Surfing the CNS Pipeline: Ripples, Swells or Waves?...• Partnering interests are mostly steady •...

Surfing the CNS Pipeline: Ripples, Swells or Waves?

Ginger S. Johnson, PhD Defined Health Harry Tracy, PhD NI Research

Co-Sponsors

[email protected]

Second Opinion Consulting

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Defined Health will also be participating in the following industry events:

ASGCT Annual Meeting | May 10 - 13, 2017 | Washington, DC | http://www.asgct.org/

ASCO Annual Meeting | June 2 - 6, 2017 | Chicago, IL | https://am.asco.org/

BIO International Convention | June 19 - 22 | San Diego, CA | http://convention.bio.org/about-bio-convention/

Rational Combination 360 | June 28 - 29, 2017 | New York, NY | http://theconferenceforum.org/rational-combinations-360/

BioPharm America | September 26 - 27, 2017 | Boston, MA | https://ebdgroup.knect365.com/biopharm-america/

LES Annual Meeting | October 22-25, 2017 | Chicago, IL | http://www.lesusacanada.org/mpage/am17

Defined Health is pleased to present:

http://www.asgct.org/�

https://am.asco.org/�

http://convention.bio.org/about-bio-convention/�





http://theconferenceforum.org/rational-combinations-360/�





https://ebdgroup.knect365.com/biopharm-america/�



http://www.lesusacanada.org/mpage/am17�

The CNS Pipeline Promises Major Shifts in the Treatment of Multiple Conditions

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2016 2017 2018 2019 2020

SMA ALS

PD Psychosis Tardive Dyskinesia Progressive MS?

Rett Syndrome? Status Epilepticus? RRMS dosing?

Depression? AD psychosis?

Chronic Migraine? Post-Partum Depression?

Dravet and Lennox-Gestaut?

Ripple Swell Wave

The CNS Pipeline: Ripples, Swells and Waves

• Forces inherent to a potential therapy (e.g., efficacy or safety/tolerability data) or external influences (e.g., regulators, payers) can either build, diminish or stop transition from a ripple to a wave.

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The CNS Macro-Climate

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Following a Spike in 2015, Funding in CNS has Adjusted but Still Strong

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• CNS: 2016 Funding down 42% from 2015 total ‒ 2015 spike pushed by a couple of outliers (Axovant, Denali)

• All of biotech industry: down 36% from 2015 total

Neuro Resources 2002 - Early 2017

Total

Funding

Partnering

NeuroPerspective

CNS Investor Funding in a Time of Uncertainty

• Jan-April 2015: $1,630.6 million

• Jan-April 2016: $819.4 million

• Jan-April 2017: $770.1 million

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NeuroPerspective

CNS Partnering: One Oversized Deal Skews Average of a Small Data Set

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NeuroDM

NeuroSx

Psychiatry

Pain

Biogen Press Release

Biogen Licenses Phase 2 Anti-Tau Antibody from BMS April 13, 2017 7:00 am EDT

"Based on encouraging safety and efficacy data, we believe BMS-986168 is a promising anti-tau candidate that may represent the next wave of medicines for Alzheimer’s disease as well as the first real answer for progressive supranuclear palsy.“ Michael Ehlers, Executive VP, R&D, Biogen

CNS Partnering 2009 - Early 2017

NeuroDM = Neurology Disease Modifying Therapy NeuroSx = Neurology Symptomatic Therapy

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CNS Funding Priorities 2009 - Early 2017

CNS Funding: Symptomatic Neurology Breaks from the Pack

• Partnering interests are mostly steady

• But a few areas are getting more attention: – Orphan neurodegenerative

disease (ALS, Huntington’s) – Neurodevelopmental disorders

(Rett syndrome, Fragile X, Autism)

– Genetic disorders (SMA, Fragile X, Huntington’s)

Not Straying from the Big Neurodegenerative Diseases, Companies are Also Interested in Orphan Disease & Genetic Disorders

12 NeuroLicensing

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Anxiety Spinal Cord Injury

Stroke TBI

Alertness/EDS PSP

Addiction ADHD

Epilepsy Insomnia

MCI/AAMI Migraine

Autism Bipolar Disorder

Fragile X Rett SMA

Nociceptive Pain Neuropathic Pain

MS Depression

Huntington’s ALS

Schizophrenia Parkinson’s Alzheimer’s

2016 2011

Partnering Agendas 2011/2016 from NeuroLicensing

CNS Partnering: Walking the Walk

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• 40% of 2011 BD therapeutic area wishlist goals translated into that company licensing or acquiring a relevant program over next five years

• 48% of BD goals in neurodegeneration

• 33% of BD goals in other areas

• 27% of licensing transactions were in therapeutic areas that had not been cited by the inlicensing company

• Big/Midsize pharmas who say they need to expand their pipelines via partnering, eventually will.

• Some Big Pharmas are re-emphasizing CNS partnering: e.g. Sanofi, AbbVie

NeuroLicensing

CNS Partnering 2017 YTD

Licensee/ Acquirer Indication Licensor Product Stage Upfront Milestone Category

Allergan Parkinsons Lysosomal Gcase Phase I U U ND

JNJ Depression Amorsa norketamine Preclinical U U PSY

Ovid Epilepsy Takeda TAK-935 Phase I U U NS

Biogen Alzheimer's BMS/ iPierian tau vaccine Phase I 300 960 ND

Otsuka ADHD Neurovance centanafadine Phase II 100 150 PSY

Celgene Neuro-degeneration Evotec iPS screening Discovery 45 250 ND

Neurocrine Parkinsons BIAL opicapone Phase I 30 115 NS

Daiichi Pain Heptares GPCR Pain Discovery 4 8 Pain

Amicus Epilepsy MiaMed CDLK replacement Preclinical 6.5 83 NS

BioHaven Migraine BMS Rimegepant Phase III 5 350 Pain

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High-Profile CNS Clinical Datasets 2016-2017

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Ripples 2016-2017

Compound Company Mechanism Indication (Clinical Phase)

idalopirdine Lundbeck 5-HT6 receptor antagonist Alzheimer’s (P3)

solanezumab Lilly beta amyloid monoclonal antibody Alzheimer’s (P3)

Intepiridine (RVT-101) Axovant 5-HT6 receptor antagonist

Alzheimer’s (P3) Dementia with Lewy Bodies (P2) Gait and Balance Impairments in Dementia (P2)

Ripples in the CNS Pipeline

• Some never advance beyond a ripple, some may advance but with modest clinical benefit.

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Intepiridine: A Ripple in Still Water

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Intepiridine: A Ripple in Still Water

• Is there clear scientific rationale behind indications in DLB and gait/balance indications?

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http://axovant.com/�

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Swells 2016-2018

Oral Acute Migraine Alternatives


lasmiditan CoLucid 5-HT1F agonist Acute migraine (P3)

rimegepant BioHaven (from BMS)

Oral calcitonin gene related peptide (CGRP) antagonist Acute migraine (P2)

ubrogepant Allergan (from Merck) Oral CGRP antagonist Acute migraine (P3)

Chronic migraine (P2)

CNS Pipeline Swell: Oral Acute Migraine Alternatives

• In a sea of generic triptans, opportunity still exists for acute migraine patients with safety/tolerability issues.

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Company Press Release

Lilly “Takes Back Control” of Migraine

Lilly and CoLucid Pharmaceuticals Announce Agreement for Lilly To Acquire CoLucid

$960 million deal will enhance Lilly's existing pain management portfolio for migraine; adds potential near-term launch to its late-stage pipeline

INDIANAPOLIS and CAMBRIDGE, Mass., Jan. 18, 2017 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) and CoLucid Pharmaceuticals, Inc. (NASD: CLCD) today announced an agreement for Lilly to acquire CoLucid for $46.50 per share or approximately $960 million. This all-cash transaction will enhance Lilly's existing portfolio in pain management for migraine, while adding a potential near-term launch to its late-stage pipeline. CoLucid Pharmaceuticals is a public biopharmaceutical company developing an oral 5-HT1F agonist (lasmiditan) for the acute treatment of migraine. CoLucid has completed the first of two pivotal Phase 3 trials. A data read-out for the second Phase 3 trial, SPARTAN, is expected in the second half of 2017. If this trial is positive, submission of lasmiditan for U.S. regulatory approval could occur in 2018. More than 36 million people suffer from migraine in the United States alone. Lasmiditan, if approved, would be a first-in-class therapy to treat migraine through a novel mechanism of action without vasoconstriction. This could be desirable in migraine patients who have, or are at risk for, cardiovascular disease, as well as those who are dissatisfied with their current therapies. … "Lasmiditan is a novel, first-in-class molecule that could represent the first significant innovation for the acute treatment of migraine in more than 20 years, and CoLucid has made significant progress in advancing this potential medicine," said David A. Ricks, Lilly's president and chief executive officer. “ …

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CoLucid website

Lasmiditan: An Answer for the Subset of Acute Migraine Patients with Cardiovascular Issues

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https://get.whotrades.com/u5/photoDC52/20741087577-0/original.jpeg�


LifeSciCapital

But, Tolerability Limits Use In the Broader Patient Population

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PIII SAMURAI Efficacy Results n = 2,231 patients

Freedom from Pain and Most Bothersome Symptoms at 2 Hours

Sumatriptan 100mg Phase 3

= placebo

3%

= placebo

= placebo

3%

= placebo

2%

Chest pressure 2%

Bothersome symptoms = photophobia, nausea, phonophobia, etc.

No significant signs of cardiovascular-related side effects.




OLINVOTM (oliceridine) Trevena

Modified mu opioid agonist; selective for G protein pathway

IV: Moderate-to-severe acute (post-surgical) pain (P3)

CR845 Cara Therapeutics

Kappa Opioid Receptor Agonists

IV: Post-op pain (P3) Oral: Chronic pain (P2)

CNS Pipeline Swell: Next Generation Opioids

• While the Opioid Epidemic goes beyond crisis, next generation opioids hit dose-limiting tolerability issues leaving a continued need for novel mechanisms.

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Next Generation Opioids

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Oliceridine Phase 3: The Agony of Victory

• Trevena Announces Positive Top-line Results from Two Phase 3 Pivotal Efficacy Studies of Intravenous Oliceridine in Moderate-to-Severe Acute Pain 21-Feb-2017

Oliceridine was specifically designed to improve on conventional IV opioid pharmacology, by binding to the same receptor and selectively activating pain-relieving pathways, while avoiding the pathway associated with opioid-related adverse effects.

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OLINVO/Oliceridine : Efficacy Comparable to Morphine (At Highest Doses)

Company presentation

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OLINVO/Oliceridine: But GI Tolerability Restricts to Lowest Doses

Company presentation

An Antidepressant of Ambiguous Speed & Tolerability


ALKS 5461 Fixed-dose combination of buprenorphine and samidorphan

Alkermes opioid receptor modulator

Major Depressive Disorder (P3)

CNS Pipeline Swell: An Antidepressant of Ambiguous Speed & Tolerability

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ALKS 5461: A Mixed Bag of Efficacy Results

• FORWARD-3 misses due to trial design, placebo effect

• FORWARD-4 borderline results

• NDA filing to be based on FORWARD-5, post hoc FORWARD-4 results, Phase II results

• The most common side effects were nausea, dizziness and fatigue.

Alkermes press release 30

Placebo-Controlled Studies Supporting Efficacy of ALKS 5461

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Is There a Swell to be Found in the

Alzheimer’s Roster?

Regarding the Amyloid Hypothesis

“Maybe we’re all just stumbling from the right questions to the wrong answers, or maybe from the right answers to the wrong questions.”

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~ Malek, R. Mr. Robot 2016

The comforting thing about the amyloid hypothesis is that it offers a well-defined path forward

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The Evolution of the Amyloid Hypothesis

AH 1.0: Amyloid plaque causes Alzheimer’s degeneration

AH 2.0: Amyloid in non-plaque form “ “

AH 3.0: Amyloid plays secondary role—e.g. setting the stage for tau-induced degeneration

34 NeuroPerspective

The Alzheimer’s Roster

Target Company Asset Stage POC Read-Out

Amyloid: mAb

Biogen aducanumab PhIII 2020 Biogen/Eisai BAN2401 PhII 2018 Genentech/AC Immune crenezumab PhIII 2020 Roche gantenerumab PhIII 2020

Amyloid: BACEi

Biogen/Eisai elenbecestat PhII/III 2018/2020 JNJ 54861911 PhIII 2023 Lilly/AstraZeneca AZD3293 PhII/III 2019 Lundbeck preclinical 2024? Merck verubecestat PhIII 2019 Novartis/Amgen CNP520 PhII 2023

pGlu AB Probiodrug PQ912 PhII 2017 Lilly LY3202626 PhII 2019

Tau

AbbVie ABBV-8E12 PhII 2021 Axon-Neuroscience AAdVac1 PhII 2019 Genentech/AC Immune RG6100 PhI 2022? Biogen (from BMS) BMS-986168 PhII-prep 2021? JNJ/AC Immune ACI-35 PhIb 2023? Merck/Alectos OGA-inhibitor PhI 2024? Roche preclinical 2024?

Early-Stage Alt Annexon, Denali, Proclara, Yumanity, more Disc-PhI 2022?

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The current array of clinical trials in Alzheimer’s will provide POC — or not — for a potential disease-

modifier — by 2021-22

NeuroPerspective

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Waves

2016 – 2018 Waves in Psychiatry

• Rapid-acting antidepressants promise a major transformation in treatment. • A shift in the treatment of insomnia is thwarted by regulators.

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Esketamine (intranasal) JNJ/Janssen N-methyl-D-aspartate

(NMDA) receptor antagonist Major Depressive Disorder (P3)

Rapastinel (IV) Allergan MDA receptor modulator with GlyB site partial agonist properties

Major Depressive Disorder (P3)

SAGE 547 Sage Proprietary formulation of endogenous neurosteroid allopregnanolone

Post-Partum Depression (P3)

Belsomra (suvorexant) Merck orexin receptor antagonist Insomnia (Marketed)

2016 – 2018 Waves in Psychiatry

Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for Suicide

FDA action marks second Breakthrough Therapy Designation for intranasal esketamine, highlighting its potential as treatment for patients with major depressive disorder who are at imminent risk for suicide and for those with treatment-resistant depression TITUSVILLE, N.J., Aug. 16, 2016 - Janssen Research & Development, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, announced today that the U.S. Food and Drug Administration (FDA) has granted a Breakthrough Therapy Designation for esketamine, an investigational antidepressant medication, for the indication of major depressive disorder with imminent risk for suicide. If approved by the FDA, esketamine would be one of the first new approaches to treat major depressive disorder available to patients in the last 50 years. This also marks the second time esketamine has received a Breakthrough Therapy Designation from the U.S. regulatory authority. Esketamine was first granted this designation for treatment-resistant depression in November 2013. Breakthrough Therapy Designation is intended to expedite development and review timelines when preliminary clinical evidence indicates the drug may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies for serious or life-threatening conditions.1 … "In the U.S. alone, there are more than 41,000 suicides each year,3 many of which result from untreated or poorly treated major depression," said Husseini K. Manji, MD, Global Head, Neuroscience Therapeutic Area, Janssen. …

38 Janssen press release

2016 – 2018 Waves in Neurology

• Treating the tough-to-treat patient

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Ocrevus Roche Anti-CD20 monoclonal Ab PPMS, RRMS (Mkt)

Epidiolex GW Pharma CB2 Dravet, Lennox-Gestaut (NDA-prep)

Trofinetide Neuren IGF-1 Rett Syndrome (PhIII-prep)

SAGE 547 Sage GABA-A Severe Status Epilepticus (PhIII)

Nusinersen Biogen/Ionis SMN gene therapy SMA (Mkt)

AVX-101 AveXis SMN gene therapy SMA Type 1 (PhIb)

Ocrevus is Positioned to be the Market Leader in MS

• Roche/Genentech undercut the price of Ocrevus at 25% compared to its comparator in RRMS (Rebif), while outperforming on efficacy and safety (no PML thus far), convenience (semi-annual IV) and a label indication for progressive MS.

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Approved by the FDA on March 28, 2017 CDP = Confirmed Disability Progression

The Competition is Fighting Back, Not with Data but with Price/Budget Impact

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Merck KGaA disses Ocrevus-Rebif price comparison as 'misleading and oversimplified’ March 30, 2017 The way Merck sees it, Ocrevus—an infusion—"is expected to be covered under the medical benefit," and products with that designation "typically do not require the manufacturer to provide discounts to payers." Self-injectable biologics including Rebif, on the other hand, are often covered under the "pharmacy benefit," and their list prices often bake in room for manufacturer discounts "to support … access for customers and patients."

Biogen CEO eyes value-based payer deals to boost pressured MS franchise April 25, 2017

Facing stepped-up competition for its critical MS business, Biogen CEO Michel Vounatsos contends his company is “ready and well-equipped” to forge ahead. And that includes "value-based and innovative contracting" with payers … Biogen “has the opportunity to benefit from a complete portfolio in MS,” And in order to “change the landscape” for its MS franchise overall, the drugmaker will work to “progress on value-based and innovative contracting,” he said.

AVXS-101: Gene Therapy for SMA

• Biogen/Ionis Nusinersen (SPINRAZA) in SMA

• $750K for first year, $375K yearly thereafter

• AveXis PhIb data for AVXS-01 in SMA

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2016 – 2018 Waves in Pain

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AMG334 Amgen, Novartis CGRP-antagonist Migraine (PhIII)

LY2951742 Lilly CGRP-antagonist Migraine (PhIII)

TEV-48125 Teva CGRP-antagonist Migraine (PhIII)

ALD403 Alder Pharma CGRP-antagonist Migraine (PhIII)

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Migraine Prophylaxis

Chronic Migraine

CGRP Monoclonal Antibodies: A Race to the Market

www.clinicaltrials.gov

Episodic Migraine

2015 2017 2016 2018

Phase 3 Study Timelines

ALD403 (ALDR) – PROMISE-2 study

AMG334 (AMGN) - ARISE study AMG334 (AMGN) – STRIVE study

ALD403 (ALDR) – PROMISE-1 study LY2951742 (LLY) - EVOLVE-1 study

LY2951742 (LLY) - EVOLVE-2 study TEV48125 (TEVA)

LY2951742 (LLY) – REGAIN study TEV48125 (TEVA)

Start date, primary completion date ( ), and study completion date as per clinicaltrials.gov

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Potential Waves 2020 and Beyond

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Glucocerebrosidase in PD (Lysosomal/Allergan)

Huntingtin isoforms in HD (Wave Life Sciences)

Complement c1q in neurodegeneration (Annexon)

Glutamate in depression, pain (Allergan, Aptinyx)

BH4 in pain (Quartet Medicine)

Biogen’s Opicinumab PhIIb (anti-lingo) in RRMS?

WAVES = Treatment Paradigm Shifts

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The CNS Pipeline Promises Major Shifts in the Treatment of Multiple Conditions

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2016 2017 2018 2019 2020

SMA ALS

PD Psychosis Tardive Dyskinesia Progressive MS?

Rett Syndrome? Status Epilepticus? RRMS dosing?

Depression? AD psychosis?

Chronic Migraine? Post-Partum Depression?

Dravet and Lennox-Gestaut?

[email protected]

Second Opinion Consulting

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Surfing the CNS Pipeline: Ripples, Swells or Waves?...• Partnering interests are mostly steady •...

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