ZYNE: Zynerba Pharmaceuticals Analysis and Research Report
2018-04-08 - by Asif , Contributing Analyst - 220 views
Zynerba Pharmaceuticals is a clinical stage specialty pharmaceutical company dedicated to the development and commercialization of innovative transdermal pharmaceutically-produced cannabinoid treatments for rare (meeting the U.S. Food and Drug Administration’s, or FDA’s, designation of an orphan disease, affecting fewer than 200,000 people in the United States) and near-rare (affecting fewer than one million people in the United States) neurological and psychiatric, or neuropsychiatric, disorders in patients with high unmet medical needs. Zynerba Pharmaceuticals is currently evaluating two patent protected product candidates, ZYN002 and ZYN001, in four neuropsychiatric indications. In 2017, the company completed three Phase 2 clinical trials for ZYN002 and two of those studies have open-label extensions that are ongoing. In 2018 the company plan to initiate additional clinical trials evaluating ZYN002 for the treatment of behavioral symptoms of Fragile X syndrome, or FXS, in pediatric and adolescent patients, Developmental and Epileptic Encephalopathies, or DEE, in pediatric and adolescent patients, and refractory focal seizures in adults with epilepsy. The company intend to study ZYN001 in patients with Tourette Syndrome, or TS, and anticipate initiating a Phase 2 clinical trial in late 2018. The company believe these product candidates will provide new treatment options for patients. In 2017 the company were also developing ZYN002 and ZYN001 for the treatment of certain pain indications. Zynerba Pharmaceuticals has decided to discontinue its development programs in the capital-intensive pain spaces.
Cannabinoids are a class of compounds derived from Cannabis plants. The two primary cannabinoids contained in Cannabis are cannabidiol, or CBD, and ∆9-tetrahydrocannabinol, or THC. Clinical and preclinical data suggest that CBD has positive effects on treating behavioral symptoms of FXS and epilepsy, and THC may have positive effects on treating TS. The company believe ZYN002 may potentially offer first‑line therapies to patients suffering from FXS, DEE and focal seizures in adults with epilepsy, and ZYN001 may potentially offer first-line therapies to patients suffering from TS.
ZYN002 is the first and only pharmaceutically-produced CBD formulated as a permeation‑enhanced gel for transdermal delivery, and is patent protected through 2030. CBD is the primary non‑psychoactive component of Cannabis. In preclinical animal studies, ZYN002’s permeation enhancer increased delivery of CBD through the layers of the skin and into the circulatory system. These preclinical studies suggest increased bioavailability, consistent plasma levels and the avoidance of first‑pass liver metabolism of CBD when delivered transdermally. In addition, an in vitro study published in Cannabis and Cannabinoid Research in April 2016 demonstrated that CBD is degraded to THC in an acidic environment such as the stomach. The company believe such degradation may lead to increased psychoactive effects if CBD is delivered orally and may be avoided with the transdermal delivery of ZYN002, which maintains CBD in a neutral pH. ZYN002, which is being developed as a clear gel with once- or twice-daily dosing, is targeting treatment of behavioral symptoms of FXS and DEE in pediatric and adolescent patients and refractory focal seizures in adults with epilepsy. Zynerba Pharmaceuticals has been granted orphan drug designation from the FDA for the use of CBD for the treatment of FXS.
ZYN001 is a pro‑drug of THC that enables effective transdermal delivery of THC via a patch and is patent protected through 2031. A pro‑drug is a drug administered in an inactive or less active form and designed to enable more effective delivery, which is then converted into an active form through a normal enzymatic process. In addition, the company expect that ZYN001 will be classified by the FDA as a new chemical entity, or NCE. Zynerba Pharmaceuticals is working with a development partner, LTS LOHMANN Therapie-Systeme AG, or LTS, to optimize the formulation of ZYN001 into a state of the art drug-adhesive matrix transdermal patch to be used in clinical studies.
In its preclinical animal studies, ZYN001 demonstrated effective skin permeation with sustained delivery and rapid conversion of ZYN001 to THC. These preclinical studies suggest increased bioavailability, consistent plasma levels and the avoidance of first‑pass liver metabolism of ZYN001. In addition, preclinical testing has shown no genotoxicity findings and safety pharmacology findings consistent with those seen with THC. ZYN001 is targeting treatment of TS.
Clinical Development Timelines
The company's key development programs and expected timelines for the development of ZYN002 and ZYN001 are shown in the chart below:
Cannabinoid Science Overview
Of the over 100 cannabinoid compounds currently identified, THC and CBD are the primary cannabinoids used for pharmaceutical purposes. THC was identified as the major psychoactive cannabinoid and subsequently found to be a partial agonist of the CB1 and CB2 receptors, suggesting a role for THC in the treatment of TS.
CBD is believed to modulate a number of systems, channels and receptors. These include channels linked to anxiety control including 5-HT1A; anti-inflammatory pathways including adenosine reuptake and modulation of TNFa release; neuronal inhibition-linked GABA channels; the endocannabinoid system by inhibition of metabolism of 2-AG and anandamide; and antiepileptic mechanisms through the equilibrative nucleoside transporter, modulation of α3 and α1 glycine receptors, and antagonism of G protein-coupled receptor 55 or GRP-55.
CBD inhibits the metabolism (breakdown) of two endocannabinoids (anandamide and 2-arachidonoylglycerol, or 2-AG). Inhibition of the metabolism of these endocannabinoids is thought to result in increased anandamide and 2-AG availability and greater CB1 and CB2 activation. Therefore, CBD acts as a facilitator of the endogenous endocannabinoid system, which modifies release of other neurotransmitters from presynaptic terminals. This modulation of neurotransmitter release from presynaptic neurons of various classes is the scientific basis for the use of CBD in the treatment of FXS.
Clinical and preclinical data suggest that THC has positive effects on treating TS and CBD has positive effects on treating FXS and epilepsy. Clinical data suggest that THC and CBD have a very high therapeutic index. Interest in cannabinoid therapeutics has increased significantly over the past several years as preclinical and clinical data has emerged highlighting the potential efficacy and safety benefits of cannabinoid therapeutics. Dronabinol and nabilone, oral formulations of THC, have been approved by the FDA. Many patients have received CBD‑enriched Cannabis and Epidiolex®, a liquid formulation of highly concentrated CBD which is currently in development by a third party. The cannabinoid therapeutics market is expected to grow significantly due to the potential benefits these products may provide over existing therapies.
ZYN002 – CBD Transdermal Gel
ZYN002 is the first and only pharmaceutically-produced CBD formulated as a permeation‑enhanced gel for transdermal delivery (see Figure 1), and is patent protected through 2030.
Figure 1 — Chemical structure and transdermal gel delivery of CBD.
ZYN002 is being developed as a clear gel that is designed to provide consistent, controlled drug delivery with convenient once‑ or twice‑daily dosing. Because CBD is virtually insoluble in water, the company use ethanol and propylene glycol as solubilizing agents and Transcutol ® HP as a permeation enhancer. All excipients in the gel have been classified as Generally Recognized As Safe, or GRAS, and have been used in transdermal products previously approved by the FDA.
The permeation enhancer in ZYN002 increases the delivery of CBD through the layers of the skin and into the circulatory system.
Transdermal delivery allows the CBD in ZYN002 to avoid stomach acid degradation and the first‑pass liver metabolism that occurs with oral or oral mucosal delivery methods. Drugs applied transdermally are absorbed across the skin into the systemic circulation, enabling the potential to have a consistent absorption with increased bioavailability.
Development of ZYN002 for the Treatment of Behavioral Symptoms of Fragile X Syndrome
FXS is a genetic condition that causes intellectual disability, anxiety disorders, behavioral and learning challenges and various physical characteristics. The impairment can range from learning disabilities to more severe cognitive or intellectual disabilities. FXS is the most common genetic cause of autism spectrum disorder. Patients with FXS may exhibit autism‑like symptoms including social avoidance, anxiety and withdrawal, social impairment (gaze avoidance, social escape behaviors) and restricted/repetitive behaviors. Currently, there are no known cures or approved therapies indicated for the treatment of FXS or its symptoms. Special education and symptomatic treatments for anxiety and irritability are employed to lessen the burden of illness. Based on the 2012 U.S. Census and the National Fragile X Foundation, FXS prevalence rates are estimated at approximately 71,000 patients in the United States. According to the National Fragile X Foundation, FXS affects 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females of all races and ethnic groups.
The company believe ZYN002 may provide an effective treatment for FXS based on its capacity to interact with the endocannabinoid system, which is compromised in patients with FXS. Specifically, CBD indirectly increases the concentration of the cannabinoids 2‑AG and anandamide, which are endogenous ligands at the CB 1 and CB 2 receptors. Furthermore, the Fragile X mental retardation protein 1 that is diminished in patients with FXS, is required for the production of 2‑AG. Therefore, FXS results in the reduction of endogenous stimulation of endocannabinoid receptors while CBD facilitates the availability of endogenous endocannabinoids, potentially attenuating the pathophysiology of the disease. The company anticipate ZYN002 may be used as first line therapy to treat patients suffering from behavioral symptoms of FXS.
Phase 2 Clinical Trials
In September 2017, the company released the results for its open-label exploratory Phase 2 clinical trial designed to evaluate the safety and efficacy of ZYN002 in children with FXS, which the company refer to as the FAB-C (Treatment of Fragile X Syndrome Anxiety and Behavioral Challenges with CBD) trial. The primary endpoint for the trial was the change in the total score of the Anxiety, Depression, and Mood Scale, or ADAMS, from baseline to week 12. The ADAMS is a 28-item scale designed to assess general anxiety, social avoidance, compulsive behavior, manic/hyperactive behavior, and depressed mood. It has been validated in patients with FXS. Twenty patients (3:1 males) aged 6 to 17 years of age (mean = 10.7) with FXS, as confirmed by molecular documentation of FMR1 full mutation, were enrolled in the open-label FAB-C study. ZYN002 was added on to other medications being administered. The first six weeks of the study were designed to titrate dosing in patients. Dosing was initiated at 50 mg daily and could be increased to 250 mg daily. Weeks 7 through 12 of the study were a maintenance period where patients were treated at the dose established at week six. At the completion of the study, patients could enter an open-label extension study for up to 12 months.
The FAB-C trial successfully met its primary endpoint, achieving a 46% improvement (p<0.0001) in the total score of ADAMS at week twelve compared to baseline.
Results for the ADAMS are summarized as follows:
|ADAMS||Baseline||Week 12||Change in Score||% Improvement||p Value|
|Total Score (primary endpoint)||33.4||18.1||-14.1||0.46||<0.0001|
|General Anxiety Subscale*||10||4.6||-4.8||0.54||<0.0001|
|Social Avoidance Subscale*||10.2||4.8||-5.1||0.53||0.0002|
|Compulsive Behavior Subscale*||2.8||1.4||-1.2||0.5||0.0262|
|Manic / Hyperactive Behavior Subscale*||9.4||6.1||-2.7||0.35||0.0003|
|Depressed Mood Subscale*||2.8||2||-0.9||0.29||0.1417|
ZYN002 also achieved clinically meaningful improvements in all measures of the Aberrant Behavior Checklist for Fragile X, or ABC-FXS, which addresses the key behavioral symptoms of FXS including social avoidance, repetitive movements, and socially unresponsive behaviors. The study achieved statistical significance across all ABC-FXS subscales compared to baseline.
Results from the ABC-FXS are summarized as follows:
|Aberrant Behavior Checklist (ABC)||Baseline||Week 12||Change in Score||% Improvement||p Value|
|Social Avoidance - "Seeks Isolation"||5.1||2.3||-2.8||0.55||0.0005|
|Stereotypy - "Repetitive Movements"||7.9||3.2||-4.9||0.59||0.0006|
|Socially Unresponsive/Lethargic - "Does Not Pay Attention"||8.7||4.1||-5.1||0.53||0.0034|
|Irritability - "Has Temper Tantrums"||18.2||10.6||-7.1||0.42||0.0096|
|Hyperactivity - "Disrupts Group Activities"||14.5||9.7||-4.1||0.33||0.0194|
|Inappropriate Speech - "Repeats Words or Phrases"||6.1||3.5||-2.4||0.43||0.0018|
The company evaluated multiple other secondary endpoints including a Clinical Global Impression of Improvement, or CGI-I, the Pediatric Anxiety Rating Scale, or PARS-R, Visual Analog Scales for Anxiety, Hyperactivity and Tantrum/Mood Lability, the Vineland Adaptive Behavior III, a Quality of Sleep measurement and the Pediatric Quality of Life, or PedsQL™. The results of the ABC-FXS and other secondary endpoints reinforce the results demonstrated in the ADAMS.
ZYN002 was shown to be very well tolerated, and the safety profile was consistent with data from earlier clinical trials and its other Phase 2 clinical trials for ZYN002. All adverse events were considered mild to moderate and no serious adverse events were reported. No patient experienced drug-related GI events during the 12-week treatment period, and no THC was detected in the plasma. Thirteen of the 18 patients who completed the study have enrolled in the open-label extension and 12 patients are still in the study as of March 5, 2018.
In March 2018, the company announced the results of a positive meeting held with the FDA regarding its planned development strategy for ZYN002 in FXS. Based on its dialogue with the FDA, the company expect to initiate a single pivotal study mid-year 2018 to support a New Drug Application, or NDA, for ZYN002 in FXS. Zynerba Pharmaceuticals is in agreement with the FDA that the primary and key secondary endpoints for the study should assess observable behaviors in patients with FXS as reported by the caregiver using the validated ABC-FXS. If the pivotal trial meets its endpoints, approval for an indication encompassing the treatment of behavioral symptoms associated with FXS may be granted.
The company plan to initiate a pivotal 14-week randomized, double blind, placebo controlled clinical trial in approximately 200 pediatric and adolescent patients in the United States, Australia and New Zealand. Patients will be randomized 1:1 to receive either one of two weight based doses of ZYN002, or one of two matching administrations of placebo. The company anticipate initiation of this pivotal clinical trial mid-year 2018. All patients will be eligible to enroll in a 12-month open-label extension after completing dosing in the pivotal study.
Development of ZYN002 for Treatment of Refractory Epileptic Seizures (Developmental and Epileptic Encephalopathies and Adult Refractory Focal Epilepsy)
Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures (transient symptoms due to abnormal neuronal activity in the brain) and by the neurobiological, cognitive, psychological, and social consequences of the condition. Focal seizures usually start in a small area of the temporal lobe or frontal lobe of the brain and quickly involve other areas of the brain that affect alertness and awareness.
The company believe that ZYN002 may provide an effective treatment for epilepsy based on the anticonvulsant effects of CBD due to its ability to reduce neuronal hyperexcitability shown in multiple in vivo models of epilepsy and clinical trials conducted by third parties. Epilepsy specialists and patient organizations have shown considerable interest in the potential therapeutic role of CBD in adults with epilepsy and, especially, children with DEE. Two companies have active CBD development programs for the treatment of patients with Dravet syndrome, or DS, Lenox-Gastaut syndrome, or LGS, infantile spasms and tuberous sclerosis complex, all of which are rare and severe forms of pediatric epilepsy. In third party clinical trials, Epidiolex has demonstrated statistically significant reductions in seizures compared to placebo in patients with DS and LGS. In an open-label interventionist trial conducted by a third party, an oral CBD solution demonstrated a statistically significant reduction in frequency of motor seizures, with the greatest reduction in patients with focal seizures (55%).
DEE is a category of rare and ultra-rare severe brain disorders that manifest with seizures or EEG abnormalities that are associated with delay or regression in cognition and/or behavior. This category includes DS, LGS, Doose syndrome, early myoclonic encephalopathy and West syndrome, among others. DS is a severe form of epilepsy that appears during the first year of life as frequent fever-related seizures. As the condition progresses, other types of seizures typically occur, including myoclonus and status epilepticus. LGS is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Affected children experience several different types of seizures, most commonly atonic, or drop, tonic and atypical absence seizures. The company believe, based on analysis and a recent publication (Aaberg et. al, Epilepsia, 2017; 58: 1880-1891) which incorporates new classification systems from the International League Against Epilepsy, or ILAE, that there are approximately 45,000 DEE patients in the United States, with the majority of those patients having DS or LGS. The company expect to initiate an open-label Phase 2 clinical trial in children aged 3 to less than 18 with DEE in the first half of 2018. Approximately 50% of the patients enrolled are expected to have DS or LGS while the other 50% will have some other type of DEE.
According to Decision Resources, in 2017 there were expected to be approximately 2.4 million epilepsy patients in the United States, of which approximately 60% suffer from focal seizures, and approximately one third of those patients (~ 500,000) are refractory to two or more anti-epileptic drugs, or AEDs.
Phase 2 Clinical Trials in Adults with Refractory Focal Epilepsy
In August 2017, the company released the results for its Phase 2 randomized, double-blind, multi-center, multi-dose clinical trial designed to evaluate the efficacy and safety of ZYN002 in adult patients with refractory epileptic focal seizures (formerly known as complex partial seizures), which the company refer to as the STAR 1 (Synthetic Transdermal Cannabidiol for the Treatment of Epilepsy) trial. In this trial, 188 patients were randomized to receive (i)195 mg of ZYN002 4.2% CBD gel every 12 hours, (ii) 97.5 mg of ZYN002 4.2% CBD gel every 12 hours or (iii) placebo gel every 12 hours for 12 weeks. Patients aged 18 to 71 years old with confirmed refractory epilepsy with focal seizures with or without secondary generalization were enrolled in this study. Enrolled patients had a median monthly seizure frequency of 10.6, and were on an average of 2.5 AEDs. The primary endpoint assessed the median percentage change in seizure frequency over the 12-week treatment period compared to the 8-week baseline period. Secondary endpoints included proportion of patients with ≥50% reduction from baseline in seizure frequency, percent change from baseline in seizure frequency, seizure-free days, and 100% seizure free. Safety and tolerability were also evaluated. The study was conducted at 14 sites in Australia and New Zealand.
Patients on the low dose of ZYN002 (n=63) achieved an 18.4% median reduction in focal seizures during the treatment period compared to baseline; patients on the high dose of ZYN002 (n=62) achieved a 14.0% median reduction in focal seizures during the treatment period compared to baseline; and patients on placebo (n=63) achieved an 8.7% median reduction in focal seizures during the treatment period compared to baseline. These results were not statistically significant.
ZYN002 was shown to be very well tolerated and the safety profile was consistent with previously released data from its Phase 1 clinical trials. Of the 188 patients in the safety database, 50% of the patients on ZYN002 (n=63) had at least one treatment emergent adverse event, compared to 41% (n=26) of patients on placebo. Two treatment emergent adverse events occurred in greater than 5% of the patients on ZYN002: fatigue (5.6%, placebo, 1.6%) and headache (5.6%, placebo, 3.2%). There were no treatment related serious adverse events reported. The discontinuation rate in the trial for ZYN002 was 10.4% compared to 1.6% in placebo.
In November 2016, the company initiated a 12-month open-label extension clinical trial, which the company refer to as the STAR 2 trial, for patients who successfully completed the STAR 1 trial. Of the 175 patients who completed the STAR 1 trial, 171 patients elected to enter the STAR 2 trial and as of March 5, 2018, 87 patients remain in the trial. Of the 171 patients who elected to participate in the STAR 2 trial, 112 patients have completed at least six months of treatment, 89 patients have completed at least nine months of treatment and 52 have completed at least twelve months of treatment within the STAR 2 trial.
In December 2017, the company presented data on the long term use of ZYN002 from the STAR 1 and STAR 2 trials. This data was collected through the middle of August 2017 in patients who reported seizure frequency data during the respective time periods in the STAR 1 and STAR 2 trial. In Figure 2 below the company grouped the data from the three dosing cohorts across the horizontal axis and the median percent change in seizures vs baseline on the vertical axis. The 195mg – 390 mg cohort represents patients who were initially randomized to the low dose (195 mg daily dose) arm in STAR 1 and then converted to the 390 mg daily dose in the STAR 2 extension study. At three, six and nine months of dosing with ZYN002 these patients had a median reduction of 18.4%, 32.7% and 65.2%, respectively. The 390mg – 390 mg cohort represents patients who were initially randomized to the high dose (390 mg daily dose) arm in STAR 1 and continued on the 390 mg daily dose in the STAR 2 extension study. At three, six and nine months of dosing with ZYN002 these patients had a median reduction of 14.0%, 30.0% and 48.5%, respectively. The Placebo – 390 mg cohort represents patients who were initially randomized to the placebo arm in STAR 1 and then received the 390 mg daily dose in the STAR 2 extension study. At three and six months of dosing with ZYN002 (in the STAR 2 trial) these patients had a median reduction of 13.4% and 26.5%, respectively. Because the data cutoff for this analysis was mid-August 2017, patients originally randomized to placebo had not yet reached the nine month treatment timeframe. The company believe that these data show a consistent pattern of seizure reduction across all cohorts once treated with ZYN002 and they also suggest that clinically meaningful responses can be achieved with longer term use of ZYN002.
Figure 2 – STAR 1 and STAR 2 Efficacy Data.
The company will update this analysis with data through December 2017 and intend to present the analysis with the updated data at a scientific meeting in 2018.
After analyzing the data from the STAR 1 and STAR 2 trials, the company believe that Zynerba Pharmaceuticals has identified an appropriate study design for a Phase 2b trial of ZYN002 in adult patients with refractory epileptic focal seizures, which may lead to statistically significant differences between ZYN002 and placebo. Modifications to the trial design from the STAR 1 and STAR 2 trials are likely to include a larger number of patients to improve the power of the study, increasing the baseline seizure frequency of patients entering the trial, increasing the trial duration and stratifying its randomization across gender and seizure rates. Finally, the company may increase the daily dose for patients randomized into a high dose arm. The company expect to initiate this trial in the second half of 2018.
Early Clinical Trials
Zynerba Pharmaceuticals has completed three Phase 1 studies for ZYN002. In June 2016, the company completed two Phase 1 clinical trials for ZYN002 in healthy volunteers and patients with epilepsy. The first Phase 1 single rising dose clinical trial for ZYN002 in healthy human subjects and in patients with epilepsy evaluated the tolerability and pharmacokinetics, or PK, profile of ZYN002. Results from this clinical trial demonstrated that ZYN002 was safe and well-tolerated at all tested dose levels and the incidence of adverse events associated with ZYN002 was similar to placebo for both healthy subjects and epilepsy patients. The second Phase 1 clinical trial was a randomized, double-blind, placebo controlled multiple rising dose clinical trial for ZYN002 in twenty-four healthy volunteers and twelve patients with epilepsy to evaluate the PK profile, pharmacodynamics, or PD, and tolerability of multiple doses (200, 250, and 500 mg) of ZYN002. Each volunteer and patient received seven days of either ZYN002 or placebo. Results from this clinical trial demonstrated that ZYN002 was safe and well-tolerated at all dose levels. The twice daily dosing provided a more favorable PK profile with comparable results between healthy volunteers and epilepsy patients.
Transdermal application of ZYN002 was very well tolerated with minimal skin erythema. Skin dryness at the application site was common for both ZYN002 and placebo gel. Overall, the incidence of adverse events associated with ZYN002 was similar to placebo in both healthy volunteers and adult epilepsy patients. There were no reports of somnolence or fatigue and a very low incidence of gastrointestinal events was observed. There were no serious adverse events or discontinuations for healthy volunteers and epilepsy patients receiving ZYN002. One healthy volunteer receiving placebo gel developed a serious adverse event suspected to be a catheter infection and was discontinued from the study. In addition, healthy volunteers and epilepsy patients had no drug related changes in performance on the Trail Making Test, a test of visual attention, psychomotor ability, and task switching; a divided attention task; and the Paced Auditory Serial Addition Task, or PASAT, a test that measures working memory and focused attention. These results indicate that ZYN002 did not produce impairment in critical areas of cognitive functioning often impacted by central nervous system drugs. No changes in mood symptoms as assessed by the Inventory of Depression and Anxiety Symptoms, or IDAS, and the Positive and Negative Affect Schedule, or PANAS were observed for ZYN002 suggesting that ZYN002 is not associated with declines in psychological health.
In July 2016, the company completed a third Phase 1 clinical trial for ZYN002 which was a randomized, double-blind, placebo controlled trial in 42 healthy volunteers. The volunteers received a range of CBD doses from 395 mg to 504 mg daily in 2.5% and 4.2% ZYN002 formulations for fourteen days. Results from this clinical trial demonstrated that ZYN002 was very well tolerated with minimal skin erythema. CBD plasma concentrations were dose dependent and did not fluctuate at steady state. The 4.2% formulation demonstrated a comparable PK and tolerability profile to the 2.5% concentration and was easier to use due to the lower volume. There were no serious adverse events or discontinuations from this clinical trial.
Overall, in the Phase 1 program, ZYN002 was demonstrated to be safe and well tolerated, provided a favorable CBD PK profile, and no THC was detected in plasma or urine.
ZYN001 – THC Pro-Drug Patch
ZYN001 is a pro‑drug of THC that is designed to enable effective transdermal delivery of THC via a patch and is patent protected through 2031. A pro‑drug is a drug administered in an inactive or less active form and designed to enable more effective delivery, which is then converted into an active form through a normal metabolic process. In addition, the company expect that ZYN001 will be classified by the FDA as an NCE.
Figure 3. Hydrolysis of ZYN001 into glyceric acid and THC.
Zynerba Pharmaceuticals is working with LTS to optimize the formulation of ZYN001 into a state of the art drug-adhesive matrix transdermal patch. The company intend to test the ZYN001 patch for application to the arm, back and thigh. The drug substance is produced synthetically and is not derived or extracted from botanicals. The excipients in the patch have been classified as GRAS, and have been used in transdermal products previously approved by the FDA.
As illustrated below in Figure 4, transdermal delivery often provides more consistent plasma levels without the peaks and valleys often associated with an oral dosage form.
Figure 4. Illustration of transdermal delivery.
Development of ZYN001 for the Treatment of Tourette Syndrome (TS)
TS is a neurological disorder characterized by repetitive, stereotyped, involuntary movements and vocalizations called tics. The early symptoms of TS are typically noticed first in childhood, with the average onset between the ages of 3 and 9 years. Tics are classified as either simple or complex. Simple motor tics are sudden, brief, repetitive movements that involve a limited number of muscle groups, including repetitive throat-clearing, sniffling, eye blinking and facial grimacing. Complex tics are distinct, coordinated patterns of movements involving several muscle groups, including bending, twisting or shrugging. According to the National Institute of Neurological Disorders and Stroke, approximately 200,000 US patients have the most severe form of TS.
While the cause of TS is unknown, the involvement of the basal ganglia and fronto-cortical circuits is supported by neurophysiological, brain imaging, and postmortem studies. Given overlap between the location of endocannabinoid receptors (i.e., CB1R and CB2R) and those areas hypothesized to be involved in TS, there has been increasing attention focused on the potential role of cannabinoids in reducing movement and behavioral symptoms of TS. In addition to anecdotal reports that cannabis may be effective in the suppression of tics, two small controlled, third-party clinical trials have investigated the effect of THC, specifically, in the treatment of TS. Both controlled studies demonstrated a significant reduction in tics with THC compared to placebo.
Recent Clinical Trials and Pre-clinical Studies
In its preclinical animal studies, ZYN001 demonstrated effective skin permeation with sustained delivery and rapid conversion of ZYN001 to THC. These preclinical studies suggest increased bioavailability, consistent plasma levels and the avoidance of first‑pass liver metabolism of ZYN001. In addition, preclinical testing has shown no genotoxicity findings and safety pharmacology findings consistent with those seen with THC. The company initiated Phase 1 clinical trials for ZYN001 in June 2017 and results from this study are expected in the first half of 2018. These data will inform the planned Phase 2 program for ZYN001, now expected to initiate in late 2018.
The success of its product candidates will depend in large part on its ability to:
- obtain and maintain patent and other legal protections for the proprietary compounds, technology, inventions and improvements the company consider important to its business;
- prosecute its patent applications and defend its issued patents;
- preserve the confidentiality of its trade secrets; and
- operate without infringing the patents and proprietary rights of third parties.
The company internally developed its intellectual property related to ZYN002 and ZYN001. Zynerba Pharmaceuticals has sought and intend to continue to seek appropriate patent protection for its product candidates, as well as other proprietary technologies and their uses, by filing patent applications in the United States and selected other countries.
As of March 8, 2018, the company owned a total of nine issued U.S. utility patents, and one allowed U.S. utility patent application. These U.S. patents and patent applications will expire between 2029 through 2031. Zynerba Pharmaceuticals has already obtained additional patent term for some of the issued patents to compensate it for delays at the United States Patent and Trademark Office, or PTO, under the patent term adjustment laws. These patents, and any pending applications that ultimately issue as patents, may also be eligible for patent term extension for delay caused by FDA regulatory review, thereby further extending their patent terms.
In addition to its U.S. intellectual property, the company own 115 corresponding foreign issued patents and five corresponding foreign applications, which will expire between 2026 and 2031.
The company's ZYN002 patent portfolio currently consists of two issued patents in the United States, six issued patents in France, Germany, Ireland, Japan, Switzerland, and the United Kingdom and one pending patent application in Canada. The issued patents claim the permeation enhanced formulation of ZYN002 and methods of use relating to ZYN002. The issued patents will expire between 2026 and 2030. Any patents that issue from its currently pending patent applications will expire in 2030.
The company's ZYN001 patent portfolio currently consists of three issued patents in the United States, one issued patent in Japan, one issued patent in Canada, issued patents in 34 countries in Europe, including France, Germany, Ireland, Italy, Spain and the United Kingdom, one allowed patent application in the United States and patent applications pending in Europe, Canada and Japan. The issued patents are composition of matter patents, which cover the chemical structure of the pro‑drug ZYN001, the D‑glyceric acid ester of THC, and other THC pro‑drugs. The issued patents will expire between 2028 and 2031. Any patents that issue from its currently pending patent applications will expire in 2028.
The rest of its patent portfolio relates to patents and applications owned by it and directed to other potential product candidates.
Trade Secrets and Proprietary Information
The company seek to protect its proprietary information, including its trade secrets and proprietary know‑how, by requiring its employees, consultants and other advisors to execute confidentiality agreements upon the commencement of their employment or engagement. These agreements generally provide that all confidential information developed or made known during the course of the relationship with it be kept confidential and not be disclosed to third parties except in specific circumstances. In the case of its employees, the agreements also typically provide that all inventions resulting from work performed for it, utilizing its property or relating to its business and conceived or completed during employment shall be its exclusive property to the extent permitted by law. Where appropriate, agreements the company obtain with its consultants also typically contain similar assignment of invention obligations. Further, the company require confidentiality agreements from entities that receive its confidential data or materials.
Research and Development
The company incurred research and development expense of $22.8 million, $16.8 million and $7.4 million for the years ended December 31, 2017, 2016 and 2015, respectively.
The active pharmaceutical ingredients, or APIs, used in ZYN002 and ZYN001 are synthesized by contract manufacturers. The company believe these contract manufacturers have sufficient capabilities to meet its projected product requirements through its planned Phase 2/3 clinical trials.
The ZYN002 gel is manufactured and filled into unit of use sachets by a contract manufacturer. The ZYN001 transdermal patch is manufactured by a contract manufacturer.
The company selected its contract manufacturers for their specific competencies in manufacturing, product design, and materials. FDA regulations require that products be produced under current Good Manufacturing Practices, or cGMPs. The company's key suppliers currently meet cGMPs and the company believe have sufficient capacities to meet its projected product requirements through Phase 3 clinical trials.
The company's Vice President of Commercial is responsible for pre-commercialization activities, including global market analysis, strategic optimization and value development associated with ZYN002 and ZYN001, as well as business development activities as the company evaluate partnering options. However, the company do not currently have a fully integrated organization for the sales, marketing and distribution of pharmaceutical products. The company may rely on licensing and co‑promotion agreements with strategic collaborators for the commercialization of its products in the United States and other territories. If the company choose to build a commercial infrastructure to support marketing in the United States, such commercial infrastructure could be expected to include a sales force supported by sales management, internal sales support, an internal marketing group and distribution support. To develop the appropriate commercial infrastructure internally, the company would have to invest financial and management resources, some of which would have to be deployed prior to any confirmation that ZYN002 or ZYN001 will be approved.
As of March 8, 2018, the company had 22 full-time employees. In addition to its full‑time employees, the company contract with third‑parties for the conduct of certain preclinical, manufacturing, accounting and administrative activities. Zynerba Pharmaceuticals has no collective bargaining agreements with its employees and none are represented by labor unions.