drugs in clinical development for neuropathic...

6/6/2013

1

Confidential | 0

CONFIDENTIAL

Drugs in Clinical Development for Neuropathic Pain Ada Silos-SantiagoJune 1st, 2013

Confidential | 1

Outline – Neuropathic Pain

• Definition and symptoms• Pathophysiology and mechanisms• Approved treatments• Drugs in clinical development for

neuropathic pain (NP)• Neuropathic pain drugs in chronic

pelvic pain syndromes

6/6/2013

2

Confidential | 2

Neuropathic Pain

• Pain caused by a lesion or disease of the somatosensory nervous system

• Peripheral and central neuropathic pain

• Neuropathic pain symptoms: - Ongoing/spontaneous pain- Evoked pain

• Allodynia – Pain due to a stimulus that does not normally provoke pain

• Hyperalgesia – Increased pain from a stimulus that normally provokes pain

IASP Definition

Cervero and Laird, 1996

Confidential | 3

Peripheral Neuropathic Pain

• Neuropathies: diabetic, post-herpetic, nerve injury

• CRPS, neuromas, plexopathies

• Cancer pain

• Chemotherapy-induced pain

• HIV Neuropathy

• Trigeminal neuralgia

• Lower back pain

• Post-surgical pain

Ab

C & Ad

PainTemperature

Tactile

6/6/2013

3

Confidential | 4

Pathophysiology of Neuropathic Pain• Peripheral sensitization – Hyperalgesia

– Release of cytokines, growth factors and other mediators– Activation of GPCRs, ion channels, TKRs

• Increased nerve excitability – Ongoing Pain– Redistribution of ion channels, changes kinetics– Gene expression

• Central sensitization – Hyperalgesia and Allodynia– Increased synaptic transmission– Synaptic plasticity

(-)

Peripheral sensitization

Hyperexcitability(ectopic discharges)

Central sensitization

PerceptionIntegration of physical, cognitive and emotional

responses

Modulation Descending

inhibitionDescending facilitation

Confidential | 5

Multiple Targets Involved in Neuropathic PainActivation & sensitizationCentral sensitization

Microglia mediators

Cytokines

AT2R

Ca++

6/6/2013

4

Confidential | 6

Neuropathic Pain is an Unmet Medical Need: FDA-approved Treatments for Neuropathic Pain

Lidocaine (patch 5%) Post-herpetic Neuralgia (PHN)

Gabapentin PHN

Carbamazepine Trigeminal Neuralgia

Ziconotide Intractable pain

Pregabalin PHN, Diabetic neuropathy Fibromyalgia Spinal cord injury

Duloxetine Diabetic neuropathy

Capsaicin (patch 8%) PHN

• Analgesic efficacy- Poor efficacy - 30-40% responder rate

• Safety and Tolerability- Most currently available drugs

have dose limiting side effects• Targeted treatments

- Need more treatments at the underlying mechanism

Issues

Confidential | 7

Site of Action for Current Treatments

LidocaineCapsaicin

Nerve Terminal

Supra-spinal*CBZGBPDLXTPGB

Dorsal Root

Ganglia*CBZ

ZiconotideCBZGBPPGBDLXT

Spinal Cord*

*TCAs and opioids –not FDA approved

6/6/2013

5

Confidential | 8

Addressing the Limitations of Current Treatments• Sixteen new analgesic drugs were approved by the

FDA in 2011 and 2012. Not one hits a new target or has a novel mechanism of action

• The approved drugs are new formulations, or old drugs approved for new conditions

• New drugs in clinical development include:– Novel mechanisms– Restricted expression pattern– Target selectivity – Nav1.7 and Nav1.8– Activity specific

Confidential | 9

Compounds in Clinical Development for Neuropathic Pain

Ph1 Ph2 Ph3

# of Assets 14 18 1

02468

101214161820

Nu

mb

er o

f T

arg

ets

6/6/2013

6

Confidential | 10

Drug in Clinical Development For Neuropathic Pain – Phase II

• NGF antibodies – Tanezumab, Fulnarumab, REGN475– Phase II in diabetic peripheral neuropathy, interstitial cystitis, chronic

low back pain, PHN, chronic prostatitis, vertebral fractures and cancer pain and Phase III in OA

• Nav1.7 antagonists – Xenon402, CNV1014802, PF-05089771– Phase II in erythermalgia, PHN

• N-Type Ca++ channel blocker – Z160– Phase II in PHN and low back pain with sacral radiculopathy

• AT-2 Receptor antagonist – EMA401– Phase II in PHN and chemotherapy-induced pain

Confidential | 11

Site of Action for Drugs in Clinical Development

Z160Spinal Cord

XEN402

Nerve Terminal

Supra-spinalZ160?

Dorsal Root

GangliaXEN402

(CNV, PF)Tanezumab

Z160EMA401

The majority of drugs in development are targeting the

periphery

6/6/2013

7

Confidential | 12

Mechanism Of Action Originator Drug Name Global Status Delivery Route

Calcium channel agonist+ VitB Merck KGaA F-0434 Phase III Oral

Nav1.7 Selective Convergence CNV1014802 Phase II Oral

Nav1.7 Selective Xenon XEN402 Phase II Oral, ointment

Nav1.7 Selective Pfizer PF-05089771 Phase II Oral

NGF antibody Pfizer Tanezumab Phase II Injectable

NGF antibody Johnson&Johnson Fulnarumab, JNJ-42160443 Phase II Injectable

NGF antibody Regeneron REGN475 Phase II Injectable

N-type Calcium channel blocker Zalicus Z160 Phase II Oral

Angiotensin II antagonist Spinifex Pharma. EMA-401 Phase II Oral

Sigma 1 receptor antagonist Esteve E-52862 Phase II Oral

P38 kinase inhibitorMAP kinase inhibitor GlaxoSmithKline losmapimod Phase II Injectable

Oral

Histamine H3 receptor antagonist Abbott ABT-652 Phase II Oral

Calcium channel antagonist Abbott ABT-639 Phase II Oral

Erythropoietin receptor agonist Araim Pharma. ARA-290 Phase II Injectable

Cannabinoid CB2 receptor agonist Kyowa Hakko Kirin KHK-6188 Phase II Oral

Potassiumchannel agonist Pfizer ICA-105665 Phase II Oral

Potassiumchannel agonistNMDA antagonist, Opioid receptor agonist Relevare Pharma. flupirtine, CNSBio

CNSB-015 Phase II Oral

Orexin receptor antagonist Merck & Co filorexantMK-4305 back up, MK-6096 Phase II Oral

Calcium channel antagonist Daiichi Sankyo DS-5565 Phase II Oral

Drugs in Clinical Development for NP – I

Confidential | 13

Drugs in Clinical Development for NP – II Mechanism Of Action Originator Drug Name Global Status Delivery Route

Serotonin and norepinephrine reuptake inhibitor Theravance TD-9855 Phase I Oral

Vanilloid receptor 1 antagonist PharmEste PHE-377 Phase I InjectableOral

Nitric oxide synthase inhibitor NeurAxon NXN-462 Phase I Oral

Bone formation stimulantCorticosteroid agonist Newron HF-0299 Phase I Oral

TRPA1 antagonist Glenmark GRC-17536 Phase I InhaledOral

Dopamine reuptake inhibitorSerotonin-norepinephrine-dopamine reuptake inhibitorAdrenergic transmitter uptake inhibitor

EuthymicsBioscience EB-1020 Phase I Oral

Vanilloid receptor 1 antagonist Daewoong DWP-05195 Phase I InjectableOral

Voltage-gated sodium channel antagonist (Nav1.7 and Nav1.8 inhibitor)

Dainippon Sumitomo Pharma. DSP-2230 Phase I Oral

Opioid mu receptor agonist Cytogel Cyt-1010 Phase I Injectable

Glycine NMDA associated antagonist VistaGen, Neurex AV-101, GLYX-13 Phase I OralInjectable

Unidentified pharmacological activity CLL Pharma. SYN-1002 Phase I Unspecified

Unidentified pharmacological activity BioLineRx BL-1021 Phase I Oral

Unidentified pharmacological activity Astellas ASP-9226 Phase I Oral

Unidentified pharmacological activity Astellas ASP-8477 Phase I Oral

Unidentified pharmacological activity Astellas ASP3652 Phase II Oral

6/6/2013

8

Confidential | 14

Inhibition of NGF Signaling for the Treatment of Neuropathic Pain

• NGF is released from epithelial cells and mast cells. The NGF receptor, TrkA, is expressed in nociceptors

• NGF signaling through TrkAphosphorylates and activates TRPV1 – sensitizes DRG neurons

• Activation of TrkA induces CGRP and SP release from nociceptorscontributing to peripheral sensitization and neurogenic inflammation

• Mutations in TrkA – CIPA • NGF levels are increased in diabetic

neuropathy, OA, IC and CPP syndromes

Pezet & McMahon, 2006

Confidential | 15

Tanezumab – Anti-NGF Antibody

• Pfizer conducted several Phase II exploratory studies across multiple pain types, in parallel, that were terminated– Post-herpetic neuralgia– Diabetic neuropathy– Cancer pain– Interstitial cystitis – Endometriosis– Osteoarthritis (Phase III)– Low back pain

6/6/2013

9

Confidential | 16

Tanezumab Improves Pain ScoresDiabetic Peripheral Neuropathy

Bramson et al., APS 2013

Confidential | 17

Tanezumab – Responders to TherapyDiabetic Peripheral Neuropathy


6/6/2013

10

Confidential | 18

No Improvement in Patient’s Global Assessment


Confidential | 19

Tanezumab has not Effect on QST or IENFs


6/6/2013

11

Confidential | 20

Tanezumab – Adverse Events Diabetic Peripheral Neuropathy


Confidential | 21

Tanezumab for the Treatment of DPN

• Tanezumab 20 mg administered by subcutaneous injection was, in general, well tolerated

• Significantly improved average diabetic peripheral neuropathy pain score compared to placebo

• No significant changes were observed in the number of intraepidermal nerve fibers or quantitative sensory testing

• The most common treatment-emergent adverse event was pain (arthralgia, pain in extremity, myalgia) followed by abnormal peripheral sensations

Summary

6/6/2013

12

Confidential | 22

Selective Na++ Channels are Targets for the Treatment of Neuropathic Pain• Na++ channels are a gene family involved in:

– Membrane excitability– Generation and propagation of action potentials– Neurotransmitter release– Regulated in pathological states

PNS– Chronic pain– OAB– Migraine

CNS– Epilepsy– Neurodegeneration– Bipolar disorders

Cardiovascular– Arrhythmia

CNS– Ataxia– Nausea– Somnolence

CarbamazepineLamotrigineLidocaine

Confidential | 23

Several Na++ Channel Blockers are Analgesic

Lamotrigine AnticonvulsantCarbamazepine AnticonvulsantMexiletine AntiarrhythmicTopiramate AnticonvulsantLidocaine Local anestheticAmitriptyline Antidepressant

Characteristics:

- non-selective inhibitors- use-dependent- cross blood brain barrier

- Their adverse events limit their dose level: dizziness, nausea, sedation, tremors

6/6/2013

13

Confidential | 24

Role of NaV1.7 in Neuropathic PainHuman Genetics

Confidential | 25

Nav1.7 Blockers in Phase II Clinical Trials

• Xenon Pharmaceuticals – XEN402 in Phase II for PHN (NCT01195636)

• Pfizer/Icagen – PF-05089771 in phase II for inherited erythermalgia(NCT01769274)

• Convergence – CNV1014802 in Phase II for lumbosacral radiculopathy (NCT01561027) and Trigeminal neuralgia (NCT01540630)

Goldberg et al., 2012; Minett et al., 2012

6/6/2013

14

Confidential | 26

Nav1.7 Blockers – Xenon402 OralExploratory trial in Erythermalgia (NCT01486446)

Goldberg et al., 2012

The amount of pain in the 2 hours after induction was reduced by 21% (P= .011), 33% (P = .004), and 88% (P = .031) in these 3 patients, respectively

XEN402: 400 mg bid

Confidential | 27

XEN402 Oral Reduces Spontaneous Pain

• Subject 1001 (ongoing pain) reported improved pain relief scores. Her total pain relief scores at 4, 6, and 8 hours (TOTPAR-4, -6, -8) showed improvement over placebo

Exploratory trial in Erythermalgia (NCT01486446)

Goldberg et al., 2012

XEN402: 400 mg bid

6/6/2013

15

Confidential | 28

Topical NaV1.7 Blocker: XEN402 Ointment

• Phase II trial (NCT01195636) topical XEN402 in PHN • Greater proportion of patients reported clinically

meaningful reductions in pain for topical XEN402 vsplacebo (p=0.049 for >30% and p=0.0078 for >50%)

• Topical XEN402 had a trend to improve sleep and other co-morbidities

• Dose limiting side effects were not observed• By treating pain locally at its source, topical XEN402

could be an effective and safe treatment both as a mono-therapy and an adjuvant to oral therapies

Post-herpetic Neuralgia – PHN

Xenon corporate web page 2013

Confidential | 29

Angiotensin II Type 2 Receptor – AT2-R

• AT2-R is expressed in control and avulsed human DRG neurons

• AT2-R is co-expressed with TRPV1 in a subpopulation of DRG neurons

• AT2-R antagonists inhibit capsaicin-induced neuronal activation as well as neuriteoutgrowth

• AT2-R is also expressed in nerves fascicles in bladder and enteric nervous system

Biology

Anand et al., 2012

6/6/2013

16

Confidential | 30

EMA-401 – Pain IntensityPHN –Primary and Secondary End Points

• Secondary endpoint: Responder rate – 57.6% of patients on EMA401 achieved ≥ 30% reduction in mean pain intensity score compared to baseline vs 35.2% Placebo, p = 0.0023

Spinifex corporate web page 2013

100 mg bid

Confidential | 31

EMA-401 – Safety and TolerabilityPost-herpetic Neuralgia

Spinifex corporate web page 2013

6/6/2013

17

Confidential | 32

N-Type Calcium Channel Blockers

• New class of analgesics that are selective for pain signal transmission• Prialt® and morphine-related drugs target this pathway. Successful in

treating severe and chronic pain but side effects• N-type specific calcium channel blockers are believed to avoid these

serious side effects

Zamponi et al., 2009

Confidential | 33

N-type Ca++ Channel Blocker – Z160

Lee and Snutch, APS 2013

6/6/2013

18

Confidential | 34

N-Type Calcium Channel Blocker – Z160 Oral

• Z160 demonstrated substantial bioavailability and solubility improvements

• Z160 is in Phase II clinical development for the treatment of neuropathic pain (PHN and lumbosacral radiculopathy)

• A previous formulation of Z160 was studied in clinical trials of over 200 subjects and was well tolerated

Pharmacokinetics and Safety – Phase I

Previous Formulation 200 mg (normalized to

225 mg)

New Formulation200 mg

Previous Formulation 200 mg (normalized to

225 mg)

New Formulation200 mg

Zalicus corporate web page 2013

Confidential | 35

Clinical Stage Assets in Functional Pain

Fibromyalgia Chronic fatigueChronic pelvic

painDysmenorrhea

Functional dyspepsia

GERD IBS Interstitial cystitisTemporomadibular

joint disorderVulvodynia

Ph3 0 1 3 2

Ph2 0 0 1 4 13 3

Ph1 3 4 2

0

2

4

6

8

10

12

14

16

18

20

# o

f C

linca

l A

sse

ts

6/6/2013

19

Confidential | 36

Pathophysiology of Visceral Pain

• Similarities with neuropathic pain– Peripheral involvement– Peripheral sensitization– Central sensitization– Altered descending inhibition– Molecular targets– Drugs for NP are used in

CPP

Malykhina, 2007

Confidential | 37

Gabapentoids in IBS: Gabapentin

• 40 patients RCT, double-blind placebo-controlled. 6 days, 500 & 600 mg/day

• Gabapentin attenuated rectal sensitivity to distension in patients with IBS

Lee et al., 2005

Pressure thresholds for discomfort of at least moderate intensity or pain

6/6/2013

20

Confidential | 38

Gabapentoids in IBS: Pregabalin• 23 patients RCT, double-blind placebo-controlled trial. 3

weeks escalated to 600 mg/day of pregabalin

Houghton et al., 2007

Confidential | 39

Gabapentoids in IBS: Pregabalin

Houghton et al., 2007

• Pregabalin increased distension sensory thresholds to normal levels in IBS patients with rectal hypersensitivity

6/6/2013

21

Confidential | 40

NGF is Released from the Bladder Epithelium

Ochodnicky et al., 2012

Confidential | 41

Tanezumab – Average Daily Pain ScoreInterstitial Cystitis

Moldwin et al., EUA 2010

6/6/2013

22

Confidential | 42

Tanezumab – Other End Points

• Single-dose Tanezumab (200 mg/kg) significantly reduced pain and urgency episode frequency per 24 hours in patients with IC

• No effect on ICSI, micturition frequency or voided volume


Confidential | 43

Tanezumab: Incidence of Adverse Events


6/6/2013

23

Confidential | 44

Summary

• In general, drugs in clinical development are targeting very selective mechanisms

• This selectivity might result in an improvement of their therapeutic index over current treatments

• By improving the therapeutic index the drug can be explored at higher doses

• However, at this moment, the efficacy of a specific selective mechanism hasn’t been demonstrated in large RCTs

• Drugs approved for neuropathic pain are now been tested in RCTs for visceral pain with promising results

Confidential | 45

drugs in clinical development for neuropathic...

Documents