It s time. for a new approach to treat chronic neurologic disease Adamas Pharmaceuticals, Inc. All Rights Reserved.

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1 It s time for a new approach to treat chronic neurologic disease

2 Forward-looking statements Statements contained in this presentation regarding expected future events are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of These statements are subject to significant risks and uncertainties, actual results could differ materially from those projected and Adamas cautions investors not to place undue reliance on the forwardlooking statements contained in this presentation. These risks and uncertainties include, without limitation, risks and uncertainties related to market conditions and satisfaction of customary closing conditions related to the public offering. There can be no assurance that Adamas will be able to complete the public offering on the anticipated terms, or at all. Risks and uncertainties relating to Adamas and its business can be found in the Risk Factors section of Adamas Form 10-K filed with the SEC on February 22, 2018, and in the preliminary prospectus supplement related to the proposed offering to be filed with the SEC. Adamas undertakes no duty or obligation to update any forward-looking statements contained in this presentation as a result of new information, future events or changes in Adamas expectations. 2

3 Investment thesis Building a multi-product neuroscience company based upon time-dependent biology approach Products designed to maximize efficacy without compromising tolerability Yields differentiated, durable and protectable products/product candidates Launching GOCOVRI for dyskinesia in people with Parkinson s disease receiving levodopa-based therapy First and only medicine approved by the FDA for this indication First medicine clinically demonstrated to reduce both dyskinesia and OFF Non-dopaminergic/glutamate pathway treatment Advancing a robust portfolio of clinically differentiated assets ADS-5102 (GOCOVRI): initiating Phase 3 program in multiple sclerosis walking; planning additional indications ADS-4101: planning End-of-Phase 2 meeting with FDA Additional research programs Financially sound $176M cash, cash equivalents and investments at end of Q4 17 $134.5M in proceeds to Adamas from January 2018 public offering 3

4 Adamas is rooted in an understanding of time-dependent biology Address neurologic disorders with significant patient, care partner and societal burden understand + map patterns create medicines to match develop for efficacy, maintain tolerability significant impact 4

5 Our approach: Sources of time dependence Disease Patterns Due to the underlying biology, the occurrence and severity of disease symptoms may change throughout the day Rate-of-Rise The speed at which drug concentration increases in the body may drive tolerability and efficacy responses Timing of Drug Response Matching the timing of drug levels to disease patterns may increase treatment benefit Pathway Sequence Drugs acting sequentially along a pathway may produce an outcome that is greater than the sum of the individual effects (synergy) 5

6 Adamas portfolio Disease Program Phase 1 Phase 2 Phase 3 Approved/ Commercial Commercial Lead Dyskinesia in Parkinson s Disease Multiple Sclerosis Walking Additional Indications GOCOVRI (amantadine) ADS-5102 (amantadine) (GOCOVRI) ADS-5102 (amantadine) (GOCOVRI) Epilepsy Partial Onset Seizures ADS-4101 (lacosamide) Alzheimer s Dementia NAMENDA XR (memantine HCl) NAMZARIC (memantine HCl & donepezil HCl) (US) Additional product candidates in research based on potential new discoveries in Parkinson s disease, multiple sclerosis, epilepsy, and psychiatry. NAMENDA XR and NAMZARIC are trademarks of Merz Pharma GmbH & Co. KGaA. 6

7 First and Only FDA-Approved Medicine for Treatment of Dyskinesia in Patients with Parkinson s Disease 1 FDA-approved medicine for treatment of dyskinesia in patients with Parkinson s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medicines. The most common adverse reactions with GOCVORI were hallucinations, dizziness, dry mouth, peripheral edema, constipation, falls and orthostatic hypotension 1 1. GOCOVRI Package Insert 7

8 Dyskinesia in people with Parkinson s disease Levodopa and disease progression drive changes that cause dyskinesia and OFF Levodopa is the gold standard treatment for Parkinson s to replace dopamine 1 As Parkinson s disease progresses, levodopa dysregulates the glutamate system leading to dyskinesia and OFF 2, 3 Motor complications affect 400k in the United States, with k impacted by dyskinesia 4-6 Economic impact of Parkinson s disease is growing as population ages: >$20B by ,8 Significant impact on activities of daily living 9 Adamas focused on designing a novel time dependent solution Dyskinesia and OFF follow a diurnal pattern, more dyskinesia during the day 10, sleep disturbed at night Hornykiewicz, J Neurol (2010) 257 (Suppl 2):S249 S252; 2. Sgambato-Faure, Progress in Neurobiology 96 (2012) 69 86; 3. Shen, Science (2008), Vol 321; 4. Data on file, Adamas Pharmaceuticals, Inc, Emeryville, CA; 5. Paralysis Agitans IMS NDTI 2012; 6. Schrag, Brain (2000), 123, ; 7. Data on file; 8. Kowal, Mov Disord (2013), Vol. 28, No. 3, ; 9. Pahwa, Poster presented at 4th World Parkinson Congress, September 20 23, 2016, Portland, OR; 10. Pahwa, JAMA Neurol (2017), 74 (8), ; 11. Bruguerolle, Clin Neuropharmacology (2002), Vol. 25, No. 4, pp ; 8

9 Impact of dyskinesia (and OFF) Physician Patient Emergence of motor complications commonly causes physicians to reduce/fractionate levodopa 1-3 Effect of this approach is to undertreat underlying Parkinson s disease, leaving patients OFF 1-3 Significant impact on ADLs, with over two thirds of Parkinson s disease patients with dyskinesia reporting mild to moderate impact on 4 : Confidence in social/public settings Walking & balance Difficulty in emotional settings Doing hobbies Care Partner Significant support for patient required due to nature of dyskinesia, often described as exhausting 5 Remove objects that may be dangerous 5 Significant embarrassment in public settings due to dyskinesia 5 Patient Physician Care Partner 1. Daneault J-F, et al. Eur Med J. 2016;1(4): Olanow CW, et al. Neurology. 2009;72(21 Suppl 4):S1-S136; 3. Adamas Market Research, March 2017; 4. Pahwa, Poster presented at 4th World Parkinson Congress, September 20 23, 2016, Portland, OR; 5. Adamas Market Research, August

10 Dyskinesia and OFF result in a narrowing therapeutic window and difficult choices With no approved treatment, physicians and patients struggle to balance dyskinesia and OFF Disease progression NMDA receptor dysregulation 1 Dyskinesia High levodopa levels result in dyskinesia Dopamine release Narrowing Therapeutic window 3 NMDA receptor dysregulation Normal buffering capacity 2 OFF Low levodopa levels result in OFF Levodopa doses: 1. Sgambato-Faure, Progress in Neurobiology 96 (2012) 69 86; 2. Carta, Brain (2007), 130, ; 3. Jankovic, Mov Disord (2005), Vol. 20, Suppl

11 GOCOVRI delivered significant reductions in dyskinesia from week 2 through 12 Effect was maintained out to Week 24 in EASE LID (Study 1) Baseline UDysRS total score: 40.1 Pooled data from Study 1 and Study 2; LS: Least squares, SE: standard error 1. Pahwa, Presentation at 69th AAN Annual Meeting, April 23-28, 2017, Boston, MA; 2. Pahwa, Poster presented at 2017 Annual Meeting of the American Neurological Association, October 15-17, 2017, San Diego, CA; 3. Pahwa, JAMA Neurol (2017), 74 (8), ; IMPORTANT SAFETY INFORMATION: Warning and Precautions with GOCOVRI, include falling asleep during activities of daily living, suicidality and depression, hallucinations/psychotic behavior. For complete safety information, please see the full GOCOVRI prescribing information. 11

12 GOCOVRI also achieved key secondary benefit of reducing OFF by ~1 hour First medicine clinically demonstrated to reduce both dyskinesia and OFF Baseline OFF time: 2.8 hours Pooled data from Study 1 and Study 2; LS: Least squares, SE: standard error 1. Tanner, 69th AAN Annual Meeting, April 23-28, 2017, Boston, MA; 2. Data on file, Adamas Pharmaceuticals, Inc., Emeryville, CA 12

13 GOCOVRI increased functional time by ~4 hours daily Key secondary benefit achieved Baseline ON time without troublesome dyskinesia: 8.4 hours Pooled data from Study 1 and Study 2; LS: Least squares, SE: standard error 1. Tanner, 69th AAN Annual Meeting, April 23-28, 2017, Boston, MA; 2. Data on file, Adamas Pharmaceuticals, Inc., Emeryville, CA 13

14 Ongoing EASE LID 2 open label safety and efficacy study supports durability for Up to 88 Weeks 1 EASE LID 2 final data to be reported mid 2018 Treatment effect maintained for 88 weeks Subjects on prior placebo, DBS and amantadine IR all showed 35% reduction in dyskinesia and OFF when switched to GOCOVRI 2,3 Discontinuations due to ADRs typically occurred early in GOCOVRI treatment SE = Standard Error. 1. Hauser, J Park Disease (2017) 7: ; 2. Isaacson, Movement Disorders Clinical Practice (2017), 3. Isaacson, Poster Presented at the XXIII World Congress of Neurology (WCN), Sept 16-21, 2017, Kyoto Japan. 14

15 GOCOVRI unlocks the potential of amantadine High drug levels upon waking, throughout the day, lower in the afternoon and evening NOTE: PK and preclinical data do not provide evidence of clinical safety or efficacy; there are no head-to-head clinical studies comparing GOCOVRI with amantadine IR. 15 QHS = at bedtime, BID = twice daily, TID = three times a day IR = immediate release 1. Hauser, Clin Pharmacokinetics (submitted). 15

16 GOCOVRI launch update 1 Sales force deployed Jan 8, Neurology Account Specialists deployed targeting 6,500 physicians Campaigns launched 3 pivotal manuscripts in hand Pleased with response of payers, physicians and patients Off to a solid start; in only 8 weeks (as of Feb 28): 742 GOCOVRI prescriptions filled quarter-to-date ~390 distinct prescribers, or 6% of target HCPs 1. As of February 28,

17 Helping patients get access to GOCOVRI Partnered with a prominent US pharmacy Facilitate access and distribution of GOCOVRI to patients Quick Start program provide patients access during insurance coverage adjudication period Co-pay assistance program for commercially insured Patient assistance program for under insured or uninsured Provision of information for government insured patients about available assistance programs Working through government and commercial payer review processes to gain formulary coverage Anticipate broad coverage for GOCOVRI, given GOCOVRI s novel indication and established clinical benefit for patients 17

18 59 neurology account specialists covering ~94% of target MDs 6 regions covering 6,500 targets 17 years pharma experience 9 years neurology experience 75% have MDS experience 90% have specialty distribution experience Colors represent the 59 territories. 18

19 GOCOVRI related publications and presentations 5 peer reviewed publications and 30 presentations at conferences GOCOVRI Scientific Congress Activity ( ) * *Estimate 19

20 Advancing the pipeline ADS-5102 (GOCOVRI) in multiple sclerosis walking ADS-5102 (GOCOVRI) in other indications ADS-4101 in epilepsy (partial onset seizures) New product discovery 20

21 Walking impairment in multiple sclerosis Among the most common symptoms reported by MS patients Progressively disabling, leading to poor quality of life and decreased independence 1 Only one approved product, which is effective for a subset of patients 2 400K MS patients in the U.S. 3, majority experience walking impairment 4 Adamas is taking ADS-5102 (GOCOVRI) forward Dysregulation of the NMDA receptor / glutamate signaling has been associated with the symptoms and progression of MS 5 Validated effects in preclinical, Phase 2 studies 6,7 Multiple Sclerosis 1. Coleman, PLoS ONE (2013) 8(1): e54756; 2. Ampyra [Package insert], Acorda Therapeutics Inc., Ardsley, NY; 3. Multiple Sclerosis Association of America website. Accessed on Jan 18, 2018; 4. Sutliff, Curr Med Res Opin (2010); 26:109 19; 5. Rossi, Plos ONE (2013) 8(6): e67357; 6. Nguyen, ECTRIMS Online Library, 2015; 7. Cohen, Multiple Sclerosis, 2018 (in press) 21

22 ADS-5102 (GOCOVRI) demonstrated statistically significant improvement in walking speed Phase 2 study results in MS Walking Clinical Trial Findings Timed 25 Foot Walk (T25FW), Speed 17% change in walking speed (p < 0.05) ~90% of ADS-5102 subjects improved, compared to ~60% of placebo Effect on walking speed did not plateau by Week 4 Trend for positive effect on TUG and 2 Minute Walk Test (2MWT) Timed Up and Go (TUG) 1. Cohen, Multiple Sclerosis Journal, (2018) 22

23 ADS-5102 (GOCOVRI) multiple sclerosis walking Phase 3 program overview Establish benefit-risk profile of ADS mg in MS Walking Phase 3 Program Non Clinical Studies Phase 2 Proof of Concept EOP2 FDA Study 1 Study 2 1 Controlled Trial Controlled Trial Study 3 Open-label Extension 1. Dependent on results of Study 1 and FDA feedback 23

24 ADS-5102 (GOCOVRI) multiple sclerosis walking Phase 3 study design Subjects ~570 subjects, randomized 1:1:1 Key Inclusion years old EDSS 6.5 T25FW 8 45 seconds, inclusive Key outcome measures Primary: T25W 20% responder analysis Key secondary: T25W, TUG, 2MWT, MSWS-12 LS Mean change from baseline Enrollment expected: early Q H Wks 4 Weeks 2 Wk 10 Weeks Screening Randomization Placebo Run-in (Single- Blind) R Up- Titration Phase 274 mg QHS ADS mg QHS ADS-5102 Placebo Maintenance Phase 24

25 Potential additional indications for GOCOVRI ADS-5102 in research and development Motor disorders Parkinson s: Delay Motor Complications Parkinson s: Wearing OFF Tardive dyskinesia Huntington s chorea Tourette syndrome Non-motor disorders Depression Anti-psychotic induced weight gain 25

26 Treatments for partial onset seizures Epilepsy results in profound physical, psychological, and social consequences 1 Reduced education Reduced independence Increased isolation 3.0 M adults with epilepsy in US 2 Partial onset seizures (POS) occur in ~2/3 of patients with epilepsy 3 30% of patients with POS have poor seizure control with current anti-epileptic drugs (AEDs) 3 Adamas confirmed seizure frequency higher during daytime Suggests advantage to maintaining high plasma concentrations of anti-epileptic medication throughout the day 4 Epilepsy 1. ILAE, Epilepsia, (2003), 44(Suppl. 6); 2. Zack, MMWR, Vol. 66 / No. 31 August 11, 2017; 3. Margolis, JAMA Neurol. (2014);71(8): ; 4. Data on file, Adamas Pharmaceuticals, Inc., Emeryville, CA 26

27 ADS-4101 (lacosamide) designed to provide benefit when seizures occur EEG studies suggest seizures have a diurnal pattern Higher frequency of seizures during the day than at night 1 Phase 1b study showed 600 mg ADS-4101 provided 1.7-fold increase in lacosamide AUC throughout the day, compared to 400 mg daily dose of VIMPAT 2 AEs incidence similar between 600 mg ADS-4101 and 200 mg VIMPAT BID 1. Data on file, Adamas Pharmaceuticals, Inc. Emeryville, CA; 2. Patni, Poster presented at American Epilepsy Society (AES) Annual Meeting, December 1 5, 2017, Washington, DC 27

28 ADS-4101 (lacosamide) epilepsy proposed development program Establish benefit-risk profile of ADS-4101 in patients with partial onset seizures (POS) Phase 3 program 1 Phase 3 Program Phase 1 Proof of Concept EOP2 FDA Study 1 Study 2 Controlled Trial Open-label Extension 1. Dependent on results of FDA feedback 28

29 ADS-4101 (lacosamide) epilepsy proposed development program Phase 3 study design Subjects ~600 subjects, randomized 1:1:1:1 Key Inclusion POS for the last 2 yrs despite prior therapy with 2 AEDs Average of 4 POS per 28 days in prerandomization period Key outcome measures Change in POS frequency per 28 days 50% responder rate (% of subjects experiencing a 50% reduction in POS frequency) FDA meeting scheduled Phase 3 enrollment expected: Screening R 3 Weeks 4 Weeks 6 Weeks 8 Weeks Baseline Period (No Study Drug) Up-Titration Period 600 mg QHS ADS mg QHS ADS mg BID Vimpat Placebo Maintenance Period 29

30 New product discovery Proven time-dependent biology approach Responsible for: GOCOVRI ADS-5102 MSW ADS-4101 Epilepsy Adamas will conduct 4-5 discovery projects per year Focus remains neurology and psychiatry Goal to nominate 1 additional clinical development program per year Psychiatry Epilepsy Parkinson s Disease Multiple Sclerosis 30

31 Adamas products protected by multiple, distinct discoveries GOCOVRI estimated exclusivity and patents* Regulatory Exclusivity New Clinical Investigation Exclusivity Aug. 24, 2020 Regulatory Exclusivity Orphan Drug Exclusivity Aug. 24, 2024 Slope Patent Family Amantadine compositions and methods of treatment with slower rate of rise, dissolution profiles Nov. 23, 2025 Jan. 22, 2028 Diurnal Patent Family Bedtime administration of ER amantadine Dec. 2, 2030 ON/OFF Patent Family Increasing ON time or reducing OFF time by administration of ER amantadine June 17, 2034 Gait Patent Family Method of improving gait (walking) by administering amantadine once-daily Nov. 3, * Reflects issued patents and patent applications 31

32 Achieved and upcoming milestones Program Date Milestone/Event GOCOVRI Commence full U.S. commercial launch ADS-5102 (GOCOVRI) Quarterly Q Q2 18 Q4 18 H2 19 Q1 19 Provide updates on commercial progress with physician and patient adoption Report final EASE LID 2 Phase 3 open-label safety and efficacy data Present data at key annual scientific meetings, including the American Academy of Neurology Annual (AAN), Movement Disorder Society (MDS); publish additional preclinical, Phase 1, and Phase 3 and HEOR results Initiate first Phase 3 study in Multiple Sclerosis walking Initiate open-label safety and efficacy study Complete enrollment of first Phase 3 study in Multiple Sclerosis Walking Select additional indications for ADS-5102 (GOCOVRI) for clinical development ADS H 18 Present Phase 1a & 1b data Conduct End-of-Phase 2 (EOP2) meeting with FDA Enroll Phase 3 study in patients with partial onset seizures (pending EOP2 meeting) Discovery By H2 20 Start clinical development of two (2) additional products 32

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