IONIS / Roche ASO Trial
The purpose of this study is to investigate the safety, tolerability and activity of the investigational drug IONIS-HTTRx in patients with early stage Huntington’s Disease.
Huntington’s Disease (HD) is caused by a mutation in the huntingtin gene. A portion of the gene is expanded and subsequently produces an expanded huntingtin protein. Mutant huntingtin interferes with cell processes and disrupts the overall function of the cell to cause the symptoms of the disease.
The new drug manufactured by IONIS pharmaceuticals, IONIS-HTTRx binds to huntingtin gene to block the production of the huntingtin protein. The drug is in a class of antisense drugs (ASO). The mode of action of IONIS-HTTRx is to bind to huntingtin RNA, telling the cell to destroy it. It is hoped that reducing the levels of the mutant protein in this way will slow or halt disease progression. Preclinical studies with IONIS-HTTRx in animal models have been promising and the purpose of this trial is to test the safety of the drug in humans.
The drug is delivered by injection into the lower back, known as an intrathecal injection (a form of ‘lumbar puncture’). Treatment by this method will mean that the antisense drug is delivered directly to the cells of the brain that are affected by the expression of the huntingtin protein.
In December 2017 it was announced that the first phase of the study had been successful in showing that the drug was safe and well tolerated in humans. The news also came that the drug had been successful in lowering mutant huntingtin in the cerebral spinal fluid.
In 2018 the open label extension study was started and is currently still ongoing. This has involved the 46 original patients who are now all being treated with IONIS-HTTRx to look at longer term safety and tolerability. The drug has now been taken over by Roche and renamed as RG6042, in September 2018 Roche announced the pivotal trial in Huntington’s disease that is due to start in 2019. This will involve a larger cohort of patients, 660 with manifest HD which means those who are formally diagnosed with clinical signs and symptoms of HD. Patients will be selected to fit the very strict inclusion/exclusion criteria determined by Roche and this trial will involve a placebo arm as well as a treatment group.
Roche are also introducing the HD Natural History study that does not involve drug treatment. This is a 16-month study that will study the natural disease progression alongside those receiving the treatment. Around 100 people will be recruited to this study which will involve regular lumbar punctures and assessments at strict timepoints.
If you would like more information about this study please contact Katie Andresen on 01223 331141 or firstname.lastname@example.org
This trial is funded by F.Hoffmann-La Roche Ltd.
EIP Pharma – Neflamapimod Study
We are currently conducting a double-blind, placebo-controlled, within-subject, crossover study of new drug called neflamapimod in patients with early-stage Huntington’s disease (HD). During this phase 2a proof of concept study, 16 HD patients will undergo two 10-week treatment periods (separated by a washout period of 8-12 weeks), during which they will receive either neflamapimod (40mg) or a placebo pill. Both they and us are blinded to what treatment they are on.
Neflamapimod is an oral small molecule, under development by EIP Pharma, which inhibits the intra-cellular enzyme p38 MAP kinase alpha (p38α), P38α is expressed in brain cells (neurons), in particular in the hippocampus, an area critical for certain types of learning and memory- especially navigation. This area of the brain we have shown to be affected in early HD (Begeti et al 2016; Harris et al 2019).
Previously it has been shown that prolonged activation of P38α can occur in other brain diseases and plays a major role in inflammation-induced synaptic toxicity. Preclinical studies have shown that neflamapimod can reverse this synaptic dysfunction and the associated deficits in spatial learning. Furthermore, a recent phase 2a clinical trial in patients with early-stage Alzheimer’s disease showed that the drug led to significant improvements in episodic memory.
Thus, the objective of this new trial is therefore to determine whether neflamapimod can improve hippocampal dysfunction in patients with early-stage HD, as assessed by two tasks which evaluate spatial learning, namely the Morris Water Maze task and the Paired Associates Learning (PAL) task.
This trial is funded by EIP Pharma.