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Pain Management- New Discoveries and Treatment Options in Abuse Deterrent Era

August 2016 | 135 pages | ID: P9BB4D5EE9EEN
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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.
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 –
  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 Studies

COMPANIES MENTIONED:

AbbVie
AcelRx pharma
Acorda Therapeutics
Actavis
Acura Pharma
Acorda Therapeutics
Altus formulations
Alkermes
Algiax Pharmaceuticals
Amorsa Therapeutics
AnGes
AstraZeneca
Balerna
Biogen
BioDelivery Sciences International Inc
Biopharma
Cara Therapeutics
Catalent
Charleston
Celltech
Collegium Pharma
Convergence
Columbia Labs
Convatech
Daiichi Sankyo
Daewoong
Depomed
Durect
Egalet
Eli Lilly
Elite Pharma
Endo
Ensyce Bioscience
EpiCept
Flamel Technologies
Flexion Therapeutics
Forest
Glenmark
Grunenthal
GlaxoSmithKline
GW Pharma
Immune Pharmaceuticals
Impax Pharmaceuticals
Inspirion
Intelli Pharmaceutics
IRX Therapeutics
Johnson and Johnson
KemPharm
Kineta
Kunwha Pharmaceutical
Medallion Therapeutics
Mallinckrodt
Nektar
Novartis
Noven
Orbis Biosciences
Orexo
Otsuka
Pain Therapeutics
Pfizer
ProPharma
Purdue
Recro pharma
Relmada Therapeutics
Reckitt Benckiser pharmaceutical
Signature Therapeutics
Spinifex pharma
SPR Therapeutics
Strativa
Teikoku
Teva
Tesa Labtec GmpH
Trevena Inc
Tris Pharma
Valeant
ViroMed
Wooddiff Lake
Xenon Pharma
XenoPort

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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