8-K
Supernus Pharmaceuticals, Inc. (SUPN)
8-K
2023-10-18
For: 2023-10-18
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UNITED STATES
SECURITIES AND EXCHANGECOMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13or 15(d) of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): October 18, 2023
Supernus
Pharmaceuticals, Inc.
(Exact name of registrant as specified in its charter)
| Delaware | 001-35518 | 20-2590184 | |
|---|---|---|---|
| (State or other jurisdiction of<br><br> <br>incorporation or organization) | (Commission<br> File Number) | (I.R.S.<br> Employer Identification No.) | |
| 9715 Key West Ave | Rockville | MD | 20850 |
| --- | --- | --- | --- |
| (Address<br> of Principal Executive Offices) | (Zip<br> Code) |
Registrant’s telephone number, including area code:
(301
) 838-2500
Not Applicable
(Former name or former address, if changed since last report.)
Securities registered pursuant to Section 12(b) of the Exchange Act
| Title of<br> each class | Trading Symbol | Name of each<br> exchange on which registered |
|---|---|---|
| Common<br> Stock, $0.001 par value per share | SUPN | The Nasdaq<br> Stock Market LLC |
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 (see General Instruction A.2. below):
¨ 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))
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). ¨
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 |
|---|
As previously announced, Supernus Pharmaceuticals, Inc. (“Supernus” or the “Company”) is hosting a Research and Development Day (“R&D Day”) today, October 18, 2023. During the R&D Day the Company will discuss and present an overview of the Company’s pipeline, with an emphasis on SPN-820/821, SPN-817 and new clinical candidates from Supernus’s discovery program. Information to access the live webcast is available at www.supernus.com in the Events & Presentations section within the Investor Relations section. The webcast will be archived on the Company’s website for 60 days following the live event. A copy of the presentation is furnished as Exhibit 99.1 hereto and is incorporated herein by reference.
The information in this Item 7.01 (including Exhibit 99.1) is being “furnished” and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, 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, whether made before or after the date of this report, except as shall be expressly set forth by specific reference in such filing.
This Current Report on Form 8-K contains “forward-looking statements” that do not convey historical information, but relate to predicted or potential future events, such as statements of our plans, strategies and intentions. These statements can often be identified by the use of forward-looking terminology such as “believe,” “expect,” “intend,” “may,” “will,” “should,” or “anticipate” or similar terminology. All statements other than statements of historical facts included in this Current Report on Form 8-K are forward-looking statements. All forward-looking statements speak only as of the date of this Current Report on Form 8-K. Except for Supernus’ ongoing obligations to disclose material information under the federal securities laws, Supernus undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. In addition to the risks and uncertainties of ordinary business operations and conditions in the general economy and the markets in which Supernus competes, the forward-looking statements of Supernus contained in this Current Report on Form 8-K are also subject to various risks and uncertainties, including those set forth in Item 1A, “Risk Factors,” in Supernus’ Annual Report on Form 10-K for the fiscal year ended December 31, 2022, and other risk factors set forth from time to time in the Company’s filings with the Securities and Exchange Commission made pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended.
| Item 9.01 | Financial Statements and Exhibits. |
|---|
(d) Exhibits
2
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| SUPERNUS PHARMACEUTICALS, INC. | ||
|---|---|---|
| DATED: October 18, 2023 | By: | /s/ Timothy C. Dec |
| Timothy C. Dec | ||
| Senior Vice President and Chief Financial Officer |
3
Exhibit 99.1
| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Supernus Pharmaceuticals<br>R&D Day<br>October 18, 2023<br>1 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Introduction and Agenda<br>2<br>Jack Khattar<br>President and Chief Executive Officer |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Safe Harbor Statement<br>3<br>This presentation and other matters discussed today or answers that may be given to questions asked include forward-looking statements within the meaning of the federal securities laws. These statements, among other things, relate to<br>Supernus’ business strategy, goals and expectations concerning its product candidates, future operations, prospects,<br>plans and objectives of management. The words “anticipate”, “believe”, “could”, “estimate”, “expect”, “intend”, “may”,<br> “plan”, “predict“, “project”, “will“, and similar terms and phrases are used to identify forward-looking statements in this<br>presentation. Supernus’ operations involve risks and uncertainties, many of which are outside its control, and any one of<br>which, or a combination of which, could materially affect its results of operations and whether the forward-looking<br>statements ultimately prove to be correct. Supernus assumes no obligation to update any forward-looking statements<br>except as required by applicable law.<br>Supernus has filed with the U.S. Securities and Exchange Commission (SEC) reports and other documents required by<br>Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended. Before you purchase any Supernus securities,<br>you should read such reports and other documents to obtain more complete information about the company’s<br>operations and business and the risks and uncertainties that it faces in implementing its business plan. You may get<br>these documents for free by visiting EDGAR on the SEC website at http://www.sec.gov. |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>AGENDA<br>Introduction<br>Corporate Overview<br>Product Candidates<br>SPN-820 – Depression<br>SPN-817 – Epilepsy<br>SPN-443 – ADHD/CNS<br>SPN-446 – Narcolepsy<br>General Q&A and Closing Comments<br>4 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Participants<br>5<br>Supernus Pharmaceuticals<br>Jack Khattar, MBA<br>President and Chief Executive Officer<br>Jonathan Rubin, M.D., MBA<br>SVP, Research and Development, Chief Medical Officer<br>Bryan Roecklein, Ph.D.<br>SVP, Corporate Development<br>Tim Dec<br>SVP, Chief Financial Officer<br>Advisor<br>Vladimir Maletic, M.D., M.S.<br>Clinical Professor, Neuropsychiatry<br>and Behavioral Science<br>University of South Carolina, School<br>of Medicine |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023E<br>147<br>93<br>12<br>215<br>302<br>409 393<br>520<br>Total Revenues ($ Millions)<br>580<br>Proven Commercial Execution & Growth Strategy<br>Total Portfolio Revenue Growth<br>667<br>Year-end 2018 inventory build by distribution channel increased 2018 net sales by<br>approximately $10 million and negatively impacted 2019 net sales.<br>* Guidance updated on August 3, 2023<br>580-620*<br>6<br>Trokendi XR®<br>LOE |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Robust CNS Pipeline to Drive Long-Term Growth<br>7<br>Program Indications Discovery Preclinical Phase 1 Phase 2 Phase 3 NDA Market<br>SPN-830 PD<br>SPN-820 Depression<br>SPN-817 Epilepsy<br>SPN-443 ADHD/CNS<br>SPN-446 Narcolepsy<br>SPN-448 CNS<br>PD = Parkinson’s Disease |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved. Development Cost<br>Strategic Overview<br>8<br>Low<br>High<br>Short Long<br>Low Risk High<br>Time to Market<br>Known Drugs<br>New Delivery<br>Clinically<br>Validated<br>Target<br>Clinically Non-Validated<br>Target<br>First in<br>Class<br>New<br>Chemical<br>Entities<br>Known Drugs<br>New Indication<br>New Market |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved. Market Value<br>Strategic Overview<br>9<br>Low<br>High<br>Oxtellar XR®<br>Trokendi XR ®<br>Clinically Non-Validated<br>Target<br>Qelbree®<br>Gocovri®<br>SPN-820<br>SPN-817<br>SPN-443<br>SPN-446<br>SPN-448<br>Short Time to Market Long |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved. Market Value<br>Strategic Overview<br>10<br>Low<br>High<br>Key Strategic Imperatives<br>Multi-Billion<br>Dollar Market<br>Value<br>Corporate<br>Development<br>Capitalize<br>on our<br>Strong<br>R&D<br>Capability<br>Complete<br>Development<br>and Launch<br>SPN-830<br>SPN-820<br>SPN-817<br>Build a<br>Multi-Billion<br>Dollar CNS<br>Franchise |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Significant Experience & Capabilities in Drug Development<br>11<br>Discovery<br>Concept<br>Validation<br>Safety<br>CMC<br>Drug<br>Candidate<br>Discovery Platform<br>Design and synthesis of<br>new compounds<br>based on structure,<br>function and disease<br>pathways<br>In vitro, PK,<br>preclinical proof of<br>concept, and<br>stability studies<br>Toxicology<br>In-house CMC/drug<br>delivery expertise &<br>GMP manufacturing<br>Validated drug<br>candidates |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>2023 2024 2025 2026<br>Supernus Near-Term Milestones<br>Above timelines represent management’s estimates that are subject to several factors that are beyond our control and actual<br>results may be significantly different from our estimates<br>12<br>SPN-830<br>Resubmission<br>SPN-830<br>Launch<br>SPN-820 Phase IIb<br>SPN-817 Phase IIa<br>SPN-443<br>Preclinical<br>SPN-443<br>IND<br>SPN-817 Phase IIb |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>13<br>Multi-Billion<br>Dollar Market<br>Value<br>Growth Potential of Existing Products<br>Qelbree® and GOCOVRI®<br>Innovative R&D Portfolio<br>SPN-830 Novel Infusion Device for PD<br>SPN-820 First in Class Novel MOA for Depression<br>SPN-817 First in Class Novel MOA for Epilepsy<br>SPN-443 Novel ADHD Stimulant with CIV Scheduling<br>Corporate Development<br>Positioned For<br>Continued Strong Growth |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Supernus Pipeline<br>14<br>Jonathan Rubin<br>SVP, Research and Development, Chief Medical Officer |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Qelbree®<br>Novel Non-Stimulant ADHD Product<br>15 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Co-administration of Qelbree with a Stimulant Provides<br>Incremental Efficacy<br>Phase IV, Open-Label, Flexible-Dose study in Children and Adolescents with ADHD<br>Primary Objective: Safety and tolerability when administered with stimulants<br>(methylphenidate or amphetamine) in children and adolescents with ADHD<br>Significant improvement from baseline ADHD-RS-5 & CGI-S scores<br>Well tolerated<br> ‒ Adverse events (AEs) included headache (17.9%), decreased appetite (12.5%), and upper<br>respiratory tract infection (10.7%)<br> ‒ 3.6% of patients discontinued due to an AE.<br>16<br>ADHD-RS-5 CGI-S<br>Baseline (BL); N=56 37.2 4.4<br>Week 4 change from BL; N=54 -13.5 -0.9<br>Week 8 change from BL; N=48 -18.2 -1.4 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Efficacy of Qelbree in Adults with ADHD and Mood Symptoms<br>60% of adults with ADHD have comorbid depression and 57% have comorbid anxiety<br>Viloxazine IR was approved in the EU for the treatment of depression<br>Phase IV, Open-label, decentralized clinical trial<br>Treatment period: 14 weeks. Qelbree 200-600mg/day. N= 750; 500 completers<br>Primary efficacy: Change from baseline in AISRS in adults with ADHD and comorbid mood<br>symptoms<br>Secondary:<br> ‒ Change from baseline in depressive symptoms (SIGMA and PHQ-8), anxiety symptoms (SIGH-A and GAD-7); work/home functioning (SDS), executive function (BRIEF-A), and sleep (PSQI)<br> ‒ Safety and tolerability<br>Expected to start 4Q 2023<br>17 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-830<br>Treatment of Hypomobility in Parkinson’s Disease<br>1818 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-830: Infusion Device Submission<br>Continuous treatment of motor fluctuations (OFF episodes) in Parkinson’s<br>disease (PD) patients that are not adequately controlled with oral levodopa<br>and one or more adjunct PD medications.<br> ‒ If approved, will give PD patients the option of a continuous daily infusion,<br>instead of “as needed” injections, with a goal of improvement in the<br>amount of ON time for patients<br>NDA resubmitted Oct 2023<br> ‒ Submission responds to FDA’s questions from Oct 2022 Complete<br>Response Letter<br>19 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820<br>First in Class, Unique Intracellular Mechanism to<br>Treat Depression<br>2020 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Depression Market Update<br>2121 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Depression – One of the Largest Therapeutic Areas with ~195M<br>Prescriptions in the U.S. per Year<br>1. NIMH Health Statistics 2. NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D Study)<br>2. Trials & Triumphs of Neuropsychiatry: TD Cowen Landscape Analysis and Key Themes<br>ADT = Antidepressant Treatment<br>22<br>Significant Number of Patients<br>do not Respond to Therapy1<br>39% refractory to first line<br>therapy<br>27% refractory to second line<br>therapy<br>32% refractory to third line<br>therapy<br>Prevalence of Major<br>Depressive Episodes in the<br>United States1<br>~21.0 million adults (~8.3%) had<br>at least one episode<br>Pandemic triggered a 25%<br>increase in prevalence<br>Gallup poll in May 2023 indicated<br>that 29% of all adults will be<br>diagnosed with depression in<br>their lifetime<br> – 36.7% , women; 20.4%, men<br>Slow Onset and Side Effects<br>are Prevalent Leading to<br>Switching or Discontinuation<br>ADTs can take up to 6 – 8 weeks<br>to reach efficacy2<br>~38% of patients experience one<br>or more side effects from SSRIs<br>(sexual and digestive)2<br>22 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Major Depressive Disorder (MDD) vs. Treatment Resistant<br>Depression (TRD)<br>23<br>DSM-5 classification with specific clinical criteria<br>Five or more symptoms during the same 2-week<br>period, at least one of the symptoms is (1)<br>depressed mood or (2) loss of interest or pleasure.<br>Depressed mood<br>Diminished interest or pleasure in activities<br>Significant weight loss<br>A slowing down of thought and a reduction of<br>physical movement<br>Feelings of worthlessness<br>Recurrent thoughts of death or recurrent<br>suicidal ideation (including plans or attempts)<br>Definition is evolving and disparate between<br>regulatory authorities and practitioners<br>FDA currently defines TRD as a failure of<br>2 or more antidepressants<br>HCPs consider TRD after the first failure<br>Regardless, payers require patients to<br>step through the older generic options<br>first<br>Major Depressive Disorder Treatment Resistant Depression<br>23 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Multiple MOAs for Treating Depression<br> • “Depression Only” TRx, Integrated IQVIA NPA & NMTA<br> • All trademarks are owned by their respective owners<br>24<br>Abbrev. Treatment Class/MOA/Description Depression<br>TRx*<br>% of<br>Total<br>Most Commonly<br>Prescribed Drug<br>SSRI Selective Serotonin Reuptake Inhibitor 60.4M 31.0% Sertraline (Zoloft®)<br>SARI Serotonin Antagonist and Reuptake Inhibitor 39.1M 20.0% Trazodone (Desyrel®)<br>NDRI Norepinephrine and Dopamine Reuptake Inhibitor 27.6M 14.1% Bupropion (Wellbutrin®)<br>SGA Second-Generation Antipsychotic (Atypical) 24.8M 12.7% Quetiapine (Seroquel®)<br>SNRI Serotonin and Norepinephrine Reuptake Inhibitor 20.7M 10.6% Duloxetine (Cymbalta®)<br>T3/T4 Tricyclic or Tetracyclic Antidepressant 18.5M 9.5% Mirtazapine (Remeron®)<br>5-HT/SSRI 5-HT1a Agonist and Serotonin Reuptake Inhibitor 3.9M 2.0% Vortioxetine (Trintellix®)<br>NMDA NMDA Antagonist 0.2M 0.1% Esketamine (Spravato®)<br>MAOI Monoamine Oxidase Inhibitor 65K 0.0% Tranylcypromine (Parnate®)<br>FGA First-Generation Antipsychotic (Typical) 4K 0.0% Haloperidol (Haldol®)<br>24<br>Total TRx: 195M |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>The Future: Faster Relief, Greater Tolerability, and Improvement<br>of Neuroplasticity for Long-Term Benefits<br>Leading brand Trintellix® differentiates with efficacy, impact on<br>DSST/Executive Function and lower sexual dysfunction side effects<br>Newer products differentiate with faster onset:<br> ‒ Spravato® – onset within 24 hours, however, restricted use due to NMDA receptor activity<br> ‒ Auvelity® – separation from placebo within 1 week<br>Monoamine products are limited. Moving towards molecules that can impact<br>neuroplasticity<br> ‒ Development of psychedelics is prevalent; however, they have significant AEs and<br>intensive therapy will be required for use<br> ‒ Could differentiate by “remodeling” neurological synapses to facilitate lasting benefits<br> ‒ Anticipated to be a $5B market1<br>25<br>1 GlobalData Forecast 2029, Projected Combined Psychedelic Brands<br> DSST: Digit Symbol Substitution Test |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Market Needs: Ideal Product Profile<br>High effect size with good responder frequency<br>Fast onset – one week or less<br>No cognitive impairment<br>No impact on sexual dysfunction<br>Positive impact on neuroplasticity for prolonged effects<br>Low to no dissociative side effects<br>At home use, as opposed to restricted use and need for intense<br>psychotherapy<br>26 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820<br>27<br>Vladimir Maletic, M.D., M.S.<br>Clinical Professor<br>Neuropsychiatry and Behavioral Science<br>University of South Carolina, School of Medicine |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>A Rapid Acting Antidepressant with Novel MOA<br>2828<br>SPN-820 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Evolution of Depression Treatment<br>1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s<br>ECT MAOIs<br>TCAs<br>Trazodone SSRIs SNRIs rTMS<br>DBS<br>glutamate<br>modulators<br>Recently-developed treatments for TRD restore neuroplasticity and do so rapidly<br>Monoamine hypothesis of depression Neuroplasticity hypothesis<br>of depression<br>ECT=electroconvulsive therapy; MAOIs=monoamine oxidase inhibitors; TCAs=tricyclic antidepressants; SSRIs=selective serotonin reuptake inhibitors; SNRIs=serotonin-norepinephrine<br>reuptake inhibitors; rTMS=repeated transcranial magnetic stimulation; DBS=deep brain stimulation<br>29 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Neuroplasticity Hypothesis of Depression<br>Dysfunctional neuroplasticity underlies depression manifestation<br> ‒ Inability of neuronal connections to undergo activity- and experience-dependent changes in strength; brain region and circuit specificity<br> ‒ Imbalance in GABA (inhibitory) and glutamate (excitatory) synapses<br> ‒ Reduced number and function of excitatory synapses; reduced neurotrophic factors,<br>e.g., BDNF<br> ‒ Reflected as altered communication between and within key brain regions<br>30 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Symptoms of Depression Reflect Disrupted Network Connectivity<br>in MDD<br>31<br>MDD = major depressive disorder; DMN = default mode network; sgACC = subgenual anterior cingulate cortex.<br>Dunlop et al. Curr Psychiatry Rep. 2019;21:87. Mulders PC, et al. Neurosci Biobehav Rev. 2015;56:330-344.<br>31 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Dysfunctional Network Connectivity and Related Symptoms in TRD<br>32<br>Idlett-Ali SL, et al. Front Hum Neurosci. 2023;17:1125074. |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Severely Depressed Subjects Have Decreased Synaptic Density<br>Holmes SE, et al. Nat Comm. 2019; 10:1529<br>VT=volume of distribution; ACC=anterior cingulate cortex; HC=healthy control; PET=positron emission tomography; SV2A=synaptic vesicle glycoprotein 2A<br>ACC<br>ACC<br>ACC<br>PET study measures synaptic<br>density by uptake of a radiolabeled<br>ligand<br> – Radioligand binds to SV2A, a synaptic<br>marker.<br>Red is high synaptic density, green<br>to blue is lower synaptic density<br>Synaptic density in critical areas<br>of the brain decreases with<br>severity of depression<br>33<br>Healthy<br>Control<br>Low<br>Severity of<br>Depression<br>symptoms<br>High<br>Severity of<br>Depression<br>symptoms<br>Synaptic Density<br>33 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Decreased Synaptic Density Between Healthy Controls and those<br>with Severe Depression is Statistically Significant<br>Holmes SE, et al. Nat Comm. 20 19; 10 :1529<br>PTSD=post-traumatic stress disorder; MDD=major depressive disorder; [11C]UCB-J =SV2A PET ligand; VT=volume of distribution; dlPFC=dorsolateral prefrontal cortex;<br>ACC=anterior cingulate cortex; HIP=Hippocampus; HC=healt hy control; n.s.=not significant<br>34 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820 MOA Video<br>3535<br>Click Here to Watch SPN-820 MOA Video |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>mTORC1 Activation in a Physiological Manner<br> • Generally, equivalent increase in mTORC1 activation between NV-5138 and leucine in peripheral organs<br>suggests low likelihood of peripheral side effects related to increased mTORC1 activation<br>Sengupta SS, et al. Sci Rep. 2019; 9:4107<br>Gastroc=gastrocnemius muscle; TA=tibialis anterior muscle; Epi=epididymal; S240/244pS6=phosphorylated pS6 ribosomal protein<br>36<br> • mTORC1 activation in the brain is increased only by NV-5138, not leucine |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>NV-5138 Shows Antidepressant Efficacy in Multiple Preclinical<br>Models<br>Model Outcome<br>Forced swim test Efficacious in standard antidepressant screening<br>(behavioral despair)<br>Novelty suppressed<br>feeding test Anti-anxiety effects<br>Female urine sniffing test Increased reward-seeking behavior<br>Sucrose preference test Normalization of hedonic behavior after chronic stress<br>Human threat test Potential anti-anxiety effects in non-human primates<br>37 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>NV-5138 Normalizes Chronic Stress-Induced Behavioral Changes<br>Relevant to Depression<br>Kato T, et al. J Clin Inv. 2019; 129(6):2542-2554<br>CUS=chronic unpredictable stress; NSFT=novelty suppressed feeding test; s=seconds<br> • NV-5138 prevents chronic<br>stress-induced decrease in<br>sucrose preference (reverses<br>anhedonia)<br> • NV-5138 prevents chronic<br>stress-induced increase in<br>latency to feed in novelty<br>suppressed feeding test<br>(decreases stress-induced<br>anxiety-like behavior)<br>Vehicle NV-5138<br>38 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>NV-5138 Normalizes Chronic Stress-Induced Decreases in<br>Synaptic Plasticity-Related Proteins in PFC<br>Kato T, et al. J Clin Inv. 2019; 129(6):2542-2554<br>CUS=chronic unpredictable stress; NS=non-stress; NV=NV-5138, V=vehicle; PSD-95=post-synaptic density protein 95; PFC=prefrontal cortex<br>GluR1 PSD-95 • NV-5138 reverses chronic stress-induced decreases in GluR1 (left)<br>and PSD-95 (right) protein<br>expression in PFC<br> • GluR1: AMPA glutamate receptor<br>subunit<br> • PSD-95: Stabilizes AMPA<br>receptors at post-synaptic<br>membrane<br>39 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>NV-5138 Induces Growth of New Dendritic Spines<br>Vehicle NV-5138<br>Stubby<br>Thin Mushroom<br>Kato T, et al. J Clin Inv. 2019; 129(6):2542-2554<br>40 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br> µm=micron; mshrm=mushroom type spine; PFC=prefrontal cortex<br>NV-5138 Increases Dendritic Spine Density in PFC<br>Kato T, et al. J Clin Inv. 2019; 129(6):2542-2554<br> • NV-5138 specifically increases thin and<br>mushroom type spines 24 hours after oral<br>administration in Rats<br> • Mushroom spines: Mature, functional<br>synapses known to be enriched in postsynaptic<br>glutamate receptors<br> • Thin spines: Malleable synapses that can<br>become mature mushroom spines with<br>increased synaptic input<br> • Increased mushroom and thin spines suggest<br>increased synaptic plasticity and growth of<br>new synapses<br>41 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>NV-5138 Increases Excitatory Responses in PFC Neurons 24 hours<br>After Oral Administration in Rats<br>Kato T, et al. J Clin Inv. 2019; 129(6):2542-2554<br>5-HT=serotonin; EPSC=excitatory post-synaptic current; PFC=prefrontal cortex; ** p<0.01 Student’s t-test<br>Slice electrophysiology (ex vivo)<br>+ serotonin or orexin<br> • NV-5138 increases evoked<br>excitatory responses following<br>application of neuromodulators<br>in PFC neurons 24 hours after<br>oral administration<br> • Effects were significant for<br>orexin and trending for 5-HT<br>(serotonin)<br> • Together with increased growth<br>of spines, this result indicates<br>increased functional<br>synapses<br>42<br>Serotonin or orexin<br>-induced<br>EPSC frequencies (% control)<br>5-HT Orexin<br>42 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>A First in Class Antidepressant<br>SPN-820<br>A first in class, small molecule that increases mTORC1 mediated synaptic function intracellularly<br>No synaptic<br>receptor modulation<br>43<br>No synaptic receptor<br>modulation<br>Improved side effect<br>profile vs. current<br>pharmaco-therapy<br>Rapid and sustained<br>antidepressant effect<br>mTORC1<br>BDNF1<br>High brain exposure<br>Rapid and transient<br>mTORC1 activation<br>in the brain<br>43<br>1BDNF=Brain Derived Neurotrophic Factor |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820<br>Pharmacology<br>4444 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>PK: Good Development Properties<br>Rapid absorption in animals across species<br> ‒ Rapid uptake in the brain (PFC)<br> ‒ No plasma protein binding<br>One major metabolite identified, not active in mTORC1 activation assay<br>Urine is primary route of excretion in rodent<br> ‒ 93% of administered dose is excreted in urine by 24 hours post dose<br>No significant in-vitro binding or modulation to major classes of CYP<br>enzymes, kinases and receptors<br>45 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Novel Intracellular Mechanism<br>Does not bind to or modulate any cell surface receptors<br> ‒ Unlikely to have abuse potential given lack of binding to targets implicated<br>in drug abuse<br>Unlike leucine, NV-5138 is not incorporated into proteins during protein<br>synthesis<br> ‒ More available at the target site in the brain than leucine<br>Antidepressant effect is mTORC1 dependent<br> ‒ Rapamycin pretreatment, which inhibits mTORC1, prevents NV-5138’s<br>antidepressant effect in rodents<br>46 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820<br>Phase 1 Studies<br>4747 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820 PK: Rapid Absorption & Once a Day<br>Half-life: 10.7 hours in plasma and 11.7 in cerebrospinal fluid (CSF)<br>Exposure in CSF is 10 times lower than plasma<br>Confirmed rapid absorption: Tmax: 0.5-1.25 hours (Plasma), 4 hours (CSF)<br>and renal excretion<br>Plasma Cmax is 13.5% lower with food and peaked 2.5 hours later<br>48 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820 Phase 1 Studies: Rapid Acting Antidepressant<br>Rapid and sustained effect<br>Improvement of core symptoms of depression with a single dose of 2400 mg/day at 4 and12<br>hours post-dose, with sustained effect to 72 hours, the last timepoint assessed<br>Rapid absorption<br>Rapid brain exposure and pathway activation confirmed by CSF drug levels<br>Plasma and CSF exposures suggest 800 to 1600 mg/day dose range for efficacy signal<br>CSF levels in adults<br>Consistent with the fully effective dose in animals<br>Rapid neuronal activation<br>Statistically significant signals on EEG bands associated with increased arousal or alertness (i.e.,<br>positive mood states), consistent with rapid change in synaptic function<br>49 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820 Phase 1 Studies: Favorable Safety Profile<br>Total of 205 subjects in Phase 1 studies<br> ‒ Single oral doses and two sequential oral doses of SPN-820 up to<br>3000mg/day were safe and well tolerated<br> ‒ Maximal tolerated dose not achieved<br> ‒ Most common AEs (mild-moderate): nausea, dizziness and headache<br> ‒ No psychiatric symptoms or dissociative effects reported<br> ‒ No suicidal effects reported<br>50 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820: Proof of Concept in TRD Subjects<br>Randomized, two-part, double-blind, placebo-controlled study of single ascending oral<br>solution dose<br>Primary endpoint: Changes from baseline to 24, 48, and 72 hours, post-dose in the MADRS<br>rating<br>Additional efficacy endpoints: HAM-D6, Inventory of Depressive Symptomatology (30-item)<br>and CGI-S ratings<br>51<br>Part A Part B<br>Healthy Subjects TRD Subjects<br>150-2400 mg 2400 mg/Placebo<br>N= 36 oral solution, N=12 placebo N=16 oral solution, N=15 placebo<br>Randomized 1:1<br>51 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820 POC Study: Rapid Acting & Sustained Efficacy<br>Efficacy with HAM-D6 shows early, large effect size, sustained to 72 hours after single dose.<br>MADRS did not show efficacy with single dose but showed small effect on acute symptoms.<br>52<br>Effect sizes: ≥ 0.2 in yellow (early improvement); ≥ 0.4 in green (clinical response).<br>MADRS= Montgomery Asberg Depression Rating Scale; HAM-D6= Hamilton Depression Rating Scale, 6 items, IDS-SR=Inventory of<br>Depressive Symptomatology (Self-Report); CGI-S= Clinical Global Impression - Severity |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820: Phase 2 Dose Selection Based on PK<br>NV-5138 CSF concentration: Day 7 after multiple doses of 800 mg and 1600 mg once<br>daily for 7 days (at steady state) versus single dose of 2400 mg on Day 1<br>53 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820: Phase 2 Dose Selection Based on Biomarkers<br>54<br>Biomarkers downstream of mTORC1 activation are increased in CSF at 800 and<br>1600 mg doses of NV-5138 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Primary efficacy: MADRS<br>Key secondary: CGI-S<br>HAM-D6<br>Onset of effect<br>Depression symptoms response and<br>remission<br>Individual disability<br>Anxiety<br>Rate of improvement<br>Safety and tolerability<br>SPN-820: Phase 2b Study<br>55<br>Multicenter, randomized, double-blind,<br>placebo-controlled, parallel design of<br>adjunctive therapy<br>Flexible dose: Treatment starts at 1600<br>mg/day and tapered down to 800 mg/day<br>Approximately 268 subjects to be<br>randomized, up to 50 sites<br>Duration:<br>o Screening period: up to 6 weeks<br>o Treatment: 5 weeks<br>55<br>Study Design Objectives |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820: Phase 2b Study Enrollment Status<br>1 Data updated as of 11 October 2023<br>56<br>Number of Subjects Overall<br>Randomized 62<br>In-Screening1 37<br>In-Treatment1 6<br>Completed 44<br>Discontinued (%) 13 (21%)<br>Discontinued due to AEs 2 (3%)<br>56 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820: Planned New Phase 2 Study in MDD<br>Optimize dosing and assess rapid onset<br> ‒ Pulsatile dosing<br> ‒ Efficacy in MDD<br> ‒ Rapid onset<br>Open–label study<br> ‒ 40 subjects with MDD<br> ‒ Rapid and sustained efficacy (2, 4, 8 and 72 hours after a single<br>administration of 2400 mg SPN-820, dosed every 3 days)<br> ‒ Evaluate rapid onset of efficacy with HAM-D6<br> ‒ Evaluate efficacy with MADRS<br>57 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820: Summary of Attributes<br>Increases mTORC1-mediated synaptic function through a first in class, unique<br>intracellular mechanism. Adjunctive therapy for patients with TRD<br>An average effect size of 0.6 has been measured with a single dose (2400mg)<br>over an initial 72-hour period using HAM-D6<br>Rapid onset of effect, beginning within hours of first dose using HAM-D6<br>Sustained effect of a single dose persists up to 72 hours in depression core<br>symptoms<br>Well-tolerated in clinical trials with no reports of dissociation or hallucinations<br>Unlikely to be a controlled substance<br>Phase 2b topline results 2025<br>58 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-820 Q & A<br>5959 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817<br>60<br>Jonathan Rubin<br>SVP, Research and Development, Chief Medical Officer |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817<br>Novel, First in Class, Highly Selective<br>Acetylcholinesterase (AChE) Inhibitor for Focal Epilepsy<br>6161 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Refractory Epilepsy Results in Switching & Polypharmacy<br>Generic ASM (e.g.,<br>NA+/Ca+ inhibitor,<br>GABA), monotherapy<br>Optimize dose<br>(evaluate at 1-4, 8<br>weeks)<br>Switch to a different<br>ASM, monotherapy<br>Combine two ASMs<br>(branded / generic)<br>Further combinations,<br>neurostimulation,<br>ketogenic diet<br>62<br>1. American Academy of Neurology Treatment Guidelines<br>ASM = Anti-Seizure Medication<br>1 2<br>3/4<br>3/4<br>5<br>62 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Epilepsy: Debilitating Disease with Significant Unmet Need<br> • 1.2% of people in the U.S. have<br>epilepsy (~3.4M people)1<br> • Focal seizures affect up to 61%<br>of people with epilepsy1<br> • 40% of patients with epilepsy<br>are drug resistant1<br> • 28.5M annual prescriptions2<br> • Can be a life-long chronic<br>disease<br> • Probability of achieving seizure<br>freedom decreases substantially<br>with each additional ASM<br>regimen attempted1<br> – 2nd 11.6%<br> – 3rd 4.4%<br> – 4th 1.2%<br> • Higher seizure frequency, AEs,<br>and employment concerns<br>reduce patient and caregiver<br>QoL3<br>Patients are looking<br>for treatments<br>resulting in better<br>seizure control,<br>improved quality of<br>life, and better<br>tolerability<br>63<br>1. Ioannou P, et al. Brain Behavior 2022; 12(9): e2589<br>2. IQVIA, NPA + NMTA, May 2023<br>3. Data on file – Epilepsy Market Research 2023<br>63 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Market Opportunity<br>All drugs that treat<br>Seizure Disorders1<br>166.5M TRx<br>Epilepsy &<br>Seizure Disorders2<br>28.5M TRx<br>1. IQVIA NPA, MAT April 2023 (includes non-seizure disorder indications as well)<br>2. IQVIA Integrated NPA + NMTA, MAT April 2023<br>Refractory Focal<br>Seizures (40%)<br>6.9M TRx<br>Focal Seizures2<br>17.2M TRx<br>Focal seizures<br>represent 60% of all<br>epilepsy/seizure<br>disorder TRx<br>Includes drugs that treat non-seizure disorders as well<br>(e.g., gabapentin/neuropathic<br>pain, lamotrigine/bipolar, etc.)<br>US Market- $2.7B<br>GlobalData Net Revenue Sept 2023<br>64 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Despite a Competitive Market, There is a Need for Effective<br>Pharmacological Treatments1<br>HCPs are aligned on treatment goals<br>Reducing seizure frequency, improving QoL, achieving seizure freedom, and reducing<br>severity of seizures are key.<br>Treatment satisfaction is low<br>Though there are many treatments available, there are few with which HCPs are truly<br>satisfied.<br>Efficacy is most important<br>Efficacy is the single-most important motivator in driving treatment choice, followed by<br>safety / drug interactions.<br>Adoption is driven by adult treaters<br>Pediatric treaters are more cautious and slower to adopt.<br>1 – Supernus Conjoint Market Research Study (June 2023)<br>65<br>Adult and pediatric treaters see value in pro-cognitive and<br>neuroprotection benefits |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Only AChE inhibitor in Development for<br>Focal Seizures<br>Ph 1 Ph 2 Ph 3<br>XEN-1101<br>(KCNQ)<br>NBI-921352<br>(Nav1.6)<br>JNJ-40411813<br>(mGlu2 PAM)<br>EQU-001<br>(Undisclosed)<br>SPN-817<br>(AChE)<br>Darigabat<br>(GABA PAM)<br>BHV-7000<br>(KCNQ)<br>ENX-101<br>(GABA PAM)<br>OV329<br>(GABA-AT)<br>66 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817<br>Huperzine A<br>Novel MOA<br>Reduce<br>Neuronal<br>Hyperactivity<br>Decrease<br>Excitation<br>Block or Inhibit<br>Na+ Channel<br>Inhibit<br>Glutamate<br>Release / Other<br>Increase<br>Inhibition<br>Activate Post-Synaptic GABA<br>Receptors<br>Inhibit GABA<br>Reuptake or<br>Breakdown<br>Increases<br>Acetylcholine<br>in the PFC and<br>hippocampus • Lyrica (pregabalin)<br> • Neurontin (gabapentin)<br> • Keppra(levetiracetam)<br> • Briviact (Brivaracetam<br> • Fycompa (perampanel)<br> • Potiga (Ezogabine)<br> • Tegretol (carbamazepine)<br> • Trileptal (oxcarbazepine)<br> • Lamictal (lamotrigine)<br> • Xcopri (cenobamate)<br> • Aptiom (Eslicarbazepine)<br> • Topamax (topiramate)<br> • Dilantin (phenytoin)<br> • Phenobarbital<br> • Klonopin (clonazepam)<br> • Valium (diazepam)<br> • Xcopri (cenobamate)<br> • Felbatol (Felbamate)<br> • Depakote (Valproic Acid)<br> • Ztalmy (ganaxolone)<br> • Gabitril (Tiagabine)<br> • Sabril (Vigabatrin)<br>A New Class of Therapy<br>67<br>All trademarks are owned by their respective owners |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817<br>Pharmacology<br>6868 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Novel MOA for the Treatment of Focal Seizures<br>Huperzine A is a potent, selective and reversible acetylcholinesterase (AChE)<br>inhibitor, an enzyme that metabolizes acetylcholine (ACh) after synaptic<br>release1,2<br>Inhibition of AChE increases extracellular levels of ACh<br>Broad and potent anti-seizure effect in different seizure and genetic models<br>of epilepsy1-4<br>69<br>1 Supernus data on file<br>2 Damar et al. (2016). Expert Rev Neurother, 16(6), 671-680<br>3 Wong et al (2016). Front Pharmacol, 7, 357<br>4 Wong et al (2021). Neuropsychopharmacology, 46(11), 2011-2020 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817 Preclinical Data: Refractory Seizures<br>70<br>(ED50 in mg/kg) 22mA 32mA 44mA<br>Phenytoin 9.4 >60 >60<br>Lamotrigine 4.4 >60 >60<br>Ethosuximide 86.9 167 >600<br>Valproic Acid 41.5 126 310<br>Levetiracetam (Keppra) 4.6 19.4 1,089<br>SPN-817 0.28 0.34 0.58-0.78<br>The 6Hz animal seizure model screens compounds as potential therapies for drug-resistant<br>partial seizures.<br> ‒ SPN-817 57x more potent than Keppra® at commonly used 32mA stimulation<br> ‒ SPN-817 was the only compound tested that produced significant seizure protection at<br>highest seizure inducing state-44mA<br>Sources: NIH Anticonvulsant Screening Program Data<br>Data on file. All trademarks are owned by their respective owners. |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Current MoA Hypothesis for Seizure Control:<br>Cholinergic Modulation of Neuronal Excitation<br>Seizures are the result of the imbalance of<br>the Excitation/Inhibition (E/I) ratio in<br>susceptible regions of the brain<br>Acetylcholine augmentation activates<br>cholinergic pathways in different cellular<br>types in the brain to restore E/I balance<br>71<br> ↑Ach<br>Activation of Ach receptors<br>located on<br>inhibitory interneurons,<br>excitatory neurons,<br>and glial cells<br> ↓ Excitation/↑ Inhibition<br>Restoration of E/I balance<br>Seizure control<br>AChE Inhibition<br>71 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: More Selective than Other Cholinesterase Inhibitors<br>More selective towards AChE than BuChE 1,2<br>Requires lower doses to block central AChE<br> ‒ Displays higher AChE inhibitory activity in various brain regions at lower<br>doses (improved therapeutic index)3<br> ‒ Donepezil exhibits similar AChE activity to SPN-817 at doses well<br>exceeding maximum prescribed/tolerated doses1<br>72<br>1Tang, X., Han, YF. (1999). CNS Drug Reviews, 5(3), 281-300<br>2Wang, R., Yan, H., & Tang, X. C. (2006). Acta Pharmacol Sin, 27(1), 1-26<br>3Zhao, Q., & Tang, X. C. (2002).Eur J Pharmacol, 455(2-3), 101-107 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>73<br>SPN-817: Phase 2a Focal Onset Impaired Awareness Seizure (FIAS)<br>Study<br>Key Inclusion Criteria:<br>Diagnosis of FIAS type epilepsy<br>Current minimum average of 5 countable seizures / week to enroll in study<br>At least 5 focal impaired awareness seizures during baseline<br>Receiving stable doses (for at least 4 weeks) of 1 to 4 currently marketed ASMs<br>Key Exclusion Criteria:<br>Seizures that are difficult to count<br>History of status epilepticus in the 6 months prior to enrollment<br>1 week<br>(96 hrs)<br>4 weeks 1 month 6 months + 1 week<br>(96 hrs)<br>Baseline<br>Diary<br>In-patient Baseline<br>Video EEG<br>Outpatient<br>Titration<br>In-patient<br>Video EEG<br>Maintenance/Extension Phase<br>*Extension Phase for those who benefit<br>from treatment |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Showed Significant Seizure Reduction in Small POC Study<br>Patients had focal impaired-awareness seizures (FIAS)<br>type epilepsy, treated with a maximum dose of 4 mg BID<br>Mean reduction in 28-day seizure rate from baseline was:<br> – 71.2% until month14 (n=3)<br> – 89.8% until month 40 (n=2)<br> – 98% until month 51 (n=1)<br>One subject has been seizure-free for >3.5 years and<br>regained his driver’s license and returned to work<br>Most TEAEs were transient, mild or moderate in intensity:<br> – Insomnia and nausea followed by nasopharyngitis, pyrexia,<br>and dizziness.<br>SF = seizure free, graph represents<br>data from 1 subject<br>74 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Phase 2a Synopsis<br>Open-label study<br>Number of study sites: up to 8 sites in Australia<br>Number of participants: approximately 35 subjects with treatment resistant<br>seizures<br>Indication: focal seizures in adults (18-65 years of age)<br>75 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Phase 2a Study Design<br>Screening Period:<br>Collection of<br>baseline seizure<br>diary for 42 days<br>Dose Titration and<br>Optimization:<br>8 weeks<br>Maintenance<br>Phase:<br>12 weeks<br>Open-label<br>Extension Period:<br>up to 52 weeks<br>76<br>Titration:<br> • All patients initiated on 0.25mg bid<br> • All will follow a personalized titration schedule<br> • Dose escalation by increments of 0.25mg or 0.5mg every<br>3-8 days, depending on tolerability, up to 4.0mg bid<br>76 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Phase 2a Endpoints<br>Primary:<br> ‒ Safety and tolerability as an adjunctive therapy in adult patients with treatment resistant seizures<br>Secondary:<br> ‒ Percent change from baseline in motor seizure frequency per 28 days<br> ‒ Improvement in seizure symptoms (CGI-I)<br> ‒ Change in seizure symptom severity (CGI-S)<br> ‒ Change in Quality of life in epilepsy (QOLIE-31-P)<br> ‒ Change in level of disability (seizure-related disability assessment scale scores, SERDAS)<br> ‒ Characterize the PK profile of huperzine A<br>Exploratory: Change from baseline:<br> ‒ In select inflammatory biomarkers in plasma (interleukin-1 receptor antagonist [IL-1RA], IL-6, IL-10, and C-reactive protein)<br> ‒ In cognitive profile as assessed by EpiTrack® and the Controlled Oral Word Association Test<br>(COWAT)<br> ‒ In seizures + interictal spikes and sleeping patterns (EEG)<br>77 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817 Phase 2a Study: Interim Data<br>7 patients completed titration at doses ranging from 1.0 mg bid to 4.0 mg bid<br> ‒ Most common TEAEs were diarrhea, nausea, headache, insomnia, and affect lability<br> ‒ All TEAEs were mild/moderate in severity<br>6 patients completed titration with available seizure diary data<br> ‒ 63.5% mean reduction in seizures per 28 days during maintenance period (n=2)<br>2 patients achieved seizure freedom (100% reduction) during titration after 8<br>weeks and 9 weeks of treatment, respectively<br>1 patient completed the study and moved into OLE with 68.3% reduction in<br>seizures over the entire treatment period<br>78 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Planned Phase 2b Treatment Resistant Focal<br>Seizures<br>7979<br>Screening<br>Phase<br>8 weeks<br>Dose Titration &<br>Optimization<br>Phase<br>9-11 weeks<br>Maintenance<br>Phase<br>12 weeks<br>Tapering<br>Phase<br>Up to 4 weeks<br>Follow-Up Phone Call<br>3 days after last dose<br>of SPN-817<br>Separate<br>Open-Label<br>Study<br>Design: Randomized, double-blind, placebo-controlled, study up to 35 weeks<br>Study population: Adults who failed to achieve seizure freedom after ≥2 ASMs and taking at least 1 ASM<br>Subjects: Approximately 436<br>Randomization: 4 arms, randomized 1:1:1:1 to SPN-817 2.0 mg bid, SPN-817 3.0 mg bid, SPN-817 4.0 mg bid<br>or placebo bid (109 subjects per arm), to achieve 76 subjects per arm in the Full Analysis Set<br>Number of sites: Up to 102 sites in the United States, Europe, Australia and Asia<br>Study Schema: |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817: Phase 2b Endpoints<br>Primary:<br> ‒ Change from baseline in focal seizure frequency per 28 days<br>Secondary:<br> ‒ Safety and tolerability<br> ‒ Pharmacokinetics (PK) of huperzine A<br>Exploratory: Change from baseline:<br> ‒ In inflammatory biomarkers in plasma<br> ‒ In cognitive performance<br> ‒ In electroencephalography (EEG)<br>80 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817 Summary:<br>Novel First in Class Selective AChE Inhibitor for Focal Seizures<br>Phase 2 long-term maintenance:<br> ‒ mean reduction in 28-day seizure rate from baseline (excluding titration) was 70% (n = 3)<br>Well-tolerated according to reported adverse events<br>Broad and potent anti-seizure effect in different seizure and genetic models<br>of epilepsy<br>Unique AChE inhibitor with high selectivity, low activity on BuChE<br>Potential for pro-cognitive, neuroprotective, and anti-inflammatory effects<br>Entering Phase 2b in 2024<br>81 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-817 Q & A<br>8282 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Break<br>8383 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-443<br>Novel MOA with Potential Stimulant-like<br>Efficacy and Reduced Abuse Liability<br>8484 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>ADHD Annual Prescriptions of 92.1M - 89% are for Stimulants<br>85<br>64%<br>25%<br>11% The market rewards<br>fast onset,<br>predictable response,<br>and good treatment<br>Amphetamines effect.<br>Methylphenidates<br>Nonstimulants<br>Source: IQVIA MAT Aug 2023 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Stimulants are Effective, But have Significant Drawbacks<br>Advantages<br>Significant treatment effect<br>Rapid onset<br>Allows for as needed dosing<br>with some patients<br>Many generics available<br>Drawbacks<br>DEA CII controlled substance<br>requirements – HCPs need to meet<br>with patients every 30 days prior to<br>writing a new prescription<br>Significant diversion related to appetite<br>suppression, stimulant effect for late<br>night studying, etc.<br>Tolerability issues: anxiety, insomnia,<br>mood swings, weight loss, etc.<br>86 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-443: Leverages Qelbree’s Commercial Investment<br>Sales force of 245 representatives<br> ‒ Established relationships with HCPs and<br>staff<br> ‒ Leverage a well-trained and educated<br>sales team<br>Well-established relationships with KOLs<br>Leadership position among ADHD societies<br>Significant resident knowledge of the market<br>87<br>Leveraging our<br>ADHD commercial<br>infrastructure would<br>provide scale<br>efficiencies and<br>faster commercial<br>ramp<br>87 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-443: NCE with Triple Reuptake Activity & Low Risk for<br>DDI or Abuse<br>Active parent and major metabolites based on preclinical models<br> ‒ All are triple monoamine transporter (NET, DAT, SERT) inhibitors<br>High blood brain barrier permeability<br>Low risk for drug-drug Interactions (DDI)<br>88 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Parent and Major Metabolites have NET, DAT & SERT Activity<br>SPN-443 and its metabolites all bind to and inhibit NET, DAT, and SERT but with varying<br>potencies<br>Metabolites could provide longer duration of effect<br>Functional Assay Transporters (IC50 in nM)<br>SPN-443 Metabolite 1 Metabolite 2<br>NET 12 0.52 53<br>DAT 110 12 63<br>SERT 1200 680 1200<br>In vitro Binding Assay (Ki in nM)<br>SPN-443 Metabolite 1 Metabolite 2<br>NET 25 0.71 270<br>DAT 120 6 10<br>SERT 670 40 110<br>MOP 280 160 >10000<br>Affinity (human isoforms) Functional Activity (human isoforms)<br>89 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>In-vivo Pharmacology: Increase in Monoamines in a Rat Model<br>Microdialysis study: SPN-443 (0.3 mg/kg intraperitoneal dosing) significantly<br>increased monoamines in the PFC, but not the nucleus accumbens:<br> ‒ Dopamine (300%)<br> ‒ Norepinephrine (391%)<br> ‒ Serotonin (141%)<br> ‒ Lack of activity in nucleus accumbens suggests low abuse potential<br>90<br>Reference: Data on File |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-443: Results from Nonclinical Safety Studies Support<br>Advancing into the Clinic<br>No evidence of genotoxicity<br>No adverse CV or CNS functional effects in safety pharmacology studies<br> ‒ Large safety margins in hERG assay<br>No dose-limiting toxicity up to 38x human equivalent dose in 14-day repeat<br>dose toxicity studies<br>91<br>Reference: Data on File |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-443: Planned FIH Study in 2024<br>Study design – Phase 1 single dose to evaluate PK in healthy adults<br>Number of subjects: Approximately 24 enrolled and 18 completers<br>Objectives:<br> ‒ Estimate PK of SPN-443 and its metabolites<br> ‒ Calculate relative bioavailability between two oral formulations<br>92<br>Study Days<br>-28 to -2 -1 1 to 7 8 to 14 15<br>Period 1 Period 2<br>Screening Entry Treatment A<br>SD PK<br>Treatment B<br>SD PK<br>EOS<br>FIH= First in Human; SD = single dose; Entry = entry and labs to confirm eligibility; EOS = End<br>of Study; PK = pharmacokinetic sampling 0 to 144 hours after the dose.<br>STUDY<br>DESIGN |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-443: Summary of Potential Attributes<br>Effect size within range of leading stimulants (1.0+)<br>DEA scheduling of IV or better<br>Well tolerated<br>Long duration of activity<br>93 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-446<br>Narcolepsy<br>9494 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Sleep Cycles<br>A single sleep cycle normally includes<br>non-REM (i.e., stages 1-3) and REM<br>(rapid eye movement, stage 4) sleep.<br>Alterations in neurocircuitry and<br>neurochemistry can alter this cycle,<br>resulting in different types of sleep<br>disorders or parasomnias.<br>Roth T, et al. Journal of Clinical Sleep Medicine 20 13; 9(9): 955- 965<br>95 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Narcolepsy Type 1 (NT1)<br>96<br>1. Szabo ST, et al. Sleep Medicine Reviews 20 19; 43: 23- 36<br> All trademarks are owned by their respective owners.<br>Xyrem®<br>22%<br>Xywav®<br>50%<br>Wakix®<br>24%<br>Lumryz™<br>1%<br>Sunosi®<br>3%<br>2. Global Data 20 23 forecast- net revenue<br>2023 US Net Revenue ~$2.4B Characterized by excessive daytime<br>sleepiness (falling asleep without<br>warning) along with daytime<br>cataplexy (sudden loss of muscle<br>tone)<br>60% of total narcolepsy population<br>Orphan indication<br>Typically associated with a loss of<br>orexin signaling<br>Diagnosed narcolepsy patients US:<br>1 per 2,000 people (~165,000) |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Need for New Therapies in NT1<br>More than 74% of patients still report issues with daily activities1<br>84% percent described impaired work or school performance and judged their<br>condition as moderate or severe1<br>70% reporting excessive daytime sleepiness every day1<br>31% suffering cataplexy daily1<br>Significant safety/tolerability concerns with sodium oxybate2<br> ‒ Black box warning<br> ‒ REMS3 program, abuse, etc.<br>97<br>1. Nat Sci Sleep. 2015; 7:51 -61. Unmet needs of patients with narcolepsy: perspectives on emerging treatment options – PMC (nih.gov)<br>2. Safety Overview of Post marketing and Clinical Experience of Sodium Oxybate (Xyrem): Abuse, Misuse, Dependence, and Diversion - PMC (nih.gov)<br>3. Unmet needs of patients with narcolepsy: perspectives on emerging treatment options - PMC (nih.gov) |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Neurocircuitry of NT1: Role of Norepinephrine (NE)<br>98<br>a) Orexin pathways that promote and maintain<br>wakefulness<br>b) Orexin pathways that suppress REM sleep and maintain muscle<br>tone during wakeful periods<br>Krahn et al (2022) Adv Ther 39:221–243<br>Reduced<br>activation of NE<br>neurons (due to<br>loss of orexin<br>neurons) leads to<br>sudden induction<br>of REM sleep<br>and cataplexy.<br>98 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-446: Shows Norepinephrine Transporter Inhibition & Activity<br>on Several Serotonin Receptors<br>SPN-446 is a NET inhibitor with activity towards different serotonin receptors1<br>99<br>1 Data on file<br>2 Mitchel and Weinshenker (2010). Biochem Pharmacol 79(6):801-809<br>Receptor Binding Agonism Antagonism<br>NET Ki= 0.11 µM IC50 = 0.085 uM<br>5-HT2C Ki=0.51 µM EC50=0.5-2.5 µM;<br>Emax=56-74%<br>5-HT2B Ki=0.97 µM IC50=1.6 µM–34 µM<br>5-HT7 Ki=0.81 µM IC50=27 µM<br>The role of NE in the transitions between awake-sleep have supported the evaluation of<br>NRI's as potential treatments for narcolepsy (Type I and II)2<br>NET inhibitors have a potential therapeutic effect in Narcolepsy Type 1 animal models |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-446: Decreases Cataplexy and REM Sleep in Preclinical<br>Models<br>Microdialysis<br> ‒ Dose dependent increase in dopamine, norepinephrine, and serotonin in<br>rat prefrontal cortex.<br>Novel Object Recognition (NOR) test<br> ‒ Improved episodic memory<br>Orexin neuron ablation (mouse model of narcolepsy type 1)<br> ‒ Decrease in cataplexy and REM sleep up to 12 hours post dosing<br>100<br>Data on file |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>SPN-446: Shows Dose Dependent Decrease in REM Sleep and<br>Cataplexy<br>Reduces cataplexy and REM<br>sleep up to 12 hours after<br>dosing at the beginning of<br>active time (ZT12 to ZT24).<br>101<br>NT1 Animal Model<br>(Conditioned orexin neuron<br>ablation or DTA mice):<br>Effects on cataplexy up to 12 hours after<br>SPN-446 administration during active time<br>101<br>Data on File |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Full Q & A<br>102 102 |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Closing Remarks<br>103<br>Jack Khattar<br>President and Chief Executive Officer |
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| © 2023 Supernus Pharmaceuticals, Inc. All Rights Reserved.<br>Strong Foundation for Future Growth<br>Successfully transitioned from a drug delivery company to a profitable<br>biopharma with strong R&D capabilities<br>Diversified commercial portfolio that continues to deliver good cashflows<br>while losing exclusivity on flagship product<br>A “first in class” pipeline of several NCEs with clear differentiation from the<br>market and future pipeline products<br>Near term catalysts with SPN-830 approval and launch, and data readouts<br>on SPN-820 and SPN-817<br>104 |
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