The press release from Roche and IONIS announcing a correlation between lowering mutant huntingtin protein and improvement in clinical measures of Huntington disease (HD) was exciting news. And it was also important for the HD community when it was featured at the American Academy of Neurology (AAN) last week.  The community felt the thrill.  However after the brief ride up the roller coaster, the reality is that we probably can't draw any useful conclusions about this report of clinical benefit.  Hard to know if it represents a "hint" or a "hype" of benefit.  Either way we need to wait for Phase 3 trial results.

What was the old (and very positive) news in the report to AAN meeting.

  • The IONIS-HTT Rx drug reduced the levels of mutant huntintin protein or mHTT (in cerebral spinal fluid) to levels predicted to lower mHHT enough in human brain using  doses extrapolated from animal studies.  
  • Levels of mHTT continued to decrease in dose related manner with each treatment. They also showed persistance of drug response for more than the month post treatment. This is similar to response of a similar drug in spinal muscular atrophy another triplet repeat neurologic disease, and is important because it suggests that though monthly treatment will be necessary for loading the drug, less frequent intervals may suffice thereafter.
  • No safety issues in use of drug for 6 months.

What was new in the AAN report?  Based on "Post hoc" analysis (studying the data after the trial was completed), three clinical measures were reported that suggested improvements that could be correlated to the larger 2 doses used in the study. Why are these results problematic?