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Company Highlights A clinical-stage specialty pharmaceutical company pioneering the development of patent-protected synthetic cannabinoid therapeutics for transdermal delivery Experienced team with deep expertise and proven track record of success in patch and gel transdermal delivery, regulatory approval and commercialization Global ownership of two proprietary product candidates intended to treat diseases with significant unmet medical need and market potential ZYN002 CBD Gel: epilepsy, osteoarthritis and Fragile X syndrome ZYN001 THC Pro-Drug Patch: fibromyalgia and peripheral neuropathic pain No royalty obligations owed on either product candidate Cash as of September 30, 2016 = $31.8 million; expected runway into 2018 to fund five phase 3 ready programs 3

Robust Pipeline Product Candidate Indication Preclinical Phase 1 Phase 2 Phase 3 NDA Filing ZYN002 CBD Gel Epilepsy in Adults with Focal Seizures Osteoarthritis Fragile X Syndrome (US FDA Orphan Drug Designation) Initiate Phase 2 End of 2H 2016 Top-line results End of 1H 2017 Top-line results End of 1H 2017 ZYN001 THC Pro- Drug Patch Fibromyalgia Peripheral Neuropathic Pain Initiate Phase 1 in 1H 2017 Initiate Phase 1 in 1H 2017 ZYN002 patent protected through 2030 ZYN001 patent protected through 2031 4

Multiple Near-term Milestones Expected 2H 2016 1H 2017 2H 2017 ZYN002 CBD Gel Epilepsy in Adults with Focal Seizures Osteoarthritis Fragile X Syndrome (Orphan Drug Designation) STAR 1 Dosing August STOP Dosing September Phase 2 Initiation STAR 1 Top Line Results STOP Top Line Results Phase 2 Top Line Results Meet with FDA Regarding Phase 3 Plans; Prepare for Phase 3 Initiation Based on Phase 2 Results / FDA Feedback ZYN001 THC Pro-Drug Patch Fibromyalgia Peripheral Neuropathic Pain Phase 1 Initiation Phase 2 Initiation Phase 2 Initiation 5

ZYN002 CBD Gel First and only patent-protected permeation-enhanced synthetic cannabidiol gel formulated for transdermal delivery CBD Structure The permeation enhancer in ZYN002 increases the delivery of CBD through the layers of the epidermis and into the circulatory system Permeation-enhanced Delivery 6

Potential Benefits of Transdermal ZYN002 vs. Oral CBD More consistent, controlled and sustained plasma level Avoids first-pass metabolism in the liver fewer drug-drug interactions Avoids the GI tract Very low incidence of gastrointestinal events Avoids degradation of CBD to THC Lower incidence of negative psychoactive effects 7

Objectives for Today Rationale for Why CBD in Epilepsy, OA, and Fragile X Syndrome? Deeper Understanding of Clinical development and status to date Opportunity to hear from Key Opinion Leaders and ask questions Understand why ZYNE is a compelling investment opportunity 8

Agenda Time Topic Presenting 08:00 Opening Comments Armando Anido, Zynerba 08:10 Overview of Cannabinoid Pharmacology Marcel Bonn-Miller, PhD, Zynerba 08:25 Zynerba Clinical Program in Epilepsy Terri Sebree, President, Zynerba 08:40 Epilepsy Jacqueline A. French, MD, NYU Langone Medical Center 08:55 Zynerba Clinical Program in Osteoarthritis Terri Sebree, President, Zynerba 09:10 Osteoarthritis Daniel J. Clauw, MD, University of Michigan Health System 09:25 Zynerba Clinical Program in Fragile X Syndrome Terri Sebree, President, Zynerba 09:40 Fragile X Syndrome Steven Siegel, MD, PhD, University of Southern California 09:55 Closing Comments Armando Anido, Zynerba 10:05 Q & A 10:30 Conclude 9

Cannabinoid Pharmacology Marcel Bonn-Miller, PhD Director of Cannabinoid Research, Zynerba Pharmaceuticals Adjunct Assistant Professor in the Department of Psychiatry at the University of Pennsylvania Perelman School of Medicine Former Research Health Science Specialist at the Center of Excellence in Substance Abuse Treatment and Education at the Philadelphia Veterans Affairs, as well as at the National Center for PTSD, and Center for Innovation to Implementation at the Palo Alto Veterans Affairs Research has focused on the interrelations between cannabis and chronic pain, HIV, PTSD, and sleep disorders Published over 100 peer-reviewed empirical publications and serves on the editorial boards of six scientific journals Dr. Bonn-Miller is a graduate of the University of Vermont with a PhD in clinical psychology and completed a joint postdoctoral fellowship at the Palo Alto Veterans Affairs & Stanford University School of Medicine Dr. Bonn-Miller is an employee of Zynerba Pharmaceuticals. The drugs discussed in this presentation have not been approved by the Food and Drug Agency (FDA). 2016 Zynerba Pharmaceuticals, Inc. All rights reserved. Zynerba is a registered trademark of Zynerba Pharmaceuticals, Inc. All other trademarks and registered trademarks are property of their respective owners. 10

A clinical-stage specialty pharmaceutical company dedicated to the development of innovative transdermal synthetic cannabinoid treatments for patients with high unmet medical needs Cannabidiol Pharmacology In Epilepsy, Osteoarthritis, and Fragile X Syndrome Marcel O. Bonn-Miller, PhD Director of Cannabinoid Research

Cannabis: Medicine Since 2737 BC Listed in the US Pharmacopeia until 1942 74% alcohol 12

Cannabis (sativa, indica, ruderalis) > 100 natural plant-derived cannabinoids Most well known and researched: Δ 9 -tetrahydrocannabinol (Δ 9 -THC): principal psychoactive constituent Cannabidiol (CBD): not euphoric Cannabinoids interact with specific receptors throughout the body to produce pharmacologic effects, mostly in the CNS and immune system. 13

Endocannabinoid System Ancient internal signaling system began evolving 600 million years ago Present in every animal except insects NIMH* (1990) discovers the exact DNA sequence encoding a THC-sensitive receptor in the rat brain Discovery of naturally-occurring transmitters endocannabinoids anandamide (1992) and 2-AG (2-arachidonoylglycerol) (1995) *National Institutes of Mental Health 14

Endocannabinoids Anandamide (N-arachidonoylethanolamine or AEA) 2-AG (2-arachidonoylglycerol) Released in response to excitatory synaptic activity In the CNS: Important in synaptic plasticity, cognitive, motor, sensory, and affective processes Neuroprotective in: Acute and chronic neurodegenerative conditions Neuroinflammatory conditions Modulate inflammatory processes Down regulate stress related signals 15

Endocannabinoid-mediated Signaling in the Nervous System 1 16

CBD Pharmacology 2 Activity at Multiple Receptors May Account for CBD Effects Low affinity for CB 1 /CB 2 receptors Stimulates the release of 2-AG Inhibits anandamide degradation and enhances its signaling 3 Agonist TRPV1 receptor: mediates pain perception/inflammation 5-HT 1A serotonin receptor Decreases depression Anxiolytic Antagonist at GPR55: modulates blood pressure and bone density Activates adenosine A 2A receptor Decreases inflammation Neuroprotection 17

CBD is Effective in a Variety of Acute Seizure Rodent Models 5-8 MES, PTZ, audiogenic seizures, penicillin, pilocarpine, transcorneal electroshock and electrical amygdala kindling Increased seizure threshold, reduced seizure severity and reduced mortality in generalized seizures Efficacy in animal models is highly predictive of efficacy in patients with epilepsy MES, maximal electroshock seizure, PTZ, pentylenetetrazole 18

CBD Effective in Acute In Vivo (Mouse) Models that Map Onto Focal Seizures 9 mes Model (% Seized) 6Hz (32mA) Model (% Seized) P<0.05 P<0.01 Ø P<0.1 P<0.05 P<0.01 CBD (mg/kg) CBD (mg/kg) 19

CBD Pharmacology: Osteoarthritis Recent behavioral and electrophysiological studies have demonstrated that cannabinoids exert anti-nociceptive effects in rodent models of osteoarthritis 10 CBD has been shown to have antihyperalgesic effects through its interaction with TRPV1 receptors 12 CBD activates the adenosine receptor (A 2A ), which has broad anti-inflammatory effects throughout the body 11 By blocking GPR55 signaling, which promotes osteoclast cell function, CBD may act to decrease bone resorption 13 20

Osteoarthritis: Inflammation and Pain 14 CB 2 is a mainly peripheral, immunomodulatory receptor with an important role in pain, inflammation, and physiological defense It attenuates inflammation and decreases injury 21

ZYN002 Significantly Reduces Inflammatory Pain in Rats 15 22

ZYN002 Significantly Reduces Inflammatory Pain in Rats 15 Knee joint circumference (% change) Results Significant reductions in: Swelling of knee joints Immune cell infiltration Spontaneous pain rating scores Dose-dependent reduction of proinflammatory markers in spinal cord and dorsal root ganglia CD11b/c CGRP TNF Paw Withdrawal Latency 23

ZYN002 for Inflammatory Pain (OA and RA) in Rats 15 ZYN002 Gel (mg/day) Plasma Concentrations (ng/ml) 0.6 3.8±1.4 3.1 17.5±4.4 6.2 33.3±9.7 62.3 1629.9±379.0 24

What is Fragile X Syndrome? Fragile X Syndrome Autism spectrum disorder Most common inherited intellectual disability Caused by a mutation in the Fragile X Mental Retardation gene located on the X chromosome Negatively affects synaptic function, plasticity and neuronal connections Results in a spectrum of intellectual disabilities, social anxiety, memory problems Normal Fragile site Fragile X 25

CBD Pharmacology: Fragile X Action Attenuates endocannabinoid signaling Increases 2-AG levels Effect May allow bypass of the FMRP protein deficiency May attenuate/reverse a biological mechanism of abnormal cellular function 16 Interacts with receptors that regulate fear and anxiety 17 5-HT 1A TRPV1 May prove beneficial in patients with FXS TRPV1, Transient receptor potential vanilloid type 1 26

CBD Effects in Fragile X Syndrome CBD may effectively treat Fragile X Syndrome 19-21 In mouse knock-out model, inhibition of the metabolism of 2-AG improves Fragile X syndrome symptoms Normal CBD inhibits the metabolism of 2-AG and thereby increasing availability to modulate neurotransmitter release Fragile site Fragile X 27

CBD Improves Social Anxiety 23 Change from baseline on Visual Analog Mood Scales (n=12) Anxiety Cognitive Impairment Oral CBD 600 mg Placebo Controls Basal Pretest Adaptation Speech Post-speech Basal Pretest Adaptation Speech Post-speech *P<0.05 versus healthy controls +P<0.05 versus CBD-treated social anxiety patients 28

Summary Cannabidiol acts as agonist or antagonist at diverse array of receptors throughout the body, leading to an opportunity of treating a range of conditions Cannabidiol may modulate the endocannabinoid system Theory and preclinical data combine to support the treatment of focal seizures, osteoarthritis, and Fragile X Syndrome with cannabidiol Translatability of examined animal models and early clinical evidence provide confidence that effects will be observed in humans 29

References 1. Russo EB, Hohmann AG. Role of cannabinoids in pain management. In: Comprehensive treatment of chronic pain by medical, interventional, and integrative approaches. Deer TR et al. (eds.) Available at: http://cannabisclinicians.org/wp-content/uploads/2015/05/russo- Hohmann-Role-of-cannabinoids-in-pain-management-from-Deer-2013.pdf. 2. Pertwee RG, Howlett AC, Abood ME, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev. 2010;62:588-631. 3. Elmes MW, Kaczocha M, Berger WT, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem. 2015;290:8711-8721. 4. Wallace MJ, Martin BR, DeLorenzo RJ. Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur J Pharmacol. 2002;452:295-301. 5. Consroe P, Wolkin A. Cannabidiol--antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. J Pharmacol Exp Ther. 1977;201:26-32. 6. Consroe P, Benedito MA, Leite JR, Carlini EA, Mechoulam R. Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol. 1982;83:293-298. 7. Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332:569-577. 30

References cont. 8. Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012;21:344-352. 9. Jones N, Hill T, Stott C, Wright S. Assessment of the anticonvulsant effects and tolerability of GW Pharmaceuticals cannabidiol in the anticonvulsant screening program. Poster presented at the American Epilepsy Society Conference Dec 4-8, 2015. 10.La Porta C, Bura SA, Negrete R, Maldonado R. Involvement of the endocannabinoid system in osteoarthritis pain. Eur J Neurosci. 2014;39:485-500. 11.Mecha M, Feliú A, Iñigo PM, Mestre L, Carrillo-Salinas FJ, Guaza C. Cannabidiol provides longlasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis. 2013;59:141-150. 12.Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol. 2004;143:247-250. 13.Whyte LS, Ryberg E, Sims NA, et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16511-16516. 14.Zubrzycki M, Liebold A, Janecka A, Zubrzycka M. A new face of endocannabinoids in pharmacotherapy. Part I: protective role of endocannabinoids in hypertension and myocardial infarction. J Physiol Pharmacol. 2014;65:171-181. 31

References cont. 15. Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain. 2016;20:936-948. 16. Jung KM, Sepers M, Henstridge CM, Lassalle O, Neuhofer D, Martin H, Ginger M, Frick A, DiPatrizio NV, Mackie K, Katona I, Piomelli D, Manzoni OJ. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun. 2012;3:1080. 17. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics. 2015;12:825-836. 18. Crawford DC, Acuña JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med. 2001;3: 359-371. 19. Di Marzo V1, Maccarrone M. FAAH and anandamide: is 2-AG really the odd one out? Trends Pharmacol Sci. 2008;29:229-233. 20. Bisogno T1, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134:845-852. 21. Grotenhermen F. Pharmacology of cannabinoids. Neuro Endocrinol Lett. 2004;25:14-23. 22. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25:121-30. 23. Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219-1226. 32

A clinical-stage specialty pharmaceutical company dedicated to the development of innovative transdermal synthetic cannabinoid treatments for patients with high unmet medical needs Zynerba Clinical Development Update Terri Sebree President

ZYN002 Phase 1 Results Trials Subjects Dose Safety & Tolerability Pharmacokinetics Cognition/Mood 1 day, 7 day, and 14 day trials 98 healthy volunteers (n=70 ZYN002; n=28 placebo) and 22 epilepsy patients (n=16 ZYN002; n=6 placebo) Daily doses levels 50 to 504 mg CBD in 1%, 2.5% and 4.2% concentrations ZYN002 was safe and well-tolerated at all dose levels and concentrations Transdermal application well-tolerated with minimal erythema No somnolence or fatigue reported Very low incidence of GI events observed Adverse events with ZYN002 in healthy volunteers and epilepsy patients were similar to placebo Favorable CBD pharmacokinetic properties, no differences between healthy volunteers and epilepsy patients CBD plasma concentrations are dose dependent and at steady state do not fluctuate No THC detected in plasma or urine Demonstrated no impairment in cognitive function based on Trail Making, Divided Attention, & PASAT No changes in mood as accessed by IDAS and PANAS 34

Zynerba Clinical Trials Program Investigating CBD in 3 major disease states with high unmet clinical needs Epilepsy STAR Osteoarthritis STOP Fragile X Syndrome 35

Epilepsy Phase 2 Clinical Trial STAR Synthetic Transdermal CAnnabidiol for the TReatment of Epilepsy 8 weeks STAR 1: ZYN2-CL-03 BID for 12 weeks STAR 2: ZYN2-CL-004 BID for 12 months Baseline Assess seizure frequency/type ZYN002 High-Dose CBD 195 mg* ZYN002 Low-Dose CBD 97.5 mg* Open-Label Extension Placebo Randomized (1:1:1), double-blind, placebo-controlled 180 adults *In 4.2% gel ZYN002 High-Dose CBD 195 mg* As needed, dose reduced to: ZYN002 Low-Dose CBD 97.5 mg* 36

ZYN2-CL-03: STAR 1 Efficacy Endpoints Primary Endpoint: Median reduction in seizure frequency per 28-day period comparing baseline with the maintenance period via daily seizure diary Secondary Endpoints Proportion of patients with 50% reduction from baseline in seizure frequency Percent change from baseline in seizure frequency Change from baseline in seizure frequency Seizure-free days 100% seizure-free 37

ZYN2-CL-03: STAR 1 Safety Assessments Adverse events Skin irritation examination Physical and neurological examinations 12-lead ECG Clinical labs 38

ZYN2-CL-03: STAR 1 Demographics* Age, years (mean, range) 39 (18-68) Gender (%) Male Female Race(%) White Asian Other 44 56 87 5 8 *As of 12 December 2016 39

ZYN2-CL-03: STAR 1 Baseline Information* Median Seizure Frequency Median Monthly 10.5 (3-330) AED Use Average=2.6 AEDs Median=3.0 AEDs Anti-Epileptic Drug Patients Anti-Epileptic Drug Patients Levetiracetam (Keppra) 39 Clonazepam 11 Carabamazepine 38 Zonisamide (Zonegran) 10 Lamotrigine 32 Oxcarbazepine 10 Perampanel (Fycompa) 29 Valproate 8 Lacosamide (Vimpat) 24 Phenytoin 3 Topiramate 16 Phenobarbitone 2 *As of 7 December 2016 40

ZYN2-CL-03: STAR 1 Enrollment* Patients n Screened 185 Randomized 105 Completed 37 Enrolled into Star 2 36 *As of 14 December 2016 41

Epilepsy Jacqueline A. French, MD, Director of Clinical Trials at the NYU Langone Medical Center Comprehensive Epilepsy Center & Professor in the Department of Neurology at NYU Langone Director of the Epilepsy Study Consortium and CSO of the Epilepsy Foundation Certified by the American Board of Psychiatry & Neurology in Neurology Published research featured in Lancet Neurology and The New England Journal of Medicine, among other respected publications; research focuses on finding new therapeutic interventions for people with epilepsy and on clinical trial methodology. Worked with the U.S. Food and Drug Administration to develop new trial designs for antiepileptic drug approval Dr. French is a graduate of Brown University s School of Medicine, trained in neurology at Mount Sinai Hospital in New York and completed fellowships in EEG and epilepsy at Mount Sinai Hospital and Yale University Dr. French is not an employee of Zynerba Pharmaceuticals and has been compensated for transportation and meals in relation with this event. The drugs discussed in this presentation have not been approved by the Food and Drug Agency (FDA). Dr. French is a member of Zynerba Pharmaceutical s Scientific Advisory board. All opinions expressed in this presentation belong to Dr. French and do not reflect the opinions of the NYU Langone Medical Center or its Comprehensive Epilepsy Center. 2016 Zynerba Pharmaceuticals, Inc. All rights reserved. Zynerba is a registered trademark of Zynerba Pharmaceuticals, Inc. All other trademarks and registered trademarks are property of their respective owners. 42

Unmet Needs in Epilepsy Management Jacqueline French, MD NYU School of Medicine

Disclosures I am President of the Epilepsy Study Consortium. All consulting is done on behalf of the consortium, and fees are paid to the consortium. The NYU Comprehensive Epilepsy Center receives salary support from the consortium; I have acted as a consultant for Acorda, Biotie, Brabant Pharma, Eisai Medical Research, Glaxo Smith-Kline, GW Pharma, Impax, Johnson and Johnson, Marathon Pharmaceuticals, Marinus, Neusentis, Novartis, Pfizer, Sage, Sunovion, SK life sciences, Supernus Pharmaceuticals, Takeda, UCB, Upsher-Smith, Ultragenyx, Vertex, Zynerba, grants and research from Acorda, Alexza, LCGH, Eisai Medical Research, Lundbeck, Pfizer, SK life sciences, UCB, Upsher-Smith, Vertex I have received grants from NINDS, Epilepsy Therapy Project, Epilepsy Research Foundation, Epilepsy Study Consortium; I am on the editorial board of Lancet Neurology, Neurology Today and Epileptic disorders, and I am an associate editor of Epilepsia. 44

Epilepsy Characterized by a pathologic and enduring tendency to have epileptic seizures Affects 0.5 to 1% of the population 2.9 million people in the US 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, genetic or systemic disorder, and the remainder have an unknown cause 45

Co-morbidities Focal Seizure types Generalized Unknown Etiology Genetic Structural Epilepsy types Metabolic Focal Generalized Combined Generalized & Focal Unknown Immune Infectious Epilepsy Syndromes Unknown 46

Focal Epilepsy/Focal Seizures Focal epilepsy occurs when a portion of the brain is/becomes electrically unstable and acts as a point of seizure onset Not a mild form of epilepsy, because once a seizure starts, it can spread to involve much or even all of the brain The most common epilepsy syndrome (affects between 66% and 75% of adults with epilepsy) 47

Evolution of a Focal Seizure Symptoms with retained awareness Impaired awareness Convulsion Seizure After-effects (Post-Ictal) 48

Focal Seizure With Impaired Awareness This happens when the seizure has spread from its starting point, and involves a larger part of the brain The loss of awareness can be very slight, or severe The patient may not remember this time, or may have a memory of a dream-like state There may be a great deal of movement, or none at all-this looks VERY different in different people The patient may or may not fall 49

Focal Seizure With Impaired Awareness Sometimes this will occur with no warning at all This is very dangerous, as the patient cannot prepare themselves or remove themselves from harm s way The patient may do VERY bizarre things, and they have no control over this-this may look like a psychiatric condition Often the brain is exhausted afterwards, leaving the patient confused, disorganized, and potentially aggressive-this can last for minutes to hours 50

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AED Therapy: Current Status and Unmet Needs We Have Treatment for two thirds of patients We Need Treatment for the one third of adult patients who are refractory Treatment for difficult pediatric syndromes 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 52

Success with Existing AED Regimens Previously Untreated Patients (n = 470) Seizure-free 1 st AED 47% Seizure-free polytherapy 3% Seizure-free monotherapy 2 nd AED 13% Seizure-free monotherapy 3 rd AED 1% Not seizure-free 36% Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319. 53

Role of CBD In Epilepsy 54

Anecdotal Reports - Sir William Gowers (1881) The fits ceased at once, a wonderful change... Devinsky et al. Epilepsia 2014 55

Evidence in Mouse Models ED 50 dose = 80 (65-96) mg/kg ED 50 dose = 144 (102-194) mg/kg Effective in a wide variety of acute seizure rodent models MES, PTZ, audiogenic seizures, penicillin, pilocarpine, transcorneal electroshock, and electrical amygdala kindling 6Hz model of therapy-resistant partial seizure Increased seizure threshold, reduced seizure severity and reduced mortality in generalized seizures Jones NA et al. J Pharmacol Exp Ther. 2010;332(2):569-577 American Epilepsy Society Meeting Dec. 2-6, 2016 56

Efficacy in Animal Models Predicts Efficacy In Patients With Epilepsy Placebo-controlled Trial (1980s) in Secondary Generalized Epilepsy 88% Improved 200-300 mg oral CBD (n=8) or placebo (n=7) for 4.5 months CBD was well tolerated No SAEs Mild somnolence Neurological exams, EEG, and ECGs within normal limits 50% Considerably Improved Cunha JM et al. Pharmacology.1980;21:175-185. 57

Two Doses of CBD are Effective in LGS Lennox-Gastaut Syndrome: Signficant reduction in drop seizures 1 with CBD (10 mg/kg and 20 mg/kg) vs placebo CBD 10 mg/kg (n=73) CBD 20 mg/kg (n=76) Placebo (n=76) -17% -37%* -42% *P=0.0016 P=0.0047 CBD Oral Solution, 100 mg/ml in sesame oil 1.Defined as atonic, tonic, or tonic-clonic seizures involving the entire body, trunk, or head that led or could have led to a fall, injury, slumping in a chair, or hitting the patient's head on a surface. 58

Significant Reductions in Convulsive and Total Seizures in Dravet Syndrome 50 40 30 Convulsive Seizures (%) Total Seizures (%) 50 P=0.0052 P=0.0123 41 P=0.0234 39 40 37 P=0.0335 29 30 20 10 13 16 20 10 9 10 0 Treatment Maintenance 0 Treatment Maintenance CBD (n=61) Placebo (n=59) American Epilepsy Society Meeting Dec. 2-6, 2016 59

Phase 3 Safety in LGS and Dravet 86-93% of patients reported mild/moderate AEs in LGS and Dravet studies, respectively Most common AEs for both studies were: Somnolence, diarrhea, decrease appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection, and convulsion Elevation in ALT or AST (> 3 X ULN)* observed 3 CBD patients withdrew from treatment 6 CBD patients withdrew from treatment All elevations resolved *No patients met standard criteria for drug-induced liver injury (Hy s law) with concurrent elevated bilirubin > 2 X ULN. American Epilepsy Society Meeting Dec 2-6, 2016 60

Summary Focal epilepsy is the most common epilepsy in adults Unmet needs remain for antiepileptic therapies There are plausible potential mechanisms of action for CBD in epilepsy Well-controlled clinical trial data demonstrating the efficacy of CBD in severe refractory epilepsies which should translate to efficacy in focal seizures in adults 61

Osteoarthritis Phase 2 Clinical Trial STOP Synthetic Transdermal Cannabidiol for Treatment of Knee Pain due to Osteoarthritis 1 week 7-10 days Every 12 hours for 12 weeks ZYN002 High-Dose: CBD 250 mg* Washout Baseline ZYN002 Low-Dose: CBD 125 mg* Placebo *In 4.2% gel Randomized (1:1:1), double-blind, placebo-controlled 300 adults 63

ZYN2-CL-005: STOP 1 Efficacy Endpoints Primary Endpoint: Change from baseline in the weekly mean of the 24-hour average worst pain score at Week 12 Secondary Endpoints Change from baseline in the WOMAC Pain, Stiffness, and Physical Function Subscales Assessments Weeks 4, 8, 12 Responder rate based on 30% reduction in worst pain severity Weeks 4, 8, 12 Responder rate based on 50% reduction in worst pain severity Weeks 4, 8, 12 Change from baseline in the weekly mean of the 24-hour average worst pain score Percentage of participants using rescue medication Physician assessment of presence of joint effusion Weeks 4, 8 Over 12 weeks Over 12 weeks 64

ZYN2-CL-005: STOP 1 Safety Assessments Adverse events Skin irritation examination Physical and neurological examinations 12-lead ECG Clinical labs 65

ZYN2-CL-005: STOP 1 Baseline Information* Worst Knee Pain Score (During Baseline) Mean=6.3 In recent OA placebo controlled studies, the worst knee pain during baseline has ranged from 6.1 to 6.7. *As of 12 December 2016 66

ZYN2-CL-005: STOP 1 Demographics* Age, years (mean, range) 62 (41-75) Gender (%) Male Female Race(%) White Asian Other 49 51 95 1 4 *As of 12 December 2016 67

ZYN2-CL-005: STOP 1 Enrollment* Patients n Screened 249 Randomized 150 *As of 14 December 2016 68

Osteoarthritis Daniel J. Clauw, MD Professor of Pain Management and Anesthesiology at the University of Michigan Health System Director of the Chronic Pain and Fatigue Research Center at the University of Michigan Oversees a multidisciplinary group that performs both mechanistic studies and clinical trials in overlapping conditions characterized by chronic pain and fatigue, including fibromyalgia, chronic fatigue syndrome, and Gulf War Illnesses Served as the first Associate Dean for Clinical and Translational Research within the University of Michigan Medical School, and PI of the UM Clinical and Translational Sciences Award (CTSA) until January 2009 Board certified in Internal Medicine and Rheumatology Dr. Clauw completed his M.D. at the University of Michigan s Medical School and completed his internal medicine residency and rheumatology fellowship at Georgetown University School of Medicine Dr. Clauw is not an employee of Zynerba Pharmaceuticals and has been compensated for transportation and meals in relation with this event. The drugs discussed in this presentation have not been approved by the Food and Drug Agency (FDA). Dr. Clauw is a member of Zynerba Pharmaceutical s Scientific Advisory board. All opinions expressed in this presentation belong to Dr. Clauw and do not reflect the opinions of the University of Michigan Health System. 2016 Zynerba Pharmaceuticals, Inc. All rights reserved. Zynerba is a registered trademark of Zynerba Pharmaceuticals, Inc. All other trademarks and registered trademarks are property of their respective owners. 69

Cannabidiol (CBD) for the Treatment of Osteoarthritis Daniel J. Clauw, MD dclauw@umich.edu Professor of Anesthesiology, Medicine (Rheumatology), and Psychiatry Director, Chronic Pain and Fatigue Research Center The University of Michigan

Disclosures Consulting Pfizer, Forest, Eli Lilly, Merck, J & J, Nuvo, Jazz, Abbott, Cerephex, Iroko, Tonix, Theravance, Samumed, Depomed, Zynerba Research support Pfizer, Cypress Biosciences, Forest, Merck, Nuvo, Cerephex, Lilly Went to the University of Michigan in the 70 s 71

Osteoarthritis (OA) A common musculoskeletal condition and long-term chronic disease involving the thinning of cartilage in joints which results in bones rubbing together, creating stiffness, pain, and impaired movement 1 Age-related Associated with multiple risk factors Obesity Lack of exercise Genetic predisposition Bone density Occupational injury Trauma Gender An estimated 31M people receive RX treatment for OA 1. http://www.who.int/medicines/areas/priority_medicines/bp6_12osteo.pdf 72

OA Patient Profile Extremely heterogeneous, from very mild symptoms and no need for medication to severely disabling Generally elderly, female>male, many comorbidities Many therapies have become less attractive over time because of limited efficacy and toxicity (NSAIDs, opioids) Surgery is definitive therapy but there are surprisingly high failure rates (especially knee arthroplasty) and rehabilitation is difficult Significant unmet need 73

OA of the Knee: Old Paradigm Classic peripheral pain syndrome Poor relationship between structural abnormalities and symptoms 1 In population-based studies 2 : o 30-40% of individuals who have grade 3/4 K/L radiographic OA have no symptoms o 10% of individuals with severe pain have normal radiographs We sometimes delude ourselves into thinking that our current therapies are adequate NSAIDs, acetaminophen, and even opioids have small effect sizes 3,4 Arthroplasty does not predictably relieve pain 1. Creamer P et. al. Br J Rheumatol. 1997; 36:726-728.; 2. Creamer P et. al. Arthritis Care Res. 1998;11:60-65.; 3 Bjordal JM et. al. Eur J Pain. 2007;11:125-1238.; 4. Zhang W et. al. Ann Rheum Dis. 2004;63:901-907. 74

OA of the Knee: New Paradigm Two alternate mechanisms are receiving increased attention Inflammation Centralized pain Was considered a non-inflammatory disease until the 1990 s Most OA patients have some low-grade inflammation Characteristics Not as severe as classic autoimmune disorders Clinically important mechanistic feature that best differentiates painful from painless OA Precise rates of inflammation depend on how hard you look (exam < imaging < biopsy) 75

Role of Cannabidiol in OA 76

Mechanisms of CBD Analgesic Action Peripheral CB 2 activation leads to fairly pronounced anti-inflammatory effect May have less effect on nociceptive pain that is not of inflammatory origin Central (presumably mainly via CB 1 ) Dissociative effects reduce: Connectivity between limbic and sensory brain regions The unpleasantness of pain 1 Lee et. al. Pain. 2013;154:124 134 77

Mechanistic Characterization of Pain Any combination may be present in a given individual Peripheral (nociceptive) Peripheral Neuropathic Centralized Pain Inflammation or mechanical damage in tissues NSAID, opioid responsive Responds to procedures Damage or dysfunction of peripheral nerves Responds to both peripheral (NSAIDs, opioids, Na channel blockers) and central (TCA s, neuroactive compounds) drug therapy Characterized by central disturbance in pain processing (diffuse hyperalgesia/allodynia) Responsive to neuroactive compounds altering levels of neurotransmitters involved in pain transmission Classic examples Acute pain due to injury Osteoarthritis Rheumatoid arthritis Cancer pain Classic examples Diabetic neuropathic Mixed Pain States pain Post-herpetic neuralgia Classic examples Fibromyalgia Irritable bowel syndrome TMJD Tension headache 78

Neural Influences on Pain and Sensory Processing Facilitation Substance P Glutamate and EAA Serotonin (5HT 2a, 3a ) Nerve growth factor + Inhibition Descending antinociceptive pathways Norepinephrineserotonin (5HT 1a,b ), dopamine Opioids GABA Cannabinoids - CBD Schmidt-Wilcke T, Clauw DJ. Nat Rev Rheumatol. Jul 19 2011. Clauw DJ. JAMA. 2014. 79

Centralization Continuum Proportion of individuals in chronic pain states that have centralized their pain Peripheral Centralized Acute pain Osteoarthritis SC disease Fibromyalgia RA Ehler s Danlos Tension HA Low back pain TMJD IBS 80

Pragmatic Advice for Using Cannabinoids in 2016 Where possible use a synthetic cannabinoid or cannabinoid extract of consistent and known potency The strongest recommendation based on current benefit:risk data: Use cannabinoids instead of opioids (ie, when all else fails) for centralized pain states Data from US suggest that legalizing cannabis in a state leads to fairly dramatic reductions in opioid overdoses 1 Use with caution in individuals under age 25 1. Bachhuber MA et. al. JAMA Int Med 2014;174(10):1668-1673. 81

Summary The endocannabinoid system is widely distributed in the human body and there is strong biological plausibility that these can be effective and safe analgesics at the right dose and in the right person CBD can exert analgesic effects in the periphery (mainly anti-inflammatory) and CNS (dissociate individuals from the sensory experience of pain) For treatment of clinical pain with cannabinoids most clinical evidence that they are effective in neuropathic and centralized pain. Animal data suggest CBD effectiveness in OA. Clinical trials are ongoing to evaluate efficacy and safety in OA populations 82

A clinical-stage specialty pharmaceutical company dedicated to the development of innovative transdermal synthetic cannabinoid treatments for patients with high unmet medical needs

Fragile X Syndrome Phase 2 Exploratory Clinical Trial Day 1 to Week 6 Weeks 6 to 12 Screening Titration Maintenance Target for enrollment is 16 patients Dosing initiated at CBD 50 mg; may be titrated up to 250 mg* Open label, doses of CBD 50 mg, 100 mg, or 250 mg* *In 4.2% gel 84

Fragile X Syndrome Steven Siegel, MD, PhD Chair of the Department of Psychiatry and Behavioral Sciences at the Keck School of Medicine, University of Southern California Held a number of faculty, hospital and administrative appointments during a 20 year tenure at the University of Pennsylvania Noted physician and researcher with an expertise in schizophrenia and psychosis and has published more than 130 manuscripts spanning topics related to drug abuse, basic research in animal models of schizophrenia and autism, as well as clinical aspects of schizophrenia Serves on the editorial board of several leading journals related to psychiatry and neurobiology Dr. Siegel received his M.D. and Ph.D. in Neurobiology at the Mount Sinai School of Medicine, completed an undergraduate degree in Neuroscience at Colgate University and finished his residency in Psychiatry and a Fellowship in Neuropsychiatry at the University of Pennsylvania before joining the faculty Dr. Siegel is not an employee of Zynerba Pharmaceuticals and has been compensated for transportation and meals in relation with this event. The drugs discussed in this presentation have not been approved by the Food and Drug Agency (FDA). Dr. Siegel is a member of Zynerba Pharmaceutical s Scientific Advisory board. All opinions expressed in this presentation belong to Dr. Siegel and do not reflect the opinions of the University of Southern California or the Keck School of Medicine. 2016 Zynerba Pharmaceuticals, Inc. All rights reserved. Zynerba is a registered trademark of Zynerba Pharmaceuticals, Inc. All other trademarks and registered trademarks are property of their respective owners. 85

Overview of Fragile X Syndrome Steven Siegel, MD PhD Chair Department of Psychiatry and Behavioral Sciences Keck School of Medicine, USC

Disclosures Consulting Zynerba Research support Astellas, Merck 87

Introduction to Fragile X Syndrome Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in males and is also a significant cause of intellectual disability in females. Leading mono-genetic cause of mental retardation X-linked disease Incidence of 1:4000 males, 1:8000 females Occurs in all racial and ethnic groups 88

Causes Are Genetic Mutation of Fragile X Mental Retardation One (FMR-1) gene on X chromosome This gene cannot produce protein necessary for normal brain development Most commonly an increase in the number of CGG trinucleotide repeats Typical: 6-44 repeats Premutation: 55-200 repeats Full mutation: > 200 repeats 89

How is Fragile X Diagnosed? DNA test: PCR to identify triplet repeat in FMR1 gene Prenatal testing Amniocentesis Chorionic villus sampling Genetic counseling PCR, polymerase chain reaction 90

Signs and Symptoms Moderate intellectual disability boys (mild for girls) Facial appearance prominent forehead, chin and protruding ears Speech and language delay Behavioral issues such as hyperactivity, temper tantrums, hand flapping, poor eye contact and problems with impulse control Emotional problems and ADHD Eye, orthopedic, heart and skin problems In the premutation carrier: Mild intellectual disability Shy personality and selective lack of speech 91

FXS Has a Substantial Financial Burden on Families 60% Families Reporting Financial Burden 52% 39% 29% Families Changing Work Hours for Caregiving 65% 48% 36% 36% FXS ASD Category ASD 1 ID FXS ASD and ID Only Only and ID Category 2 ASD Only ID Only Ouyang et al. Res Dev Disabil. 2014;35:1518-1527. ASD, autism spectrum disorder; ID, intellectual disability 92

Anxiety is Common in FXS Families Reporting Anxiety in the Affected Child 67% 54% 45% 25% FXS ASD and ID Ouyang et al. Res Dev Disabil. 2014;35:1518-1527. Category 1 ASD Only ID Only 93

Treatments for FXS Currently no known cure Special education services Diet Behavioral therapy Drugs Stimulants Antipsychotics 94

Why Might CBD Work When So Many Other Medicines Have Failed? 95

Rationale for CBD in FXS Clinical presentation includes anxiety, behavior issues Influenced by the endocannabinoid system CBD A rational choice for FXS based on mechanistic activity Decreased anxiety (primary endpoint) Increased frustration tolerance (secondary endpoint) Future endpoints: Increased attention Increased cognitive function Decreased irritability Increased social function 96

A Compelling Investment Opportunity Why Zynerba Could Be the Next Explosive Growth Cannabinoid Company We believe ZYN002 (CBD gel) for focal seizures is a significantly de-risked lead candidate Reliable animal models show efficacy of CBD in epilepsy Third party studies have shown activity of CBD in reducing focal seizures STAR 1 trial is well powered to show clinical benefit versus placebo Zynerba s transdermal approach has significant benefits Patent protection Synthetic manufacturing process can be scaled for large volume markets Attractive COGS and no royalty obligations should result in high gross margins Consistent, controlled blood levels of drug and potentially a better safety profile than oral formulations Focused on valuable unmet medical need markets ~ 1.5 million adult epilepsy patients in the US with focal seizures; ~ 31 million OA patients; and Orphan designation for Fragile X Syndrome Major clinical milestones with ZYN002 anticipated over next 6 months 98

Closing Summary Rationale for Why CBD in Epilepsy, OA, and Fragile X Syndrome? Deeper Understanding of Clinical development and status to date Opportunity to hear from Key Opinion Leaders and ask questions Understand why ZYNE is a compelling investment opportunity 100