M1 receptor agonists(Muscarinic acetylcholine receptor M1 agonists), M4 receptor agonists(Muscarinic acetylcholine receptor M4 agonists), mAChRs antagonists(Muscarinic acetylcholine receptor antagonists)

Therapeutic Areas

Other DiseasesNervous System Diseases

Active Indication

SchizophreniaAlzheimer DiseaseAcute schizophrenia+ [2]

Inactive Indication

Pain

Originator Organization

Karuna Therapeutics, Inc.

Active Organization

Karuna Therapeutics, Inc.

Zai Lab (Shanghai) Co., Ltd.PPD Pharmaceutical Development (Beijing) Co. Ltd.

Inactive Organization

The Fifth People's Hospital of Shenyang

Drug Highest PhaseNDA/BLA

First Approval Date-

Regulation-

Structure

Molecular FormulaC14H23N3OS

InChIKeyJOLJIIDDOBNFHW-UHFFFAOYSA-N

CAS Registry131986-45-3

View All Structures (2)

Clinical Trials associated with Trospium Chloride/Xanomeline

NCT06126224 / RecruitingPhase 3

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease

This is a Phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of KarXT in male and female subjects who are aged 55 to 90 years and have mild to severe Alzheimer's Disease (AD) with moderate to severe psychosis related to AD.
The primary objective of the study is to evaluate the efficacy of KarXT compared with placebo in the treatment of subjects with psychosis associated with AD as measured by the Neuropsychiatric Inventory-Clinician (NPI-C): Hallucinations and Delusions (H+D) score.

Start Date26 Dec 2023

Sponsor / Collaborator

Karuna Therapeutics, Inc.

CTRI/2023/08/056449 / Not yet recruitingNot Applicable

Explorative and Correlative Study of Karuna (à¤?à¤° ?à¤£à¤¾): As a Correlates of Human Personality, Life Satisfaction, And Mental Health - Karuna

Start Date16 Aug 2023

Sponsor / Collaborator-

NCT05980949 / Enrolling by invitationPhase 3

A Phase 3 Global, Multicenter, Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer's Disease

This is a Phase 3 global, multicenter, 52-week, open-label extension (OLE) rollover study for subjects completing study CN012-0026 or CN012-0027. Subjects (randomized or non-randomized) who complete the 38-week CN012-0026 or CN012-0027 study will be eligible to enroll in CN012-0028.
The primary objective of the study is to assess the long-term safety and tolerability of KarXT in subjects with psychosis associated with Alzheimer's Disease.

Start Date11 Jul 2023

Sponsor / Collaborator

Karuna Therapeutics, Inc.

100 Clinical Results associated with Trospium Chloride/Xanomeline

100 Translational Medicine associated with Trospium Chloride/Xanomeline

100 Patents (Medical) associated with Trospium Chloride/Xanomeline

Literatures (Medical) associated with Trospium Chloride/Xanomeline

01 Feb 2024·Clinical autonomic research : official journal of the Clinical Autonomic Research Society

Muscarinic control of cardiovascular function in humans: a review of current clinical evidence

Review

Author: Palma, Jose-Alberto

PURPOSE:

To review the available evidence on the impact of muscarinic receptor modulation on cardiovascular control in humans.

METHODS:

In this narrative Review we summarize data on cardiovascular endpoints from clinical trials of novel subtype-selective or quasi-selective muscarinic modulators, mostly PAMs, performed in the last decade. We also review the cardiovascular phenotype in recently described human genetic and autoimmune disorders affecting muscarinic receptors.

RESULTS:

Recent advancements in the development of compounds that selectively target muscarinic acetylcholine receptors are expanding our knowledge about the physiological function of each muscarinic receptor subtype (M1, M2, M3, M4, M5). Among these novel compounds, positive allosteric modulators (PAMs) have emerged as the preferred therapeutic to regulate muscarinic receptor subtype function. Many muscarinic allosteric and orthosteric modulators (including but not limited to xanomeline-trospium and emraclidine) are now in clinical development and approaching regulatory approval for multiple indications, including the treatment of cognitive and psychiatric symptoms in patients with schizophrenia as well as Alzheimer's disease and other dementias. The results of these clinical trials provide an opportunity to understand the influence of muscarinic modulation on cardiovascular autonomic control in humans. While the results and the impact of each of these therapies on heart rate and blood pressure control have been variable, in part because the clinical trials were not specifically designed to measure cardiovascular endpoints, the emerging data is valuable to elucidate the relative cardiovascular contributions of each muscarinic receptor subtype.

CONCLUSION:

Understanding the muscarinic control of cardiovascular function is of paramount importance and may contribute to the development of novel therapeutic strategies for treating cardiovascular disease.

01 Jan 2024·Lancet (London, England)Q1 · MEDICINE

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial

Q1 · MEDICINE

Article

Author: Paul, Steven M ; Correll, Christoph U ; Zhu, Haiyuan ; Sawchak, Sharon ; Kaul, Inder ; Miller, Andrew C ; Brannan, Stephen K ; Kakar, Rishi ; Breier, Alan

BACKGROUND:

New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M₁ and M₄-preferring muscarinic receptor agonist that does not block D₂ dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis.

METHODS:

EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161).

FINDINGS:

From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]).

INTERPRETATION:

In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D₂ dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia.

FUNDING:

Karuna Therapeutics.

02 Dec 2023·Expert opinion on investigational drugs

Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal

Review

Author: Dean, Brian

INTRODUCTION:

Successful phase 3 trials of KarXT in people with schizophrenia herald a new era of treating the disorder with drugs that do not target the dopamine D2 receptor. The active component of KarXT is xanomeline, a muscarinic (CHRM) M1 and M4 agonist, making muscarinic receptors a viable target for treating schizophrenia.

AREAS COVERED:

This review covers the process of taking drugs that activate the muscarinic M1 and M4 receptors from conceptualization to the clinic and details the mechanisms by which activating the CHRM1 and 4 can affect the broad spectrum of symptoms experienced by people with schizophrenia.

EXPERT OPINION:

Schizophrenia is a syndrome which means drugs that activate muscarinic M1 and M4 receptors, as was the case for antipsychotic drugs acting on the dopamine D2 receptor, will not give optimal outcomes in everyone within the syndrome. Thus, it would be ideal to identify people who are responsive to drugs activating the CHRM1 and 4. Given knowledge of the actions of these receptors, it is possible treatment non-response could be restricted to sub-groups within the syndrome who have deficits in cortical CHRM1 or those with one of the cognitive endophenotypes that may be identifiable by changes in the blood transcriptome.

145

News (Medical) associated with Trospium Chloride/Xanomeline

24 Jun 2024

·www.biospace.com

5 FDA Decisions to Watch in the Second Half of 2024

Pictured: FDA headquarters with money and pill bottles/Taylor Tieden for BioSpace There has been no shortage of landmark approvals from the FDA this year. From the first tumor-infiltrating lymphocytes therapy to the first gene therapy for a rare pediatric disease to the first targeted therapy for MASH, 2024 has already seen its fair share. Along with being the first TIL therapy, Amtagvi is also the first one-time cell therapy for a solid tumor. Meanwhile, Orchard’s Lenmeldy offers a glimmer of hope to children with metachromatic leukodystrophy, a fatal genetic metabolic disease, and Rezdiffra is Madrigal’s first approved product. While the first half of the year belonged to cell and gene therapy, the second half is dominated by FDA decisions for other modalities in cancer and diseases of the brain. Here are five target action dates to watch for in the second half of 2024: Eli Lilly’s Donanemab Indication: Alzheimer’s disease PDUFA: Unknown Eli Lilly is one step closer to the long-anticipated decision on its Alzheimer’s therapy, donanemab, after an advisory committee voted unanimously in favor of the anti-amyloid antibody. In June, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee deemed donanemab to be an effective treatment for Alzheimer’s patients with mild cognitive impairment and mild dementia and said the benefits outweighed the risks. Donanemab has not had the smoothest regulatory path. The FDA refused accelerated approval for the candidate in January 2023, taking issue with a Phase II trial design that allowed patients to end treatment when amyloid plaques had been cleared past a certain pre-defined level. This meant that fewer than 100 patients were on donanemab for 12 continuous months, something the regulator requested in its Complete Response Letter. Lilly submitted for traditional approval of donanemab in the second quarter of 2023. In the Phase III TRAILBLAZER-ALZ 2 study, study participants with low-medium levels of tau saw their cognitive decline decrease by around 35% on two different clinical rating scales compared to placebo. Across all amyloid-positive early symptomatic participants, these numbers were 22% and 29%, respectively. If approved, donanemab will be a direct competitor of Biogen and Eisai’s Leqembi, which received the FDA’s full nod in July 2023. Adaptimmune’s afami-cel Indication: Advanced synovial sarcoma PDUFA: Aug. 4 Riding the momentum in the cell and gene therapy space, Adaptimmune is anticipating approval of its T cell therapy afami-cel on or before August 4. If approved, afami-cel would be the first engineered T cell therapy for solid tumors and “the first effective treatment option for synovial sarcoma in more than a decade,” according to Adaptimmune. Synovial sarcoma, which makes up 5% to 10% of soft tissue sarcomas, typically affects individuals under 30, with a five-year survival rate of 20% for metastatic cases. In the SPEARHEAD-1 trial, nearly 40% of patients experienced clinical responses, with a median response duration of around 12 months. Median overall survival was approximately 17 months, contrasting with historical data of less than 12 months for those who received two or more prior lines of therapy; 70% of responders to afami-cel were alive two years after treatment. If successful, afami-cel would be the first product in Adaptimmune’s sarcoma franchise. Lykos Therapeutics’ MDMA Indication: Post-traumatic stress disorder PDUFA: Aug. 11 One of the most-watched FDA decisions this summer, an approval for Lykos Therapeutics’ MDMA-assisted post-traumatic stress disorder (PTSD) therapy would be paradigm-changing. However, on June 4, an FDA advisory committee—the first held for a potential new PTSD treatment this century—voted overwhelmingly against such an approval. In a 10-1 tally, the FDA’s Psychopharmacologic Drugs Advisory Committee said the candidate’s potential benefits do not outweigh its risk, even with a strict risk evaluation and mitigation strategy. Seven out of nine external advisors voted that Lykos had not provided sufficient proof of MDMA’s efficacy in PTSD. A key issue highlighted in FDA briefing documents was that of “functional unblinding,” where “the vast majority” of trial participants were able to accurately guess their treatment assignment. Lykos is backing its New Drug Application with two pivotal Phase III studies, MAPP1 and MAPP2, in which the MDMA-assisted regimen “demonstrated clinically meaningful improvements in PTSD symptoms,” according to the company’s briefing documents. If ultimately approved, Lykos’s therapy would be the first psychedelic drug for a neuropsychiatric disease in the U.S. Bristol Myers Squibb’s KarXT Indication: Schizophrenia PDUFA: Sept. 26 By September 26, the FDA will render a decision on another highly anticipated neuropsychiatric treatment: Bristol Myers Squibb’s KarXT (xanomeline-trospium). BMS came into possession of KarXT following its December 2023 acquisition of Karuna Therapeutics. If approved, KarXT, an investigational muscarinic antipsychotic treatment, would represent the first new drug class for schizophrenia in “several decades,” according to a Karuna press release announcing acceptance of the NDA. Unlike existing schizophrenia treatments, KarXT does not directly block dopamine receptors. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism believed to improve positive, negative and cognitive symptoms in patients with schizophrenia. Combined data from three completed registrational and placebo-controlled trials show “statistically significant and clinically meaningful improvements,” Karuna reported in November. In April, BMS revealed interim data from a fourth study showing the drug can elicit significant and sustained symptom improvement in patients with schizophrenia. More than 75% of KarXT-treated patients saw at least a 30% improvement in symptoms at 52 weeks of follow-up, according to data presented at the Annual Congress of the Schizophrenia International Research Society 2024 conference. Daiichi Sankyo and AstraZeneca’s Dato-DXd Indication: Non-small cell lung cancer PDUFA: Dec. 20 Daiichi Sankyo and AstraZeneca are looking to add Dato-DXd (datopotamab deruxtecan) to a limited club—antibody drug conjugates (ADCs) approved to treat non-small cell lung cancer (NSCLC). The partners are specifically seeking approval for Dato-DXd to treat adults with locally advanced or metastatic nonsquamous NSCLC who have previously received systemic therapy. AstraZeneca and Daiichi Sankyo are backing the Biologics License Application with data from the Phase III Tropion-Lung01 study, in which Dato-DXd reduced the risk of disease progression or death by 25% compared to chemotherapy. Median progression-free survival was 4.4 months, and the overall response rate was confirmed in 26.4% of patients. In terms of overall survival, high-level results “numerically favored” DatoDXd in the overall trial population, but were not statistically significant, the companies reported in May. Clinically significant improvement was demonstrated in a prespecified subgroup of patients. “We’re very optimistic about this, and we think that [Dato-DXd] can be an important drug for non-squamous non-small cell lung cancer patients,” Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, told BioSpace in May. If approved, Dato-DXd could be the first TROP2-directed ADC for lung cancer. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

Phase 3Clinical ResultDrug ApprovalCell TherapyPhase 2

24 Jun 2024

·www.biospace.com

PureTech Health: Results of the Tender Offer - June 24, 2024

BOSTON--(BUSINESS WIRE)-- PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) (“PureTech” or the “Company”), a clinical-stage biotherapeutics company dedicated to changing the lives of patients with devastating diseases, today announces the results of the Tender Offer, as set out in the Shareholder circular published by the Company on 20 May 2024 (the ‘’Circular’’). Capitalised terms used in this announcement but not defined have the meanings given to them in the Circular. The Tender Offer for the Company’s Ordinary Shares closed at 1:00 p.m. London time on Thursday 20 June 2024 (the “Ordinary Share Closing Date”), and the Tender Offer for the Company’s ADSs closed at 5:00 p.m. New York City time on Tuesday 18 June 2024 (the “ADS Closing Date”). The maximum aggregate number of Ordinary Shares (including Ordinary Shares represented by ADSs) that could be purchased pursuant to the Tender Offer was 33,500,000 Ordinary Shares (including Ordinary Shares represented by ADSs) at a fixed price of 250 pence per Ordinary Share (equivalent to £25.00 per ADS) (the “Tender Price”) for maximum aggregate amount of $100 million. Valid tenders were received in respect of 172,408,704 Ordinary Shares (including Ordinary Shares represented by ADSs). As the Tender Offer was oversubscribed by 140,867,938 Ordinary Shares (including Ordinary Shares represented by ADSs), not all of the Ordinary Shares (including Ordinary Shares represented by ADSs) that have been validly tendered will be accepted and purchased. Therefore, tenders will be scaled down pro-rata to the total number of Ordinary Shares (including Ordinary Shares represented by ADSs) so tendered by that Shareholder, such that the total cost of Ordinary Shares (including Ordinary Shares represented by ADSs) purchased pursuant to the Tender Offer does not exceed $100 million or the total number of validly tendered Ordinary Shares (including Ordinary Shares represented by ADSs) does not exceed 33,500,000 Ordinary Shares, as described in paragraphs 2.14 of Part V of the Circular. If any fractions arise from the scaling-down as stated above, the number of Ordinary Shares tendered by each Shareholder shall be rounded down to the nearest whole Ordinary Share (or to nil, as the case may be) and purchased in the Tender Offer and the balance of the total number of Ordinary Shares (including Ordinary Shares represented by ADSs) so tendered by that Shareholder will not be accepted and purchased in the Tender Offer and will be returned to Shareholders, as described in paragraphs 2.15 of Part V of the Circular. In total 31,540,670 Ordinary Shares (including Ordinary Shares represented by ADSs) will be purchased in accordance with the terms and subject to the conditions of the Tender Offer at the Tender Price, for a total cost of $100 million. This represents approximately 12 per cent of the Issued Ordinary Share Capital of the Company. As detailed in the Circular, the Company will buy back the successfully tendered Ordinary Shares (including Ordinary Shares represented by ADSs) from Jefferies International Limited ("Jefferies") and, following such repurchase, cancel such Ordinary Shares (including Ordinary Shares represented by ADSs), thereby reducing its total Issued Ordinary Share Capital and total voting rights from 270,859,250 to 239,318,580 Ordinary Shares (including Ordinary Shares represented by ADSs), excluding 18,608,909 Ordinary Shares held in treasury. This figure may be used by Shareholders as the denominator for the calculations by which they will determine if they are required to notify their interest in, or a change to their interest in, the Company under the Transparency Regulations and the Disclosure Guidance and Transparency Rules of the Financial Conduct Authority. It is anticipated that the proceeds will be payable as follows: Shareholders of Ordinary Shares the proceeds payable to the Company's Shareholders for Ordinary Shares held in Certificated Form purchased under the Tender Offer will be despatched in the form of a cheque by or on 3 July 2024; and the proceeds payable to the Company’s Shareholders for Ordinary Shares in Uncertificated Form purchased under the Tender Offer will be paid through CREST by or on 25 June 2024. ADSs Holders the proceeds payable for successfully tendered Ordinary Shares represented by ADS Holders who hold ADSs on the books of the Depositary will be despatched in the form of a cheque by or on 3 July 2024, at the risk of the person entitled thereto; and the proceeds payable for successfully tendered Ordinary Shares represented by ADSs held by ADS Holders who hold ADSs through a bank, broker or other nominee participant of DTC will be made to DTC by or on 3 July 2024. The Company intends to rely on the Tier II exemption from Rule 14e-1(c) on prompt payment where the Company will follow English law and practice. All cash payments of proceeds for successfully tendered Ordinary Shares represented by ADSs under the Tender Offer will be made (i) by Jefferies in pounds sterling by CREST payment to the nominee account of the Depositary, in respect of Ordinary Shares underlying the ADSs, and then (ii) after conversion thereof by the Tender Agent, in US dollars, (a) in the case of ADS Holders whose ADSs are held on the books of the Depositary, by cheque, and (b) in the case of payment to Cede & Co., as nominee for DTC, by wire transfer issued by a US bank, in each case in respect of ADSs purchased in the Tender Offer. The actual amount of US dollars received will depend upon the exchange rate obtained when such currency is exchanged. In all cases, fluctuations in the US dollar/pound sterling exchange rate are at the risk of the tendering ADS Holders who will receive their consideration in US dollars. The attention of Shareholders and ADS Holders is drawn to Part VI of the Circular, which provides a summary of certain material UK tax and US federal income tax consequences for Shareholders and ADS Holders of accepting the Tender Offer or receipt of the Special Dividend (if any). Jefferies will implement the Tender Offer by acquiring, as principal, the successfully tendered Ordinary Shares (including Ordinary Shares represented by ADSs) at the Tender Price. Ordinary Shares (including Ordinary Shares represented by ADSs) purchased by Jefferies pursuant to the Tender Offer will be purchased as principal and such purchases will be market purchases in accordance with the provisions of the Act, the Prospectus Regulation Rules, the Listing Rules, the rules of the London Stock Exchange, the Disclosure Guidance and Transparency Rules and the Takeover Code. Immediately following completion of the Tender Offer, Jefferies shall exercise its right to sell such Ordinary Shares (including Ordinary Shares represented by ADSs) to the Company, at the Tender Price, pursuant to the Option Agreement. About PureTech Health PureTech is a clinical-stage biotherapeutics company dedicated to giving life to new classes of medicine to change the lives of patients with devastating diseases. The Company has created a broad and deep pipeline through its experienced research and development team and its extensive network of scientists, clinicians and industry leaders that is being advanced both internally and through its Founded Entities. PureTech’s R&D engine has resulted in the development of 29 therapeutics and therapeutic candidates, including two that have received both U.S. FDA clearance and European marketing authorization and a third (KarXT) that has been filed for FDA approval. A number of these programs are being advanced by PureTech or its Founded Entities in various indications and stages of clinical development, including registration enabling studies. All of the underlying programs and platforms that resulted in this pipeline of therapeutic candidates were initially identified or discovered and then advanced by the PureTech team through key validation points. For more information, visit or connect with us on X (formerly Twitter) @puretechh. Important Notices This announcement is neither an offer to purchase nor a solicitation of an offer to sell Ordinary Shares (including Ordinary Shares represented by ADSs). The Tender Offer is made only pursuant to the Circular, the related Tender Form with respect to the Ordinary Shares and the related Letter of Transmittal with respect to the ADSs, which Shareholders were advised to read in full. Jefferies, which is authorised and regulated by the Financial Conduct Authority in the United Kingdom (“FCA”), is acting exclusively for the Company as financial advisor and broker in connection with the Tender Offer and is not, and will not be, responsible to anyone other than the Company for providing the protections afforded to its clients nor for providing advice in connection with the Tender Offer or any other matters set out in this announcement. Apart from the responsibilities and liabilities, if any, which may be imposed on Jefferies under the Financial Services and Markets Act 2000, as amended or the regulatory regime established thereunder: (i) neither Jefferies or any persons associated or affiliated with Jefferies accepts any responsibility whatsoever or makes any warranty or representation, express or implied, in relation to the contents of this announcement, including its accuracy, completeness or verification or for any other statement made or purported to be made by, or on behalf of it, the Company or the directors of the Company, in connection with the Company and/or the Tender Offer; and (ii) Jefferies accordingly disclaims, to the fullest extent permitted by law, all and any liability whatsoever, whether arising in tort, contract or otherwise (save as referred to above) which it might otherwise be found to have in respect of this announcement or any such statement. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements that relate to our expectations around our therapeutic candidates and approach towards addressing major diseases, our future prospects, developments, and strategies, and statements regarding the intent, belief or current expectations regarding the Tender Offer, including the timing of payment and return of Ordinary Shares not accepted for payment. The forward-looking statements are based on current expectations and are subject to known and unknown risks, uncertainties and other important factors that could cause actual results, performance and achievements to differ materially from current expectations, including, but not limited to, those risks, uncertainties and other important factors described under the caption "Risk Factors" in our Annual Report on Form 20-F for the year ended December 31, 2023 filed with the SEC and in our other regulatory filings. These forward-looking statements are based on assumptions regarding the present and future business strategies of the Company and the environment in which it will operate in the future. Each forward-looking statement speaks only as at the date of this press release. Except as required by law and regulatory requirements, we disclaim any obligation to update or revise these forward-looking statements, whether as a result of new information, future events or otherwise. THE INFORMATION CONTAINED IN THIS ANNOUNCEMENT IS NOT FOR RELEASE, PUBLICATION OR DISTRIBUTION IN WHOLE OR IN PART, DIRECTLY OR INDIRECTLY IN OR INTO AUSTRALIA, CANADA, JAPAN, NEW ZEALAND, SINGAPORE, THE REPUBLIC OF SOUTH AFRICA OR ANY OTHER JURISDICTION WHERE TO DO SO WOULD CONSTITUTE A VIOLATION OF THE RELEVANT LAWS OR REGULATIONS OF SUCH JURISDICTION. THIS ANNOUNCEMENT CONTAINS INSIDE INFORMATION FOR THE PURPOSES OF ARTICLE 7 OF THE UK VERSION OF THE MARKET ABUSE REGULATION (EU 596/ 2014) AS IT FORMS PART OF UK LAW BY VIRTUE OF THE EUROPEAN UNION (WITHDRAWAL) ACT 2018, AS AMENDED. View source version on businesswire.com: Contacts PureTech Health plc Public Relations publicrelations@puretechhealth.com Investor Relations IR@puretechhealth.com Jefferies International Limited Ed Matthews +44 (0)20 7548 4107 ematthews1@jefferies.com Jee Lee +44 (0)20 7029 8545 Jee.Lee@jefferies.com UK/EU Media Ben Atwell, Rob Winder +44 (0) 20 3727 1000 puretech@fticonsulting.com US Media Nichole Bobbyn +1 774 278 8273 nichole@tenbridgecommunications.com Source: PureTech Health plc View this news release online at:

20 Jun 2024

·www.biospace.com

PureTech Announces Change of Board Role

Raju Kucherlapati, PhD, distinguished Professor of Medicine at Harvard Medical School, has transitioned to the role of Chair of the Board of Directors on a permanent basis BOSTON--(BUSINESS WIRE)-- PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to changing the lives of patients with devastating diseases, today announces that Raju Kucherlapati, PhD, has been appointed Chair of the Board of Directors, effective immediately, following his role as interim Chair since June 2023. This press release features multimedia. View the full release here: Raju Kucherlapati, PhD, has been appointed Chair of the PureTech Board of Directors. (Photo: Business Wire) “On behalf of the Board, I am delighted to welcome Raju as the Chair on a permanent basis,” said Bharatt Chowrira, PhD, JD, Chief Executive Officer of PureTech. “Raju’s exceptional leadership and strategic vision have been instrumental to PureTech’s innovation and success, particularly over the last year while he served as interim Chair. The Board has carefully considered Raju’s skills, knowledge and expertise, as well as his long-term involvement in the evolution of PureTech and his exemplary leadership during his tenure as interim Chair. The Board determined that Raju’s skills and in-depth knowledge of PureTech will be valuable over the coming years as PureTech continues to grow and evolve. Raju continues to exercise objective judgement and promote constructive challenge in the Board’s decision-making process. I look forward to continuing to work together and benefitting from Raju’s wise counsel as PureTech enters an exciting period of growth, with multiple catalysts that can deliver value to patients and shareholders.” Dr. Kucherlapati commented: “It has been an honor to serve as interim Chair of PureTech at such an exciting time for the business. The Company successfully delivered against its milestones in 2023 and remains dedicated to identifying and developing medicines with the potential to transform lives. I look forward to continuing in my role as Chair and leveraging my expertise, alongside the rest of the Board, to guide the Company going forward.” Dr. Kucherlapati has served as a member of PureTech’s Board of Directors since 2014. He is currently Chair of the Board’s Nomination Committee and sits on the Audit and Remuneration Committees. Dr. Kucherlapati will continue his current Board committee responsibilities until a replacement is identified at an appropriate time. The Company is actively engaged in a search to expand its independent Board membership and has had several promising conversations. An update will be provided in due course. Dr. Kucherlapati is the Paul C. Cabot Professor of Genetics and Professor of Medicine at Harvard Medical School and currently serves on the Board of Directors of KEW Inc. He was a founder and formerly a board member of Abgenix (acquired by Amgen for $2.2 billion), Cell Genesys and Millennium Pharmaceuticals (acquired by Takeda for $8.8 billion). He was the first scientific director of the Harvard-Partners Center for Genetics and Genomics. He is a fellow of the American Association for the Advancement of Science and a member of the National Academy of Medicine. Dr. Kucherlapati received his PhD from the University of Illinois. He trained at Yale and has held faculty positions at Princeton University, University of Illinois College of Medicine and the Albert Einstein College of Medicine. He was a member of the presidential commission for the study of bioethical issues during the Obama administration. About PureTech Health PureTech is a clinical-stage biotherapeutics company dedicated to giving life to new classes of medicine to change the lives of patients with devastating diseases. The Company has created a broad and deep pipeline through its experienced research and development team and its extensive network of scientists, clinicians and industry leaders that is being advanced both internally and through its Founded Entities. PureTech's R&D engine has resulted in the development of 29 therapeutics and therapeutic candidates, including two that have received both U.S. FDA clearance and European marketing authorization and a third (KarXT) that has been filed for FDA approval. A number of these programs are being advanced by PureTech or its Founded Entities in various indications and stages of clinical development, including registration enabling studies. All of the underlying programs and platforms that resulted in this pipeline of therapeutic candidates were initially identified or discovered and then advanced by the PureTech team through key validation points. For more information, visit or connect with us on X (formerly Twitter) @puretechh. Cautionary Note Regarding Forward-Looking Statements This press release contains statements that are or may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation those related to Seaport’s development plans and our future prospects, developments and strategies. The forward-looking statements are based on current expectations and are subject to known and unknown risks, uncertainties and other important factors that could cause actual results, performance and achievements to differ materially from current expectations, including, but not limited to, those risks, uncertainties and other important factors described under the caption "Risk Factors" in our Annual Report on Form 20-F for the year ended December 31, 2023, filed with the SEC and in our other regulatory filings. These forward-looking statements are based on assumptions regarding the present and future business strategies of the Company and the environment in which it will operate in the future. Each forward-looking statement speaks only as at the date of this press release. Except as required by law and regulatory requirements, we disclaim any obligation to update or revise these forward-looking statements, whether as a result of new information, future events or otherwise. View source version on businesswire.com: Contacts PureTech Public Relations publicrelations@puretechhealth.com Investor Relations IR@puretechhealth.com UK/EU Media Ben Atwell, Rob Winder +44 (0) 20 3727 1000 puretech@fticonsulting.com US Media Nichole Bobbyn +1 774 278 8273 nichole@tenbridgecommunications.com Source: PureTech Health plc Smart Multimedia Gallery Photo Raju Kucherlapati, PhD, has been appointed Chair of the PureTech Board of Directors. (Photo: Business Wire) Logo View this news release and multimedia online at:

Executive ChangeAcquisition

100 Deals associated with Trospium Chloride/Xanomeline

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	NDA/BLA	US	Karuna Therapeutics, Inc.	28 Sep 2023
Alzheimer Disease	Phase 3	CN	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	BE	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	CA	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	CL	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	GR	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	HU	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	MX	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	PE	Karuna Therapeutics, Inc.	23 Jun 2023
Alzheimer Disease	Phase 3	PL	Karuna Therapeutics, Inc.	23 Jun 2023

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05643170 (CTgov)	Phase 3	Schizophrenia	4	Trospium Chloride Capsules	manmblkwpw(ovdqqelrbf) = jewsetlhry htiebkimtw (kkgmodjxzm, rscinbojhe - eqnmdbnqnq) View more	-	12 Jun 2024
NCT04659174 \| NCT04820309 (EMERGENT-5, Corporate Publications) Manual	Phase 3	Schizophrenia	718	KarXT	kpvemmlusk(bhphiyhozv) = 62% of participants reported at least one. The most common treatment-related adverse events (≥5%) were nausea, vomiting, constipation, dry mouth, dyspepsia, dizziness, hypertension, and diarrhea, of which nearly all were mild or moderate in severity and transient in nature. kjkyyzhate (amjggbeusx ) View more	Positive	06 Apr 2024
NCT04659174 (EMERGENT-4, Corporate Publications) Manual	Phase 3	Schizophrenia	110	KarXT	gbygcidpxz(mpanbxplsf) = ienwzcnqdg ntgmjztkub (cmsvkhsayo ) View more	Positive	06 Apr 2024
EMERGENT-3 (NEWS) Manual	Clinical	Schizophrenia	314	KarXT (EMERGENT-1)	ozevimpjxn(bgzualkkkt) = ztsagysgsc cmauxykben (ajsqnctvvy ) View more	Positive	08 Jan 2024
				placebo (EMERGENT-1)	ozevimpjxn(bgzualkkkt) = ahynbattgp cmauxykben (ajsqnctvvy ) View more
NCT04659161 (EMERGENT-2, Pubmed \| Lancet)	Phase 3	Schizophrenia	252	KarXT	nspnuvfmzh(bxflxajrch) = rmujkokoek bymorabiyq (qqvcrnnlia ) View more	Positive	01 Jan 2024
				Placebo	nspnuvfmzh(bxflxajrch) = ecuftymwxa bymorabiyq (qqvcrnnlia ) View more
NCT04659161 (EMERGENT-2, Corporate Publications) Manual	Phase 3	Schizophrenia	252	KarXT	bohywbwoeq(gdocauudls) = jbjekyxtvy qhtkcmnnad (fckekoymxz ) View more	Positive	14 Dec 2023
				Placebo	bohywbwoeq(gdocauudls) = zweyfzgvwv qhtkcmnnad (fckekoymxz ) View more
NCT04659161 (CTgov)	Phase 3	Psychotic Disorders \| Schizophrenia	252	Trospium Chloride Capsules (KarXT)	jhogoffiyx(ahuqejrymo) = eehipulqms fkjgqhfgnk (sdhjsqooio, vzpmnravfv - qcdpooptxu) View more	-	12 Dec 2023
				Placebo (Placebo)	jhogoffiyx(ahuqejrymo) = vrtwkqnnzb fkjgqhfgnk (sdhjsqooio, xakcrukydx - rhylfevvvh) View more
Corporate Publications Manual	Phase 1	Schizophrenia	133	KarXT	injncmkpdl(ttifmgnxca) = gbrpgvskys ompshbocvb (yjnwhoguci )	Positive	16 Nov 2023
NCT04659161 (EMERGENT-2, Corporate Publications) Manual	Phase 3	Schizophrenia	252	KarXT	sqwkcpynpb(pqqztiyojr) = ixjzsccccn dfvquudzio (fdtrnhjdxb ) View more	Positive	08 Aug 2022
				Placebo	sqwkcpynpb(pqqztiyojr) = lymmepnwkx dfvquudzio (fdtrnhjdxb ) View more
NCT03697252 (EMERGENT-1, Pubmed \| Br Dent J) Manual	Phase 2	Schizophrenia	182	xanomeline	yrobjodsdg(mrbxdtgjbp) = gthztrobgs glpavimpbq (jahntxcsej )	Positive	25 Feb 2021
				Placebo	yrobjodsdg(mrbxdtgjbp) = xzvzlkevjj glpavimpbq (jahntxcsej )

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Leverages most recent intelligence information, enabling fullest potential.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

Trospium Chloride/Xanomeline

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation