Roche ended two Huntington’s disease programs: one lowered biomarkers but did not slow the disease, while the other stopped after animal data
Roche ended two Huntington’s disease programs: one lowered biomarkers but did not slow the disease, while the other stopped after animal data
In the GENERATION HD2 trial, tominersen reduced levels of mutant huntingtin, the protein that causes Huntington’s disease, and neurofilament, a marker of nerve cell damage. After 16 months, the clinical course of the disease did not differ between people who received the drug and those who received placebo. At the same time, Roche discontinued an early trial of the more selective drug RG6496 because data from a parallel animal study showed that repeated doses were not acceptable.
On 9 July, Roche announced that it was ending both programs. Huntington’s disease is caused by an inherited error in the HTT gene. This error causes the body to produce mutant huntingtin, which gradually damages the nervous system and impairs a person’s ability to control movement, think, and manage daily life.
Tominersen is administered into the cerebrospinal fluid. It is an antisense oligonucleotide, a short molecule that instructs cells to produce less huntingtin. The drug reduces both the mutant and normal forms of the protein. GENERATION HD2 enrolled 301 people in 15 countries and compared tominersen with placebo in people with early-stage disease.
Roche reports that the biological effect was substantial. Mutant huntingtin levels fell in the cerebrospinal fluid, while levels of neurofilament light chain fell in both blood and the fluid surrounding the brain. Neurofilament light chain is a protein whose concentration rises when neurons are damaged. However, measures of the ability to move, think, and live independently showed no difference from placebo.
This result separates two questions that are often treated as one. Can a treatment change a molecular marker of the disease? Yes, tominersen showed that this is possible in humans. Is that change sufficient to preserve brain function? In this trial, it was not.
The second discontinued program, RG6496, was an attempt to make the intervention more precise by suppressing only the mutant copy of the gene in people with a suitable genetic variant. Three participants each received a single dose, with no problem identified. Longer animal studies then showed that the drug could not be administered repeatedly. Without repeated dosing, it could not serve as a treatment for a chronic disease. Roche did not disclose the specific finding that led to this decision.
This result does not determine the future of the entire approach of lowering huntingtin. The full GENERATION HD2 data have not yet been published, and questions remain about when treatment should begin, what dose should be used, and which brain regions the drug must reach. Still, the current conclusion is firm: a biomarker cannot be treated as a substitute for preserved human function. The next therapy must demonstrate both parts of that chain.