Progress Towards Therapies for Transthyretin Amyloidosis

Transthyretin is one of the few proteins in the body that can misfold in a way that encourages other copies of the protein to also misfold, forming solid aggregates called amyloid that disrupt tissue structure and function. The resulting condition, transthyretin amyloidosis, clogs up cardiac tissue and thereby contributes to a fraction of all heart failure cases. It is thought to be a major cause of mortality in supercentenarians. Approved therapies targeting a more aggressive form of the condition resulting from a mutated transthyretin gene will not be useful against the much more common version of the condition, as they target the mutated form of the protein. New therapies in development might prove to be useful, however. Everyone accumulates at least some degree of this amyloid in old age, so it is a part of the field worth keeping an eye on.

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 disease, heart 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. 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.

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. The most common kind of amyloid afflicting the aging heart is composed of malformed transthyretin (TTR). 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."

Scientists recently reported the results of a phase 1 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. 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 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. NNC6019 was developed 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. 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 of this trial - 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 no other anti-amyloid therapy.



impressive. I had no idea that SENS had a project that had Astrazeneca as a partner. Wow!

Posted by: matt at August 18th, 2023 8:58 AM

You'd probably make more money fixing "liver spots" using similar techniques.
It would certainly be a proof of concept.

Posted by: Rob at August 19th, 2023 6:20 PM
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