En busca del opioide ideal.

Nuevas moléculas

Luz Romero PhD

Sebastià Videla MD PhD

Barcelona, 1 de diciembre de 2017 Guión

EN BUSCA DEL OPIOIDE IDEAL

ESTADO ACTUAL DE LA INVESTIGACIÓN EN OPIOIDES

Ø Analgesia: • “Farmacología nueva” • Combinaciones

Ø Indicaciones diferentes a analgesia: • “Farmacología nueva”: Antagonistas opioides • Combinaciones (antagonistas opioides + otros) Guión

EN BUSCA DEL OPIOIDE IDEAL

ESTADO ACTUAL DE LA INVESTIGACIÓN EN OPIOIDES

Ø Analgesia: • “Farmacología nueva” • Combinaciones

Ø Indicaciones diferentes a analgesia: • “Farmacología nueva”: Antagonistas opioides • Combinaciones (antagonistas opioides + otros) δ κ Receptor Types µ Opioid NOP

Current NC-IUPHAR Previous Presumed Recommended Nomenclature Effects Endogenous Ligands Nomenclature (2000) (1996)

Analgesia, sedation, euphoria, -endorphin (not selective) β vomiting, respiratory , (not selective) OP3 , pruritus, anorexia, µ, mu, or MOP -1 (tentative) urinary retention, miosis, physical endomorphin-2 (tentative) dependence

enkephalins (not selective) Analgesia (without many adverse OP1 δ, delta, or DOP β-endorphin (not selective) effect), not well understood

A Analgesia, respiratory depression, OP2 κ, kappa, or KOP α-

Nociceptin/orphanin FQ OP4 Analgesia and tolerance NOP (ORL-1) (N/OFQ)

Localization of opioid receptors

OPIOIDE → afinidad selectiva por los receptores opioides centrales y periféricos ⇒ inhiben: 1) la transmisión de la entrada nociceptiva, y 2) la percepción del dolor Localization of opioid receptors

OTRAS ACCIONES → efectos adversos Ideal opioid ?

Action Receptor Benefit inhibition µ, δ, κ, NOP Addiction µ > κ Euphoria and sedation µ Dysphoric and κ Physical dependence µ > κ; δ? Tolerance µ, κ, δ Respiratory depression µ, δ Muscle Pain / Stiffness µ Miosis µ, κ Nausea, vomiting µ, κ, δ Risk Gastrointestinal motility µ, δ? Bladder motility µ Diuresis: Inhibition µ Stimulation κ Bradycardia µ > δ = κ Hypotension δ = κ > µ Endocrine actions: Prolactin release µ GH release δ > κ ACTH release µ, κ ADH inhibition κ LH Inhibition µ, δ Ideal opioid – ‘holy grail’

↑ Benefit-Risk relationship = = Benefit ↓ Risk

Nature. 2016 Sep 8;537(7619):170-171. Ideal opioid – ‘holy grail’

↑ Benefit-Risk relationship = = Benefit ↓ Risk

Action Receptor

Benefit Pain inhibition µ, δ, κ, NOP

Addiction µ > κ Respiratory depression µ, δ Risk Nausea, vomiting µ, κ, δ Constipation µ, δ? Tolerance µ, κ, δ Why investigate in ? Why investigate in opioids ?

1.- Fracaso de la investigación clínica en demostrar la eficacia de nuevos mecanismos de acción / nuevas dianas terapéuticas implicados en analgesia Why investigate in opioids ? Why investigate in opioids ?

Other a Mechanism of Action Other b Alpha a. MC SuGA TREK FGF Other TRPs OREs PDEs H1 MMPs Other GFs Antisense Other AD GCH TLRs MAPK H+ sens. ASICs PTH ILs TNF NKs Muscar. ETs NGF NTs Other CIT VIP CC / CXCRs SST CRFs Glutamate NE-uptake BDNF σ1 Gal NO PXs GABA NMDA Adenosine FAAH GDNF

CCK HCNs ORL-1 Bradykinin Potassium Calcium GL O. Kinases VRs mGluRs AMPA / K CBs 5-HT NPY HIST COX Sodium NNRs ACh CGRP NE / NA Opioids BSAEDs Prostanoids Project Selection

Preclinical & Clinical Validation

Potential Competitive Advantages; Value Added

Product Profile Discontinued pain between 2009-2014

Phase I 34% Phase II 56% Phase III 9%

1. BVT-115959 (Adenosine A2a) 1. BL-1021 (Sodium channels) 1. Bicifadine (NA/5-HT transpoters) 2. AZD-2066 (mGluR5) 2. NCX-1236 () 3. AZD-2516 (mGluR5) 2. Esreboxetine (NA transporter, Alpha 2) 4. LY-545694 (Glu Kainate) 3. PF-3557156 (PDE 7A) 3. MoxDuo (morphine + ) 5. PH-797804 (P38 kinase) 4. SEP-227900 (D-amino-acid oxidase) 6. PF-4480682 (GABA A, PDE 5) 7. KHK-6188 (CB2) 5. SEP-228432 (DA/NA/5-HT transporters) 8. Placulumab (TNF alpha) 6. NSD-644 (DA/NA/5-HT transporters) 9. AZD-1940 (CB1/2) 10. Ataciguat (Guanylate cyclase) 7. SAR-114137 (Cathepsin S/K) 11. ADL-5859 (Opioid Delta) 8. GPI 5693 (Glutamate Carboxypeptidase II) 12. Radiprodil (Glu NMDA) 13. Sofinicline (Nicotinic alpha4, beta2) 9. AZD 6088 (Muscarinic M1) 14. AZD-2423 (Chemokine CCR2) 10. BI-660848 (Undefined) 15. SC-75416 (COX-2) 16. ASP-3652 (Undefined) 11. SAR-407899 (Rho-kinase) 17. Indantadol (MAO A/B; Glu NMDA) 18. Z-160 (Calcium channel N-type)

Sponsor terminated 1 Strategic 4 Unspecified 15 REASON FOR DISCONTINUATION: Adverse effects 2 Lack of efficacy/Low efficacy 8 32 drugs Low efficacy + safety 1 Pharmaceutical characteristics 1

Adapted from: Expert Opin Investig Drugs. 2015;24(12):1631-46. Discontinued pain drugs between 2015-2016

Phase I 40% Phase II 47% Phase III 13%

1. ALKS-7106 ( ) 1. PF-05089771 (Nav1.7 blocker) 1. Fulranumab (recombinant IgG2 2. ASP-9226 (Undefined) 2. PF-489791 (PDE-5 inhibitor) anti-NGF mAb) 3. LY-2969822 (mGlu2/3 agonist) 3. Senrebotase (Endopeptidase 2. (topical gel) (Alpha 2 4. PHE-377 (TRPV1 antagonist) modulator) agonist) 5. ODM-108 (TRPA1 inhibitor) 4. 10% (vaginal gel) (Na 6. BIA-102474 (FAAH inhibitor) channel inhibitor) 5. ASP-8477 (Undefined) 6. Dexisometheptene (Imidazoline I1R agonist) 7. AZD-5213 (H3 )

Sponsor terminated 0 Strategic 2 Unspecified 7 REASON FOR DISCONTINUATION: Adverse effects 1 Lack of efficacy/Low efficacy 4 15 drugs Low efficacy + safety 1 Pharmaceutical characteristics 0

Source: Integrity, Cortellis, Companies website. Discontinued opioid drugs between 2010-2016

Phase I 19% Phase II 44% Phase III 31%

1. JDTic ( dependence) 1. AZD-2327 (; Depression) 1. (Constipation) 2. AZD-7268 (Anxiety; Depression) 2. KRP-110 (Pruritus) 2. (inhaled TAIFUN) 3. PF-4856880 (NeP; Pain) 3. MT-7716 (Alcoholism) 4. PF-4856881 (Pain; Postherpetic (Cancer pain) neuralgia) 3. Fentanyl (transdermal matrix 5. hemiadipate patch) (Cancer pain; Pain) hydrochloride (oral tablet, 4. (orally Discovery 6% formulated with abuse-deterrent ), (Opiate dependence) disintegrating tablet) 6. Fentanyl (inhaled, liposomal), (Premature ejaculation; 1. Tramadol + PDE5 inhibitor (Cancer pain; Pain) Erectile dysfunction) 7. LY-2940094 (Alcoholism; Major (Premature ejaculation; 5. MoxDuo (morphine + depressive disorder) Erectile dysfunction) oxycodone) DELTA agonist 4 DELTA antagonist; MU antagonist 1 KAPPA antagonist 1 MU agonist 6 TARGET-BASED ACTIONS MU agonist; PDE 5 inhibitor 1 16 drugs MU antagonist 1 NOP agonist 1 NOP antagonist 1

Source: Integrity, Cortellis, Companies website. Why investigate in opioids ?

1.- Fracaso nuevos mecanismos de acción en analgesia

2.- Los agonistas opioides continúan siendo hasta el momento los mejores analgésicos de que disponemos Why investigate in opioids ?

1.- Fracaso nuevos mecanismos de acción en analgesia

2.- Agonistas opioides → los mejores analgésicos

3.- Los efectos analgésicos de los opioides son debidos a la activación del sistema opioide endógeno (SOE) ⇒ principal mecanismo inhibitorio que modula de forma fisiológica la transmisión nociceptiva en mamíferos Why investigate in opioids ?

1.- Fracaso nuevos mecanismos de acción en analgesia

2.- Agonistas opioides → los mejores analgésicos

3.- Sistema opioide endógeno

4.-

https://www.google.es/search?q=dolar+dinero&espv=2&biw=1536&bih=716&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjwye- v7pTSAhXDcBoKHcLBBNMQ_AUIBigB#imgrc=854OLB6sp4hFlM. Opioid Consumption by Countries — ME minus , mg/capita, 2014 Pain & Policy Studies Group (PPSG) - International Control Board (INCB) The graph shows the aggregate amount of 6 principal opioids countries consumed in morphine equivalence as it relates to their Development Index score

Fentanyl Morphine Oxycodone

https://ppsg.medicine.wisc.edu/chart. Opioid Consumption in Spain

Consumo extrahospitalario - Sistema Nacional de Salud Oxycodone Consumption

Source: QuintilesIMS, Disease Insights, Chronic Pain, Oct 2016 Launched drugs acting on opioid receptors

Source: Integrity, Cortellis. Guión

EN BUSCA DEL OPIOIDE IDEAL

ESTADO ACTUAL DE LA INVESTIGACIÓN EN OPIOIDES

Ø Analgesia: • “Farmacología nueva” • Combinaciones

Ø Indicaciones diferentes a analgesia: • “Farmacología nueva”: Antagonistas opioides • Combinaciones (antagonistas opioides + otros) Searching for the ideal opioid - ANALGESIA

Novel pharmacology: 1. MOP agonist: Biased µ-opioid receptor ligands

2. Mul-mechanisc ligands

3. KOP / NOP agonist

Combinaons: 1. COMBOs: OPIOIDS and others (NSAIDs, )

2. COMBOs: OPIOIDS AGONIST and OPIOIDS ANTAGONIST

3. COMBOs: OPIOIDS ANTAGONIST and OTHERS Searching for the ideal opioid: Novel Pharmacology

1. MOP agonist: Biased µ-opioid receptor ligands

7-transmembrane G-protein coupled receptor

Reduced neurotransmier release

Intracellular changes occurring following the binding of an opioid agonist to a G-protein coupled opioid receptor

Rev Pain. 2008 Mar;1(2):2-5. / Br J Pain. 2012 Feb;6(1):11-6. Searching for the ideal opioid: Novel Pharmacology

1. MOP agonist: Biased µ-opioid receptor ligands

↑ Benefit-Risk relationship = = Benefit ↓ Risk Searching for the ideal opioid: Novel Pharmacology

1. MOP agonist: Biased µ-opioid receptor ligands

Label: pain

Pain Pruritus IDBS- Pulmonary Phase D Hypertensio n TRV130 ( III MU ago biased X ) MU ago, slow NKTR-181 III X brain entry Searching for the ideal opioid: Novel Pharmacology

1. MOP agonist: Biased µ-opioid receptor ligands

Oliceridine (TRV130): Biased µ-opioid agonist

Beer safety vs. opioids: Phase III reduced nausea, completed voming and hypovenlaon Searching for the ideal opioid: Novel Pharmacology

2. Mul-mechanisc ligands • Multarget opioid ligands

Cebranopadol

Cebranopadol: μ-opioid + NOP agonist Beer safety vs. opioids: reduced 7 Phase II respiratory depression completed and abuse potenal

GIC-1001

K ago peripheral

Phase II Pain & IBS On going Searching for the ideal opioid: Novel Pharmacology

3. KOP agonist

Label: pain, pruritus, pulmonary hypertension

Pain Pruritus IBS- Pulmonary Phase D Hypertensio n (iv) III CR285 () K ago peripheral X X (po) III Searching for the ideal opioid: combinations

1. COMBOs: OPIOIDS AGONIST and others (NSAIDs, benzodiazepines)

Label: Pain (synergy), Pain (preventing OIC &/or OINV), Anxiety, Cough

Pain Pain Anxiety Cough Phase (synergy) (prevenng OIC &/or OINV) Tramadol/ Approved X / / Submied X X acetaminophen

Tramadol. III X

II /triazolam X X (discount?) Searching for the ideal opioid: combinations

2. COMBOs: OPIOIDS AGONIST and OPIOIDS ANTAGONIST

Label: Pain (preventing OIC &/or OINV), Depression

Pain Depression Phase (prevenng

OIC &/or OINV) Oxycodone/ Approved X

3. COMBOs: OPIOIDS ANTAGONIST and others

Label: Pain

Phase Pain Naltrexone/clonidine III X Searching for the ideal opioid: OTHER INDICATIONS

Other indicaons (≠ analgesia): 1. Antagonist: MOP / KOP / NOP

2. COMBOs: OPIOIDS ANTAGONIST and others

3. KOP / NOP agonist

4. COMBOs: OPIOIDS AGONIST and others (NSAIDs, benzodiazepines, )

5. COMBOs: OPIOIDS AGONIST and OPIOIDS ANTAGONIST Searching for the ideal opioid: OTHER INDICATIONS

1. Antagonist: MOP / KOP / NOP

Label: OIC, OINV, Depression, Neurobehavioral disorder

OIC &/ Depressio Neurobehavior Phase or OINV n al disorder Naldemedin MU antago Submitted X e peripheral MU antago II X peripheral

CERC-501 II K antago X

BTRX-246040 II ORL1 antago X Searching for the ideal opioid: OTHER INDICATIONS

2. COMBOs: OPIOIDS ANTAGONIST and OTHERS

Label: Schizophrenia, Charcot Marie Tooth type 1

Charcot Marie Phase Schizophrenia Tooth type 1 /olanzapine III X

Naltrexone/Baclofen/ III X Searching for the ideal opioid: OTHER INDICATIONS

3. KOP / NOP agonist

Label: pain, pruritus, pulmonary hypertension

Pain Pruritus IBS-D Pulmonary Phase Hypertensio n Difelikefalin III K ago peripheral X X

Asimadoline II K ago peripheral X X

SER-100 II ORL1 part ago X Searching for the ideal opioid: OTHER INDICATIONS

4. COMBOs: OPIOIDS AGONIST and others (NSAIDs, benzodiazepines, )

Label: Pain (synergy), Pain (preventing OIC &/or OINV), Anxiety, Cough

Pain Pain Anxiety Cough Phase (synergy) (prevenng OIC &/or OINV)

Hydrocodone/guaifenesin Submied X Searching for the ideal opioid: OTHER INDICATIONS

5. COMBOs: OPIOIDS AGONIST and OPIOIDS ANTAGONIST

Label: Pain (preventing OIC &/or OINV), Depression

Pain Depression Phase (prevenng

OIC &/or OINV)

Buprenorphine/samidorphan III X Searching for the ideal opioid – ANALGESIA - Future

Mul-mechanisc ligands

↑ Benefit-Risk relationship = ↑ Benefit ↓ Risk Searching for the ideal opioid – ANALGESIA - Future

Mutants Receptors as therapeuc agent

The generation of the MORS196A knock-in mouse line supported our initial hypothesis that activation of the mutant receptor with antagonist could produce antinociceptive responses with minimal chronic side effects. Searching for the ideal opioid – ANALGESIA - Future

Mutants receptors as therapeuc agent Thomas Sydenham (10-09-1624, † 29-12-1689), médico inglés

“Láudano de Sydenham“: Preparación farmacéutica compuesta de opio, azafrán, vino blanco y otras sustancias que se utilizaba como analgésico.

In 1680, Thomas Sydenham: “Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as ”