SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): August 7, 2023
PRAXIS PRECISION MEDICINES, INC.
(Exact name of registrant as specified in its charter)
(State or other jurisdiction
Praxis Precision Medicines, Inc.
99 High Street, 30th Floor
Boston, Massachusetts 02110
(Address of principal executive offices, including zip code)
(Registrant’s telephone number, including area code)
(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|| |
Name of each exchange
on which registered
|Common Stock, $0.0001 par value per share|| ||PRAX|| ||The 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 2.02. Results of Operations and Financial Condition.
On August 9, 2023, Praxis Precision Medicines, Inc. (the “Company”) announced its financial results for the quarter ended June 30, 2023. 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 August 9, 2023, 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 8.01. Other Events.
On August 7, 2023, the Company announced the results from an analysis of EEG activity for subjects in the recent Phase 1 study that demonstrated pharmacodynamic activity across all dose levels for study subjects who received PRAX-628 at first administration as compared with subjects who received placebo. In the Phase 1 study, PRAX-628 was administered to 40 healthy participants (PRAX-628 n=30, placebo n=10). Single ascending dose (“SAD”) cohorts evaluated PRAX-628 doses ranging from 5 to 45 mg and multiple ascending dose (“MAD”) cohorts evaluated PRAX-628 doses of 20 and 30 mg. EEG data were collected over the course of day 1 in the SAD cohort and over three separate days during the course of the 10-day MAD treatment period. qEEG analysis showed a pharmacodynamic effect at all dose levels and was significantly different from placebo at the Tmax timepoint (~2h) for the SAD and all timepoints for the MAD portion.
The Company has begun a Phase 2 study for PRAX-628 in patients with a photo-paroxysmal response to evaluate drug activity and dose finding, and is expected to report topline results in the second half of 2023. Based on these studies and the preclinical results, the Company intends to advance PRAX-628 into a Phase 2 study in focal epilepsy in the first half of 2024.
On August 8, 2023, the Company announced further data from two additional analyses of the Essential1 study for ulixacaltamide.
Open-Label Extension (“OLE”)
Following completion of the initial 8-week double-blind treatment phase in Essential1, eligible patients had the option to continue their access to ulixacaltamide in an OLE phase. Participants who continued to the OLE phase remained blinded for a six-week lead-in period.
•There was no change to the overall safety results through 14 weeks of treatment.
•65 patients who completed the double-blinded portion of Essential1 were eligible to participate in the OLE and completed the week 14 assessment. All patients eligible to participate in the OLE phase were enrolled in Essential1 under version 4 of the clinical protocol.
•Patients who were eligible and continued on ulixacaltamide (n= 39) experienced an additional mean improvement in the modified Activities of Daily Living 11 (“mADL11”) of 1.7 points from 3.09 at week 8 (95% CI: 0.98, 5.2) to 4.81 (95% CI: 2.38, 7.23) after 14 weeks of treatment.
•Patients who switched from placebo during the double-blind phase of Essential1 to ulixacaltamide treatment during the OLE 6-week lead-in (n= 26) experienced mean improvement in mADL11 of 3.15 points, from 1.21 at week 8 (95% CI: -1.04, 3.46) to 4.36 (95% CI: 1.68, 7.05).
Randomized Withdrawal Sub-Study
Following the announcement of the Essential1 study topline results, the Company amended the open-label protocol to further assess the criteria to be used in the upcoming randomized withdrawal Phase 3 study. In this sub-study, patients were re-randomized in a blinded fashion to either receive placebo or continue to receive ulixacaltamide.
Twenty-one patients who completed assessments at week 14 of the OLE were eligible to participate in the blinded sub-study. Patients were evaluated weekly over a total of six weeks, with 11 patients assigned to ulixacaltamide and 10 to placebo for the initial three-week period, crossing over to either placebo or ulixacaltamide for an additional three-week period. Blinded rescue was triggered for patients on placebo if loss in the mADL11 exceeded two points at any timepoint.
•Patients who switched from ulixacaltamide to placebo experienced an average loss of effect in their mADL11 per week of 47% (mean loss of effect of -1.15 points/week), compared to 6% improvement in global mean change per week (mean improvement of 0.16 points/week) for the periods receiving ulixacaltamide. In addition, 10 patients assigned to placebo met the rescue criteria to restart ulixacaltamide.
•85% of the patients who received ulixacaltamide (17 of 20) and 52% who received placebo maintained their mADL11 within three points compared to baseline, confirming the definition of patient stability to be used in the Phase 3 program.
•No new safety signals emerged and there was no change to the overall safety results observed in the eight-week double-blind treatment phase.
The results from the sub-study supported a number of proposed design elements for the upcoming Phase 3 randomized withdrawal study, including the responder criteria and feasibility of rescuing patients with ulixacaltamide.
This Current Report on Form 8-K contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding the clinical development of PRAX-628 and ulixacaltamide. The forward-looking statements included in this Current Report on Form 8-K are subject to a number of risks, uncertainties and assumptions, including, without limitation, uncertainties inherent in clinical trials, the expected timing of submission for regulatory approval or review by governmental authorities and other risks as described in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, its Quarterly Reports on Form 10-Q and its other filings with the Securities and Exchange Commission. These statements are based only on facts currently known by the Company and speak only as of the date of this Current Report on Form 8-K. As a result, you are cautioned not to rely on these forward-looking statements and the Company undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.
Item 9.01. Financial Statements and Exhibits.
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: August 9, 2023
|By:|| ||/s/ Marcio Souza|
| ||Marcio Souza|
| ||Chief Executive Officer|
Praxis Precision Medicines Provides Corporate Update and Reports Second Quarter 2023 Financial Results
On track to initiate Phase 3 studies for ulixacaltamide in Q4 2023 after favorable End-of-Phase 2 meeting with FDA
PRAX-628 Phase 1 study showed consistent safety profile and target engagement in measures of qEEG activity at all doses with first administration
Praxis will hold an R&D Portfolio Day on October 2
Cash of $124.3 million as of June 30, 2023 expected to support runway into Q1 2025
BOSTON, August 9, 2023 — 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 and reported financial results for the second quarter 2023.
“Our four clinical-stage programs continue to make great progress, and we are excited to be advancing ulixacaltamide into Phase 3,” said Marcio Souza, president and chief executive officer of Praxis. “Our epilepsy portfolio continues to advance, with studies ongoing in each of our three clinical-stage programs that we expect to read out by the end of the year. We are planning to hold an R&D portfolio day on October 2 to elaborate on our science and clinical progress, including more details about the Phase 3 program for ulixacaltamide and additional data from the Essential1 study.”
Recent Business Highlights and Upcoming Milestones:
Cerebrum™ Small Molecule Platform
•In June 2023, Praxis shared the outcomes of its end-of-phase 2 (EOP2) meeting with the U.S. Food and Drug Administration (FDA) and is planning to initiate two Phase 3 studies as part of the registrational program, using mADL11 as the primary outcome measure. One study will be a parallel control design and the other using a randomized withdrawal design. Both trials will evaluate essential tremor patients at a 60 mg dose of ulixacaltamide for 12 weeks after a short titration period. The EOP2 meeting confirmed other program aspects including safety database, clinical pharmacology and toxicology requirements for registration. Praxis intends to begin enrolling patients in the fourth quarter of 2023, with read outs expected in the second half of 2024.
•In August 2023, Praxis shared the results of two additional analyses of the Essential1 dataset that showed durable effect to 14 weeks and maintenance of the safety profile seen in the Essential1 study.
oIn the open-label extension (OLE) phase, patients who continued on ulixacaltamide experienced an additional mean improvement in mADL11 of 1.7 points from week 8 to after 14 weeks of treatment, while patients who switched from placebo during the Essential1 double blind phase to ulixacaltamide during the 6-week OLE experienced mean improvement in mADL11 of 3.15 points.
oIn a randomized withdrawal sub-study, patients who switched from ulixacaltamide to placebo experienced an average loss of effect in their mADL11 per week of 47% (mean loss of effect of -1.15 points/week), compared to 6% improvement in global mean change per week (mean improvement of 0.16 points/week) for the periods receiving ulixacaltamide.
•In May 2023, Praxis announced initial results from the PRAX-628 Phase 1 safety study, which demonstrated a favorable safety and tolerability profile in healthy volunteers at concentrations more than 15-fold the Maximal Electrical Seizure model (MES EC50) and predicted therapeutic range at least 3-fold wider than current market leader based on an MES model. In August 2023, Praxis announced additional data from the Phase 1 study from an analysis of EEG activity that demonstrated pharmacodynamic activity across all dose levels for study subjects who received PRAX-628 at first administration as compared with subjects who received placebo.
•In June 2023, Praxis announced it had initiated a Phase 2 proof of concept study evaluating PRAX-628 in epilepsy patients with a Photo Paroxysmal Response (PPR). The study evaluates the potential effect of PRAX-628 on reducing pre-seizure EEG activity for photo-sensitive patients. The study is expected to read out by year-end 2023 and, upon completion of the PPR study, Praxis plans to initiate a Phase 2 study to evaluate PRAX-628 for the treatment of focal epilepsy in the first half of 2024.
•Praxis expects topline results from the PRAX-562 Phase 2 EMBOLD study for the treatment of pediatric patients with developmental and epileptic encephalopathies (DEEs) in the fourth quarter of 2023. The EMBOLD study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial to evaluate the safety, tolerability, efficacy (motor seizure frequency) and pharmacokinetics of PRAX-562 in pediatric participants aged 2 to 18 years with DEEs, followed by an open-label extension. Approximately 20 participants with SCN2A-DEE or SCN8A-DEE are expected to be enrolled.
Solidus™ Antisense Oligonucleotide (ASO) Platform
•Praxis is currently dosing the first dose cohort (Part 1) of the PRAX-222 EMBRAVE study for the treatment of pediatric patients with early-onset SCN2A-DEE in the U.S. Following collection of the safety and efficacy data from Part 1 of the EMBRAVE study, the data will be evaluated and submitted to the FDA to support further dose escalation. Part 1 of the EMBRAVE study is a 21-week open label cohort, in which participants will receive PRAX-222 for up to 13 weeks, designed to determine the safety and tolerability of intrathecal delivery of PRAX-222. Topline results are expected in the second half of 2023.
•In June 2023, Praxis completed an underwritten public offering, which extended Praxis’ cash runway into the first quarter of 2025. Praxis sold 64,449,690 shares of common stock at a public offering price of $0.95 per share, including the exercise in full by the underwriters of their option to purchase up to 9,299,690 shares of common stock, and pre-funded warrants to purchase up to an aggregate of 7,050,000 shares of common stock at a public offering price of $0.9499 per share. The net proceeds from the offering were approximately $63.4 million, after deducting underwriting discounts and commissions and other offering expenses payable by Praxis. The proceeds will be used to advance the development of ulixacaltamide into two Phase 3 studies for essential tremor, to continue clinical development of PRAX-562, PRAX-222 and PRAX-628 for various epilepsies, and for working capital and other general corporate purposes.
Second Quarter 2023 Financial Results:
As of June 30, 2023, Praxis had $124.3 million in cash and cash equivalents, compared to $100.5 million in cash, cash equivalents and marketable securities as of December 31, 2022. The increase of $23.8 million primarily reflects $63.4 million in net proceeds from Praxis’ June 2023 underwritten public offering and $24.1 million in net proceeds from at-the-market offerings of shares of Praxis’ common stock, partially offset by cash used in operations of $64.1 million during the six months ended June 30, 2023.
Praxis recognized $0.8 million in collaboration revenue during the three months ended June 30, 2023 related to its Option and License Agreement with UCB.
Research and development expenses were $25.6 million for the three months ended June 30, 2023, compared to $43.6 million for the three months ended June 30, 2022. The decrease in research and development expenses of $18.0 million was primarily attributable to $19.6 million in decreased expenses related to Praxis’ Cerebrum™ platform and $4.0 million in decreased personnel-related expenses, partially offset by $5.7 million in increased expenses related to the Solidus™ platform, which includes a $6.9 million one-time milestone related to the initiation of the EMBRAVE study. General and administrative expenses were $10.1 million for the three months ended June 30, 2023, compared to $16.8 million for the three months ended June 30, 2022. The decrease in general and administrative expenses of approximately $6.6 million was primarily due to a decrease in consulting costs, professional fees and personnel-related expenses.
Praxis reported a net loss of $34.3 million for the three months ended June 30, 2023, including one-time milestone expense of $6.9 million related to the PRAX-222 program, and $5.8 million of stock-based compensation expense, compared to $60.2 million for the three months ended June 30, 2022, including $7.6 million of stock-based compensation expense.
As of June 30, 2023, Praxis had 128.5 million shares of common stock outstanding.
Praxis Precision Medicines is a clinical-stage biopharmaceutical company translating insights from genetic epilepsies into the development of therapies for CNS disorders characterized by neuronal excitation-inhibition imbalance. Praxis is applying genetic insights to the discovery and development of therapies for rare and more prevalent neurological disorders through our proprietary small molecule platform, Cerebrum™, and antisense oligonucleotide (ASO) platform, Solidus™, using our understanding of shared biological targets and circuits in the brain. Praxis has established a diversified, multimodal CNS portfolio including multiple programs across movement disorders and epilepsy, with four clinical-stage product candidates. For more information, please visit www.praxismedicines.com and follow us on Facebook, LinkedIn and Twitter.
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 the anticipated timing of our clinical trials and the development of our product candidates, 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 clinical trials, data readouts and the results thereof, and submissions for regulatory approval or review by governmental authorities; regulatory approvals to conduct trials; Praxis’ anticipated cash runway; and other risks concerning Praxis’ programs and operations as described in its Annual Report on Form 10-K for the year ended December 31, 2022, its Quarterly Reports on Form 10-Q 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.
Praxis Precision Medicines
PRAXIS PRECISION MEDICINES, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
(Amounts in thousands)
|June 30, 2023||December 31, 2022|
|Cash and cash equivalents||$||124,300 ||$||61,615 |
|Marketable securities||— ||38,874 |
|Prepaid expenses and other current assets||5,529 ||10,351 |
|Property and equipment, net||759 ||971 |
|Operating lease right-of-use assets||2,494 ||2,901 |
|Other non-current assets||416 ||416 |
|Total assets||$||133,498 ||$||115,128 |
|Liabilities and stockholders’ equity|
|Accounts payable||$||8,010 ||$||14,672 |
|Accrued expenses||13,317 ||15,850 |
|Operating lease liabilities||3,010 ||3,500 |
|Deferred revenue||3,536 ||5,000 |
|Common stock||13 ||5 |
|Additional paid-in capital||708,023 ||606,918 |
|Accumulated other comprehensive loss||— ||(173)|
|Total liabilities and stockholders' equity||$||133,498 ||$||115,128 |
PRAXIS PRECISION MEDICINES, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(Amounts in thousands, except share and per share amounts)
Three Months Ended
Six Months Ended
|Collaboration revenue||$||781 ||$||— ||$||1,464 ||$||— |
|Research and development||25,614 ||43,620 ||51,118 ||96,272 |
|General and administrative||10,127 ||16,774 ||23,397 ||32,971 |
|Total operating expenses||35,741 ||60,394 ||74,515 ||129,243 |
|Loss from operations||(34,960)||(60,394)||(73,051)||(129,243)|
|Other income, net||648 ||200 ||1,284 ||332 |
|Total other income||648 ||200 ||1,284 ||332 |
|Net loss per share attributable to common stockholders, basic and diluted||$||(0.49)||$||(1.32)||$||(1.17)||$||(2.83)|
|Weighted average common shares outstanding, basic and diluted||69,740,719 ||45,542,600 ||61,467,774 ||45,499,131 |
CORPORATE OVERVIEW August 2023
2 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, and (viii) our ability to meet any specific milestones set forth herein. 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 for the year ended December 31, 2022, our Quarterly Reports on Form 10-Q 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. Forward-looking statements
3 Developing Treatments Inspired By The Genetics of Epilepsy ENABLED BY TWO PLATFORMS CEREBRUM™ SMALL MOLECULE PLATFORM Cerebrum™ utilizes deep understanding of neuronal excitability and neuronal networks and applies a series of computational and experimental tools to develop orally available precision therapies PRAX-628 Ulixacaltamide (PRAX-944) PRAX-562 PRAX-020 PRAX-050 SOLIDUS™ ANTISENSE OLIGONUCLEOTIDE (ASO) PLATFORM PRAX-090 PRAX-222 PRAX-080 PRAX-100 Solidus™ is an efficient, targeted precision medicine discovery and development engine for ASOs anchored on proprietary, computational methodology
4 PHASE TWO Targeting movement disorders & epilepsies connected by neuronal imbalance *PRAX-020 (KCNT1) is a research collaboration with UCB +PRAX-080 (PCDH19 ), PRAX-090 (SYNGAP1) & PRAX-100 (SCN2A-LoF) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health PRECLINICAL PHASE ONE REGISTRATION ENABLINGPLATFORM PRAX-020* KCNT1 PRAX-050 Undisclosed PRAX-090+ SYNGAP1 PRAX-100+ SCN2A LoF PRAX-080+ PCDH19 CEREBRUM™ SMALL MOLECULE PLATFORM SOLIDUS™ ASO PLATFORM PRAX-222 SCN2A GoF DEE Ulixacaltamide Essential Tremor PRAX-562 DEEs PRAX-628 Focal Epilepsy
5 Leveraging genetics to efficiently translate insights into therapies GENETICS Focus on therapeutic targets identified through human genetics TRANSLATIONAL TOOLS Translational tools validate potential of target and product candidate and can provide early proof of biology EFFICIENT & RIGOROUS Efficient, rigorous clinical development paths to proof- of-concept in humans PATIENT-GUIDED Patient-guided development strategies to deliver on what patients actually need
6 What to expect from Praxis in 2023 1Q23 2Q23 3Q23PLATFORM 4Q23 CEREBRUM™ SMALL MOLECULE PLATFORM SOLIDUS™ ASO PLATFORM PRAX-628 Ph 1 Topline Results PRAX-562 Ph 2 EMBOLD Study Topline Results DEEs PRAX-222 EMBRAVE Study First Dose Cohort (Part 1) Topline Safety Results SCN2A GoF DEE Ulixacaltamide End-of-Ph 2 FDA Meeting Essential Tremor Ulixacaltamide Ph 2b Essential1 Study Topline Results Essential Tremor Ulixacaltamide Ph 3 Initiation Essential Tremor MID YEAR PRAX-628 Phase 2 PPR study Topline Results Focal Epilepsy
7 CEREBRUM™ SMALL MOLECULE PLATFORM
8 Q4 2023 ET Phase 3 Initiation Ulixacaltamide (PRAX-944) Essential Tremor KEY UPCOMING MILESTONES
9 Essential Tremor (ET) is the most common movement disorder… SOURCE: 1. GHOSH (2016) (P.231, C.1, PH.1, L.1-2), 2. Elble RJ. Curr Neurol Neurosci Rep. 2013 Jun;13(6):353. 3. Putzke JD, et al. J Neurol Neurosurg Psychiatry. 2006 Nov;77(11):1235-7. 4. Vetterick, C., Lyons, K.E., Matthews, L.G. et al. The Hidden Burden of Disease and Treatment Experiences of Patients with Essential Tremor: A Retrospective Claims Data Analysis. Adv Ther (2022). https://doi.org/10.1007/s12325-022-02318-8 Up to 7 million people in the United States may have ET1 Hallmark feature is action tremor that primarily affects the hands2,3 Action tremors significantly disrupt daily living for people with ET Almost all ET patients suffer from at least one comorbid condition (e.g. depression, anxiety, sleep disorders, cognitive dysfunction)4
10 Approximately 1 million people are diagnosed with ET and on treatment, while another 1 million patients are estimated to remain untreated 0 medications have been developed specifically for ET & only 1 medication was approved for ET >50 years ago Of patients who seek treatment, ~40% discontinue within 2 years, or 200,000 patients annually …but ET often remains undiagnosed, misdiagnosed, undertreated and untreated SOURCE: Vetterick, C., Lyons, K.E., Matthews, L.G. et al. The Hidden Burden of Disease and Treatment Experiences of Patients with Essential Tremor: A Retrospective Claims Data Analysis. Adv Ther (2022). https://doi.org/10.1007/s12325-022-02318-8 Many ET patients are frequently misdiagnosed, leading to ET diagnosis about 1.5 years after an initial movement disorder diagnosis 40%
11 Essential tremor has a large market potential and limited competition compared with other diseases Source: Evaluate Pharma US Sales by Product (#) number of drugs with branded revenue report by company *US products sales are not indication specific $0 $1 $2 $3 $4 $5 $6 - 1 2 3 M AR KE T VA LU E (U S 20 22 P RO DU CT S AL ES *, $B N) US PATIENT POPULATION, MILLIONS Rheumatoid Arthritis / 30 drugs Multiple Sclerosis / 26 drugs Tardive Dyskinesia / 2 drugs Parkinson’s Disease / 15 drugs Essential Tremor now / 0 drugs Essential Tremor future $35 $15 INDICATION / NUMBER OF BRANDED COMPETITORS 7
12 Essential1 Phase 2 Study • Clinically meaningful effect • Well tolerated safety profile Active 2023 as ulixacaltamide marches towards Phase 3 Continue to generate supportive data and de-risk Phase 3 trial design 1mADL11 comprises 11 elements of the TETRAS Activities of Daily Living, excluding social impact, individually scored MARCH JUNE AUGUST Q4 EoP2 FDA Meeting • Confirmed mADL111 as primary endpoint • 60 mg as dose for the Phase 3 trials: one parallel design, one randomized withdrawal study Essential1 Additional Data • Patients on ulixacaltamide for 14 weeks see gain in efficacy • Patients switching from ulixacaltamide to placebo lose efficacy Initiate Phase 3 studies
13 T-type calcium channels are gatekeepers of neuronal firing patterns in the Cerebello-Thalamo-Cortical (CTC) circuit Source: Based on Milosevic 2018 figured on actual ET patient intraoperative real-time single-unit recordings of action potentials of individual neurons 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 Deep Brain Stimulation reduces burst firing and tremor
14 Ulixacaltamide is a differentiated, selective T-type calcium channel blocker in development for movement disorders Source: Praxis Data on file, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9310641/ Highly selective for T-type calcium channels Potential for effectiveness across range of neuronal activity levels Highly potent across all three T-type isoforms
15 Ulixacaltamide’s wide dosing range and modified release formulation supports late-stage development and registration potential Source: Praxis Data on fil. 1. Profile for 20mg dose 0 5 10 15 20 25 30 35 40 45 50 0 6 12 18 24 Ul ix ac al ta m id e Pl as m a Co nc en tr at io n (n g/ m L) Time (h) SUSTAINED EXPOSURE1 WITH BLUNTED CMAX Source: Praxis Data on file PREDICTABLE PK, FLEXIBILITY IN TITRATION & WIDE DOSING RANGE UP TO ~120 MG IN PATIENTS 5mg 10mg 20mg 60mg 80mg 100mg 120mg DOSES TESTED IN ET PATIENTS
16 mADL11 as Phase 3 endpoint has been successfully used in the Phase 2 program 1. Speaking 2. Feeding with a spoon 3. Drinking from a glass 4. Hygiene 5. Dressing 6. Pouring 7. Carrying food trays, plates or similar items 8. Using keys 9. Writing 10. Working 11. Overall disability with most affected task 0 = Slightly abnormal. Tremor is present but does not interfere with __. 1 = Mildly abnormal. Spills a little. 2 = Moderately abnormal. Spills a lot or changes strategy to complete task. 3 = Severely abnormal. Cannot drink from a glass or uses straw or sippy cup. Each measure is individually scored from 0-3: TOTAL SCORE OF UP TO 33 Modified ADL11 items: -2.69 -0.88 Improvement in mADL11in 8 weeks - Essential1 Study p = 0.042 1 Results from Essential1 study results. mITT: Modified Intention to Treat population, p values are nominal ULIXACALTAMIDE (n=78) PLACEBO (n=38)
17 -5.00 -4.00 -3.00 -2.00 -1.00 0.00 8 10 12 14 CH AN GE IN M AD L1 1 V. B AS EL IN E (D AY 0 ) Ulixacaltamide treated patients continue to benefit after 14 weeks on treatment 1.7 point1 improvement week 8 to week 14 for patients remaining on ulixacaltamide beyond the Essential1 readout • Patients originally on drug continue to show durable effect through 14 weeks ESSENTIAL1 OLE: CHANGE IN mADL11 FROM BASELINE, BY STUDY WEEK 1Improvement in the mADL11 of 1.7 points from 3.09 at Week 8 (95% CI: 0.98, 5.2) to 4.81 (95% CI: 2.38, 7.23) after 14 weeks of treatment Maintained Ulixa, n=39
18 5.00 4.00 3.00 2.00 1.00 0.00 8 10 12 14 CH AN GE IN M AD L1 1 V. B AS EL IN E (D AY 0 ) 3.2 point2 improvement week 8 to week 14 for patients moving from placebo to ulixacaltamide Transition from placebo to ulixacaltamide supports benefit of treatment 1.7 point1 improvement week 8 to week 14 for patients remaining on ulixacaltamide beyond the Essential1 readout • Patients originally on drug continue to show durable effect through 14 weeks • Patients originally on placebo experience similar benefit as those seen in the drug arm during the first 8 weeks of Essential1Placebo Placebo=> Ulixa, n=26 Maintained Ulixa, n=39 ESSENTIAL1 OLE: CHANGE IN mADL11 FROM BASELINE, BY STUDY WEEK 1Improvement in the mADL11 of 1.7 points from 3.09 at Week 8 (95% CI: 0.98, 5.2) to 4.81 (95% CI: 2.38, 7.23) after 14 weeks of treatment 2Improvement in mADL11 of 3.2 points, from 1.21 at Week 8 (95% CI: -1.04, 3.46) to 4.36 (95% CI: 1.68, 7.05)
19 Randomized withdrawal randomized study supports design of proposed Phase 3 Sub-study design summary: Patients were re-randomized in a blinded-fashion to either receive placebo or continue to receive ulixacaltamide. Twenty-one patients who completed assessments at Week 14 of the OLE were eligible to participate in the blinded sub-study. Patients were evaluated weekly over a total of 6 weeks, with 11 patients assigned to ulixacaltamide and 10 to placebo for the initial 3-week period, crossing over to either placebo or ulixacaltamide for an additional 3-week period. Blinded rescue was triggered for patients on placebo if loss in the mADL11 exceeded 2 points at any timepoint. *Mean change in effect of the mADL11 • Patients who switched from ulixacaltamide to placebo experienced an average loss of effect in their mADL11 per week of 47%* • Patients who remained on ulixacaltamide had an average improvement of 6% per week -47% 6% -50% -40% -30% -20% -10% 0% 10% Placebo Ulixacaltamide AVERAGE WEEKLY CHANGE IN mADL11 V. PRIOR WEEK OVER STUDY PERIOD UN FA VO RA BL E F AV OR AB LE
20 Randomization Randomized Withdrawl Study Placebo-Controlled Parallel Group Study • Single dose (60 mg) • Control for intention tremor, family history and propranolol use by arm • Agreement on the size of safety database for registration to include 300 subjects for 6 months of exposure and 100 subjects for 12 months of exposure • Agreement on planned and completed clinical pharmacology and toxicology studies On-track for targeted NDA submission in 2025 Phase 3 program comprised of two complementary 12-week studies mADL11 as primary endpoint Day: 1-84* 60 mg 1: 1 Ra nd om iz at io n Placebo 60 mg Day: 1-56* 60 mg Placebo 57-84 Study Readout Study Readout * Includes two-week titration
21 PRAX-562 SCN2A, SCN8A & OTHER DEEs KEY UPCOMING MILESTONES Q4 2023 Ph 2 EMBOLD Study Topline Results
22 Preclinical and emerging clinical data demonstrate PRAX-562 has the potential to be a first- and best- in-class small molecule for DEEs Superior selectivity for disease-state NaV channel hyperexcitability Convenient auto-titration regimen with stable PK Unprecedented therapeutic window with potential for superior safety and efficacy PRAX-562 SCN2A, SCN8A + OTHER DEEs FORMULATED FOR PEDIATRIC USE SMALL MOLECULE
23 Persistent sodium current (INa) is a critical driver of pathological hyperexcitability in CNS disorders
24 % INHIBITION OF hNaV1.6 PERSISTENT INa COMPARISON OF POTENCY AND SELECTIVITY Broader in vitro panel indicates PRAX-562 has best-in-class preferences 0.01 0.1 1 10 100 1000 10000 0 20 40 60 80 100 Concentration (µM) % In hi bi tio n Carbamazepine Lamotrigine Cenobamate PRAX-562 Persistent INa IC50 (nM) Ratio of persistent to peak inhibition PRAX-562 141 60 Carbamazepine 77,520 30 Cenobamate 73,263 23 Lidocaine 68,230 19 Lamotrigine 78,530 16 Lacosamide 833,100 n/a* Valproic Acid <10% @ 1 mM No inhibition MORE SELECTIVE HIGHER POTENCY
25 MES EFFICACY sLMA TOLERABILITY Our mechanistic hypothesis translates to a wide therapeutic index in vivo for PRAX-562 Therapeutic Index (TI) = TC50 / EC50 CD-1 mice; (n=12/group) **p<0.01 vs. Veh ED50: 2 mg/kg Molecule Plasma Therapeutic Index PRAX-562 17.2x PRAX-562 (mg/kg, PO) PRAX-562 (mg/kg, PO) CD-1 mice; (n=20/group) ANOVA/Dunnett **p<0.01 vs. Veh TD50: 44 mg/kg Veh 0.3 1 3 10 0 20 40 60 M ES La te nc y (s ec ) ** ** Veh 10 20 40 0 10000 20000 30000 40000 50000 60000 70000 To ta l D Is ta nc e Tr av el le d (m m ) ** **
26 IN VIVO POC IN SCN2A SPONTANEOUS SEIZURES1 IN VIVO POC IN SCN8A AUDIOGENIC EVOKED SEIZURES2 PRAX-562 completely inhibits seizures in SCN2A and SCN8A GoF mutation mouse models 1 PRAX-562 inhibition of spontaneous seizures in Q54 GoF mice. 2 PRAX-562 inhibition of audiogenic seizures in N1768D D/+ mice Pr op or tio n w ith S ei zu re s 100% 50% 0% % C ha ng e in S ei zu re s PRAX-562 (mg/kg, PO) PRAX-562 (mg/kg, PO) Veh Sidack’s post hoc comparison test *p<0.05 vs. Veh **p<0.001 vs. Veh **Significant protection vs. Veh χ2 2 = 16.0, Fisher’s p = 0.0002 ** Veh 0.3 1 3 10 -100 -50 0 50 * ** ** +50% -50% -100%
27 PRAX-562 Phase 1 summary Source: Praxis data on file; https://investors.praxismedicines.com/news-releases/news-release-details/praxis-precision-medicines-provides-corporate-update-and-5 * Co-administration of supra-therapeutic doses of PRAX-562 and oxcarbazepine led to additive sodium blocking effects, including resulting in SAEs All TEAEs mild to moderate as stand-alone therapy*, with headache & dizziness most common TEAEs Significant changes observed between placebo and 90 mg of PRAX-562 on qEEG and on ASSR biomarkers PRAX-562 has been generally well tolerated in over 130 healthy volunteers No MTD at exposures multiple fold above therapeutic range indicates potential for superior therapeutic index
28 PRIMARY ENDPOINT: Incidence and severity of treatment- emergent adverse events (TEAEs) KEY SECONDARY: Change from baseline in monthly (28 day) motor seizure frequency PRAX-562 Phase 2 EMBOLD study topline data expected 4Q23 * Two distinct cohorts in early-onset SCN2A-DEE and SCN8A-DEE patients + Participants receive either 0.5 mg/kg/day PRAX-562 QD for 16 weeks or 0.5 mg/kg/day PRAX-562 QD for 12 weeks & matching placebo QD for 4 weeks. Participants in the PRAX-562/placebo arm will receive placebo for 4 consecutive weeks during the 16-week treatment period, with timing of placebo administration blinded for both participants and investigator. Dose adjustment is permitted to a max of 1.0 mg/kg/day and a min of 0.25 mg/kg/day. Safety Follow- Up SAFETY FOLLOW-UP PERIOD (4 WEEKS) DOUBLE-BLIND TREATMENT PERIOD (16 WEEKS) PRAX-562 1:1 Randomization N=~20 (~10 SCN2A/~10 SCN8A)* OLE TREATMENT PERIOD (48 WEEKS) PRAX-562 0.5 mg/kg/day Placebo for 4 weeks/PRAX-562 for 12 weeks+ 0.5 mg/kg/day
29 PRAX-628 Focal Epilepsy KEY UPCOMING MILESTONES 2H 2023 Topline Results from Phase 2 PPR study
30 Focal epilepsy affects ~2 million people in the US alone Most common type of epilepsy in adults and children - occurs in 60% of epilepsy cases Most common age of onset is in the first year of life and in the 6th and 7th decade~ 50% have family history but genetics is not well understood Defined as epilepsy that originates in one side or area of the brain and affects one side of the body
31 Preclinical and Phase 1 data demonstrate potential of PRAX-628 as best-in-class treatment for focal epilepsy Superior selectivity for hyperexcitable state of sodium channels in the brain associated with disease Favorable safety and tolerability profile across broad concentration range in healthy volunteers Unprecedented therapeutic window could translate to superior safety and efficacy PRAX-628 FOCAL EPILEPSY FUNCTIONALLY SELECTIVE SMALL MOLECULE qEEG analysis confirms CNS activity for doses above 5mg
32 PRAX-628: Road to Phase 2 focal epilepsy study DECEMBER MAY AUGUST 2H ’23 Phase 1 Study qEEG Analysis Confirmed pharmacodynamic activity across all dose levels for study subjects who received PRAX-628 Topline results Phase 2 PPR study 1H’24 Initiate Phase 2 Focal study Phase 1 Safety Study Demonstrated a favorable safety and tolerability profile in healthy volunteers2022 AES: Pre-clinical data shows potent anticonvulsant activity, wide preclinical protective index, compared with standard NaV- targeting AEDs
33 PREFERENTIAL ACTION AGAINST HYPEREXCITABILITY BIOPHYSICAL “LEVERS” TO ACHIEVE PREFERENTIAL ACTION Restoring physiological neural activity by precisely modulating biophysics A. Reduce pro-excitatory channel function • Inhibit persistent current B. Dynamic block of channels during high activity • Inhibit voltage dependent current • Inhibit use dependent current C. Maintain channel availability during low activity • Reduce potency against steady state peak current STIMULATION LEVEL epileptic range untreated ideal drug NE UR AL A CT IV IT Y non preferring drug
34 C. MARGINS BETWEEN DISEASE CURRENT INHIBITION TO TONIC BLOCK OF HEALTY CURRENT PRAX-628 delivers improved potency and separation to tonic (toxic) inhibition 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration (µM) P er si st en t I N a In hi bi tio n (% ) hNaV1.6 Persistent INa Cenobamate PRAX-628 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration (µM) Vo lta ge D ep en de nt In hi bi tio n (% ) VDB hNaV1.6 Peak INa PRAX-628 Cenobamate 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration (µM) A ct iv ity D ep en de nt In hi bi tio n (% ) UDB-10Hz hNaV1.6 Peak INa Cenobamate PRAX-628 PRAX-628 CENOBAMATE Persistent INa 68 24 Voltage Dependent 121 35 Activity Dependent 44 1.3 MARGIN TO TONIC BLOCK (TOXIC ACTIVITY) A. REDUCE PRO-EXCITATORY CHANNEL FUNCTION B. DYNAMIC BLOCK OF CHANNELS DURING HIGH ACTIVITY Source: Praxis data on file
35 PRAX-628 has unprecedented margins over best in class ASM’s based on MES efficacy and clinical tolerability in humans Source: Praxis data on file Cenobamate Cmax: >46,100 ng/mL, 400 mg Cmax (Vernillet et al 2020) XEN1101 Cmax: >107 ng/mL (Phase 1 data) x MES EC50 = multiple of predicted human EC50 based on the rodent MES model 0 2 4 6 8 10 12 14 16 18 CENOBOMATE XEN-1101 PRAX-628 xM ES E C5 0 Additional tolerated margin for PRAX-628 No tolerability concerns toxicity and tolerability levels Clinically Tolerated Exposures HUMAN EQUIVALENT OF MOUSE MES EC50 NG/ML MULTIPLE OF MES EC50 TOLERATED CLINICALLY Cenobamate 9,600 4.8x XEN-1101 42 2.5x PRAX-628 24 >15.5x* Additional tolerated margin for PRAX-628
36 Reduction of photosensitivity frequency range relative to baseline or PBO is ASM activity is indicative of AED efficacy 18 Hz 60 Hz 2 Hz BASELINE: PLACEBO WITH DRUG LI GH T FR EQ UE NC Y PPR present PPR eliminated PARTIAL RESPONSE 1 References: First Pub: C.D. Binnie Electroencephalography and clinical neurophysiology A, 1986, 63, 35-41; LEV paper: DGA Kasteleijn-Nolst Trenité Epilepsy Research 25(1996) 225-230; DGA Kasteleijn-Nolst Trenité Neurology 93(6) 2019 e559-e567 cenobamate paper • The PPR Photosensitivity Model has been used to assess many AEDs1 • Partial or complete suppression of PPR photosensitivity range by drug versus PBO correlates to drug efficacy in a small sample size (4-6 patients) • Dosing starting at 15mg Ranges Which Trigger PPR Response COMPLETE RESPONSE
37 SOLIDUS™ ASO PLATFORM
38 2H 2023 EMBRAVE Study First Dose Cohort (Part 1) Topline Safety Results PRAX-222 SCN2A-GoF ASO KEY UPCOMING MILESTONES
39 Preclinical data suggest PRAX-222 has potential to be disease- modifying for early onset SCN2A gain-of-function DEE Dose-dependent reduction in interictal spikes, seizures and increased survival Survival benefit extended with repeat dosing Improvement in behavioral and locomotor activity PRAX-222 INTRATHECALLY-ADMINISTERED ASO for SCN2A GoF DEE
40 PRAX-222 EMBRAVE study initial dose cohort (Part 1) results expected 2H23 GOAL: Assess preliminary safety of PRAX-222 21-week study Open label design screening / baseline observation UP TO 8 WEEKS 4 WEEKS 4 WEEKS 4-5 WEEKS monitoring monitoring PRAX-222 IT Dose PRAX-222 IT Dose PRAX-222 IT Dose PRAX-222 IT Dose monitoring ongoing treatment OPTIONAL OPEN LABEL EXTENSION SAFETY ANALYSIS FDA REVIEW N=4
41 PRAX-222 is an ASO designed to down-regulate SCN2A expression in patients with gain-of-function mutation
42 SCN2A mRNA KNOCKDOWN SCN2A PROTEIN KNOCKDOWN In vitro, PRAX-222 down-regulates both mRNA and protein ASOs were administered at P30 and brains were collected 14 days post-ICV for qPCR analysis D o s e (µ g ) % c o n tr o ls 1 1 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 A S O -C tr l 2 0 0 µ g ED50: 33 µg ED80: 170 µg ASO-Ctrl WT ASO-Ctrl Q/+ ASO-811 Q/+ 0 200 400 600 N or m al iz ed a ct in **** ASO-CTRL ASO-SCN2AASO- TRL / WT MOUSE SCN2A GOF R1883Q/+ MOUSE ASO-SCN2A 10 µm Nav1.2 AnkG ASO-CTRL
43 PRAX-222 increases survival in SCN2A GoF mice ***p<0.001 ****p<0.0001 All experiments conducted with SCN2A R1882Q mouse model SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION SCN2A GOF model ASO-Ctrl (n=39) ASO-SCN2A ED80 (n=49) ASO-SCN2A ED50 (n=22) 0 20 40 60 80 0 25 50 75 100 Postnatal day % s ur vi va l **** **** ASO injection (icv, P1) RE-DOSING SIGNIFICANTLY EXTENDS SURVIVAL SCN2A GOF model 0 50 100 150 200 0 25 50 75 100 Postnatal day % s ur vi va l **** *** ASO-Ctrl (n=11) ASO-SCN2A ED80 (n=13) ASO-SCN2A ED50 (n=15) ASO injections (icv, P1, P28) ADMINISTRATION POST-DISEASE ONSET ALSO EXTENDS SURVIVAL SCN2A GOF model 0 50 100 150 200 0 25 50 75 100 Postnatal day % s ur vi va l **** **** ASO-Ctrl (n=8) ASO-SCN2A ED80 (n=15) ASO-SCN2A ED50 (n=15) ASO injection (icv, P15)
44 Simulated mRNA knockdown in human cortex in pediatric patients Achieves distribution in key areas of brain based on NHP data PRAX-222 PK/PD modeling informs starting dose and proposed escalation based on level of knockdown anticipated to achieve clinical benefit and tolerability Source: Praxis data on file. Median and 95% prediction interval illustrated Target knockdown 100 80 60 40