Selective Muscarinic Receptor Agonists

(KarXT)

Brain / Nervous System

TRIAL PHASE
MECHANISMINDICATION(S)PRODUCT NAMEPreclinicalPhase 1Phase 2Phase 3
Selective Muscarinic Receptor Agonists
Schizophrenia, Alzheimer’s Disease, Bipolar Disorder
Karuna
(KarXT )

Brain / Nervous System

Selective Muscarinic Receptor Agonists
INDICATION(S):Schizophrenia, Alzheimer’s Disease, Bipolar Disorder
NAME:Karuna (KarXT )
STAGE:Phase 1
Untapped neurotransmitter systems

Our selective muscarinic receptor agonists are being advanced for the treatment of serious central nervous system (CNS) disorders. KarXT (Karuna-Xanomeline-Trospium), our lead program, selectively targets M1/M4 muscarinic receptors in the brain while blocking their activation in peripheral tissues to significantly improve the safety profile while enabling this new class of drugs that showed impressive efficacy to advance to patients. This novel product candidate has the potential to be one of the most promising new mechanisms for treating people with psychosis and cognitive deficits in serious CNS disorders like schizophrenia and Alzheimer’s disease that affect tens of millions of patients.

  • Patient Need & Market Potential
    • Psychosis and severe cognitive impairments are debilitating features of schizophrenia and Alzheimer’s disease and other mental illnesses that affect tens of millions of people.
    • Prognosis for these patients is poor with no existing medicines that sufficiently and safely treat psychosis and cognition
    • Antipsychotics are the mainstay therapy; however, drugs currently in use all rely on the same fundamental mechanism of action and, despite widespread use, the prognosis for patients remains poor – only 30% live independently, 10-20% maintain full time employment, and, tragically, 5% end their life with suicide 
    • Current antipsychotics only address positive symptoms, but patients often experience residual positive symptoms throughout their lives; negative and cognitive symptoms are left untreated
    • Current antipsychotics are associated with serious side effects, including potentially irreversible movement disorders (tardive dyskinesia), metabolic dysfunction, glucose intolerance, weight gain, sedation and cardiovascular mortality in the elderly
    • There is a desperate need for new treatments in schizophrenia that treat the positive symptoms, and also address the negative and cognitive symptom, and that have a good safety profile
  • Our Approach to Solving the Problem
    • Xanomeline, a muscarinic agonist which we have exclusively licensed, has been previously studied (by Eli Lilly & Co) in double-blind, placebo-controlled trials in schizophrenia and Alzheimer’s disease, where it has demonstrated impressive efficacy for treating psychosis and had beneficial effects on cognition. [See publications below].  Xanomeline to our knowledge is the only muscarinic agonist that has demonstrated human efficacy in schizophrenia and Alzheimer's 
    • Xanomeline however had some tolerability concerns associated with peripheral activation of muscarinic receptors (but without the serious side effects associated with the current anti-psychotics) and its development was discontinued
    • By pairing xanomeline with trospium chloride, a muscarinic antagonist that acts only in the periphery (outside the brain or central nervous system) and has been approved in the US and Europe for the treatment of overactive bladder, we believe our selective muscarinic receptor modulators can alleviate the tolerability issues seen with xanomeline while maintaining the excellent efficacy profile
  • Intellectual Property
    • Our selective muscarinic receptor agonists program has broad worldwide intellectual property coverage, including exclusive rights to six issued patents and several pending patent applications 
    • The filings cover pharmaceutical compositions, methods of use, and methods of production for treatment of disorders ameliorated by muscarinic receptor activation.
    • Team
    • We have assembled a seasoned team with strong expertise in neuroscience drug research and development 
    • Key advisors include Dr. Edmund Harrigan, who previously served as Senior Vice President of Worldwide Safety and Regulatory for Pfizer; Dr. Bennett Shapiro, previously the Executive Vice President of Research for Merck; Dr. Alan Breier, currently Professor of Psychiatry and Vice Chair for Clinical Research at Indiana University School of Medicine and Chief of the Psychotic Disorders Program; and Dr. Atul Pande, the former Senior Vice President, Head of Neuroscience, and Senior Advisor, Pharmaceutical R&D at GlaxoSmithKline.  
    • The program was developed and is being run by Dr. Andrew Miller; and Dr. Stephen Brannan.
  • Milestone Achieved
    • Xanomeline has been dosed in over 800 patients, and has demonstrated excellent efficacy in reducing psychosis and improving cognition in placebo-controlled human trials in both people with Alzheimer’s disease and schizophrenia [See publications below]
    • In a double-blind, placebo-controlled monotherapy trial in schizophrenia patients, xanomeline showed a significant 24-point reduction over placebo was observed in the Positive and Negative Syndrome Scale [See publications below]
    • In December 2016, we announced positive results from a tolerability proof of concept study in which KarXT was shown to significantly reduce the incidence of prespecified cholinergic adverse events by a clinically meaningful extent (46% p=0.016) compared to xanomeline alone, and each individual cholinergic adverse event was reported at a lower rate in the KarXT treatment arm; furthermore, no severe or serious adverse events were reported.
  • Collaborations
    • We licensed Xanomeline from Eli Lilly and our advisors include the former Chief Medical Officer of Lilly and the academic investigators that ran the initial Xanomeline study 
    • Our Selective Muscarinic Receptor Agonists program received the Wellcome Trust’s Translation Fund Award, consisting of an unsecured convertible note of up to $3.84 million from the Wellcome Trust for the combination tolerability proof of concept study
  • Expected Milestones and Timing
    • We expect to initiate a Phase 2 trial of KarXT in the first half of 2018, with the goal of replicating existing efficacy data with xanomeline in people with schizophrenia while alleviating tolerability issues

If successful, KarXT could provide a new mechanism for treating schizophrenia, a field in which treatments have relied on the same fundamental mechanisms for the last half-century. In December 2016, our selective muscarinic receptor agonists had a positive readout in its tolerability proof-of-concept study, and we expect to initiate a Phase 2b trial in the first half 2018 to demonstrate KarXT safety and efficacy in people with schizophrenia.


 Core Proprietary Technology

Previous Studies with Xanomeline

Phase II Study of Xanomeline in Alzheimer’s Disease


Proof of Concept Study of Xanomeline in Schizophrenia



Selective Muscarinic Receptor Agonists Tolerability Proof of Concept Study

Study Design Highlights


Data & Key Findings