ALS drugs that may enter a phase III trial in 2019
Arimoclomol is an experimental drug developed by CytRx Corporation. Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases.
Heat shock transcription factor 1 (HSF1), a central coordinator of the chaperone response, helps cells managing proteins that are misfolded or aggregated. HSF1, which is activated during times of stress, switches on multiple genes, including the gene encoding the disaggregase Hsp40.
NurOwn is an experimental cell-based therapy by BrainStorm Cell Therapeutics that contains autologous cultured mesenchymal bone marrow stromal cells secreting neurotrophic factors including BDNF, GDNF and HGF, as a possible treatment for patients with ALS.
Brainstorm’s NurOwn therapy consists of bone marrow stem cells taken from each individual person, differentiated into cells that make neuroprotective growth factors, and infused back into muscle or the spinal cord.
Brainstorm’s therapeutic differs from that of the better-known Neuralstem, Inc., of Rockville, Maryland, which is transfusing neural stem cells from fetal tissue into the spinal cords of people with ALS.
Though it has great potential for clinical applications, the differentiation of MSCs is precisely regulated and coordinated by mechanical and molecular signals from the extracellular environment and involves complex pathways at the transcriptional and post-transcriptional levels that remain largely unexplored.
MSC-NTF cells are Mesenchymal Stromal Cells (MSC) induced to express high levels of neurotrophic factors (NTFs) using a culture-medium based approach.
ODM-109 aims in part, to improve breathing in ALS by improving the performance of muscles in the diaphragm. The drug candidate, also known as oral levosimendan, increases the force of contraction of certain muscles by boosting the calcium sensitivity of troponin C.
The drug candidate is an oral formulation of levosimendan. An intravenous formulation of levosimendan, marketed under the name Simdax, is clinically approved in some countries for the treatment of acute heart failure. Levosimendan's positive inotropic and vasodilator effects are tied to its abilities to increase calcium sensitivity and open ATP-sensitive potassium positive ion (K+) channels (mitoKATPchannels)
Levosimendan favourably affects mitochondrial adenosine triphosphate synthesis, conferring cardioprotection and possible neuronal protection during ischemic insults. In a model of spinal cord injury, levosimendan has been reported to attenuate neurologic motor dysfunction. This finding is supported by the fact that the selective mitoKATPchannel opener, diazoxide, is an effective neuroprotectant, as has been demonstrated in an ischemia reperfusion study in rats.
IONIS-SOD1Rx is a generation 2.0 antisense drug specifically designed to inhibit production of mutant superoxide dismutase (SOD1). SOD1 mutations account for approximately 20% of familial ALS cases.
This drug is the result of a collaboration between Biogen and IONIS Pharmaceuticals (formerly ISIS). A Phase III clinical trial is recruiting participants as of April 2019. Study completion is expected in May 2020.
Researchers are also considering antisense treatment for another genetic form of ALS caused by expansions in the C9ORF72 gene. Antisense oligonucleotides are single strands of DNA or RNA that are complementary to a chosen sequence. The antisense oligonucleotide works by targeting and attaching itself to the stretch of RNA with the mistake so that the protein cannot be formed,, so prevent accumulation of these outside the nucleus.
Part of Isis’ success stems from chemically modifying oligonucleotides to make them last longer in the body and bind more tightly to their target RNAs.
SOD1Rx, like Kynamro, includes 2′-O-methoxyethyl sugars on its backbone. This modification typifies Isis’ second generation of oligonucleotide chemistry, but the company has developed other options. For SOD1 antisense, they plan to make it more potent before starting further safety trials, probably with higher doses and longer treatment times.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.