Zynerba Pharmaceuticals : August, 2020 Corporate Presentation

Corporate Overview

August 2020

Forward-Looking Statements

THE STATEMENTS IN THIS PRESENTATION MAY INCLUDE FORWARD-LOOKING STATEMENTS WITHIN THE MEANING OF THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995. THESE STATEMENTS, AMONG OTHER THINGS RELATE TO THE FUTURE OPERATIONS, OPPORTUNITIES OR FINANCIAL PERFORMANCE OF ZYNERBA PHARMACEUTICALS, INC. WE MAY, IN SOME CASES, USE TERMS SUCH AS "PREDICTS," "BELIEVES," "POTENTIAL," "PROPOSED," "CONTINUE," "ESTIMATES," "ANTICIPATES," "EXPECTS," "PLANS," "INTENDS," "MAY," "COULD," "MIGHT," "WILL," "SHOULD" OR OTHER WORDS THAT CONVEY UNCERTAINTY OF FUTURE EVENTS OR OUTCOMES TO IDENTIFY THESE FORWARD-LOOKING STATEMENTS. SUCH STATEMENTS ARE SUBJECT TO NUMEROUS IMPORTANT FACTORS, RISKS AND UNCERTAINTIES THAT MAY CAUSE ACTUAL EVENTS OR RESULTS TO DIFFER MATERIALLY FROM THE COMPANY'S CURRENT EXPECTATIONS, INCLUDING THE FOLLOWING: THE COMPANY'S CASH AND CASH EQUIVALENTS MAY NOT BE SUFFICIENT TO SUPPORT ITS OPERATING PLAN FOR AS LONG AS ANTICIPATED; THE RESULTS, COST AND TIMING OF THE COMPANY'S CLINICAL DEVELOPMENT PROGRAMS, INCLUDING ANY DELAYS TO SUCH CLINICAL TRIALS RELATING TO ENROLLMENT OR SITE INITIATION; CLINICAL RESULTS FOR THE COMPANY'S PRODUCT CANDIDATES MAY NOT BE REPLICATED OR CONTINUE TO OCCUR IN ADDITIONAL TRIALS AND MAY NOT OTHERWISE SUPPORT FURTHER DEVELOPMENT IN A SPECIFIED INDICATION OR AT ALL; ACTIONS OR ADVICE OF THE U.S. FOOD AND DRUG ADMINISTRATION AND FOREIGN REGULATORY AGENCIES MAY AFFECT THE DESIGN, INITIATION, TIMING, CONTINUATION AND/OR PROGRESS OF CLINICAL TRIALS OR RESULT IN THE NEED FOR ADDITIONAL CLINICAL TRIALS; THE COMPANY'S ABILITY TO OBTAIN AND MAINTAIN REGULATORY APPROVAL FOR ITS PRODUCT CANDIDATES, AND THE LABELING UNDER ANY SUCH APPROVAL; AND THE COMPANY'S EXPECTATIONS REGARDING ITS ABILITY TO OBTAIN AND ADEQUATELY MAINTAIN SUFFICIENT INTELLECTUAL PROPERTY PROTECTION FOR ITS PRODUCT CANDIDATES. THESE AND OTHER RISKS ARE DESCRIBED IN OUR FILINGS WITH THE SECURITIES AND EXCHANGE COMMISSION, AVAILABLE AT WWW.SEC.GOV. ANY FORWARD-LOOKING STATEMENTS THAT THE COMPANY MAKES IN THIS PRESENTATION SPEAK ONLY AS OF THE DATE OF THIS PRESENTATION. THE COMPANY ASSUMES NO OBLIGATION TO UPDATE FORWARD-LOOKING STATEMENTS WHETHER AS A RESULT OF NEW INFORMATION, FUTURE EVENTS OR OTHERWISE, AFTER THE DATE OF THIS PRESENTATION.

© 2020 Zynerba Pharmaceuticals, Inc. All rights reserved. Zynerba and Zygel are trademarks of Zynerba Pharmaceuticals, Inc. All other trademarks and registered trademarks are property of their respective owners.

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Zynerba Pharmaceuticals (NASDAQ: ZYNE)

A Rare/Near-Rare Neuropsychiatric Company

• Deep pipeline focused on high unmet medical needs; translating into multi-billion dollar market opportunity with Zygel™(Cannabidiol Gel)
• Currently pursuing four neuropsychiatric indications:
• • Fragile X syndrome (FXS) - pivotal trial complete
  • Developmental and epileptic encephalopathies (DEE) - Phase 2 complete
  • Autism spectrum disorder (ASD) - Phase 2 complete
  • 22q11.2 deletion syndrome (22q) - Phase 2 ongoing
• Experienced team
• • Proven development and commercialization track record in transdermal delivery, orphan diseases, neurology, and psychiatry
• Well capitalized with cash runway expected into 4Q2021
• Multiple expected near term milestones

3

Deep Clinical Pipeline

Zygel

Cannabidiol Gel

Expected Milestones

Discussions with FDA in 2H2020 to discuss pivotal results in FXS patients with full methylation

Results of discussions with FDA on clinical path forward in 3Q2020

Discuss clinical path forward with

FDA in 2H2020

Completion of enrollment once COVID-19 restrictions in Australia are eased

*Orphan Drug Designation

4

Zygel (ZYN002) Cannabidiol (CBD) Gel

Differentiated Transdermal	Unique	Neuropsych
Mechanism
Indications
	of Action

First & only patent-	Formulation	CBD modulates	Potential utility in rare /
protected (2038),	delivers CBD	multiple receptors and	near-rare
permeation-enhanced,	through the	mediates numerous	neuropsychiatric
pharmaceutically-	epidermis and into	pathways, including	conditions
produced CBD gel	the circulatory	the endocannabinoid	FDA Fast Track and
	system	pathway
			Orphan Drug
			designations in FXS

5

Fragile X Syndrome (FXS)

6

Fragile X Syndrome (FXS) Overview

• Rare genetic developmental disability
• Leading known cause of both inherited intellectual disability and autism spectrum disorder
• Symptoms linked to deficiencies in the endocannabinoid (EC) system
• • System of neurotransmitters regulates emotional responses, behavioral reactivity to context, social interaction
  • Mutation in FMR1 gene on the X chromosome causes dysregulation of the EC system and results in core cognitive, social, and behavioral symptoms of FXS
  • CBD modulates EC system
  • • Increases availability of endocannabinoids (anandamide, 2-AG)
• Affects ~71K people in U.S.
• No approved drugs indicated for FXS

7

Fragile X Syndrome (FXS) Overview

Full Methylation (FMet) of FMR1 Gene is a Biomarker for Disease Impact

• FMR1 gene codes for production of FMRP which is vital to synapse development
• Mutation manifests as multiple repeats of a DNA segment (CGG) in FMR1
• • No Fragile X: Segment repeats 5 to 40 times; normal production of FMRP
  • Premutation Fragile X: Segment repeats 50 to 200 times; reduced FMRP production
  • Full mutation FXS: Segment repeats >200 times; usually causes severely impacted or non-functionalFMR1 and leads to core FXS behaviors
• Methylation of FMR1 also plays a role in determining functionality of the gene
• • At ≥90% methylation ("full methylation" or "FMet"), FMR1 is silenced
  • No FMRP is produced: Systems and processes affected by FMRP become dysregulated
• Patients with full mutation FXS and full methylation of FMR1 are generally the most severely impacted by the disorder: lower IQ, more impacted behaviors
• • ~60% of patients with full mutation FXS are believed to fall into this category

8

CONNECT-FX: A Pivotal Trial In FXS

Clinical study Of CaNNabidiol (CBD) in ChildrEn and AdolesCenTs

with Fragile X (CONNECT-FX)

12 weeks*		12 months

Treatment

212 patients randomized

Three through 17 years of age

Zygel (n=110)

250 mg daily

500 mg daily

Screening	(weight-based dose)	Open label extension (OLE)

Placebo (n=102)

Mirrors Zygel administration

Patients randomized (1:1) to receive

either Zygel or placebo

*2 weeks placebo period, followed by 12 weeks treatment.

9

CONNECT-FX

Baseline Characteristics

	Placebo	Zygel	Total
n
102	110	212
Age (years)
9.8	9.6	9.7
Sex - Males, n (%)
78 (76%)	81 (74%)	159 (75%)
Weight (kg)
Median
34.3	36.8	35.7
Range (Min, Max)
15.6, 104.7	14.6, 87.0	14.6, 104.7
>35kg, %
48%	56%	52%
Baseline
psychoactive	66%	57%	62%
medications, %

10

CONNECT-FX: Qualitative Caregiver Reported Behavioral Survey

Utilizing the Qualitative Caregiver Reported Behavioral Survey, caregivers were asked to describe

their most important behavioral challenges at baseline

Top 10 Classifications of Behavioral Challenges

0%	10%	20%	30%	40%	50%	60%	70%	80%	90%	100%
Anxiety								66%
Aggression						42%
Temper Tantrums				33%
Easily distracted				30%
Irritable/Whiny				29%
Excessive Activity				28%
Repetitive Speech				26%
Communication issues				23%
Elopement				22%
Seeks Isloation from others				22%

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CONNECT-FX: A Pivotal Trial In FXS

• Primary endpoint:
• • Change from baseline to end of treatment in ABC-CFXS Social Avoidance subscale
• Key secondary endpoints:
• • Change from baseline to end of the treatment in
  • • ABC-CFXS Irritability subscale score
    • ABC-CFXS Socially Unresponsive/Lethargic subscale score
  • Improvement in Clinical Global Impression (CGI-I) at end of treatment, anchored to FXS behaviors
• Aligned with FDA's 'Voice of the Patient' Guidance
• • Captured qualitative data on clinical relevance of FXS behaviors

Zygel did not statistically significantly separate from placebo on the primary or

key secondary endpoints in the full analysis set

12

CONNECT-FX: Rationale for Pre-Planned Ad Hoc Analysis

Building on the Scientific Evidence

BackgroundCONNECT-FX

• Methylation of genes is considered to be important in numerous pathological disorders including FXS
• Methylation has been associated with the mechanism of mGluR5 in FXS
• Currently, treatment options are limited for many of these disorders
• The degree of methylation can influence the severity of FXS symptoms

• Pre-plannedanalysis of the most severely impacted patients defined by patients having ≥90% methylation ("full methylation" or "FMet") of the impacted FMR1 gene
• • 80% of the patients enrolled in CONNECT-FX were FMet
• Analysis to explore differences in two groups:
• • FMet group (n=167)
  • Non-FMetgroup (n=42)

13

CONNECT-FX

Full Data Set, FMet and Non-FMet

Patient Disposition: FMet Group Comprised 80% of Full Data Set Patients

Patients	Full Data Set	FMet	Non-FMet Group
Group
Randomization (ITT)	212	169	42
Full Analysis set
210	167	42

• One patient did not receive study medication after randomization and one patient did not have post-baseline efficacy assessments resulting in 210 patients in Full Analysis set
• One patient with FMR1 gene deletion was not included in either the FMet or Non-FMet groups

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CONNECT-FX: Demographics and Baseline Characteristics

Similar in the Full Data Set and FMet Group

		Full Data Set Group		FMet Group
	Placebo	Zygel	Total	Placebo	Zygel	Total
n	102	110	212	77	92	169
Age (years)
9.8	9.6	9.7	9.6	9.2	9.4
Sex - Males (%)
78 (76%)	81 (74%)	159 (75%)	54 (70%)	65 (71%)	119 (70%)
Weight (kg)
Median
34.3	36.8	35.7	33.9	35.7	35.0
Range (Min,
15.6, 104.7	14.6, 87.0	14.6, 104.7	15.6, 104.7	14.6, 87.0	14.6, 104.7
Max)
>35kg, %	48%	56%	52%	46%	53%	50%
Baseline
psychoactive	66%	57%	62%	65%	54%	59%
medications, %

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Pre-Planned Ad Hoc Results: Fmet Group

Zygel Achieved Statistical Significance on Social Avoidance: Changes From Baseline to Week 12 (ABC-CFXS)

Primary

Endpoint

Secondary Endpoints

		Placebo			Zygel
		N=76			N=91
Endpoints	Baseline	Week 12	Week	Baseline	Week 12	Week	Treatment	Treatment
	Mean	Mean	12	Mean	Mean	12	Difference	p-value
	(SE)	(SE)	Median	(SE)	(SE)	Median	/ Odds
			Percent			Percent	Ratio†
			Change			Change
Social	7.18 (0.32)	5.41	-21.1	7.12	4.32	-40.0	-1.00	0.020*
Avoidance	(0.42)	(0.29)	(0.33)
Irritability	28.0	24.11	-11.6	29.36	22.69	-24.3	-2.30	0.091
(1.56)	(1.56)	(1.37)	(1.42)
Socially	13.17	10.29		13.30	9.03
Unresponsive	-20.5	-30.8	-1.17	0.135
(0.85)	(0.80)	(0.68)	(0.67)
/Lethargic
CGI-I	-	35.7%		-	51.1%		1.88†	0.056

*Statistically significant

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CONNECT-FX:ABC-CFXS Social Avoidance Changes From Baseline to Week 12 in FMet Group

In placebo group, the most common change (mode) in

Social Avoidance was zero

Each dot represents a

patient

Number of patients

24

22

20

18

16

14

12

10

8

6

4

2

0

Placebo

mode = 0

Placebo (n=75)

Improvement

-12

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

Change from baseline to week 12

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CONNECT-FX:ABC-CFXS Social Avoidance Changes From Baseline to Week 12 in FMet Group

Zygel group demonstrated greater improvement versus placebo

Number of patients

24

22

20

18

16

14

12

10

8

6

4

2

0

Nearly twice (1.9x) as many Zygel children experienced changes of

4 or more points relative to placebo (n=36 vs n=19)

Zygel

mode = −4

3.5-times as many Zygel children made improvements of 7 or more points in Social Avoidance relative to placebo (n=14 vs n=4)

Each dot represents a

patient

Placebo

mode = 0	Placebo (n=75)
		Zygel (n=88)

Values greater than zero

Placebo: 9/75 = 12.0%

Zygel: 12/88 = 13.6%

-12

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

Change from baseline to week 12

Data represent observed cases: 4 patients did not	18
have Week-12ABC-CFXS assessment

CONNECT-FX: Caregiver Global

Impression-Change: FMet Group

Change from Baseline to Week 12: Broad Shifts Towards

Global Improvement

Social	Irritable and
Avoidance	Disruptive	Social
and Isolation	Behaviors	Interactions
70		p=0.002*

Overall

Behavior

of patients

		p=0.038*
60
					p=0.028*
50
40

p=0.052

Much better Moderately better A little better

Percentage

30
20
10
0		Placebo	Zygel	Placebo	Zygel
Placebo	Zygel

*Statistically significant

P-values indicate "betterment" on Zygel vs "betterment" on placebo

	Placebo n=76
	Zygel n=91
Placebo	Zygel

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Zygel Advantages Observed in Social Avoidance Are Supported by Caregiver and Clinical Global Impression Improvements in FMet Group

Primary Endpoint: ABC-CFXS Social Avoidance Subscale

• Statistically significantly improvement vs. placebo (p=0.020*)

Caregiver Global Impression - Change at Week 12 (Four Domains)

• Statistically significant improvement vs. placebo in Social Interactions (p=0.002*)
• Statistically significant improvement vs. placebo in Irritable & Disruptive Behaviors (p=0.028*)
• Statistically significant improvement vs. placebo in Social Avoidance & Isolation (p=0.038*)
• Trend toward statistical significance in improvement in Overall Behavior vs. placebo (p=0.052)

Clinical Global Impression - Improvement** (anchored to FXS behaviors; clinician rated)

• Trend toward statistical significance vs. placebo (p=0.056)

• Statistically significant
• Not specific to Social Avoidance

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CONNECT-FX: Safety

Zygel Was Very Well Tolerated in FXS Patients

• Zygel was very well tolerated
• • Safety profile consistent with previously released data from all other Zygel trials
  • No safety signal identified
• No serious or severe adverse events reported during the study
• All treatment-emergent adverse events (TEAEs; any event, whether unrelated or related to study drug) were mild or moderate
• • Most common treatment-related TEAE: application site pain
  • • Zygel: 6.4%; placebo: 1.0%
  • Seven total psychiatric disorder TEAEs; 5 were in placebo group
• Laboratory values for chemistry and hematology comparable between placebo and Zygel groups; no clinically relevant abnormalities in either group
• • No clinically significant changes to liver function tests

21

Next Steps in Fragile X Program

• Discuss CONNECT-FX data and the pathway for submitting a New Drug Application (NDA) with FDA
• Pivotal data to be published and presented at upcoming medical meetings

22

Autism Spectrum Disorder (ASD)

in children and adolescents

23

ASD in Pediatrics Overview

• Near-raredisorder affecting ~1MM pediatric and adolescent patients
• Symptoms include
• • Irritability
  • Anxiety
  • Restricted, repetitive patterns of behavior
  • Impairments in social communication
  • Deficits in verbal and non-verbal communication
  • Deficits in developing, understanding and maintaining relationships
• Most diagnosed after age 4; can be diagnosed as early as age 2
• Significant unmet medical need
• • Accelerating rate of diagnosis but only two FDA approved products
  • • Both atypical antipsychotics have significant side effect profile
    • Neither approved to address the key symptoms of social impairment and anxiety

24

Rationale for Developing Zygel in ASD

• Newer studies suggest ASD is linked to disruption in the EC system
• • Altered anandamide signaling may contribute to ASD-related social and communication impairments
  • EC system modulates many cellular functions and molecular pathways altered in ASD: imbalanced GABAergic, glutamatergic transmission, oxidative stress, immune dysregulation and altered energy metabolism
• Clinical and anecdotal data demonstrate that children dosed with CBD displayed an improvement in social avoidance and anxiety
• • CBD may modulate the EC system and improve certain autism-related behaviors
• Two recent US patents directed to methods of treating ASD by transdermally administering synthetic or purified cannabidiol, respectively, provide IP protection to 2038

25

BRIGHT Phase 2 Trial in ASD

Positive Topline Data Reported on May 27, 2020

Open-LaBel ToleRabIlity and Efficacy Study of ZYN002 Administered as a

Transdermal Gel to CHildren and AdolescenTs with Autism Spectrum Disorder

			14 Weeks: COMPLETE		24 Weeks
			37 patients enrolled
			Three through 17 years of age
Screening			Zygel			Open label extension
			14 Weeks
			Weight based dosing:
			250 mg to 500 mg daily

Efficacy assessments (primary efficacy assessment = week 14 vs baseline) :

• Aberrant Behavior Checklist (ABC-C) • Clinical Global Impression - Improvement (CGI-I) and

• Parent Rated Anxiety Scale - Autism	Severity (CGI-S)
	Spectrum Disorder (PRAS-ASD)	• Qualitative Caregiver Reported Behavioral Problems Survey
•	Autism Parenting Stress Index
•	Autism Impact Measure (AIM)

26

BRIGHT Trial Patient Populations

Baseline Patient Population: BRIGHT

Patients enrolled (n)	37
Included in safety analysis	37
Included in efficacy analyses	36*
Discontinuations	9
Patients completing 14-week trial	28

* One patient was lost to follow up and did not have post-dosing efficacy assessments

27

BRIGHT Trial Patient Demographics

Baseline Patient Demographics

Patients enrolled, n	37
Age, years
Mean (range)	9.2 (3-16)
Sex, n (%)
Male	34 (91.9%)
Female	3 (8.1%)
Race, %	70.3%
White
Asian	8.1%
Native Hawaiian or other Pacific Island	2.7%
Other	18.9%
Time to diagnosis, years	5.4
Underlying medication, %
Subjects entering with ≥1 underlying medication	92%
Subjects entering with ≥1 underlying	65%
psychotropic medication (includes anti-
depressants, anxiolytics and antipsychotics)

28

Strong Safety and Tolerability Profile in BRIGHT Trial in ASD

• Well tolerated; consistent with previously released data
• Fewer than half of patients experienced an adverse event (AE); most were mild and transient
• Only 14% of patients experienced a treatment-related AE
• • All application site-related
• No severe or serious AEs reported during the study.

29

Percent Improvement in ABC-C Subscale Scores at Week 14 vs. Baseline

Statistical Significance Achieved in All Subscales

Mean % Improvement from Baseline

45

40

35

30

25

20

15

10

5

0

P=0.0002*	p<0.0001*
p<0.0001*	p<0.0001*
42.5%		p<0.0001*
39.1%
39.1%	36.4%	35.6%
		42.6%

Baseline: 30.3	Baseline: 7.4	Baseline: 12.3	Baseline: 25.1	Baseline: 37.0
Irritability	Inappropriate	Stereotypy	Social withdrawal	Hyperactivity
	Speech
		ABC-C Subscales

• Statistically significant

30

ABC-C Responses Supported by Other Efficacy Assessments

Results of other efficacy assessments support the results demonstrated in the ABC-C, including:

• Parent Rated Anxiety Scale - Autism Spectrum Disorder (PRAS-ASD):
• • Mean improvement of 46% at week 14 from baseline (p<0.0001)
• Clinical Global Impression - Improvement (CGI-I)
• • 57% of patients were rated by clinician as Very Much or Much Improved at week 14
• Zynerba intends to present additional data at future medical meetings

Next steps: Meet with FDA in 2H2020 to discuss clinical path forward

31

22q11.2 Deletion Syndrome

(22q)

32

22q Overview

• Most common contiguous gene deletion syndrome
• Rare disorder: ~81K patients in US
• Midline condition with abnormalities affecting palate, face, heart and other organs; surgically corrected in infancy
• Neuropsychiatric illnesses (anxiety disorders, ASD) and learning disabilities common and impactful
• • 22q associated with increased anxiety, withdrawn behavior and social interaction problems
  • Early onset of neuropsychiatric symptoms disrupts development and quality of life, and heightens risk of later psychotic disorders
  • • 25-foldincreased risk of developing schizophrenia vs. 1% lifetime risk in general population

33

22q Patient Management

• Two primary stages of 22q patient management:
• • During infancy, doctors address acute physical concerns, such as anomalies of heart and palate, with surgery
  • Once the physical concerns are stabilized, focus shifts to managing neuropsychiatric symptoms, such as anxiety and autistic behaviors
• No currently approved drugs indicated for 22q

34

Rationale for Developing Zygel in 22q

• CBD may treat neuropsychiatric symptoms in 22q due to activity as:
• • Modulator of endocannabinoid system
  • Agonist at serotonin1A receptors
  • Antagonist at GPR55 receptors
• Early control of anxiety may delay the development of psychosis
• Phase 2 study underway in pediatric and adolescent patients with 22q
• Enrollment delayed due to COVID-19 travel restrictions in Australia; topline results timeline to be announced following lifting of restrictions

35

INSPIRE Phase 2 Trial in 22q

Enrollment Ongoing

Assessing the Impact of Zygel (Transdermal CBD Gel) on Pediatric Behavioral and Emotional Symptoms of 22q11.2 Deletion Syndrome

14 Weeks

24 Weeks

Target:

20 patients

Six through 17 years of age

Screening		Zygel			Open label extension
	14 Weeks

Weight based dosing:

250 mg to 500 mg daily

Efficacy assessments (week 14 vs baseline) include:

• Aberrant Behavior Checklist-Community(ABC-C)
• Anxiety, Depression and Mood Scale (ADAMS)
• Qualitative Caregiver Reported Behavioral Problem Survey
• Clinical Global Impression - Severity and Improvement

36

DEE

Developmental and Epileptic Encephalopathies

37

DEE Patients are Medically Fragile

• Group of rare / ultra rare childhood-onset epilepsies with impaired or regressed developmental progress
• Cognitive impairment, psychiatric problems, and behavioral disturbances are phenotypic
• Medically fragile population
• • Comorbidities include cerebral palsy, chronic respiratory infections, gait disturbances, movement disorders, scoliosis, and feeding problems
  • Includes wheelchair bound individuals with feeding tubes
• Most common and debilitating seizure types in DEEs are:
• • Focal impaired-awareness seizures (FIAS) - formerly known as complex partial
  • Focal to bilateral tonic-clonic and generalized tonic-clonic seizures (TCS) - commonly known as convulsive seizures (CS)

38

BELIEVE Phase 2 Trial in DEE

Completed; Reported Positive Topline Results on 9/18/19

Open LaBel Study to Assess the Safety and Efficacy of ZYN002

Administered as a TransdermaL Gel to ChIldren and AdolEscents with

DeVelopmental and Epileptic Encephalopathy

Six months		Six months

48 patients enrolled

Three through 17 years of age

Screening		Titration		Maintenance	Open label extension
	4 Weeks		22 Weeks

Weight based dosing:

Zygel 250 mg to 1000 mg daily

39

BELIEVE: Clinically Meaningful Seizure Reductions from Baseline and Sustained through Six Months in DEE

Median Percent Reduction

1. %

1. %

1. %

1. %

1. %

1. %

1. %

Median Percent Reduction from Baseline,

FIAS and CS

			58%
44%	44%	47%	51%

16%

Month 1	Month 2	Month 3	Month 4	Month 5	Month 6
N=33	N=33	N=33	N=32	N=32	N=29

40

BELIEVE: Percentage of Patients with ≥35% and ≥50% Reduction in FIAS and TCS

≥35% and ≥50% Reduction in FIAS and TCS by Time Point, mITT Population With

FIAS and/or TCS at Baseline (n = 33)

Data reported at the 2020 American Academy of

Neurology (AAN) Science Highlights Virtual Session

41

BELIEVE Safety

Zygel Well Tolerated in this Six Month Trial: No Safety Signal Identified

• All events in six month period, whether unrelated or related to study drug, reported as adverse AEs (e.g.: influenza, runny nose, scrapes, etc.)
• As a result and as anticipated, most patients experienced an AE
• • Most were mild and transient
  • Only one patient discontinued due to an AE (application site reaction)
• Most common treatment-related adverse events occurred in only four patients each:
• • Application site dryness, application site pain, and somnolence (all four patients exhibiting somnolence were taking concomitant clobazam)
• Low rate of serious adverse events (SAEs)
• • Only two SAEs deemed possibly drug-related (LRTI and status epilepticus)
  • No drug-related hepatic, gastrointestinal, or lethargy-related SAEs
• Tolerability profile consistent with the safety database for Zygel

42

BELIEVE: Qualitative Assessments of Behavioral and Cognitive Improvements

• Epilepsy and Learning Disabilities Quality of Life (ELDQOL) scale
• • Statistically significant reductions from baseline in subscale scores for seizure severity, behavior, and mood observed at month 6 (p<0.01)
• Qualitative caregiver feedback on improvements included:
• • Any improvement: 84% (n = 36)
  • Improved vitality: 58% (n = 25)
  • Improvement in seizures: 51% (n = 22)
  • Improved cognition/concentration: 47% (n = 20)
  • Improved socially avoidant behaviors: 44% (n = 19)
  • Improvement in irritability: 33% (n = 14)
  • School improvement: 28% (n = 12)
  • Medical improvement: 14% (n = 6)

Data reported at the 2020 American Academy of

Neurology (AAN) Science Highlights Virtual Session

43

BELIEVE: Qualitative Assessments of Behavioral and Cognitive Improvements

• Good Day/Bad Day comparing baseline to month six:
• • "Good day" and "fantastic day" reports increased from 52% to 70%
  • "Terrible day" and "bad day" reports decreased from 12% to 4%

Data reported at the 2020 American Academy of

Neurology (AAN) Science Highlights Virtual Session

44

Compelling Results Suggest a Potential Pathway to Pivotal Trials

Results of FDA Discussions Regarding Clinical Path Forward Expected in 3Q2020

• Zynerba engaging with FDA on next clinical steps
• Efficacy results:
• • Clinically meaningful reductions in seizures beginning in month two and sustained through six months
  • Suggest improvements on important behavioral symptoms
• Safety results:
• • Zygel was well tolerated
  • Consistent with previously reported Zygel studies
• Zynerba approach to FDA approval will likely focus on most common and disabling seizure types in DEE, rather than patient syndromes

45

Planned Approach to FDA

All DEE Patients with Consciousness Impairing Seizures

Syndromes and encephalopathies

Dravet LGSWest

Doose	Ohtahara	Landau-
Kleffner

Hypoxic-	Early
ischemic	myoclonic
enceph.	epilepsy
CDKL5	Other
enceph.	Syndromes

Zynerba Planned Approach

Seizure type

		Convulsive
Focal	Bilateral	Generalized	Focal	Absence	Other
Impaired	Tonic	Tonic	Seizure
aware
Awareness	Clonic	Clonic		types

Consciousness impairing seizures

46

Financial Strength

• Clean balance sheet
• • No debt, 29.3 M shares outstanding (as of August 6, 2020)
• Cash and cash equivalent position of $77.0M as of June 30, 2020
• Cash runway expected to be sufficient to fund operations and capital requirements into the fourth quarter of 2021

47

Expected Clinical Milestones in 2020

1Q 2020		2Q 2020		3Q 2020		4Q 2020

FXS

	Report pivotal		Discuss results in fully-methylated
	CONNECT-FX
		FMR1 FXS with FDA
	topline results

DEE

ASD

22q

		Results of FDA
		discussions on
		clinical path
Report Ph. 2		Discuss clinical path forward in ASD
BRIGHT topline
	with FDA
results

Enrollment delayed due to COVID-19 travel restrictions in Australia. Topline results timeline to be determined following lifting of restrictions

48

Corporate Overview

August 2020