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): February 28, 2022
(Exact name of registrant as specified in its charter)
(State or other jurisdiction of incorporation) | (Commission File Number) | (I.R.S. Employer Identification No.) | ||||||
Praxis Precision Medicines, Inc.
(Address of principal executive offices, including zip code)
(617 ) 300-8460
(Registrant’s telephone number, including area code)
Not Applicable
(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 | Trade Symbol(s) | Name of each exchange on which registered | ||||||||||||
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 2.02. Results of Operations and Financial Condition.
On February 28, 2022 , Praxis Precision Medicines, Inc. (the “Company”) announced its financial results for the quarter and full year ended December 31, 2021. A copy of the press release is being furnished as Exhibit 99.1 to this Current Report on Form 8-K.
Item 7.01. Regulation FD Disclosure.
On February 28, 2022, the Company updated its corporate presentation for use in meetings with investors, analysts and others. The presentation is available in the “Investors + Media” portion of the Company's website at investors.praxismedicines.com and a copy is furnished as Exhibit 99.2 to this Current Report on Form 8-K.
The information in this Current Report on Form 8-K under Items 2.02 and 7.01, including Exhibit 99.1 and Exhibit 99.2 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, as amended (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, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
Exhibit No. | Description | |||||||
| 99.1 | ||||||||
| 99.2 | ||||||||
| 104 | Cover Page Interactive Data File (embedded within the inline XBRL document) | |||||||
SIGNATURE
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 hereunto duly authorized.
| PRAXIS PRECISION MEDICINES, INC. | |||||||||||
Date: | By: | /s/ Marcio Souza | |||||||||
| Marcio Souza | |||||||||||
| Chief Executive Officer | |||||||||||
Praxis Precision Medicines Provides Corporate Update and Reports Fourth Quarter and Full Year 2021 Financial Results
PRAX-114 Phase 2/3 monotherapy MDD Aria Study topline results expected in June 2022
PRAX-944 Phase 2a ET topline results expected in May 2022; to include open-label and placebo-controlled withdrawal data
PRAX-222 seamless study in SCN2A-DEE expected to initiate in 2Q22
Cash and investments of $275.9 million as of December 31, 2021 supports runway into 2Q23
BOSTON, Mass., February 28, 2022 — Praxis Precision Medicines, Inc. (NASDAQ: PRAX), a clinical-stage biopharmaceutical company translating genetic insights into the development of therapies for central nervous system (CNS) disorders characterized by neuronal excitation-inhibition imbalance, today provided a corporate update, including a video highlighting recent business and pipeline progress, and reported financial results for the fourth quarter and full year 2021.
“With screening now closed in all sites in the PRAX-114 Aria Study, we are emboldened by the progress in our psychiatry franchise, and broadly across our pipeline,” said Marcio Souza, president and chief executive officer of Praxis. “There is a clear unmet need for a fast-acting, durable depression treatment with a differentiated tolerability profile relative to both existing treatment options and other drugs in development, which allows patients to remain on drug throughout an episode of depression. We look forward to reporting topline results from the Aria Study in June, followed shortly thereafter by results from the Acapella Study, and intend to initiate a Phase 3 trial in MDD later this year. With additional topline data expected from PRAX-114 studies for PTSD and ET, as well as from PRAX-944 for ET, 2022 is shaping up to be a transformative year for Praxis and we are eager to share our continued progress and growth.”
Recent Business Highlights and Upcoming Milestones:
Psychiatry
•Praxis expects topline results from the PRAX-114 Phase 2/3, placebo-controlled Aria Study for monotherapy treatment of Major Depressive Disorder (MDD) in the second quarter of 2022, in June. The Aria Study is intended to serve as one of two trials required by the U.S. Food and Drug Administration (FDA) to demonstrate clinical efficacy to support registration of PRAX-114 for monotherapy treatment of MDD.
•The Company expects topline results from the PRAX-114 Phase 2, placebo-controlled, dose-ranging Acapella Study for treatment of MDD in mid-2022. The Acapella Study is intended to provide additional understanding of the dose range and to evaluate the safety and efficacy of PRAX-114 at doses of 10, 20, 40 and 60 mg.
•Praxis initiated a PRAX-114 Phase 2, placebo-controlled study for treatment of post-traumatic stress disorder (PTSD) in the fourth quarter of 2021 and has started dosing participants. Topline results are expected in the second half of 2022. The trial is designed to evaluate the safety, tolerability and efficacy of a nightly dose of 40 mg of PRAX-114 for 4 weeks in approximately 80 participants with PTSD, using the CAPS-5 total score as the primary endpoint.
Movement Disorders
•In December 2021, Praxis reported preliminary open-label data from the second of two cohorts of its PRAX-944 Phase 2a trial for daytime treatment of essential tremor (ET), evaluating safety and efficacy in participants titrated up to 120 mg per day. Enrollment of study participants was subsequently completed. Topline open-label and placebo-controlled, randomized withdrawal results are expected in the second quarter of 2022, in May.
•The Company expects topline results from the PRAX-944 Phase 2b Essential1 Study for daytime treatment of ET in the second half of 2022. Essential1 is a placebo-controlled, dose-ranging clinical trial designed to evaluate the safety, tolerability and efficacy of PRAX-944 at 20, 60 or 100 mg per day.
•Praxis expects to initiate a PRAX-114 Phase 2, placebo-controlled, crossover study for daytime treatment of ET to evaluate safety, pharmacokinetics (PK) and efficacy of 10 and 20 mg of PRAX-114 in the first quarter of 2022. Topline results are expected in the second half of 2022.
•Praxis intends to initiate a Phase 2, placebo-controlled trial to evaluate the safety, PK and efficacy of PRAX-944 as a non-dopaminergic treatment for the motor symptoms of Parkinson's disease in the second quarter of 2022.
Epilepsy
•Praxis plans to initiate a PRAX-562 Phase 2, placebo-controlled trial for treatment of developmental epileptic encephalopathies (DEEs) in the second quarter of 2022.
•Praxis intends to initiate a seamless study of PRAX-222, its lead antisense oligonucleotide (ASO) candidate, for the treatment of SCN2A-DEE in the second quarter of 2022.
•In January 2022, the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) granted Orphan Drug Designation (ODD) to PRAX-222 for the treatment of SCN2A-DEE. Previously, in January 2021, the FDA granted both ODD and Rare Pediatric Disease (RPD) designation to PRAX-222 for the treatment of SCN2A-DEE.
•In December 2021, the EMA COMP granted ODD to PRAX-562 for the treatment of SCN8A-DEE and SCN2A-DEE. Previously, in January 2021, the FDA granted both ODD and RPD designation to PRAX-562 for the treatment of SCN8A-DEE and SCN2A-DEE.
•In December 2021, Praxis presented data from two of its rare epilepsy programs, PRAX-562 and its KCNT1 inhibitor, at the American Epilepsy Society 2021 Annual Meeting. Presentations on PRAX-562 focused on its potent anticonvulsant activity in SCN2A-DEE and SCN8A-DEE mouse models and its mechanistic distinction relative to standard-of-care sodium channel inhibitors, with greater potency and selectivity for persistent sodium current. The presentation on KCNT1 focused on the compound’s in vitro and in vivo profiling, including its efficacy in a KCNT1 gain-of-function mouse model.
•In December 2021, Praxis entered into a research collaboration with Cerebral Therapeutics, Inc., with an exclusive option to in-license delivery technology for intracerebroventricular administration of its ASOs.
•Praxis intends to develop PRAX-628, a small molecule with unique NaV channel binding kinetics that favor inhibition of pathological neuronal activity underlying aberrant brain function, such as that seen in the initial indication of focal onset seizures. The Company anticipates use in other common forms of epilepsy and CNS excitability disorders more generally. PRAX-628 is currently in IND-enabling toxicology studies.
Other Exploratory CNS Indications
•Praxis plans to initiate a PRAX-562 Phase 2, placebo-controlled trial for treatment of rare adult cephalgias in the first quarter of 2022, including a cohort of participants with Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) and Short-lasting Unilateral Neuralgiform headache with Autonomic symptoms (SUNA), and a cohort of participants with Trigeminal Neuralgia (TN).
General Corporate Updates
•In December 2021, Praxis announced the appointment of Megan Sniecinski as chief business officer, the promotions of Alyssa Wyant to chief regulatory and quality officer and Karl Hansen, Ph.D., to chief technical operations officer, and the decision by chief scientific officer and co-founder, Steven Petrou, Ph.D., to fully dedicate his time to Praxis upon stepping down from his role as Director of the Florey Institute of Neuroscience and Mental Health and Head of the Florey Department at The University of Melbourne.
Fourth Quarter and Full Year 2021 Financial Results:
As of December 31, 2021, Praxis had $275.9 million in cash, cash equivalents and marketable securities, compared to $296.6 million in cash and cash equivalents as of December 31, 2020. This decrease of $20.7 million primarily reflects cash used in operations of $124.6 million during the year ended December 31, 2021, partially offset by $105.7 million in net proceeds from the follow-on public offering of shares of the Company’s common stock in May 2021 and at-the-market offerings during the fourth quarter of 2021. The company’s cash, cash equivalents and marketable securities as of December 31, 2021 are expected to fund operations into the second quarter of 2023.
Research and development expenses were $43.5 million for the fourth quarter of 2021, compared to $16.3 million for the fourth quarter of 2020. Research and development expenses were $120.3 million for the year ended December 31, 2021, compared to $45.0 million for the year ended December 31, 2020. The increase in research and development expenses for full year 2021 of $75.3 million was primarily attributable to $43.6 million in increased expenses related to the Company’s franchises, $17.6 million in increased personnel-related costs due to increased headcount and $8.8 million in increased expenses for other exploratory CNS indications.
General and administrative expenses were $15.1 million for the fourth quarter of 2021, compared to $9.4 million for the fourth quarter of 2020. General and administrative expenses were $47.1 million for the year ended December 31, 2021, compared to $17.0 million for the year ended December 31, 2020. The increase in general and administrative expenses for full year 2021 of $30.1 million was primarily attributable to $14.6 million in increased personnel-related costs due to increased headcount, $9.9 million in increased professional fees and a $5.6 million increase in other general and administrative expenses.
Praxis reported a net loss of $58.6 million for the fourth quarter of 2021, including $6.1 million of stock-based compensation expense, compared to $25.7 million for the fourth quarter of 2020, including $3.8 million of stock-based compensation expense. Praxis reported a net loss of $167.1 million for the year ended December 31, 2021, including $22.7 million of stock-based compensation expense, compared to a net loss of $61.8 million for the year ended December 31, 2020, including $5.2 million of stock-based compensation expense.
As of December 31, 2021, Praxis had 45.3 million shares of common stock outstanding.
Conference Call and Webcast
Praxis will host a Q&A session focused on today’s corporate update and financial results for the fourth quarter and full year 2021 via a conference call and webcast today, February 28, 2022, at 8:30 a.m. ET. To access the conference call, please dial (833) 398-1037 (local) or (914) 987-7735 (international) at least 10 minutes prior to the start time and refer to conference ID 8993704. A live audio webcast of the event may also be accessed through the Events & Presentations page of the Investors + Media section of the company’s website at https://investors.praxismedicines.com/events-and-presentations. A replay of the webcast will be available on Praxis’ website approximately two hours after the completion of the event and will be archived for 30 days following the event.
About Praxis
Praxis Precision Medicines is a clinical-stage biopharmaceutical company translating genetic insights into the development of therapies for CNS disorders characterized by neuronal excitation-inhibition imbalance. Praxis is applying insights from genetic epilepsies to both rare and more prevalent neurological and psychiatric disorders, using our understanding of shared biological targets and circuits in the brain. Praxis has established a broad portfolio with multiple programs, including product candidates across psychiatric disorders, movement disorders, epilepsy and other exploratory CNS indications, with three clinical-stage product candidates. For more information, please visit www.praxismedicines.com and follow us on LinkedIn and Twitter.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws, including express or implied statements regarding Praxis’ future expectations, plans and prospects, including, without limitation, statements regarding expectations, plans and timing for our clinical data, the anticipated timing of our clinical trials and regulatory filings, the development of our product candidates, including the design of our clinical trials and the treatment potential of our product candidates, and the sufficiency of our cash, cash equivalents and marketable securities, and as well as other statements containing the
words “anticipate,” “believe,” “continue,” “could,” “endeavor,” “estimate,” “expect,” “anticipate,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “seek,” “should,” “target,” “will” or “would” and similar expressions that constitute forward-looking statements under the Private Securities Litigation Reform Act of 1995.
The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation: uncertainties inherent in clinical trials; the expected timing of submissions for regulatory approval or review by governmental authorities; regulatory approvals to conduct trials; risks, uncertainties and assumptions regarding the impact of the continuing COVID-19 pandemic on Praxis’ business, operations, strategy, goals and anticipated timelines, Praxis’ ongoing and planned preclinical activities, Praxis’ ability to initiate, enroll, conduct or complete ongoing and planned clinical trials and Praxis’ timelines for regulatory submissions; and other risks concerning Praxis’ programs and operations are described in additional detail in its Annual Report on Form 10-K for the year ended December 31, 2021 to be filed and other filings made with the Securities and Exchange Commission. Although Praxis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on information and factors currently known by Praxis. As a result, you are cautioned not to rely on these forward-looking statements. Any forward-looking statement made in this press release speaks only as of the date on which it is made. Praxis undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.
Investor Contact:
Alex Kane
Praxis Precision Medicines
investors@praxismedicines.com
617-300-8481
Media Contact:
Ian Stone
Canale Communications
Ian.stone@canalecomm.com
619-849-5388
PRAXIS PRECISION MEDICINES, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
(Amounts in thousands)
(Unaudited)
| December 31, | |||||||||||
| 2021 | 2020 | ||||||||||
| Assets | |||||||||||
| Cash and cash equivalents | $ | 138,704 | $ | 296,608 | |||||||
| Marketable securities | 137,207 | — | |||||||||
| Prepaid expenses and other current assets | 11,498 | 5,718 | |||||||||
| Property and equipment, net | 1,213 | 82 | |||||||||
| Operating lease right-of-use assets | 3,653 | 754 | |||||||||
| Other non-current assets | 472 | 15 | |||||||||
| Total assets | $ | 292,747 | $ | 303,177 | |||||||
| Liabilities and stockholders’ equity | |||||||||||
| Accounts payable | $ | 10,780 | $ | 4,088 | |||||||
| Accrued expenses | 26,844 | 10,869 | |||||||||
| Operating lease liabilities | 4,311 | 763 | |||||||||
| Common stock | 5 | 4 | |||||||||
| Additional paid-in capital | 567,598 | 437,007 | |||||||||
| Accumulated other comprehensive loss | (176) | — | |||||||||
| Accumulated deficit | (316,615) | (149,554) | |||||||||
| Total liabilities and stockholders' equity | $ | 292,747 | $ | 303,177 | |||||||
PRAXIS PRECISION MEDICINES, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(Amounts in thousands, except share and per share amounts)
(Unaudited)
| Three Months Ended December 31, | Year Ended December 31, | ||||||||||||||||||||||
| 2021 | 2020 | 2021 | 2020 | ||||||||||||||||||||
| Operating expenses: | |||||||||||||||||||||||
| Research and development | $ | 43,511 | $ | 16,272 | $ | 120,257 | $ | 44,976 | |||||||||||||||
| General and administrative | 15,146 | 9,440 | 47,075 | 16,992 | |||||||||||||||||||
| Total operating expenses | 58,657 | 25,712 | 167,332 | 61,968 | |||||||||||||||||||
| Loss from operations | (58,657) | (25,712) | (167,332) | (61,968) | |||||||||||||||||||
| Other income: | |||||||||||||||||||||||
| Other income, net | 70 | 6 | 271 | 140 | |||||||||||||||||||
| Total other income | 70 | 6 | 271 | 140 | |||||||||||||||||||
| Loss before benefit from income taxes | (58,587) | (25,706) | (167,061) | (61,828) | |||||||||||||||||||
| Benefit from income taxes | 5 | — | — | 8 | |||||||||||||||||||
| Net loss | $ | (58,582) | $ | (25,706) | $ | (167,061) | $ | (61,820) | |||||||||||||||
| Accretion and cumulative dividends on redeemable convertible preferred stock | — | (950) | — | (8,996) | |||||||||||||||||||
| Gain on repurchase of redeemable convertible preferred stock | — | — | — | 493 | |||||||||||||||||||
| Net loss attributable to common stockholders | $ | (58,582) | $ | (26,656) | $ | (167,061) | $ | (70,323) | |||||||||||||||
| Net loss per share attributable to common stockholders, basic and diluted | $ | (1.30) | $ | (0.87) | $ | (3.94) | $ | (7.86) | |||||||||||||||
| Weighted average common shares outstanding, basic and diluted | 44,964,580 | 30,703,886 | 42,454,055 | 8,950,152 | |||||||||||||||||||
PAGE 1CONFIDENTIAL C O R P O R A T E OVERVIEW F E B R U A R Y 2 0 2 2
PAGE 2CONFIDENTIAL Forward-looking statements This presentation may contain “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 relating to our business, operations, and financial conditions, including but not limited to express or implied statements regarding the current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development plans, our preclinical and clinical results and other future conditions. Any forward-looking statements in this presentation are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this presentation, including, without limitation, risks relating to: (i) the success and timing of our ongoing clinical trials, (ii) the success and timing of our product development activities and initiating clinical trials, (iii) the success and timing of our collaboration partners’ product development activities, (iv) our ability to obtain and maintain regulatory approval of any of our product candidates, (v) our plans to research, discover and develop additional product candidates, (vi) our ability to enter into collaborations for the development of new product candidates, (vii) our ability to establish manufacturing capabilities, and our and our collaboration partners’ abilities to manufacture our product candidates and scale production, (viii) our ability to meet any specific milestones set forth herein, and (ix) uncertainties and assumptions regarding the impact of the COVID-19 pandemic on our business, operations, clinical trials, supply chain, strategy, goals and anticipated timelines. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. For further information regarding the risks, uncertainties and other factors that may cause differences between our expectations and actual results, you should review the “Risk Factors” section of our Annual Report on Form 10-K filed for the year ended December 31, 2021 and other filings with the Securities and Exchange Commission. Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party sources to be reliable as of the date of this presentation, we have not independently verified, and make no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while we believe our own internal research is reliable, such research has not been verified by any independent source.
PAGE 3CONFIDENTIAL A PATIENT-GUIDED CNS COMPANY D E V E L O P I N G N E W C L A S S E S O F T R E A T M E N T S Inspired By Human Genetics & The Biology Of Epilepsy
PAGE 4CONFIDENTIAL Targeting Common & Rare Diseases Connected By Neuronal Imbalance The biology of epilepsy offers insights into brain function for CNS disorders Targets Elucidated By Genetics SCN1A SCN9A SCN10A SCN11A CACNA1A KCNA1 SLC1A3 SETX RFC1 DRD3 HTT FMR1 OPA1 SYNGAP1 SHANK3 CDKL5 DNM1 UNC79 TRIM3 PCDH19 CACNA1G GABRB3 KCN1A GABRB3 KCNT1 SCN1A SCN8A SCN2A CACNA1A TPH2 FKBP2 HTR2A PAIN MOVEMENTDEPRESSION EPILEPSY Hypoexcitability Disease States E/I Balance Hyperexcitability Disease States
PAGE 5CONFIDENTIAL Development informed by TRANSLATIONAL TOOLS Targets identified through GENETICS Clinical development paths to POC RIGOROUS and EFFICIENT Development strategies are PATIENT-GUIDED Praxis is built on four key pillars
PAGE 6CONFIDENTIAL Broad portfolio of highly differentiated programs across multiple CNS disorders PRECLINICAL PHASE 1 PHASE 2 REGISTRATIONAL ENABLINGPROGRAMMECHANISM OF ACTIONFRANCHISE * SCN2A-LOF, SYNGAP1 & PCDH19 ASOs are a collaboration with The Florey Institute PRAX-114 Phase 2 trial for ET, PRAX-944 Phase 2 trial for PD and PRAX-562 trials for SUNCT/SUNA/TN and for DEEs have not initiated PRAX-944 PRAXIS-040 PSYCHIATRY Nav1.2 downregulation PRAX-562 PRAX-222 PRAX-020 EPILEPSY Small molecule ASO Undisclosed T-type calcium channel blocker Persistent sodium current blocker Potassium channel T 1 blocker MOVEMENT DISORDERS Small molecule Small molecule Small molecule Nav1.2 upregulation SCN2A-LOF* ASO GABAA receptor PAM PRAX-114 Small molecule PRAX-944 Essential Tremor PRAXIS-040 UNDISCLOSED PSYCHIATRY TARGET PRAX-944 PD PRAX-222 SCN2A-DEE PRAX-020 KCNT1 PRAX-562 DEEs OTHER CNS PRAX-114 Essential Tremor PRAX-562Persistent sodium current blocker SCN8A Small molecule PRAX-628 Focal Epilepsy Activity dependent sodium current blocker PRAX-628 Small molecule SCN2A LoF ASO SCN2A-DEE PRAX-562 SUNCT/SUNA/TN PCDH19 ASO PCDH19 SYNGAP1 ASO SYNGAP1 PRAX-114GABAA receptor PAM Small molecule PRAX-114 MDD PRAX-114 PTSD PRAXIS-050 Small molecule Undisclosed PRAXIS-050 UNDISCLOSED MOVEMENT TARGET RAS GTPase activating protein (SynGAP) upregulation SYNGAP1* ASO Protocadherin-19 downregulation PCDH19* ASO PRAXIS-030 UNDISCLOSED EPILEPSY TARGET Undisclosed PRAXIS-030 Small molecule
PAGE 7CONFIDENTIAL PROGRAM Q4 2022Q1 2022 Q3 2022 Q2 2022 INDICATION Upcoming catalysts throughout portfolio in 2022 PRAX-562 PRAX-114 PRAX-944 Initiate Phase 2 Trial DEEs MDD PTSD ET PD Phase 2b Essential1 Study Topline Initiate Phase 2 Trial ET Phase 2 ToplinePRAX-114 PRAX-944 PSYCHIATRY MOVEMENT DISORDERS EPILEPSY Initiate Phase 2 Trial Phase 2 Topline Phase 2 Acapella Study Topline Phase 2/3 Aria Study Topline Phase 2a Part B Topline OTHER SUNCT/SUNA/TNPRAX-562 Initiate Phase 2 Trial PRAX-222 SCN2A -DEE Initiate Seamless Trial PRAX-114 Phase 2/3 Aria Study topline results expected in June 2022; PRAX-944 Phase 2a Part B topline results expected in May 2022 Phase 1 Topline ASSR Biomarker
PAGE 8CONFIDENTIAL DARE for MORE
PAGE 9CONFIDENTIAL PSYCHIATRY PRAX-114 GABAA Receptor PAM Depression Post-traumatic Stress Disorder 2Q 2022 Ph 2/3 Monotherapy MDD Aria Study Topline MID-2022 Ph 2 MDD Dose-Ranging Acapella Study Topline 2H 2022 Ph 2 PTSD Topline KEY UPCOMING MILESTONES
PAGE 10CONFIDENTIAL Major depressive disorder is a growing and debilitating disorder with substantial unmet need despite numerous treatment options Source: Rush et al 2006, Masand et al 2003, Kupfer et 2005, DSM-5 2013, ExpressScripts MDD Report 2020 MAJOR DEPRESSIVE DISORDER (MDD) ~19 million Americans and an estimated 300 million people worldwide affected by MDD Slow onset of action for existing treatment options Low response rate Limiting safety profile can lead to discontinuation of treatment Feeling sad or empty Lack of appetite Thoughts of death or suicide Poor memory, concentration, and decision-making Insomnia or lack of sleep Anger and irritability 1 2 3
PAGE 11CONFIDENTIAL Preference for extrasynaptic GABAA receptors has the potential of marked antidepressant effect with an improved tolerability profile GABA: Gamma-aminobutyric acid; GABAA PAMs: GABAA receptor positive allosteric modulators Potentiation Fold Potentiation α4β3δ: extrasynaptic GABAA receptor α1β2γ2: synaptic GABAA receptor * Equivalent of full activation by GABA PRAX-114 shows 10.5-Fold greater potentiation of extrasynaptic than synaptic GABAA receptors Dosing α4β3δ %* α1β2γ2 % α4β3δ/ α1β2γ2 PRAX-114 Oral 300% 29% 10.5 Zuranolone Oral 300% 117% 2.6 Ganaxolone IV, Oral 300% 794% 0.4 Zulresso IV 300% 306% 1.0 Sedation Anxiolysis Antidepressant Synaptic GABAA Receptor Extrasynaptic GABAA Receptor Source: PRAXIS data Source: Praxis Data on file
PAGE 12CONFIDENTIAL Extrasynaptic GABAA preference allows PRAX-114 the potential to achieve high-levels of GABAergic activation with improved tolerability PRAX-114 shows robust qEEG signal and target activation No MTD identified up to 80mg Tolerability profile maintained throughout dose escalation Exposure-dependent rates of somnolence resolved 1 to 3 hours post-dosing, consistent with peak concentrations Fo ld C ha ng e re la tiv e to b as el in e Time (hours) 0.0 1.0 2.0 3.0 0 4 8 12 16 20 24 PRAX-114 30 mg beta PRAX-114 60mg beta PRAX-114 30 mg alpha PRAX-114 60mg alpha *** * ** *** N= 7-9 human subjects per dose, PRAX-114 doses compared to placebo control at each timepoint, *p < 0.05, ** p < 0.01, *** p < 0.001 1.6x - beta target activation 1.7x - 40 mg tablet projected beta
PAGE 13CONFIDENTIAL Effect of high-fat meal on pharmacokinetics *FDA Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies Increase in exposure with food* No food Effect* Decrease in exposure without food* PRAX-114 Cmax PRAX-114 AUC0-t 0.0 0.5 1.0 1.5 2.0 PRAX-114 Cmax PRAX-114 AUC0-t Fe d / F as te d Ra tio (9 0% c on fid en ce in te rv al ) PRAX-114 suspension formulation (30 mg) PRAX-114 can be dosed at bedtime with or without food
PAGE 14CONFIDENTIAL Phase 2a combined* HAM-A anxiety and HAM-D insomnia item results Phase 2a combined* HAM-D monotherapy & adjunctive results Visit HAM-D Monotherapy Mean (SD) N=14 HAM-D Adjunctive Mean (SD) N=38 Day 1 (BL) 25.2 (1.82) 24.7 (2.90) Day 8 (CFB) -17.6 (4.77) -13.4 (7.94) Day 15 (CFB) -16.6 (5.23) -12.2 (7.02) Visit HAM-A Anxiety Rating Scale Mean (SD) N=52 HAM-D Insomnia Item Total (max score of 6) Mean (SD) N=52 Day 1 (BL) 22.4 (4.16) 4.2 (1.3) Day 8 (CFB) -12.4 (7.55) -2.8 (1.9) Day 15 (CFB) -11.6 (6.67) -3.1 (1.7) PRAX-114 Phase 2a: rapid and marked improvement in depression scores *Combined results include Part A MDD cohort (N=33; 2-week treatment), Part B PMD cohort (N=6; 2-week treatment) & Part C MDD cohort (N=13; 4- week treatment); results show change from baseline (CFB) at Day 8 & Day 15
PAGE 15CONFIDENTIAL Estimated somnolence rate of approximately 10% for 40 mg tablet (1.7x beta power) administered at nighttime Low rates of somnolence with PRAX-114 at targeted exposure level β-EEG Multiple 2.1 2.1 1.7 1.7 So m no le nc e AE % 60 mg Daytime/Nighttime Phase 2a Part A (N=13) 0 10 20 30 40 50 60 60 mg Nighttime Phase 2a Part C (N=13) 45 mg Daytime/Nighttime Phase 2a Part A (N=13) 40 mg Projected* Nighttime *Estimated somnolence rate for PRAX-114 40 mg tablet is derived by combining somnolence AE data from all 45 mg nighttime dosing cohorts. This estimate does not reflect data from any patients dosed at the 40 mg level and there is no guarantee that actual data for patients dosed at the 40 mg level will reflect such estimates. **Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) was administered during the inpatient phase of Part A of the Phase 2a to assess potential for daytime somnolence; one participant in PMD cohort of Phase 2a study discontinued treatment due to AEs of moderate daytime sedation and mild feeling abnormal No evidence of decreased alertness in the morning after administration of PRAX- 114 in Phase 2a trial in MDD patients**
PAGE 16CONFIDENTIAL • Integration of a placebo control reminder script for patients at every visit • Inclusion of the AiCure smartphone-based adherence monitoring system with structured site intervention 3 PRAX-114 clinical program leverages best practices in conduct of MDD trials OPTIMIZED TRIAL DESIGN & EXECUTION • Enrollment of sites with a known track-record of high-quality data generation • Experienced raters, adequate resources, low frequency of operational issues and proven performance in running studies successfully during the pandemic HIGH QUALITY SITE SELECTION • Enrollment of patients with at least one prior episode of MDD (associated with a lower placebo response rate) 1 • Two-level subject & data quality procedure using the SAFER independent clinical interview to confirm eligibility 2 RIGOROUS PATIENT SELECTION Key Operational Controls 1: Sonawalla SB, Rosenbaum JF. Placebo response in depression. Dialogues Clin Neurosci. Mar 2002;4(1):105-13. 2: Freeman MP, Pooley J, Flynn MJ, et al. Guarding the Gate: Remote Structured Assessments to Enhance Enrollment Precision in Depression Trials. J Clin Psychopharmacol. Apr 2017;37(2):176-181. doi:10.1097/JCP.0000000000000669 3: https://aicure.com/
PAGE 17CONFIDENTIAL PRAX-114 monotherapy MDD Phase 2/3 Aria Study topline data expected 2Q 2022* Ph 2/3 1:1 RANDOMIZED PLACEBO CONTROLLED IN MONOTHERAPY MDD 1 2 3 4 5 6 -114 40 mg+ PLACEBO WEEK KEY SECONDARY ENDPOINT HAM-D17 at Day 29 PRIMARY ENDPOINT HAM-D17 at Day 15 ~200 participants First of two registrational trials for monotherapy MDD KEY INCLUSION CRITERIA Ages 18-65 HAM-D17 ≥ 23 At least one prior episode of MDD KEY EXCLUSION CRITERIA Treatment-resistant depression Current antidepressant treatment PHASE 2/3 OUTPATIENT NIGHTLY DOSING FOLLOW-UP * Topline results expected in June 2022 +PRAX-114 administered in tablet formulation clinicaltrials.gov/ct2/show/NCT04832425; https://theariastudy.com/
PAGE 18CONFIDENTIAL PRAX-114 MDD Phase 2 Acapella Study topline data expected mid-year 2022 Ph 2 RANDOMIZED PLACEBO CONTROLLED DOSE-RANGING IN MDD 1 2 3 4 5 6 -114 60 mg PLACEBO WEEK KEY SECONDARY ENDPOINT HAM-D17 at Day 29 PRIMARY ENDPOINT HAM-D17 at Day 15 ~125 participants Dose-ranging study to evaluate safety and efficacy of PRAX-114 at doses of 10, 20, 40 and 60 mg KEY INCLUSION CRITERIA Ages 18-65 HAM-D17 ≥ 20 At least one prior episode of MDD KEY EXCLUSION CRITERIA Treatment-resistant depression PHASE 2 OUTPATIENT NIGHTLY DOSING FOLLOW-UP +PRAX-114 administered in tablet formulation clinicaltrials.gov/ct2/show/NCT04969510 -114 40 mg -114 20 mg -114 10 mg+
PAGE 19CONFIDENTIAL PRAX-114 has broad potential in psychiatry disorders such as PTSD POST- TRAUMATIC STRESS DISORDER (PTSD) Dysfunction of GABA pathway is associated with chronic stress and symptoms of PTSD 1 2 Post-traumatic Stress Disorder is a debilitating psychiatric disorder that leads to social, occupational and interpersonal dysfunction Profound unmet need, meaningful link to PRAX-114 MOA, and complementarity to MDD program ADULT PTSD ESTIMATED US PREVALENCE 11M Intrusive thoughts Insomnia & Nightmares Flashbacks Anxiety Mood symptoms Negative cognition
PAGE 20CONFIDENTIAL Dosing has started in PRAX-114 PTSD Phase 2 study Ph 2 1:1 RANDOMIZED PLACEBO CONTROLLED IN PTSD 1 2 3 4 5 6 -114 40 mg + WEEK PRIMARY ENDPOINT CAPS-5 Total Score at Day 29 ~80 participants To evaluate safety, tolerability and efficacy of PRAX-114 for treatment of adults with PTSD KEY INCLUSION CRITERIA Ages 18-65 CAPS-5 ≥ 30 PTSD diagnosis with duration of >6 months TOPLINE DATA EXPECTED 2H22 OUTPATIENT NIGHTLY DOSING FOLLOW-UP At Day 15, PRAX-114 participants who have not reached a 20% improvement in CAPS-5 total score may increase to 60 mg 40 or 60 mg PLACEBO +PRAX-114 administered in tablet formulation clinicaltrials.gov/ct2/show/NCT04969510
PAGE 21CONFIDENTIAL MOVEMENT DISORDERS PRAX-944 T-Type Calcium Channel Inhibitor Essential Tremor Parkinson’s disease 2Q 2022 PRAX-944 Ph 2a ET Part B Randomized Withdrawal Topline 2Q 2022 Initiate PRAX-944 Ph 2 PD Trial KEY UPCOMING MILESTONES 2H 2022 PRAX-944 Ph 2b ET Essential1 Study ToplinePRAX-114 GABAA Receptor PAM Essential Tremor 2H 2022 PRAX-114 Ph 2 ET Topline
PAGE 22CONFIDENTIAL Movement Disorder franchise focus for 2022 PRAX-944: for Essential Tremor Identify dose for registrational study Essential1 Study Topline Data: 2H2022 PRAX-944: for Parkinson’s disease Demonstrate motor improvement Initiate Ph2 Study 2Q2022 PRAX-114: for Essential Tremor Demonstrate well- tolerated GABAA-PAM with daytime dosing Ph2 Study Topline Data: 2H2022
PAGE 23CONFIDENTIAL Why Essential Tremor matters Most common movement disorder ~7x the prevalence of Parkinson’s disease1 Daytime action tremor that primarily affects the hands3,4 ~ 50% of patients have a family history2,3 Heterogeneous condition with progressive disability3 SOURCE: 1. GHOSH (2016) (P.231, C.1, PH.1, L.1-2), 2. LIU (2016) (P.1009, C.1, PH.2, L.1-3 3. ) 3. Elble RJ. Curr Neurol Neurosci Rep. 2013 Jun;13(6):353. 4. Putzke JD, et al. J Neurol Neurosurg Psychiatry. 2006 Nov;77(11):1235-7. 5.
PAGE 24CONFIDENTIAL ET burden of disease extends beyond the tremor 1. LOUIS ED, ET AL. PARKINSONISM RELAT DISORD. 2015;21(7):729-735. 2. HOLDING SJ, ET AL. CHRONIC ILLN. 2015 MAR;11(1):69-71. 3.SHALASH AS, ET AL. TREMOR OTHER HYPERKINET MOV (N Y). 2019;9. 4. JANICKI SC,ET AL. THER ADV NEUROL DISORD. 2013;6(6):353-368. 5. LOUIS ED, ET AL. EUR J NEUROL. 2007 OCT;14(10):1138-46. Social embarrassed by their tremor1,2 Mood symptoms of social isolation, depression, and anxiety1-5 Self feel negative about themselves1
PAGE 25CONFIDENTIAL 3M Total Addressable Market Our focus is on elevating the standard of care to capture the $4B+ US ET market 7M US Prevalence 1.5M Total Treated Market1 $4B+ US ET Market Opportunity2 PRIMARY MARKET RESEARCH AND PRAXIS INTERNAL MODELING AND PROJECTIONS 1. CLAIMS ANALYSIS INDICATES THAT 50% OF DIAGNOSED PATIENTS ARE ON TREATMENT; 2. BASED ON MINIMUM OF RANGE FOR NET PRICE ESTIMATES FROM PRAXIS COVERING ANALYSTS AS OF 16-DECEMBER-2021- $3.6K
PAGE 26CONFIDENTIAL Praxis treatments could allow patients to fit the right therapy to their needs to realize improved outcomes • Patients could initiate ET treatment sooner • Patients could treat as needed • Patients could maintain ET therapy As needed Chronic PRAX-114 PRAX-944 +
PAGE 27CONFIDENTIAL Tackling Movement Disorders through two mechanisms of action GABAA RECEPTORS T-TYPE CALCIUM CHANNELS CEREBELLO-THALAMO-CORTICAL (CTC) CIRCUIT PRAX-944PRAX-114
PAGE 28CONFIDENTIAL Mutations in T-type calcium channels (TTCC) are genetically linked to familial ET TTCC drive burst firing in the CTC circuit Burst firing in the CTC circuit correlated with tremor in patients with ET and PD Deep Brain Stimulation reduces burst firing and tremor T-Type calcium channels are gatekeepers of neuronal firing patterns in the CTC circuit SOURCE: BASED ON MILOSEVIC 2018 FIGURE ON ACTUAL ET PATIENT INTRAOPERATIVE REAL-TIME SINGLE-UNIT RECORDINGS OF ACTION POTENTIALS OF INDIVIDUAL NEURONS
PAGE 29CONFIDENTIAL PRAX-944 is designed to enable once daily dosing and a well-tolerated safety profile Sustained exposure with blunted MR Cmax allows for potential of sustained efficacy and improved tolerability 0 5 10 15 20 25 30 35 40 45 50 0 6 12 18 24 PR AX -9 44 P la sm a Co nc en tr at io n (n g/ m L) Time (h) Mean PRAX-944 Concentration-Time Profiles after single 20 mg Modified Release (MR) oral dose MR formulation is well-tolerated Titration and fit for purpose formulation are key to tolerability profile No MTD identified up to 120 mg per day Majority of AEs have been mild, transient and resolved without intervention
PAGE 30CONFIDENTIAL KEY TAKEAWAYS • Dose-dependent reduction in sigma-band power • Effect observed over >20x dose range • Provides confidence that PRAX-944 is reaching functionally relevant brain concentrations and targets PRAX-944 showed robust PK:PD relationship to guide dosing SOURCE: PRAXIS STUDY-944-105; PRAXIS DATA ON FILE 5mg 10mg 20mg 60mg 80mg 100mg 120mg
PAGE 31CONFIDENTIAL Enrollment completed in PRAX-944 Phase 2a ET study DAYS 1-14 Safety Follow- up Screening/ Baseline PART A DAYS 15-21 Completed Open-Label Titration of PRAX-944 up to 40 mg CLINICALTRIALS.GOV/CT2/SHOW/NCT05021978 *Topline results expected in May 2022 DAYS 29-42 1:1 RANDOMIZATION Open-Label Titration of PRAX-944 up to 120 mg Stable Period at High Dose PRAX-944 PLACEBO RANDOMIZED WITHDRAWAL (DAYS 43-56) DAYS 57-64DAYS 1 -28 PART B Screening/ Baseline Safety Follow- up Preliminary data Topline Results: 2Q 2022*
PAGE 32CONFIDENTIAL Percent change in TETRAS score (N=6)Change from baseline in TETRAS score (N=6) PRAX-944 Phase 2a ET Part A data shows dose dependent reduction in tremor amplitude ON TREATMENT WASHOUT PERFORMANCE SCALE (PS) UPPER LIMB (UL) PERFORMANCE SCALE (PS) UPPER LIMB (UL) ON TREATMENT WASHOUT
PAGE 33CONFIDENTIAL Preliminary Part B data: TETRAS Combined Upper Limb (CUL) and TETRAS Activities of Daily Living (ADL) Preliminary data as of 10-Dec-2021 cutoff; ongoing CLINICALTRIALS.GOV/CT2/SHOW/NCT05021978 * 8 of 12 patients enrolled and dosed completed per protocol ; Part B Patient 1 discontinued after Day 21 assessment at 40mg due to an AE, 2 participants at same site discontinued at 20 mg, but had protocol violations related to eligibility, 1 participant discontinued at 20mg due to an AE % C H A N G E IN TE TR A S CU L 80% 60% 40% 20% 0% -20% -40% -60% 80% 60% 40% 20% 0% -20% -40% -60% DAY 21 DAY 42 DAY 21 DAY 42 % C H A N G E IN TE TR A S A DL 13.0 15.5 18.0 19.5 21.0 21.0 21.5 24.5 35.5Baseline CUL 1* 2 3 4 5 6 7 8 9 Im pr ov em en t Im pr ov em en t Part B Participants
PAGE 34CONFIDENTIAL Preliminary Part B data: modified ADL by baseline CUL score PRELIMINARY DATA AS OF 10-DEC-2021 CUTOFF; ONGOING CLINICALTRIALS.GOV/CT2/SHOW/NCT05021978; *PART B PATIENT 1 DISCONTINUED AFTER DAY 21 ASSESSMENT; **PART B PATIENT 2 DAY 42 – MODIFIED ADL INCLUDED MISSING DATA FOR ONE ITEM; % CHANGE CALCULATED BASED ON IMPUTED WORST SCORE Modified ADL as suggested by FDA: • Score of 1 re- coded as 0; highest score of 3 • Exclude social impact • Include: handwriting and spirals 80% 60% 40% 20% 0% -20% -40% -60% -80% -100% % C H A N G E IN M O DI FI ED A DL DAY 21 DAY 42 Im pr ov em en t PART B PARTICIPANTS 1* 2** 3 4 5 6 7 8 9 13.0 15.5 18.0 19.5 21.0 21.0 21.5 24.5 35.5Baseline CUL
PAGE 35CONFIDENTIAL Dose-ranging study to evaluate safety, tolerability and efficacy of PRAX-944 for treatment of adults with ET KEY INCLUSION CRITERIA Ages 18 or older Diagnosis of ET for at least 3 years TETRAS UL score ≥10 TOPLINE DATA EXPECTED 2H22Randomized, double-blind, placebo-controlled study in ~112 participants Enrollment ongoing for PRAX-944 ET Phase 2b Essential1 Study Day -28 to -1 Day 57-70 Safety Follow Up PRAX-944 20 mg Screening PLACEBO Day 1-56 PRAX-944 100 mg 1:1:1:1 Randomization Titration Period Titration Period clinicaltrials.gov/ct2/show/NCT05021991 Titration Period PRAX-944 60 mg
PAGE 36CONFIDENTIAL α4β3δ %* α1β2γ2 % α4β3δ/ α1β2γ2 300% 29% 10.5 PRAX-114: Evidence suggests central role of extrasynaptic GABAA receptors targeting tremor pathophysiology Α4Β3Δ: EXTRASYNAPTIC GABAA RECEPTOR; Α1Β2Γ2: SYNAPTIC GABAA RECEPTOR; * EQUIVALENT OF FULL GABA ACTIVATION SOURCE: PRAXIS DATA ON FILE Without ExtrasynapticWith Extrasynaptic Potentiation Fold Potentiation PRAX-114 has greater potentiation of extrasynaptic GABAA receptors 4 3 * 1 2 2 4 3 / 1 2 2 .
PAGE 37CONFIDENTIAL PRAX-114 ET Phase 2 study designed to evaluate safety, tolerability, PK and efficacy of daytime dosing KEY QUESTION: Is there a dose that enables reduction in tremor without somnolence or sedation? TOPLINE DATA: 2H2022 Safety Follow Up PRAX-114 10, 20 mg or PLACEBO PERIOD 1 PERIOD 2 PERIOD 3 Washout PRAX-114 10, 20 mg or PLACEBO PRAX-114 10, 20 mg or PLACEBO 1:1:1 Randomization Study Design: Randomized, double-blind, placebo-controlled, cross-over study N = ~15 participants Washout
PAGE 38CONFIDENTIAL PRAX-944 has potential to be a non-dopaminergic therapy for motor function for Parkinson’s disease patients Dopamine promotes movement Dopamine related motor and non- motor complications
PAGE 39CONFIDENTIAL Why Parkinson’s disease matters? Affects ~1 million people in the US, with 85% of patients treated pharmacologically Progressive disability motor and non-motor symptoms Incidence is age related. Average age of onset is early 60s. High risk in men. 1. HTTPS://WWW.PARKINSON.ORG/UNDERSTANDING-PARKINSONS/STATISTICS 2. GLOBAL DATA REPORT: PARKINSON'S DISEASE - GLOBAL DRUG FORECAST AND MARKET ANALYSIS TO 2029, APRIL 2021 3.CLAIMS ANALYSIS; SECONDARY RESEARCH
PAGE 40CONFIDENTIAL Blocking T-type Calcium Channels improves motor activity in 6-OHDA model of Parkinson’s disease Burst firing in STN of 6-OHDA Parkinson’s model BURST FIRING IN STN OF 6-OHDA PARKINSON’S MODEL BLOCK OF BURST FIRING IMPROVES MOVEMENT IN 6-OHDA PARKINSON’S MODEL PAN ET AL (2016) J CLIN INVEST DOI: 10.1172/JCI88170
PAGE 41CONFIDENTIAL PRAX-944 study to evaluate motor function in Parkinson’s disease patients expected to initiate in 2Q22 CLINICAL MEASUREMENTS: Motor function KEY QUESTION: Does PRAX-944 demonstrate motor improvement in patients? Safety Follow Up PRAX-944 Titration 5 mg to 100 mg DAY 1-49 DAY 50-77 PRAX-944 Titration Maintenance DAY 78-84 PLACEBO PLACEBO 2:1 Randomization N= ~42
PAGE 42CONFIDENTIAL EPILEPSY PRAX-562 PRAX-222 ASO 2Q 2022 PRAX-562 Ph 1 ASSR Biomarker Topline 2Q 2022 Initiate PRAX-562 Ph 2 DEE Trial 2Q 2022 Initiate PRAX-222 Seamless SCN2A-DEE Trial KEY UPCOMING MILESTONES PRAX-020 PRAX-628 SCN2A-LOF ASO SYNGAP1 ASO PCDH19 ASO
PAGE 43CONFIDENTIAL PRAX-562: Block of persistent sodium current can reduce neuronal hyperexcitability and impact multiple disease states Standard sodium channel blockers target peak sodium current and disrupt AP, leading to side effects Modulation of persistent sodium current reduces hyperexcitability without disrupting AP • Standard sodium channel blockers are an important class of medicines in neurology and psychiatry, broadly used in epilepsy, pain, migraine and bipolar disorder • All standard NaV blockers target peak sodium current • In general, efficacy is limited by side effects Source: Schachter et al. antiseizure drugs UptoDate 2020, Praxis data PRAX-562 Representative AP TracesCarbamazepine Representative AP Traces
PAGE 44CONFIDENTIAL PRAX-562 has broad potential in rare CNS conditions such as DEEs Source: Eltze et al. 2013 ; Howell et al 2018 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY (DEE) DEE is a group of monogenic disorders with severe seizure, developmental delay & high mortality rate 1 2 A pathologic feature of many DEEs is the dysregulated neuronal activity leading to hyperexcitability and seizure This phenomenon is observed in pediatric epilepsies with an identified genetic cause, such as SCN8A, SCN2A and others Caused by a single gene mutation~40% CHILDREN WITH DEEs WORLDWIDE 200K+
PAGE 45CONFIDENTIAL PRAX-562 mediated persistent current block protects mice from seizure with a wide therapeutic window in-vivo PRAX-562 shows robust anti-seizure activity without impairment of locomotor activity TD50: 44 mg/kg CD-1 mice; (n=12/group) ED50: 2 mg/kg Veh 1 0.3 1 3 10 0 20 40 60 M ES L at en cy (s ec ) ** PRX-562 (mg/kg, PO) ** PRAX-562 showed significantly improved TI as compared to currently prescribed sodium channel blockers Molecule Brain Therapeutic Index PRAX-562 16.4x Carbamazepine 5.9x Lamotrigine 4.6x Therapeutic Index (TI) = TC50 / EC50 PRAX-562 had an increased ratio between drug levels that demonstrated preclinical anti-seizure activity versus those that caused toxicity Source: Praxis Data as of Sept. 3, 2020
PAGE 46CONFIDENTIAL Treatment with PRAX-562 has shown significant reduction of seizures in genetic pediatric epilepsy animal models PRAX-562 elicited dose-dependent prevention of seizures in SCN2A* mouse model PRAX-562 elicited dose-dependent prevention of seizures in SCN8A* mouse model *FDA granted orphan drug and rare pediatric designation for PRAX-562 for treatment of SCN2A-DEE and SCN8A-DEE PRAX-562 inhibition of audiogenic seizures in D/+ mice Plasma [PRAX-562] (ng/mL) 100 100010 0.00 0.25 0.50 0.75 1.00 Pr op or tio n of m ic e w ith S ei zu re EC50= 114 ng/mL post-dosepre-dose 0 5 10 15 Se iz ur es p er 3 0 m in ut es Seizure Frequency Baseline seizure frequency was measured for 30 minutes prior to treatment (Pre) and then again 30 minutes after treatment (Post). Symbols represent mean + SEM, n=6-10 per symbol. Vehicle 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg Highest dose (120 mg) in human MAD is >6x mouse EC50 at 24h trough
PAGE 47CONFIDENTIAL PRAX-222 is expected to initiate seamless trial for SCN2A-DEE in 2Q22 PRAX-222: ASO to treat SCN2A GoF Epilepsy • Severe early onset epilepsy estimated to affect thousands of patients worldwide • Antisense oligonucleotide (ASO) to down-regulate SCN2A expression Increased Survival with Single ASO Dose at PN Day 1 ASO injection (icv, P15)ASO injections (icv) Untreated (n=21)* Phenytoin 20mg/kg (n=9)* ASO injection (icv) ASO-SCN2A ED80 (n=15) ASO-SCN2A ED50 (n=15) ASO-Ctrl (n=8) ASO-SCN2A ED80 (n=13) ASO-SCN2A ED50 (n=15) ASO-Ctrl (n=11) ASO-SCN2A ED80 (n=49) ASO-SCN2A ED50 (n=22) ASO-Ctrl (n=39) Postnatal days Postnatal daysPostnatal days Redosing Significantly Extends Survival Administration Post-Disease Onset Also Extends Survival Source: Praxis Data; *Data separate from experiment **All mice with zero seizure at baseline were excluded from the analysis; If all mice were included, the values would be 273%, -80%, -87%, -83% for vehicle, 30mg/kg, 75mg/kg and 150mg/kg group
PAGE 48CONFIDENTIAL PROGRAM Q4 2022Q1 2022 Q3 2022 Q2 2022 INDICATION Upcoming catalysts throughout portfolio in 2022 PRAX-562 PRAX-114 PRAX-944 Initiate Phase 2 Trial DEEs MDD PTSD ET PD Phase 2b Essential1 Study Topline Initiate Phase 2 Trial ET Phase 2 ToplinePRAX-114 PRAX-944 PSYCHIATRY MOVEMENT DISORDERS EPILEPSY Initiate Phase 2 Trial Phase 2 Topline Phase 2 Acapella Study Topline Phase 2/3 Aria Study Topline Phase 2a Part B Topline OTHER SUNCT/SUNA/TNPRAX-562 Initiate Phase 2 Trial PRAX-222 SCN2A -DEE Initiate Seamless Trial PRAX-114 Phase 2/3 Aria Study topline results expected in June 2022; PRAX-944 Phase 2a Part B topline results expected in May 2022 Phase 1 Topline ASSR Biomarker