S-pindolol benzoate (ACM-001.1)

S-pindolol has been described as an anabolic/catabolic transforming agent1. A clinical development programme for a new salt of S-pindolol (ACM.001.1) is underway with a Pharmacokinetic and Pharmacodynamic (PKPD) study which was initiated in December 2021. 

A Phase 2b/3 clinical development programme is in planning to confirm and expand upon the positive results demonstrated in a proof of concept Phase 2a trial, ACT-ONE2.

 

Mode of action

S-pindolol (ACM-001) is an anabolic/catabolic transforming agent with a multifunctional effect on three key pharmacological targets relevant for cancer cachexia:

  Reduction of catabolism by β-1receptor antagonism3,4,5

•  Increased anabolism and muscle growth, through partial β2 receptor agonism1

  Improvement in appetite and fatigue via central 5-HT1a antagonism6,7,8,9,10,11

This trio of anti-catabolic and pro-anabolic pharmacology makes S-pindolol (ACM-001) a unique candidate for development in cancer cachexia.

Clinical data

The ACT-ONE Phase II clinical study of S-pindolol (ACM-001) was a proof of concept exploratory, randomised, double-blind, placebo-controlled study in 87 patients with NSCLC (non-small-cell lung cancer) or colorectal cancer (CRC). The trial demonstrated that S-pindolol (ACM-001) was well-tolerated and that patients receiving high-dose S-pindolol (ACM-001) showed a median weight gain of 2.74kg compared to a median 1.09kg weight loss in patients receiving placebo over a 4-month period2.

Patients receiving S-pindolol (ACM-001) also demonstrated improved hand-grip strength.

Actimed initiated a pharmacokinetics and pharmacodynamics (PK/PD) study in December 2021 for S-pindolol benzoate (ACM-001.1). The study is being conducted in healthy subjects in two parts. It will compare S-pindolol benzoate to pindolol and will investigate PK across a range of doses of S-pindolol benzoate. This study will profile S-pindolol benzoate and is a prelude to the Phase 2b/3 clinical programme in patients with cancer cachexia which is in planning.

 

UK Patent

In May 2022, Actimed obtained a new UK patent (GB 2593902 B) covering new salts of S-pindolol for use in the treatment or prevention of cachexia with an expiry date in 2040. 

Additionally, an international patent application has been filed under the Patent Cooperation Treaty (PCT) and was published in October 2021, which seeks to extend patent protection for new S-pindolol salts to all relevant major international markets out to 2041.

 

 

Reference

1Pötsch MS, Tschirner A, Palus S, von Haehling S, Doehner W, Beadle J, Coats AJ, Anker SD, Springer J. The anabolic catabolic transforming agent (ACTA) espindolol increases muscle mass and decreases fat mass in old rats. J Cachexia Sarcopenia Muscle.. 2014 Jun;5(2):149-58

2A Coats et al Espindolol for treatment and prevention of cachexia: the ACT-ONE trial. J Cachexia Sarcopenia Muscle 2016; 7: 355–365

3Clark BJ and Bertholet A. (1983). Effects of pindolol on vascular smooth muscle. Gen. Pharmacol.; 14: 117-119

4Jeppsson AB, Johansson U and Waldeck B. (1984). Steric aspects of agonism and antagonism at betaadrenoreceptors: experiements with the enantiomers of terbutaline and pindolol. Act. Pharmacol. Toxicol
(Copenh).; 54(4): 285-291

5Boucher M, Duchene-Marullaz P and Moundanga JL. (1986). Studies on the stereoisomers of betaadrenoreceptor
antagonists in conscious A-V blocked dogs. Br. J. Pharmacol.; 89(1): 119-127

6Newman-Tancredi A, Chaput C, Gavaudan S, Verriele L, Millan MJ. Agonist and antagonist actions of (-) pindolol, at recombinant, human serotonin 1A (5-HT1A) receptors.  Neuropsychopharmacology. 1998  May; 18(5):395-398

7Andree B, Thorburg SO, Halldin C, Farde L. Pindolol binding to 5-HT1a receptors in the human brain confirmed with positron emission tomography. Psychopharmacology (Berl). 1999 June; 144(3) 303-305

8Martinez D, Hwang D, Mawlawi O, Slifstein M, Kent J, Simpson N, Parsey RV, Hashimoto T, Huang Y, Shinn A, Van Heertum R, Abi-Dargham A, Caltabiano S, Malizia A, Cowley H, Mann JJ, Laruelle M. Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology. 2001 Mar;24(3):209-29

9Castro ME, Harrison PJ, Pazos A, Sharp T. Affinity of (+/-)-pindolol, (-)-penbutolol, and (-)-tertatolol for pre- and postsynaptic serotonin 5-HT(1A) receptors in human and rat brain. J Neurochem. 2000 Aug;75(2):755-62

10Yan H and Lewander T. Differential tissue distribution of the enantiomers of racemic pindolol in the rat. Eur Neuropsychopharmacol. 1999 Dec; 10(1): 59-62

11Olver Js, Cryan JF, Burrows GD, Norman TR. Pindolol augmentation of antidepressants: a review and rationale. Aust. NZ. J. Psychiatry 2000 Feb;34 (1): 71-79