UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, DC 20549
FORM 8-K
CURRENT REPORT
PURSUANT TO SECTION 13 OR 15(d) OF THE
SECURITIES EXCHANGE ACT OF 1934
Date of Report (Date of earliest event reported): December 9, 2019
Aquestive Therapeutics, Inc.
(Exact name of Registrant as specified in its charter)
|
Delaware
|
001-38599
|
82-3827296
|
|
(State or Other Jurisdiction of Incorporation or Organization)
|
(Commission File Number)
|
(I.R.S. Employer Identification No.)
|
30 Technology Drive
Warren, NJ 07059
(908) 941-1900
(Address, Including Zip Code, and Telephone Number, Including Area Code, of Registrant’s Principal Executive Offices)
Not Applicable
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| ☐ |
Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
|
| ☐ |
Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
|
| ☐ |
Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
|
| ☐ |
Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
|
Securities registered pursuant to Section 12(b) of the Act:
|
Title of each class
|
Trading Symbol(s)
|
Name of each exchange on which
registered
|
|
Common Stock, par value $0.001 per share
|
AQST
|
Nasdaq Global Market
|
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934
(§ 240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to
Section 13(a) of the Exchange Act. ☐
| Item 7.01 |
Regulation FD Disclosure.
|
Aquestive Therapeutics, Inc. (the “Company”) is furnishing the investor presentation attached as Exhibit 99.1 to this report for use at the Investor & Analyst Libervant™ (diazepam) Buccal Film Update Forum on
Monday, December 9, 2019 at the American Epilepsy Society (AES) 2019 Annual Meeting. This investor presentation references the clinical data found in poster presentations conducted at that meeting which will be posted to the Company’s website (under
“Newsroom” and “Presentations”) at the time of each presentation.
The Company also has been notified that a pre-IND meeting has been scheduled for February 4, 2020 with CDER of the US Food and Drug Administration to discuss AQST-108’s clinical development strategy.
The information in this Item 7.01 (including Exhibit 99.1) is being furnished pursuant to Item 7.01 and shall not be deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of
1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed to be incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be
expressly set forth by specific reference in any such filing.
|
Item 8.01
|
Other Events.
|
The Company was named as a defendant in a lawsuit filed by Neurelis, Inc. in the Superior Court of California on December 5, 2019. The complaint alleges, among other things, that the Company has made
false and disparaging statements about Neurelis’ product candidate, Valtoco, and engaged in other activities to delay potential FDA approval of Valtoco. The complaint seeks injunctive relief and unspecified monetary damages plus attorneys’ fees. The
Company believes these claims to be meritless and the Company intends to vigorously defend this lawsuit.
|
Item 9.01
|
Financial Statements and Exhibits
|
(d) Exhibits
| Exhibit Number | Description | |
| 99.1 |
|
Investor presentation for use at the Investor & Analyst Libervant™ (diazepam) Buccal Film Update Forum on Monday, December 9, 2019 at the American Epilepsy Society (AES) 2019 Annual Meeting |
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|
Dated: December 9, 2019
|
Aquestive Therapeutics, Inc.
|
|
|
By:
|
/s/ John T. Maxwell
|
|
|
Name: John T. Maxwell
|
||
|
Title: Chief Financial Officer
|
||
Exhibit 99.1
Investor and Analyst Update on LIBERVANT™ December 9, 2019
Forward Looking Statement 2 Certain statements in this presentation and associated oral statements
made by management may constitute "forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “believe,” "anticipate," "plan," "expect," "estimate," "intend," "may," "will," or the
negative of those terms, and similar expressions, are intended to identify forward-looking statements. These forward-looking statements may include, but are not limited to, statements about our growth and future financial and operating results
and financial position, ability to advance Libervant to the market, regulatory approvals and pathways, clinical trial timing and plans, short-term and long-term liquidity and cash requirements, cash funding and cash burn, business strategies,
market opportunities, and other statements that are not historical facts. These forward-looking statements are based on our current expectations and beliefs and are subject to a number of risks and uncertainties that could cause actual results
to differ materially from those described in the forward-looking statements. Such risks and uncertainties include, but are not limited to, risks associated with the Company's development work, including any delays or changes to the timing, cost
and success of our product development activities and clinical trials; the risks of delays in FDA approval of our drug candidates or failure to receive approval; the risks inherent in commercializing a new product (including technology risks,
financial risks, market risks and implementation risks and regulatory limitations); risk of development of our sales and marketing capabilities; risk of legal costs associated with and the outcome of our patent litigation challenging third
party at risk generic sale of our proprietary products; risk of sufficient capital and cash resources, including access to available debt and equity financing and revenues from operations, to satisfy all of our short-term and longer term cash
requirements and other cash needs, at the times and in the amounts needed; risk of failure to satisfy all financial and other debt covenants and of any default; risk related to government claims against Indivior for which we license,
manufacture and sell Suboxone and which accounts for the substantial part of our current operating revenues; risks related to the outsourcing of certain sales, marketing and other operational and staff functions to third parties; risk of the
rate and degree of market acceptance of our products and product candidates; the success of any competing products, including generics; risk of the size and growth of our product markets; risk of the effectiveness and safety of our products and
product candidates; risk of compliance with all FDA and other governmental and customer requirements for our manufacturing facilities; risks associated with intellectual property rights and infringement claims relating to the Company's
products; risk of unexpected patent developments; the impact of existing and future legislation and regulatory provisions on product exclusivity; legislation or regulatory action affecting pharmaceutical product pricing, reimbursement or
access; claims and concerns that may arise regarding the safety or efficacy of the Company's products and product candidates; risk of loss of significant customers; risks related to legal proceedings, including patent infringement,
investigative and antitrust litigation matters; changes in governmental laws and regulations; risk of product recalls and withdrawals; uncertainties related to general economic, political, business, industry, regulatory and market conditions
and other unusual items; and other risks and uncertainties affecting the Company including those described in the "Risk Factors" section and in other sections included in the Company's Annual Report on Form 10‑K filed with the SEC on March 14,
2019 and in our quarterly reports on Form 10-Q. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which speak only as of the date made. All subsequent forward-looking statements attributable to
us or any person acting on our behalf are expressly qualified in their entirety by this cautionary statement. The Company assumes no obligation to update forward-looking statements or outlook or guidance after the date of this press release
whether as a result of new information, future events or otherwise, except as may be required by applicable law.This presentation shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be
any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.
Welcome 3 Requested an accelerated review, which is not guaranteed but, if granted, on track to
potentially launch in early July* Commercial-stage, specialty pharmaceutical company with comprehensive capabilities to advance medicines from pipeline to market Completed rolling submission of New Drug Application (NDA) to U.S. Food and
Drug Administration (FDA) for Libervant™ (diazepam) Buccal Film for management of seizure clusters on November 27 If assigned a traditional review, on track to potentially launch in early November* Advancing a late-stage pipeline that
features promising treatments for patients and caregivers living with complex conditions, including hard to manage epilepsies and anaphylaxis *Subject to and assuming FDA approval obtained in this time period, which cannot be assured.
Program Overview Gary Slatko, MDChief Medical Officer
5 Agenda Topic Time Speaker Opening Remarks 4:00 pm Keith Kendall Program Overview Gary
Slatko, MD Treatment Landscape for Epilepsy Rescue: The Unmet Need 4:10 pm Lawrence J. Hirsch, MD LIBERVANT Clinical Development Program: Key Studies and Findings Early-Phase Program Healthy Volunteer Studies With Diazepam Buccal Film
(DBF)Development of a Weight-Based Dosing RegimenPharmacokinetics of DBF in Adult Patients Dosed Under Interictal and Ictal/Periictal Conditions 4:25 pm Allen H. Heller, MD, MPH Demonstrating Comparability: Pharmacokinetics of Diazepam
Buccal Film in Adult Patients With Epilepsy: Comparison With Diazepam Rectal Gel 4:40 pm Michael A. Rogawski, MD, PhD Outpatient Administration: Safety and Tolerability Associated With Chronic Intermittent Use of Diazepam Buccal Film in
Pediatric, Adolescent, and Adult Patients With Epilepsy 4:55 pm Syndi Seinfeld, DO, MS Panel Discussion/Q&A 5:10 pm Moderator: Dr. SlatkoPanelists: Drs. Hirsch, Heller, Rogawski, Seinfeld Closing Remarks 5:30 pm Keith Kendall
6 Key challenges: comparability, safety, and usability Robust clinical development programHealthy
volunteer studiesPatient studiesIn-clinic single doseOutpatient chronic, repeated useKey findingsFavorable pharmacologyValidated weight-based dosing regimenComparable diazepam exposure to reference listed drugExpected diazepam safety profile
without local safety issuesReadily administered by patients and caregiversClinical sections of NDA filed November 27, 2019Meets FDA timelines and expectations LIBERVANT (diazepam buccal film; DBF) Development: Overview FDA, US Food and Drug
Administration; NDA, New Drug Application.
Today’s Program ClinicalPK Comparative PK Outpatient Safety &
Administration Practice Dr. HirschHow many patients Treatments availableWhat patients needNew options Seizure
RescueTreatmentLandscape Dr. HellerHealthy subject studiesDose proportionalityWeight-based regimenBioavailabilityReliability of DBF Dr. RogawskiComparable PKValidation of regimenTime to effectConsistent, less variableHigh-fat meal
findings Dr. SeinfeldOutpatient intermittent useLow rate related TEAEsHigh success first tryPatient self-administer 23%Local AEs rare No administration injuries AllDiscussionPractice implicationsQuestions AE, adverse event; DBF, diazepam
buccal film; PK, pharmacokinetics; TEAE, treatment-emergent adverse event. 7
Treatment Landscape for Epilepsy Rescue: The Unmet Need Lawrence J. Hirsch, MDProfessor of NeurologyYale
UniversityNew Haven, Connecticut
Definitions Clinically and in the literature, the most commonly used definitions for cluster seizures
are:2-3 seizures occurring within 24 hours2 seizures occurring within 6 hoursStatistical definitions (prevalence usually lower with these)3-4 times the patient’s usual seizure rateDiffering from a Poisson distributionVirtually all humans and
almost all rodents have nonrandomly distributed seizures; that is, everyone clusters to a degree 9
Prevalence of Cluster Seizures(2-3 seizures within 6-24 hours; not necessarily distinguishable from
habitual seizures) Best estimate after a literature review and our prospective trial1Patients with refractory epilepsy (ongoing seizures at any rate)40% will have a cluster seizure in a given year3.2 million patients with epilepsy in the
United States13% (~425,000) will have a cluster seizure in a given yearSeizure cluster patients in 2 recent studies experienced an average of 10.7 and 12.7 cluster episodes per year1,2Main risk factors for having a cluster seizureFrequent
seizuresPrior cluster seizures or status epilepticus 1. Detyniecki K, et al. Epilepsy Behav. 2018;88:349-56. 2. Seinfeld S, et al. Poster presented at: Annual Meeting of the American Epilepsy Society; December 6-10, 2019; Baltimore, MD. 10
Consequences of Cluster Seizures, From a Review1 of Retrospective Studies Higher risk of status
epilepticus, emergency department (ED) visits, injury, loss of work/study, lower quality of life (QOL) for patient and caregiver, and possibly higher mortality if cluster seizures occur while on treatment2Postictal psychosis 1. Jafarpour S, et
al. Seizure. 2019;68:9-15; 2. Sillanpää M, Schmidt D. Brain. 2008;131(pt 4):938-44; 11
Prospective Study of Rescue Medication Use for Cluster Seizures1 Rescue medication useOnly 28% of
patients with active epilepsy had a rescue medication prescribedIncluding only 15% of those in the intermediate-risk group, even though 30% went on to have cluster seizuresDuring the year-long study follow-up, only 11% of patients actually used
a rescue medication. Of these:74% used oral lorazepam Not a labeled indication14% used intranasal midazolam Off label use of iv in a spray2% used rectal diazepam Indicated for this useRescue medications were used in 3% of 6-hour cluster
cases 1. Detyniecki K, et al. Epilepsy Behav. 2018;88:349-56. 12
Why Are Rescue Medications So Underused? Per the literatureNo seizure action plan in usePoor
physician–patient communicationConcerns about limited route(s) of administration For adultsLack of an approved nonrectal option (until late 2019)No one who can administer rescue medication 13
Rescue Therapies Currently Available in the United States Rectal diazepam (Diastat): only approved
option until late 2019Oral lorazepam (Ativan); clonazepam, including clonazepam ODT (orally disintegrating tablets); similar medications (but slow onset)Nasal midazolam: approved and recently introduced Non-medicineVagus nerve stimulator magnet
swipeDeep brain stimulator (extra stimulation) 14
Systematic Review of Benzodiazepines for Seizure Emergencies1 Broader inclusion, 75 studiesConclusions:
for out-of-hospital use, buccal, IN, and IM are all comparable and better options than rectal or IV Time to Seizure Cessation Following Drug Administration IM, intramuscular; IN, intranasal; IV, intravenous. 1. Haut SR, et al. Epilepsy
Behav. 2016;63:109-17. 15
16 Although benzodiazepines are considered the treatment of choice for terminating cluster seizures,1,2
currently available drug formulations are suboptimal in terms of:Onset of actionDosing accuracyPortabilityEase of administrationRoute of administration1,3,4 Ideal properties of a pharmacologic agent for treatment of cluster seizures4Effective
against a variety of seizure typesQuickly absorbed with rapid onset of actionPredictable and consistent interpatient bioavailabilityEasily prepared and administered by anyoneSustained duration of actionMinimal side effects Improving Treatments
for Cluster Seizures 1. Penovich PE, et al. Neurologist. 2017;22:207-14; 2. Haut SR. Curr Opin Neurol. 2015;28:143-50; 3. Tatum WO. Epilepsy Behav. 2002;3:535-8; 4. Cereghino JJ. Curr Treat Options Neurol. 2007;9:249-55.
New Treatment Advances to the Rescue! Company UCB Aquestive Neurelis Engage Ther. Xeris
Pharma Epalex Corp. Crossject Product Nayzilam LIBERVANT Valtoco (NRL-1) STAP-0011 XeriJect Diazepam EP-103 Zeneo
Midazolam2 Generic Midazolam Diazepam Diazepam Alprazolam Diazepam Propofol Midazolam Administration Intranasal Bucccl Intranasal Inhaled Injection Intranasal Transdermal Phase Approved Filed Filed Phase 2 Phase
1 Preclinical Preclinical Orphan Designation October 2009 November 2016 November 2015 NA May2016 August2016 February 2018 Patent Expiration Unknown 2030+ January2035 December 2022 December 2023 Unknown Unknown Sources:
EvaluatePharma, accessed February 2019; BioMedTracker, accessed February 2019; US FDA, accessed February 2019. 17
Monitoring Devices: A Reasonable Precaution1-6 Supervision leads to decreased risk of sudden unexpected
death in epilepsy (SUDEP)7Devices can help with early intervention when a convulsive seizure occursHaving a caretaker present during or immediately after a seizure is an advantageDevice technology is quickly evolving and will play a major role
in the treatment of epilepsy 1. Ryvlin P, et al. Epilepsia. 2018;59(suppl 1):61-6. 2. Zhao X, Lhatoo SD. Curr Neurol Neurosci Rep. 2018;18(7):40; 3. Jory C, et al. Seizure. 2016;36:4-15;4. van Andel J, et al. Epilepsy Behav. 2016;57(pt
A):82-9; 5. Ulate-Campos A, et al. Seizure. 2016;40:88-101; 6. Van de Vel A, et al. Seizure. 2016;41:141-53;7. Nashef L, et al. Epilepsia. 1997;38(11 suppl):S1-2. 18
Conclusions Cluster seizures are common, especially in patients with frequent seizures, and are
potentially harmfulRescue medication is effective but greatly underusedTreating early is beneficialMost patients should have a clear seizure action plan, preferably in writing and reviewed regularlyMany better options for treating cluster
seizures or prolonged seizures are just now becoming availableAnd not just rectal!Combining seizure alarms and rescue therapies can help prevent injuries, status epilepticus, ED visits, and possibly sudden death 19
Allen H. Heller, MD, MPHFounder and CEO Pharma Study Design, LLCClinical Professor of Preventive
MedicineKeck School of MedicineUniversity of Southern CaliforniaLos Angeles, California Healthy Volunteer Studies With Diazepam Buccal Film (DBF)Development of a Weight-Based Dosing Regimen Pharmacokinetics of DBF in Adult Patients Dosed Under
Interictal and Ictal/Periictal Conditions
Property of Aquestive Therapeutics, Inc. 21 Healthy Volunteer Studies Aquestive conducted a series of
phase 1 studies using diazepam buccal film (DBF) and diazepam rectal gel (DRG) in healthy adultsDBF was dose-proportional—maximum plasma concentration (Cmax) increased in proportion to the dose—whereas DRG was less than dose-proportional for
CmaxDBF showed higher bioavailability than DRG (more of the dose was absorbed) DBF (given its oral administration) showed a food effect (reduced Cmax after a fatty meal) but no change in the amount absorbedDBF absorption was more reliable than
DRG absorption
DBF Exhibits Dose-Proportional Pharmacokinetics in Healthy Adults From Heller AH, et al. Presented at:
Annual Meeting of the American Academy of Neurology; April 21-28, 2018; Los Angeles, CA; Neurology. 2018;90(15 suppl):P4.272. Mean Cmax Values by Diazepam Dose AUC0-t, area under the plasma concentration time curve from time zero until last
measurable concentration; Cmax, maximal plasma concentration; DBF, diazepam buccal film. Mean AUC0-t Values by Diazepam Dose 22
DRG Does Not Exhibit Dose-Proportional Pharmacokinetics Mean Cmax Values by Diazepam Dose Mean AUC0-t
Values by Diazepam Dose DBF DBF From Heller AH, et al. Presented at: Annual Meeting of the American Academy of Neurology; April 21-28, 2018; Los Angeles, CA; Neurology. 2018;90(15 suppl):P4.273. AUC0-t, area under the plasma
concentration time curve from time zero until last measurable concentration; Cmax, maximal plasma concentration; DBF, diazepam buccal film; DRG, diazepam rectal gel. 23
Proposed Weight-Based Dosing Regimen for DBF The weight-based dosing regimen for DBF was modeled to
account for differences between DBF and DRG (linear pharmacokinetics and food effect associated with oral dosing)The proposed dosing regimen for DBF is designed such that, after a moderate-fat meal, the Cmax of diazepam from DBF is comparable
to that from DRG Cmax, maximal plasma concentration; DBF, diazepam buccal film; DRG, diazepam rectal gel. 24
DRG 20 mg (n=31) DRG 12.5 mg (n=32) DRG 5 mg (n=33) DBF 15 mg (n=33) More Reliable Absorption With
DBF Than With DRG DBF produces peak plasma levels similar to DRG using lower doses In a comparative PK study in healthy adults,1 3 subjects exhibited extremely low diazepam concentrations after one or more doses of DRG, whereas all subjects
exhibited expected concentrations after DBF2 Mean Diazepam Plasma Concentration (All Subjects) DBF, diazepam buccal film; DRG, diazepam rectal gel.1. Heller AH, et al. Presented at: Annual Meeting of the American Academy of Neurology; April
21-28, 2018; Los Angeles, CA; Neurology. 2018;90(15 suppl):P4.273. 2. Heller AH, et al. Presented at: Annual Meeting of the American College of Clinical Pharmacology; September 15-17, 2019; Chicago, IL; Clin Pharmacol Drug Dev.
2019;8(S1):3. Hours Subject 1 Subject 2 Subject 3 ng/mL ng/mL ng/mL ng/mL Hours Hours Hours 25
Pharmacokinetics of DBF in Adult Patients Under Interictal and Ictal/Periictal Conditions in Epilepsy
Monitoring Unit An in-clinic study of patients with epilepsy compared diazepam exposure after a fixed 12.5-mg dose of DBF under an interictal condition (not during seizure) and an ictal/periictal condition (during or shortly after
seizure)1The 21 subjects who received both treatments, per protocol, had comparable diazepam exposure (Cmax) and AUC0-4hbetween the two conditions—indicating seizure activity did not affect diazepam exposure from DBF1A more recent study2 used
simulation to predict diazepam exposure based on the earlier study1 if DBF were administered according to the proposed weight-based dosing regimen AUC0-4h, area under the concentration curve assessed until 4 hours; Cmax, maximal plasma
concentration; DBF, diazepam buccal film.1. Rogawski MA, et al. Presented at: Annual Meeting of the American Epilepsy Society; November 30-December 4, 2018; New Orleans, LA.2. Heller AH, et al. Presented at: Annual Meeting of the American
Epilepsy Society; December 6-10, 2019; Baltimore, MD. 26
Results Mean Plasma Diazepam Concentration After Administration of DBF Under Interictal and
Ictal/Periictal Conditions: Fixed Dose vs Weight-Based Dosing (Simulated)1 Predicted plasma concentrations based on data from 21 patients with valid profiles for both interictal and ictal/periictal conditions. Each time point is mean of
concentration data from 16-21 patients. Error bars indicate standard error of mean. A. Mean plasma concentration after DBF at fixed dose of 12.5 mg B. Mean plasma concentration predicted if DBF administered according to proposed weight-based
dosing regimen DBF, diazepam buccal film.1. Heller AH, et al. Presented at: Annual Meeting of the American Epilepsy Society; December 6-10, 2019; Baltimore, MD. 27
Conclusions: DBF Pharmacokinetics and Weight-Based Dosing Simulation DBF demonstrates a superior PK
profile: linearity, bioavailability, reliabilityA weight-based dosing regimen was modeled from healthy volunteer studies adjusting for fed conditions; testing in adults with epilepsy confirmed that diazepam exposure is not affected by seizure
activity The simulated weight-based dosing regimen (average dose, 14.9 mg/kg) predicts geometric mean Cmax values greater than 200 ng/mL under both interictal and ictal/periictal conditions, well within the range generally considered
therapeutic for diazepam antiepileptic activityThe predicted geometric mean Cmax values in this simulation are consistent with values found in a later single-dose PK study1 in which patients were dosed using the DBF weight-based regimen that
was simulated here Cmax, maximal plasma concentration; DBF, diazepam buccal film; PK, pharmacokinetics.1. Rogawski MA, et al. Presented at: Annual Meeting of the American Epilepsy Society; December 6-10, 2019; Baltimore, MD. 28
PK of DBF in Adult Patients With Epilepsy: Comparison With DRG Study Design and PatientsRandomized,
multicenter, single-dose, open-label, 2-treatment, 2-sequence crossover study (NCT03953820)Adult patients on a stable regimen of antiseizure drugs randomized to receive a single dose of DBF and a single dose of DRG in crossover fashionDRG:
Dosed according to the FDA-approved weight-based regimen; DBF: dosed according to the weight-based regimen Treatments administered after a moderate-fat meal; 28-day washout. A subset of patients (n=10) was also administered DBF after an
optional high-fat meal (exploratory analysis) Study AssessmentsKey PK parameters of interest included: Cmax (maximal plasma concentration)Tmax (time to Cmax)AUC0-t (area under concentration-time curve from time zero to last nonzero
concentration)AUC0-inf (AUC from time zero extrapolated to infinity)Adverse events were monitored throughout the study DBF, diazepam buccal film; DRG, diazepam rectal gel; FDA, US Food and Drug Administration; PK, pharmacokinetics.1. Diastat
C-IV (diazepam rectal gel) [package insert]. San Antonio, TX: DPT Laboratories; 2016. Weight-Based Dosing Weight (kg) DBF Dose DRG Dose1 38-50 10 mg 10 mg (2 mL) 51-62 12.5 mg 12.5 mg (2.5 mL) 63-75 15 mg 15 mg (3
mL) 76-87 15 mg 17.5 mg (3.5 mL) ≥88 17.5 mg 20 mg (4 mL) 29
Pharmacokinetics of Diazepam Buccal Film in Adult Patients With Epilepsy: Comparison With Diazepam Rectal
Gel Michael A. Rogawski, MD, PhD Professor of Neurology and PharmacologySchool of Medicine, University of California DavisDavis, California
Key Findings Geometric mean Cmax values after DBF were comparableCmax values for DBF significantly less
variable than for DRG (P<0.0001)
Key Findings Geometric Mean Cmax Stratified by Weight Groups (N=28) Geometric mean Cmax values were
less variable with DBF than with DRG across patient weight categories Cmax, maximal plasma concentration; DBF, diazepam buccal film; DRG, diazepam rectal gel.aIncludes 4 patients with weight 112-124.5 kg. 32
Key Findings Parameter DBF DRG Ratio of Geometric Means, DBF/DRG (%)a 90% CI (%) for Ratiob Cmax
(ng/mL), geometric mean 204.26 211.22 96.70 70.53, 132.58 AUC0-t (ng•h/mL), geometric meanc 7290.40 5682.09 128.31 95.93, 171.61 AUC0-inf (ng•h/mL), geometric meanc 8672.09 6880.96 126.03 103.67, 153.21 Tmax (h),
median 1.0 0.517d NA NA PK Parameters After Administration of DBF and DRG (N=28) aCalculated using least-square means according to formula e(Difference) x 100. b90% geometric CI using ln-transformed data. cN=27. dP<0.05 vs
DBF. AUC0-t, area under the plasma concentration time curve from time zero until last measurable concentration; AUC0-inf, AUC from time zero extrapolated to infinity; Cmax, maximal plasma concentration; CI, confidence interval; DBF, diazepam
buccal film; DRG, diazepam rectal gel; PK, pharmacokinetics; SD, standard deviation; Tmax, time to Cmax. AUC0-t and AUC0-inf values were higher for DBF than DRGThe longer Tmax for DBF vs DRG was reached earlier than the Tmax of 1.5 hours
reported in the DRG product labelingAfter moderate-fat meal, 3/28 subjects after DRG, but not after DBF, did not achieve plasma concentration ≥70 ng/mLFor DBF after high-fat meal, geometric mean Cmax (174 ng/mL) and DBF/DRG ratio (82.5%)
reflect similar exposure level to DRG* 33
Conclusions For patients with epilepsy after a moderate-fat meal, a single dose of DBF provides
comparable overall exposure to diazepam to DRG with significantly less variability than DRG when each is administered according to its respective weight-based dosing regimenThese results confirm pharmacometric modeling and validate the proposed
weight-based dosing regimen for DBFUnlike DRG, the geometric mean values for Cmax after DBF was less variable and consistently ≥150 ng/mL for each of the weight categories; and there were no low responders to DBF after a moderate-fat meal The
results support the use of DBF as an easily administered alternative to DRG for patients with epilepsy who experience seizure emergencies despite antiseizure medications Cmax, maximal plasma concentration; DBF, diazepam buccal film; DRG,
diazepam rectal gel. 34
Safety and Tolerability Associated With Chronic Intermittent Use of Diazepam Buccal Film in Pediatric,
Adolescent, and Adult Patients With Epilepsy Syndi Seinfeld, DO, MS Director of EpilepsyJoe DiMaggio Children’s Hospital Miami, Florida
Introduction and Objective Cluster seizures and other bouts of more frequent or more severe seizures
occur in many patients with epilepsy despite treatment with antiepileptic medications, and can lead to injury, hospitalization, status epilepticus, and risk of death1-3Available treatment options for these episodes are suboptimal, particularly
in terms of speed of onset of action and ease of administration1,4,5Currently, diazepam rectal gel and midazolam nasal spray are the only treatments approved by the FDA for patients with refractory epilepsy having bouts of increased seizure
activity6,7Objective: The primary objective of this ongoing study (NCT03428360) is to assess the safety and tolerability of outpatient self- or caregiver- administered DBF in people with epilepsy The usability of DBF is being assessed as a
secondary objective DBF, diazepam buccal film; FDA, US Food and Drug Administration.1. Penovich PE, et al. Neurologist. 2017;22:207-14; 2. Jafarpour S, et al. Seizure. 2019;68:9-15; 3. Sillanpää M, Schmidt D. Brain. 2008;131(pt 4):938-44; 4.
Tatum IW. Epilepsy Behav. 2002;3:535-8; 5. Cereghino JJ. Curr Treat Options Neurol. 2007;9:249-55; 6. Diastat C-IV (diazepam rectal gel) [package insert]. San Antonio, TX: DPT Laboratories; 2016; 7. Nayzilam [package insert]. Smyrna, GA: UCB,
Inc.; 2019. 36
Administration and DosingStudy participants were instructed to administer DBF for treatment of seizure
episodes occurring in their home environments in which a benzodiazepine would ordinarily be administered for seizure rescueDBF was dispensed at weight- and age-based doses ranging from 5 to 17.5 mg, which could be adjusted with aging or change
in body weight during the study DBF could be administered for up to 5 seizure episodes per month; administration of a second dose was permitted within 4 to 12 hours after the first dose Methods Outcomes of InterestAdverse eventsOccurring
during study or up to 30 days after last study drug administration or until all drug-related toxicities are resolved, whichever is later DBF administration and usabilityAssessed by patients and/or caregivers, recorded after each use of study
drug , including successful placement/buccal insertion of DBF, oral cavity retention of DBF, and ability to open packaging and remove DBF Study Design and PatientsOngoing, phase 3, multicenter, open-label, long-term safety and tolerability
studyInterim data from patients receiving ≥1 dose of DBF as of May 2019 are reported here Eligible patients include males and females between ages 2 and 65 years, inclusive, with established diagnosis of epilepsy who were deemed in need of
benzodiazepine treatment for bouts of increased seizures at least once monthly on average DBF, diazepam buccal film. 37
Results As of May 31, 2019, 72 patients had enrolled, used DBF at least once Mean (SD) duration on study
at interim analysis cutoff date was 192.0 (97.0) daysDBF dose administeredMean (SD): 8.7 (10.1) mgMedian (range): 5 (1-49) mg Characteristic Adults (n=59) Adolescents (n=7) Pediatric(n=6) Age, mean (SD), y 31.9 (10.5) 14.1 (1.5) 7.5
(2.7) Female, n (%) 27 (45.8) 6 (85.7) 2 (33.3) Race, n (%) White 45 (76.3) 4 (57.1) 4 (66.7) Black 4 (6.8) 2 (28.6) 1 (16.7) Other 10 (16.9) 1 (1.4) 1 (1.7) Ethnicity, Hispanic or Latino, n (%) 12 (20.3) 2
(28.6) 3 (50.0) BMI, mean (SD), kg/m2 26.0 (6.4) 22.1 (4.5) 16.1 (3.0) Duration of epilepsy, mean (SD), y 20.2 (11.7)a 12.3 (4.2)b 6.6 (3.0)c an=44; bn=4; cn=5. BMI, body mass index; DBF, diazepam buccal film; SD, standard
deviation. 38
Overall, 34 patients (47.2%) have reported 90 AEs7 treatment-related AEs occurred in 5 (6.9%) patients;
all were mild in severity and resolved 13 serious AEs were reported by 9 (12.5%) patients; none were considered treatment-relatedNo patient discontinued study participation because of an AELocal buccal discomfort was reported by 1 adult and
resolved within 1 dayThere were no reports of injury during buccal placement of DBF Results (cont’d) aAll data reported as number (%) of patients, number of events. AEs Reported in >2% of Overall Population Treatment-Related
AEs aDefined as AE categorized as having “possible” or “probable” relationship to study drug. bAll treatment-related AEs were mild in severity. AEa Overall Population(N=72) Seizure 4 (5.6), 6 Pyrexia 4 (5.6), 4 Dizziness 3 (4.2),
3 Nausea 3 (4.2), 3 Somnolence 3 (4.2), 3 Weight decreased 3 (4.2), 3 Cough 2 (2.8), 2 Dehydration 2 (2.8), 2 Gastroenteritis viral 2 (2.8), 2 Lethargy 2 (2.8), 2 Vomiting 2 (2.8), 2 Weight increased 2 (2.8),
2 Treatment-Related AEa,b Pediatric (n=6) Adolescent (n=7) Adult(n=59) Total (N=72) Number (%) of Patients, Number of Events Somnolence 0 0 1 (1.7), 1 1 (1.4), 1 Lethargy 0 0 1 (1.7), 1 1 (1.4), 1 Altered
consciousness 0 0 1 (1.7), 1 1 (1.4), 1 Mouth swelling 0 1 (14.3), 1 0 1 (1.4), 1 Oral discomfort 0 0 1 (1.7), 1 1 (1.4), 1 Gait disturbance 0 0 1 (1.7), 1 1 (1.4), 1 Skin sensitization 0 0 1 (1.7), 1 1 (1.4), 1 AE,
adverse event; DBF, diazepam buccal film. 39
Medication Administration Of the 471 DBF exposures:At least 107 (22.7%) were self-administered by the
patientThe majority (308 or 65.4%) occurred within 5 minutes of a seizureThere were no administration-related injuries in this study or over the almost 1000 exposures in the DBF program8 patients were exposed to a second DBF dose on 14 use
occasions within the recommended 4-12 hours after the first DBF exposure There were no instances of adverse events of interest DBF, diazepam buccal film. 40
DBF usability data were reported by 64 patientsMean (SD) administrations per patient: 7.4 (7.7)All
patients had first-attempt success at DBF administration on at least one use occasionAlmost all patients successfully administered DBF on first or second attempt (97.7%) Results Success Rates for DBF Insertion Stratified by Number of Attempts
(N=471 Use Occasions) DBF, diazepam buccal film; SD, standard deviation. 41
There were no cases of unsuccessful placement owing to swallowing of DBF before it adhered to buccal
mucosa (Table)Patients and caregivers reported no difficulty opening the packaging in the majority of use occasions Patients and caregivers reported no difficulty removing DBF from inner packaging in nearly all (96.6%) use occasions Results
(cont’d) Overview of Reported Reasons for Unsuccessful Placement of DBF aRespondents could choose more than 1 reason for unsuccessful insertion attempt; 35 reasons were given for 28 unsuccessful attempts. Reasons for Unsuccessful Insertion
Attempts Unsuccessful Attempts Based on 471 Use Occasions, n (%)a Clenching jaw/won’t open mouth 10 (2.1) Excessive drooling 9 (1.9) Spit out before DBF adhered to buccal mucosa 7 (1.5) Clenching jaw/won’t open mouth/excessive
drooling 1 (0.2) Other 8 (1.7) DBF, diazepam buccal film. 42
Conclusions In this observational study of chronic intermittent administration and use, DBF was found to
be safe and well tolerated by pediatric, adolescent, and adult patients with epilepsy experiencing seizure emergencies Treatment-related AEs, including somnolence, were relatively uncommon after DBF use, and all treatment-related AEs were mild
in severity Patients were able to self-administer DBF; administration near time of seizure was common; there were no administration-related injuries, and local AEs were rareDBF ultimately was successfully placed on nearly all (99.6%) use
occasions and readily used without difficulty when administered by patients and caregivers These results support the further development and use of DBF as an easily administered alternative to diazepam rectal gel for patients with epilepsy who
experience cluster seizures and other bouts of more frequent or more severe seizures despite treatment with antiepileptic medications AE, adverse event; DBF, diazepam buccal film. 43
Panel Discussion/Q&A Gary Slatko, MDLawrence J. Hirsch, MDAllen H. Heller, MD, MPHMichael A.
Rogawski, MD, PhDSyndi Seinfeld, DO, MS
Discussion for Panel What would a medication like this—that’s easy to carry and could be quickly
administered—mean for patients with epilepsy and caregivers?How does this buccal formulation compare with nasal formulations? Our data show a strong preference for oral formulations—what do your patients say?How could new seizure detection
devices affect use of these rescue medications? 45
Closing Remarks Keith Kendall President and Chief Executive Officer