Zevra Therapeutics, Inc. · NASDAQ:ZVRA
Zevra Therapeutics — Kempharm — The 9th Pain & Migraine Therapeutics Summit (September 2015)
43 slides from Zevra Therapeutics's conference presentation, Sep 23, 2015
Slide 1: The Search for New Pain Therapeutics with Low Inherent Abuse Potential — A Case for Prodrugs
September 23, 2015 The 9th Pain & Migraine Therapeutics Summit The Search for New Pain Therapeutics with Low Inherent Abuse Potential — A Case for Prodrugs Sven Guenther, Ph.D. Exhibit 99.1
Slide 2: Cautionary Note Regarding Presentation Information
Cautionary Note Regarding Presentation Information This presentation has been prepared by KemPharm, Inc. (the “Company”) for informational purposes only and for only the actual attendees of this presentation. Nothing contained in this presentation is, or should be construed as, a recommendation, pro
Slide 3: Disclosure Statement
Disclosure Statement I have relevant financial relationship(s) with some of the products described, reviewed, evaluated, or compared in this presentation. Financial Executive Vice President of Research and Development at KemPharm, Inc. Nonfinancial No relevant relationship(s) to disclose.
Slide 4: Opioid Analgesics
Opioid Analgesics
Slide 5: Anatomy of Opioid Receptors
Anatomy of Opioid Receptors1-13 Four types of opioid receptors: μ (MOP), δ (DOP), κ (KOP), nociceptin/orphanin (NOP) Pharmacological evidence and binding studies suggest subtypes Appear to have different functions/effects Example μ1: analgesia μ2: analgesia, GI transit, respiratory depression, itchi
Slide 6: Opioid Receptor Subtype Functions
Opioid Receptor Subtype Functions14 Receptor Subtype Function MOP μ1 analgesia μ2 analgesia, GI transit, respiratory depression, itching μ3 various including NO release DOP δ1 analgesia, cardioprotection δ2 analgesia, cardioprotection, thermoregulation KOP κ1a analgesia, feeding κ1b κ2a analgesia, d
Slide 7: Binding Profiles of Common Opioid Agonists
Binding Profiles of Common Opioid Agonists15 Most current opioid analgesics have some cross-receptor activity Mixed modes of action can have positive and negative outcomes Response to opioids varies by patient Receptor type/subtype ratios Receptor concentrations Localization and receptor tissue dist
Slide 8: Opioid Receptor Biased Agonism
Opioid Receptor Biased Agonism16,17 Opioid receptors are G-protein coupled receptors (GPCR) G-proteins are heterotrimeric (trimer of Gα and Gβγ subunits) Inactive receptor is bound (coupled) to Gαβγ Binding of agonist to receptor activates G-protein Gα dissociates and both subunits activate effector
Slide 9: Possible Improvements
Possible Improvements18-21 Targeting specific opioid receptor subtypes with desired functions only Find biased opioid agonist that suppress undesired signal pathways Find new opioids with mixed mechanism of action to allow for lower doses with equal efficacy (e.g., opioid receptor agonist plus NMDA
Slide 10: Case Studies – New Opioid Agonists
Case Studies – New Opioid Agonists
Slide 11: Selective Opioid Receptor Agonist – CR845
Selective Opioid Receptor Agonist – CR845 Developed by CARA® Therapeutics CR845 Selective agonist which binds to κ-opioid receptors located on peripheral, pain-sensing nerves Does not effectively cross blood-brain-barrier Route of administration: IV Potential benefits Peripheral analgesia No euphori
Slide 12: Novel Opioid Modulator for Pain – ALKS 7106
Novel Opioid Modulator for Pain – ALKS 7106 Developed by Alkermes®, plc ALKS 7106 Opioid modulator without abuse-deterrent formulation Specific intrinsic receptor activity (subtype specific?) Rapid entry into CNS ~ 30-fold more potent than morphine Potential benefits Ceiling effect on neurotransmitt
Slide 13: New μ-Opioid Receptor Agonist – NKTR-181
New μ-Opioid Receptor Agonist – NKTR-181 Developed by Nektar® Therapeutics NKTR-181 Known μ-opioid agonist conjugated with polymer to form new molecular entity Addition of polymer slows entry into the brain Potential benefits Similar analgesia to oxycodone Less Drug Liking in human abuse potential s
Slide 14: μ-Opioid Receptor Biased Agonist – TRV130
μ-Opioid Receptor Biased Agonist – TRV130 Developed by Trevana TRV130 Biased binding to μ-opioid receptor Activates G-protein signal pathway Reduced β-arrestin recruitment and associated signals β-arrestin mediated signal pathways may be responsible for certain side-effects of non-biased agonists (e
Slide 15: Status – Opioid Analgesics
Status – Opioid Analgesics Many different opioids identified and available Multiple opioid receptor functions and mechanisms explored to decouple side-effects (e.g., respiratory depression and euphoria) from analgesic effects Despite considerable research no significantly improved products available
Slide 16: Prodrugs
Prodrugs
Slide 17: Definitions
Definitions Prodrug: inactive molecule that releases an effective moiety (or “prometabolite”) after administration “Effective moiety”: molecule which participates directly in the pharmacological action (binding) responsible for efficacy “Prometabolite”: active precursor of an effective moiety
Slide 18: Drug Metabolism
Drug Metabolism Prodrug Strong/weak activity? “Prometabolite”?
Slide 19: Possible Prodrug Properties
Possible Prodrug Properties Involves a chemical modification of an effective moiety that is reversed in vivo Examples of properties prodrugs can modify/improve compared to original effective moiety Bioavailability Pharmacokinetics Metabolism Physicochemical properties Solubility Stability Tissue tar
Slide 20: Case Studies – Prodrugs
Case Studies – Prodrugs
Slide 21: Ligand Activated Therapy (LAT) Platform Technology
Ligand Activated Therapy (LAT) Platform Technology Select FDA-approved and widely prescribed drug for improvement Chemically modify using a ligand to create an NME prodrug Ligands – GRAS or demonstrated to be safe NME prodrugs generate composition-based patents Following ingestion, normal human meta
Slide 22: Prodrugs as an Abuse Deterrent Platform
Prodrugs as an Abuse Deterrent Platform Inert molecule selectively metabolized in the GI tract can potentially eliminate non-oral routes of abuse Enzyme profile present in GI tract not found elsewhere Prodrugs have different metabolic stability via non-oral routes New molecule requires chemical mani
Slide 23: Prodrugs in Development
Prodrugs in Development KemPharm has generated a number of prodrugs of highly abused opioids and advanced those candidates into development KP201 (benzhydrocodone hydrochloride) Currently formulated as IR product with APAP Standalone KP201 next logical product to best utilize prodrug properties KP51
Slide 24: KP201/APAP Overview
Treatment of Acute Moderate to Moderately Severe Pain KP201/APAP Overview
Slide 25: KP201 Product Features
KP201 Product Features Prodrug composed of hydrocodone and benzoic acid Entirely new chemical entity: benzhydrocodone First commercial product is intended to be IR with APAP KP201 potentially provides High tamper resistance Resistance to non-oral routes of abuse Expedited 505(b)(2) regulatory pathwa
Slide 26: KP201 µ-Opioid Receptor Pharmacology
KP201 µ-Opioid Receptor Pharmacology KP201 has very poor binding affinities to all opioid receptors Intact KP201 does not impart clinical opioid effects Not an effective moiety Does not produce euphoria Effective moiety hydrocodone (μ-opioid receptor agonist), is “cloaked” by prodrug Binding affinit
Slide 27: KP201/APAP Tamper Resistant Properties – In Vitro Studies
KP201/APAP Tamper Resistant Properties – In Vitro Studies Extraction of API (KP201) only yields inactive prodrug Hydrocodone not released through Physical manipulation (e.g., grinding) Common solvent extraction (e.g., “alcohol dose dumping”, “cold water extraction”) KP201 is chemically stable under
Slide 28: Ongoing Tampering Studies
Ongoing Tampering Studies KP201.T01 Designed to determine the extractability of KP201 from the IR formulation and to evaluate conditions that may potentially hydrolyze the prodrug to hydrocodone to demonstrate the stability KP201 compared to the little effort required to isolate hydrocodone from cur
Slide 29: KP201.A01: Oral Abuse Potential Trial Design
KP201.A01: Oral Abuse Potential Trial Design Assessment of Drug Liking, exposure levels and safety of KP201/APAP compared to Norco® after oral administration in nondependent, recreational opioid users (N=61) Single-center, randomized, double-blind, active- and placebo-controlled crossover trial KP20
Slide 30: KP201.A01: Drug Liking Scores (Emax)
KP201.A01: Drug Liking Scores (Emax)
Slide 31: KP201.A01: Pharmacokinetics (Hydrocodone)
KP201.A01: Pharmacokinetics (Hydrocodone) HC = hydrocodone APAP = acetaminophen Norco® = hydrocodone bitartrate/APAP Cmax diff. = difference in Cmax comparing KP201/APAP and Norco® Cmax diff. = -11.5% Cmax diff. = -10.0%
Slide 32: KP201.A03: Intranasal Pharmacokinetic Study Design
KP201.A03: Intranasal Pharmacokinetic Study Design Assessment of pharmacokinetics of KP201 API compared to hydrocodone bitartrate (HB) API in nondependent, recreational opioid users (N=24) Single-center, randomized, double-blind, single-dose, 2-way crossover trial KP201 API (13.34 mg) vs. HB API (15
Slide 33: KP201.A03: Intranasal Pharmacokinetics
KP201.A03: Intranasal Pharmacokinetics PK curve from study KP201.103 (equivalent oral dose of KP201/APAP) Cmax diff. = -36.0% AUClast diff. = -20.3% Tmax diff. = +1.25 hour HC = hydrocodone HB = hydrocodone bitartrate APAP = acetaminophen IN = intranasal Cmax diff. = difference in Cmax comparing KP2
Slide 34: KP511 Overview
Treatment of Moderate to Severe Pain KP511 Overview
Slide 35: KP511 Product Features
KP511 Product Features KP511 is a prodrug of hydromorphone Bioequivalent release of hydromorphone demonstrated in rats Potential properties based on preclinical data Significantly reduced IN and IV bioavailability (abuse deterrence) Highly tamper resistant Limited oral bioavailability at high doses
Slide 36: KP511 Reduced Abuse Potential
KP511 Reduced Abuse Potential 2.0 mg/kg (hydromorphone eq.) Average data from 2 studies (N=10) %-AUC = 25% %-Cmax = 22% 0.2 mg/kg (hydromorphone eq.) 1 study (N=5) %-AUC = 5% %-Cmax = 6% Intranasal Intravenous Note: HM refers to hydromorphone hydrochloride. Studies conducted in rats.
Slide 37: KP511 Potential Oral Overdose Protection
KP511 Potential Oral Overdose Protection AUC Note: HM refers to hydromorphone hydrochloride. Studies conducted in rats.
Slide 38: KP511 Tamper Resistant Properties
KP511 Tamper Resistant Properties Extraction of API (KP511) from formulation only yields inactive prodrug with inherent pharmacological abuse protection Hydromorphone cannot be released through Physical manipulation (e.g., grinding) Solvent extraction (e.g., “alcohol dose dumping”, “cold water extra
Slide 39: A Case for Prodrugs
A Case for Prodrugs Known to be efficacious a priori Modify well-known metabolism vs complex, not completely understood mechanism of action Are able to effectively address abuse of IR and ER opioid products Reduced development path Flexible application allows for future improvements as abusers becom
Slide 40: Future Outlook
Future Outlook Prodrugs Combine prodrugs with an ER-ADF could provide double barrier Identify prodrugs with reduced abuse potential and inherent ER properties, i.e., no ER formulation required Create prodrugs of more potent opioid agonists Add novel, advanced formulations to enhance benefits of uniq
Slide 41: Thank you!
Thank you!
Slide 42: References
References Pasternak GW, Pan YX. Mu opioids and their receptors: evolution of a concept. Pharmacol Rev. 2013, 65(4), 1257-317. Pasternak GW. Opiate pharmacology and relief of pain. J Clin Oncol. 2014, 32(16), 1655-61. Walwyn WM, Miotto KA, Evans CJ. Opioid pharmaceuticals and addiction: the issues,
Slide 43: References
References Dietis N, Rowbotham DJ, Lambert DG. Opioid receptor subtypes: fact or artifact?. Br J Anaesth. 2011, 107(1), 8-18. Pasternak GW. Opioids and their receptors: Are we there yet?. Neuropharmacology. 2014, 76 Pt B, 198-203. Smith HS, Peppin JF. Toward a systematic approach to opioid rotation.
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