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): November 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 7.01. Regulation FD Disclosure.
On November 28, 2022, Praxis Precision Medicines, Inc. (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 99.1 to this Current Report on Form 8-K.
The information in this Current Report on Form 8-K under Item 7.01, including Exhibit 99.1 attached hereto, is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, 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 November 28, 2022, the Company announced plans to initiate the PRAX-562 Phase 2 EMBOLD study for the treatment of pediatric patients with developmental and epileptic encephalopathies (“DEEs”), following U.S. Food and Drug Administration authorization to proceed with the study as proposed by the Company, up to the planned maximum dose of 1.0 mg/kg/day. The EMBOLD Study is expected to initiate in the U.S in the first quarter of 2023, with two distinct cohorts in early-onset SCN2A-DEE and SCN8A-DEE patients. Topline results for both cohorts are expected in the second half 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 will be enrolled in a total of 2 distinct cohorts (n≈10 for SCN2A-DEE and n≈10 for SCN8A-DEE).
Forward-Looking Statements
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 PRAX-562 Phase 2 EMBOLD study. 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 Quarterly Report on Form 10-Q for the quarter ended June 30, 2022 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.
(d) Exhibits
Exhibit No. | Description | |||||||
| 104 | Cover page from this Current Report on Form 8-K, formatted in Inline XBRL | |||||||
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: November 28, 2022 | By: | /s/ Marcio Souza | |||||||||
| Marcio Souza | |||||||||||
| Chief Executive Officer | |||||||||||
CORPORATE OVERVIEW November 2022
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, (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 Quarterly Report on Form 10-Q filed for the quarter ended June 30, 2022 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 New Classes of Treatments INSPIRED BY THE GENETICS OF EPILEPSY GABRB3 KCNT1 SCN1A CACNA1A KCNA1 SLC1A3 SETX RFC1CACNA1G GABRB3 KCN1A SCN8A SCN2A DRD3 HTT FMR1 OPA1 SYNGAP1 SHANK3 CDKL5 DNM1 UNC79 TRIM3 PCDH19 CACNA1A EPILEPSY MOVEMENT
4SCN2A-LOF, SYNGAP1 & PCDH19 ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health Targeting movement disorders & epilepsies connected by neuronal imbalance PRECLINICAL PHASE ONE PHASE TWO REGISTRATION ENABLINGFOCUS AREA MOVEMENT DISORDERS PRAX-050 Undisclosed PRAX-944 Essential Tremor PRAX-944 Parkinson’s Disease EPILEPSY PRAX-562 DEEs PRAX-090 (ASO) SYNGAP1 PRAX-100 (ASO) SCN2A LoF PRAX-030 Undisclosed PRAX-020 KCNT1 PRAX-080 (ASO) PCDH19 PRAX-222 (ASO) SCN2A GoF DEE 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 Upcoming readout for late-stage program for Essential Tremor PRAX-944 PH 2B ESSENTIAL1 STUDY TOPLINE RESULTS EXPECTED IN 1Q23 Cash runway into 1Q24 to advance each clinical-stage program through value inflecting milestones $124 MILLION IN CASH & INVESTMENTS AS OF THE END OF 3Q22 Topline data expected for each of three clinical-stage epilepsy programs PRAX-222 FIRST-IN-PATIENT EMBRAVE STUDY PRAX-562 FIRST-IN-PATIENT EMBOLD STUDY PRAX-628 FIRST-IN-HUMAN PHASE 1 STUDY POC data in Parkinson's disease PRAX-944 PH 2 PD STUDY TOPLINE RESULTS EXPECTED IN 2H23 Deep early-stage pipeline enabling continuous advancement of new programs DEVELOPMENT CANDIDATE NOMINATION FOR PRAX-080 ASO FOR PCDH19
7 MOVEMENT DISORDERS PRAX-944 T-Type Calcium Channel Inhibitor Essential Tremor Parkinson’s Disease KEY UPCOMING MILESTONES 2H 2023 PRAX-944 Ph 2 PD Study Topline 1Q 2023 PRAX-944 Ph 2b ET Essential1 Study Topline
8 Essential tremor 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
9 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 Many ET patients are frequently misdiagnosed, leading to ET diagnosis about 1.5 years after an initial movement disorder diagnosis 40% 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
10 PRAX-944 is a differentiated, selective T-type calcium channel blocker in development for ET and Parkinson’s disease 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
11 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 and PD Deep Brain Stimulation reduces burst firing and tremor
12 Wide dosing range and modified release formulation for PRAX-944 may support tolerability & efficacy profile Source: Praxis Data on file 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 tra tio n (n g/ m L) Time (h) SUSTAINED EXPOSURE WITH BLUNTED CMAX Source: Praxis Data on file PREDICTABLE PK, WIDE DOSING RANGE UP TO ~100 MG & FLEXIBILITY IN TITRATION 5mg 10mg 20mg 60mg 80mg 100mg 120mg ESSENTIAL1 STUDY DOSES
13 MODIFIED ADLs IN RANDOMIZED WITHDRAWAL MEAN % CHANGE FROM DAY 42 Marked functional benefit observed in PRAX-944 treated patients in Ph 2a study; withdrawal of PRAX-944 results in regression to baseline severity MODIFIED ADLs IN OPEN LABEL MEAN % CHANGE FROM BASELINE *Nominal p-value based on ANCOVA Source: Praxis Data on file from Part B of Phase 2a study *p<0.05 139% Day 42 (N=11) Day 56 (N=6 PRAX-944, N=5 Placebo) 8% Placebo PRAX-944-42% Day 42 (N=11) Day 70 (N=11) -10% *p<0.003 IM PR OV EM EN T W OR SE NI NG PRAX-944 TREATED OFF DRUG
14 Source: clinicaltrials.gov/ct2/show/NCT05021991 PRAX-944 Phase 2b Essential1 study topline results expected 1Q23 *Composite sum of items 1 to 11 of TETRAS-ADL subscale and items 6 (bilateral) and 7 of TETRAS-PS; modified ADL score is calculated as the sum of all 13 items and ranges from 0 to 42 clinicaltrials.gov/ct2/show/NCT05021991 Screening: Day-28 to -1 Safety Follow-Up: Day 57 to 70 Safety Follow-Up Screening PLACEBO Intervention (Titration and Maintenance): Day 1 to 56 PRAX- 944 100 mg Randomization Titration Period Titration Period PRAX-944 60 mg PRIMARY ENDPOINT: Change from baseline to Day 56 in the Modified ADL*, functionally relevant & FDA- suggested endpoint STUDY POWERING: 33 evaluable participants per regimen provides 80% power to detect 0.6 effect size between pooled PRAX-944 and placebo groups, or placebo adjusted difference of 3.6 pts in mADL at Day 56 (SD=6) Optional Extension: Day 57 to 189 Double-Blind Lead-in Period (43 days) Open Label Period (90 days) Safety Follow-Up (14 days) ~130 participants
15 Modified ADLs: A modified measure of TETRAS activities of daily living (ADLs) that is functionally relevant and FDA recommended 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 12. Social Impact TETRAS ADL measures observed: 0 = Normal 1 = Slightly abnormal. Tremor is present but does not interfere with __. 2 = Mildly abnormal. Spills a little. 3 = Moderately abnormal. Spills a lot or changes strategy to complete task. 4 = Severely abnormal. Cannot drink from a glass or uses straw or sippy cup. Each measure is individually scored from 0-4: TOTAL SCORE OF UP TO 48 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 12. Handwriting 13. Spirals (x2) 14. Social impact 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 42 Modified ADL measures observed:
16 PRAX-944 has potential to be a non-dopaminergic therapy for motor function for people with Parkinson’s disease Dopamine promotes movement Dopamine related motor and non- motor complications
17 T-type calcium channels modulate the motor circuit in Parkinson’s disease and overlap with target for Deep Brain Stimulation Mcgregor mm, nelson ab. Neuron. 2019. Doi:10.1016/j.Neuron.2019.03.004 Tai c-h et al. J clin invest. 2011. Doi:10.1172/jci46482 THALAMO-CORTICAL PATHWAY IMBALANCE IN PD STN-Healthy STN-PD PRAX -944 DBS CEREBELLO-THALAMO-CORTICAL PATHWAY
18 Blocking T-type calcium channels with Ni2+ improves motor function in burst firing model of movement deficit in Parkinson’s disease Pan et al (2016) j clin invest doi: 10.1172/jci88170 BURST FIRING IN STN OF 6-OHDA PARKINSON’S MODEL BLOCK OF BURST FIRING IMPROVES MOVEMENT IN 6-OHDA PARKINSON’S MODEL
19 PRIMARY ENDPOINT: Change from baseline to Day 77 in the International Parkinson and Movement Disorder Society (MDS) Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (motor examination) score in the OFF state PRAX-944 Phase 2 Parkinson’s disease study topline data expected 2H23 Safety Follow- Up DAY 50-77 Maintenance DAY 92-98 PRAX-944 Titration from 5 mg up to 100 mg DAY 1-49 Titration PLACEBO 1:1 Randomization N= ~80 DAY 78-91 PRAX-944 50/25 mg Taper-down PLACEBO PRAX-944 100 mg PLACEBO
20 4Q 2022 Initiate PRAX-222 EMBRAVE Study 4Q 2022 Initiate PRAX-628 Ph 1 Trial KEY UPCOMING MILESTONESEPILEPSY PRAX-562 (DEEs) PRAX-222 (SCN2A-GOF ASO) PRAX-020 (KCNT1) PRAX-628 (Focal Epilepsy) PRAX-100 (SCN2A-LOF ASO) PRAX-090 (SYNGAP1 ASO) PRAX-080 (PCDH19 ASO) PRAX-030 (Undisclosed) 1Q 2023 Initiate PRAX-562 Ph 2 EMBOLD Study
21 Delivering first and best-in-class precision medicines for 25,000+ rare epilepsy patients LGS: Lennox-Gastaut Syndrome; TSC: Tuberous Sclerosis Complex Source: Ambit Genetic Testing and Claims Data Analysis; EvaluatePharma; Sanders S. J. et al. Trends Neurosci. (2018); Wolff M. et al Brain (2017); U.S. DIAGNOSED PREVALENCE FOR RARE EPILEPSY PROGRAMS (PATIENTS ≤20 YEARS OF AGE) $742M ’21 sales $1.5B ’26 sales (consensus est.) First- and best-in-class PRAX precision medicines U.S. MARKET SIZE 1,500 1,000 1,250 1,600 2,250 8,000 PCDH19LGS, TSC, Dravet SCN8A GoF SCN2A GoF 25,000+ pts KCNT1 SYNGAP1 SCN2A LoF 35,000
22 Preclinical and emerging clinical data demonstrate PRAX-562 has the potential to be a first- and best-in-class NaV blocker 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 PAN-NAV BLOCKER SMALL MOLECULE
23 Persistent sodium current (INa) is a critical driver of pathological hyperexcitability in the 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 *solubility concerns 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 Vixotrigene (BIIB074) 3,676 14 Lacosamide 833,100 n/a* Valproic Acid <10% @ 1 mM No inhibition MOST SELECTIVE MOST POTENT
25 MES EFFICACY sLMA TOLERABILITY 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 ) ** ** Veh 0.3 1 3 10 0 20 40 60 M ES La te nc y (s ec ) ** ** Our mechanistic hypothesis translates to a wide therapeutic index in vivo 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
26 IN VIVO POC IN SCN2A SPONTANEOUS SEIZURES1 IN VIVO POC IN SCN8A AUDIOGENIC EVOKED SEIZURES2 PRAX-562 completely blocks 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 Veh 0.3 1 3 10 -100 -50 0 50 * ** ** +50% -50% -100% 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 **
27 PRAX-562 Phase 1 summary 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 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 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 2H23 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 * 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. Placebo+ 0.5 mg/kg/day
29 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 in animal models PRAX-222 INTRATHECALLY-ADMINISTERED ASO for SCN2A GOF DEE
30 PRAX-222 is an ASO designed to down-regulate SCN2A expression in patients with gain-of-function mutation
31 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
32 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION RE-DOSING SIGNIFICANTLY EXTENDS SURVIVAL ADMINISTRATION POST-DISEASE ONSET ALSO EXTENDS SURVIVAL PRAX-222 increases survival in SCN2A GoF mice ***p<0.001 ****p<0.0001 All experiments conducted with SCN2A R1882Q mouse model 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) 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) 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)
33 Simulated mRNA knockdown in human cortex in pediatric patients Achieves distribution in key areas of brain based on NHP data 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
34 PRAX-222 EMBRAVE study initial dose cohort 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
35 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
36 Preclinical data demonstrates PRAX-628 will be a best-in-class NaV blocker for focal epilepsy Superior selectivity for disease-state NaV channel hyperexcitability PK differentiated for broad epilepsy population Unprecedented therapeutic window translating to superior safety and efficacy PRAX-628 FOCAL EPILEPSY PAN-NAV ACTIVITY DEPENDENT BLOCKER SMALL MOLECULE
37 LOW DISEASE-STATE DEPENDENCE THIN THERAPEUTIC INDEX HIGH DISEASE-STATE DEPENDENCE WIDE THERAPEUTIC INDEX Our internal discovery effort focused on developing a NaV blocker with high disease state dependence and wide therapeutic index Source: Praxis data on file 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, µM % In hi bi ti on o f hN a V 1. 6 Lamotrigine (LTG) 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, µM % In hi bi ti on o f hN a V 1. 6 Carbamazepine (CBZ)LAMOTRIGINE CARBAMAZEPINE 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, µM % In hi bi tio n of hN a V 1. 6 PRAX-628 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, µM % In hi bi tio n of hN a V 1. 6 PRAX-562 PRAX- 8P - 62 “NaV Fingerprint” Persistent INa Inhibition Peak INa, UDV-10Hz (Disease-State Dependence) Inhibition Peak INa, Tonic Block Inhibition
38 PRAX-628 has unique pharmacological properties that enable acute dosing in a broader patient population Modeling 90mg, single dose of PRAX-628 or PRAX-562. Preclinical simulation recapitulates PRAX-562 clinical data. 0 4 8 9 6 1 4 4 0 .1 1 1 0 Preclinical Simulation of Human PK 90 mg Single Dose Time (h) Un bo un d Pl as m a Co nc . ng /m L PRAX-628: 36 hr predicted half-life PRAX-562: >120 hr predicted half-life
39 Molecule Plasma Therapeutic Index PRAX-628 16.7x MES EFFICACY sLMA TOLERABILITY PRAX-628 protects mice from seizures with a wide therapeutic window Therapeutic Index (TI) = TC50 / EC50 CD-1 mice; (n=8/group veh, n=10 PRAX) ANOVA/Dunnett (PRAX) **p<0.01 vs. Veh ED50: 0.67 mg/kg PRAX-628 (mg/kg, PO) PRAX-628 (mg/kg, PO)CD-1 mice; (n=10/group) ANOVA/Dunnett **p<0.01 vs. Veh TD50: 10.3 mg/kg Veh 0.3 1 3 10 0 20 40 60 M ES La te nc y (s ec ) ** ** 0 20000 40000 60000 80000 100000 To ta l D is ta nc e Tr av el le d (m m ) Veh 3 5.6 10 20 ** **
40 PRAX-222 (SCN2A GoF DEE) PRAX-628 (FOCAL EPILEPSY) PRAX-562 (SCN2A, SCN8A) Three epilepsy drugs expected in clinic by first quarter 2023 Initiate EMBRAVE Study: 4Q22+ Initiate Phase 1 Study: 4Q22 Initiate EMBOLD Study: 1Q23 PRAX-222 and PRAX-562 each received Orphan Drug Designations for severe pediatric epilepsy indications from the FDA and EMA, and Rare Pediatric Disease designation from the FDA. + Initial dose cohort; following collection of safety and efficacy data from first cohort, the data will be evaluated and submitted to the FDA to seek authorization for further dose escalation
