About SLS-005 (Trehalose)
Trehalose is a low molecular weight disaccharide (0.342 kDa) that protects against pathological processes in cells
It has been shown to penetrate muscle and cross the blood-brain barrier
Two U.S. patents for parental administration of trehalose exist for patients with OPMD and SCA3; both are expected to expire in 2033. In addition, Orphan Drug Designation for OPMD, Sanfilippo syndrome and SCA3 has been secured in the U.S. and in the EU
Trehalose Mechanism of Action
- Mayer AL, Higgins CB, Heitmeier MR, et al. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Scientific Reports. 6 (38586).
Available at: https://www.nature.com/articles/srep38586#f1 Accessed February 2019.
- Uchida K, Unuma K, Funakoshi T, et al. Activation of Master Autophagy Regulator TFEB During Systemic LPS Administration in the Cornea. Journal Toxicol Pathol. 2014;27(2):153–8.
SLS-005 (trehalose) for Amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease)
Amyotrophic lateral sclerosis (ALS) is a group of rare neurological diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary muscle movement. Voluntary muscles produce movements like chewing, walking, and talking. The disease is progressive, meaning the symptoms get worse over time. Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease.
Mutations in the C9orf72, SOD1, FUS, and TARDBP genes can cause familial ALS and contribute to the development of sporadic ALS. These mutations contribute to the death of motor neurons and ALS affected motor neurons develop a buildup of protein aggregates such as TDP-43 and SOD1.
In in-vivo studies of ALS, trehalose has been shown to increase the clearance of TDP-43, decrease SOD1 and SQSM1/p62 aggregates and monomers, delay the progression of the disease, preserve ventral horn motor neurons and increase muscle fiber size.
Seelos’ Phase IIb/III trial plans to enroll 160 patients with either familial or sporadic ALS in a double-blind placebo-controlled trial. Patients will be randomized 3:1 (drug:placebo) and studied with a primary endpoint measuring the change from baseline on Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score at 24 weeks. Secondary endpoints will also be measured at 24 weeks, including the change from baseline in slow vital capacity, muscle strength, quality of life measurements as well as additional signs of disease progression.
Induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration
- Impairment of TFEB has been demonstrated as a key element in the pathogenesis of ALS
- Immortalized motor neuron cell line (NSC34)
- Trehalose exposure
- TFEB translocated to the nucleus
- Activates genes for autophagy
- Increased clearance of TDP-43
- Rusmini P, Cortese K, Crippa V, et al. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy. 2019;15(4):631-651. doi:10.1080/15548627.2018.1535292
- Wang Y, Liu FT, Wang YX, et al. Autophagic Modulation by Trehalose Reduces Accumulation of TDP-43 in a Cell Model of Amyotrophic Lateral Sclerosis via TFEB Activation. Neurotox Res. 2018;34(1):109-120. doi:10.1007/s12640-018-9865-7
Trehalose delays the progression of ALS by enhancing autophagy in motoneurons
- Intraperitoneal injection (or IP injection) and oral trehalose (combined)
- Improves survival of male>female
- Delays progression of the disease
- Decreased SOD1 aggregates and monomers
- Preserved ventral horn motor neurons
- Induced autophagy
- Castillo K, Nassif M, Valenzuela V, et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy. 2013;9(9):1308-1320. doi:10.4161/auto.25188
SLS-005 (trehalose) for Sanfilippo Syndrome, OPMD, and SCA3
Trehalose, which is currently an investigational molecule, has demonstrated favorable safety and efficacy in 59 patients
across two Phase II studies in rare diseases (OPMD and SCA3).
Additional trehalose studies are ongoing/planned in ALS and Sanfilippo Syndrome in the US
Seelos is currently collaborating with Team Sanfilippo Foundation (TSF). Upon approval by the FDA, TSF will begin a
Phase IIb/III clinical trial in up to 20 patients with Sanfilippo syndrome with Seelos providing the clinical supply of trehalose.
- Sanfilippo syndrome (or MPS III) is an inherited monogenic lysosomal storage disorder divided into four subtypes
- Occurrence of 1 in every 70,000
- Progressive disorder, with life expectancy of 10–20 years
- Orphan designation (US/EU)
- Rare disorder
- PolyQ muscular disease caused by mutations in PABPN1 gene
- Orphan designation (US/EU)
- Fast track designation (US)
- Largest cluster among French in Quebec, Canada (1 in 1000)
- Additional clusters in Bukhara Jews of Israel and in Hispanics of New Mexico
Type 3 (SCA3)3
- SCA3 (or Machado-Joseph disease) is an autosomal dominant cerebellar ataxia (ADCA I) due to CAG repeat expansions in ataxin
- Adult-onset neurological PolyQ disease that begins between the ages of 20 and 50
- Orphan designation (US/EU)
- Most commonly affects individuals of Portuguese/ Azorean descent
- Lavery C, Hendriksz CJ, Jones SA. Mortality in patients with Sanfilippo syndrome. Orphanet Journal of Rare Diseases, 2017;12(1):168.
- Source: Oculopharyngeal Muscular Dystrophy. National Organization for Rare Disorders (NORD). Available at: https://rarediseases.org/rare-diseases/oculopharyngeal-muscular-dystrophy/. Accessed March 2019.
- Coutinho P, Andrade C. Autosomal dominant system degeneration in Portuguese families of the Azores Islands: a new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. Neurology. 1978;28 (7) 703- 709
Trehalose Reduced Storage of Unprocessed Macromolecules in Sanfilippo Syndrome
- Mauri V.. Trehalose-mediated enhancement of glycosaminoglycan degradation in the lysosomal storage disorder Mucopolysaccharidosis III. Inaugural-Dissertation zur Erlangung der Doktorwürde der Hohen Medizinischen Fakultät der Universität zu Köln. 2014. Available at: https://d-nb.info/1047324342/34 Accessed February 2019.