defined health insight series briefing: gene and cell ......pharma, biotech and specialty...

Defined Health Insight Series Briefing: Gene And Cell Therapies – It’s Show Time!

Mike Rice, Principal, Defined Health

Cambridge, MA

January 16, 2018

2Insight Series Briefing – Advanced Therapeutics© Defined Health, 2018

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• Co-Sponsor Acknowledgements

• Introduction of Our Speaker, Mike Rice

• Snapshot of Topics for Discussion

• Webinar Discussion

• Responding to Audience Q&A

• Wrap-up

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Co‐sponsored by:

• Mike leads Gene and Cell Therapeutics and Rare Diseases practices at Defined

Health. He also co-heads the oncology practice focusing on hematologic

malignancies and genetically defined cancers.

• Mike has had over a decade of experience creating new biotech ventures from

academic inventions pertaining to nucleic acids and cellular platforms applied

across monogenetic diseases and oncology.

• He has been recognized for his extensive intellectual property and publication

portfolio pertaining to cancer genetics, recombinational DNA repair, gene

therapy, diagnostics, and agricultural trait improvement.

Today’s Webinar Presenter

Mike Rice, MS, MBA, Principal, Defined Health


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The information in this report has been obtained from what are believed to be reliable sources and has been verified wheneverpossible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change.

The opinions and information set forth herein are expressed solely for the benefit of the addressee and only for the purpose(s) for which the report was produced. Without the prior written consent of Defined Health, this report may not be relied on in whole or in part for any other purpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law.

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Co‐sponsored by:

Today's Agenda

• Gene and Cell Therapy, “Advanced Therapy”, is Among the Hottest Investment Sectors in Biotechnology

• Advanced Therapies Integrate an Array of Technologies, Devices, and Services to Provide a Therapeutic Solution

• Advanced Therapies Begin to Enter US market; OTAT RMAT Designation Opens The Door for FDA Approval

• Commercializing Advanced Therapies Will Require Business Model Innovations to Make “Living Drugs” Accessible

• Advanced Therapies Case Studies

• Breakthrough Therapy Seeking FDA Approval for Severe Rare Disorders With No Current Effective SOC

• Breakthrough Therapy Seeking FDA Approval for Emerging rare Disease Market with Established SOC

• Late entrant breakthrough therapy in Mid‐Size Orphan Indications with Established SOC

• Gene Therapies Position to Become Breakthrough Treatments in Immense Indications

• Questions and Discussion

10

Gene Therapy Is Among The Hottest Investment Sectors In Biotechnology


Co‐sponsored by:

Pharma Has Benefitted Significantly by Investing in Biologics

0 5,000 10,000 15,000

Herceptin (trastuzumab) ‐ Roche

Enbrel (etanercept) ‐ Pfizer

Protonix (pantoprazole) ‐ Pfizer

Nexium (esomeprazole) ‐ AZN

Norvasc (amlodipine) ‐ Pfizer

Plavix (clopidogrel) ‐ BMS

Rituxan (rituximab) ‐ Roche

Epogen (epoetin alfa) ‐ Amgen

Advair (fluticasone; salmeterol) ‐ GSK

Lipitor (atorvastatin) ‐ Pfizer

EvaluatePharma

0 5,000 10,000 15,000

Lyrica (pregabalin) ‐ Pfizer

Crestor (rosuvastatin) ‐ AZN

Remicade (infliximab) ‐ J&J

Herceptin (trastuzumab) ‐ Roche

Avastin (bevacizumab) ‐ Roche

Advair (fluticasone, salmetero) ‐ GSK

Rituxan (rituximab) ‐ Roche

Lantus (insulin glargine recombinant) ‐ Sanofi

Sovaldi (sofosbuvir) ‐ Gilead

Humira (adalimumab) ‐ AbbVie

Top-Selling Products (WW Sales $M) 2006 vs. 2016(coded by conventional vs. biologics)

2006 2016BiologicConventional


Co‐sponsored by:

Gene/Cell Therapies Next Advancement Beyond Conventional Biologics

• ImmuneModulators

• SMIs

• Chaperones

• Substrate Reduction

• Transcription / Translation enhancers

• Epigenetics

• Plasma/tissue derived proteins

• Recombinant Proteins– Clotting factors– Cytokines– Hormones– Growth factors

• EnzymeReplacement

• Plasma derivedPolyclonal Igs

•Monoclonal antibodies

•mAB fragments

• Scaffolds

• Intrabodies

• ImmuneModulators

• Exon skipping

• Antisense

• RNAi /miRNA

• Aptamers/ Ribozyme

• Viral vectors‒ Retro/‒ Lentiviral‒ AdV‒ AAV

• Non‐viral‒Plasmids/‒Fragments

• Gene editing with Meganucleases‒ Zinc Fingers‒ TALENS‒ CRISPR/Cas9

• Autologous and allogeneic Cell therapy

• Other cells:‒ e.g. ES, iPS

•Mitochondrial transfer

• Devices‒ Encapsulation‒ Scaffolds‒ Implants‒ Micro‐organs‒ Aphaeresis

Increasing Complexity of Therapeutic InterventionsIncreasing Complexity of Therapeutic Interventions

Small Molecule Modulators

Protein Augmentation

AntibodiesPeptides and Nucleic Acids

Gene Correction Gene Correction & Augmentation

Cell Therapy / Regen Med


The End of the Beginning or The Beginning of New Treatment Paradigms?Recent Advancements in Gene Therapies 30 Years After PoC

1990 2000 2010 2020

Strimvelis (GSK):

ADA‐SCID

May 2016

EMA Approval

R/R DLBCL

Oct 18, 2017

FDA Approval

R/R B‐Cell ALL

Aug 30 2017

FDA Approval

biallelic RPE65 mutation‐associated IRD

Dec 19, 2017

FDA Approval


Co‐sponsored by:

Over The Last 30 Years, Gene Therapy Platforms Diversified And Players Have Grown In Number

ARM tracks >850 Regenerative Medicines companies (460 US, 234 Europe and 122 Asia, 38 RoW)

Company Websites; Alliance for Regenerative Medicine State of the Industry report 2018; https://alliancerm.org/event/sotibriefing

Adoptive Cellular Immuno-oncology (IO)

Gene EditingGene Augmentation

AAV

AdV

Lenti‐Retro

Plasmid

Other

Partners


Co‐sponsored by:

Venture Financing Of Gene Therapy Platforms And Company IPOs Accelerated In Recent Years

BCIQ, Company website

IPOV

C F

ina

ncin

g

2016

Feb 2016: $106 M

July 2016: $85 M

Feb 2016: $50M Series A

2017

Feb 2016: $109M

Oct 2016: $62 M

Feb 2017: $24 M

Apr 2017: $98 M

Aug 2016: $25M Series AFeb 2016: $1.5M Seed

May 2016: $31M Series A

Dec 2016: $225M Series A

May 2017: $50M Series BNov 2016: $49M Series A




May 2016: $124 M

Sep 2017: $46 M

Sep 2017: $86 M

Sep 2016: $1.1M Series A

Feb 2017: $23M Series B

Jun 2017: $45M Series B

Aug 2017: Undisclosed Seed

Nov 2017: $7.5M Seed


Co‐sponsored by:

Although a Slow Year for IPOs, 2017 Marked a Spike in Follow‐on and Venture Investment

Total global investment in gene and cell therapies about $4.2B in 2017 – Up from $3.3B in 2017

Does not include $13.5B in acquisitions in 2017 vs. $1B in 2016 (Driven by $11.9B acquisition of Kite by Gilead)

BCIQ Financings Chart

41

9 95

129

14 13

25

18 18

31

24

38

2013 2014 2015 2016 2017

Nu

mb

er o

f Fi

nan

cin

gs

All IPO financings All follow‐on financings All venture financings

Annual Sum of Amount raised by Financing Type


Co‐sponsored by:

BioPharma Acquisitions and Alliances In Gene Therapy

Gene Therapy Deal Timeline 2015-2017

BCIQ, Company website

2015

Feb 2015$845M

Parkinson’s Disease

Jan 2015$6M

Hemophilia A&B

Jan 2015$11M+CRISPR platform

Apr 2015$64M

VC Funding

April 2015$1BCV

2016

Dec 2015$105MRare

diseases

Sept 2015$845M

Acquisition - CV

Aug 2015$53MCV

Aug 2015$124MRare

diseases

Oct 2015$337M

IBD

Oct 2015$105M

2017

Jan 2016UndisclosedRare disease

Jan 2016UndisclosedAAV tech

May 2016UndisclosedAAV tech

Aug 2016Undisclosed

Retinal disease

Apr 2017UndisclosedAAV tech

May 2017UndisclosedRare disease

May 2017$545M

Hemophilia A

Aug 2016$495MRare

diseases

Jan 2017Acquisition -Undisclosed

Gene delivery

Sep 2017Acquisition -

$151MRare disease

Jun 2017Undisclosed

DMD

Nov 2017UndisclosedPromoter

Dec 2017UndisclosedRare disease

18

Gene Therapy Integrates An Array Of Technologies, Devices, And Services To Provide A Therapeutic Solution


Co‐sponsored by:

Gene Therapy Defined…FDA Definition Evolving as New Technology and Therapeutic Approaches Emerge

Human gene therapy is the administration of genetic material to modify or manipulate the expression of a gene product or to alter the biological properties of living cells for therapeutic use.1

https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm573960.htm


Co‐sponsored by:

Therapeutic strategies to modulate transcription and/or translation of transferred genetic material and/or by integrating into the host genome:

Therapeutic strategies to modulate transcription and/or translation of transferred genetic material and/or by integrating into the host genome:

Gene Therapy Defined…Several Mechanisms Used to Modify a Person’s Genes to Treat or Cure Disease


Augmentation

• Complement a defective gene (recessive mutation) product with a normal gene or express therapeutic protein at supraphysiologic levels

Knockout

• Delete or interrupt a detrimental gene (dominant negative) to avoid toxic buildup or inactivation of normal allele

Edit

• Correct or modify a specific mutant allele to restore gene product function

Cytoreduction

• Lysis or destruction of affected tissue such as hypertrophy or cancer

Targeting

• Targeted delivery of payload or destruction of a antigen tagged cell, or infectious agent


Co‐sponsored by:

Viral or non‐viral 'vectors' are Required to Deliver the Nucleic Acids to the Proper Tissues and Cell Types Using Either in-vivo or an ex-vivo Method

In vivo gene transfer: rDNA viral or non‐viral vector is the drug

• Cloned genes are transferred directly into the tissues of the patient. This may be the only possible option in tissues where individual cells cannot be cultured in vitro in sufficient numbers (e.g. brain cells) and/or where cultured cells cannot be re‐implanted efficiently in patients.

• Liposomes and certain viral vectors are increasingly being employed for this purpose.

• Vector‐producing cells (VPCs) can be used to transfer the gene to surrounding disease cells. The success of this approach is crucially dependent on the general efficiency of gene transfer and expression.

Ex vivo gene transfer: Genetically modified cells as therapeutics

• Transfer of cloned genes into cells grown in culture in vitro. Those cells which have been transformed successfully are selected, expanded by cell, then introduced into the patient.

• To avoid immune system rejection of the introduced cells, autologous cells are normally used: the cells are collected initially from the patient to be treated and grown in culture before being reintroduced into the same individual.

• Only applicable to tissues that can be removed from the body, altered genetically and returned to the patient where they will engraft and survive for a long period of time (e.g. HSCs and skin cells).


Ex-vivo onlyEx-vivo only

In-vivo onlyIn-vivo only

Key:

Delivery Technology

Viral

AAV

Lentivirus

Adenovirus

Other Virus

Undefined

Retrovirus

Non‐viral

Plasmid

Other non‐viral

Liposome/ Nanoparticle

Undefined

Undefined

Undefined

Other

Pseudo‐adenoviral in nano‐particle


Co‐sponsored by:

Delivery: Viral Vectors Used In Majority Of Pipeline – Most Advanced In Clinical Development

181

77

67

23

29

1210 9 8

1

Non‐Malignant Gene Therapy Agents in WW Clinical Development by MOA/Tech, n=417*

Unspecified Cell Therapy Synthetic Nucleic Acid

Viral: Adeno‐Associated Viral: LentiviralOther Non‐Viral: Plasmid

Viral: Adenovirus Non‐Viral: NanoparticleViral: Retroviral Viral: Sendai Virus

Clarivate Analytics Cortellis; DH Analysis; *Excludes oncology and infectious disease agents

144

107

46

73

41

17

1615

221010

5

Oncology Gene Therapy Agents in WW Clinical Development by MOA/Tech, n=506

Adoptive Cell Therapy Other VaccineViral: Adenovirus Non‐Viral: DNA/RNAOther Viral: RetrovirusNon‐Viral: Biophysical Viral: LentivirusViral: Other Virus Non‐Viral: LNPViral: Modified Vaccinia Gene Editing


Co‐sponsored by:

Delivery: Cross‐Comparison Of Viral Gene Therapy Platforms

Technology Capacity Delivery* Integration Pros/Cons

Adenovirus (AdV) < 8kB In vivo EpisomalP: high packaging capacityC: elicits a potent immune response; transiently expressed

transgene

Adeno‐Associated Virus (AAV)

< 5kB In vivo EpisomalP: non‐pathogenic; infects dividing or non‐dividing cellsC: prior exposure immune rejection; DNA lost through

cell division

Herpes simplex virus vectors

150 kb In vivo IntegratingP: neuronotropic featuresC: difficulty to keep virus action under control

Poxvirus vectors >25 KB In vivo CytoplasmicP: high stable insertion capacity, simple construction, high

expression levelsC: complex structure and biology, risk of cytopathic effects

Retrovirus < 8kB Ex vivo IntegratingP: stable integration into host genomeC: random insertion tumorigenesis risk; only infects

dividing cell types

Lentivirus 8‐10kB Ex vivo IntegratingP: infects dividing or non‐dividing cells; reduced tendency

to cause cancerC: theoretical tumorigenesis risk

*Indicates how a technology is being used in its current format


Co‐sponsored by:

What’s In The Gene Therapy Pipeline? Bolus Of Pre‐PoC Projects – However, Increasing Inventory Of Late/Approved Gene & Cell Therapies Crossing all Therapeutic Areas

1988

448 504 9 2 50

500

1000

1500

2000

2500

Nu

mb

er

of

Age

nts

in D

eve

lop

me

nt

WW Gene Therapy PipelineNumber of Agents in Development by Phase, n=3117

Clarivate Analytics Cortellis; DH Analysis

506

199

76

57

48

40

40

39

2927

2313

13

12

WW Clinical‐Stage Gene Therapy PipelineNumber of Agents in Development by TA*, n=1129

Oncology

Infectious disease

Cardiovascular

CNS Disorder

Sensory

Musculoskeletal

Metabolic/Endocrine

Immune

Hematology

Dermatological

Other

Respiratory

Gastrointestinal

Genitourinary


Co‐sponsored by:

Therapeutic Intervention: Genome‐Editing Platforms Facilitate Specific DNA Alterations

Gene editing refers to methods that target a double‐stranded break in the genome, then directs a specific DNA sequence alteration

Four families of engineered nucleases:

• Meganucleases (MEGAs): highly specific due to large recognition site (dsDNA sequences of 12 to 40 base pairs)

• Zinc finger nucleases (ZFNs): fusion of a zinc finger DNA‐binding domain to a DNA‐cleavage domain

• Transcription activator‐like effector nucleases (TALENs): fusion of TALE DNA binding domain to a DNA cleavage domain

• Clustered regularly interspersed short palindromic repeats (CRISPRs): Delivery of Cas9 (an RNA‐guided DNA endonuclease enzyme) and appropriate guide RNAs into a cell used to cut the genome at a desired location

Proc Natl Acad Sci USA 93 (3): 1156–60.; Nature Biotechnology 29 (2): 135–6.; Nature Reviews Genetics 11 (3): 181–190; Annual Review of Chemical and Biomolecular Engineering Vol. 7:637‐662 (June 2016) https://doi.org/10.1146/annurev‐chembioeng‐080615‐034711

Meganucleases, ZFN, TALEN, and CRISPR/Cas9 genome‐editing Tools


Co‐sponsored by:

Therapeutic Intervention: Emerging Therapeutic Gene Editing Approaches Enabling Treatment Beyond Augmentation

a) Homology‐directed repair (HDR): Gene edited HSCs can correct numerous disorders where HSCT is beneficial, eg. Hemoglobinopathies, immunodeficiencies, some LSDs

b) Gene Knock out by nonhomologous end‐joining (NHEJ)

• Genes with beneficial loss‐of‐function phenotypes are targeted by to confer resistance to HIV infection (CCR5) or reduce cholesterol levels (PCSK9).

• Dominant negative or gain of function alleles can be disabled with NHEJ

c) Safe harbor integration of transgenes serves as a platform for addressing systemic protein deficiencies in the liver, notably the AAVS1 and albumin loci

a) Antivirals: TALENs or CRISPR/Cas9 targeting latent viral genomes can be used to reduce HBV or HIV viral load

b) Antibacterials: Bacteriophage delivery of CRISPR/Cas9 can be used to selectively eliminate strains of bacteria

a) Altered Splice site mutations can be corrected by HDR; for example, a splice mutation causing a mouse model of hereditary tyrosinemia was corrected in the liver

b) Gene deletions: removal of nonessential regions of mutated genes can restore the reading frame to cored certain diseases, such as Duchenne muscular dystrophy

c) Engineered transcription regulators and epigenome modulators: Gene expression could be regulated directly. For example, engineered transcriptional repressor of phospholamban improved cardiac function in HF models

Abbreviations: BCL11A, B-cell lymphoma/leukemia 11A; CCR5, C-C chemokine receptor type 5; FAH, fumarylacetoacetate hydrolase; GOI, gene of interest; HBV, hepatitis B virus; HLA, human leukocyte antigen; HPV, human papillomavirus; IL2RG, interleukin 2 receptor gamma; mutHTT, mutant Huntington protein; PCSK9, proprotein convertase subtilisin/kexin type 9; PD1, programmed cell death protein 1; SMA, spinal muscular atrophy; SMN2, survival of motor neuron 2; WT, wild type; Annual Review of Chemical and Biomolecular Engineering Vol. 7:637‐662 (June 2016) https://doi.org/10.1146/annurev‐chembioeng‐080615‐034711


Co‐sponsored by:

In Vivo Gene Editing Already in the Clinic

All three of Sangamo's in vivo genome editing product candidates have received FDA Fast Track and Orphan Drug designations.

Additionally, SB‐318 for MPS I and SB‐913 for MPS II have received Rare Pediatric Disease designations from the FDA.

https://investor.sangamo.com/press‐releases/detail/381/sangamo‐announces‐treatment‐of‐first‐patient‐in‐landmark

Sangamo Announces Treatment of First Patient in Landmark Phase 1/2 Clinical Trial Evaluating In Vivo Genome EditingSangamo aims to treat MPS II by using genome editing to insert a corrective gene into a precise location in the DNA of liver cells with the goal of enabling a patient's liver to produce a lifelong and stable supply of an enzyme he or she currently lacks.

Without that enzyme, called iduronate‐2‐sulfatase (IDS), people with MPS II suffer debilitating buildup of toxic carbohydrates in cells throughout their body. Approximately one in 100,000 to one in 170,000 people are born with MPS II. Many people with MPS II receive weekly infusions of enzyme replacement therapy (ERT), the current standard‐of‐care treatment. Within a day of receiving ERT, however, IDS quickly returns to near undetectable levels in the blood.

"Even with regular infusions of ERT, which has markedly improved functional health outcomes, patients endure progressive damage to heart, bones and lungs. Many patients with MPS II die of airway obstruction, upper respiratory infection or heart failure before they reach the age of 20," said Paul Harmatz, M.D., a pediatric gastroenterologist and a principal investigator for the CHAMPIONS study at the UCSF Benioff Children's Hospital Oakland, where the first subject in the study was treated.

The CHAMPIONS study, which is also screening subjects at hospitals specializing in the care of patients with MPS II, including hospitals in Chapel Hill, Chicago, Minneapolis and Philadelphia, is an open‐label clinical study designed to assess the safety, tolerability and preliminary efficacy of the SB‐913 investigational genome editing therapy in up to nine adult males with MPS II.

SB‐913 makes use of Sangamo's zinc finger nuclease (ZFN) genome editing technology to insert a corrective gene into a precise location in the DNA of liver cells. To restrict editing to liver cells, the ZFNs and the corrective gene are delivered in a single intravenous infusion using AAV vectors that target the liver. The ZFNs enter the cells as inactive DNA instructions in a format designed only for liver cells to unlock. Once "unlocked", the ZFNs then identify, bind to and cut the DNA in a specific location within the albumin gene. Using the cells' natural DNA repair processes, liver cells can then insert the corrective gene for IDS at that precise location.

The ability to permanently and precisely integrate the therapeutic IDS gene into the DNA differentiates Sangamo's in vivo genome editing approach from conventional AAV cDNA gene therapy and from lenti‐ or retroviral‐based gene therapies that insert genes randomly into the genome.

Two additional clinical trials are underway in the United States to evaluate Sangamo's in vivo genome editing therapeutics for hemophilia B and MPS I, which is also known as Hurler or Hurler‐Scheie syndrome. All three trials use ZFNs designed to edit liver cells at the same location in the albumin gene, but differ in delivering the corrective gene relevant to the respective disease.

"As a physician, I feel a real sense of responsibility toward the patients who are participating in these three clinical trials," said Ed Conner, M.D., chief medical officer of Sangamo. "We have been working closely with the FDA and the NIH Recombinant DNA Advisory Committee to make sure that we are thoroughly and prudently developing this new class of medicines."

“For the first time, a patient has received a therapy intended to precisely edit the DNA of cells directly inside the body. We are at the start of a new frontier of genomic medicine," said Dr. Sandy Macrae, CEO of Sangamo Therapeutics.

“For the first time, a patient has received a therapy intended to precisely edit the DNA of cells directly inside the body. We are at the start of a new frontier of genomic medicine," said Dr. Sandy Macrae, CEO of Sangamo Therapeutics.


Co‐sponsored by:

Vertex and CRISPR Therapeutics to Co‐Develop and Co‐Commercialize CTX001 as CRISPR/Cas9 Gene Edited Treatment for Sickle Cell Disease and β‐Thalassemia

CTX001 is an investigational ex vivo CRISPR gene‐edited therapy for patients suffering from β‐thalassemia and sickle cell disease in which a patient’s hematopoietic stem cells are engineered to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells.

At ASH 2017, CRISPR Therapeutics presented preclinical data that showed greater than 90% editing of hematopoietic stem cells at the target site, leading to clinically relevant increases in fetal hemoglobin.

• Based on this date, Clinical Trial Application for CTX001 submitted in Europe to support initiation of Phase 1/2 clinical study in β‐thalassemia in 2018

• CRISPR Tx and Vertex will co‐develop and co‐commercialize CTX001 for the treatment of hemoglobinopathies.

• A Phase 1/2 trial will be designed to assess the safety and efficacy of CTX001 in adult transfusion dependent β‐thalassemia patients.

• The companies plan to file a US IND Application for a Phase 1/2 trial in sickle cell disease in 2018

http://ir.crisprtx.com/phoenix.zhtml?c=254376&p=irol‐newsArticle&ID=2322215

Vertex and CRISPR Therapeutics to Co‐Develop and Co‐Commercialize CTX001 as CRISPR/Cas9 Gene Edited Treatment for Sickle Cell Disease and β‐ThalassemiaBoston and Cambridge, MA and Zug, Switzerland – December 12, 2017 ‐ Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) and CRISPR Therapeutics AG (NASDAQ: CRSP) today announced that the companies will co‐develop and co‐commercialize CTX001, an investigational gene editing treatment, as part of the companies’ previously announced collaboration aimed at the discovery and development of new gene editing treatments that use the CRISPR/Cas9 technology. CTX001 represents the first gene‐based treatment that Vertex exclusively licensed from CRISPR Therapeutics as part of the collaboration. For CTX001, CRISPR and Vertex will equally share all research and development costs and profits worldwide. A Clinical Trial Application was submitted earlier this month for CTX001 to support the initiation of a Phase 1/2 trial in β‐thalassemia in 2018 in Europe, and an Investigational New Drug (IND) Application is planned for submission in 2018 to support the initiation of a Phase 1/2 trial in sickle cell disease in the U.S. Preclinical data presented for CTX001 at the American Society for Hematology on December 10, 2017 showed clinically relevant increases in fetal hemoglobin and a high editing rate that support the advancement of CTX001 into the planned trials in β‐thalassemia and sickle cell disease in 2018.

“Over the past two years, we’ve made significant progress with CRISPR Therapeutics on the discovery and preclinical development of multiple CRISPR/Cas9‐based treatments, and we’re pleased to select CTX001 as the first of these treatments to move into clinical development as part of our collaboration,” said David Altshuler, M.D., Ph.D., Vertex’s Executive Vice President, Global Research and Chief Scientific Officer. “The addition of CTX001 to our clinical development pipeline provides us with a near‐term opportunity to generate the first proof‐of‐concept clinical data for a CRISPR/Cas9‐based medicine in two genetic diseases that are highly aligned with our research strategy.”

“The submission of a Clinical Trial Application for CTX001 in Europe, supported by the robust data presented at the recent ASH Annual Meeting, reflect the advances we have achieved in translating the potential of CRISPR/Cas9 science into transformative therapies. We now look forward to working closely with Vertex as we initiate clinical trials next year,” commented Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. “The study of CTX001 in β‐thalassemia will be the first company‐sponsored clinical trial of a CRISPR‐based therapy and is a major step forward for both the treatment of certain inherited blood diseases and for our collaboration with Vertex.”


Co‐sponsored by:

However, Technological Improvements Are Needed To Realize the Full Potential of CRISPR

https://www.biorxiv.org/content/early/2018/01/05/243345.full.pdf+html; https://www.statnews.com/2018/01/08/immunity‐crispr‐cas9/ ; https://www.statnews.com/2017/05/30/crispr‐stocks‐off‐target/

“New Cas editing enzymes are being described all the time from bacterial species that are not human pathogens (and so there would be no chance to develop the pre-existing antibodies),” Jacob Corn, of the University of California, Berkeley, who was not involved with the new paper, wrote in an email. “I also know some people have already been working on making Cas enzymes that would be invisible to the immune system.”

A letter1 in Nature Methods pointing out potentially dangerous flaws in the CRISPR‐Cas9 genome editing system gave biotech investors a sinking feeling on Tuesday, and stocks in genome‐editing companies had the same experience. By the close of trading Editas Medicine had fallen nearly 12 percent, Crispr Therapeutics was down more than 5 percent, and Intellia Therapeutics had plunged just over 14 percent.

But the truth was, the concerns outlined in the letter were hardly new.

Researchers have been aware for many months that using CRISPR can lead to the “off‐target” effects described in the Nature Methods letter, written by scientists at Stanford University. To put it plainly, the tool can inadvertently alter DNA2 in regions of the genome that weren’t targeted for editing. The letter reinforces that this is a problem.

The key news here is that, assuming the Stanford results hold (this wasn’t a peer‐reviewed paper), scientists might have to abandon the quick‐and‐dirty way they had hoped to track down such off‐target effects and instead turn to whole‐genome sequencing. Silver lining department: If there is any winner to emerge from the finding, it is likely to be companies that make genome sequencers.

CRISPR‐Cas9 works by sending a biological bloodhound, called guide RNA, to sniff out a target, then snip out unwanted DNA and insert DNA that can act therapeutically. (The Stanford scientists repaired a mutation that made mice blind.) But if the genome has multiple regions similar to the target, the CRISPR package can mess with them, too, causing unknown problems.

30

Gene Therapies Begin To Enter US Market; OTAT RMAT Designation Opens The Door For FDA Approval


Co‐sponsored by:

Creation Of FDA Office Of Tissues And Advanced Therapies (OTAT) And RMAT Designation Expediting Review Of Gene/Cell Therapies

Regenerative medicine therapies are defined as:

• Cell therapy

• Tissue engineering product

• Human cell/tissue product

• Any combination product using the above

RMAT designation given to drugs intended to cure serious/life‐threatening conditions where preliminary clinical data suggests the potential to address an unmet need

• Requested with new IND or as an amendment to an existing IND

• The agency has 60 days to review the request for RMAT designation

Analogous to breakthrough therapy designation

• More frequent FDA interactions

• Include fast track features

Must apply separately for accelerated approval or priority reviewFDA, Federal Register, BCIQ

The RMAT designation gives the sponsor of a new drug access to:

• Increased meeting opportunities with FDA, in a manner comparable to those offered to sponsors of breakthrough‐designated therapies

• Type B development meetings are normally restricted to one each at pre‐IND, end of Phase II/pre‐Phase III and pre‐BLA submission

• Priority review reduces the BLA assessment from 10 months to 6 months

• Accelerated approval, which bases approval on an effect on a predictive surrogate endpoint or an intermediate clinical endpoint. May require post‐approval clinical studies as well as real‐world data such as patient registries and health record analysis

• Option to qualify for fast‐track approval allows for “rolling review” of the BLA, which can be submitted for assessment following agreement of a review timetable with CBER

Created in 2016, the Regenerative Medicine Advanced Therapy (RMAT) designation was established under the 21st Century Cures Act to help reduce development times in the field of regenerative medicine


Co‐sponsored by:

Recent And Expected Upcoming US/EU Approvals

EvaluatePharma

Anti‐CD19 CAR‐T (ZIOPHARM): NHL

UCARTCS1 (Cellectis): ALL

SPK‐8011 (Spark): Hemophilia A

BMN‐270 (BioMarin): Hemophilia A

DTX401 (Dimension): Glycogen Storage

VY‐AADC01 (Voyager): Parkinson's

Ad‐RTS‐hIL‐12 (ZIOPHARM): Breast Cancer

AT132 (Audentes): Myotubular Myopathy

AT342 (Audentes): Crigler‐Najjar

AAV‐CNGB3 (AGTC): ACHM

SAR422459 (Sanofi): Stargardt

Pexa‐Vec (Transgene): Hepatoma

SPK‐TPP1 (Spark): Batten

NeoCart (Histogenics): Cartilage

JCAR014 (Juno): CLL

CMV‐CTL (Atara): CMV Infections

DCCI‐10 (Cytori): Burns

JCAR017 (Juno): NHL

BPX‐501 (Bellicum): GvHD

JCAR015 (Juno): ALL

MAGE‐A10 (Adaptimmune): NSCLC

LentiGlobin (bluebird): β‐Thalassemia

SPK‐7001 (Spark): CHM

DTX301 (Dimension): Urea Cycle

ABO‐102 (Abeona): MPS III

AMT‐060 (uniQure): Hemophilia B

EB‐101 (Abeona): EB

Cx601 (TiGenix/Takeda): Crohns

ATA129 (Atara): EBV cancers

PLX‐PAD (Pluristem): PAD

Habeo (Cytori): Scleroderma

ECCI‐50 (Cytori): UI

AVXS‐101 (AveXis): SMA

Lenti‐D (bluebird): ALD

LN‐144 (Iovance): Melanoma

NurOwn (BrainStorm): ALS

NK‐92 (NantKwest): NE Tumor

ECCO‐50 (Cytori): Osteoarthritis

MultiStem (Pfizer): Stroke

StrataGraft (Mallinckrodt): Burns

2016 / 2017 2018 2019 2020

Strimvelis (GSK): ADA‐SCID

Kymriah (Novartis): ALL

Yescarta (Gilead): DLBCL

Luxturna (Spark): LCA/RP

Gen

e Tr

ansf

erC

ell T

her

apy

33

Commercializing Gene Therapies Will Require Business Model Innovations To Make “Living Drugs” Accessible


Co‐sponsored by:

Analysts Forecast Rapid Growth Of Advanced Therapies Off An Almost Nonexistent Base Over The Next Decade ($7.7B In 2022F US Sales)

$75 $136 $605

$1,192

$2,709

$5,026

$7,765

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Cell Therapy Gene Therapy

EvaluatePharma; Leerink, NIGHTSTAR THERAPEUTICS PLC: Initiating at OP; A White Knight for Retinal Dystrophies, Oct 2017

Given the unique nature of advanced therapeutics, there is uncertainty as to how the market might grow and mature over the long‐term


Co‐sponsored by:

Regardless Of How Innovative Your Technology, All Therapeutic Approaches Face Increasing Pressure On TPPs; Gene Therapy Firms Encounter Unique Challenges

Biology more tractable but risk still associated with clinical translation

• Scale‐up, delivery, stability, immunogenicity

• Safety – e.g. anaphylaxis, insertional mutagenesis, cytokine storm

More favorable regulatory environment

• However, innovative clinical endpoints necessary

Does not fit nicely into pharma scalability model

• Complicated IP and stacking royalties

• Individualized vs. one‐size fits all

• Involves devices and process

Manufacturing: Reproducibility, scalability, high cost of goods

Market access: Value‐based pricing in different payer systems

• Degree of improvement – restore to normal or somewhere in between?

• Durability – short effect of long term cure?

Bioethics: Boundaries of use, testing in vulnerable populations


Co‐sponsored by:

Usually “One Off”

treatments

Limited follow Limited follow up duration at

time of reimbursement

dossier submission

Gene and Cell Therapies

Promising long‐term benefits

Strong uncertainty on sustainability of effects

Pharma and biotech companies communicating to financial investors prices based on multiples of expensive drugs for chronic therapies – Unlikely to be accepted by payers

Pharma and biotech companies suggesting annuity programs – May be impossible currently from a practical point of view in most health systems

Emerging Gene Therapies Are Likely To Be Associated With Significant Payer Value Uncertainty

© Therapeutic Challenges Analysis, 2016 , Compass Strategic Consultants


Co‐sponsored by:

Pricing and Market for Gene and Cell Therapies

Brand Company Indication Price Comments

GlyberaUniQure/

Chiesi

Lipoprotein lipase deficiency patients who have acute and chronic pancreatitis attacks

$1M+

• First gene therapy approved in Europe; however, none of the price setting markets provided access. HTA groups in Germany and France concluded that the benefit is insufficient to justify reimbursement.

• UniQure decided not to renew marketing authorization in Europe and abandoned plans for commercialization in the US

Strimvelis GSK

Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA‐SCID) or “bubble boy syndrome”

$714,000(£594,000)

• Extremely rare condition affecting ~15 patients per year in Europe• Faced reimbursement and payment hurdles ‐ despite the money back guarantee

and pay‐for‐performance pricing model, GSK struggled to make Strimvelis a commercial success

Kymriah NovartisB-cell precursor ALL for patients <25 years $475,000

• First CAR‐T therapy approved in the US• Outcomes‐based reimbursement model ‐ full payment only if the patients

respond to therapy 30 days after initiating treatment

YescartaGilead/

Kite Pharma

Relapsed/refractory large B-cell lymphoma, including DLBCL

$373,000

• Second CAR‐T therapy approved in the US for a much larger patient population• Has a boxed warning for cytokine release syndrome (CRS) and neurologic

toxicities, thus part of a REMS program• CMS and some private insurers lack billing codes for CAR‐T treatments; Yescarta

reimbursement situation still being worked out with CMS and private insurers

Luxturna csConfirmed biallelic RPE65 mutation-associated retinal dystrophy

$850,000 or $425,000/eye

• Three innovative programs to improve access:‐ Outcomes‐based rebate linked to short‐ and long‐term efficacy‐ Installment payment option negotiated with CMS with greater rebates tied to

clinical outcomes‐ Agreement with commercial payers for alternative contracting to “buy and bill”

• Favorable for US launch anticipated based on these programs


Co‐sponsored by:

However, Given The Unique Nature Of “Advanced Therapeutics,” There Is Uncertainty As To How The Market Might Grow And Mature Over The Long‐Term

For any particular player, unique challenges exist to sustain growth beyond lifecycle of initial products.

For example, assume a successful launch of “one‐and‐done” curative treatment for a rare inherited monogenetic disease. Initial uptake into prevalent pool is soon tempered once “warehoused” patients are cured. Future sales come from few newly diagnosed entering treatment eligibility.

EvaluatePharma; Leerink, NIGHTSTAR THERAPEUTICS PLC: Initiating at OP; A White Knight for Retinal Dystrophies, Oct 2017

High unmet need, severe conditions

6K prevalence, 30% eligible

300 new annual births

$1M One‐time treatments

Stage‐gapped development pipeline for ultra‐rare monogenetic disease

New product launched every 3 years

Equates durable cure

Rapid uptake, 4 years to peak

Limited competition

NIGHTSTAR THERAPEUTICS

Depictive Revenue Forecast for a Portfolio of One-Time Treatments and Implications of Pipeline Portfolio Strategy

• R&D effort needed to support pipeline that delivers new products to new rare disease populations in rapid succession


Co‐sponsored by:

Sustaining a Gene Therapy Franchise: Scenarios and Implication to Pipeline Portfolio Strategy

What if TPP of product:

• Does not support the clinical value and payers constrain access or demand high rebates?

• Does not avoid all clinical complications, needs other support? Not durable, benefit only 5 years?

What if new product launches are delayed or pipeline projects fail?

What if drug developer pursues broad indication after derisking platform in monogenetic disease?

$0

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GENE THERAPY MONOGENE PORTFOLIO($US MILLIONS)

MonoGene 1 MonoGene 2 MonoGene 3 MonoGene 4

MonoGene 5 MonoGene 6 MonoGene 7 MonoGene 8

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$500

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GENE THERAPY MIXED PORTFOLIO($US MILLIONS)

MonoGene 1 MonoGene 2 Broad Indication 1

40

Advance Therapies Case Studies

41

Breakthrough Therapy Seeking FDA Approval for Rare Disorders With No Current Effective SOC: Inherited Retinal Dystrophies


Co‐sponsored by:

Inherited Retinal Dystrophies (IRDs) are Degenerative Diseases of the Retina Characterized by Marked Clinical and Genetic Heterogeneity

IRDs may be syndromic or non‐syndromic and vision impairment may vary from poor peripheral or night vision to complete blindness, with severity usually increasing with age

IRDs are caused by abnormalities of retinal cells (e.g., photoreceptors) and/or defects in the phototransduction pathways that convert light into neuronal signals perceived by the brain

IRDs is a group of rare blinding conditions caused by one of more than 220 different genes and can be categorized into broad groups depending on the type of photoreceptor affected and whether the clinical manifestations are limited to the eye (i.e., non-syndromic)

Prog Retin Eye Res. 2016 Sep 10; Transl Pediatr. 2015 Apr;4(2):139‐63

Inherited Retinal Degenerations

Rod & Rod‐Cone Dystrophies

• Retinitis pigmentosa:• Dominated by night‐blindness

and loss of peripheral vision.• 25% patients over 45 are

legally blind.• <1% no light perception• Congenital stationary night

blindness (CSNB)

Cone & Cone‐Rod Dystrophies

• Progressive CORDs:• Central and color vision lost

first.• Depending on mutation, light

perception only from 50% by age 60 to nearly 100% at age 50.

• Achromatopsia

Generalized Non‐Syndromic

• Leber congenital amaurosis (LCA):• Symptoms develop within the

first year of life and include poor vision, nystagmus, and no measurable light response on ERG

• Choroideremia

Syndromic

• Usher syndrome• Visual loss is part of more

widespread disease.• 50‐75% of patients retain

vision of 20/40 or better• Bardet‐Biedl, others

70% 10% 5% 15%


Co‐sponsored by:

There are 75 Products in Development for One or More Inherited Retinal Dystrophies, with Gene or Cell Therapies Comprising ~60% of the Pipeline

Retinitis Pigmentosa (RP) and Leber’s Congenital Amaurosis (LCA) Gene/cell therapy pipeline is competitive; but market is fragmented with numerous patient segments

The eye is an ideal organ for gene‐replacement therapy given its accessibility, immune privilege, small size and compartmentalization

Clinical studies have already shown that in vivo gene addition approaches can benefit specific groups of RP patients (e.g., RPE65 for patients with LCA Gene editing approaches are also being developed with PoC studies focused on LCA patients with mutations in CEP290, a gene too large to address with AAV vectors

Adis R&D Insight; Clarivate Analytics Cortellis; DH Analysis; *products may be in development for more than one indication

Gene therapy, 38

Small molecule, 17

Other biologic, 12

Cell therapy,

9

# Products by Type

58

10 83

0

10

20

30

40

50

60

70

RP LCA Usher Syndrome Other IRD

# Products by Indication*


Co‐sponsored by:

Spark Therapeutics' Luxturna, Indicated for Biallelic RPE65‐mediated IRDs, Likely to be the First In Vivo Gene Addition Therapy Approved by the FDA

http://ir.sparktx.com/static‐files/eb8d4229‐6ab2‐48b9‐9d0e‐c1b1d604caf7

Luxturna (voretigene neparvovec) is an AAV2 viral vector expressing the gene for human RPE65 which is administered to the retinal pigment epithelium by sub‐retinal injection

• RPE65 was chosen largely because its small enough to fit into AAV vectors and because it was believed, that RPEs are easier to transduce than photoreceptors


Co‐sponsored by:

Spark Therapeutics' Luxturna, Indicated for Biallelic RPE65‐mediated IRDs, is Likely to be the First In Vivo Gene Addition Therapy Approved by the FDA

In the pivotal trial, Luxturna showed statistically significant and clinically meaningful improvement following:

• Primary endpoint of mean bilateral MLMT change score (patients’ ability to navigate a mobility course under a variety of specified light levels)

• Gain in functional vision based on MLMT in 93% (27/29) with 72% achieving maximum improvement (to 1 lux) – no product‐related SAEs observed

• 3‐year data (n=20) and 4‐year data (n=4) from Phase 3 add evidence to durability of effect; no statistically significant signs of a waning of therapeutic effect

• Met two of three secondary endpoints

• There were no drug‐related serious adverse events observed and no deleterious immune responses

http://ir.sparktx.com/static‐files/eb8d4229‐6ab2‐48b9‐9d0e‐c1b1d604caf7; https://www.genengnews.com/gen‐news‐highlights/fda‐advisory‐panel‐unanimously‐recommends‐approval‐of‐spark‐therapeutics‐gene‐therapy‐luxturna/81255043

The FDA’s Advisory Committee voted 16 to 0 to recommend approval of Luxturna (Priority Review PDUFA date of Jan 12, 2018)

Luxturna will be indicated as a one‐time gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65‐mediated inherited retinal dystrophies.


Co‐sponsored by:

LUXTURNA Launched At $850k With Payment Linked To Both Short‐term Efficacy (30‐90 Days) And Longer‐Term Durability (30 Months) Measures

“We believe that access to therapy is a shared responsibility among Spark Therapeutics, payers, health benefit providers,

physicians and treatment centers. We have been working with stakeholders across the health care sector to help ensure that appropriate patients have access to a product that challenges all of the current conventions of how patients are treated, how

products are delivered and how payments are handled.”

Jeffrey D. Marrazzo, CEO of Spark Therapeutics

http://sparktx.com/investors‐media/media/; https://www.fiercepharma.com/pharma/spark‐prices‐gene‐therapy‐luxturna‐at‐850k‐grabbing‐top‐spot‐pharma‐s‐costliest‐drugs

Spark sets off gene therapy debate with $850K sticker on Luxturna Spark sets off gene therapy debate with $850K sticker on Luxturna There's a new medicine atop of pharma's global pricing charts, and it's Spark Therapeutics' Luxturna. After winning FDA approvalin December, the company said Wednesday its gene therapy will cost $850,000, or $425,000 per eye before discounts.

To soften the blow, Spark is introducing outcomes‐based deals with Harvard Pilgrim and Express Scripts affiliates—and it's in talks for more. Under those arrangements, the company won't collect full payment if its superpricey drug doesn't work. The company is also working on a proposal with the Centers for Medicare and Medicaid Services that would allow payments over multiple years.

Luxturna treats a rare inherited disease that can lead to blindness and works by delivering a gene called RPE65 into a patient'sretinal cells, which then produce a protein to restore vision loss.

While $850,000 is a staggering figure on its face, the price actually came in lower than a $1 million estimate by Wall Streetanalysts. Before the launch, Spark CEO Jeffrey D. Marrazzo said the one‐time treatment offers "a value in excess" of $1 million.

In a statement Wednesday, Marrazzo said his company believes "access to therapy is a shared responsibility among Spark Therapeutics, payers, health benefit providers, physicians and treatment centers."

To that end, the company has "been working with stakeholders across the health care sector to help ensure that appropriate patients have access to a product that challenges all of the current conventions of how patients are treated, how products are delivered and how payments are handled," the helmsman said.

But even though Evercore ISI analyst Steve Breazzano said the price came in "generally within expectations," the company quickly ran into criticism from patient advocates.

"Spark Therapeutics is charging as much for Luxturna as they think they can get away with," Patients for Affordable Drugs president David Mitchell said in a statement shortly after the announcement. "Our system cannot handle unjustified prices like this, and the new payment models announced today are merely a way to disguise a price that is simply too high."

Breazzano said Spark is "clearly focused on moving away from this one‐time upfront payment to an annuity‐like model with payments over multiple years." But for now, those efforts are in early stages, according to the analyst.

How does Luxturna's price compare to some of pharma's other superpricey drugs? The first year of Biogen's Spinraza costs $750,000—the med is $375,000 for subsequent years—while BioMarin's Brineura, approved last year, costs $702,000 before discounts. Both are recurring treatments versus the one‐time nature of Luxturna. UniQure's Glybera, now discontinued, cost $1.2 million in Europe, but its commercial use was limited and the drugmaker opted to stop pouring resources into marketing the drug.

Spark's gene therapy approval followed FDA clearance of CAR‐T cell therapies from Novartis in August and Gilead in October. Novartis also has an outcomes‐based contract on its Kymriah, which costs $475,000 to treat a rare form of acute lymphoblastic leukemia. Both drugmakers plan to expand the technology into other uses.


Co‐sponsored by:

ICER Releases Its Evidence Report on Luxturna for Public Comment

https://www.statnews.com/2018/01/12/price‐gene‐therapy‐childhood‐blindess/?utm_source=STAT+Newsletters&utm_campaign=3098c86d3c‐Daily_Recap&utm_medium=email&utm_term=0_8cab1d7961‐3098c86d3c‐149648341

At $850,000, price for new childhood blindness gene therapy four times too high, analysis saysThe $850,000 list price for a new medicine that treats a genetic form of childhood blindness is about four times too high for the value the drug provides, a nonprofit that studies the cost‐effectiveness of new drugs said Friday, though it added that the price of the drug is cost‐effective for select patients and with certain assumptions.

The report from the Institute for Clinical and Economic Review focused on the medicine Luxturna, the first‐of‐its‐kind gene therapy approved for the U.S. market and the most expensive medicine by list price. It is the latest flashpoint in the debate over how to afford an innovative medicine —in this case, a therapy that corrects a genetic mutation in people’s cells — that carries, and in some views, deserves, a pricey list cost.

In its report, ICER said a cost‐effective price for Luxturna would be $153,000 to $217,000 — a discount of 75 percent or more. ICER cited a lack of data that Luxturna causes permanent improvements in vision as a key reason that its developer, Spark Therapeutics, should not be charging so much.

ICER reached its suggested list price for Luxturna by assuming that a 15‐year‐old person (the average age of the patients enrolled in the clinical trials) would experience improvements for a decade or two and taking into account the benefits to the health care system. It added that when it also took into account the benefits related to education, caregiver burdens, and productivity, the drug’s list price should still be cut in half.

ICER, however, did say that the drug’s list price met its standards for “cost‐effectiveness thresholds” when it analyzed treating 3‐year‐old patients. In that case, it took into account both medical and societal benefits, and assumed the vision improvements would last for the patients’ whole lives.

Ahead of Spark’s pricing announcement earlier this month, some analysts forecasted the price could reach $1 million. Between the list price coming in under those expectations and the reimbursement arrangements the company struck, some experts credited Spark with crafting a thoughtful payment plan and picking a price that was in the range of other medicines that pushed the boundaries of what past therapies could do.

The Food and Drug Administration approved Luxturna in December to treat people with a rare and progressive retinal disease caused by a mutation in the RPE65 gene. People with the mutation can eventually go completely blind.

The pricing of gene therapies like Luxturna has been closely watched, and raised a fascinating question: How much are we willing to pay for a cure?

While Luxturna is a one‐time therapy, it does not “cure” people born with mutated RPE65 genes; instead, it is meant to stop disease progression and restore some visual strength. But other gene therapies in pipelines could, by replacing faulty genes with functional ones, actually amount to cures. If they are able to reverse or prevent disease — and avoid all the future medical costs that accompany long‐lasting conditions — how much is fair for the drug makers to recoup?

Spark has said it is negotiating deals with health plans to repay them should patients not be successfully treated. It is also discussing allowing insurers to pay for the therapy over several years instead of all at once.

“While the evidence is clear the therapy improves vision for patients over several years, the long-term duration of this benefit remains unknown,” Dr. David Rind, ICER’s chief medical officer, said in a statement. “Assuming a 10- to 20-year period of benefit, at list price the treatment does not meet standard cost-effectiveness thresholds, even after accounting for the broader societal benefits improved vision has on productivity and education costs.”

48

Late Entrant Breakthrough Therapy In Mid‐size Orphan Indications With Established SOC: Hemophilias


Co‐sponsored by:

Hemophilia A is a Relatively Large, Mature Clotting Factor Replacement Market

Overview

Brief Description

• X‐linked congenital bleeding disorder caused by more than 1,300 mutations in coagulation factor VIII (FVIII). • Some of these mutations change single base pairs, while others delete or insert multiple base pairs. The most common mutation in

people with severe Hemophilia A is an inversion involving a large segment of the FVIII gene.• Persons with hemophilia cannot form blood clots when needed to stop bleeding, resulting in abnormal bleeding after an injury or

spontaneously‐into their joints, muscles, and soft tissues. • Bleeding into the head, abdomen, kidneys, intestines, and major joints and muscle groups can be life‐ or limb‐threatening. • Mild patients typically only have problems with bleeding following major trauma and surgery, moderate patients often have

bleeding issues after an injury has occurred, and people with severe hemophilia (60% of the hemophiliac A population), sufferfrom bleeding after most injuries and often have bleeding into joints and muscles.

Market Size and Epidemiology

• Market Size: Global sales for Factor VIII products is >$5B and expected to reach $6B+ by 2024.• WW ~330,000 people affected by Hemophilia A, representing 80‐85% of the total hemophilia population. • Occurs in about one in 5,000 male births and affects about 25,000 individuals in the United States

Disease Demographics

• As an X‐linked recessive trait, hemophilia generally affects males on the maternal side. • Rarely, diagnosed in homozygous females, and heterozygous females due to X‐inactivation. • As many as 1/3 of all cases are the result of spontaneous mutation where there is no prior family history.

SOC

Treatment Algorithm

• On‐demand and prophylactic replacement therapy consisting of an IV infusion of clotting factor VIII.• Several long‐acting recombinant versions recently entered the market to decrease frequency of prophylactic infusions. • Also, new products are entering the market that are designed to overcome inhibitor formation.• Minority of patients develop inhibitory antibodies against clotting factors, rendering them ineffective.

hemophilia.org; EvaluatePharma; UpToDate; Hum. Mol. Genet. (1994) 3 (7): 1035‐1039, http://www.fiercepharmamarketing.com/story/biogens‐alprolix‐nod‐just‐first‐tremor‐hemophilia‐market‐shake/2014‐04‐02, Poseida presentation, Publications supplied by Poseida, healthcare.globaldata.com, hemophilia.org, UpToDate, DH Assumptions


Co‐sponsored by:

Factor VIII/Hemophilia A Competitive Landscape

Although questions remain about the long‐term safety and durability of Roche/Chugai’s bispecific FIXa/X antibody, ACE910 has the potential to change the management of inhibitors in the near term and could disrupt the broader hemophilia A landscape in the long term if proven to be as effective as Factor VIII replacement in the on‐demand and prophylaxis treatment settings

Alnylam’s ALN‐AT3 (fitusiran), an RNAi agent designed to knock down antithrombin showed promising efficacy, safety and tolerability Phase 1b data at WFH 2016

• Cohorts in the 80 mg optimal fixed dose having median ABRs of zero

Several gene therapies for Hemophilia A are in development (Spark/Pfizer, UniQure, Dimension/Bayer, BioMarin, and Shire). BioMarin reported encouraging data from a cohort of eight hemophilia A patients dosed with AAV5‐based gene therapy BMN 270 in April 2016

• Six of the eight patients were dosed at the highest dose of 6x103 mg/kg, and all patients were raised from “severe” levels of FVIII to “moderate, mild, or normal” as defined by the WFH

• Shire is also looking to advance hemophilia A gene therapy BAX 888 into the clinic in late 2016, while Shire has discontinued BAX 335, their lead FIX gene therapy program

Evaluate Pharma (Obizur and Nuwiq sales are captured in the “Other” category)

Global sales of FVIII drugs are projected to grow from ~$6B to $7.5B over the next 5‐7 years

Long‐acting products are expected to drive growth but disruptive innovation could change the future landscape


Co‐sponsored by:

Numerous Gene Therapy Approaches Advancing with Clinical PoC in Both Hemophilia A and B

Preclinical

Phase 1

Phase 2

Phase 3

Marketed

Adis Insight; Thomson Reuters Cortellis

autologous stem cell therapy(University of California Davis)

enzyme/protein replacement therapy

(Immusoft)

Factor VIII gene restoration therapy

(ToolGen/Seoul National University/K‐STEMCELL)

genetically engineered cell strains

(Sernova Corp)

hematopoietic Factor VIII gene therapy

(Discovery Genomics/Univ. of Minnesota)

LG 889(Opus Bio/Expression/

Emory)BAX 888(Shire/Baxalta)

BMN 270(BioMarin/UCL/

St Jude)

DTX 201(Dimension/Bayer)

Factor VIII gene therapy(Sangamo BioSciences)

GREF8(Greffex)

Research programme: haemophilia A gene therapy

(uniQure)

SPK8011(Spark Therapeutics)

SB‐FVIII(Sangamo BioSciences)

2bFVIII gene therapy(Medical College of Wisconsin)

Research program: hemophilia A/B gene therapy

(Biogen/TIGET)

Retroductal gene delivery systems

(Genteric Inc,)

Cell therapy, ex vivo, autologous

Gene therapy, in vivo, AAV

Gene therapy, in vivo,

gene editing

Gene therapy, in vivo, lentiviral

Gene therapy, other


Co‐sponsored by:

BioMarin’s Valoctocogene Roxaparvovec Phase 1/2 Clinical Trial has Shown Promising Preliminary Data

BMN 270 is designed to address the underlying genetic defect that prevents the expression of functional Factor VIII by using an adeno‐associated virus (AAV) vector to deliver a functional copy of the factor VIII gene to a patients' own cells with the aim of a single infusion of BMN 270 providing a long‐lasting increase in Factor VIII levels

The current Phase 1/2 study is evaluating the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A

• The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for human‐coagulation factor VIII and to determine the change from baseline of factor VIII expression level at 16 weeks after infusion

In April 2016, BioMarin presented preliminary data on the first 8 patients in the BMN 270 Phase 1/2 trial

• Two high dose patients showed increasing levels of factor VIII above 50% (normal activity)

• Five of six high dose patients show factor VIII levels above 5% (mild hemophilia)

• The first three patients were not administered prophylactic corticosteroids. Two of these patients experienced elevated alanine aminotransferase (ALT) levels

http://investors.bmrn.com/releasedetail.cfm?releaseid=965945

Patient Characteristics:


Co‐sponsored by:

New 1.5 Year Results Demonstrate Sustained Factor VIII Levels within the Normal Range in Severe Hemophilia A for Most Patients

SAN RAFAEL, Calif., Dec. 11, 2017 /PRNewswire/ ‐‐ BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced updates on valoctocogeneroxaparvovec (formerly BMN 270), an investigational gene therapy treatment for severe hemophilia at ASH.

http://investors.biomarin.com/2017‐12‐11‐BioMarin‐Highlights‐New‐Results‐for‐Gene‐Therapy‐Valoctocogene‐Roxaparvovec‐at‐the‐2017‐American‐Society‐of‐Hemophilia‐ASH‐Meeting

With the 4e13 vg/kg dose, the three patients with the longest follow‐up (at week 48) have Factor VIII activity levels that are in or near to the normal range with both median and mean values of 49%.

Median annualized bleed and factor VIII use rates for the 4e13 vg/kg cohort were zero after Week 4 and when their Factor VIII activity rose above 5%.

Mean annualized bleed and factor VIII use rates for the 4e13vg/kg cohort were 0.6 and 2.0, respectively.

With the 6e13 vg/kg dose, at 78 weeks post infusion, the median and mean Factor VIII levels of the 6e13 vg/kg cohort were 90 and 89%, respectively.

Median annualized bleed and factor VIII use rates for the 6e13 vg/kg were zero after Week 4.

Mean annualized bleed and factor VIII use rates for the 6e13 vg/kg cohort were 0.5 and 6.1, respectively.


Co‐sponsored by:

• Sangamo’s IND application for ZFP Therapeutic (SB FIX) for hemophilia B and (SB‐525) for hemophilia A was approved by the FDA

• The two hemophilia programs are the first in a platform of IVPRP assets that use intravenous AAV‐delivered ZFP/ZFNs to target the albumin locus and drive permanent expression of therapeutic proteins for a wide range of deficiency diseases, including the hemophilias, LSDs and other metabolic diseases

FDA Approved Sangamo BioSciences’ IND Applications for In Vivo ZFP/ZFN Genome‐Editing Programs for Hemophilia A and B

http://investor.sangamo.com/releases.cfm


Co‐sponsored by:

Recently Approved, Hemlibra, A Once Weekly Is Designed To Overcome Inhibitor Formation And Can Be Offered To Hemophilia A Patients With Or Without FVIII Inhibitors

HEMLIBRA® (emicizumab‐kxwh) is approved by the FDA as a prophylactic medicine used to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A with factor VIII inhibitors. It is given once a week subcutaneously (under the skin).

Emicizumab is a bi‐specific antibody against activated factor IX (FIXa) and factor X (FX), which mimics the cofactor function of FVIII. 1 It possesses a favorable safety and efficacy profile in severe hemophilia A patients irrespective of the presence of FVIII inhibitors. 2‐4

• FIRST new FDA‐approved medicine to treat hemophilia A with inhibitors in nearly 20 years

• FIRST bispecific monoclonal antibody approved to treat hemophilia A with inhibitors

• ONLY treatment option for hemophilia A with inhibitors that can be self‐administered once weekly by injection subcutaneously

• Provided improvement in Haem‐A‐QoL questionnaire

Source: 1. ADIS R&D Insight 2. Vontobel Research, July 2015 3. UBS Global Research, August 2015 4. ISTH meeting, June 2015


Co‐sponsored by:

Alnylam’s RNAi Therapeutic Targeting Anti‐Thrombin Shows Early Potential

At the 2016 ASH Conference, Alnylam Pharmaceuticals presented data that illustrated potential benefit for its Antisense RNA therapy, fitsurian

At the conference the company’s interim data showed that 56% of hemophilia A and B patients on fitsurian haven’t bled since starting therapy

• Phase 1 data includes 16 hemophilia patients

There has not been significant safety problems in the Phase 1 trial, however, a few patients have seen a rise in liver enzymes, which may signal potential issues

Alnylam expects to begin a late‐stage trial in 2017

https://www.bloomberg.com/news/articles/2016‐12‐03/alnylam‐hemophilia‐drug‐shows‐early‐success‐among‐hard‐to‐treat; http://www.xconomy.com/national/2016/12/06/ash‐roundup‐car‐t‐shuffle‐hemophilia‐updates‐checkpoint‐progress‐more/#; ASH 2016: Abstract 2572

57

Breakthrough Therapy Seeking FDA Approval For Emerging Rare Disease Market With Established SOC: Spinal Muscular Atrophy


Co‐sponsored by:

SMA is the Most Common Monogenic Cause of Infant Mortality

Spinal muscular atrophy (SMA) is an autosomal recessive inherited disorder caused by biallelic deletions in the survival motor neuron gene 1 (SMN1) gene on chromosome 5q13.2

Deficiency of SMN protein leads to degeneration of the anterior horn cells in the spinal cord, which results in progressive muscle weakness and atrophy

Individuals with SMA have difficulty performing the basic functions of life, like breathing and swallowing. However, SMA does not affect a person’s ability to think, learn, and build relationships with others

The incidence of spinal muscular atrophy ranges from 4 to 10 per 100,000 live births, and the carrier frequency of disease‐causing SMN1 mutations ranges from 1/90 to 1/47

There are four primary types of SMA—I, II, III, and IV—based on age of onset and highest physical milestone achieved

• ~94% of patients with clinically typical SMA carry homozygous deletions of exon

• Disease severity in SMA generally correlates inversely with SMN2 gene copy number.

CureSMA; UpToDate.com

SMN protein and phenotypic expression appear to be related in part to a modifying gene, called SMN2 which is 99% identical.

• main difference is a C to T transition in exon 7 of the SMN2

• leads to production of a truncated, nonfunctional SMN protein.

However, SMN2 can produce some functional, full‐length SMN protein which partially compensates SMN protein synthesis.


Co‐sponsored by:

Spinraza is the First and Only Approved Drug for Treatment of SMA in US, Europe, Japan and Other Geographies

Spinraza (nusinersen) is an antisense oligonucleotide that is designed to increase expression of the SMN protein, which is deficient in SMA

Spinraza is administered by intrathecal injection; each dose is 12 mg per 5 mL supplied in a single vial

• Initiated with four loading doses; the first three loading doses are given at 14 day intervals, while the fourth loading dose is given 30 days after the third; Thereafter, a maintenance dose is given once every 4 months

The cost of each dose is listed as $125,000

CureSMA; UpToDate.com; https://www.spinraza‐hcp.com/en_us/home/about/mechanism‐of‐action.html

FDA approval was based mainly upon an interim analysis of the multicenter, double‐blind, unpublished ENDEAR trial

• Enrolled infants with SMA who were <7 months of age were randomly assigned to intrathecal nusinersen or sham treatment

• In an interim analysis of 82 eligible patients, improvement in motor milestones (eg, head control, sitting, kicking in supine position, rolling, crawling, standing, and walking) as measured by the Hammersmith Infant Neurological Examination (HINE) was observed in 40 percent of patients treated with nusinersen, versus none for those who received the sham procedure

• In addition, the FDA noted that data from uncontrolled, open label studies evaluating nusinersen for symptomatic patients (ages 30 days to 15 years) and presymptomatic patients (ages 8 to 42 days) were supportive of the clinical benefit as was seen in the ENDEAR trial


Co‐sponsored by:

Spinraza Discussion Quickly Turned from Breakthrough Therapy to Value and Access Debate


Co‐sponsored by:

Although Spinraza has the potential to change the course of SMA, a number of ethical challenges revolve around its use

Spinal Muscular Atrophy Researchers Identify Spinraza Ethical ChallengesSpinal Muscular Atrophy Researchers Identify Spinraza Ethical ChallengesIn an article in the journal JAMA Pediatrics, they maintained that the healthcare system needs to address six issues to ensure that SMA patients “benefit from treatment, are protected from harm, and are treated fairly.” The title of the piece is “Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal Muscular Atrophy,” The group, led by Dr. Alyssa M. Burgart of Stanford University, said the biggest challenge is cost.

Spinraza’s pricetag is $750,000 the first year, and $375,000 each year thereafter. A cost that hefty can make insurers reluctant to cover the treatment, the group said. It also creates the possibility of hospitals bearing partial or full costs if an insurer refuses to reimburse them. In fact, this is a major reason why some hospitals are not offering Spinraza (nusinersen) treatments, the team wrote.

A second ethical challenge is the possibility that people with similar levels of disease severity will receive different treatments because of cost. This generates “concerns for the just distribution of healthcare,” the scientists wrote. While unequal health insurance coverage is an inherent flaw of the U.S. healthcare system, Spinraza’s enormous cost makes the problem particularly daunting. Healthcare insurers and hospitals are not the only ones bearing the cost burden, the team wrote. The lifelong cost of the therapy may force families to opt out of treatment or become impoverished.

The third ethical challenge is dealing with limited information on Spinraza’s long‐term effectiveness. Since Spinraza trials involved small patient samples and were relatively short term, the verdict is out on whether most patients will benefit long term. It is also not clear if the improvements seen in the trials will translate into improvements in muscle strength and function when doctors treat patients. While patients and their families may be prepared to accept these uncertainties, health insurers may not be. This may lead to situations in which insurers approve a treatment only if patients can prove with arbitrarily determined measurements that it is effective. Limited access to such testing may further disadvantage a patient, the team argued. In addition, there is no agreement on what a treatment benefit is. This has a bearing on a third ethical issue — informed consent. If a treatment is failing to provide benefits, a doctor may decide that it should be dropped. Since there is no consensus on what a treatment benefit is, patients, families and physicians may find themselves holding differing views on the issue. The best way to deal with this is to discuss it before a patient starts treatment, the team contended. “Although these complex discussions occur at the bedside, institutions should ensure that clinicians [doctors] and patients have the support they need while facing prognostic uncertainty,” they wrote.

The fourth ethical challenge is how to allocate treatment. Granting access to everyone who is eligible will likely lead to treatment delays. The question is: Who gets treatment first. As an example, doctors may need to use special procedures to administer a spinal tap drug, including sedating a patient and having them hospitalized afterward. Researchers agree that Spinraza should be started as soon as possible. Logistical obstacles could cause delays that make it less effective. Since drug administration resources are limited, hospitals may need to come up with ways to decide who gets priority access to treatment. These could include allocation criteria, case by case circumstances, or even lotteries. Each method has pros and cons in terms of fairness and other considerations.

Availability of treatment centers, which also affects therapy allocation, is the fifth ethical challenge revolving around Spinraza. While it is possible to open more centers with the expertise to administer Spinraza, this solution is also linked to cost. Some centers may choose not to offer Spinraza or to develop the expertise needed to administer it, leaving just a few centers to tackle patients’ needs. “Such a system may increase overall wait times and strain the participating centers in an unsustainable and unfair fashion,” the team argued. “Patients who live far from a participating center may not have the resources or clinical stability to travel, creating further disequilibrium of justice.”

The sixth ethical challenge is ensuring transparent communication between patients, families, doctors and others in the SMA community about these issues. On the one hand, patients and families need reliable information about a medical center’s care processes to make treatment decisions. This means the centers need to be up‐front about how they allocate resources. The transparency will help patients obtain Spinraza at a center that offers the most advantages for their situation. “As we pass through the initiation phase of nusinersen treatment among prevalent and newly diagnosed patients, pressure must be applied to reduce the cost and its effect on access, learn more details of medication benefit and safety, and examine different ways to initiate treatment and manage clinical workflows for this therapy,” the researchers concluded.

https://smanewstoday.com/2017/12/20/spinal‐muscular‐atrophy‐researchers‐shine‐spotlight‐on‐spinraza‐ethical‐challenges/


Co‐sponsored by:

Recent Published Results on AVXS‐101, an AAV9‐Based Gene Therapy, Signify Potential to Offer Patients a One‐Time Durable Treatment for SMA Type 1 and Possibly Broader Subtypes

AveXis presented a positive interim analysis of data from 15 SMA Type 1 patients in its ongoing Phase 1 safety trial of AVXS‐101, a one‐time, intravenous AAV9 based gene therapy carrying SMN complementary DNA encoding the missing SMN protein

AVXS‐101 was safe and tolerable. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone

Efficacy endpoints:

• time until death or need for permanent ventilatory assistance

• Comparison of CHOP INTEND scale of motor function (0 to 64)

• Motor milestones in the high‐dose cohort with scores in studies of the natural history of the disease (historical cohorts)

ASGCT; AveXis website; J. Mendell http://www.nejm.org/doi/full/10.1056/NEJMoa1706198

As of data cutoff, all 15 patients were alive and event‐free at 20 months, compared with survival rate of 8% in a historical cohort

Of the 12 patients who had received the high dose:

• a rapid increase from baseline in CHOP INTEND score followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in a historical cohort

• 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently


Co‐sponsored by:

Aside from Supportive Care and Unapproved Agents such as AVXS‐101, Spinraza is the Only Available Disease Modifying Therapy

Muscle relaxants are used to reduce spasticity; Botulinum toxin is used to treat jaw spasms or drooling

Physical therapy, occupational therapy, exercise and rehabilitation are recommended to improve posture, prevent joint immobility and slow muscle weakness and atrophy

Assistive devices such as supports or braces, orthotics, speech synthesizers and wheelchairs may help some people retain independence

If feeding and swallowing problems are severe, then feeding tubes are used such as a gastrostomy tube or a nasogastric tube

Breathing support includes negative pressure ventilators and bi‐level positive airway pressure support helps in coping with breathing problems; Tracheostomy is often recommended in severe cases

Orthopedic complications: spine‐straightening surgery is performed to cure spinal curvature permanently; Custom seating systems, seating aids and a body jacket is used to prevent severe scoliosis

CureSMA; UpToDate.com; EvaluatePharma

Rapid uptake of Spinrazain US, Rollout to Europe,

Japan and RoW

Rapid uptake of Spinrazain US, Rollout to Europe,

Japan and RoW

Possible entry of AVXS‐101

Possible entry of AVXS‐101

Peak and outyears uncertain, depends on approval and

durability of AVXS‐101

Peak and outyears uncertain, depends on approval and

durability of AVXS‐101

64

Gene Therapy for Very Large Prevalent Populations – Among The Highest Medical Needs – Cardiac Failure and Alzheimer


Co‐sponsored by:

Potential of GT Beyond Rare Disorders? CVD and Alzheimer’s Disease Remains The Largest Cause Of Mortality, Morbidities and Healthcare Expenditure

CDC, AHA

Total Medical and Indirect CVD Costs

Current 2035

$555 billion $1.1 trillion

Coronary Heart Disease: 16.8 million adults in the US

• $188 billion medical and indirect costs annually (47% direct)

Congestive Heart Failure: 5.8 million adults in the US

• $29 billion medical and indirect costs annually (62% direct)


Co‐sponsored by:

$2B Cardiac Gene Therapy – SERCA2a and S100A1

Exclusive license for S100A1 gene therapy program for chronic heart failure

• 10‐target collaborations providing exclusive rights to BMS in CVD

• Leverage BMS clinical and commercial expertise in CV disease

• $140 million received to date

• $2.3 billion in potential milestones, double‐digit royalties

• All R&D paid by BMS; with QURE exclusive manufacturer

• BMS has 9.9% stake in uniQure; Warrants to own up to 19.9%

NCT01643330, Hulot, J‐S et al. Eur. Heart J. 37, 1651–1658 (2016). Greenberg, B et al. JACC Hear. Fail. 2, 84–92 (2014). Ritterhoff, J et al. Gene Ther. 19, 613–621 (2012); http://uniqure.com/uniQure_Corporate_Presentation_November‐1.pdf

S100A1 enhances the activity of both ryanodine receptors and SERCA2a

AAV‐S100A1 gene therapy for the one‐time treatment of CHF

Designed to selectively restore cardiac deficiency of the calcium‐binding protein in advanced CHF patients

S100A1 is a master regulator of myocardial function ‐ promotes cardiac contractile and relaxation


Co‐sponsored by:

AAV delivered therapeutic antibodies to target key pathological features of Alzheimer’s Disease

3rd generation AAV vectors created by isolating novel capsids, molecular evolution and structure based engineering in the goal to improve upon the current repertoire of AAV vectors::

• improve the standard applications of gene therapy focusing on enhanced delivery and potency

• circumventing pre‐existing and induced humoral immunity

• Improve ease or scale of manufacturing

• Improve suitability for genome editing, which requires targeting of stem‐like and progenitor cells rather than post‐mitotic cells, which are the target of gene replacement therapy.

https://www.med.upenn.edu/gtp/

Johnson & Johnson pens Alzheimer’s gene therapy pactby Nick Paul Taylor

Jan 5, 2018 7:30am

J&J hopes to use AAV viral delivery to trigger the expression of therapeutic antibodies in the brain.

Johnson & Johnson has formed an Alzheimer’s gene therapy research pact with the University of Pennsylvania. The partnership brings together J&J’s anti‐Alzheimer’s antibodies and the university’s adeno‐associated viruses (AAVs) in a bid to open up a new frontier in the fight against the disease.

J&J hopes to use AAV viral delivery to trigger the expression of therapeutic antibodies in the brain. These antibodies, J&J’s contribution to the partnership, will target the key pathological features of Alzheimer’s in a bid to treat disease.

If successful, the effort will open up a way to get biologics into the brain to treat Alzheimer’s and other diseases affecting the organ. Currently, the blood‐brain barrier limits the use of antibodies to treat brain diseases.

The workaround being pursued by J&J is underpinned by AAV research performed by Jim Wilson, M.D., Ph.D., and others at the university's gene therapy program. Wilson and his collaborators have been working for more than two decades to improve AAVs, leading to the current effort to create what they see as the third generation of AAV vectors.

Wilson and his collaborators hope these vectors will improve delivery and potency, while bypassing humoral immunity, and open the door to AAV‐enabled genome editing. J&J has exclusive global rights to products resulting from the collaboration.

The Big Pharma unveiled the hookup with the university in one of its periodic updates on its partnering activity. The latest drop also brought news that J&J is working with Dermala, a resident of the San Diego JLABS site, on microbiome‐derived treatments for skin conditions and that it is collaborating with a GPCR expert to discover drugs against obesity and other metabolic diseases.

The collaborations are part of a big network of alliances J&J has built up in recent years as it has tried to hit upon a more effective way of accessing innovation.


Co‐sponsored by:

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Mike Rice, MS, MBA,

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[email protected]

www.definedhealth.com

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Consultant, Defined Health

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Associate Principal, Defined Health


Co‐sponsored by:

Join us for the upcoming web panel discussion

Bispecifics in Oncology and IO:Anything One Can Do, Can Two Do Better?

Linda Pullan, Moderator

Pullan Consulting

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AmgenJeff Bockman

Defined Health

Ezio Bovini,

MacroGenics

Chris Hurff

Takeda

Taylor Schreiber

Shattuck Labs

TUESDAY, JAN. 30, 2018 | 8A PT / 11A ET

Ali Tehrani

Zymeworks


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thank you for being with us today.

Defined Health Insight Series Briefing: Gene And Cell Therapies – It’s Show Time!

Mike Rice, Principal, Defined Health

Cambridge, MA

January 16, 2018


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