KARUNA

(KarXT)

Product Candidate**
PureTech Ownership
Initial Indications
Preclinical
Phase 1
Phase 2
Phase 3
KarXT
20.3% (Karuna)R
Schizophrenia, Dementia-related psychosis, Pain

Initial Indication(s):

Schizophrenia, Dementia-related psychosis, Pain

Patient Population:

Schizophrenia (~2.7M),
Dementia-related Psychosis (~1.2M),
Pain

Collaborators:

teva NYU memorialSloanKet

Key Differenciation:

Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across CNS disorders, including schizophrenia and dementia-related psychosis, as well as pain. Pending the outcome of an end of Phase 2 meeting with the FDA, Karuna's lead program is expected to enter a Phase 3 study by the end of 2020.



KarXT
Schizophrenia, Dementia-related psychosis, Pain
20.3% (Karuna)R
Phase 2

Initial Indication(s):

Schizophrenia, Dementia-related psychosis, Pain

Patient Population:

Schizophrenia (~2.7M),
Dementia-related Psychosis (~1.2M),
Pain

Collaborators:

teva NYU memorialSloanKet

Key Differenciation:

Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across CNS disorders, including schizophrenia and dementia-related psychosis, as well as pain. Pending the outcome of an end of Phase 2 meeting with the FDA, Karuna's lead program is expected to enter a Phase 3 study by the end of 2020.

Targeting muscarinic receptors in the brain while overcoming GI tolerability issues

Founded by PureTech Health, Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across central nervous system (CNS) disorders, including schizophrenia and Alzheimer’s disease, psychosis, as well as pain. 

KarXT (Karuna-XanomelineTrospium) is Karuna’s lead investigational product candidate. It consists of xanomeline, a novel muscarinic acetylcholine receptor agonist that has demonstrated efficacy in placebo-controlled human trials in schizophrenia and Alzheimer’s disease, and trospium chloride, an FDA-approved and well-established muscarinic receptor antagonist that has been shown not to measurably cross the blood-brain barrier. KarXT is designed to selectively stimulate M1/M4 muscarinic receptors in the brain without stimulating muscarinic receptors in peripheral tissues to significantly improve tolerability.

This novel product candidate has the potential to be one of the most promising new mechanisms for the treatment of people with psychosis and cognitive impairments in serious CNS disorders that affect tens of millions of people. 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, we reported positive results from our tolerability proof-of-concept study and are currently conducting a Phase 1 study using a proprietary co-formulation of xanomeline and trospium. A Phase 2 trial to evaluate the efficacy and safety of KarXT in people with schizophrenia is expected to begin in the third quarter of 2018.

  • Patient Need & Market Potential
    • Psychosis and cognitive impairments are debilitating features of schizophrenia and Alzheimer’s disease and other mental illnesses that affect tens of millions of people, but there are no existing medicines that sufficiently and safely treat psychosis and cognition impairments.
    • 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 – 70 percent don’t live independently, 80-90 percent don’t maintain full time employment, and tragically 5 percent end their life with suicide.
    • Current antipsychotics only address psychosis, also known as positive symptoms (e.g. hallucinations and delusions), but patients often experience residual positive symptoms throughout their lives; while negative and cognitive symptoms are left untreated. There are no approved treatments for the negative (e.g. apathy, loss of motivation) or cognitive symptoms (e.g. changes in working memory and attention) of schizophrenia, or the treatment of psychosis associated with Alzheimer’s disease.
    • 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 could address the positive, negative, and cognitive symptoms and are free of the problematic safety issues with existing medicines.
    • In addition to clinical data, xanomeline has shown potent activity preclinically in a number of models of analgesia, demonstrating the potential of KarXT to treat a variety of pain indications, including acute, inflammatory and neuropathic pain, and addressing the need for non-opioid pain medications.
  • Our Approach to Solving the Problem
    • Xanomeline, a muscarinic agonist that Karuna exclusively licensed, was previously studied (by Eli Lilly & Co) in randomized, double-blind, placebo-controlled trials in schizophrenia and Alzheimer’s disease, demonstrating efficacy in the treatment of psychosis and beneficial effects on cognition. To PureTech’s knowledge, xanomeline is the only muscarinic agonist that has demonstrated human efficacy in either schizophrenia or Alzheimer’s disease.
    • Eli Lilly discontinued development of xanomeline given tolerability issues associated with the activation of peripheral muscarinic receptors (but did not observe the serious side effects associated with the current antipsychotics).
    • By pairing xanomeline with trospium chloride, a muscarinic antagonist that does not measurably cross the blood-brain barrier and has been approved in the U.S. and Europe for the treatment of overactive bladder, Karuna believes KarXT could potentially alleviate the tolerability issues seen with xanomeline while maintaining the excellent efficacy profile previously demonstrated. In Karuna’s Phase 1 tolerability proof-of-concept study, KarXT was significantly better tolerated than xanomeline plus placebo and no serious or severe adverse events were reported.
  • Intellectual Property
    • Karuna has broad intellectual property coverage worldwide, including exclusive rights to six (6) patent applications which cover pharmaceutical compositions of its clinical candidate and methods of use for the treatment of disorders ameliorated by muscarinic receptor activation.
  • Team
    • Karuna has assembled a seasoned team, including some of the pre-eminent neuroscience drug research and development experts.
    • In August 2018, Dr. Steven Paul (former President of Lilly Research Laboratories and Co-founder of Sage and Voyager) was appointed Chief Executive Officer and Chairman of the Board of Karuna. Dr. Andrew Miller (previously PureTech Health) is Founder and Chief Operating Officer.
    • Key advisors include Dr. Jeff Jonas (Chief Executive Officer at Sage Therapeutics), Dr. Edmund Harrigan (previously Senior Vice President at Pfizer), Dr. Alan Breier (Indiana University School of Medicine and previously Chief Medical Officer at Eli Lilly), and Dr. Atul Pande (previously Senior Vice President at GlaxoSmithKline).
  • Milestone Achieved
    • In October 2018, Karuna announced the initiation a Phase 2 study in schizophrenia. The dose selection to be carried forward into Phase 2 is supported by results from Karuna’s Phase 1 dose-ranging study that enrolled 69 healthy volunteers and successfully demonstrated tolerability at dose levels exceeding those shown to be efficacious in previous studies of xanomeline alone. The co-formulation also achieved exposure levels equivalent to or higher than the separate dosage forms used previously.
    • In November 2019, Karuna announced that KarXT achieved the primary endpoint of its Phase 2 clinical trial for the treatment of acute psychosis in patients with schizophrenia, demonstrating a statistically significant and clinically meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale, or PANSS, score compared to placebo (p<0.0001) and also demonstrated improved tolerability as compared to placebo. The number of discontinuations due to treatment emergent adverse events (AEs) were equal in the KarXT and placebo arms (n=2 in each group). One serious adverse event (SAE) was experienced in the drug treatment arm, in which the patient discontinued treatment and subsequently sought hospital care for worsening psychosis, meeting the regulatory definition of an SAE.
    • In 2019, Karuna initiated an experimental medicine study evaluating the effect of KarXT on induced pain in healthy volunteers.
    • In December 2019, Karuna initiated a Phase 1b clinical trial of KarXT designed to demonstrate the safety and tolerability of KarXT in healthy elderly volunteers with the goal of selecting the most appropriate doses to carry forward into future studies in patients with dementia-related psychosis.
    • Current treatments are associated with severe side effects, including sedation, extrapyramidal side effects such as motor rigidity, tremors and slurred speech, and significant weight gain, sometimes resulting in the complications of diabetes, hyperlipidemia, hypertension and cardiovascular disease. The clinical benefit of current antipsychotics is further limited by poor adherence to medication regimens.
    • Xanomeline has been dosed in studies enrolling over 800 patients and has demonstrated efficacy in reducing psychosis and shown beneficial effects on cognition in placebo-controlled human trials in both Alzheimer’s disease and schizophrenia.
  • Collaborations
    • In April 2019, Karuna completed an $82 million Series B financing round, including the issuance of $7 million in shares upon conversion of debt into equity.
    • In August 2018, Karuna completed a $42 million Series A financing round, including the issuance of $22 million in shares upon conversion of debt into equity.
    • Karuna licensed xanomeline from Eli Lilly, and company advisors and management include the former Chief Medical Officer and former Executive Vice President of Research and Development from Eli Lilly.
    • Karuna received a second Wellcome Trust Translational Fund Award for up to $8 million. The funding is being used to further advance clinical development of KarXT through the Phase 2 study in patients with schizophrenia.
  • Expected Milestones and Timing
    • Karuna anticipates holding an end of Phase 2 meeting with FDA in Q2 2020. Based on the outcome of that meeting, Karuna expects to initiate its Phase 3 clinical trial by the end of 2020.
    • Karuna anticipates topline results from a Phase 1b clinical trial for the treatment of experimentally induced pain in healthy volunteers in mid-2020.
    • Karuna expects topline results from a Phase 1b clinical trial in healthy elderly volunteers to assess the safety and tolerability of KarXT for the treatment of dementia-related psychosis by the end of 2020.

KarXT is being evaluated in a Phase 2 study in people with schizophrenia experiencing acute psychosis. Karuna has a worldwide exclusive license for xanomeline and has a patent portfolio more broadly covering selective muscarinic targeting enabled by the KarXT approach. 


 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