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Barriers and Facilitators to the Development of Novel Analgesics

William K. Schmidt, PhD

President, NorthStar Consulting, LLCDavis, California, USA

National Academy of SciencesSeptember 22, 2016, Washington, D.C.

Barriers and Facilitators to the Development of Novel Analgesics

Conflict of Interest

PresenterWilliam Schmidt: Research support, consulting fees, or lecture honoraria in the past year from more than 35 pharmaceutical, biotech, and venture capital firms.

Disclaimer: Unapproved indications; non-confidential; personal opinions• Data do not represent trade secrets• Opinions presented in this discussion are entirely those of

the speaker and do not necessarily reflect the opinions of his client companies or employers.

Development history: TEV-48125 / Labrys LBR-101 / RN-307:Genentech (discovery) → Rinat Neurosciences (2001) → Pfizer (2006) → Labrys (2013) → Teva (2014)

CAUTION: Unapproved drug;Current status = Phase 3 clinical trials;Expected completion in Sept. 2018

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Funding for Early Research & Development• Pharmaceutical / Biotech Industry

– Good at fast-follower approach– Good at formulation development– Good at large Phase 2b & Phase 3 clinical trials– Most early R&D in analgesia discontinued

• Academic Laboratories– Excellent at early discovery (NIH funding)– Universities encourage spin-off companies

Bayh-Dole Act / Patent and Trademark Law Amendments Act (1980)

– Financing is hard for spin-off analgesic assets

Abstract: whether [rodent models] predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy … successful translation requires several models for each indication …

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Challenges for Early Clinical Development

* Hamilton MD. Trends in Mid-Stage Biotech Financing. Tuck School of Business, Dartmouth University (2011)

“Although capital is difficult to come by for any small biotech, firms with drugs in the "mid-stage" of development have a

particularly difficult time raising funds.”

*

“Valley of Death”for early development

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Challenges for Early Clinical Development

Barriers:• Challenges and solutions to perceived non-predictable

preclinical → clinical translation • Difficulty in achieving Angel or Venture Capital funding

prior to human POC clinical trials

Facilitators:• DOD grant support• NIH SBIR funding• NIH Blueprint Neurotherapeutics funding

The soluble epoxide hydrolase (sEH) as a therapeutic target

for pain

Discovery and early development at University of California, Davis

EicOsisEicOsis Therapeutics LLC

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Inflammatory Inflammatory

EicOsis Target:Soluble Epoxide Hydrolase (sEH)

A key regulatory enzyme in the Cytochrome P540 (CYP450) pathway

Prostaglandins Leukotrienes

CYP450

Biomarker: EETs:DiHETsPredict efficacy

EETs (epoxyeicosatrienoic acids)

Analgesic and anti-inflammatory mediators

sEH

DiHETs

COX Inhibitors• Include NSAIDs (~$10B sales)• Dose limiting cardio

tox and GI tox• sEHI synergize to

improve efficacy and decrease tox

LOX InhibitorsTreats asthma (~$4B annually)

Regulatory Lipid (e.g. Arachidonic Acid) in Cell Membrane

sEH inhibition is a novel pathway in the regulatory lipid cascade

Anti-Inflammatory

Cyclooxygenase (COX) pathway

Lipoxygenase (LOX) pathway

EicOsis sEH Inhibitors (sEHI)↑ EETs

EETs (epoxyeicosatrienoic

acids)Analgesic and anti-

inflammatory mediators

Hammock, et al. report sEH enzyme

(Science, 1980)

DISCOVERY: Early sEH inhibitors safe in humans clinical trial (2006)

DISCOVERY: sEH inhibitors treat pain in rodents (2005)

DISCOVERY: sEH inhibitors treat pain in cats, dogs, horses (2010-2013)

EicOsis spun outof UC Davis to develop sEH

inhibitors as first in class

treatments for pain(2013)

Ota and Hammock Science. 207. 1980

Gill and Hammock Nature. 291. 1981

sEH inhibition is a novel pathway in the regulatory lipid cascade

KI (nM) for human sEH

AUDA6.8 ± 0.2

t-AUCB1.5 ± 0.2

TUPS14 ± 4

TPAU57 ± 6

TCC96 ± 5DCU

30 ± 2

0 10 20 30 40 50 60 70 80 90 100 110 120

t-TUCB9 ± 1

Sorafenib17 ± 4

TPPU27 ± 2

APAU or AR9281(UC1153)

125 ± 15

Rank order of sEH inhibitors on recombinant human sEH

Data from Liu et al. 2009 Mol Cancer Ther 8:2193-2203

Development compound EC5026 = 50 pM (2500x more potent than APAU with longer duration of action)

K i was determined with 3H t-DDPO and affinity purified recombinanthuman soluble epoxide hydrolase. All compounds are kinetically reversibletight binding inhibitors.

EicOsis

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OOH

O

OOHsEH

OHOH

sEH inhibitors reveal new biology and new players in pain and inflammation

14,15- epoxyeicosatrienoic acid(intracellular anti-inflammatory

& analgesic lipids)

14,15- dihydroxyeicosatrienoic acid(inactive sEH metabolite)

Inhibition of sEH blocks both inflammatory and neuropathic pain

without affecting sensorimotor parameters

EicOsis

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NN

OO

OH

O

OF

FF

H H

EC1728

EET

EicOsis

sEH is expressed in CNS, PNS and DRG of the rat

Brain (neocortex)

PNS (superior cervical ganglia)

Dorsal Root Ganglia

Neuronal cell cultures from embryonic rat pups (E19)

Red stainSomato-dendriticcytoskeletalproteinMAP-2 Green stain

sEH+ MAP-2

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Analgesic effects summary ■ Wide spectrum non-sedative analgesic activity profile

● Inflammatory pain● Neuropathic pain● Early and late phase of arthritic pain● No pain, no gain (inactive in the absence of pain)

■ Synergy with NSAIDs on inflammatory pain ■ Non-opioid profile■ No addiction liability shown in rodent tests

EicOsis

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sEHI lead 0.3 mg/kgVehicle Pregabalin 10 mg/kg(Neurontin®)

EicOsis lead compounds are more potent and longer acting than pregabalin in the rat, STZ-induced diabetic pain

0 1 2 3 4 5 640

60

80

100

hours post oral administration

perc

ent o

f hea

lthy

base

line

less pain

morepain

Pre-diabetes baseline

EicOsis

Clinical Case Study: Equine laminitis (neuropathic pain)

Hulahalla, three year old thoroughbred filly, was suffering from severe laminitis and failed to respond to NSAIDs, steroids, or gabapentin. The photo is three hours after treatment with EC1728, a soluble epoxide hydrolase inhibitor. (Guedes et al., Vet Anaesth Analg 2013).

Laminitis is severe inflammation of hoof leading to intense pain, tissue destruction, and morbid hypertension. Outcome is fatal in 70% of

cases with conventional treatment.

Pre-treatment 3 hr Post -treatment

Before: unresponsive to drugs and ALL conventional therapy

After single i.v. doseof EC1728 (sEH inhibitor)

Scheduled for euthanasia

Hulahalla- treatment with sEH inhibitor progressively decreased pain (n=1)

y-axis, visual analog pain scale. EC1728 administered daily x 6 days.

EicOsis

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One week

Hulahalla is alive today and teaching UC Davis students to ride; no recurrent laminitisIn replicate studies, 8 of 10 horses responded favorably to treatment with EC1728 (Guedes et al., 2016)

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Initial Funding for sEH Inhibitor Project

• NIH Funding to academic lab– 30+ years $50 M

• SBIR Phase I grant to EicOsis– 1 year $0.3 M

• SBIR Phase II grant to EicOsis– 2 years $1.5 M

• Friends, Family, Angel < $2 M• Venture / Pharma Funding $0• Funds for Clinical Development ???

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NIH Blueprint Neurotherapeutics Grant

"Development of an Oral Analgesic for Neuropathic Pain" is funded through the National Institutes of Health (NIH) Blueprint for Neuroscience Research to advance compounds through Phase 1 clinical trials for diabetic neuropathic pain

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EicOsis Development Timeline

• Spinoff from University of California Dec 2013• NIH Blueprint Therapeutics grant Jan 2016• IND filing; Phase 1 clinical trials 2017• INAD filing (animal pain studies) 2017

Bottom Line: this project would not have advanced without the NIH public-private partnership.

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Challenges for Early Clinical Development

Solutions:

• NIH and/or Department of Defense funding often enables discovery & early development of new therapeutic targets

• Venture Capital and/or Big Pharma will generally show interest only after clinical Proof-of-Concept is established

• Better animal models (double-blind, “unbiased” freely moving animals, natural pain vs. experimental pain), biomarkers, improved target imaging, and improved in vitro techniques may facilitate better preclinical → clinical translation