Emraclidine

Last updated

Emraclidine
Emraclidine.svg
Clinical data
Other namesCVL-231; PF-06852231
Identifiers
  • 1-(2,4-dimethyl-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)-2-[1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl]ethanone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C20H21F3N4O
Molar mass 390.410 g·mol−1
3D model (JSmol)
  • CC1=CC(=NC2=C1CN(C2)C(=O)CC3CN(C3)C4=CC(=NC=C4)C(F)(F)F)C
  • InChI=1S/C20H21F3N4O/c1-12-5-13(2)25-17-11-27(10-16(12)17)19(28)6-14-8-26(9-14)15-3-4-24-18(7-15)20(21,22)23/h3-5,7,14H,6,8-11H2,1-2H3
  • Key:DTCZNKWBDTXEBS-UHFFFAOYSA-N

Emraclidine (developmental code names CVL-231, PF-06852231) is an investigational antipsychotic for the treatment of both schizophrenia and Alzheimer's disease psychosis developed by Cerevel Therapeutics. [1] [2] On November 11, 2024, AbbVie announced that phase 2 clinical trials did not show an improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline when compared to the placebo group. [1] [3] [4]

Contents

Mechanism of action

Emraclidine is a positive allosteric modulator that selectively targets the muscarinic acetylcholine receptor M4 subtype. The M4 receptor subtype is expressed in the striatum of the brain, which plays a key role in regulating acetylcholine and dopamine levels. An imbalance of these neurotransmitters has been linked to psychotic symptoms in schizophrenia. Unlike other muscarinic receptors, M4 receptor subtypes are selectively expressed in the striatum and activation of these receptors has been shown to indirectly regulate dopamine levels without blocking D2/D3 receptors, which may lead to unwanted motor side effects seen in current antipsychotics. [5] Activation of the M4 receptor subtype may also have antipsychotic effects by reducing cortical glutamatergic hyperactivity, which is associated with schizophrenia, especially in early onset of disease. [5] Knock-out mouse data suggests M4 receptors drive the antipsychotic activity of xanomeline, with M1 receptors believed to contribute to GI side effects. [6]

History

In June 2021, Cerevel first announced positive results from a phase 1b trial evaluating emraclidine in schizophrenia patients. In the phase 1b trial, both treatment groups, assessing 30 mg once daily and 20 mg twice daily, showed clinically meaningful and statistically significant improvements in PANSS total score and were generally well-tolerated compared with placebo after six weeks of treatment. [7] The study demonstrated promising efficacy and safety profiles, supporting further clinical development. [8]

In June 2022, Cerevel initiated two phase 2 trials, EMPOWER-1 and EMPOWER-2, designed to be registration-enabling studies for emraclidine in schizophrenia. [9]

In November 2024, AbbVie announced that both EMPOWER-1 and EMPOWER-2 trials did not meet their primary endpoints, as emraclidine failed to demonstrate a statistically significant reduction in the PANSS total score compared to placebo. [10]

Clinical data

In a phase 1b trial, emraclidine 30mg once daily (n=27) demonstrated clinically meaningful and statistically significant improvement in PANSS total score at 6 weeks of 12.7 points (Cohen's d=0.68, p=0.023) least squares (LS) mean reduction compared with placebo in schizophrenia patients with acute psychosis. Emraclidine 20mg twice daily (n=27) demonstrated an 11.1 point (Cohen's d=0.59, p=0.047) improvement. [11] The trial also suggested that emraclidine was not associated with extrapyramidal side effects and weight gain, and that selective activation of the M4 receptor resulted in infrequent gastrointestinal side effects. [12] Results from the phase 1b trial were followed up by two 6-week phase 2 trials.

The EMPOWER program evaluated emraclidine in schizophrenia patients with an acute exacerbation in two placebo-controlled clinical trials studying multiple doses to explore the therapeutic dose range of emraclidine. In phase 2 trial EMPOWER-1, those receiving placebo (n=127) saw a LS mean change in PANSS of -13.5, while those receiving emraclidine 10 mg once daily (n=125) and 30mg once daily (n=127) saw an LS mean change in PANSS of -14.7 and -16.5, respectively. [10] In EMPOWER-2, those receiving placebo (n=128) saw an LS mean change in PANSS of -16.1 , while those receiving emraclidine 15 mg once daily (n=122) and 30mg once daily (n=123) saw an LS mean change of -18.5 and -14.2, respectively. [10] In these phase 2 trials, emraclidine was well-tolerated, with a safety profile comparable to that seen in the previous phase 1b trial. The most commonly reported adverse events were headache, dry mouth, and dyspepsia. [13]

Society and culture

In August 2024, AbbVie completed the acquisition of Cerevel Therapeutics, expanding its neuroscience pipeline with emraclidine. [14]

Following the announcement of phase 2 trial results, AbbVie's shares were down more than 12% compared to the previous close, representing a $40 billion decrease in market capitalization. Shares of Bristol Myers Squibb, which sells Cobenfy, a medicine that emraclidine would have competed against, rose around 12%. [15] AbbVie later disclosed a $3.5 billion impairment charge related to the unsuccessful development of emraclidine in January 2025. [16]

Further reading

See also

References

  1. 1 2 "Emraclidine - Cerevel Therapeutics". AdisInsight. 28 August 2024. Retrieved 20 October 2024.
  2. ↑ "Emraclidine". Cerevel Therapeutics. 4 January 2020. Retrieved 2023-02-15.
  3. ↑ Clinical trial number NCT05227690 for "A Trial of 10 and 30 mg Doses of CVL-231 (Emraclidine) in Participants With Schizophrenia" at ClinicalTrials.gov
  4. ↑ "AbbVie Provides Update on Phase 2 Results for Emraclidine in Schizophrenia". AbbVie News Center. Retrieved 2025-04-06.
  5. 1 2 Krystal JH, Kane JM, Correll CU, Walling DP, Leoni M, Duvvuri S, et al. (December 2022). "Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial". Lancet. 400 (10369): 2210–2220. doi:10.1016/S0140-6736(22)01990-0. PMID   36528376. S2CID   254705359.
  6. ↑ Yohn SE, Conn PJ (July 2018). "Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia". Neuropharmacology. 136 (Pt C): 438–448. doi:10.1016/j.neuropharm.2017.09.012. PMC   5844786 . PMID   28893562.
  7. ↑ "Cerevel Therapeutics Announces Positive Topline Results for CVL-231 in Phase 1b Clinical Trial in Patients with Schizophrenia". AbbVie News Center. 2021-06-29. Retrieved 2025-04-10.
  8. ↑ "Cerevel Therapeutics Announces Positive Topline Results for CVL-231 in Phase 1b Clinical Trial in Patients with Schizophrenia". AbbVie News Center. 2021-06-29. Retrieved 2025-04-10.
  9. ↑ "Cerevel Therapeutics Announces Positive Results in Emraclidine Ambulatory Blood Pressure Monitoring Trial". AbbVie News Center. 2022-12-19. Retrieved 2025-04-10.
  10. 1 2 3 "AbbVie Provides Update on Phase 2 Results for Emraclidine in Schizophrenia". AbbVie News Center. 2024-11-11. Retrieved 2025-04-10.
  11. ↑ Guido A, Santoro PE, DE Cata DA, Peruzzi L, Chieffo DP, Gualano MR, et al. (March 2024). "Prevalence of burnout and psycho-emotional disorders among non-health workers: a single tertiary care pediatric oncology center experience". Minerva Pediatrics. 96 (8): 667–678. doi: 10.1016/j.biopsych.2024.03.014 . PMID   38512345.
  12. ↑ "Emraclidine Delivers Positive Results in Phase Ib Trial". The Medicine Maker. December 20, 2022. Retrieved 2025-04-15.
  13. ↑ "AbbVie Provides Update on Phase 2 Results for Emraclidine in Schizophrenia" (Press release). AbbVie. November 11, 2024. Retrieved April 16, 2025.
  14. ↑ "AbbVie Completes Acquisition of Cerevel Therapeutics". AbbVie News Center. 2024-08-01. Retrieved 2025-04-10.
  15. ↑ Bell J (November 11, 2024). "On Wall Street, 'flat out' failure of AbbVie schizophrenia drug leaves analysts stunned". BioPharma Dive. Retrieved April 15, 2025.
  16. ↑ "AbbVie takes $3.5B hit after emraclidine's phase 2 flop in schizophrenia". Fierce Biotech. 2025-01-10. Retrieved 2025-04-10.
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