or placebo. Note that both of these volunteers had “wild-type” (non-mutant, age-related) cardiac amyloidosis. Credit: N Engl J Med 389(3):239-250.

The investigators also measured blood biomarkers of heart muscle damage in the volunteers — and while the results had a lot of noise, the data are consistent with a therapeutic effect of removing amyloid. Nothing much changed for the first four months of treatment with either NI006 or the placebo. But after an additional eight months of treatment, both markers of cardiac injury began to trend downward — and promisingly, the improvements were greatest in people who had received higher doses of NI006 from the outset. (Look at the Figure below, and compare the number of people who took NI006 from the beginning (represented by the red dots) that either hug the overall trend line or are even below it, versus how many who were originally on placebo who had to wait until the extension phase to get NI006 (the yellow dots) and are above the trend line, with many having enjoyed no reduction in damage markers at all).

This may mean that it takes a while for the heart muscle to recover after amyloid is removed, or that the muscle is only able to recover once some minimum amount of amyloid has been removed. Either way, it’s a great sign that removing TTR amyloid has a real, functional benefit to the health of the aging heart.

Treatment with NI006 during the long extension period appeared to reduce both markers of heart muscle injury. Credit: N Engl J Med 389(3):239-250.

Over the course of the trial, some of the volunteers progressed to outright heart failure or developed heart rhythm problems. Unfortunately, these are exactly the expected outcomes in people with this level of cardiac amyloidosis, and similar proportions of people in the placebo and treatment groups suffered them. Again, it was only toward the end of the trial that people’s hearts seemed to begin to recover from the injury inflicted by having lived with amyloid in their hearts for so long, and the benefit was most apparent in people who had received the highest dose of NI006 from the very beginning, suggesting that it would take longer for amyloid removal to begin saving lives in such advanced patients.

A few side effects could reasonably be attributed to NI006, but none were deal-breakers. Three people developed an inflammatory reaction during the initial four months, but all three chose to stay on for the entire trial. Two had rapid reductions in platelet count shortly after an infusion, but no bleeding problems resulted, and their levels returned to normal in a couple of weeks. The most common side-effect that looked specific to NI006 was muscle pain: nearly all of these cases resolved with a shot of steroids, though two people found them intolerable or worrisome and dropped out of the trial. Fortunately, no subject developed an immune reaction against NI006, as sometimes happens with antibody therapies.

Because this was such a small study, we will have to wait for larger trials before we can be fully confident in the results. But even before its results were published, a second AmyloSENS therapy targeting TTR amyloid passed its own early-stage trial and was snapped up by a large pharma company to take into advanced testing.

Hot on the Heels: NNC6019

By definition, Phase I trials are preliminary — but the Phase I trial for NNC6019 was even more tentative than that for NI006. This author guesses that the reason for this was budgetary constraints. By the time they began human testing of NI006, Neurimmune had already partnered with pharma goliath AstraZeneca to develop it. By contrast, NNC6019 (then known as PRX004) entered clinical testing backed only by its original developer, the much smaller biotech firm Prothena. Prothena’s shallower pockets have limited the funding — and therefore the ambition — for the trial. Still, all the results look promising, and it’s moving ahead.

Prothena developed NNC6019 by immunizing mice with a short stretch of TTR protein that is normally shielded from the immune system through its appropriate folding, but which can be exposed when TTR has twisted out of its normal conformation. They then harvested the antibodies the mice produced in response to the normally-shielded fragment and screened them for properties that would make an antibody useful as an AmyloSENS therapy for TTR amyloidosis. Four of the isolated antibodies selectively bound to TTR that had dropped out of its normal cloverleaf structure and could prevent single TTR units from sticking together to form fibrils of amyloid. They also could “feed” the abnormal TTR proteins or aggregates to macrophages for elimination. And most importantly, the prototypes of NNC6019 excised TTR amyloid from heart tissue donated from patients with either genetic or aging-driven TTR cardiac amyloid while leaving normal heart, liver, pancreas, and brain tissue alone.

A: NNC6019 targets a segment of the TTR protein that is shielded when the protein is properly assembled (left) but exposed in disassembled TTR or TTR amyloid (right). B: The mouse prototype of NNC6019 delivers mutant but not normal TTR proteins into the autophagy system in human macrophages. C: Prototype NNC6019 delivers TTR amyloid (seen in red) to phagocytes (macrophages), which engulf it for degradation. Credits: Amyloid 23(2):86-97; Prothena investor conference call, December 9, 2020.

For its Phase I trial, Prothena recruited 21 people with mutations in their TTR genes. Although about two-thirds of the volunteers had TTR cardiac amyloid, this preliminary trial focused on a different problem that often afflicts mutation carriers: peripheral neuropathy. In addition to the heart, TTR amyloid is prone to stick to the inner surfaces of the channels surrounding a person’s nerves, which narrows the gap between the channel and the nerve. This leads to nerve dysfunction as the narrowing channel impinges on the nerves. In peripheral neuropathy, which is the most common such problem, the affected nerves run down the arms and legs, and their dysfunction manifests as numbness and muscle weakness in a person’s hands and feet.*

There was no placebo control group in this trial: everyone got an infusion of NNC6019 once a month, and the dose each person received ramped up with each session until they reached one of six final doses. After this initial period, seventeen subjects stuck with it for an additional nine-month extension study, though disruptions caused by the COVID-19 pandemic meant that only seven of them were able to receive every single dose available to them from the beginning of the trial to the end of the extension period.

With only seven subjects to fully evaluate and no placebo control group, we have to be careful not to cling too tightly to the results — but those results were quite positive. The seven subjects who had received all doses of NNC6019 suffered barely any worsening on the score of their neuropathy: an increase of 1.29 points, versus a typical 9.2-point exacerbation over a comparable time. And neuropathy didn’t progress at all in the two subjects who were receiving only NNC6019 and not tafamidis (see below) or any other anti-amyloid therapy. And three subjects enjoyed an improvement in their neuropathy scores by a mean of 3.3 points. Moreover, heart function improved over the course of the trial in all seven of the fully-treated subjects; again, the effect was particularly noticeable in the subjects who were not receiving any other therapy.*

NNC6019 appears to have greatly slowed the trajectory of nerve dysfunction and improved heart function in the evaluable subgroup of volunteers. NIS = Neuropathy Impairment Scale; GLS = Global Longitudinal Strain, an early indicator of stiffening of the heart’s main pumping chamber. Credit: Prothena investor conference call, December 9, 2020.

There were few side effects, and fewer still that the clinicians thought could be attributed to the antibodies — and no serious toxic reactions or life-threatening events at all. And as with NI006, NNC6019 did not trigger any subject in this trial to form antibodies against the antibody, and it did not affect the volunteers’ levels of normal, non-aggregated TTR.

Following their Phase I success, Prothena signed an agreement with Novo Nordisk to develop the antibody, and got its first milestone payment of $40 million at the end of last year. The two companies are now recruiting volunteers for a Phase II clinical trial that will pit NNC6019 against TTR cardiac amyloid. Ninety-nine people with existing heart dysfunction caused by TTR amyloid will be randomly assigned to receive either a lower dose of NNC6019, a higher dose, or a placebo in infusion once a month for a year. The researchers will test to see if NNC6019 improves the distance that volunteers can walk in six minutes, as well as their blood markers of heart muscle damage. They will secondarily investigate whether it lowers amyloid burden in the heart and improves the objective function and subjective symptoms of their hearts and nerves, and monitor side effects. If the results are positive, Prothena will receive another milestone payment and Novo Nordisk would presumably take NNC6019 forward into a definitive Phase III trial.

Brew Your Own

By an encouraging coincidence, a tantalizing report of three exceptional patients came out shortly before the NI006 Phase I trial was published that supports the effectiveness of antibodies to remove cardiac amyloid and restore heart function. 

Instead of using biotechnologically-produced antibodies targeting TTR amyloid, this study reported three unprecedented cases of people who had developed TTR-driven cardiac amyloid only to later experience its spontaneous regression. 

The three patients were British men being treated at the University College London (UCL) Centre for Amyloidosis, which provides all the specialized treatment for amyloid diseases in the UK besides Alzheimer’s. After the first patient reported that his heart function symptoms had improved, they scanned his heart — and to their surprise, found that his cardiac amyloid had almost completely disappeared and his heart tissue had begun to return to normal, with no evidence of scarring in the tissue.

UCL scientists then scoured the records of all their patients with confirmed TTR amyloidosis and associated heart function, looking for similar cases amongst those who had undergone an initial detailed assessment followed by at least one annual followup appointment. These thorough examinations include at least two imaging studies, an exercise stress test, a six-minute walking endurance test, blood tests for markers of heart damage, and a standard assessment for heart failure. Such detailed evaluations would allow the researchers to pick up on any additional cases of reversals like their first patient.

Out of 1,663 patients that had undergone a baseline assessment and at least one annual followup, the investigators found two more cases. Both of them reported that their symptoms had improved, and different imaging methods confirmed that all three had indeed enjoyed a near-complete retreat of their cardiac amyloid. One of them had also enjoyed a substantial improvement in exercise capacity.

Imaging on the first patient shows the disappearance of cardiac amyloid. Credit: New Engl J Med 388(23):2199-2201.

What could have caused this unheard-of elimination of cardiac amyloid? A striking clue came from a biopsy of one of the three men’s heart muscle. What was left of the amyloid was riddled with macrophages (a kind of immune cell specialized in internalizing foreign matter from damaged tissues) and showed evidence of an atypical inflammatory response. By contrast, not one of the other 286 patients in their patient population who had undergone heart muscle biopsies showed these signs. That suggested to the researchers that something was recruiting the macrophages to infiltrate the amyloid deposits and gobble them up.

It occurred to the scientists that this unheard-of immunological clearance might be orchestrated by antibodies that the patients had somehow mounted against their cardiac amyloid deposits. To find out, the investigators took blood samples from all three of their spontaneous clearance patients to see if they had antibodies that target cardiac amyloid. Sure enough, all three patients’ blood contained high levels of antibodies that bound specifically to TTR amyloid in human and mouse tissue samples. The same antibodies also captured “synthetic” amyloid prepared from pure TTR protein in their lab. No such antibodies existed in the 350 blood samples the clinic had retained from patients at their clinic who had followed the usual trajectory of ever-worsening amyloid disease.

The study authors end their letter in the New England Journal of Medicine with the somewhat coy statement that “the clinical recovery of these patients establishes the unanticipated potential for reversibility of [TTR cardiac amyloid] and raises expectations for its treatment” — emphasis added. The letter’s lead author was more explicit in a UCL press release: “our data indicates that this is highly likely” that “these antibodies caused the patients’ recovery” “and there is potential for such antibodies to be recreated in a lab and used as a therapyWe are currently investigating this further, although this research remains at a preliminary stage.”

Better Therapy for Everybody

A little more than five years ago, there was no therapy available to target TTR amyloid itself. Back then, doctors would do their best to keep their patients with TTR amyloid alive and functional for as long as they could, using multiple drugs to manipulate fluid retention, blood pressure, and heart rate. But the patients’ hearts became progressively more dysfunctional every day as TTR inexorably tightened its grip on their hearts.

Today, people suffering from TTR amyloid can get a drug called tafamidis (brand name Vyndamax®) that binds to TTR proteins and makes them less prone to fall out of their proper cloverleaf conformation, thus slowing the rate at which new cardiac amyloid accumulates. Tafamidis thereby both lowers the risk that people with TTR cardiac amyloid will be hospitalized for cardiovascular problems and delays the threat of death. But even with tafamidis, the molecular attack on TTR cardiac amyloid disease patients’ hearts keeps worsening, leading to daily struggle and, ultimately, shorter lives.

Moreover, because cardiac amyloid continues to accumulate, tafamidis only really works if you catch the disease at or before the early stages of heart failure. In people in a more advanced state of heart dysfunction, tafamidis doesn’t reduce the death rate — and actually increases the risk of hospitalization.

There’s a similar story for a competing drug that works through a different mechanism. Patisiran/Onpattro® doesn’t stabilize existing TTR molecules: it turns off their production entirely by “silencing” the working copy of the gene that codes for it. No TTR produced means no TTR can aggregate and infiltrate the heart. This does work as expected, and it was approved first for patients with nerve problems related to mutated forms of TTR and more recently for cardiac amyloidosis. However, it’s only been approved for people with disease caused by TTR mutations: it’s one thing to turn off the production of a mutant protein that rapidly leads to nerve pain and an early death, and quite another to shut down the production of an otherwise-healthy protein that has essential functions in the body and whose slow aggregation takes much longer to cause harm. And even after pulling the plug on that rapidly-aggregating protein, it isn’t entirely clear that Onpattro lowers the risk of hospitalization or early death in these patients.

Pharma companies are currently running trials with several additional experimental therapies for people with TTR mutations, but these are mostly in the same vein as tafamidis or Onpattro: drugs that  either stabilize mutant TTR through a different mechanism or that turn off the production of TTR entirely. None of these approaches offer any hope of rooting out the molecular corruption already pervasive in the diseased heart tissue. With therapies like these, the only hope for patients to “recover” healthy heart function is to remove their amyloid-shackled hearts entirely and start more or less afresh with a too-scarce transplanted organ.

If they make it through clinical trials, NI006, NNC6019, or engineered versions of the antibodies in the blood of UCL’s rare patients offer something radically different: the ability to remove the damaged proteins already present in the oppressed heart. We will have to wait for further trials to know for sure, but so far, these candidate AmyloSENS approaches seem to do just that, and in the process to reduce injury to the heart muscles, opening up the aging heart to beat free again.

* TTR amyloid similarly pathologically coats the channels for other nerves in the body, leaving mutation carriers especially prone to carpal tunnel syndrome and spinal stenosis (which constricts the spinal cord, causing numbness or weakening in the legs and feet, and in severe cases loss of bladder or bowel control or sexual dysfunction). Scientists have only started to ask whether TTR amyloid causes neuropathies in people with normal TTR protein

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