EP-4741013-A2 - COMBINATION THERAPY FOR TREATING AMYOTROPHIC LATERAL SCLEROSIS USING PRIDOPIDINE AND ANOTHER ACTIVE AGENT

Abstract

Treating a human subject afflicted with ALS by administering a therapeutically effective amount of pridopidine or pharmaceutically acceptable salt thereof in combination with Compound 1 and/or Compound 4.

Inventors

• GEVA, MICHAL
• HAYDEN, MICHAEL

Assignees

• Prilenia Neurotherapeutics Ltd.

Dates

Publication Date

20260513

Application Date

20210213

Claims (10)

1. A composition comprising pridopidine or a pharmaceutically acceptable salt thereof for use in treating amyotrophic lateral sclerosis (ALS) in a subject wherein the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, Compound 4 or a pharmaceutically acceptable salt thereof, or a combination thereof, wherein Compound 1 and Compound 4 have the following structures:
2. The composition for use according to claim 1, wherein the composition comprises pridopidine or a pharmaceutically acceptable salt thereof, and Compound 1 or a pharmaceutically acceptable salt thereof.
3. The composition for use according to claim 1, wherein the composition comprises pridopidine or a pharmaceutically acceptable salt thereof, and Compound 4 or a pharmaceutically acceptable salt thereof.
4. The composition for use according to claim 1, wherein the composition comprises pridopidine or a pharmaceutically acceptable salt thereof, Compound 1 or a pharmaceutically acceptable salt thereof and Compound 4 or a pharmaceutically acceptable salt thereof.
5. The composition for use according to any of claims 1 to 4, wherein the ALS is sporadic or familial ALS.
6. The composition for use according to any of claims 1 to 5, wherein the composition is effective to delay the onset, lessen the decline, or improve a symptom of the ALS in the subject.
7. The composition for use according to claim 6, wherein the symptom is muscle stiffness, muscle weakness, muscle wasting, muscle cramps, difficulty speaking, difficulty swallowing, difficulty breathing, difficulty chewing, difficulty walking, fasciculations, worsening posture, difficulty swallowing, difficulty in handwriting, difficulty in cutting food and handling utensils, difficulty in dressing, dyspnea, or orthopnea.
8. The composition for use according to claim 6, wherein the composition further lessens pseudobulbar disease progression, reduces progression of muscle fiber wasting, and/or improves muscle contraction in the subject afflicted with ALS.
9. The composition for use according to any of claims 1 to 8, wherein the amount of pridopidine or pharmaceutically acceptable salt thereof administered is 10 mg per day to 135 mg per day.
10. The composition for use according to any of claims 1 to 9, wherein the pridopidine is pridopidine hydrochloride.

Description

FIELD OF THE INVENTION Provided herein is a method for treating a human subject afflicted with ALS by administering to the subject a therapeutically effective amount of pridopidine or pharmaceutically acceptable salt thereof in combination with sodium phenylbutyrate (PB), tauroursodeoxycholic acid, a combination of sodium phenylbutyrate (PB)/tauroursodeoxycholic acid (i.e. AMX0035), Zilucoplan, verdiperstat, CNM-Au8 nanocrystalline gold, SLS-005 or ICI4 as combination or add-on therapy. BACKGROUND OF THE INVENTION Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord (Peters 2015). This rapidly progressing fatal disease leads to weakness of limb, respiratory, and bulbar muscles. Patients progressively lose control of voluntary muscles, leading to loss of limb function and the ability to chew, swallow, speak and eventually breathe. ALS is a rare condition, having a mean incidence rate of 2.8/100,000 in Europe and 1.8/100,000 in North America, and a mean prevalence rate of 5.40/100,000 in Europe and 3.40/100,000 in North America (Bozzoni 2016). In ~90% of cases, there is no apparent genetic mutation underling the disease (sporadic ALS). Approximately 5% to 10% of ALS cases are familial (fALS) and caused by a genetic mutation. There are >25 genes which are recognized as associated and causative of ALS. The most common disease-causing mutations are C9ORF72 (33.7% of fALS) and SOD1 (14.8% of fALS) (Zou et al. 2017). ALS patients experience signs and symptoms of progressive muscle atrophy and weakness, increased fatigue, and problems with swallowing, which typically lead to aspiration pneumonia, respiratory failure, and death. Progressive functional deficits lead to an overall loss of independence and death. ALS begins in the limbs in about two-thirds of patients, most often in the arms. The first symptoms are usually unilateral and focal. Early findings include foot drop, difficulty walking, loss of hand dexterity or difficulty lifting the arms over the head. Eventually, limb function can be lost, leading to dependence on caregivers. Patients may fall or lose the ability to walk all-together. Bulbar-onset disease, often occurring in older women, appears to have a worse prognosis (Chiò et al. 2009). Non-motor symptoms of ALS include behavioral disturbances, dysexecutive impairment, and frontotemporal dementia. Overt frontotemporal dementia occurs in approximately 15% of patients, but as many as 50% are impaired by neuropsychological tests (Lomen-Hoerth et al. 2003; Gordon et al. 2011). Changes involve language, judgment, personality, affect and executive function. Patients with ALS and dementia have shorter survival, possibly as a result of poor decision-making ability (Olney et al. 2005). The median survival is 2 to 4 years from onset; only 5-10% of patients survive beyond 10 years (Chiò et al. 2013). There is currently no known disease-modifying therapy for the treatment of ALS. Two approved drugs are riluzole and edatavone. Riluzole slows the rate of progression of the disease and prolongs survival by 2 or 3 months and edaravone slows physical decline (Jaiswal 2018). The pathophysiological mechanism of ALS appears to be multifactorial, and several mechanisms contribute to neurodegeneration. These include impaired autophagy, mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. Early pathological events in ALS include perturbations in axonal transport, formation of toxic protein aggregates and NMJ disruption. All of these lead to axonal degeneration and motor neuron death (Ionescu et al. 2019). The neuropathological features of ALS include muscle atrophy, loss of anterior horn cells, and sclerosis of the spinal cord lateral columns (Martel 2016). Gliosis, defined as activation of astrocytes and microglia, is also a hallmark of ALS. Pridopidine Pridopidine (formerly ACR16, Huntexil®) is a unique compound in clinical development for the treatment of Huntington's disease (HD) and ALS. The chemical name of pridopidine is 4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine, and its Chemical Registry Number is CAS 346688-38-8 (CSID:7971505, 2016). The Chemical Registry number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790 2016). Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459 and PCT Application Publication No. WO 2017/015609. U.S. Patent No. RE46,117 discloses pridopidine for the treatment of a variety of diseases and disorders. Pridopidine is a highly potent and selective Sigma-1 receptor (S1R) agonist developed by Prilenia for the treatment of neurodegenerative and neurodevelopmental disorders. The S1R is an intracellular ligand-operated protein located mainly at the Mitochondria Associated Membranes (MAM) and is implicated in cellular di