Puretech Ownership1
Therapeutic Candidate2
Initial Indication(s)
Stage of Development
3.1% Equity plus Royalties, Milestone Payments & Sublicense Revenues
KarXT
Schizophrenia
Phase 3
Schizophrenia (adjunctive)
Phase 3
Psychosis in Alzheimer's disease
Phase 3
KAR-2618
Mood & Anxiety Disorders
Phase 1
1 As of February 23, 2023, PureTech’s percentage ownership of Karuna was approximately 3.1% on an outstanding voting share basis. We have a right to royalty payments as a percentage of net sales from Karuna of any commercialized product covered by the granted license, as well as rights to certain sublicense income, pursuant to a license agreement between us and Karuna.
2 Therapeutic candidates are investigational and have not been cleared by the FDA for use in the U.S.
Advancing transformative medicines for people living with psychiatric and neurological conditions
- Karuna is advancing a pipeline of novel drug candidates for the potential treatment of various psychiatric and neurological conditions.
- KarXT (xanomeline-trospium) is an oral investigational medicine with a novel mechanism of action mediated via muscarinic cholinergic receptors, that is currently being evaluated in ongoing Phase 3 clinical trials as a potential treatment for schizophrenia as a monotherapy and adjunctive therapy, as well as psychosis in Alzheimer’s disease (AD). Comprised of muscarinic agonist xanomeline and muscarinic antagonist trospium, it is designed to preferentially stimulate muscarinic receptors in the central nervous system. KarXT is the first potential medicine of its kind with a truly new and unique dual mechanism that does not rely on the dopaminergic or serotonergic pathway to treat symptoms of serious mental illness. This approach has the potential to provide a differentiated therapy, and, if approved, to beneficially impact the lives of millions of people with serious mental illness.
- Xanomeline was previously evaluated by Eli Lilly and Company, or Eli Lilly, in randomized, double-blind, placebo-controlled trials in schizophrenia and AD. In the double-blind, placebo-controlled trial in AD, xanomeline demonstrated dose-dependent reductions in symptoms of psychosis and related behaviors, including hallucinations, delusions and agitation, as compared to patients on placebo, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale and the Clinician Interview-Based Impression of Change.
- Xanomeline is a muscarinic agonist that has demonstrated potential therapeutic benefit in schizophrenia and AD, yet its 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 adverse events, or ChAEs, which led Eli Lilly to discontinue the clinical development of xanomeline. By pairing xanomeline with trospium chloride, Karuna believes KarXT could potentially maintain the therapeutic benefit of xanomeline while ameliorating its ChAEs.
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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., one of the core team members who was involved in 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 and now Karuna’s Chief Scientific Officer (formerly Chief Executive Officer). Karuna completed an initial public offering on the Nasdaq Global Market in July 2019.
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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, or MS. Despite its prevalence, there are no existing medicines that sufficiently and safely treat psychosis or cognitive impairments in people with schizophrenia.
- Schizophrenia is a severe and debilitating disorder affecting approximately 21 million people worldwide. There are approximately 2.7 million adults living with schizophrenia in the U.S., of which approximately 40% 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 an estimated life loss of nearly 30 years compared to the general population and often struggle to maintain employment, live independently or maintain meaningful interpersonal relationships.
- Schizophrenia is a complex psychiatric syndrome, defined by three major sets of symptoms: positive symptoms, also known as psychosis, negative symptoms and cognitive symptoms. 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. Current approved antipsychotics treat positive symptoms and are not indicated to treat negative or cognitive symptoms of schizophrenia. Despite treatment, current antipsychotics have modest efficacy, with many patients failing to adequately respond to treatment, and are associated with burdensome side effects, such as 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. Up to 74% of patients cycle through multiple medicines within 18 months, with many failing to find an effective and/or tolerable therapy.
- An estimated 8 million people are living with dementia in the U.S., with AD as the leading cause of dementia, consisting of 60-80% of all cases. Symptoms of psychosis may present those living with dementia, including 30-50% of individuals with AD, amounting to ~3.2 million adults with AD psychosis in the U.S. Symptoms become more prevalent with increased disease severity.
- There is an unmet need for new treatments in schizophrenia that could address the positive, negative and cognitive symptoms, and are not associated with common problematic side effects associated with current dopamine-blocking therapies. There are currently no approved treatments for psychosis in Alzheimer’s disease.
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Milestones Achieved & Development Status
- o In March 2023, Karuna announced positive topline results from the Phase 3 EMERGENT-3 trial evaluating the efficacy, safety, and tolerability of its KarXT in adults with schizophrenia. The trial met its primary endpoint, with KarXT demonstrating a statistically significant and clinically meaningful 8.4-point reduction in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo (-20.6 KarXT vs. -12.2 placebo; p<0.0001) at Week 5 (Cohen's d effect size of 0.60). Consistent with prior trials, KarXT demonstrated an early and sustained statistically significant reduction of symptoms from Week 2 (p<0.05) through the end of the trial as assessed by PANSS total score. KarXT also demonstrated reductions in positive and negative symptoms of schizophrenia as measured by PANSS positive, PANSS negative, and PANSS negative Marder factor subscales. KarXT was generally well tolerated, with a side effect profile substantially consistent with previous trials of KarXT in schizophrenia.
- In August 2022, Karuna announced positive results from the Phase 3 EMERGENT-2 trial evaluating the efficacy, safety and tolerability of its lead investigational therapy, KarXT (xanomeline-trospium), in adults with schizophrenia. The trial met its primary endpoint, with KarXT demonstrating a statistically significant and clinically meaningful 9.6-point reduction in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo (-21.2 KarXT vs. -11.6 placebo; p<0.0001) at Week 5 (Cohen’s d effect size of 0.61). KarXT also met key secondary endpoints in the trial, demonstrating a statistically significant reduction in both positive symptoms (e.g., hallucinations or delusions) and negative symptoms (e.g., difficulty enjoying life or withdrawal from others) of schizophrenia as measured by the PANSS positive, PANSS negative and PANSS negative Marder factor subscales. KarXT was generally well tolerated, with a side effect profile substantially consistent with prior trials of KarXT in schizophrenia.
- In February 2023, Karuna provided updates to its EMERGENT program, which is evaluating KarXT for the potential treatment for schizophrenia as a monotherapy.
- The EMERGENT program: The clinical program evaluating KarXT for the treatment of schizophrenia as a monotherapy consists of the completed positive registrational EMERGENT-1 and EMERGENT-2 trials, one Phase 3 trial evaluating the efficacy and safety of KarXT (EMERGENT-3), and two Phase 3 trials evaluating the long-term safety of KarXT (EMERGENT-4 & EMERGENT-5).
- Results from the Phase 3 EMERGENT-2 trial in schizophrenia were presented at the 2022 Neuroscience Education Institute and the 2022 American College of Neuropsychopharmacology Annual Meeting in the fourth quarter of 2022. The presentations included new efficacy analyses on pre-specified secondary endpoint measures. In the trial, KarXT demonstrated statistically significant reduction in Clinical Global Impression-Severity (CGI-S) score when compared to placebo at Week 5 (p<0.0001). Additionally, a greater proportion of patients in the KarXT arm had a >30% reduction in Positive and Negative Syndrome Scale (PANSS) compared to placebo at Week 5 (p<0.0001).
- In February 2023, Karuna provided updates to its ARISE program, which is evaluating KarXT as an adjunctive treatment for schizophrenia. The ARISE program consists of the ARISE trial, a six-week outpatient trial evaluating the efficacy and safety of KarXT compared to placebo, and ARISE-2, an optional open-label extension trial of ARISE evaluating the long-term safety of KarXT.
- Karuna initiated the Phase 3 ARISE trial evaluating the safety and efficacy of KarXT compared to placebo as an adjunctive treatment for schizophrenia in adults who experience an inadequate response to current standard of care in November 2021. Participants in this trial will continue their currently prescribed atypical antipsychotic therapy at the same dose or regimen schedule as prior to entry in the study, and will receive a flexible dose of KarXT or placebo based on tolerability and clinical response as determined by a clinician.
- In February 2023, Karuna announced updates to its Phase 3 ADEPT program, which is evaluating KarXT for the treatment of psychosis related to AD. The ADEPT program consists of the ongoing ADEPT-1 trial and two planned trials evaluating the efficacy and long-term safety of KarXT (ADEPT-2 & ADEPT-3).
- In the first quarter of 2023, Karuna announced exclusive global license agreement for Goldfinch Bio’s investigational TRPC4/5 product candidates. Karuna obtained an exclusive global license to develop, manufacture, and commercialize multiple TRPC4/5 investigational therapies, including lead clinical-stage candidate KAR-2618 (formerly GFB-887), a TRPC4/5 inhibitor for the treatment of mood and anxiety disorders.
- In December 2022, Karuna appointed Bill Meury as President and Chief Executive Officer. Mr. Meury is a distinguished pharmaceutical leader with more than 25 years of operational and commercial experience delivering transformative medicines to patients. Mr. Meury’s predecessor, Steve Paul, M.D., transitioned to President of Research and Development and Chief Scientific Officer and continues to serve as a member of the board following the effective date
- In August 2022, Karuna completed a follow-on public offering of its common stock, from which it received gross proceeds of $862.5 million.
- 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 in 2021. The results suggest that KarXT can be administered to elderly volunteers at doses that 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 adverse events (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 November 2021, Karuna and Zai Lab (Shanghai) Co., Ltd. (Zai) announced their entry into an exclusive license agreement for the development, manufacturing and commercialization of KarXT in Greater China, including mainland China, Hong Kong, Macau and Taiwan. Under the terms of the agreement, Karuna received a $35.0 million upfront payment and is eligible to receive certain development and regulatory milestone and sales milestone payments, as well as royalties based on annual net sales of KarXT in Greater China. Zai Lab will fund substantially all development, regulatory and commercialization activities in Greater China. PureTech is also eligible to receive certain sublicense payments and royalties on sales of any commercialized product covered by the license agreement between us and Karuna pursuant to the terms of such license agreement.
- In February 2021, Karuna announced that results from the Phase 2 EMERGENT-1 trial evaluating KarXT for the treatment of schizophrenia were published in the New England Journal of Medicine (NEJM).
- In March 2021, Karuna completed a follow-on public offering of its common stock, from which it received net proceeds of $270.0 million.
- In November 2021, Karuna appointed Charmaine Lykins as Chief Commercial Officer. Ms. Lykins has over 25 years of psychiatry and neuroscience-focused pharmaceutical launch experience across multiple organizations recognized as leaders in developing and commercializing medicines for central nervous system disorders.
- 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.
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Expected Milestones
- Karuna plans to submit a New Drug Application t othe FDA for KarXT in schizophrenia in mid-2023, with a potential launch in the second half of 2024, if approved.
- Karuna expects to initiate the Phase 3 ADEPT-2 and ADEPT-3 trials evaluating KarXT for the treatment of psychosis in Alzheimer’s disease in 2023.
- Karuna anticipates topline data from the Phase 3 ARISE trial in patients with schizophrenia in the first half of 2024.
- Karuna plans to initiate a Phase 1B open-label clinical trial to evaluate the effect of KarXT on 24-hour ambulatory blood pressure in adults with schizophrenia early in the second quarter of 2023.
- Karuna anticipates topline data from the Phase 3 ADEPT-1 and ADEPT-2 trials in patients with psychosis related to AD in 2025.
- Karuna expects to share details on the planned development of KAR-2618 (formerly GFB-887) for the treatment of mood and anxiety disorders in the second half of 2023.
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.
The key innovation behind the KarXT, which was invented at PureTech, was built around two validated drugs: xanomeline, a novel muscarinic agonist, and trospium, an approved muscarinic antagonist. We were able to ameliorate the GI tolerability issues of xanomeline by pairing it with a gut-restricted muscarinic antagonist to develop a novel formulation that enabled a new approach for the potential treatment of schizophrenia and other serious psychiatric and neurological conditions, an area of major unmet need. KarXT now represents a potential first-in-class and best-in-class therapy for schizophrenia.
Press Releases
PureTech Founded Entity Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia
March 20, 2023
PureTech to Receive up to Approximately $115.4 Million from Sale of a Portion of Founded Entity Shares
August 9, 2022
PureTech Founded Entity Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-2 Trial of KarXT in Schizophrenia
August 8, 2022
PureTech Receives Approximately $100 Million from Sale of a Portion of Founded Entity Shares
November 10, 2021
PureTech Founded Entity Karuna Therapeutics and Zai Lab Announce Strategic Collaboration for Development, Manufacturing, and Commercialization of KarXT in Greater China
November 9, 2021
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