8-K
false 0001771917 0001771917 2022-08-08 2022-08-08

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

 

 

FORM 8-K

 

 

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): August 8, 2022

 

 

Karuna Therapeutics, Inc.

(Exact name of Registrant as Specified in Its Charter)

 

 

 

Delaware   001-38958   27-0605902

(State or Other Jurisdiction

of Incorporation)

 

(Commission

File Number)

 

(IRS Employer

Identification No.)

 

99 High Street, Floor 26

Boston, Massachusetts

    02110
(Address of Principal Executive Offices)     (Zip Code)

Registrant’s Telephone Number, Including Area Code: 857 449-2244

(Former Name or Former Address, if Changed Since Last Report)

 

 

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

 

Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

 

Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

 

Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

 

Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

 


Title of each class

 

Trading

Symbol(s)

 

Name of each exchange

on which registered

Common stock, par value $0.0001   KRTX   NASDAQ Global Select Market

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).

Emerging growth company  

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  

 

 

 


Item 7.01

Regulation FD Disclosure.

On August 8, 2022, Karuna Therapeutics, Inc. (the “Company”) announced topline results from its Phase 3 EMERGENT-2 trial evaluating the efficacy, safety, and tolerability of its lead investigational therapy, KarXT (xanomeline-trospium), in adults with schizophrenia. A copy of this press release is attached hereto as Exhibit 99.1 and is incorporated into this Item 7.01 by reference.

The information in this Item 7.01 and Exhibit 99.1 attached hereto is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934 (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, except as expressly set forth by specific reference in such filing.

 

Item 8.01

Other Events.

In connection with the announcement of its Phase 3 EMERGENT-2 trial results, the Company is hosting an investor call to present the data from the trial. A copy of the slide presentation to be presented during the investor call is attached hereto as Exhibit 99.2 and is incorporated into this Item 8.01 by reference. The Company undertakes no obligation to update, supplement or amend the materials attached hereto as Exhibit 99.2.

 

Item 9.01

Financial Statements and Exhibits.

(d) Exhibits

 

99.1    Press Release issued by the Company, dated August 8, 2022.
99.2    Company presentation, dated August 8, 2022.
104    Cover Page Interactive Data File (embedded within the Inline XBRL document)


SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.

 

Date: August 8, 2022     By:  

/s/ Troy Ignelzi

      Troy Ignelzi
      Chief Financial Officer
EX-99.1

Exhibit 99.1

Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-2 Trial of KarXT in Schizophrenia

Trial met primary endpoint, with KarXT demonstrating a statistically significant 9.6-point reduction in PANSS Total Score compared to placebo at Week 5 (p<0.0001)

Trial also met key secondary endpoints, demonstrating statistically significant reductions in positive and negative symptoms 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

The Company plans to submit a New Drug Application (NDA) with the U.S. Food & Drug Administration (FDA) in mid-2023

Conference call and webcast to take place today at 8:00 a.m. ET

BOSTON—August 8, 2022— Karuna Therapeutics, Inc. (NASDAQ: KRTX), a clinical-stage biopharmaceutical company driven to create and deliver transformative medicines for people living with psychiatric and neurological conditions, today announced positive topline results from its 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 the 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 demonstrated an early and sustained statistically significant reduction of symptoms, as assessed by PANSS total score, starting at Week 2 and maintained such reduction through all timepoints in the trial.

“We are thrilled that these topline results from the Phase 3 EMERGENT-2 trial confirm what was seen in our Phase 2 EMERGENT-1 trial and underscore the potential for KarXT, with its novel and unique mechanism of action, to redefine what successful treatment looks like for the 21 million people living with schizophrenia worldwide, and potentially usher in the first new class of medicine for these patients in more than 50 years,” said Steve Paul, M.D., chief executive officer, president and chairman of Karuna Therapeutics. “These results represent our second positive registrational trial. We look forward to continuing to gather long-term safety data to support our submission of a New Drug Application with the U.S. Food and Drug Administration for KarXT as a treatment for schizophrenia, which we expect to occur in mid-2023.”

KarXT also met key secondary endpoints in the Phase 3 EMERGENT-2 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. Results at Week 5 include:

 

   

2.9-point reduction in the PANSS positive subscale with KarXT compared to placebo (-6.8 KarXT vs. -3.9 placebo, p<0.0001).

 

   

1.8-point reduction in the PANSS negative subscale with KarXT compared to placebo (-3.4 KarXT vs. -1.6 placebo, p=0.0055).


   

2.2-point reduction in the PANSS negative Marder factor subscale with KarXT compared to placebo (-4.2 KarXT vs. -2.0 placebo, p=0.0022).

KarXT was generally well tolerated. Overall discontinuation rates were similar between KarXT and placebo groups (25% vs. 21%). The overall treatment-emergent adverse events (TEAEs) rate for KarXT and placebo was 75% and 58%, respectively. Discontinuation rates related to TEAEs were similar between KarXT (7%) and placebo (6%). Equal rates of serious TEAEs were observed between KarXT and placebo (2% in each group) and included suicidal ideation, worsening of schizophrenia symptoms, and appendicitis. None of the serious TEAEs were determined to be drug related. The most common TEAEs (>5%) in the KarXT arm were all mild to moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, gastroesophageal reflux disease (acid reflux), abdominal discomfort, and diarrhea. Mean blood pressure measures were similar between KarXT and placebo throughout the trial, and no syncopal events were observed. In the subset of patients with a TEAE of blood pressure increases, mean blood pressure at endpoint was similar to baseline and did not lead to trial discontinuation. Similar to prior trials, an increase in heart rate was associated with KarXT treatment and decreased in magnitude by the end of the trial. Consistent with EMERGENT-1, KarXT was not associated with common problematic side effects of current treatments, including sedation (somnolence), weight gain, and extrapyramidal symptoms.

“Despite the number of available treatment options, there continues to be a tremendous unmet need in the treatment of schizophrenia, placing an immense burden on both patients and their caregivers,” said Rishi Kakar, M.D., chief scientific officer, Segal Trials and lead investigator of the Phase 3 EMERGENT-2 trial. “These data build on the growing body of clinical evidence supporting the potential of KarXT as a new and differentiated approach for schizophrenia, demonstrating notable improvements across both positive and negative symptoms, while not being associated with common problematic side-effects of current therapies, such as weight gain, sedation and movement disorders. This unique profile of KarXT has the potential to provide a new meaningful treatment option for our patients and their families beyond the current standard of care.”

The EMERGENT program consists of the completed positive Phase 2 EMERGENT-1 and Phase 3 EMERGENT-2 trials, as well as three ongoing trials evaluating the acute efficacy and long-term safety of KarXT (EMERGENT-3, EMERGENT-4, and EMERGENT-5). Topline data from the Phase 3 EMERGENT-3 trial are expected in the first quarter of 2023. The data from our EMERGENT program will be used to support submission of an NDA with the U.S. FDA for KarXT as a treatment for schizophrenia, which is expected in mid-2023. Additional analysis of data from the Phase 3 EMERGENT-2 trial is ongoing, with plans to present these results at future medical meetings.

Conference Call and Webcast Information

Karuna will hold a webcast and conference call this morning at 8:00 a.m. ET to share results from an interim analysis of its Phase 3 EMERGENT-2 trial of KarXT for the treatment of schizophrenia.

A live webcast of the presentation will be available on the Investor Relations page of Karuna’s website at investors.karunatx.com. A replay of the webcast will also be archived for up to 30 days on Karuna’s website following the conference.


About the Phase 3 EMERGENT-2 Trial

The Phase 3 EMERGENT-2 trial is a double-blind, placebo-controlled, five-week, inpatient trial evaluating the efficacy, safety, and tolerability of our lead investigational therapy, KarXT, as compared to placebo in adults with schizophrenia in the United States. The primary endpoint was change from baseline in Positive and Negative Syndrome Scale (PANSS) total score, a scale for measuring schizophrenia symptom severity, of KarXT compared to placebo at Week 5. Key secondary endpoints included change from baseline in PANSS positive, PANSS negative and PANSS negative Marder factor subscale of KarXT compared to placebo at Week 5.

A total of 252 adults (between the ages of 18-65 years) with a confirmed diagnosis of schizophrenia who were experiencing symptoms of psychosis enrolled in the trial. Patients were randomized 1:1 to receive either a flexible dose of KarXT (n=126) or placebo (n=126) two times a day (BID) for five weeks. On Days 1-2, patients received a dose of 50/20 KarXT (50mg xanomeline/20mg trospium) BID or matching placebo. On Day 3, patients escalated to a dose of 100/20 BID, and starting on Day 8, patients could increase to 125/30 BID based on tolerability. In the trial, 81% of patients on KarXT compared to 90% on placebo titrated to the highest dose level (125/30).

About KarXT

KarXT (xanomeline-trospium) is an oral, investigational M1/M4-preferring muscarinic agonist in development for the treatment of psychiatric and neurological conditions, including schizophrenia and psychosis in Alzheimer’s disease. 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.

About Schizophrenia

Schizophrenia is a chronic and often debilitating mental illness that impacts how one thinks, feels, and behaves. It is characterized by positive symptoms (hallucinations and delusions), negative symptoms (difficulty enjoying life and withdrawal from others), and cognitive impairment. Together these symptoms can severely impact quality of life and productivity, with only 10% of people gainfully employed and many struggling to meet adult milestones – such as living independently. The life expectancy of people living with schizophrenia is reduced by 10-20 years compared to the general population. Schizophrenia affects approximately 21 million people worldwide and is most commonly treated with antipsychotics. Unfortunately, many people with schizophrenia continue to experience limited efficacy or problematic side effects while on antipsychotic therapy, and up to 74% of patients discontinue medication before 18 months. When schizophrenia treatment is discontinued, it can lead to impacts on health including relapse, hospitalization, and longer time to remission.

About Karuna Therapeutics

Karuna Therapeutics is a clinical-stage biopharmaceutical company driven to create and deliver transformative medicines for people living with psychiatric and neurological conditions. At Karuna, we understand there is a need for differentiated and more effective treatments that can help patients navigate the challenges presented by serious mental illness. Utilizing our extensive knowledge of neuroscience, we are harnessing the untapped potential of the brain in pursuit of novel pathways to develop medicines that make meaningful differences in peoples’ lives. For more information, please visit www.karunatx.com.


Forward-Looking Statements

This press release contains forward looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements regarding our expectations about the timing of our ongoing and planned clinical trials and regulatory filings, our goals to develop and commercialize our product candidates, and other statements identified by words such as “could,” “expects,” “intends,” “may,” “plans,” “potential,” “should,” “will,” “would,” or similar expressions and the negatives of those terms. Forward looking statements are not promises or guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in such forward-looking statements. These factors include risks related to our limited operating history, our ability to obtain necessary funding, our ability to generate positive clinical trial results for our product candidates and other risks inherent in clinical development, the timing and scope of regulatory approvals, changes in laws and regulations to which we are subject, competitive pressures, risks relating to business interruptions resulting from the coronavirus (COVID-19) pandemic, and other risks set forth under the heading “Risk Factors” of our Annual Report on Form 10-K for the year ended December 31, 2021. Our actual results could differ materially from the results described in or implied by such forward looking statements. Forward-looking statements speak only as of the date hereof, and, except as required by law, we undertake no obligation to update or revise these forward-looking statements.

Investor Contact:

Alexis Smith

518-338-8990

asmith@karunatx.com

Media Contact:

Falon Moran

media@karunatx.com

EX-99.2

Slide 1

Topline results: Phase 3 EMERGENT-2 trial of KarXT in schizophrenia August 8, 2022 Exhibit 99.2


Slide 2

Forward looking statements This presentation and other related material may contain a number of “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements regarding Karuna’s expectation about any or all of the following: (i) the timing, progress and results of preclinical studies and clinical trials for KarXT and other product candidates it may develop, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work and the period during which the results of the trials will become available; (ii) Karuna’s research and development plans, including its plans to explore the therapeutic potential of KarXT in additional indications; (iii) Karuna’s plans to develop and commercialize KarXT and other product candidates; and (iv) the timing of and Karuna’s ability to obtain and maintain marketing approvals for its product candidates. Forward-looking statements can be identified by terms such as “could,” “expects,” “intends,” “may,” “plans,” “potential,” “should,” “will,” “would,” or similar expressions and the negative of those terms. Karuna has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect its business, financial condition and results of operations. Although Karuna believes that such statements are based on reasonable assumptions, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond Karuna’s control, you should not rely on these forward-looking statements as predictions of future events. These risks and uncertainties include, among others: outcomes of Karuna’s planned and ongoing clinical trials and studies may not be favorable; one or more of Karuna’s product candidate programs may not proceed as planned for technical, scientific or commercial reasons; availability and timing of results from preclinical studies and clinical trials; uncertainty about regulatory approval to conduct clinical trials or to market products; uncertainties regarding intellectual property protection; risks relating to business interruptions resulting from the coronavirus (COVID-19) pandemic; and those risk and uncertainties described under the heading “Risk Factors” in Karuna’s Annual Report on Form 10-K for the year ended December 31, 2021, and filed with the Securities and Exchange Commission on February 24, 2022, and in any other subsequent filings made by Karuna with the U.S. Securities and Exchange Commission, which are available at www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. Karuna disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this presentation, other than to the extent required by law.


Slide 3

Introduction Steve Paul, M.D. Chief Executive Officer, President, and Chairman of the Board Phase 3 EMERGENT-2 trial results Steve Brannan, M.D. Chief Medical Officer Next steps for KarXT Andrew Miller, Ph.D. Founder and Chief Operating Officer Closing remarks and Q&A Steve Paul, M.D. Andrew Miller, Ph.D. Troy Ignelzi Chief Financial Officer Agenda


Slide 4

Karuna means “compassion in action” in Sanskrit Our purpose is to create and deliver transformative medicines for people living with psychiatric and neurological conditions


Slide 5

KarXT (xanomeline-trospium): a novel m1/m4-preferring muscarinic agonist Sources: Brannan et al. 2021, Shekar et al. 2008, Bodick et al. 1997 Unique pharmacology enables potential use in complex mental illness Xanomeline stimulates both M1 & M4 receptors in the brain These receptors are expressed in brain regions implicated in psychosis and cognition, suggesting modulation of these receptors could treat these symptoms Approach is supported by clinical evidence demonstrating the antipsychotic activity and pro-cognitive properties of xanomeline and KarXT M1 & M4 Relative Expression Low High M1 M4 M1 M4


Slide 6

Need for new, differentiated treatments for schizophrenia Sources: GBD 2017, Patel et al. 2014, Remington et al. 2016, Goff et al. 2011, Liebermann et al. 2005 Chronic psychiatric condition affecting 21M+ people globally Schizophrenia is one of the leading causes of disability worldwide, with onset in late-teens / early-adulthood No approved treatments for negative & cognitive symptoms Up to 74% of patients discontinue medication before 18 months, with many failing to find an effective and/or tolerable therapy Approved antipsychotics all rely on the same pathway and approach – inhibiting dopaminergic and serotonergic signaling in the brain Positive Hallucinations Delusions Disorganized thoughts Negative Withdrawal Social isolation Apathy Lack of motivation Cognitive Memory impairment Attention deficits Poor concentration Reduced executive function


Slide 7

Robust registrational program to support NDA submission requirements Submission of an NDA for KarXT in schizophrenia expected in mid-2023 NDA = New Drug Application; *Additional analysis ongoing EMERGENT-1 NCT03697252 EMERGENT-2 NCT04659161 EMERGENT-3 NCT04738123 EMERGENT-4 NCT04659174 EMERGENT-5 NCT04820309 Phase 2 Phase 3 Phase 3 Phase 3 Phase 3 Efficacy and safety of KarXT vs. placebo Efficacy and safety of KarXT vs. placebo Efficacy and safety of KarXT vs. placebo Long-term safety & tolerability of KarXT Long-term safety & tolerability of KarXT 5-week, 1:1 randomized, flexible-dose, double-blind, placebo-controlled inpatient trial 5-week, 1:1 randomized, flexible-dose, double-blind, placebo-controlled inpatient trial 5-week, 1:1 randomized, flexible-dose, double-blind, placebo-controlled inpatient trial 52-week, open-label, outpatient extension of EMERGENT-2 & 3 52-week, open-label, outpatient trial Complete Complete* Topline data expected 1Q 2023 Enrolling Enrolling


Slide 8

Phase 3 EMERGENT-2 trial results Steve Brannan, M.D. Chief Medical Officer


Slide 9

Phase 3 EMERGENT-2 trial design KarXT dose is expressed as xanomeline/trospium (mg/mg) *Washout of prior oral lithium and/or antipsychotics; †Optional increase in dose based on tolerability determined by a clinician PANSS = Positive & Negative Syndrome Scale; CFB = change from baseline; BID = twice daily Double-blind Inpatient Treatment Period Days 1-35 Screening Period* <2 weeks KarXT (n=126) Placebo (n=126) KEY Patients randomized Start of trial (Day 0) End of trial & primary endpoint (Week 5) Flexible dosing & titration schedule of KarXT BID vs. matching placebo BID R KarXT 50/20 Days 1-2 KarXT 100/20 Day 3-7 KarXT 125/30† Days 8-35 R Select Eligibility Criteria 18-65 years of AD Confirmed diagnosis of schizophrenia and experiencing symptoms of psychosis PANSS total score between 80 and 120 Primary Endpoint: CFB in PANSS total score compared to placebo at Week 5 Key Secondary Endpoints CFB in PANSS positive subscale compared to placebo at Week 5 CFB in PANSS negative subscale compared to placebo at Week 5 CFC in PANSS negative Marder factor subscale compared to placebo at Week 5


Slide 10

Demographics and baseline characteristics *Mean age represented in years; PANSS = Positive & Negative Syndrome Scale iTT population KarXT​ (n=126) Placebo​ (n=126) Mean age* ​ 45.6 46.2 Sex, n (%)​ Male Female 95 (75.4) 31 (24.6) 95 (75.4) 31 (24.6) Race, n (%) Asian Black White Other 2 (1.6) 97 (77.0) 26 (20.6) 1 (0.8) 1 (0.8) 92 (73.0) 31 (24.6) 2 (1.6) Baseline PANSS​ total score 98.3 97.9 Baseline PANSS positive​ score 26.8 26.7 Baseline PANSS negative​ score 22.9 22.9 Baseline PANSS negative Marder factor score​ 22.9 22.5


Slide 11

Primary endpoint: PANSS total score at Week 5 All efficacy analyses performed using the modified intent-to-treat (mITT) analysis set, defined as all randomized participants who received at least one dose of study medication at baseline and at least one post-baseline PANSS assessment (KarXT n=117, placebo n=119) Cohen’s d effect size of 0.61 Baseline Week 2 Week 3 Week 4 Week 5 **** **** ** * 9.6-point reduction in PANSS total score at Week 5, p<0.0001 (-21.2 KarXT vs. -11.6 placebo) * ** **** p<0.05 p<0.01 p<0.0001


Slide 12

Secondary endpoint: PANSS positive subscale at Week 5 All efficacy analyses performed using the modified intent-to-treat (mITT) analysis set, defined as all randomized participants who received at least one dose of study medication and had a baseline and at least one post-baseline PANSS assessment (KarXT n=117, placebo n=119) Baseline Week 2 Week 3 Week 4 Week 5 **** *** ** 2.9-point reduction in PANSS-positive subscale score at Week 5, p<0.0001 (-6.8 KarXT vs. -3.9 placebo) ** *** **** p<0.01 p<0.001 p<0.0001


Slide 13

Secondary endpoint: PANSS negative subscale at Week 5 All efficacy analyses performed using the modified intent-to-treat (mITT) analysis set, defined as all randomized participants who received at least one dose of study medication and had a baseline and at least one post-baseline PANSS assessment (KarXT n=117, placebo n=119) Baseline Week 2 Week 3 Week 4 Week 5 ** * 1.8-point reduction in PANSS-negative subscale score at Week 5, p=0.0055 (-3.4 KarXT vs. -1.6 placebo) p<0.05 p<0.01 * **


Slide 14

Secondary endpoint: PANSS negative Marder factor subscale at Week 5 All efficacy analyses performed using the modified intent-to-treat (mITT) analysis set, defined as all randomized participants who received at least one dose of study medication at baseline and at least one post-baseline PANSS assessment (KarXT n=117, placebo n=119) Baseline Week 2 Week 3 Week 4 Week 5 ** * 2.2-point reduction in PANSS negative Marder factor subscale score at Week 5, p=0.0022 (-4.2 KarXT vs. -2.0 placebo) p<0.05 p<0.01 * **


Slide 15

Summary of safety and tolerability data KarXT was generally well tolerated, with a side effect profile substantially consistent with prior trials Overall discontinuation rates were similar between KarXT and placebo groups (25% vs. 21%) Incidence rates of TEAEs were 75% (KarXT) and 58% (placebo) Discontinuation rates related to TEAEs were similar between the two groups (7% KarXT and 6% placebo) Four serious TEAEs (2% per treatment group) – none of which were determined to be drug related KarXT (suicidal ideation, n=2) and placebo (worsening of schizophrenia symptoms, n=1; appendicitis, n=1) KarXT was not associated with common problematic side effects of current therapies – such as somnolence, weight gain or extrapyramidal motor symptoms The most common (>5%) TEAEs in the KarXT group were mild to moderate in severity, with a majority cholinergic in nature TEAEs (>5%) included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, acid reflux, abdominal discomfort, and diarrhea Rates of headache, abdominal discomfort, and diarrhea were comparable to placebo Mean blood pressure measures for KarXT were similar to placebo at each time point throughout the trial, consistent with prior trials In the subset of patients with a recorded TEAE of increased blood pressure, mean blood pressure at endpoint was similar to baseline and did not lead to trial discontinuation Consistent with prior trials, increase in heart rate was associated with KarXT treatment and decreased in magnitude by the end of the trial No syncope observed Summary of safety and tolerability of safety population (KarXT n=125, placebo n=126) TEAE = treatment emergent adverse events


Slide 16

Next steps for KarXT Andrew Miller, Ph.D. Founder & Chief Operating Officer


Slide 17

Summary of EMERGENT-2 topline results TEAE = treatment emergent adverse events; AEs = adverse events; EPS = extrapyramidal symptoms Clinically meaningful and statistically significant improvements in positive and negative symptoms of schizophrenia as measured by the primary and key secondary outcome measures Early and sustained reduction of symptoms observed at Week 2 and maintained through all timepoints in the trial KarXT was not associated with weight gain, EPS, or sedation, which are common AEs of current antipsychotic medications Most common TEAEs ( > 5%) were mild to moderate in severity and mostly cholinergic in nature Generally well tolerated, with a side effect profile substantially consistent with prior trials of KarXT Overall discontinuation rate similar between KarXT (25%) and placebo (21%), consistent with EMERGENT-1


Slide 18

Robust Phase 3 EMERGENT clinical program to support NDA submission requirements NDA submission of KarXT in schizophrenia expected mid-2023 NDA = New Drug Application; NDA = New Drug Application *Additional analysis ongoing (EMERGENT-2) FDA has indicated EMERGENT-1, one successful Phase 3 efficacy and safety trial (e.g., EMERGENT-2), and additional safety data to meet regulatory requirements would be acceptable to support NDA filing in schizophrenia EMERGENT-1 NCT03697252 EMERGENT-2 NCT04659161 EMERGENT-3 NCT04738123 EMERGENT-4 NCT04659174 EMERGENT-5 NCT04820309 Phase 2 Phase 3 Phase 3 Phase 3 Phase 3 Efficacy and safety of KarXT vs. placebo Efficacy and safety of KarXT vs. placebo Efficacy and safety of KarXT vs. placebo Long-term safety & tolerability of KarXT Long-term safety & tolerability of KarXT 5-week, 1:1 randomized, flexible-dose, double-blind, placebo-controlled inpatient trial 5-week, 1:1 randomized, flexible-dose, double-blind, placebo-controlled inpatient trial 5-week, 1:1 randomized, flexible-dose, double-blind, placebo-controlled inpatient trial 52-week, open-label, outpatient extension of EMERGENT-2 & 3 52-week, open-label, outpatient trial Complete* Complete Topline data expected 1Q 2023 Enrolling Enrolling


Slide 19

Expanding KarXT’s potential utility in psychiatry *Additional analysis ongoing Five ongoing late-stage trials across large psychiatric conditions PROGRAM PRECLINICAL PHASE 1 PHASE 2 PHASE 3 STATUS / UPCOMING MILESTONE Schizophrenia Complete Schizophrenia Complete* Topline data Q1 2023 Enrolling Enrolling Schizophrenia (adjunctive) Psychosis in adults with an inadequate response to standard of care Topline data 1H 2024 Enrolling Psychosis in Alzheimer’s disease Planned initiation 3Q ‘22 Planned initiation 2023 Planned initiation 2023 EMERGENT-2 EMERGENT-3 EMERGENT-4 (open-label extension) EMERGENT-5 ARISE ADEPT-1 ARISE (open-label extension) ADEPT-2 ADEPT-3 (open-label extension) EMERGENT-1


Slide 20

Closing remarks and Q&A Steve Paul, M.D., Chief Executive Officer, President and Chairman of the Board Andrew Miller, Ph.D., Founder & Chief Operating Officer Troy Ignelzi, Chief Financial Officer


Slide 21

Thank you