Drug Whisperer (July-August 2023)

1. Could an Already Approved Sleeping Pill be Repurposed for Alzheimer’s Disease Prevention?
2. Could Orally Dosed Semaglutide (Instead of Injections) be on the Horizon in the Near Future
3. Colchicine Could Benefit Post-PCI Patients when Combined with a P2Y12 Inhibitor?

1. Could an Already Approved Sleeping Pill be Repurposed for Alzheimer’s Disease Prevention?

OBJECTIVE: In Alzheimer’s disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-β levels and amyloid plaques in mouse models overexpressing amyloid-β, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-β, tau, and phospho-tau.

METHODS: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-β, tau, and phospho-tau via immuno precipitation and liquid chromatography-mass spectrometry.

RESULTS: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-β ~10% to 20% compared to placebo starting 5 hours after drug administration.

INTERPRETATION: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-β concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treat insomnia and may have potential as a repurposed drug for the prevention of Alzheimer’s disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27-40.

Lucey BP, et al. Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS. Ann Neurol. 2023 Jul;94(1):27-40. doi: 10.1002/ana.26641. Epub 2023 Apr 20.

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2. Could Orally Dosed Semaglutide (Instead of Injections) be on the Horizon in the Near Future?

BACKGROUND: Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes.

METHODS: This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0-10·5% (64-91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete.

FINDINGS: Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA1c was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA1c at week 52 were -1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, -1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] -0·27, 95% CI -0·42 to -0·12; p=0·0006), and -2·0 percentage points (0·06) with 50 mg (ETD -0·53, -0·68 to -0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related.

INTERPRETATION: Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified.

Aroda VR, et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial.  Lancet. 2023 Jun 23;S0140-6736(23)01127-3. doi: 10.1016/S0140-6736(23)01127-3. Online ahead of print.

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3. Colchicine Could Benefit Post-PCI Patients when Combined with a P2Y12 Inhibitor?

BACKGROUND: After a brief period of dual antiplatelet therapy, P2Y12 inhibitor monotherapy in the absence of aspirin effectively reduces bleeding without increasing recurrent ischemia in patients undergoing percutaneous coronary intervention (PCI). In addition, early anti-inflammatory therapies may have clinical benefits in acute coronary syndrome (ACS) patients.

OBJECTIVES: The aim of this study was to investigate the feasibility of ticagrelor or prasugrel P2Y12 inhibitor monotherapy combined with colchicine immediately after PCI in patients with ACS.

METHODS: This was a proof-of-concept pilot trial. ACS patients treated with drug-eluting stents were included. On the day after PCI, low-dose colchicine (0.6 mg daily) was administered in addition to ticagrelor or prasugrel maintenance therapy, whereas aspirin therapy was discontinued. The primary outcome was any stent thrombosis at 3 months. The key secondary outcomes were platelet reactivity measured by the VerifyNow assay (Accriva) before discharge and a reduction in high-sensitivity C-reactive protein (hs-CRP) over 1 month.

RESULTS: We enrolled 200 patients, 190 (95.0%) of whom completed the 3-month follow-up. The primary outcome occurred in 2 patients (1.0%): 1 definite and 1 probable stent thrombosis. The level of platelet reactivity overall was 27 ± 42 P2Y12 reaction units, and only 1 patient had high platelet reactivity (>208 P2Y12 reaction units). The hs-CRP levels decreased from 6.1 mg/L (IQR: 2.6-15.9 mg/L) at 24 hours after PCI to 0.6 mg/L (IQR: 0.4-1.2 mg/L) at 1 month (P < 0.001), and the prevalence of high-inflammation criteria (hs-CRP ≥2 mg/L) decreased from 81.8% to 11.8% (P < 0.001).

CONCLUSIONS: In ACS patients undergoing PCI, it is feasible to discontinue aspirin therapy and administer low-dose colchicine on the day after PCI in addition to ticagrelor or prasugrel P2Y12 inhibitors. This approach is associated with favorable platelet function and inflammatory profiles. (Mono Antiplatelet and Colchicine Therapy [MACT]; NCT04949516).

Lee SY, et al. P2Y12 Inhibitor Monotherapy Combined With Colchicine Following PCI in ACS Patients: The MACT Pilot Study. JACC Cardiovasc Interv. 2023 Aug 14;16(15):1845-1855. doi: 10.1016/j.jcin.2023.05.035.

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