ash complement factor d symposium - jefferies · are detailed in the "risk factors"...

Corporate OverviewJune 7, 2016 | Jefferies 2016 Healthcare Conference

NASDAQ:ACHN©2016 Achillion Pharmaceuticals. All rights reserved.

Forward-Looking StatementsThis presentation includes forward-looking statements about Achillion Pharmaceuticals, Inc. and its business, including, without limitation, statements regarding drug discovery, clinical development, regulatory approval processes, market opportunities, intellectual property, competition, and financial results. All statements other than statements relating to historical matters (including statements to the effect that we “believe,” “expect,” “anticipate,” “plan,” “target,” “intend” and similar expressions) should be considered forward-looking statements. These forward-looking statements are subject to risks and uncertainties that may cause actual events or results to differ materially from our current expectations. These risks and uncertainties are detailed in the "Risk Factors" sections of our annual report on Forms 10-K and 10-Q, and subsequent filings with the SEC.

All forward-looking statements contained in this presentation speak only as of the date hereof, and we undertake no obligation to update any of these statements, except as required by law.

2June 2016 Corporate Overview

Achillion: Strength Across the Continuum

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POWERING sustainable, highly-productive discovery engine

DEVELOPING a pipeline of potent and specific complement factor D inhibitors for rare and other diseases

PURSUING best-in-class therapy for HCV through Janssen worldwide collaboration

FOCUSING on patient needs and marketplace dynamics

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We are rapidly becoming a fully-integrated commercial pharmaceutical company

through our highly disciplined, science-driven, and patient-

focused approach.

June 2016 Corporate Overview

Complement SystemThe Alternative Pathway and Factor D Inhibition

Complement System

June 2016 Corporate Overview5

The Complement system is one of our defense mechanisms that plays an important role in coordinating immune responses

Complement activation and regulation are induced by more than 30 proteins that are present in plasma (fluid phase) and on cell surfaces (solid phase)

Activation of Complement is achieved by three distinct pathwayso Classical pathway

o Lectin pathway

o Alternative pathway

Activation of these pathways leads to:o Recognition and elimination of pathogens

o Recruitment of adaptive immunity

o Facilitation of removal of apoptotic cells

Source: Data on file. Achillion Pharmaceuticals, Inc. www.achillion.com

The Complement System: Activation

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Complement factor D



The Complement System: Regulation


REGULATORS• Factor H• CR1• Factor I• CD55 (DAF)• CD59


The Complement System: Inhibiting Factor D


• Cleaves factor B, leading to formation of C3 convertase

• Plays an essential role in alternative pathway activation and amplification loop

Complement Factor D


Dysregulation of Alternative Pathway and Human Disease


Source: V. Michael Holers. 2008.

Alternative Pathway-Mediated Diseases


Age-Related Macular Degeneration

• Genetic variants in AP proteins (C3, FB, FH) associated with AMD risk

• Patients have elevated plasma levels of AP proteins (FD, FB, C3a & others)

• C3, FD & FB are present in the vitreous and Bruch’s membrane

• AP activation occurs in a disease-stage specific fashion

Paroxysmal Nocturnal Hemoglobinuria

• Characterized by deficiency of complement regulatory proteins CD55 & CD59

• Leads to red cell lysis through AP and TCC dysregulation

• Patients have both C3d and MAC deposition on RBCs

• Regulation of the MAC with eculizumab provides only partial protection, need to prevent AP deposition of C3 on RBCs

C3 Glomerulopathy

• Umbrella term inclusive of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)

• Patients have uncontrolled fluid-phase AP activation that results in deposition of C3 in the renal glomerulus

• Uncontrolled AP activation can be associated with autoantibodies to, mutations in, or genetic variations in complement components


SCIENCE DRIVEN. PATIENT FOCUSED.Complement Factor D Platform

Factor D is an Attractive Drug Target

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Plays a central role in AP and overall complement system

An attractive “control point” for complement amplification

Lowest plasma concentration of all complement components, representing a highly “druggable” target

Amenable to potent inhibition by small-molecule drugs

Validated target

Promising therapeutic approach for AP-mediated rare diseases and serious conditions


Complement Protein

Molecular Weight

Plasma Concentration

(μg/ml)

PlasmaConcentration

(μM)

Factor D 24,000 2 0.083

C5 190,000 75 0.4

C3 185,000 1200 6.49


Early, rigorous assessment of drug-like properties enhances potential for successful development

ACHILLION FACTOR D INHIBITORS

Robust Engine


>1300 small molecule factor D

inhibitors Primary pharmacology

Secondary pharmacology

ADME/SafetyRoute of admin Lead

programs

OPHTHALMIC OPHTHALMIC

COMPOUND | PROGRAM DELIVERY INHIBITOR PHASE PARTNER

FACTOR D INHIBITOR CANDIDATE PORTFOLIO

ACH-4471PNH Oral Factor D 1

C3 Glomerulopathy (C3G) Oral Factor D 1

Dry AMDHighly water soluble inhibitorsPotential >3 month delivery

Ophthalmic Factor D Preclinical

COPDCrystalline inhibitors Favorable lung PKNo systemic exposure

Inhalation Factor D Preclinical

HEPATITIS C VIRUS CANDIDATE PORTFOLIO

HCV | Triple / Doublet Regimens Oral odalasvir + ALS-335 ± simeprevir 2

HCV | Odalasvir Oral NS5A 2

Complement Pipeline

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Achillion Discovery Engine


Strategy for Factor D Inhibitors Develop and commercialize factor D inhibitor for rare diseaseso ACH-4471

Oral dosing

Potential for QD or BID dosing

Initial indications: PNH and C3G

Progress factor D inhibitors for ophthalmic diseaseso Physico-chemical properties ideally suited for ocular delivery

o Potential for extended ( ≥ 3 months ) delivery

o Indication: Dry AMD


ACH-4471Pharmacology


ACH-4471 prevents complement-mediated hemolysis with IC50 = 17 nM

Ex-vivo PK/PD analyses with ACH-4471 (N=8) confirmed that an exposure of > 100 ng/mL is sufficient for complete inhibition of complement AP activity (EC50 = 15.84 nM)

Cynomolgus monkeys dosed orally ACH-4471 (200 mg/kg, Q12H)

Complete and sustained suppression of AP activity was demonstrated for >24 hours oral dosing

AP, alternative pathway; fD = Factor D Morgan BP et al. 56th Annual Meeting of the American Society of Hematology; 2014; abstract 4817. Data on File. Achillion Pharmaceuticals, Inc. 2015.

ACH-4471Summary of ADME / PK and Safety Characteristics ABSORPTION

Highly permeable with low efflux potential. Most likely not a substrate for intestinal Pgp and BCRP transportersRapid absorption after PO dosing: Oral bioavailability is 30% - 70%

DISTRIBUTIONHighly bound to plasma with a free fraction of 8% in human plasma. Minimal partitioning into blood cellsSteady state volume of distribution (Vss) is moderate

METABOLISMLow inhibition potential against all major CYP-450 isozymesNo time-dependent inhibition of CYP3A4Low metabolic turnover in human liver microsomesNot an inducer of human P450 enzymes

SAFETY ASSESSMENTSafety margins achieved in repeat dose toxicity studies support clinical development



ACH-4471Differentiated Pharmacological Approach to PNH

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Goal of providing consistent and potent inhibition of complement alternative pathway

Effectively block C3 fragment deposition on cells, in contrast to C5-targeted therapies

Inhibition of hemolysis in patients carrying C5 mutation (Arg885His)o Ability to treat non-responders to C5 monoclonal

antibody treatment

Oral agent with daily dosing enables improved infection risk-management


Paroxysmal Nocturnal Hemoglobinuria (PNH)

PATIENT 2

% h

emol

ysis

chan

ge

20

40

60

80

100

120

0

ACH-3856ACH-4471

ECU

trea

ted

0.1 1 10 100 1000nM

PATIENT 1

PATIENT 3

% h

emol

ysis

chan

ge

20

40

60

80

100

120

0

ACH-3856ACH-4471

ECU

trea

ted

Patient 1 IC50 (nM) IC90 (nM)

ACH-4471 27 110

ACH-3856 17 56


ACH-4471 14 26

ACH-3856 10 4520

40

60

80

100

0

ACH-3856ACH-4471

Trea

tmen

t na

ïve

ACH-4471Dose-Dependent Reduction of Hemolysis of PNH Erythrocytes

67% Type III RBCs

15% Type III RBCs

0.1 1 10 100 1000


ACH-4471 4 14

ACH-3856 3 6

97% Type III RBCs

0.1 1 10 100 1000

% h

emol

ysis

chan

ge

120

nM

nM

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Brodsky et al. 51st ASH Meeting, Dec. 2015. Data on file, Achillion Pharmaceuticals, Inc.


ACH-4471 Significantly Reduces C3b/iC3b Deposition on PNH Erythrocytes

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1 nM 300 nM30 nM

0.01 0.1 1 10 100 1000

% C

3c p

ositi

ve c

ells

0

10

20

30

40

50

ACH-4471 concentration (nM)

43.8% 22.4% 1.5%

IC50 = 32 nM

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Brodsky et al. 51st ASH Meeting, Dec. 2015. Data on file, Achillion Pharmaceuticals, Inc.


C3 Glomerulopathy (C3G): Rare Renal Disease


C3G: A renal disease due to persistentover-activity of the alternative pathway

C3G: Umbrella term for patients with:o Predominant

C3 deposition on renal biopsy

o Evidence of AP over-activation

DDD – those with C3G who have characteristic dense deposits on renal biopsy

C3GN – those with C3G who do not have characteristic dense deposits on renal biopsy

The incidence is about 3–10 cases per million per year

There is no approved treatment for C3G

ACH-4471C3G: Scientific Rationale


Uncontrolled fluid phase activation of alternative pathway results in:

• Consumption of AP components

• Low serum C3 levels

• Deposition of C3 breakdown products in the glomerulus

• Damage to the glomerulus

• Glomerular dysfunction• Decreased filtration rate• Blood in urine• Protein in urine• Elevated BP

Scientifically logicalo C3G is a disease that is due to over-activity of the alternative pathway (AP) o ACH-4471 inhibits AP activity o Factor D believed to be a “brake” that can impact over-activityo Plan to initiate clinical development by end of 2016


REGULATORSFactor HCR1Factor ICD55 (DAF)CD59

ACH-4471Clinical Program - Next StepsPHASE 1 (FIRST-IN-HUMAN) PROGRAM

Single-ascending dose (SAD) healthy volunteer study initiated Feb. 2016o Assessing safety, tolerability and PK/PDo Interim SAD results to be presented at EHA on June 10th

Multiple-ascending dose (MAD) healthy volunteer study targeted for 2Q16o Interim MAD results anticipated 3Q16

PHASE 2 DEVELOPMENT PROGRAMPNH: Proof-of-concept trial

o Improvement in lactate dehydrogenase (LDH), a sensitive marker of hemolysiso Assess safety o Establish PK/PD (pharmacodynamics)o Expect to initiate and generate interim results by the end of 2016

C3G: Proof-of-mechanism trial o Improvement in C3 levels relative to baselineo Assess safety o Establish PK/PD (pharmacodynamics)o Targeting study initiation by the end of 2016


ACHILLION FACTOR D INHIBITORSHighly Differentiated Target Product Profiles

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Orally bioavailable, potent and specific

Bind to factor D with high affinity resulting in inhibition of alternative pathway (AP)

Effectively block C3 fragment deposition on cells, in contrast to C5-targeted therapies

Demonstrate complete suppression of complement activity after oral dosing ex vivo

Safety assessment supports clinical development

Represent a promising oral therapy for PNH, C3G and other complement-mediated diseases



Goal of introducing a disruptive approach to treating complement-mediated diseases with AP-specific inhibition

PURSUING BEST-IN-CLASS ANTIVIRAL THERAPY FOR HCVAchillion – Janssen Worldwide HCV Collaboration

COMPOUND | PROGRAM DELIVERY INHIBITOR PHASE PARTNER

FACTOR D INHIBITOR CANDIDATE PORTFOLIO

ACH-4471PNH Oral Factor D 1

C3 Glomerulopathy (C3G) Oral Factor D 1

Dry AMDHighly water soluble inhibitorsPotential >3 month delivery

Ophthalmic Factor D Preclinical

COPDCrystalline inhibitors Favorable lung PKNo systemic exposure

Inhalation Factor D Preclinical

HEPATITIS C VIRUS CANDIDATE PORTFOLIO

HCV | Triplet / Doublet Regimens Oral odalasvir + ALS-335 ± simeprevir 2

Achillion-Janssen HCV Collaboration

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Achillion Discovery Engine



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Creates potentially best-in-class combined pipeline to benefit HCV patients

Access global development and

commercial infrastructure fully funded by Janssen

Potentially accelerates time to participate in

worldwide HCV market

Attractive economics, including royalties from the mid-teens to low-twenties



Phase 2a Safety, PK and Efficacy Trialo Triplet regimen: odalasvir + AL-335 + simeprevir

Durations of 6 and 8 weeks ongoingo Doublet regimen: odalasvir + AL-335

Duration of 8 weekso Interim top-line results anticipated 3Q 2016o Additional cohorts could explore durations ranging from 4 – 12 weeks

Phase 2b Trial Efficacy, Safety and PK Trialo 4-arm trial evaluating doublet and triplet regimens for 6 and 8 weeks (n=100/arm)

GT 1-6 Treatment-naïve and treatment-experienced Patients with/without cirrhosis

o Anticipate study start in 3Q


Clinical development program: Once daily treatment for HCV

Achillion Financial SummaryCapitalization and Ownership

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Balance Sheet Metrics As of 3/31/2016Cash And Equivalents $444 million

Debt Obligations $0.5 million

Shares Outstanding 136.4 million

Top Shareholders† Position

Johnson & Johnson Development Corp. 18.4 million (13%)

RA Capital 11.2 million (8%)

Orbimed Advisors 9.6 million (7%)

Point72 Asset Management 8.9 million (7%)

Fidelity Management & Research 8.9 million (7%)

Vanguard Group 7.6 million (6%)

Blackrock Institutional 7.4 million (5%)

Janus Capital Management 7.0 million (5%)

Millennium Management 5.8 million (4%)

State Street Global 4.1 million (3%)

T. Rowe Price 4.1 million (3%)

† Based upon most recent SEC filings as of 3/31/16.


Achillion: Positioned for Success

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STRONG financial position to advance programs through value inflection points and towards commercialization

HIGH VALUE targets for complement inhibition aimed at addressing patient needs for both rare and broader diseases

PURSUING best-in-class therapy for HCV through Janssen worldwide collaboration

INNOVATION taking place throughout the organization aimed at meeting the needs of patients and changing marketplace dynamics

“

“

Understanding the binding of factor D at the molecular level

provides us an exquisite target to inhibit a critical

control point in the alternative pathway within the

complement cascade.


ash complement factor d symposium - jefferies · are detailed in the "risk factors"...

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