Industry partners from these first five companies are working closely with the Healey Center Trial Design Team, the Northeast ALS Consortium (NEALS) and Berry Consultants to tailor the arm of the HEALEY ALS Platform Trial to their experimental treatment.

Zilucoplan, a small macrocyclic peptide inhibitor of complement component 5 [C5], developed by Ra Pharmaceuticals, Inc.

The complement system, as part of the innate immune system, is a group of proteins that evolved to protect humans from bacterial infections. In many diseases, inappropriate complement activation and deposition can occur damaging tissues and organs. Robust experimental data supports a role for complement activation and deposition in both the peripheral and central nervous systems in amyotrophic lateral sclerosis (ALS). Zilucoplan, a new drug candidate developed by Ra Pharmaceuticals, Inc. binds complement component 5 (C5) and inhibits tissue damage caused by pathological complement activation. Clinical data in a Phase 2 trial of zilucoplan in another neuromuscular condition generalized myasthenia gravis, demonstrated rapid, clinically meaningful and statistically significant improvements, as well as a favorable safety and tolerability profile. Zilucoplan has been designed for convenient “in-home” use by patients and is self-administered as a small volume, subcutaneous administration.

Verdiperstat, an oral myeloperoxidase inhibitor, developed by Biohaven Pharmaceutical Holding Company Ltd.

Microglia are the primary immune cells of the central nervous system. The presence of large numbers of activated microglia is one of the hallmarks of neurodegeneration in ALS. Myeloperoxidase (MPO) is a powerful pro-oxidant enzyme that is present in activated immune cells, including microglia. MPO is believed to increase oxidative stress and inflammation levels in the brain and spinal cord. Inhibiting MPO is anticipated to ameliorate these pathological mechanisms, which are strongly implicated in the onset and progression of ALS. Verdiperstat (BHV-3241) is a potential first-in-class, potent, selective, brain-permeable, irreversible myeloperoxidase enzyme inhibitor. Verdiperstat has been studied in approximately 250 people in Phase 1 and 2 clinical trials. It was generally safe and well-tolerated and has shown the potential to reduce microglial activation.

Bioenergetic Nanocatalysis (CNM-Au8, nanocrystalline gold) developed by Clene Nanomedicine, Inc.

Motor neurons consume significant energy in order to function normally. In ALS, corrupted energy metabolism together with increased cellular stress lead to motor neuron degeneration. CNM-Au8 is a new class of medicine that provides an energetic assist to impaired motor neurons, helping them improve their ability to function more normally. CNM-Au8 acts catalytically to both support bioenergetic reactions inside cells and eliminate the harmful waste byproducts of cellular metabolism. Oral delivery of CNM-Au8 resulted in both neuroprotection and remyelination in multiple animal studies. Each 2 oz dose of CNM-Au8 is a concentrated, liquid suspension of pure gold nanocrystals that study participants drink every morning. These extremely small nanocrystals travel through the body and enter the brain and motor neuron cells where they enhance the ability of these cells to survive and communicate by supporting cellular metabolism. CNM-Au8 was demonstrated to be safe and well-tolerated by healthy volunteers in a Phase 1 study.

Pridopidine, a highly selective S1R agonist, developed by Prilenia Therapeutics

Pridopidine is a selective Sigma-1 receptor (S1R) agonist developed by Prilenia for the treatment of neurodegenerative and neurodevelopmental disorders. S1R regulates key cellular pathways, commonly impaired in neurodegeneration. Of particular interest is its role in the pathogenesis of ALS which is supported by human genetic and postmortem studies as well as by preclinical models. Pridopidine demonstrates robust neuroprotective effects in numerous preclinical models of neurodegenerative diseases including models of ALS. Compelling preclinical data supports the therapeutic potential of pridopidine in ALS. In ALS SOD1G93A motor neurons (MNs), pridopidine exerts neuroprotective effects via activation of the S1R. Specifically, pridopidine increases MN survival, improves BDNF and GDNF axonal transport, and restores the neuro-muscular junction (NMJ) synaptic activity. In vivo, pridopidine treatment of SOD1G93A mice reduces toxic protein aggregates and ameliorates muscle fiber wasting.

Clinical support for the validity of the S1R as a potential target for ALS can be derived from a prior trial using a non-selective S1R agonist, showing S1R activation may enhance bulbar and speech function in ALS patients. Pridopidine in vivo target engagement in humans is validated by PET imaging, providing support of the optimal clinical dose. Prior clinical data with pridopidine demonstrates a favorable safety and tolerability profile and provides evidence for a beneficial effect on functional outcome in another neurodegenerative disease.

IC14 immunotherapy, developed by Implicit Bioscience Ltd.

While ALS is likely driven by a multitude of possible environmental triggers on a complex genetic background, the immune system plays an important role in both controlling disease before symptoms appear and also determining its rate of progression thereafter. The target of Implicit Bioscience's IC14 immunotherapy is CD14, a master regulator of the healthy function of the immune response to infection and injury, particularly the response of the brain's most common immune cells, microglia. In some diseases like ALS, it is thought that chronically hyper-activated CD14 loses this ability to balance the immune response to worsening background triggers, and itself becomes part of the cause of cell death, resulting in neuronal death and loss of muscle control and function. High levels of soluble CD14 (sCD14) in patient blood appear to be closely associated with rapid ALS disease progression. By potently targeting and blocking both sCD14 and CD14 on immune cells, Implicit Bioscience’s immunotherapy IC14 can switch off this damaging hyper-activation, allowing the immune response to return to a less lethal, more balanced regulation of the response to background disease triggers. It is hoped that this rebalancing of the immune response may result in ALS disease remission in the same manner as is observed in intervention with some other immunotherapies in multiple sclerosis.