Phase 3 Trial Research

ALS PLATFORM TRIAL :

Recent introduction of platform trials in the field of ALS research has been a revolutionary step. HEALEY ALS Platform Trial is the first ALS platform trial, accelerating the path to new ALS therapies.

Advantages of Platform Trial

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

ALS PLATFORM TRIAL :

Phase 3 Trials: Small Molecules

AMX0035:

Completed Phase 1/2 trial

Combination of two compounds – sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA)
Minimizes cellular mechanisms linked to cell death
The CENTAUR trial of AMX0035 was a 24 week, randomized, double-blind, placebo-controlled phase II clinical trial completed in late 2019, which demonstrated statistically significant treatment benefits for people with ALS.
The Phase 3 PHOENIX trial of AMX0035 for the treatment of ALS will assess the safety and efficacy

AMX0035:

CU-ATSM :

It is a low-toxicity PET-imaging agent, with excellent ALS patient blood-brain barrier penetration

It selectively releases of copper in cells with damaged mitochondria

Previous results – When compared to the historical cohort over a six-month period showed

CU-ATSM :

VERDIPERSTAT (AZD3241) In Phase 2/3 :

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

VERDIPERSTAT (AZD3241) In Phase 2/3 :

PRIDOPIDINE In Phase 2/3:

IBUDILAST (MN-166) In Phase 2B/3:

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.

IBUDILAST (MN-166) In Phase 2B/3:

RAVULIZUMAB:

The 50-week global study, called CHAMPION-ALS, will evaluate approximately 350 adults across a broad patient population

It will be administered intravenously every 8 weeks

RAVULIZUMAB:

GM 6 In Phase 2/3:

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

GM 6 In Phase 2/3:

ARIMOCLOMOL:

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.

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.

ARIMOCLOMOL:

MASITINIB CURRENTLY IN PHASE 3:

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

MASITINIB CURRENTLY IN PHASE 3:

Phase 3 - GENE THERAPY:

BIIB067: TOFERSEN IN PHASE 3:

JACIFUSEN IN PHASE 3:

Cell Therapy For ALS

LITERATURE REVIEW: 2009-2021:

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.

LITERATURE REVIEW: 2009-2021:

AUTOLOGOUS BONE MARROW STEM CELLS:

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.

Clinical Trials

NUROWN (MSC-NTF CELLS) PHASE 3:

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).

UMBILICAL CORD MESENCHYMAL STEM CELLS:

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.

UMBILICAL CORD MESENCHYMAL STEM CELLS:

NSI-566 HSSC IN PHASE 3:

Human spinal cord derived neural stem cell line (HSSC).
Treated patients had a median survival of 4.7 years, versus control (2.3 years median survival).
Mean ALSFRS – R at 24 months significantly differed between treated vs. control cohorts .
Treated 30.1+8.6 vs. PRO-ACT database 24.0 + 10.2, P= 0.048.
Treated 30.7+ 8.8 vs. ceftriaxone treatment 19.2 + 9.5, P0.0023.

NSI-566 HSSC IN PHASE 3:

Know more about clinical trial phase 2 research

Phase 3 Trial Research