Drug to Treat Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis (hATTR) is an inherited disorder that results in the gradual progressive deposit of abnormal protein called amyloid in the body's organs and tissues. Currently the only treatment for hATRR is liver transplant. Replacing the liver stops the production of abnormal transthyretin (TTR) proteins. Diflunisal is tired in some patients, but use is based on a single 130 patient trial. 
 
Three drugs in development, tafamidis, inotersen and patisiran, represent potential breakthroughs in the treatment of hATTR. Because no treatment outside of liver transplant exists, these three drugs may become preferred treatment choices. Patisiran shows some evidence of disease reversal, but all three drugs appear to have their greatest effect when started early. 
 
Tafamidis is a once daily oral drug, while inotersen is given as a weekly subcutaneous injection and patisiran is an intravenous infusion given every three weeks. All three drugs are investigational in the U.S., but tafamidis has been available in Europe since 2011. The FDA asked for additional clinical trials before the drug could be approved.
 
The CEO of Alnylam said that patisiran will have a six-figure price. Some analysts have projected a cost in the range of $200,000 to $400,000. Cost estimates for inotersen or tafamadis are not available. Analysts estimate that tafamidis may have a cost advantage over inotersen and patisiran.
 
In early May 2018, the FDA delayed review of inotersen to allow more time to evaluate the drug’s application. The drug will now be reviewed in the fall. The PDUFA date for patisiran is August 11. The NDA for tafamidis has not been filed. None of the pivotal trials for inotersen or patisiran have been published, so our first indication of the strength of the data may be when the FDA releases a review of the drugs.
 
The clinical effects of inotersen and patisiran are based on the elimination of all TTR production long-term toxicities. TTR transports thyroxine and retinol, so it will be important to monitor the results of long term trials to determine if a lack of TTR creates adverse events. 
 
These drugs act on TTR and not on correcting the mutation that causes the abnormal TTR to be produced.  Because the alternate is liver transplantation, the drugs will likely be the preferred treatment until a genome edit is created to correct the abnormal protein mutation.