Rescheduling of Hydrocodone combinations from Class III to Class II, clear-cut regulatory guideline for Abuse Deterrent drug formulation NDA & ANDA (solid oral) filing and CDC guideline for Prescribing Opioids for Chronic Pain (2016) are definite steps taken by FDA in last two years for creating “Abuse Deterrent Era” in a short span to stop opioid abuse and reversing opioid epidemic in USA. There were around 18,893deaths involving prescription of opioids in the United States in 2014 which was up 16% from 2013 as per NCHS (National Center for Health Statistics).
Around +6 plus extended release abuse deterrent formulations with Abuse deterrent (AD) labels are approved in last two years (Xtampza ER, MorphaBond ER, Hysingla ER, Embeda ER, Targiniq ER, Oxaydo) and are expected to provide improvements over existing formulations for abuse deterrent purpose. But they have some limitation for restricting abuse mainly through oral intake- swallowing a number of intact tablets or capsules. Despite, Extended release (ER) Abuse Deterrent Formulations partly control Opioids abuse (through nasal or injection routes), ER opioids has high potential of abuse, its AD formulation add significant value to create “Abuse Deterrent Era” in the coming time.
Around 20 plus Abuse Deterrent Formulations of opioids are in the pipeline and most of them are ER formulations which use different AD tech platform to make its ADF. Amongst these pipeline ADF drugs, 6 are of Hydrocodone, 8 are of Morphine and 6 are of Oxycodone based ADF formulations.
New NCEs targeting Opioids receptor are in pipeline which reduces Opioids abuse by its MoA (slow rate of entry in Brain) and may have potential to deal with reducing opioid abuse through restricting oral intake in coming years.
US Opioids market is of $8b in size and of which extended release formulations contribute 50%. ADF ER formulations and its generic versions & New NCEs targeting Opioid receptor will drive the growth of opioid market in US and Europe in coming years.
In this report, we have discussed a number of novel delivery technologies employed in the formulating abuse deterrent product, technologies employed in enhancing patient compliances, emerging novel mechanisms and late stage pipeline drugs in the management of pain.
Late stage NCE pipeline drugs (Cebranopadol, Mirogabalin, NKT-181, AVP-923,…) and Novel technologies targeting formulation change in old generic drugs (ORB-201, OX-51, ARX-04,CL-108, once daily Pregabalin..) for pain management has potential to reduce opioids use in future to treat pain. While TRKA receptor antagonist, NAV1.7 sodium channel modulator inhibitor and angiotension II antagonist are few new MoA which has promising drug in clinical development for moderate to severe pain management.
BioDelivery Sciences International Inc
Johnson and Johnson
Reckitt Benckiser pharmaceutical
Tesa Labtec GmpH
Table of Contents
1. Executive Summary a. ER formulation of Opioids- An initial target for pipeline Abuse deterrent drugs & a high priority by Regulators? b. Late stage pipeline drugs and new MoA – which has potential to reduce Opioid use in moderate pain? c. New FDA guidelines for Oral solid abuse deterrent generic formulations - A kick start of generic cycle for ADF formulations? d. Key pipeline ER abuse deterrent drugs, its ROA, tech platform etc e. Possible implications of rescheduling Hydrocodone from CIII to CII on Opioids market & ADF development.
2. Management of Pain Introduction Classification of Pain (Type and Intensity) Treatment of chronic pain – current approach Market Size of pain and current therapeutic options (acute, chronic pain and neuropathic pain) Unmet medical need and market opportunities in overall Pain management Overview of Marketed drugs for moderate to severe pain and neuropathic pain Limitations of non-opioids drugs and overview of marketed drugs Non-steroidal Anti-inflammatory Drugs (NSAID) – Mechanism of action Necessity for non-opiate treatment –Drug abuse deterrent and tolerance Opioid Abuse deterrent Epidemic- A Whistle Blower for FDA to take Stringent Action and start of abuse deterrent Era ER opioids vs. IR opioids- Abuse deterrent potential
3. FDA Schedule for controlled substances and advantage of Schedule III over II Hydrocodone rescheduling to Class II – o Prescription trend post rescheduling Advantage to other Opiates & advantage to ER ADF opioids to grow due to rescheduling
4. FDA Perspective on Abuse deterrent formulations (Opioids) FDA perspective on Abuse deterrent Opioids- Observations from early experience with Abuse deterrent formulation development. FDA view of the Evolution of the Abuse deterrent Opioid market Tools FDA Intends to use to move the market toward its goal ADF Labeling – Importance and advantage for reimbursement, REMS need Our view on FDA guidelines for Abuse deterrent Formulation developments Our view on FDA guidelines for Generic Abuse deterrent Formulation developments
5. Approved Abuse deterrent Formulations by FDA - Development , label claim, Technology and current prescription trend Common Manufacturing approach for making ADF formulation Abuse deterrent drugs approval from FDA in 2014- its Technology platform and current prescription trend in US Abuse deterrent approval from FDA in 2015- its Technology platform and current prescription trend in US Recently approved ER Formulation of Patent expired molecules for pain management Nucynta ER Gralise Horizant
6. Abuse Deterrent Technology Platforms employed in marketed drugs and pipeline a. AVERSION b. IMPEDE c. NEXAFED d. LIMITX e. DETERx f. PODRAS g. IntelliPaste h. nPODDDS i. INTAC j. ORADUR k. Implantable pump for intrathecal delivery l. OPTIGEL Lock m. Small molecule delivery n. Bio-MD-prodrugs platform o. Ligand activated Therapy (LAT) p. NOBUSE q. EGALET r. ABUSOLVE s. Inspirion delivery Technologies t. Intellitab Technology u. Trigger lock platform –Micropump v. Proprietary / OraGuard Technology w. Pain Therapeutics x. Fenrock y. Smart Patch PNS system z. ALO-02/Troxyca ER aa. BeadTek and INTELLITAB technology bb. Acuform Technology cc. OROS Technology dd. Resistec Technology ee. SENTRYBOND Technology
7. Pipeline analysis of Novel Technologies and new mechanisms in Pain management
Novel Technologies- a. Multi-day formulation of Tramadol b. Bio-MD Platform c. Orexo- Sublingual technology d. Fentanyl based therapy formulation modification (micro and nano tab) e. Acorda Therapeutics f. Bilayered oral formulation- Charleston lab g. ZilrettaTM h. Steroidal intraarticular injection i. Intrathecal drug delivery system j. Oromucosal delivery
New mechanisms in Pain management a. Angiotension II antagonist b. Anti-NGF c. Ligand Activate Therapy d. Nav1. 7 inhibitor e. GPCR –Dimer Screen Technology f. CB agonist g. Kappa Receptor agonists h. TrkA receptor antagonist i. MAP kinase inhibitor j. Opioid alternatives (dexmedetomidine) k. Peptide Therapeutics (conopeptide) l. TRPV1 antagonist m. Gene therapy n. Others
8. Late stage pipeline developments in neuropathic pain a. Cebranopadol (oral, once daily, Grunenthal/ Depomed, PhIII, chronic pain)-A potential threat to abuse deterrent formulations b. Mirogabalin- Key MOA diff vs. Lyrica, Pros & Cons analysis based on reported PhII data c. CL-108 d. Hydromorphone e. Convergence/ biogen Idec- CNV-2197944 f. Convergence/ biogen Idec- CNV-1014802 g. Sativex h. Once daily pregabalin i. Topical clonidine gel j. Topical ketamine and amitraline k. Amorsa therapeutics l. Pregabalin CR m. Eladur n. GRC-17536 o. DWP05195 p. AVP-123 q. Algiax Pharmaceuticals
Appendix – I FDA Guidelines for the development of abuse Deterrent Formulations Types of Abuse deterrent formulation as per current guidance Pre market studies Post market studies Labeling Recommendations
Appendix- II General Principles for Evaluating the Abuse deterrent Generic Solid Oral Opioid Drug Products Need for regulatory filing and other key requirements Route of Abuse deterrent Comparative in Vitro Studies Other Consideration Data Analysis Additional
List of Tables
Table-1(A): Key pipeline ER Abuse Deterrent Drugs, its ROA, techplatform Table-1(B): Key pipeline ER Abuse Deterrent Drugs, its ROA, techplatform Table-1(C): Key pipeline ER Abuse Deterrent Drugs, its ROA, techplatform Table-1(D): Key pipeline ER Abuse Deterrent Drugs, its ROA, techplatform Table-2: Non-Injectable Opioid Pain TRx+share-US Table-3: Classification Based on Intensity of Pain 2013-2014 Table-4: Marketed Fentanyl Dosage Forms (Us): Transdermal Patches, Buccal And Sublingual Tablets And Films For Pain Relief Table-5: Commonly Used Opioids for Pain Management Table-6: Marketed Drugs for Neuropathic Pain Table-7: Drug Enforcement Authority (DEA) Controlled Substances Schedule Criteria Table-8: Summary of Controlled Substances Act requirements Table-9: Overview of pivotal studies conducted in the ALO-02 development program Table-10: Benefits of Sublingual Microtablets vs. IV morphine Patient Controlled Analgesia Table-11: Marketed formulation of Oromucosal product Table-12: Microgabalin –WW ongoing key clinical trials
List of Charts
Chart -1: Classification of Pain Chart-2: Pain is multi-factorial Chart-3: Pain Relief ladder-WHO Chart-4: Neuropathic Pain market size and projection through 2020 Chart-5: Medicine spending in 2020 US$ by geography, product type and disease area Chart-6: Specialty Medicines and Leading therapy areas in 2020 Chart-7: Number of Death from Prescription drugs Chart-8: Number of Death from Heroin Chart-9: Hydrocodone prescription volume has noticeably declined since up-scheduling Chart-10: Total opioid market TRx and sales growth Chart-11: Recent long acting opioids TRx launches Chart-12: NUCYNTA ER prescription trend-us post launch in June 2015 Chart-13: Abuse Deterrent pipeline in development-Acura pharma Chart-14: DETERx Multiparticulate system Chart-15: Design element of DETERx as used in Xtampza Chart-16: Pipeline of Collegium Pharma Chart-17: Pipeline of Intellipharmaceuticals Chart-18: Abuse Deterrent Technology platform of Elite Pharmaceuticals Chart-18(a): Abuse Deterrent Technology platform- One Bead System Chart-18 (b): Abuse Deterrent Technology platform- Two Bead System Chart-19: Guardian Technology combines abuse deterrent- features with a precision zero-order profile Chart-20: Egalet product pipeline using GuardianTM Technology Chart-21: Egalet’s guardian technology as used in ARYMO and Egalet-002 Chart-22: OraguardTM Manufacturing process used for Vantrela ER Chart-23: Diagram of the cross-section of an ALO-02 pellet Chart-24: Zohydro ER’s BeadTek technology-PEO Gels in liquids Chart-25: Exalgo’s OROS Delivery technology- Deigned for ER not ADF Chart-26: Stratum Tech platform- Orbis Bioscience Chart-27: Tramadol in Vitro Pharmacokinetic Chart-28: PF614: Prodrug of Oxycodone (ER Oxycodone) Chart-29: Pipeline of Enysce Bioscince Chart-30: ZilrettaTM cilical phase study for pain Chart-31: Biodelivery science International BEMA technology Chart-32: Product in pipeline utilizing BEMA technology Chart-33: Advance in Orodispersible film for drug delivery Chart-34: Cara therapeutics drug development Chart-35: Cebranopadol overview Chart-36: Cebranopadol MOA- Uniquely differentiate Chart-37: Cebranopadol phase II clinical trial summary Chart-37 (a): Cebranopadol phase II clinical trial summary Chart-37 (b): Cebranopadol phase II clinical trial summary Chart-38: Cebranopadol reduced Abuse Deterrent potential Chart-39: Daiichi sankyo (Efficacy result of mirogabalin vs. Lyrica/Pregabalin) Chart-40: A flow chart depicting a tier-based approach to evaluating the extractability of Opioid from an intact product for ingestion
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