Clinical Trials Updates

Novartis VIBRANT-HD Trial of Branaplam:

Branaplam is an oral therapy that Novartis is repurposing to modify HTT mRNA throughout the brain and the body, resulting in lower levels of HTT protein. In April, 2022, Novartis temporarily suspended dosing, based on a recommendation from the Independent Data Monitoring Committee, due to findings suggestive of potential peripheral neuropathy in some participants. Data is being collected on participants, which will inform potential next steps for the trial.

PTC Therapeutics PIVOT-HD Trial of PTC518
Similar in some respects to branaplam, PTC518 is an oral, small molecule-splicing modifier that was specifically designed to lower huntingtin mRNA and protein. PTC-518 is hoping to begin a Phase 2 study, having completed an initial 12-week placebo-controlled phase focused on PTC518 pharmacology and pharmacodynamics. The Phase 2 study is a placebo-controlled phase focused on determining PTC518 effect on mHTT, but the duration of this trial has not been disclosed. Given the potential toxicity issues with branaplam, we are waiting to see if PTC-518 and similar medications have a clear path forward.

uniQure AMT-130 Trial
AMT-130 is a HTT lowering drug, packaged in AAV (adeno-associated virus), and delivered into the striatum. The high-dose arm of the Phase 3 trial has been suspended pending investigation into three patients (out of 14) who had adverse reactions that required hospitalization. These patients presented with an encephalitis-like phenotype that resolved over time.

Earlier safety trials with patients receiving the lower dose did not experience these safety concerns. It is currently unclear if these side effects are from the drug, or the procedure itself, but the low-dose arm is proceeding as planned. uniQure still expects to complete the five-year trial and will issue further updates in early 2023.

WAVE PRECISION-HD Trial of Wave ASO
The Wave anti-sense oligonucleotide (ASO) is engineered to selectively lower mutant HTT by targeting certain single nucleotide polymophisms (SNPs). This strategy could potentially leave healthy huntingtin intact. Previous iterations of an ASO did not lower mHTT protein. However, Wave is developing a third ASO with a novel chemical structure that is currently undergoing evaluations in sites in Europe.

In September, 2022, Wave announced an update on the SELECT-HD study. They disclosed that CSF mutant huntingtin (mHTT) protein in cerebrospinal fluid was reduced after study participants received a single dose of either 30 or 60 mg WVE-003 in the SELECT-HD study. In contrast, unlike mHTT, wtHTT was not reduced over the same 85 days as compared to baseline, a result consistent with allele-selectivity.

They found a mean mHTT reduction from baseline of 22% (median reduction 30%) at day 85 after participants received just a single dose of WVE-003. Eighteen participants have been dosed in the SELECT-HD trial (30 mg, n=4; 60 mg, n=4; 90 mg, n=4; placebo, n=6). Participants enrolled at 30 mg, 60 mg and placebo had adequate follow-up to day 85 for biomarker analysis. Single doses of WVE-003 up to 90 mg appeared generally safe and well-tolerated.

Prilenia’s PROOF-HD Trial of Pridopidine
Prilenia Therapeutics continues the study of pridopidine, a selective sigma 1 receptor, in HD patients where the primary outcome measure is total functional capacity. HSG fully recruited ahead of schedule and the study has entered the open label extension portion of the study. Top line results for the study are anticipated by the end of the second quarter of 2023.

Neurocrine Biosciences KINECT-HD Trial of Valbenazine (Ingrezza®)
The KINECT-HD trial demonstrated valbenazine is efficacious in reducing chorea in Huntington’s disease. This trial also incorporated wearable movement sensors which were used as a secondary endpoint to detect changes in chorea. Given the positive results, it is expected that Neurocrine will file for a label change to approve the use of valbenazine for chorea in HD.

Roche Revives Tominersen
Tominersen is an ASO drug, delivered intrathecally. Designed by Ionis and developed by Roche, it targets the HTT messenger RNA to lower all forms of huntingtin protein. In a Phase 1/2a trial, the drug was found to reduce concentrations of mutant huntingtin. There were mild and moderate adverse events for 98% of patients, but many were consistent with lumbar puncture side effects. There were no severe or dose-limiting adverse events.

The large Phase 3 study was halted due to safety concerns which included increase ventricular size and worsening clinical outcomes in the treated group.

Roche determined to modify the dose of ASO (lower dose) and select a population that have milder symptoms to reassess the efficacy of this compound. Based on a retrospective review of the GENERATION HD1 data, the team at Roche hypothesize that tominersen might benefit younger patients with less advanced symptoms. The new 16-month study, GENERATION HD2, will test this hypothesis.