KARUNA

(KarXT)

TRIAL PHASE
Product Candidate
PureTech Ownership
Initial Indications
Preclinical
Phase 1
Phase 2
Phase 3
KarXT
31.6% (Karuna) R
Schizophrenia, AD Psychosis, Pain

Initial Indication(s):

Schizophrenia, psychosis in Alzheimer's, pain

Patient Population:

~2.7M (Schizophrenia)
~5.7M (with Alzheimer's; ~50% develop psychosis)

Collaborators:

Lilly

Key Differentiation:



KarXT
Schizophrenia, AD Psychosis, Pain
31.6% (Karuna) R
2

Initial Indication(s):

Schizophrenia, psychosis in Alzheimer's, pain

Patient Population:

~2.7M (Schizophrenia)
~5.7M (with Alzheimer's; ~50% develop psychosis)

Collaborators:

Lilly

Key Differentiation:



Targeting muscarinic receptors in the brain while overcoming GI tolerability issues

Founded by PureTech, Karuna is targeting muscarinic cholinergic receptors for the treatment of psychosis and cognitive impairment across central nervous system (CNS) disorders, including schizophrenia and psychosis in AD, 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 preferentially 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.
    • There are approximately 2.7 million adults living with schizophrenia and approximately 5.7 million people living with AD in the United States. Up to 50% of the estimated 5.7 million patients with AD in the United States experience psychosis at some point during the course of their disease. 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. People with schizophrenia have a ten to fifteen year reduction in life expectancy compared to the general population, struggle to maintain employment or live independently and are often unable to maintain meaningful interpersonal relationships.
    • Current antipsychotics only address psychosis, also known as positive symptoms (e.g. hallucinations and delusions), but despite treatment patients often experience residual positive symptoms throughout their lives. 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 have modest efficacy in many patients and significant side effects. At least half of patients fail to adequately respond to current antipsychotic drugs. Additionally, current treatments are often associated with severe side effects, including sedation, extrapyramidal side effects such as motor rigidity, tremors and slurred speech and significant weight gain 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.
    • There is an unmet 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 therapeutic benefits 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) 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
    • Karuna is currently conducting a Phase 2 clinical trial of KarXT for the treatment of acute psychosis in patients with schizophrenia and expects topline results in late 2019. The safety and tolerability of KarXT and dose selection in this trial is supported by results from Karuna’s two Phase 1 healthy volunteer studies in over 140 patients with KarXT. As disclosed in its public filings, Karuna observed in its first Phase 1 randomized, double-blind placebo-controlled study that the addition of trospium to xanomeline was associated with clinically meaningful reductions in the rate of the most common treatment-emergent cholinergic adverse events, or ChAEs, than reported with xanomeline plus placebo, including nausea, vomiting, diarrhea and excess sweating and salivation.
    • Karuna’s second Phase 1 study was a randomized, double-blind, placebo-controlled multiple ascending dose trial of KarXT. The study successfully demonstrated tolerability at xanomeline 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 April 2019, Karuna completed an $82.1 million Series B financing round, including the issuance of $7.1 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.
    • 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
    • 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 of acute psychosis in patients with schizophrenia.
  • Expected Milestones and Timing
    • Karuna expects to read out topline results from its Phase 2 clinical study of KarXT for the treatment of acute psychosis in patients with schizophrenia by late 2019.
    • Karuna expects to initiate a Phase 1b clinical trial for the treatment of experimentally induced pain in healthy volunteers in the second half of 2019, with initial data expected in 2020, and a Phase 1b clinical trial in healthy elderly volunteers to assess the safety and tolerability of KarXT for the treatment of psychosis in AD in 2019

       

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