Background
Clene is a biopharmaceutical company developing nanotherapeutics aimed at treating failure in cellular energy production. Their lead candidate is CNM-Au8, an oral liquid aimed at enhancing energy production in neurons and oligodendrocytes (cells that produce insulation for neurons to conduct signals). It is reported by the company to also increase resistance to oxidative stress and decrease the levels of potentially toxic misfolded proteins. CNM-Au8 is currently being tested in clinical trials as a potential treatment to slow progression of ALS/MND.
Trial Design & Results
On November 2, 2021, Clene announced the results from their phase 2 RESCUE-ALS clinical trial. The study was a randomized, placebo-controlled, trial of 45 participants, dosed daily with 30mg, and evaluated over 36 weeks. The primary outcome for this clinical trial was percent change in a measure called MUNIX, which estimates the number of motor neuron/muscle connections. There were several other secondary and exploratory outcomes.
There was no significant change between treated and placebo groups for MUNIX, forced vital capacity, ALSFRS-R at 36 weeks. However, this trial was small and trends in each of these measures favouring CNM-Au8 suggest that a larger trial, better powered to see subtle, but potentially meaningful effects, will be valuable. Some exploratory endpoints, including a responder analysis, defined here as someone with less than a six point decline in the ALSFRS-R over 36 weeks, demonstrated a significant difference for CNM-Au8 over placebo, as did the quality of life ALSSQOL-SF score. Futher exploratory endpoints around disease progression as measured by death or initiation of tracheostomy, NIV or gastrostomy tube, and observed versus predicted survival over 96 weeks, including an open label extension, both favoured CNM-Au8 as well. A pre-specified analysis of limb onset participants demonstrated a stronger trend towards efficacy than the full cohort.
CNM-Au8 appears, to date, to be well tolerated without any significant safety concerns.
CNM-Au8 was subsequently tested in the HEALEY Platform Trial, where 161 participants were randomized to 30 mg CNM-Au8, 60 mg CNM-Au8, or placebo, with a 3:1 treatment to placebo ratio, and measured over 24 weeks. The primary endpoint of change from baseline in ALSFRS-R was not met, nor were secondary endpoints of the Combined Assessment of Function and Survival joint rank test (CAFS) or change in respiratory function as measured by slow vital capacity (SVC). An exploratory analysis of survival is described in press as >90% reduction in risk of death or permanently assisted ventilation in the 30 mg group but it is important to note that this represents one individual of 59 in the treated arm vs. four individuals of 41 in the placebo arm. One individual less in the placebo group or one more in the treatment group would significantly shift this statistic so the percentage benefit should be received with caution. It is not abnormal to have only zero or one individuals in the treated group across most six-month ALS trials.
On March 8, 2023, an additional press release described delays to clinical worsening in the treatment group of the HEALEY Platform trial. Another described a reduction in neurofilament light (NfL) levels for people treated with CNM-Au8 vs. those on placebo, suggesting this is indicative of neuroprotection as less NfL in blood has been used to demonstrate less neurons dying. Usually, this data is expressed as a change in NfL levels after treatment compared to the same group before treatment so the value or strength of an effect described here is unclear. It is also important to note that these are still small numbers and should be interpreted with caution.
In April 2022, Clene announced the intent to pursue a multi-national 300 participant, Phase 3 clinical trial which would be critical to determining whether any signals seen in the RESCUE-ALS and HEALEY trials can be confirmed in a larger study.
Summary
The Scientific Advisory Council (SAC) believes that there is insufficient evidence at this time to conclude that CNMAu8 provides any benefit to people with ALS/MND and looks forward to a potential Phase 3 clinical trial that will provide clearer evidence for/against its efficacy.
International Alliance of ALS/MND Associations
June 2023
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.