Recently published results from the open-label Lighthouse trial investigating safety of the drug Triumeq in people with MND revealed the treatment was safe and ready to progress to a larger Phase 3 clinical trial.
The trial was held in Australia and recruited 40 people with MND who all received the active drug; this was because the aim of the trial was to see whether Triumeq, which is already licensed to treat HIV, has a potential as a treatment for MND.
Why HIV drugs?
One of the possible triggers of MND has been suggested to be a group of ‘fossil’ viruses that, over many millions of years of evolution, have left traces of their DNA within our genome. When activated, these ‘retroviruses’ have the ability to merge into our cells, by copying their DNA into our genome, which leads to incorporation of the two DNAs into one. When the affected cell then creates new proteins, partial copies of the virus are produced with it.
Retroviruses have been linked to MND because of findings of a particular retrovirus, called human endogenous retrovirus (HERV-K), in the brains and motor neurons of people with the disease. Although some studies failed to confirm this finding, researchers deemed this to be a promising area of therapeutic focus.
A specific group of anti-retroviral drugs that inhibit the activity of retroviruses and are highly effective in treating HIV (a different type of retrovirus with very different effects on the body) were deemed to have the potential to reduce the amount of the HERV-K virus, making it a promising option for the treatment of MND.
What happened in the study?
The trial recruited 40 people with MND who were first observed for 10 weeks to establish their predicted disease progression that could be then compared to their actual progression while on the drug. This stage was then followed up by 24 weeks of daily dose of Triumeq in the form of a tablet.
Throughout the duration of the study, participants were assessed using outcome measures such as the ALS Functional Rating Scale (ALSFRS-R) and breathing capacity (Forced Vital Capacity; FVC). Samples of blood and urine were collected at four timepoints to measure levels of two biomarkers: urinary p75 and neurofilaments.
What did the measures tell us?
Overall, the drug was found to be well-tolerated by the participants and safe to administer in the dose it was given.
The measures currently used in clinical trials to monitor disease progression showed improvement after receiving the treatment. A statistically significant reduction in disease progression was observed on the ALSFRS measure, indicating a change from decline by 1.12 points per month during the observation period to 0.76 points per month while on the treatment. Breathing progression stabilised after 18 weeks on the treatment, also indicating a positive change.
Although the above results are encouraging, measuring ‘markers’ of the body’s mechanisms in response to the drug may be a more objective way of assessing Triumeq’s effectiveness. In this trial, two biomarkers that have been suggested to be linked with MND progression were analysed to provide more information on the effect of the drug as well as value of the biomarker as a potential outcome measure in clinical trials.
Neurofilaments. These proteins form the skeleton of a neuron and are released into blood when the neuron is damaged. An increased amount of these neurofilaments in blood indicates greater damage to neurons and therefore disease progression. In this trial, the levels of neurofilaments remained stable in both the observational as well as the treatment phase. This could be explained by the relatively short time span of the measured period, possibly suggesting that neurofilaments might not be a sensitive-enough measure to detect changes in very short clinical trials. Rather, it might be more valuable as a ‘prognostic biomarker’, predicting how rapidly person’s disease will progress.
P75. This protein is released from injured motor neurons and can be found in urine, and previous reports suggested that this marker increases as the disease progresses. Therefore, decrease of p75 levels would indicate improvement. In this trial, the levels were initially abnormally increased, followed by a rapid decline back to the pre-treatment levels by the end of the study. As suggested by the authors, the initial increase could have been caused by an inflammatory reaction known to occur in HIV patients treated by retroviral drugs, which was then taken over by the potentially positive effect of Triumeq, leading to reduction in p75 levels.
As there is currently only one drug licensed to treat MND in the UK, the relentless search for new treatments is ongoing. This trial is a good example of drug repurposing, where a drug that is already used for one condition is taken into later clinical trial stage to test its safety and effectiveness in a different condition. Triumeq was shown to be safe with positive effects as assessed by the ALSFRS measure and, more importantly, objective biomarkers such as p75. However, it is important to remember this was a small and short-term trial that did not include a placebo arm for comparison, so the results do have to be treated with caution.
A Phase 3 clinical trial is now being planned to be rolled out internationally in order to assess the effectiveness of Triumeq in a large number of people in a placebo-controlled trial.
The full paper can accessed here: Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial (2019).