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): April 27, 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:
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Securities registered pursuant to Section 12(b) of the Act:
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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 April 27, 2022, Praxis Precision Medicines, Inc. (the “Company”) held its previously announced 2022 Epilepsy Day. A copy of the slide presentation for Epilepsy Day, which has been made available through the Events & Presentations page of the Investors + Media section of the Company’s website, is attached as Exhibit 99.1 to this Current Report on Form 8-K (the “Form 8-K”).
The information in this Item 7.01 of this Form 8-K and Exhibit 99.1 attached hereto 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 any of 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 a filing.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
Exhibit No. | Description | |||||||
| 99.1 | ||||||||
| 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: April 27, 2022 | By: | /s/ Marcio Souza | |||||||||
| Marcio Souza | |||||||||||
| Chief Executive Officer | |||||||||||
EPILEPSY DAY APRIL 27, 2022
2 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. Words such as, but not limited to, “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” “would,” “should” and “could,” and similar expressions or words, identify forward-looking statements. 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’ ongoing and planned clinical trials, (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 Praxis’ expectations and actual results, you should review the “Risk Factors” section of our Annual Report on Form 10-K filed for the period 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.
3 Developing New Classes of Treatments INSPIRED BY THE GENETICS OF EPILEPSY PSYCHIATRY GABRB3 KCNT1 SCN1A CACNA1A KCNA1 SLC1A3 SETX RFC1 CACNA1G GABRB3 KCN1A SCN8A SCN2A DRD3 HTT FMR1 OPA1 SYNGAP1 SHANK3 TPH2 FKBP2 HTR2A CDKL5 DNM1 UNC79 TRIM3 PCDH19 CACNA1A EPILEPSY MOVEMENT
4 Praxis is built on four key pillars DEVELOPMENT INFORMED BY TRANSLATIONAL TOOLS TARGETS IDENTIFIED THROUGH GENETICS CLINICAL DEVELOPMENT PATHS TO POC ARE RIGOROUS & EFFICIENT DEVELOPMENT STRATEGIES ARE PATIENT-GUIDED
5 >1M w/ Refractory Seizures We aim to address unmet need in the $3B+ US common epilepsy market Source: CDC, EvaluatePharma; Tang F. et al. Front. Neurol. (2017) 3.5M US Prevalence $3B+ US Common Epilepsy Market Opportunity
6 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
7 MOVEMENT DISORDERS EPILEPSY PSYCHIATRY PRECLINICAL IND / PHASE ONE PHASE TWO REGISTRATION ENABLING PRAX-562 DEEs PRAX-020 KCNT1 PRAX-628 Focal Epilepsy PRAX-080 (ASO) PCDH19 PRAX-090 (ASO) SYNGAP1 PRAX-100 (ASO) SCN2A LoF PRAX-030 Undisclosed PRAX-050 Undisclosed PRAX-114 Essential Tremor PRAX-944 PD PRAX-944 Essential Tremor PRAX-040 Undisclosed FOCUS AREA PRAX-114 MDD PRAX-114 PTSD Our portfolio includes the largest targeted epilepsy pipeline in development PRAX-222 (ASO) SCN2A GoF DEE *PRAX-222 in collaboration with Ionis. SCN2A-LOF, SYNGAP1 & PCDH19 ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health.
8 DANIEL FRIEDMAN, M.D., MSc. Professor of Neurology at NYU Grossman School of Medicine and Co-director of the Video-EEG laboratory at NYU Langone Medical Center • MD from Case Western Reserve University School of Medicine; neurology residency training at the Hospital of the University of Pennsylvania and his epilepsy/clinical neurophysiology fellowship at the Neurological Institute/Columbia University Medical Center. • Serves on the executive committees of the North American SUDEP Registry and the Epilepsy Study Consortium as well as the professional advisory board of the Epilepsy Foundation of America. Introductions JACQUELINE FRENCH, M.D. Professor of Neurology at NYU Grossman School of Medicine and President, Director and Founder of the Epilepsy Study Consortium • Trained in Neurology at Mount Sinai Hospital in New York; fellowship training in EEG and epilepsy at Mount Sinai hospital and Yale University. • Serves as the Chief Medical/Innovation Officer of the Epilepsy Foundation. • Past president of the American Epilepsy Society; past Secretary of the American Society of Experimental Neurotherapeutics. • Recipient of the American Epilepsy Society Lennox Award (2017) and Service Award (2005), the Epilepsy Foundation Hero award (2013), and is an ILAE Ambassador for Epilepsy.
9 • Unmet Needs in Epilepsy Management: Challenges with clinical management of epilepsy today and possibility for precision-based therapies tomorrow Today’s Agenda JACQUELINE FRENCH, M.D. STEVE PETROU, Ph.D. DANIEL FRIEDMAN, M.D., MSc. • Praxis Epilepsy Innovation Strategy: Using genetics to elucidate new epilepsy targets with high probability of success • Our Science in Action: A deep-dive into our disease modifying epilepsy programs • Accelerating towards Registration: Our clinical development strategy for most advanced epilepsy programs • Perspectives from Clinical Practice: Shortcomings of existing treatment landscape provide opportunities for differentiation BERNARD RAVINA, M.D., MSc. Q&A SESSION • Q&A Panel with Speakers
10 Unmet Needs in Epilepsy Management Jacqueline French, MD NYU School of Medicine Unmet Needs in Epilepsy Management Jacqueline French, M.D. NYU School of Medicine
11 Disclosures • I receive salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Adamas, Aeonian/Aeovian, Alterity Therapeutics Limited, Anavex, Arkin Holdings, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Biogen, BioMarin Pharmaceutical Inc., BioXcel Therapeutics, Bloom Science Inc., BridgeBio Pharma Inc., Cavion, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Coda Biotherapeutics, Corlieve Therapeutics, Crossject, CuroNZ, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel Inc, Equilibre BioPharmaceuticals, Fortress Biotech, Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knopp Biosciences, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte Inc., Neumirna Therapeutics, Neurocrine, Neuroelectrics USA Corporation, Neuropace, NxGen Medicine Inc., Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Passage Bio, Pfizer, Praxis, PureTech LTY Inc., Rafa Laboratories Ltd, Redpin, Sage, SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Inc., Ventus Therapeutics, West Therapeutic Development, Xenon, Xeris, Zogenix, Zynerba. • I have also received research support from the Epilepsy Study Consortium (Funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, Vogelstein Foundation) Epilepsy Study Consortium/Epilepsy Foundation (Funded by UCB), GW/FACES and NINDS. • I am on the editorial board of Lancet Neurology and Neurology Today. I am Chief Medical/Innovation Officer for the Epilepsy Foundation. • I have received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Arvelle Therapeutics, Inc., Biogen, Cerevel, Clinical Education Alliance, Engage, Lundbeck, NeuCyte, Inc., Neurocrine, Otsuka, Sage, UCB, Xenon, Zogenix.
12 Incidence of epilepsy • By a conservative estimate, 50 million people worldwide have epilepsy1 • The annual incidence ranges from 20-70 cases per 100,000 • Overall, 5% of persons report a seizure at some time in their lives (excluding febrile seizures) • Incidence rates are highest in childhood, plateau from 15-65 years of age, and rise again among the elderly • About 30% of patients with seizures have an identifiable neurologic or systemic disorder, and the remainder have either idiopathic or cryptogenic epilepsy • The diagnosis is based on the description of the seizures and the clinical context in which they occur, often supplemented by the results of electroencephalography 1. Brodie MJ and Dichter MA. N Engl J Med. 1996;334(3):168-175.
13 Antiseizure medicine: 2022 1st Generation • Phenytoin • Carbamazepine • Sodium Valproate • Phenobarbital • Primidone 2nd Generation • Felbamate • Gabapentin • Lamotrigine • Topiramate/ • Tiagabine • Oxcarbazepine • Levetiracetam 3rd Generation • Zonisamide • Pregabalin • Lacosamide • Rufinamide • Vigabatrin • Clobazam • Perampanel • Eslicarbazepine • Cannabidiol (Epidiolex) • Brivaracetam • Cenobamate • Fenfluramine • Ganaxolone
14 Outcome with initial drug therapy-all comers as of 2000 Kwan P and Brodie MJ. N Engl J Med. 2000;342(5):314-319. Seizure Free First drug monotherapy 47% Second drug monotherapy 13% Third drug monotherapy 1% Duotherapy 3% Total seizure free 64%
15 How far have we advanced? • Studies in the 1980’s established the critical ratio of treatment response in both adults and children: - 60-70% respond to ASM - 30-40% are “treatment resistant” • With 20 new ASMs in the last few decades, we would anticipate a change in the ratio • Unfortunately, there has not been a substantial change in this ratio in recent times
16 Seizure Free 20001 Seizure free 20122 First drug monotherapy 47% 49.5 Second drug monotherapy 13% Third drug monotherapy 1% Duotherapy 3% 6% Total seizure free 64% 68% Outcome with initial drug therapy 1. Kwan P and Brodie MJ. N Engl J Med. 2000;342(5):314-319. 2. Brodie et al, Neurology. 2012 ;78(20):1548-54
17 We Have Treatment for two thirds of patients AED Therapy: Current status and unmet needs We Need • Treatment for the one third of adult patients who are refractory • Treatment for difficult pediatric syndromes – Many now identified as monogenetic • Ability to predict efficacy/tolerability • Improved options for newly-diagnosed patients – Finding treatments that do not impact quality of life • Attention to comorbidities: depression, cognitive slowing, memory impairment • Antiepileptogenic/disease modifying therapy
18 Adherence burden • About 2/3 of patients can have seizures controlled with a new ASM • But these people are burdened by a daily requirement to take ASM, with dire consequences if even a single day is missed • This can be a lifetime obligation!
19 We have no problem finding new drugs with novel mechanisms* • Brivaracetam - binds SV2A & blocks voltage-gated Na+ channels • 2-deoxy-glucose inhibits glycolysis • Ganaxolone - GABAA-PAM tonic inhibition • Huperzine A - NMDA antagonist • Cenobamate - inhibits voltage gated sodium channels and positive GABAA modulator • CVL-865 - α2/3/5 preferring GABA-PAM • JNJ-40411813 - mGluR2 PAM • XEN901 - Selective Nav1.6 sodium channel blocker • XEN1101 - K+ Channel opener *Presented at Eleventh Eilat Conference (April 6-10, 2012)
20 Novel mechanisms • To date, novel mechanisms have not translated into better efficacy or tolerability
21 Antiepileptic drug? • ILAE is considering an “official” name change for the venerable Antiepileptic Drug, dividing drugs into: - Anti-seizure medication (ASM) - Disease modifying Epilepsy Medication (DMEM) • This is to highlight that most medications do not alter the course of epilepsy and are essentially “symptomatic therapy”. - What does this mean? Anti-seizure medicine: like treating a cough Disease modifying medicine: Like treating pneumonia
22 Can we predict a better drug? • A drug could differentiate in a number of important ways: - Disease modifying - Targeted at a specific population - Clear and indisputable advance in treating resistant epilepsy - Seizure freedom - Better tolerability - Less issues for women of childbearing potential - Specific efficacy in difficult syndromes (eg Dravet, Lennox-Gastaut) - Longer acting
23 Seizure freedom is important • In add-on studies, less than 5% of subjects are able to obtain seizure freedom, even for the 3 months of randomization • There is a great opportunity to develop a new therapy that increases rate of seizure freedom, or even 75-90% seizure reduction
24 But it all comes down to risk vs benefit • Don’t forget that the balance of adverse effects/risk of harm to benefit is important, even to individuals with treatment resistant epilepsy Source: h.fraimow
25 Can better side effect profile lead to better efficacy? % achieving Seizure Freedom Dose Toxicity 10 40 20 50 30 Maximum Benefit
26 Precision therapy? • Recent studies of emerging anti-seizure drugs in orphan diseases - Dravet syndrome • Fenfluramine • Cannabidiol - Lennox-Gastaut syndrome • Clobazam (US) • Rufinamide • Cannabidiol • Fenfluramine • Is this “precision medicine”? - To date, these studies have only determined the drug under study is more effective than placebo in a specific syndrome. - The studies have not proven either that the drug is more effective than other potential therapies, or that the drug will be more effective for this syndrome than for any other syndrome tested.
27 Precision therapy with Disease Modifying Epilepsy Medications (DMEM) • Targeted drugs (The hope for the future) - Correct pathology caused by a specific mutation or mutations - Everolimus and Tuberous sclerosis complex (TSC) • A mutation in TSC1 or TSC2 causes hyperactivity of the mammalian target of rapamycin (mTOR) pathway. • Everolimus “normalizes” mTOR pathway, and is truly a “targeted” treatment for TSC - Targeted genetic therapies • Gene replacement therapies • Anti-sense oligonucleotides (ASO’s)-In genetic diseases with “haploinsufficiency” (one bad gene copy) can eliminate nonsense protein from “bad” MRNA, allow good copy to take over production Mutated DNA Copy Mutated proteins
28 Do epilepsy patients represent a satisfied market? • In one word, No! • Many issues with existing ASMs • 1/3 continue to have seizures • 1/3 (by estimation) have dose-related side effects • No disease modifying treatments
29 Do neurologists treating epilepsy patients represent a satisfied market? • In a word, No! • All but 3 of the new ASMs either: - require long titration with complex instructions or - Have complicated pharmacokinetic interactions • Many patients continue to have seizures • Many ASMs have potential for life-threatening interaction • Co-morbidities such as depression, cognitive dysfunction not addressed
30 Praxis Epilepsy Innovation Strategy Steve Petrou, Co-founder and CSO
31 WHY EPILEPSY? WHY NOW?
32 Carolyn • 16 yrs – early morning tonic clonic seizures, myoclonus • 23 yrs-psychosis Our understanding of the genetics of epilepsy has come a long way in the eighty years since Lennox Lennox series (studied 1941) Eleanor • 17 yrs – early morning tonic clonic seizures, myoclonus • 22 yrs-psychosis
33 What distinguishes epilepsy, if anything? Very common Migraine, Depression Common Epilepsy, Autism, Schizophrenia, Alzheimer’s Disease Not common Multiple Sclerosis, Motor Neuron Disease etc. Essentially all neurological disorders have complex genetic inheritance
34 Today, the field has an outsized understanding of epilepsy genetics relative to other CNS (and non-CNS) diseases Perucca et al. Annu Rev Genomics Hum Genet 2020 OMIM: Online Mendelian Inheritance in Man ; a catalog of human genes and genetic disorders
35 Today, the field has an outsized understanding of epilepsy genetics relative to other CNS (and non-CNS) diseases Perucca et al. Annu Rev Genomics Hum Genet 2020 OMIM: Online Mendelian Inheritance in Man ; a catalog of human genes and genetic disorders
36 Classes of genes identified in genetic epilepsy are critical to other neurological disorders Adapted from Ellis CA, Petrovski S, Berkovic SF. Epilepsy genetics: clinical impacts and biological insights, The Lancet Neurology, Volume 19, Issue 1, 2020, Pages 93-100 Ion channels mTOR pathway Synaptic support Chromatin regulation
37 Framework for evaluating each epilepsy gene and new opportunities for therapy development EF FE C T S IZ E (O D D S R A T IO ) ALLELE FREQUENCY Rare Large effect size Common Small effect size Rare Small effect size Common Large effect size
38 The majority of epilepsy-causing variants fall within these two quadrants EF FE C T S IZ E (O D D S R A T IO ) ALLELE FREQUENCY Rare Large effect size Common Small effect size 1 2 Rare Small effect size Common Large effect size Rare monogenic epilepsies Common polygenic epilepsies
39 Current understanding of the landscape of genetic and acquired epilepsies P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES
40 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES GABAergic system genetically implicated in both epilepsy and mood disorders with separate roles for phasic and tonic inhibition PRAX-114 GABA Epilepsy
41 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES CACNA1G genetically implicated in epilepsy and tremor and ataxia due to involvement in neurophysiological rhythm generation common to seizures movement disorders PRAX-944 CACNA1G PRAX-114 Epilepsy
42 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES PRAX-222 PRAX-562 PRAX-020 PRAX-030 PRAX-080 PRAX-090 PRAX-100 RARE EPILEPSIES Epilepsy PRAX-944 PRAX-114
43 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES PRAX-222 PRAX-562 PRAX-020 PRAX-030 PRAX-080 PRAX-090 PRAX-100 PRAX-944 PRAX-114 Treatment of focal onset epilepsy requires next generation sodium channel blockers designed with activity dependence PRAX-628 Epilepsy
44 Non-Epilepsy Praxis targeting the largest and untapped segment Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES PRAX-944 PRAX-114 Praxis future pipeline exploiting new genetics of common epilepsy Epilepsy PRAX-222 PRAX-562 PRAX-020 PRAX-030 PRAX-080 PRAX-090 PRAX-100 PRAX-628
45 TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE TARGETS IDENTIFIED THROUGH GENETICS These three imperatives guide our epilepsy portfolio build PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE PRAX-944 SMALL MOLECULE PRAX-114 SMALL MOLECULE Focus on nodes of pathophysiological convergence informed by genetics Focus on implicated genes in common diseases *PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. PRAX-080* ASO PRAX-100 * ASO PRAX-020 SMALL MOLECULE PRAX-090* ASO PRAX-030 SMALL MOLECULE PRAX-222* ASO Focus directly on underlying genetic defects in rare epilepsy
46 Our Science in Action Steve Petrou, Co-founder and CSO
47 Leveraging our understanding of genetics to discover and develop therapies enabled by a translational toolkit and strategic collaborations DEVELOPMENT INFORMED BY TRANSLATIONAL TOOLS MULTISCALE DISEASE MODELS: Molecular, Neuronal, Network, Brain, Behavior BIOMARKERS: qEEG, Biofluids, Endophenotypes PATIENT STRATIFICATION: Genomics, Informatics, Functional genomics STRATEGIC COLLABORATIONS
48 Focus on nodes of pathological convergence informed by genetics
49 Voltage-gated sodium channels (NaV) are the key arbiters of neuronal excitability in the CNS Debanne, D., Campanac, E., Bialowas, A., Carlier, E. and Alcaraz, G., 2011. Axon physiology. Physiological reviews, 91(2), pp.555-602. Nav1.1 Nav1.1
50 Persistent sodium current (INa) is a critical driver of pathological hyperexcitability in the CNS disorders
51 SCN8A GoF DEE patients have elevated persistent INa Increased persistent INa in patient neurons (P1, P2) relative to control (C2)
52 SCN2A GoF DEE patients have elevated persistent INa Increased persistent INa in disease neurons relative to WT
53 • Praxis sodium channel “functional” selectivity drug discovery program • Design molecules with in vitro profile including • preference for persistent current • rapid binding and unbinding kinetics • Goal is to selectively dampen hyperexcitable neuronal activity sparing physiological activity to enhance tolerability and allow higher dosing for better efficacy “Next generation” sodium channel blocker program at Praxis No drug Drug o u tp u t input
54 PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE Genetics SCN8A gain-of-function SCN2A gain-of-function TSC +other DEEs US Diagnosed Prevalence >10,000 patients* Symptoms Early-onset seizures Developmental delay Intellectual disability Treatment Refractory to symptomatic agents *Lead indications only
55 Standard NaV blockers do not preferentially target disease-state hyperexcitability, driving limiting side effect profile Source: Praxis data on file “NaV Fingerprint” Persistent INa Inhibition Peak INa, UDV-10Hz (Disease-State Dependence) Inhibition Peak INa, Tonic Block Inhibition 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N a V 1 .6 Lamotrigine (LTG) 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N a V 1 .6 Carbamazepine (CBZ)LAMOTRIGINE CARBAMAZEPINE
56 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N a V 1 .6 Carbamazepine (CBZ) We discovered PRAX-562 as a more potent and selective persistent INa blocker, more disease-state selective, with a wider therapeutic window Source: Praxis data on file 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N a V 1 .6 Lamotrigine (LTG)LAMOTRIGINE CARBAMAZEPINE 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N a V 1 .6 PRAX-562AX-562 “NaV Fingerprint” Persistent INa Inhibition Peak INa, UDV-10Hz (Disease-State Dependence) Inhibition Peak INa, Tonic Block Inhibition
57 % INHIBITION OF hNaV1.6 PERSISTENT INa (SAME DATA AS ON PRIOR SLIDE) 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) % I n h ib it io 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
58 MES EFFICACY sLMA TOLERABILITY Veh 10 20 40 0 10000 20000 30000 40000 50000 60000 70000 T o ta l D Is ta n c e T ra v e ll e d ( m m ) ** ** Veh 0.3 1 3 10 0 20 40 60 M E S L a te n c y ( s e c ) ** ** 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
59 IN VIVO POC IN SCN2A SPONTAEOUS 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% P ro p o rt io n w it h S e iz u re s 100% 50% 0% % C h a n g e in S e iz u 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 **
60 IMPROVES SCN2A GoF SURVIVAL1 IMPROVES SCN8A GoF SURVIVAL2 0 100 200 300 0 50 100 Age (days) % S u rv iv a l Control Tool compound 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 90 100 Age (days) % S u rv iv a l Control Tool compound Modulating persistent current increases survival in the same genetic models *p<0.005; n=18-20 per group; Cox proportional hazards model **p<0.001; n=29-32; Mantel-Cox log-rank test 1)Q54 GoF mice. 2)N1768D D/+ mice. Start Start dose Withdrawal * ** Data indicates PRAX-562 mechanism is disease modifying
61 PRAX-562 is highly efficacious in KCNQ2 and KCNC1 DEE models 1WT and KCNQ2 +/K556E mice were treated with PRAX-562 at 10 mg/kg or vehicle 1-hr prior to PTZ injection (100 mg/kg s.c.); N=10 per group 2N=10-14 per group Source: Praxis data on file. KCNQ2 K556E PTZ SEIZURE MODEL1 KCNC1 R320H PTZ SEIZURE MODEL2 0 5 10 15 20 25 0 50 100 Time to seizure with hind limb extension (min) % W it h o u t s e iz u re s Kcnq2 +/- VC Kcnq2 +/- PRAX-562 10mg/kg 0 10 20 30 40 50 0 50 100 Time to seizure with hind limb extension (min) % W it h o u t s e iz u re s Kcnc1 +/- VC Kcnc1 +/- PRAX-562 10mg/kg
62 PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE Disease Adult focal epilepsy US Diagnosed Prevalence ~2,000,000 patients (most common type of epilepsy) Symptoms Focal motor and non-motor seizures Treatment Anti-epileptic drugs (AEDs) >30% refractory to available AEDs
63 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, M % I n h ib it io n o f h N a V 1 .6 Lamotrigine (LTG) 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N a V 1 .6 Carbamazepine (CBZ) LAMOTRIGINE CARBAMAZEPINE 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, µM % I n h ib it io n o f h N a V 1 .6 PRAX-628 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N 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
64 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) U n b o u n d P la s m a C o n c . n g /m L PRAX-628: 36 hr predicted half-life PRAX-562: >120 hr predicted half-life
65 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 E S L a te n c y ( s e c ) ** ** 0 20000 40000 60000 80000 100000 T o ta l D is ta n c e T ra v e ll e d ( m m ) Veh 3 5.6 10 20 ** **
66 Focus directly on underlying genetic defects in rare epilepsy
67 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics SCN2A gain-of-function US Diagnosed Prevalence 1,500 patients Symptoms Early-onset, fatal seizures Severe movement disorders Global developmental delay Intellectual disability Treatment No therapies approved Refractory to symptomatic agents
68 PRAX-222 is an ASO designed to down-regulate SCN2A expression in patients with gain-of-function mutation
69 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 g ED50: 33 µg ED80: 170 µg ASO-Ctrl WT ASO-Ctrl Q/+ ASO-811 Q/+ 0 200 400 600 N o rm a li z e d a c ti n **** ASO-CTRL ASO-SCN2AASO- TRL / WT MOUSE SCN2A GOF R1883Q/+ MOUSE ASO-SCN2A 10 µm Nav1.2 AnkG ASO-CTRL
70 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION A single dose of PRAX-222 increases survival well beyond standard of care 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 u rv iv a l **** **** ASO injection (icv, P1)
71 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION RE-DOSING SIGNIFICANTLY EXTENDS SURVIVAL A second dose of PRAX-222 significantly extends survival of SCN2A GoF mice 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 u rv iv a l **** **** ASO injection (icv, P1) SCN2A GOF model 0 50 100 150 200 0 25 50 75 100 Postnatal day % s u rv iv a l **** *** ASO-Ctrl (n=11) ASO-SCN2A ED80 (n=13) ASO-SCN2A ED50 (n=15) ***p<0.001 ****p<0.0001 All experiments conducted with SCN2A R1882Q mouse model ASO injections (icv, P1, P28)
72 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION RE-DOSING SIGNIFICANTLY EXTENDS SURVIVAL ADMINISTRATION POST-DISEASE ONSET ALSO EXTENDS SURVIVAL PRAX-222 also extends survival of SCN2A GoF mice if first administered later in life, well after disease onset 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 u rv iv a l **** **** ASO injection (icv, P1) SCN2A GOF model 0 50 100 150 200 0 25 50 75 100 Postnatal day % s u rv iv a 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 u rv iv a l **** **** ASO-Ctrl (n=8) ASO-SCN2A ED80 (n=15) ASO-SCN2A ED50 (n=15) ASO injection (icv, P15) ***p<0.001 ****p<0.0001 All experiments conducted with SCN2A R1882Q mouse model
73 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics KCNT1 gain-of-function US Diagnosed Prevalence ~1,250 patients Symptoms Intractable infantile-onset seizures Developmental plateau, regression Psychiatric and behavioral problems Treatment No therapies approved Refractory to symptomatic agents
74 PRAX-020 is a small molecule designed to selectively inhibit KCNT1 GoF variants Source: Praxis data on file. -4 -3 -2 -1 0 1 2 0 50 100 PRAX-020 Inhibition of KCNT1 GoF Variants Concentration (M) % I n h ib it io n
75 PRAX-020 REDUCES SEIZURES* …AND DECREASES INTERICTAL SPIKE FREQUENCY PRAX-020 eliminates seizures in KCNT1 transgenic mice and suppresses interictal spikes *In 24 hours Source: Praxis data on file. PRAX-020 Dose (mg/kg, PO) Veh Low dose High dose -100 -50 0 50 100 M e a n % C h a n g e f ro m B L Seizures -6 0 6 12 18 24 0 1 2 3 Time (h) Post Dose R e la ti v e S p ik e C o u n t N o rm a li z e d t o 2 4 h B a s e li n e Veh High dose Low dose p= 0.0796 CD-1 mice; (n=12 veh, n=5- 7/group PRAX) ANOVA/Dunnett (vs. veh)
76 PRAX-020 KCNT1 inhibition may translate to rescue of behavioral and cognitive phenotype Source: Praxis data on file. 24 48 0 2 4 6 Nesting score Time (hrs) N e s ti n g S c o re Vehicle (n=7) PRAX-020 (n=9) ns ✱✱ No nesting Nesting
77 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics X-linked, PCDH19 dominant-negative US Diagnosed Prevalence 2,250 patients, mostly females Symptoms Intractable refractory seizure clusters Intellectual disability Behavioral deficits Impaired executive function Treatment No therapies approved Refractory to symptomatic agents
78 In PCDH19, hemizygous null patients and hemizygous non-mosaic male carriers are asymptomatic and preserve ability to form normal neuron networks Source: Beyond the Ion Channel; Depienne C. et al PLOS Genetics (2009) Wild-type PCDH19 Variant PCDH19 Normal sorting Same adhesion properties Unaffected individual (male or female) Healthy Hemizygous null patients HealthyNo PCDH19 No PCDH19 Normal sorting Same adhesion properties Hemizygous non-mosaic male carriers Healthy Abnormal sorting Different adhesion properties PCDH19 patients (female and mosaic males) PCDH19 Disease 1 2 3 4
79 We aim to knock down PCDH19 to restore cell-cell adhesion and rescue phenotype Source: Beyond the Ion Channel; Depienne C. et al PLOS Genetics (2009) Wild-type PCDH19 Variant PCDH19 Normal sorting Healthy HealthyNo PCDH19 Normal sorting Healthy Abnormal sorting PCDH19 Disease PCDH19 ASO therapy treatment outcome
80 PCDH19 ASO MRNA KNOCKDOWN Hits identified achieve >90% in vitro knockdown PCDH19 mRNA Source: Data on file. On track to deliver lead candidate in 2023 0 20 40 60 80 100 0 20 40 60 80 100 % B a s e lin e P C D H 1 9 m R N A Low dose High dose >90% knockdown
81 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics SYNGAP1 loss-of-function US Diagnosed Prevalence 1,600 patients Symptoms Intellectual disability Early-onset, refractory seizures Behavioral deficits Treatment No therapies approved Refractory to symptomatic agents
82 SYNGAP1 is a synaptic RAS GTPase activating protein Source: Weldon, M. et al . Journal of Neurodevelopmental Disorders. (2018)
83 Re-expression of SYNGAP1 in adult mice improves measures of seizure and memory Source: Creson et al., eLife (2019) Improvements in: SYNGAP1 restoration EEG ✓ Seizures ✓ Memory ✓ SYNGAP1 haploinsufficiency is the cause of disease, so ASO-mediated up-regulation could rescue disease phenotype
84 Hits identified achieve approx. 3-fold improvement in SYNGAP1 expression Source: Data on file. SYNGAP1 ASO MRNA UP-REGULATION On track to deliver lead candidate in 2023 1.5x 2.5x 0.5x 2.0x 1.0x 3.0x Top ASOs Avg. fold change in SYNGAP1 expression Up-regulation Down-regulation
85 Focus on implicated genes in common diseases
86 PRAX-114 SMALL MOLECULE PRAX-944 SMALL MOLECULE TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE Imputed - Current Direct - Future
87 PRAX-114 SMALL MOLECULE PRAX-944 SMALL MOLECULE TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE In development for MDD, PTSD, and ET, but inspired by the role of the GABAA receptor in epilepsy
88 GABAA receptors with delta (δ) subunit dysfunction give rise to epilepsy Source: Dibbens, L.M. et al. Human Mol Genet. (2004)
89 PRAX-114 preferentially potentiates the delta (δ) subunit of the GABAA receptor, which sits in the extrasynaptic space Source: Dibbens, L.M. et al. Human Mol Genet. (2004); Praxis data on file 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 Synaptic GABAA Receptor Extrasynaptic GABAA Receptor
90 PTZ-INDUCED TONIC SEIZURES PTZ-INDUCED CLONIC SEIZURES PRAX-114 protects 100% of animals from PTZ-induced tonic and clonic seizures PRAX-114 has demonstrated anti-seizure effect in preclinical epilepsy models Source: Praxis data on file. Veh1 VPA Veh2 3 10 30 0.0 0.2 0.4 0.6 0.8 1.0 N u m b e r o f S e iz u re s PRAX-114 (mg/kg, PO) ** CD-1 mice (n=12/group) t-test (VPA) ANOVA/Dunn (PRAX) *p<0.05 vs. Veh **p<0.01 vs. Veh **** * Veh 1 VPA Veh 2 3 10 30 0 1 2 3 4 5 N u m b e r o f S e iz u re s PRAX-114 (mg/kg, PO) ** CD-1 mice (n=12/group) t-test (VPA) ANOVA/Dunn (PRAX) **p<0.01 vs. Veh ****
91 PRAX-114 SMALL MOLECULE PRAX-944 SMALL MOLECULE TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE Direct - Future
92 GWAS studies have elucidated common polygenic risk variants among genetic generalized epilepsy patients (N=15,212 epilepsy cases; 3,769 GGE) Polygenic risk variants are those above the line • SCN1A • KCNN2 • GABRA2 • PCDH7 • PNPO • GRIK1 MANHATTAN PLOT FOR GWAS ANALYSIS OF GENETIC GENERALIZED EPILEPSY Genome-wide significance threshold
93 Disruption potential comparable to bi- and tri-specific antibodies in immuno-oncology space Source: Suurs, F. V. et al. Pharmacology & Therapeutics. (2019); Ma, J., et al. Front Immunol. (2021) Dozens of bispecific antibodies in clinical development Emerging clinical data show polyspecific antibodies produce greater efficacy by targeting multiple tumor antigens at once
94 TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE TARGETS IDENTIFIED THROUGH GENETICS These three imperatives guide our epilepsy portfolio build PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE PRAX-944 SMALL MOLECULE PRAX-114 SMALL MOLECULE Focus on nodes of pathophysiological convergence informed by genetics Focus on implicated genes in common diseases *PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. PRAX-080* ASO PRAX-100 * ASO PRAX-020 SMALL MOLECULE PRAX-090* ASO PRAX-030 SMALL MOLECULE PRAX-222* ASO Focus directly on underlying genetic defects in rare epilepsy
95 Unmet Needs in Epilepsy Management Jacqueline French, MD NYU School of Medicine Perspectives from Clinical Practice: Shortcomings of existing treatment landscape provide opportunities for differentiation Daniel Friedman, M.D., MSc.
96 Disclosures • Receive salary support from the Epilepsy Study Consortium (which has received funding from multiple pharmaceutical companies including Biogen, Cerivell, Crossject, Eisai, Engage, SK Lifesciences, Xenon, Zynerba) • Consultant for Eisai, Neurelis • Research support from Empatica, Epitel, Epilepsy Foundation, NIH, CDC, NSF • Honorarium/Travel from Medtronics, Eisai, Epilepsy Foundation • Scientific advisor board: Receptor Life Sciences • Ownership interest: Neuroview Technology, Receptor Life Sciences
97 Case presentation • 28 year old woman with a history of depression presents to the office after an ER visit for a witnessed convulsive seizure. • Evaluation in the emergency room was unremarkable. • Upon careful history taking, for several years she has had rare episodes where she hears a “buzzing” in her ears and then feels confused for a few seconds that she attributed to panic attacks. • An MRI and EEG are ordered….
98 Case presentation Focal cortical dysplasia Left temporal spikes
99 Navigating therapeutic choices • Patient is diagnosed with epilepsy • Next step is symptomatic treatment – prevention of recurrent seizures − To reduce risks of mortality from seizures- accidents, drownings, SUDEP − To reduce risks of morbidity from seizures- fractures, burns, long term cognitive and psychiatric changes − To improve quality of life, allow for safe driving • How do we pick an anti-seizure medication?
100 ASMs for common epilepsies – Where are we now? Adapted from Loscher & Schmidt Epilepsia 2011 GEN1 GEN2 1. Kwan P and Brodie MJ. N Engl J Med. 2000 2. Brodie et al , Neurology, 2012 64% sz-free1 68% sz-free2
101 Despite the high number of marketed ASMs, more choices are needed 28 yr old woman with depression and new onset focal epilepsy Phenobarbital Phenytoin Carbamazepine Valproate Gabapentin Felbamate Lamotrigine Vigabatrin Topiramate Oxcarbazepine Leviteracetam Zonisamide Pregabalin Lacosamide Clobazam Ezogabine/Retigabine Eslicarbazepine Perampanel Brivaracetam Cenobamate
102 Who is on oral contraceptives and is concerned about weight gain 28 yr old woman with depression and new onset focal epilepsy Phenobarbital Phenytoin Carbamazepine Valproate Gabapentin Felbamate Lamotrigine Vigabatrin Topiramate Oxcarbazepine Leviteracetam Zonisamide Pregabalin Lacosamide Clobazam Ezogabine/Retigabine Eslicarbazepine Perampanel Brivaracetam Cenobamate Despite the high number of marketed ASMs, more choices are needed
103 Who is on oral contraceptives and is concerned about weight gain 28 yr old woman with depression and new onset focal epilepsy Phenobarbital Phenytoin Carbamazepine Valproate Gabapentin Felbamate Lamotrigine Vigabatrin Topiramate Oxcarbazepine Leviteracetam Zonisamide Pregabalin Lacosamide Clobazam Ezogabine/Retigabine Eslicarbazepine Perampanel Brivaracetam Cenobamate Who wants to have children in the near future Despite the high number of marketed ASMs, more choices are needed
104 Where is there room for improvement? Outcome of interest Target of current therapy Kerr Acta Neurologica 2012
105 Where is there room for improvement? Kerr Acta Neurologica 2012
106 Efficacy -2 -1 0 1 2 3 4 5 6 7 8 seizure free 75-99% reduction 50-74% reduction 0-50% reduction Seizures and QOL in DRE change in QOLIE31 change in QOLIE89 Seizure freedom is perhaps the largest single driver of QOL in patients with DRE focal epilepsy From Birbeck et al, Epilepsia 2002
107 Where is there room for improvement? Kerr Acta Neurologica 2012
108 Tolerability Type Examples Acute, predictable (related to mechanisms of action), serum concentration dependent, common Fatigue, vertigo, ataxia, CNS depression, cognitive changes, diplopia, tremor, mood changes Acute, unpredictable (related to individual vulnerability), rare Rash, immunological reactions, liver toxicity, bone marrow toxicity, aseptic meningitis Chronic, related to cumulative exposure, common, predictable Bone density loss, weight changes, neuropathy, visual field changes, gingival hyperplasia, connective tissue disorder Pharmacodynamic and kinetic drug interactions, predictable Added CNS toxicity, decreased OCP effectiveness, hepatotoxcity • Medication side effects are significant burden for people with epilepsy • Adverse events are a large contributor to negative QOL • Multiple types of intolerability:
109 Teratogenicity & neurodevelopmental outcomes Rates of major congenital malformations for ASMs in monotherapy from 3 prospective registriesInsufficient data for newer ASMs like lacosamide, perampanel, brivaracetam Tomson et al, Curr Opinion Neurol 2019
110 Where is there room for improvement? Kerr Acta Neurologica 2012
111 Comorbidities • Depression, anxiety, memory disturbance are common focal/IGE epilepsy comorbidities • More common among drug- resistant patients • Causes include: • Seizures • Medication effects • Underlying biological abnormalities leading to epilepsy Keezer et al Lancet Neurol 2016
112 Where is there room for improvement? Kerr Acta Neurologica 2012
113 Disease modification Current therapies are symptomatic – treat seizures & not underlying disorder • Do not address the underlying mechanisms that lead to altered seizure thresholds, comorbid symptoms • Need to be taken chronically No treatments: • Alter the underlying mechanism leading to increased seizure susceptibility • Prevent epilepsy after a high-risk injury • Turn drug-resistant epilepsy into drug- sensitive epilepsy
114 Promise of identifying novel targets for therapy • Improved efficacy • Disease modification - remittance of epilepsy, change DRE -> treatment responsive • Modify comorbidities • Improve tolerability • Limit off target effects and neurodevelopmental outcomes
115 Conclusions Despite 18+ marketed ASMs for focal and generalized seizures, options fall short for many patients with common epilepsies, too • Lack of efficacy • Intolerable side effects • Limited choices for women who may become pregnant • Burden of daily of medication taking Shortcomings of available ASM present opportunities for differentiation of new therapies
116 Accelerating Path towards Registration Bernard Ravina, CMO
117 PRAX-222 (SCN2A) PRAX-562 (SCN2A, SCN8A, TSC, +other DEEs) PRAX-628 (FOCAL EPILEPSY) Advancing best-in-class therapies for epilepsies
118 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
119 Patients experience significant seizure burden from birth Note: each horizontal line corresponds to a unique patient identifier. Patient record demographics (N=15): 7 males, 8 females. Average age of seizure onset at 5.1 days (range: 1-44 days). Source: Praxis data on file. EARLY ONSET SCN2A SEIZURE HISTORY PER PATIENT
120 Significant burden of disease through lifetime of early onset SCN2A patients ASM: Antiseizure Medications Note: Hospital Duration is the mean total days in hospital for all patients over the duration of the medical records. Source: Praxis data on file. MEDICATIONS DIAGNOSTIC & THERAPEUTIC PROCEDURES HOSPITALIZATIONS HOSPITALIZATION DURATION (DAYS) 14.5 26.3 First Year of Life Lifetime 21.1 40.0 First Year of Life Lifetime 4.3 10.9 First Year of Life Lifetime 69.1 98.6 First Year of Life Lifetime Avg. of 9 unique ASMs (range 2-14) alone in first year Median 17 days in hospital per year
121 IEDS DETECTED IN 11-YEAR-OLD WITH EARLY ONSET SCN2A MEDIAN IED BURDEN PER EEG Patient-guided insights drive development, such as EEG measure of interictal epileptiform discharges (IEDs) 0- 2m 2m -6 m 6m -1 y 1y -2 y 2- 4y 4- 8y 8- 16 y 0 10 20 30 40 50 60 Age IE D b u rd e n Early Onset SCN2A DEE (N=12) Age-matched Healthy Controls (N=1,249) Source: Praxis data on file.
122 Design principles for the PRAX-222 seamless trial submitted to FDA Seamless Placebo-controlled Patient Population Statistical considerations Endpoints Dose Multiple parts to identify and confirm a safe, efficacious dose and optimize dosing schedule Placebo controlled, with confirmatory phase design parameters informed by earlier phase Pediatric patients with confirmed SCN2A variant and baseline threshold of countable seizures Each patient contributes data to more than one stage of the study Collect data on seizure frequency and neurodevelopment, cognition assessments Dose, escalation, and dosing interval informed by clinical safety data and a priori rules
123 Simulated mRNA knockdown in human cortex in pediatric patients Safely 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 Median and 95% prediction interval illustrated Target knockdown 100 80 60 40 Source: Praxis data on file.
124 Next steps for PRAX-222 Clinical Program • Further characterize the population • Quantify EEG seizure burden, IED, variability in seizure frequency as potential biomarker Enroll observational study Ongoing Initiate PRAX-222 Seamless Study Mid-2022 • Assess safety, tolerability, PK and efficacy of ascending doses in pediatric patients (aged 2-18 yrs) with early onset SNC2A DEE Observational study: https://www.scn2a.com
125 Preclinical and emerging clinical data demonstrate PRAX-562 will 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 translating to superior safety and efficacy PRAX-562 SCN2A, SCN8A, TSC, +other DEEs PAN-NAV BLOCKER SMALL MOLECULE
126 PRAX-562 path to rapid clinical proof of concept in DEEs PHASE 1 HEALTHY VOLUNTEERS SAD/MAD, ASSR Biomarker w/ 14-day Treatment Duration PHASE 2 DEEs (SCN2A, SCN8A, and TSC) Seizure Reduction, Safety PHASE 1 HEALTHY VOLUNTEERS PK, ASSR Biomarker w/ 28-day Treatment Duration TO BE INITIATED 2H22TOPLINE REPORTED 4Q21 • Well tolerated with no MTD at exposures above therapeutic range (EC50) • Approximately 4-5 day half life • Dose dependent reduction in ASSR READOUT IN 2Q22 • No MTD at exposures multiple fold above therapeutic range (EC50) • PK approaches steady state after 28 days Targeting efficient path to registration
127 PRAX-562 EXPOSURES ON DAY 1 EXPOSURES AT 28 DAYS, WELL ABOVE PREDICTED THERAPEUTIC EXPOSURE* PRAX-562 in healthy volunteers safely exceeds projected therapeutic exposure 0 2 4 6 8 10 12 14 16 18 20 22 24 10 10,000 100 1,000 120mg 90mg 45mg 30mg Mean PRAX-562 Concentration (ng/mL) Time Post-Dose, Day 1 (hours) MES-derived EC50 MES-derived EC90 10 100 1,000 10,000 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Mean PRAX-562 Concentration (ng/mL) Time Since First Dose (Days) 90mg Cmax 90mg Ctrough *Preliminary data from 562-102 study from first 12 participants enrolled in the study; CMax is representative of concentration at 2.5 hours post-dose. Source: Praxis data on file.
128 SCN8A DEE patients experience significant disease burden SCN8A SEIZURE HISTORY PER PATIENT Source: Praxis data on file.
129 SCN8A DEE patients experience significant disease burden MEDICATIONS DIAGNOSTIC & THERAPEUTIC PROCEDURES HOSPITALIZATIONS HOSPITALIZATION DURATION (DAYS) 6.6 17.6 LifetimeFirst Year of Life 9.3 27.6 First Year of Life Lifetime 3.3 9.9 First Year of Life Lifetime 27.6 62.8 First Year of Life Lifetime Median 6 days in hospital per year Source: Praxis data on file.
130 PRAX-562 in DEEs: Path to clinical proof of concept Rapid proof of concept Endpoints Initial patient population Open-label to identify a safe, efficacious dose and optimize dosing schedule in patients Collect data on seizure frequency and neurodevelopment, cognition assessments Pediatric patients with confirmed SCN2A, SCN8A, or TSC and baseline threshold of countable seizures
131 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
132 PRAX-628 clinical development program for focal epilepsy IND-ENABLING TOX 28-day GLP Tox PHASE 2 FOCAL EPILEPSY Seizure Reduction, Safety PHASE 1 HEALTHY VOLUNTEERS SAD/MAD, ASSR Biomarker w/14-day Treatment Duration ONGOING TO BE INITIATED 4Q22 TO BE INITIATED 2023
133 PRAX-222 (SCN2A) PRAX-562 (SCN2A, SCN8A, TSC) PRAX-628 (FOCAL EPILEPSY) Three epilepsy drugs in clinic by end of 2022 Initiate Seamless Study: Mid-2022 Initiate Phase 2 Study: 2H22 Initiate Phase 1 Study: 4Q22 PRAX-222 and PRAX-562 received Orphan Drug Designations for severe pediatric epilepsy indications from the FDA and EMA, and Rare Pediatric Disease designation from the FDA
134 Developing New Classes of Treatments INSPIRED BY THE GENETICS OF EPILEPSY PSYCHIATRY GABRB3 KCNT1 SCN1A CACNA1A KCNA1 SLC1A3 SETX RFC1 CACNA1G GABRB3 KCN1A SCN8A SCN2A DRD3 HTT FMR1 OPA1 SYNGAP1 SHANK3 TPH2 FKBP2 HTR2A CDKL5 DNM1 UNC79 TRIM3 PCDH19 CACNA1A EPILEPSY MOVEMENT
