Trehalose Granted Orphan Drug Designation for Treatment of Patients with ALS


Seelos Therapeutics will soon enroll patients in its phase 2b/3 trial of SLS-005 in amyotrophic lateral sclerosis.

Warren W. Wasiewski, MD, FAAP, chief medical officer, Seelos Therapeutics

Warren W. Wasiewski, MD, FAAP

The FDA has granted an orphan drug designation (ODD) to Seelos Therapeutics’ drug SLS-005 (Trehalose) for the treatment of amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease.1

The therapy is believed to impact autophagy through Transcription Factor EB (TFEB), which plays a key role in lysosomal and autophagy gene expression, and thus increase clearance of the protein aggregates that build up in motor neurons of patients with ALS, such as TDP-43, SOD1, and SQSm1/p62.

"Several preclinical studies have demonstrated the potential of trehalose as a treatment for ALS, demonstrating preservation of motor neurons, motor function and prolonged survival. We are excited to start our clinical program for this devastating disease," said Warren W. Wasiewski, MD, FAAP, chief medical officer, Seelos, addressing planned trials in a statement.2

Seelos will conduct a 24-week phase 2b/3 trial of 160 patients with either familial or sporadic ALS in a double blind, placebo-controlled trial. Change will be measured from baseline to 24 weeks using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Slow vital capacity, muscle strength, quality of life measurements, and other signs of disease progression will be studied.

"ALS is a debilitating disease which currently lacks a cure and there is significant evidence suggestive of trehalose having the potential to alter or slow the progression of ALS," said Raj Mehra, PhD, chairman and CEO, Seelos, in a related press release.2 “The FDA signoff to begin this pivotal study allows Seelos to focus on ALS as the lead indication for SLS-005.” 

The agent is a low weight disaccharide that is able to cross the blood-brain barrier. Protein aggregates such as TDP-43, SOD1, and SQSm1/p62 develop as a result of mutations in the c9orf72, SOD1, FUS, and TARDBP genes. Clearing the aggregates has been shown to delay the progression of the disease, preserve motor neurons, and increase muscle fiber size. The activation of TFEB is also beginning to be investigated as a possible mediation of other diseases that involve harmful protein aggregation.1,2

READ MORE: Prosetin Gets Orphan Drug Status for ALS

Trehalose has been shown to reduce aggregation of misfolded proteins and harmful detritus in animal studies, however, the effects of trehalose are not conclusive, and its mechanism remains largely theorized. 

He-Jin Lee, PhD, associate professor, Department of Anatomy, Research Institute of Medical Science, Konkuk University, and colleagues reviewed the numerous investigations on trehalose in order to reach a consensus on its actions on the body.3 Lee and colleagues stated in their paper that “neuroprotective effects of trehalose have been fairly consistent in many different neurodegenerative disease models. It has been hypothesized that trehalose directly acts on neurons and induce autophagy, thereby promoting the clearance of protein aggregates. However, careful examination of the literature raised a question as to whether trehalose can directly induce the autophagic process. A recent paper, indeed, showed that trehalose treatment of neuronal cells hampers the progression of autophagosomes to autolysosomes. Furthermore, it is not clear whether and how much trehalose can be delivered to the brain parenchyma when it is administered to the animals.”

The authors propose that “trehalose intake exerts neuroprotective effects in neurodegenerative disease models through a direct or indirect mechanism, which may involve the gut microbiota.”

Earlier this year, trehalose was also granted ODD for the treatment of patients with Mucopolysaccharidosis type III (MPS III), also known as Sanfilippo syndrome, another rare neurodegenerative disease that involves the accumulation of protein and waste aggregates.4

1.Seelos Therapeutics receives US orphan drug designation for SLS-005 (Trehalose) in Amyotrophic Lateral Sclerosis. News release. Seelos Therapeutics. November 19, 2020. Accessed November 24, 2020.
2. Seelos Therapeutics Receives FDA May Proceed Notice to Initiate a Phase IIb/III Trial of SLS-005 in Amyotrophic Lateral Sclerosis. News Release. Seelos Therapeutics. August 10, 2020. Assessed November 24, 2020.
3. Lee H, Yoon Y, Lee S. Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction. Cell Death Dis. 2018; 9:712. doi: 10.1038/s41419-018-0749-9
4. FDA Grants Orphan Drug Status to SLS-005 for Treating Sanfilippo. News release. Seelos Therapeutics. May 7, 2020. Accessed November 24, 2020.
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