Results from a Phase I/IIa study of IONIS-HTTRx (RG6042) in Huntington’s disease (HD) were presented in a plenary session at the 2018 annual meeting of the American Academy of Neurology (AAN). Results demonstrated correlations between reductions in mutant huntingtin (mHTT) – the disease-causing protein – and clinical improvements in HD.
The randomised, placebo-controlled dose escalation study included 46 people with early stage HD. Participants were treated for 13 weeks with monthly intrathecal injections of 10 mg, 30 mg, 60 mg, 90 mg or 120 mg of IONIS-HTTRx (RG6042) or placebo (3:1 active to placebo). The primary objective of the study was to evaluate the safety and tolerability of the drug. In addition, the effects of the drug on mHTT protein levels in the cerebrospinal fluid (CSF) were examined.
IONIS-HTTRx (RG6042) is designed to reduce the production of all forms of the huntingtin protein, including its mutated variant, which is the driver of HD. It is an antisense drug, consisting of nucleotides linked together in short, specific DNA or RNA sequences (oligonucleotides), which block transcription or translation of a targeted protein.
Results from the Phase I/IIa study showed that IONIS-HTTRx (RG6042) was well-tolerated, with only minor adverse events that were considered unrelated to the drug. In addition, up to 60% (mean 40%) dose-dependent reductions in mHTT levels were observed in the CSF of treated participants at the two highest doses of 90 mg (p<0.01) and 120 mg (p<0.01). Furthermore, mHTT levels decreased progressively during the study (last measurement at three months), and according to a mathematical model, the highest reductions in the protein levels were predicted to occur at approximately six months after the first dose.
Post-hoc analysis explored the degree of mHTT reduction, and correlated it with improved scores at three months on several clinical measures commonly used in HD clinical studies: Total Motor Score (TMS): rho=0.39 (p=0.007); Symbol Digit Modalities Test (SDMT): rho=-0.30 (p=0.044); Stroop Word Reading Test (SWRT): rho=0.08 (p=0.60); and Total Functional Capacity (TFC) score: rho=-0.27 (p=0.066). In addition, there was a significant correlation between the reduction in mHTT levels and the Composite Unified Huntington’s Disease Rating Scale (cUHDRS) score at day 85 (rho=-0.41, p=0.004).
Overall, the clinical results demonstrate that targeting the toxic mHTT protein with IONIS-HTTRx (RG6042) has the potential to be disease-modifying. Going forward, an open-label extension (OLE) study for patients who participated in the Phase I/IIa study is ongoing.
PR Newswire. New Data from IONIS-HTTRx Phase 1/2 Study Demonstrates Correlation Between Reduction of Disease-causing Protein and Improvement in Clinical Measures of Huntington’s Disease. Available at www.prnewswire.com; Dated Apr 24, 2018, 12:15 ET.