leanne bloedon (aegerion) rare disease day 2016 conference

Proprietary & Confidential. © 2015 Aegerion Pharmaceuticals, Inc. All Rights Reserved.

LeAnne Bloedon, MS, RD Senior Director, Clinical Science Aegerion Pharmaceuticals, Inc.

CORD’s Rare Disease Day Conference March 10, 2016

Development of Juxtapid®

for Homozygous FH: a story of perseverance & collaboration

Proprietary & Confidential. © 2015 Aegerion Pharmaceuticals, Inc. All Rights Reserved. 2

Aegerion’s Vision

DEVELOPING AND COMMERCIALIZING

CLINICALLY IMPACTFUL THERAPIES FOR PATIENTS WITH RARE, DEBILITATING

DISEASES WITH UNMET MEDICAL NEED


z

History of Juxtapid & Aegerion Pharmaceuticals

3

1990s 2002 2004 2006 2007 2010

BMS donates certain rights to lomitapide to the University of

Pennsylvania (Penn)

Aegerion obtains certain license for exclusive worldwide rights to Juxtapid from Penn

2012

Completes enrollment of

pivotal Phase III clinical trial for

adult patients with HoFH

Submits marketing applications for lomitapide in US and EU for HoFH

Based on 56 weeks data

2013

FDA approves JUXTAPID for

the treatment of HoFH

FDA grants Juxtapid orphan drug designation

for the treatment of HoFH

Penn completes Proof of Concept trial for patients with HoFH

EMA approves LOJUXTA for the

treatment of HoFH

2014

Health Canada approves

JUXTAPID for the treatment of

HoFH

BMS conducts early clinical trials of Juxtaapid

as a broad, monotherapy treatment before

discontinuing

Penn obtains funding from FDA’s ODP for P3

study

First patient enrolled in P3

2008 2015

Aegerion Acquires

Myalept™ from AstraZeneca

Juxtapid reduces LDL-C significantly in Watanabe rabbit (HoFH model)


Homozygous Familial Hypercholesterolemia: Disease Overview

●  HoFH is a serious, rare genetic form of hypercholesterolemia that is inherited from both parents

●  Patients with HoFH inherit a genetic mutation from each parent in the low density lipoprotein receptor (LDL-R) or other genes known to affect LDL-R function

●  A loss of LDL-R function results in extreme elevation of LDL (“bad”) cholesterol levels. HoFH patients often develop premature and progressive atherosclerosis, a narrowing or blocking of the arteries.

●  Conventional lipid lowering medications (e.g. statins, ezetimibe) primarily exert their effect by upregulating LDL-Rs and therefore have limited response in patients with HoFH

●  Apheresis is the standard recommended therapy for patients with HoFH, which is a mechanical procedure that temporary reduces LDL-C.

Proprietary. © 2015 Aegerion Pharmaceuticals, Inc. All Rights Reserved.

HoFH Prevalence

•  Historically, the prevalence of HoFH was reported as 1 in 1,000,0001 •  Recent data indicate that HoFH, while still rare, may be more

common2

•  Based on a 2013 estimate of FH prevalence of 1 in 200, reported in the European Heart Journal, the calculated prevalence of HoFH would be between 3.33-6.25 per 1,000,0002-4

•  Founder effects make the prevalence of HoFH more common in certain populations that have descended from relatively small founding populations5-7

– 1 in 270,000 in the French-Canadian population

1.  Goldstein JL, et al. J Clin Invest. 1973;52(7):1544-1568. 2.  Nordestgaard BG, et al. Eur Heart J. 2013;34(45):3478a-3490a. 3.  Benn M, et al. J Clin Endocrinol Metab. 2012;97(11):3956-3964. 4.  Goldberg AC, et al. J Clin Lipidol. 2011;5(3 suppl):S1-S8.

5.  Moorjani S, et al. Arteriosclerosis. 1989;9(2):211-216. 6.  Kusters DM, et al. Neth Heart J. 2011;19(4):175-182. 7.  Seftel HC, et al. Br Med J. 1980;281(6241):633-636.


Indication and Clinical Use

•  JUXTAPID (lomitapide) is indicated as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce low-density lipoprotein cholesterol (LDL-C) in adult patients with homozygous familial hypercholesterolemia (HoFH). Due to its benefit-risk profile, the prescribing of JUXTAPID should be limited to physicians experienced in the diagnosis and treatment of familial hypercholesterolemia. The effect of JUXTAPID on cardiovascular morbidity and mortality has not been determined.

Geriatrics (≥ 65 years of age) •  Clinical studies of JUXTAPID did not include sufficient numbers of patients with HoFH

aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

Pediatrics (< 18 years) •  The safety and effectiveness in pediatric patients have not been established. There is a risk of hepatotoxicity with Juxtapid, including hepatic steatosis and elevations in aminotransferases (liver enzymes).

- Juxtapid Product Monograph and Data on File, Aegerion Pharmaceuticals (2014).


Juxtapid development: it all began with a rare disease…

Microsomal Triglyceride Transfer Protein (MTP) as a therapeutic target for HoFH originated from the discovery that MTP was the gene that causes abetalipoproteinemia, a very rare disease characterized by extremely low levels of LDL cholesterol1

Abetalipoproteinemia is: •  A rare autosomal recessive disease caused by mutations in the gene encoding MTP

affecting ~ 1:1,000,0002

•  Characterized by extremely low levels of VLDL and LDL cholesterol3

•  Clinical manifestations include: gastrointestinal (diarrhea, steatorrhea), neurologic, hematologic, hepatic and ophthalmologic symptoms

Could inhibiting MTP, which is independent of the LDL-R, significantly reduce LDL cholesterol?

1.  Wetterau JR, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992. 258: 999-1001.

2.  Wetterau JR, et al. Biochimica Biophysica Acta. 1997;1345(2):136-150. 3.  Benayoun L, et al. Mol Genet Metab. 2007;90(4):453-457.

4. Hussain MM, et al. Nutr Metab (Lond). 2012;9:14. 5. Linton MF, et al. J. Lipid Res. 1993;34(4):521-541. 6. Wetterau JR, et al. Science. 1998;282(5389):751-754.


Microsomal Triglyceride Transfer Protein (MTP)

•  MTP is an intracellular lipid-transfer protein found in the lumen of the Endoplasmic Reticulum, responsible for binding and shuttling individual lipid molecules between membranes1

•  Normal concentrations and function of MTP are necessary for the proper assembly and secretion of ApoB-containing lipoproteins in the liver (VLDL) and intestine (chylomicrons)2

1. Hussain MM, et al. J Lipid Res. 2003;44(1);22-32. 2. Liao W, et al. J Lipid Res. 2003;44(5):978-985.

Liver Cell

ER Lumen

Cytoplasm

MTP

Intestinal Epithelial Cell

ER Lumen

Cytoplasm

MTP


Juxtapid, a MTP Inhibitor

•  Juxtapid binds and inhibits MTP, thereby preventing the assembly of ApoB-containing lipoproteins in the liver (VLDL) and the intestine (chylomicrons)

•  Inhibition of VLDL results in reduced LDL-C in the blood

Hussain MM, et al. J Lipid Res. 2003;44(1):22-32.

Decreases Secretion into Bloodstream

ApoB-48

MTP

Intestinal Cell Chylomicron

Diet Source TGs

Cholesterol

ApoB-100

MTP

Liver Cell

VLDL Liver Source

TGs Cholesterol


Legislation to Support Development to Treat Rare Diseases

●  The Orphan Drug Act of 1983 was passed in the US to encourage pharmaceutical companies to develop drugs to treat diseases which affect fewer than 200,000 people in the US


z

History of Juxtapid & Aegerion Pharmaceuticals

11

1990s 2002 2004 2006 2007 2010

BMS donates certain rights to lomitapide to the University of

Pennsylvania (Penn)

Aegerion obtains certain license for exclusive worldwide rights to Juxtapid from Penn

2012

Completes enrollment of

pivotal Phase III clinical trial for

adult patients with HoFH

Submits marketing applications for lomitapide in US and EU for HoFH

Based on 56 weeks data

2013

FDA approves JUXTAPID for

the treatment of HoFH

FDA grants Juxtapid orphan drug designation

for the treatment of HoFH

Penn completes Proof of Concept trial for patients with HoFH

EMA approves LOJUXTA for the

treatment of HoFH

2014

Health Canada approves

JUXTAPID for the treatment of

HoFH

BMS conducts early clinical trials of Juxtaapid

as a broad, monotherapy treatment before

discontinuing

Penn obtains funding from FDA’s ODP for P3

study

First patient enrolled in P3

2008 2015

Aegerion Acquires

Myalept™ from AstraZeneca

Juxtapid reduces LDL-C significantly in Watanabe rabbit (HoFH model)

P2 study in broad hypercholesterolemia

showed significant ↓ LDL-C but high incidence of

GI side effects & attrition rate


Factors Contributing to the Development of Juxtapid for HoFH

Development of Juxtapid for HoFH was made possible due to perseverance, collaboration, and securing the right capabilities & resources.

●  The Orphan Drug Act provides a pathway to pursue an indication in orphan disease

●  Big pharma (BMS) was open to other opportunities for a shelved product ●  Identification & Collaboration with global academic experts in HoFH ●  Government and foundation funding opportunities to support proof of

concept studies ●  FDA grants Juxtapid orphan drug designation for HoFH ●  Aegerion knowledge of rare disease development and commercialization

capabilities & infrastructure


Areas to consider targeting

● Identify researchers and clinicians working on rare disorders in Canada & globally

● Connect stakeholders working in rare disease

● Identify and make stakeholders aware of funding opportunities for proof of concept studies

● Support pathways for legislation in Canada that would encourage stakeholders to develop new treatments for rare disorders

● Create opportunities where pharmaceutical companies with drugs no longer in development would have incentives for treating rare disorders

leanne bloedon (aegerion) rare disease day 2016 conference

Government & Nonprofit