Prilenia announces the publication of data elucidating a mechanism of the neuroprotective potential of pridopidine

– This new research adds to the growing understanding of pridopidine as a highly selective S1R agonist that has shown neuroprotective properties in multiple models
– Research details the role of pridopidine’s mechanism of action in autophagy, a cellular process critical to maintaining neuronal health
– By enhancing autophagy, pridopidine may reduce toxic protein aggregation that characterizes neurodegenerative diseases

Newswise — NAARDEN, NL, May 25 2022 — Prilenia Therapeutics BVa clinical-stage biotechnology company focused on the urgent mission of developing novel therapies to slow the progression of neurodegenerative and neurodevelopmental disorders, today announced the publication of its research in the peer-reviewed journal Autophagy which support the potential neuroprotective properties of pridopidine by enhancing autophagy in a model of amyotrophic lateral sclerosis (ALS).

Pridopidine is an oral, highly selective and potent Sigma-1 receptor (S1R) agonist currently in late-stage development for the potential treatment of Huntington’s disease (HD) and ALS. In clinical studies to date, pridopidine (45 mg twice daily) has demonstrated a similar safety and tolerability profile to placebo (Geva, 2022).

S1R is highly expressed in the brain and spinal cord where it regulates several processes commonly impaired in various neurodegenerative diseases. Activation of S1R by pridopidine stimulates multiple cellular pathways, including autophagy, essential for neuron function and survival, and may lead to neuroprotective effects (Maurice, 2021).

Autophagy is the process by which a cell removes old or damaged proteins (Fleming et al., 2022). By enhancing autophagy, pridopidine may reduce the toxic protein aggregation that characterizes neurodegenerative diseases such as HD, ALS, Alzheimer’s disease and Parkinson’s disease.

The shuttle of molecules from the cytoplasm to the nucleus (nucleocytoplasmic shuttle), via the nucleopore complex, is essential for neuronal function and survival. A critical step in autophagy is the transport of the transcription factor EB (TFEB) into the nucleus, where it upregulates the expression of autophagy-related genes (Cunningham et al., 2020). This nucleocytoplasmic process is altered in various neurodegenerative diseases, including ALS (Coyne et al., 2020).

“This study confirms that pridopidine plays an important role in maintaining the health of a neuronal cell by activating S1R which in turn interacts with specific proteins to initiate the autophagic process,” said Tsung-Ping Su, Ph. .D., Chief, Cell Pathobiology Section, National Institute on Drug Abuse (NIDA) located in Baltimore, MD. “Although this article primarily focuses on a model of ALS, our results also suggest the promise of a pharmacological approach targeting S1R in various diseases in which autophagy is impaired.”

Highlights of the article titled “Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine” to understand:

• This new research shows that pridopidine activates the S1R by facilitating its dissociation from the ER protein BiP, freeing the S1R to interact with other protein partners.
• Activated S1R stabilizes the nucleopore complex by interacting with POM121 (a core nucleopore protein), facilitating translocation of TFEB into the nucleus.
• Translocation of TFEB into the nucleus initiates the autophagic process by upregulating the expression of autophagy genes, leading to neuroprotection.

G4C2 repeats in the c9orf72 gene are the most common cause of familial ALS (fALS) (DeJesus-Hernandez et al., 2011). This study used a cellular model of motor neurons overexpressing G4C2 repeats that destabilizes the nucleopore and reduces nucleocytoplasmic transport of TFEB, resulting in impaired autophagy and neurodegeneration. In this model, pridopidine activation of the S1R rescues the TFEB shuttle and upregulates autophagy, leading to neuroprotection.

“Our collaborations with leading researchers as well as our close working relationships within the HD and ALS communities are important as we improve our understanding of pridopidine’s mechanism of action and its impact on neurodegenerative diseases,” said Dr. Michael R. Hayden, CEO. and founder of Prilenia. “The data published in Autophagy reinforce the results of previous studies indicating that pridopidine may offer neuroprotective effects. We look forward to sharing additional information about pridopidine as data from our late-stage clinical studies becomes available. »

This new research adds to the growing understanding of the mechanism of action of pridopidine as a highly selective S1R agonist, which has previously been shown to improve impaired cellular functions in neurodegenerative diseases such as mitochondrial function, ER stress, energy production, trophic factor availability and synaptic plasticity (Geva et al., 2016; Naia et al., 2021; Ryskamp et al., 2017; Smith-Dijak et al., 2019) .

About pridopidine

Pridopidine (45 mg twice daily) is a highly selective oral Sigma-1 receptor agonist that has shown a similar safety and tolerability profile to placebo in clinical studies to date.

Pridopidine is currently being evaluated as a potential treatment for people living with Huntington’s disease in PROOF-HD, a global Phase 3 clinical trial. The study, which includes 59 sites and 499 participants, completed enrollment ahead of schedule and with numbers above the end-2021 enrollment goal. Prilenia recently received Fast Track designation for pridopidine for the treatment of HD.

In addition to PROOF-HD, pridopidine is being evaluated as a potential treatment for people living with ALS in the HEALEY ALS Platform Trial. This study represents the first of its kind in ALS and is designed to accelerate the development of promising new treatments. The study was fully enrolled in early 2022, ahead of schedule, and includes 163 participants at 52 sites. Pridopidine has received orphan drug designation for ALS in the United States and Europe.

About Prilenia

Prilenia is a clinical-stage biotech startup founded in 2018 focused on the urgent mission of developing novel therapies to slow the progression of neurodegenerative diseases and neurodevelopmental disorders. Prilenia is backed by a group of highly respected investors including: Forbion, Morningside, Sands Capital, SV Health Investors, Sectoral Asset Management, Talisman, Amplitude Ventures and the ALS investment fund. The company is based in Naarden, the Netherlands, Herzliya, Israel and Boston, MA in the United States.

For more information, visit www.prilenia.com and follow us on LinkedIn and Twitter.

^©2022 Prilenia Therapeutics BV