A number of new drugs for TTR amyloidosis are in various stages of development around the world, offering hope for the near future to patients with TTR amyloidosis. These include IONIS-TTRRx (described below), patisiran, ALN-TTRsc, CPHPC+anti-SAP antibodies, doxycycline and TUCA.
IONIS-TTRRx is a new, first in class drug developed by Ionis Pharmaceuticals with the aim of reducing the supply of TTR protein in patients with TTR amyloidosis. IONIS-TTRRx is currently in clinical trials in patients with FAP. Studies to evaluate IONIS-TTRRx in patients with FAC or SSA may initiate in the near future. It is not yet licensed and is only available at present to patients with FAP who are participating in these trials.
IONIS-TTRRx directly targets and reduces TTR production at the level of the genetic machinery inside the liver cells. When TTR production is decreased in this manner, the supply of TTR protein is reduced, which should reduce or prevent the formation of new TTR amyloid deposits in the tissues. Slowing or halting new deposits should slow or even stop further disease progression. Because IONIS-TTRRx reduces production of both variant and wild type TTR, this drug has the potential to be beneficial for patients with all three types of TTR amyloidosis (FAP, FAC, and SSA). A short-term clinical trial in healthy volunteers demonstrated that IONIS-TTRRx was well-tolerated and dramatically reduced TTR concentrations in the blood.
All three types of TTR amyloidosis are caused by deposition of misfolded TTR molecules within amyloid deposits in the tissues. In FAP and FAC these deposits consist of both misfolded ‘variant’ TTR and misfolded ‘wild type’ TTR. In SSA the deposits consist of wild type TTR only. The IONIS-TTRRx molecule is designed to bind tightly to TTR mRNA, whether or not there is a mutation in the TTR gene. Thus the drug prevents the translation step in protein production for both variant TTR and wild type TTR.
It is hoped that decreasing the amount of both variant and wild type TTR protein in the blood will reduce the formation of TTR amyloid deposits, slowing or halting disease progression in all types of TTR amyloidosis. After liver transplantation for FAP, wild type TTR from the new liver may continue to deposit as amyloid fibrils. IONIS-TTRRx has the potential to be more effective than liver transplantation in treating FAP, since it targets both the production of wild type TTR and variant TTR.
A Phase 1 trial tested IONIS-TTRRx in healthy volunteers. IONIS-TTRRxwas well-tolerated and caused rapid, durable reductions in the concentration of TTR protein in the blood. On average TTR concentration was reduced by 75%, and in some patients, TTR levels were below detectable limits. Five different doses were studied in this trial and on the basis of the results the 300 mg dose was identified as appropriate for the subsequent Phase 3 trial.
A randomized, controlled, double blind phase 3 multicenter trial of IONIS-TTRRx was initiated in December 2012. The purpose of the trial is to determine whether IONIS-TTRRx can slow or stop the nerve damage caused by TTR deposits in patients with familial amyloid polyneuropathy (FAP). This study aims to enroll about 200 patients with early to mid stage neuropathy. Patients will be randomized 2:1, meaning that 2/3 of the patients will receive IONIS-TTRRx and 1/3 will receive placebo for 65 weeks. The official study title is: A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of IONIS-TTRRx in Patients with Familial Amyloid Polyneuropathy.
Each patient taking part in the trial will be randomly assigned to one of 2 groups:
This is a double blind trial. This means that neither the doctors running the trial nor the patients participating will know which patients are receiving IONIS-TTRRx and which patients are receiving placebo. There is 2:1 randomization, meaning that 2/3 of the patients will receive IONIS-TTRRx and 1/3 will receive placebo. After the Phase 3 study is completed, all eligible patients can participate in the open label extension study, where all subjects will receive IONIS-TTRRx.
The main (primary) outcome measures will be change in baseline score in two standardized measures for assessing the severity of neuropathy:
In addition, the level of TTR in blood will also be measured throughout the study to determine if IONIS-TTRRx lowers levels of TTR as a secondary outcome measure.
Ionis has led the pharmaceutical industry in the development of a new drug class called antisense oligonucleotides. These drugs are the most advanced form of “RNA Therapeutics” and exert their effect by a type of therapy called ‘gene silencing’. They shut down protein production by the target gene, and thus silence its effects, rather than repairing a faulty gene or by treating the protein after it is made. Ionis Pharmaceuticals is the only company to have RNA Therapeutics-based drug approved for treating patients. Furthermore, Ionis currently has a wide variety of antisense oligonucleotide drugs at various stages of pre-clinical and clinical development for a broad range of diseases. These drugs aim to treat a diverse spectrum of different diseases, including conditions for which there are no traditional drugs available.