Puretech Ownership1
Therapeutic Candidate2
Initial Indication(s)
Stage of Development
8.2% Equity plus Royalties
KarXT

Schizophrenia

Phase 3
Dementia-related psychosis
Phase 2 Ready

1 As of April 30, 2021, PureTech’s percentage ownership of Karuna was approximately 8.2 percent on an outstanding voting share basis. PureTech Health has a right to royalty payments as a percentage of net sales from Karuna.
2 Therapeutic candidates are investigational and have not been cleared by the FDA for use in the United States.

Advancing transformative medicines for people with psychiatric and neurological conditions
  • Karuna is developing novel therapies with the potential to transform the lives of people with disabling and potentially fatal neuropsychiatric disorders, including schizophrenia and dementia-related psychosis.
  • KarXT combines xanomeline, a muscarinic receptor agonist that has demonstrated decreases in multiple psychotic symptoms and improvements incognitive symptoms in placebo-controlled human trials in schizophrenia and AD, and trospium chloride as further described below, 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 in order to achieve meaningful therapeutic benefit in patients with psychotic and cognitive disorders.
  • Xanomeline was previously studied by Eli Lilly and Company (Eli Lilly) in randomized, double-blind, placebo-controlled trials in schizophrenia with acute psychosis and Alzheimer’s Disease (AD), demonstrating dose-dependent decreases in multiple psychotic symptoms and related behaviors, including hallucinations, delusions and agitation, as compared to patients on placebo in the treatment of psychosis and improvements in symptoms as measured by both the Alzheimer’s Disease Assessment Scale-Cognitive Subscale and the Clinician Interview-Based Impression of Change plus caregiver interview standards.
  • To our knowledge, xanomeline is the only muscarinic agonist that has demonstrated potential therapeutic benefit in humans in either schizophrenia or AD. Like all muscarinic receptor agonists studied to date, however, xanomeline’s tolerability has been limited by side effects arising from muscarinic receptor stimulation in peripheral tissues, leading to nausea, vomiting, diarrhea and increased salivation and sweating, collectively referred to as cholinergic AEs (ChAEs), which led Eli Lilly to discontinue development of xanomeline. By pairing xanomeline with trospium chloride, Karuna believes KarXT could potentially maintain efficacy of xanomeline while ameliorating its ChAEs.
  • Program Discovery Process by the PureTech Team
    • We were interested in developing a new approach to treat schizophrenia that was effective but did not have the debilitating side effects of the current class of antipsychotics, realizing that any potential new approaches could have wider applicability. We engaged with a group of leading schizophrenia experts who were most excited about muscarinic agonists, pointing to the data generated by Eli Lilly with xanomeline, which was not advanced at that time due to tolerability issues. We invented and broadly filed patents to cover the concept of combining a muscarinic receptor agonist with a peripherally acting antagonist, and we in-licensed xanomeline from Eli Lilly in May 2012. Andrew Miller, Ph.D., the core team member who was running this program at PureTech became Karuna’s Chief Operating Officer and we built a team of leading drug developers and neuroscientists around him, including Steven Paul, M.D., an expert in CNS drug discovery and development. Karuna completed an initial public offering on the Nasdaq Global Market in July 2019.
    • Dr. Paul was formerly Executive Vice President for Science and Technology and President of the Lilly Research Laboratories at Eli Lilly and was involved in the original xanomeline work at Eli Lilly. Dr. Paul was also a Co-Founder of Sage Therapeutics and Voyager Therapeutics, where he also served as Chief Executive Officer, and the former Scientific Director of the National Institute of Mental Health.
  • Patient Need & Market Potential
    • Psychosis is a prominent and debilitating symptom that occurs in many neuropsychiatric disorders, including schizophrenia, dementia, bipolar disorder, major depressive disorder and inflammatory neurological diseases, such as multiple sclerosis (MS), 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 about 8.4 million people living with dementia in the United States, of which approximately 40 percent are diagnosed with the disease, with around 1.2 million experiencing symptoms of psychosis. 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, such as hallucinations and delusions, but despite treatment patients often experience residual positive symptoms throughout their lives. There are no approved treatments for the negative symptoms, such as apathy, reduced social drive and loss of motivation, or cognitive symptoms, such as changes in working memory and attention, all of which currently lack any approved treatments. 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.
    • 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. There are currently no approved treatments for dementia-related psychosis.
  • Milestones Achieved & Development Status
    • In June 2021, Karuna announced data from its completed Phase 1b trial evaluating the safety and tolerability of KarXT in healthy elderly volunteers, which followed a preliminary analysis of data from the first two cohorts in the trial announced earlier this year. The results suggest that KarXT can be administered to elderly volunteers at doses which achieve xanomeline blood levels similar to those reported in the Phase 2 EMERGENT-1 trial in adults with schizophrenia while maintaining a favorable tolerability profile. Data from the trial also suggest that a lower dose ratio of trospium to xanomeline, compared to the ratios used in Phase 1 trials in healthy adult volunteers and in the Phase 2 EMERGENT-1 trial evaluating KarXT in adults with schizophrenia, was better tolerated by healthy elderly volunteers. The treatment-related AEs were similar to those observed in prior trials of KarXT, and a majority (>80%) were rated mild in severity. One serious AE of urinary retention was reported in Cohort 1. Karuna believes the report of urinary retention was related to a higher dose of trospium used in Cohort 1 compared to doses used in Cohorts 2 and 3, where urinary retention was not observed. No serious or severe AEs were observed in Cohorts 2 and 3. Consistent with prior trials of KarXT, blood pressure in healthy elderly volunteers receiving KarXT was similar to placebo, and no syncopal events were observed. Heart rate increases observed in the trial were also consistent with prior trials of KarXT.
    • In the February 2021 post-period, Karuna announced that results from the EMERGENT-1 Phase 2 clinical trial evaluating KarXT for the treatment of schizophrenia were published in the New England Journal of Medicine.
    • In June 2020, Karuna announced next steps in the EMERGENT program, the clinical program evaluating KarXT for the treatment of adults with schizophrenia, following the completion of a successful End-of-Phase 2 meeting with the FDA. The first Phase 3 trial, EMERGENT-2, was initiated in December 2020. This five-week, 1:1 randomized, flexible-dose, double-blind, placebo-controlled, inpatient trial will enroll approximately 250 adults in the U.S. and evaluate the change in Positive and Negative Syndrome Scale (PANSS) total score at Week 5 of KarXT versus placebo as the primary outcome measure. EMERGENT-4, a 52-week, outpatient, open-label long-term safety and tolerability extension trial of EMERGENT-2 and EMERGENT-3, was initiated in the first quarter of the 2021 post-period.
    • In November 2019, Karuna announced topline results from EMERGENT-1, its Phase 2 clinical trial of KarXT for the treatment of acute psychosis in patients with schizophrenia, in which KarXT met the trial’s primary endpoint with a statistically significant (p<0.0001) and clinically meaningful 11.6 point mean reduction in total PANSS scores over placebo at week five (-17.4 KarXT vs. -5.9 placebo). Karuna also observed a statistically significant 3.2 point mean reduction from baseline in the PANSS-positive subscale (-5.6 KarXT vs. -2.4 placebo) and a statistically significant 2.3 point mean reduction from baseline in the PANSS-negative subscale (-3.2 KarXT vs. -0.9 placebo) at week five (p<0.0001 and p<0.001, respectively). The total PANSS, PANSS-positive subscale, and the PANSS-negative subscale had statistically significant separation at every assessment throughout the trial. The safety and tolerability of KarXT and dose selection for the Phase 2 clinical trial was 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 ChAEs than reported with xanomeline plus placebo, including nausea, vomiting, diarrhea and excess sweating and salivation. The overall ChAE rate was 64 percent on xanomeline plus placebo compared to 34 percent on KarXT (p=0.016). The rate of ChAEs for volunteers receiving KarXT (34 percent) was similar to the rate observed in volunteers receiving placebo during the lead-in period (32 percent), suggesting that the tolerability of KarXT was more similar to the placebo lead-in period than to treatment with xanomeline plus placebo.

     

     

    • Karuna’s second Phase 1 study was a randomized, double-blind, placebo-controlled multiple ascending dose trial of KarXT. This trial evaluated twice-a-day dosing of the proprietary KarXT co-formulation containing fixed ratios of xanomeline and trospium, rather than the three-times-a-day dosing previously used with xanomeline. The study demonstrated tolerability at xanomeline dose levels exceeding those shown in previous studies of xanomeline alone. The co-formulation also achieved exposure levels equivalent to or higher than the separate dosage forms used previously.
    • Karuna has an exclusive license for xanomeline from Eli Lilly and has a patent portfolio more broadly covering selective muscarinic targeting enabled by the KarXT approach.
  • Expected Milestones
    • Karuna plans to initiate a Phase 2 trial evaluating KarXT in dementia-related psychosis in the first half of 2022.
    • Karuna plans to initiate the second efficacy trial in its EMERGENT program, EMERGENT-3, in the first half of 2021.
    • EMERGENT-5, a 52-week, outpatient, open-label long-term trial evaluating the safety of KarXT in adults with schizophrenia who have not been enrolled in the EMERGENT-2 or EMERGENT-3 trials, is expected to commence in the first half of 2021.
    • Karuna remains on track to initiate a Phase 2 trial evaluating KarXT for the treatment of psychosis in patients with schizophrenia who have an inadequate response to current standard of care therapies in the second half of 2021. The trial will evaluate the efficacy and safety of KarXT when dosed in conjunction with background antipsychotic treatment and its potential to improve symptoms in patients who have not achieved an adequate response on their current antipsychotic treatment.

5 Not the preferred analysis; figure shows analysis of CGI-S as a continuous variable.

Note: Karuna has an active IND on file with the FDA for KarXT. Karuna also has ongoing discovery efforts to expand its pipeline. We do not control the clinical or regulatory development of Karuna’s product candidates. We do not have any board designees on Karuna’s board of directors and we are not responsible for the development or commercialization of its therapeutic candidate. We have an interest in Karuna’s therapeutic candidates through our equity interest as well as our right to royalty payments as a percentage of net sales of any commercialized product covered by the granted license pursuant to a license agreement between us and Karuna. Karuna is well protected with a robust intellectual property portfolio. The disclosure above is qualified in its entirety by reference to Karuna’s public filings with the SEC. Karuna was incorporated in July 2009.

Karuna announced topline results from EMERGENT-1, its Phase 2 clinical trial of KarXT for the treatment of acute psychosis in patients with schizophrenia, in which KarXT met the trial’s primary endpoint with a statistically significant (p<0.0001) and clinically meaningful 11.6 point mean reduction in total PANSS scores over placebo at week five (-17.4 KarXT vs. -5.9 placebo). The company announced next steps in the EMERGENT program, the clinical program evaluating KarXT for the treatment of adults with schizophrenia, following the completion of a successful End-of-Phase 2 meeting with the FDA. Karuna initiated the first Phase 3 study (EMERGENT-2) in December 2020.


Press Releases

PureTech Founded Entity Karuna Therapeutics Announces Results from Phase 1b Trial Evaluating the Safety and Tolerability of KarXT in Healthy Elderly Volunteers

June 23, 2021


PureTech Founded Entity Karuna Therapeutics Announces Pricing of Public Offering of Common Stock

March 2, 2021


PureTech Founded Entity Karuna Therapeutics Announces New England Journal of Medicine Publication of Data from EMERGENT-1 Phase 2 Trial Evaluating KarXT in Schizophrenia

February 25, 2021


PureTech Receives Approximately $118 Million from Sale of Portion of Founded Entity Shares

February 10, 2021


PureTech Receives Approximately $100 Million from Sale of Minority Portion of Founded Entity Shares

August 26, 2020


Publication of Shareholder Circular in Respect of Authority to Implement Potential Disposals of Shares in Founded Entity

August 26, 2020


PureTech Founded Entity Karuna Announces Positive Outcome of End-of-Phase 2 Meeting with the FDA for KarXT for the Treatment of Acute Psychosis in Patients with Schizophrenia

June 23, 2020


PureTech Receives $45 Million from Sale of a Minority Portion of Founded Entity Shares

May 26, 2020


PureTech Receives $200 Million from Sale of a Minority Portion of Affiliate Shares

January 23, 2020


PureTech Affiliate Karuna Therapeutics Announces Pricing of $250 Million Public Offering of Common Stock

November 21, 2019


PureTech Affiliate Karuna Therapeutics Announces KarXT Met Primary Endpoint in Phase 2 Clinical Trial of Acute Psychosis in Patients with Schizophrenia

November 19, 2019


PureTech Affiliate Karuna Therapeutics Announces Closing of Initial Public Offering and Full Exercise of the Underwriters’ Option to Purchase Additional Shares

July 2, 2019


PureTech Affiliate Karuna Announces Pricing of Upsized Initial Public Offering and Approval to List on Nasdaq

June 28, 2019


PureTech Health Affiliate Karuna Files Public Registration Statement for Proposed Initial Public Offering

June 3, 2019


PureTech's Karuna Files Confidential Submission of Draft Registration Statement for Proposed Initial Public Offering

April 26, 2019


PureTech Health Affiliate Karuna Therapeutics Completes Extended $80 Million Series B Financing

April 1, 2019


PureTech’s Affiliate Karuna Announces $68 Million Series B Financing

March 18, 2019


PureTech Health Affiliate Karuna Announces Appointment of Chief Financial Officer

March 5, 2019