Trial Data Provide Proof-of-concept for CRX-1008 as Leptomeningeal FAP Treatment

CRX-1008, an investigational therapy also known as SOM0226 or tolcapone, is safe and well-tolerated by patients as a treatment for familial amyloid polyneuropathy (FAP), and can stabilize the TTR protein in the brain, new clinical trial data show.

The findings provide a proof-of-concept for CRX-1008 as a treatment for FAP, including for the leptomeningeal form of the disease, which mainly affects the central nervous system.

Results were presented at the XVII International Symposium on Amyloidosis, by John Berk, MD, the trial’s principal investigator and assistant director of the Amyloidosis Center at Boston University School of Medicine. The symposium was held as an online event Sept. 14-18.

FAP, also known as hereditary transthyretin amyloidosis (hATTR), is a rare disease caused by mutations in the TTR gene, which provides the instructions to make the transthyretin (TTR) protein. Normally, this protein — which transports thyroid hormones in the plasma and cerebrospinal fluid surrounding the brain and spinal cord — is present in the body in a stable tetramer, which is a group of four protein units. However, mutant TTR clumps together to form fibrils, which build up in the body and cause toxicity.

Originally developed as a treatment for Parkinson’s disease, CRX-1008 was approved under the brand name Tasmar in the 1990s. But the medication also appears to be a stabilizer of TTR, meaning it can bind to TTR and help the protein stay in its normal tetramer form, rather than forming abnormal clumps.

Of note, CRX-1008 is able to cross the blood-brain barrier or BBB. As its name suggests, the BBB regulates what substances from the blood can get into the brain. This barrier has evolved to protect the brain from toxins, but it also can pose a barrier for treatments, since many medications cannot get through it. Since it can cross the BBB, CRX-1008 has the potential to address variants of FAP that affect the central nervous system, comprised of the brain and spinal cord.

The oral therapy is being developed by SOM Biotech and Corino Therapeutics.

The new findings come from a Phase 1 clinical trial (NCT03591757) that enrolled 10 people with hereditary leptomeningeal transthyretin amyloidosis (hATTR-leptomeningeal), a form of FAP characterized by TTR fibrils forming in the central nervous system. The trial was sponsored by Boston University (BU), in collaboration with Corino.

All of the participants were given CRX-1008, taken by mouth, for 28 days. For the first 14 days, participants were given 300 mg/day (100 mg taken three times per day); for the second half of the trial, the dose was doubled (200 mg taken three times per day).

The trial’s main goal was to assess how the treatment changed TTR stability, both in the blood and in the cerebrospinal fluid.

On average, CRX-1008 treatment increased the concentration of TTR tetramers (specifically, stabilized TTR) in the blood by 55%. In the CSF, CRX-1008 treatment decreased the concentration of monomeric TTR (specifically, unstable TTR) by an average of 48%.

The treatment was generally well-tolerated; no adverse events or safety concerns related to the investigational medication were reported.

“These new clinical research findings suggest that CRX-1008 may be the first hope for patients with hATTR-leptomeningeal, treating both peripheral and central manifestations of hATTR,” Berk said in a press release.

No available therapies exist for hATTR patients with amyloid-related impairments of the central nervous system, the company noted.

“We are looking forward to conducting additional clinical trials designed to confirm the potential benefits of CRX-1008 in patients with both peripheral and central manifestations of hATTR, generating data needed for regulatory approval,” added Michael Roberts, PhD, CEO of Corino.