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Near the conclusion of 2018, Roche and Genentech announced that the first ever Phase 3 clinical trial to test a huntingtin-lowering drug would begin in 2019 1. After Phase1 and 2 trials that test the safety and effectiveness of a new drug are performed, Phase 3 trials aim to demonstrate whether or not a drug candidate offers a treatment benefit to a population of interest (in this case, HD patients). The study was named “GENERATION -HD1” after the research team was inspired by HD families to hope that “this will be the last generation to suffer” 2. The acronym stands for “Global EvaluatioN of Efficacy and Safety of Roche/Genentech AnTIsense OligoNucleotide for Huntington’s Disease.” The study aims to evaluate the efficacy and safety of an intrathecally administered drug called RG4042, or tominersen, in adult patients with manifest HD. 

In an initial Phase I/II trial done by Ionis Pharmaceuticals and Roche, tominersen was shown to significantly reduce the levels of mutant HTT protein, the protein affected by the mutation responsible for HD, in the cerebral spinal fluid (CSF), the liquid surrounding the brain and spinal cord, of early stage patients 3. Some participants who received either of the two highest doses showed an average reduction of 40% in HTT levels in their CSF, while others experienced even greater reduction of up to 60%2. Dr. C. Frank Bennett, senior vice president of research and franchise leader for the neurological programs at Ionis Pharmaceuticals mentioned in a press release that “… We were pleased that this antisense approach, which targets all forms of the huntingtin protein, proved to be safe and well tolerated in this study”4.

This study was followed by a “GEN-PEAK” Phase I trial, which aimed to test the pharmacokinetics, or how the body affects a medicine, and pharmacodynamics, which assesses the interactions between the body and a compound, of tominersen when injected directly into the spinal canal 5. This trial was placed on hold after two cases of infection occurred during the study; however, the infections resulted to be linked to the device used to take samples of patients’ CSF and not to due to tominersen. Currently, the trial is actively recruiting 20 participants at sites in the Netherlands and United Kingdom6. 

Given the promising results from initial phase I/II trials that helped researchers understand an appropriate and safe treatment dose, the GENERATION -HD1 phase III study was launched to evaluate the effectiveness and safety of tominersen when given every 2-4 months over a period of 25 months. The study has enrolled 909 patients with manifest HD at around 80-90 sites in approximately 15 different countries around the world, including 20 sites in the U.S. and six in Canada. Prior to official acceptance into the study, all candidates were required to undergo a medical screening to check for any serious medical conditions, abnormal vital signs, or irregular general laboratory tests.

GENERATION -HD1 is a randomized, placebo-controlled study. This means that the participants will be randomly assigned to either the “experimental group”, or the group that will receive tominersen treatment, or the “control group”, or the group that will receive the placebos. A placebo is a harmless version of the treatment designed to have no effect on the participants who take it. All participants, regardless of group, are required to receive their respective tominersen treatment or placebo the same amount of times. This is also a double-blind study, meaning neither the participants nor the researchers are aware of who is receiving the treatment, or who is in the experimental group.



Inclusion Criteria

Researchers focused on recruiting patients demonstrating symptoms of the manifest stage of HD based results from previous studies, and the ability to measure these symptoms as indications of improvement or not. 

Key inclusion criteria required in order to have qualified for enrollment in 2019 include:

1.A clinical diagnosis of manifest HD (defined as a DCL score of 4)

The Huntington Disease Rating Scale (UHDRS) diagnostic confidence level (DCL) is the standard measure used for clinical diagnosis in at-risk individuals and is based solely on the motor evaluation [ref]Biglan, K. M., Zhang, Y., Long, J. D., Geschwind, M., Kang, G. A., Killoran, A., Lu, W., McCusker, E., Mills, J. A., Raymond, L. A., Testa, C., Wojcieszek, J., & Paulsen, J. S. (2013). Refining the diagnosis of huntington disease: The PREDICT-HD study. Frontiers in Aging Neuroscience, 5(APR). [ref/]. The DCL ranges from 0 to 4, where a patient who is unimpaired would qualify for a DCL score of 0, while a patient with motor impairments that are unequivocal signs of HD would qualify for a DCL score of 4. When tracking HD’s impact of motor function, the first diagnosis of a DCL score of 1 represents the onset of motor impairments, and that of 4 indicates the onset of HD diagnosis [ref]Liu, D., Long, J. D., Zhang, Y., Raymond, L. A., Marder, K., Rosser, A., McCusker, E. A., Mills, J. A., & Paulsen, J. S. (2015). Motor onset and diagnosis in Huntington disease using the diagnostic confidence level. Journal of Neurology, 262(12), 2691–2698.[ref/].

2.Be between the ages 25-65 years

3.Genetically confirmed disease by direct DNA testing with a CAP score >400

A CAP score [ref] Update on Huntington’s Program and Clinical Trials from Roche/Genentech – YouTube. (n.d.). Retrieved January 21, 2021, from [ref/] measures how long an individual has lived with their mutation burden. The formula to calculate this score is:

CAP score = [Age in the years at study start] x [CAG – 33.66]

It has been shown in studies that variability in CAP scores results in different patterns of progression overtime on key clinical outcomes, such as the DCL or the total functional capacity score. Because of this, by using an objective CAP score criteria, the researchers can make sure that the trial’s participants will have a certain sensitivity to changes resulting from the treatment, should there be any change, and will allow these changes to be measurable.

4.Independence scale >= 70:

This scale is intended to clinically evaluate a candidate’s baseline functional status, given that the trial will be a 25 month intervention period. An independence scale score of 70 or higher thus means that a candidate is able to maintain self-care and core activities of daily living (ADLs). This not only allows the researchers to confirm that the candidate is able to functionally participate in the study for the length of the study period, but further confirm that the candidate is someone who would benefit from this treatment, and allows these benefits to be measurable.

5.Be ambulatory (able to walk) and verbal


Exclusion Criteria

Exclusion criteria for qualifying for the study included having any active serious medical condition, clinically significant laboratory, or vital sign abnormally during screening that, in the investigator’s judgment, precluded the patient’s safe participation in and completion of the study. Additionally, candidates who were pregnant, breastfeeding, or intended to become pregnant during the study or within 5 months after the final treatment dose did not qualify to participate.

The estimated completion date of the study is July 9, 2022.

  1. Huntington’s Disease Society of America (2018) Looking Back. Moving Forward.  []
  2. Ibid. [] []
  3. Rodrigues, F. B., Ferreira, J. J., & Wild, E. J. (2019). Huntington’s disease clinical trials corner: June 2019. Journal of Huntington’s Disease, 8(3), 363–371. []
  4. IONIS-HTT Rx (RG6042) Top-Line Data Demonstrate Significant Reductions of Disease-Causing Mutant Huntingtin Protein in People with Huntington’s Disease. (n.d.). Retrieved January 21, 2021, from []
  5. A Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO7234292 (RG6042) in CSF and Plasma, and Safety and Tolerability Following Intrathecal Administration in Patients With Huntington’s Disease – Full Text View – (n.d.). Retrieved January 21, 2021, from []
  6. Ibid  []