In PHASE 3– Ibudilast (MN 166), Ravulizumab, Verdiperstat, Arimoclomal, GM604, CuATSM, Tofersen, Jacifusen, NurOwn, NSI-566 HSSC, DNL747, Masitinib, Trametinib, RNS60

• Irreversible myeloperoxidase (MPO) inhibitor.
• Reduces oxidative stress and neuro-inflammation
• Consistently shown neuroprotective efficacy in mice models
• Demonstrated significant neuroprotection in multiple brain areas, as well as functional recovery

• A phosphodiesterase inhibitor
• Has anti-inflammatory and neurotrophic effect
• Phase 2a trial – MN-166 in combination with riluzole more effective than riluzole alone.
• In phase 2 trial the primary goal was to test safety
• MN-166 is expected to be effective in patients with a short ALS history

MediciNova Receives a Notice of Intention to Grant for a New Patent Covering the Combination of MN-166 (ibudilast) and Riluzole for the Treatment of Amyotrophic Lateral Sclerosis (ALS) in Europe

• Ibudilast (MN-166) in ALS- an open label, safety and pharmacodynamic trial showed
• No significant reduction in brain glial activation measured by PBR28-PET SUVR.
• No significant reduction in serum neurofilament light levels over 36–40 weeks.
• Adverse event related dose reductions/discontinuations common.

GM6 affects multiple pathways to treat ALS and promote motor neuron survival by slowing degeneration, neurogenesis and anti-inflammatory effects.

Phase 2 A trial results

• Respiratory symptoms significantly better
• Decreased ALS biomarkers (TDP, Tau and SOD1)
• Slower funtional decline in ALS-FRSr
• Symptomatic improvement

Completed PHASE 3:

• Arimoclomol increases expression of number of hear shock proteins (HSPs).
• HSPs can bind to misfolded or faulty proteins and help to remove it from the cells
• HSP70 is found to bind with the faulty SOD1 protein and remove it
• Arimoclomol also acts on the muscle resulting in better preservation of muscle innervation.
• Arimoclomol also acts on the muscle result gin better preservation of muscle innervation.

ORARIALS – 01 pivotal trial of arimoclomol in amyotrophic lateral sclerosis (ALS) did not meet its primary and secondary endopoints to show benefit in people living with familial ALS.

• Tyrosine-kinase inhibitor
• Phase 2 results show that Masitinib showed a significant benefit with acceptable safety in ALS patients with a baseline ALSFRS-R progression rate of 1.1 points/month.
• Progression slowed down in treatment group

Studies suspended due to a potential risk of ischemic heart disease – a condition of recurring chest pain or discomfort.

• Inhibits the S0D1mRNA and reduces production of the toxic protein.
• Has the potential to slow disease progression and support rapid path patients.
• On ALS FRS- R Scale there was an average decline of 1.1 points compared to an average decline of 5.3 points in the placebo group.

• 41 Pre-clinical studies using multiple cell types show that stem cell migrate, engraft and differentiate in to target cells; restore lost tissue function.
• In animal studies, they improved motor performance as measured on rotarod (test measuring rodent balance, grip strength, endurance, and motor coordination), decelerate disease pathology and safely extend survival
• 27 clinical studies, using 21 different cell types, show a robust safety profile and efficacy in mitigating the hostility of a degenerating prognosis.
• A systematic review and meta – analysis of clinical studies by Moura et al., 2016 highlight the benefits of stem cell therapy in humans.
• Stem cell also bring about paracrine effects directly or indirectly by modulating the local secretome and regulating neurotrophic factors such as GDNF, BDNFM vascular endothelial growth factor (VEGF), insulin – like growth factor (IGF)-1, NGF and Neurotrophin (NT)-3.

10‐year retrospective clinical study showed improved survival in ALS patients following intrathecal autologous bone marrow mononuclear cell therapy alongwith standard treatment

None of the patients reported any major adverse events related to cell therapy. Kaplan Meier analysis estimated survival duration in the cell therapy group was significantly higher than the control group (91.7 months vs 49.7 months). Premenopausal women and preandropausal men showed better responses.

• A higher rpoportion of treated participants experienced >1.5 points/ months ALSFRS-R slope improvement compared to placebo at all time points and was significant in rapid progressors at 4 and 12 weeks (P= 0.004 and 0.045, respectively).
• CSF neurotrophic factors increased and CSF inflammatory biomarkers decreased in treated participants (< 0.05) post transplantation.
• A single dose transplantation of MSC – NTF cells is safe and demonstrated early promising signs of efficacy.

In February 2021, the U.S Food and drug administration (FDA) found that high level data from the phase III trial of NurOwn in ALS was not sufficient to support a Biologics License Application (BLA).

A case-control study involving 67 ALS patients were treated with intrathecal Wharton’s jelly mesenchymal stem cells (WJ-MSC). The treated patients were paired with 67 reference patients from the PRO-ACT database The results showed.

• Two-fold increased median survival time. In terms of progression, three responses were noted: decreased progression rate ( 31.3%), no change in rate ( 49.3%) and increased progression rate (19.4%).
• No serious adverse drug reactions were seen