Combination Therapy of CST-2032/CST-107 Shows Promise in Treating Cognitive Impairment in Phase 2a Trial

New additional data from a phase 2a trial (NCT05104463) assessing CuraSen Therapeutics’ combination adrenergic activator, CST-2032/CST-107, showed significant improvement with the treatment across several cognitive domains in patients with mild cognitive impairment (MCI) or mild dementia from either Alzheimer disease (AD) or Parkinson disease (PD). These findings suggest that the combination therapy may benefit these patient groups impacted by adrenergic function; however, larger, longer studies are needed to confirm.¹

Among 55 patients with AD (n = 30) or PD (n = 25) who completed the study, 25 of those with AD who also had MCI demonstrated a 0.36 effect size on the Digit Symbol Substitution test on day 14 (P = 0.02) of treatment. On the same day, this group had a 0.66 effect size for happy expression (P = 0.04) and 0.91 effect size for surprise expression on assessment of facial expression recognition response time. In patients with PD who also had MCI (n = 21), findings showed a 0.52 effect size on day 14 with the Stop Signal test (P = 0.04).

"As a clinician with limited treatment options for my patients with mild cognitive impairment, I was very encouraged to see the significant effects of the CST-2032/CST-103 adrenergic combination in a range tests of cognition, including those for complex attention, memory, executive function and social awareness. We are looking forward to testing this combination in longer studies, with the potential to improve quality of lives for patients and their caregivers," principal investigator Tim Anderson, BSc(Hons), MBChB, MD, FRACP, clinical director of New Zealand Brain Research Institute and professor of medicine at University of Otago, told NeurologyLive^®.

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Presented at the 2024 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), held March 5-9 in Lisbon, Portugal, this randomized, placebo-controlled, double-blinded crossover study assessed 64 patients with MCI or mild dementia who had either AD or PD. The trial aimed to establish safety and tolerability of CST-2032/CST-107, identify the optimal dosage, and identify cognitive tests that are responsive to agonist stimulus in a 2-week treatment period.

Investigators had the study held at several sites in the United States and New Zealand. Patients received either 3 mg of daily CST-2032 with 3 mg of nadolol for 14 days, or matching placebo, followed by a wash-out period of at least 7 days before crossing over to the other treatment arm. Measures of cognition assessed in the trial were the Digit Symbol Substitution Test, Cambridge Neuropsychological Test Battery (CANTAB), and the facial expression recognition task. According to a statement, blood samples from participants are in the process of being analyzed for any AD biomarkers, and DNA samples for AD and PD genotyping.¹

Both CST-2032 and CST-103 are oral, brain-permeant, β2 adrenoceptor (β2-AR) agonists delivered in combination with CST-107 to inhibit peripheral effects of β2-AR agonism. These treatment candidates enable reactivation of brain adrenergic function lost early in the progression of neurodegenerative diseases. CureSen stated that the company plans to initiate longer studies with both CST-2032/CST-107 and CST-103/CST-107 in patients with AD and PD with MCI later in 2024, as well as to develop fixed-dose combination tablets for each of these treatment candidates.

“These encouraging data build on earlier results presented at October 2023’s CTAD conference, reinforcing that treatment with CST 2032/CST-107 can produce meaningful quality-of-life cognitive improvements for patients with AD and PD, particularly those with mild cognitive impairment, rapidly and safely,” Anthony Ford, PhD, chief executive officer at CuraSen, said in a statement.¹ “The robust, collective data set from both CST-2032 and CST-103 demonstrate that this novel mechanism of action for restoring adrenergic function to the brain is a highly compelling strategy to address unmet symptoms of neurodegeneration. We plan to evaluate additional doses and refine optimal patient profiles in our upcoming phase 2 studies, with the goal to significantly increase cognitive performance and ultimately, halt disease progression.”

Previous data presented at the 2023 AD/PD conference, held March 28 to April 1 in Gothenburg, Sweden, showed that a combination of CST-103 and CST-107 improved performance in tests of cognition and was well tolerated among patients with PD with REM sleep behavior disorder (RBD). CuraSen also presented positive data on CST-2032 in healthy volunteers and patients with MCI.²

The phase 2 proof-of-concept study enrolled 25 patients with PD and RBD who were blinded to oral CST-103 or placebo for 2 weeks, with cognition evaluated by multiple measures including the CANTAB. Locus coeruleus (LC) integrity, a primary source of forebrain noradrenaline and one of the earliest signs of pathology in neurodegenerative disorders, was quantified using neuromelanin-MRI. CST-107, a ß2 antagonist with negligible central nervous system absorption, was co-administered with CST-103 to inhibit known peripheral effects of ß2-AR agonists.

Results showed that on neuromelanin MRI, conducted in 18 of the 25 individuals, the median observed LC integrity in patients with PD and RBD were below those of previously measured age-matched healthy controls. After 1, 7, or 14 days of dosing with CST-103/CST-107, several cognitive domains witnessed improvement, most notably, statistically significant increases relative to placebo were observed in the number of words recalled immediately (1.12 words; P = .003) and at 45 minutes (1.72 words; P = .003) after presentation of an 18-item word list.

REFERENCES
1. CuraSen Therapeutics Announces Oral Presentation of Additional Positive Phase 2a Data with CST-2032/CST-107 in Patients with Alzheimer’s or Parkinson’s Disease at AD/PD™ 2024 International Conference. News Release. Published March 7, 2024. Accessed March 19, 2024. https://www.curasen.com/curasen-therapeutics-announces-oral-presentation-of-additional-positive-phase-2a-data-with-cst-2032-cst-107-in-patients-with-alzheimers-or-parkinsons-disease-at-ad-pd-2024-i/
2. CuraSen Therapeutics to present phase 2 data showing rapid-onset cognition and mood benefit with CST-103/CST-107 (Clenbuterol/Nadolol) in Parkinson’s disease at the Alzheimer’s Disease and Parkinson’s Disease (AD/PD’23) conference. News release. March 30, 2023. Accessed March 30, 2023. https://www.curasen.com/curasen-therapeutics-to-present-phase-2-data-showing-rapid-onset-cognition-and-mood-benefit-with-cst-103-cst-107-clenbuterol-nadolol-in-parkinsons-disease-at-the-alzheimers-disease/