Experimental treatments for FAP

Last updated April 2, 2024, by Marisa Wexler, MS
Fact-checked by Marta Figueiredo, PhD

 

Several experimental treatment approaches are being developed for familial amyloid polyneuropathy (FAP), also known as hereditary transthyretin amyloidosis with polyneuropathy — some of which target the underlying cause of the inherited disease.

The progressive disorder is caused by mutations in the TTR gene, which provides instructions to make a protein called transthyretin or TTR. As a result of such mutations, an abnormal form of the protein is produced.

This protein is prone to forming toxic clumps, called amyloid fibrils, that accumulate and damage primarily nerves, ultimately leading to disease symptoms.

Though several approved therapies can help to ease symptoms and slow the progression of FAP, there isn’t yet a cure for the disease. A number of experimental treatments are being developed to improve outcomes in these patients, with the most advanced approaches focused on stabilizing the TTR protein or altering TTR’s genetic code.

TTR stabilizers

The transthyretin protein is normally stable in a tetramer, or a complex of four proteins bound together. In FAP, however, the tetramer configuration isn’t stable, instead breaking down and freeing the individual transthyretin proteins that are prone to misfolding and forming toxic clumps.

Several experimental FAP therapies aim to stabilize the transthyretin tetramer, thereby helping to prevent the formation of toxic protein clumps, and slowing or halting disease progression.

Vyndaqel (tafamidis meglumine) for FAP

Vyndaqel (tafamidis meglumine) is an oral transthyretin stabilizer developed by Pfizer that’s approved in the European Union and several other countries for adults with FAP.

In the U.S., however, an application requesting Vyndaqel’s approval was rejected in 2012, with the U.S. Food and Drug Administration (FDA) noting that additional trials would be needed to confirm the therapy’s efficacy.

Since then, the FDA has cleared Vyndaqel and its new formulation Vyndamax (tafamadis free acid) to treat transthyretin amyloid cardiomyopathy (ATTR-CM), a FAP-related disorder marked by heart damage. Those approvals came in 2019; Pfizer said at the time that it would continue to work on a potential approval for FAP in the U.S.

In a Phase 2/3 clinical trial (NCT00409175) and its extension, the therapy showed the ability to slow FAP progression, reducing the accumulation of disability related to nerve damage (neuropathy) compared with a placebo, and stabilizing neuropathy’s impact on life quality.

Long-term data from a subsequent extension Phase 3 trial (NCT00925002) supported Vyndaqel’s ability to slow neuropathy progression and indicated that starting treatment early was associated with better neurological outcomes.

Diflunisal

Diflunisal is an oral anti-inflammatory drug that’s been approved for decades to treat pain and some forms of arthritis. It’s sometimes used off-label, or for an indication for which it was not specifically approved, to slow disease progression in FAP patients.

The medication was originally developed by Merck under the brand name Dolobid; however, only generic versions are currently available in the U.S.

Lab studies have shown diflunisal can stabilize the transthyretin tetramer, with the results of a Phase 2/3 trial (NCT00294671) in FAP patients indicating it slowed the progression of nerve damage compared with a placebo.

CRX1008 (tolcapone)

CRX1008 is an oral therapy in development by Corino Therapeutics that contains tolcapone as its active ingredient. Tolcapone is a molecule that’s approved under the brand name Tasmar as an add-on treatment for Parkinson’s disease.

The molecule was found to stabilize the transthyretin protein in preclinical studies, which prompted a proof-of-concept Phase 2a trial (NCT02191826) to evaluate whether the drug could be repurposed for the treatment of FAP.

The results showed that CRX1008 led to transthyretin stabilization at levels expected to be clinically meaningful in most study participants. But multiple daily doses may be needed to sustain TTR stabilization throughout the day, the studies found.

Gene-editing therapy

A more recently developed technology called gene editing can be used to alter the genetic code of living cells. Gene-editing therapy targeting the TTR gene is being investigated for FAP.

NTLA-2001

NTLA-2001 is a gene-editing therapy that’s being co-developed by Intellia Therapeutics and Regeneron Pharmaceuticals for the treatment of FAP and ATTR-CM.

The therapy uses a gene-editing technology known as CRISPR-Cas9, and is designed to disrupt the TTR gene in the liver, where most transthyretin protein is made. This is expected to reduce transthyretin production, ultimately preventing the formation and accumulation of the toxic protein clumps that drive disease progression.

Early data from a Phase 1 trial (NCT04601051) involving both FAP and ATTR-CM patients showed that NTLA-2001, given as a one-time intravenous or into-the-vein infusion, was safe and resulted in rapid and sustained reductions in transthyretin levels.

Intellia now is running a pivotal Phase 3 study to test the therapy in adults with ATTR-CM, and also has plans to launch a similar Phase 3 trial in FAP. Such pivotal trials are expected to support regulatory applications seeking the therapy’s potential approval for these indications.

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