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World Advanced Therapies and Regenerative Medicine CongressLondon | May 15 - 17, 2019

Implementing Strategic Development and Innovating Disruptive Business Models for Transformative Cell and Gene Therapies

Moderator: Michael C. Rice, Principal, Cello Health BioConsulting

Panelists:• Sam Hall, Partner, Apple Tree Partners• RA Session, Chief Business Officer, BridgeBio-Gene Therapy• Jean-Philippe Combal, Co-Founder & CEO, Vivet Therapeutics• Chip Baird, Chief Financial Officer, bluebird bio


Advanced Therapeutic Sector is a Healthy and Dynamic EcosphereARM tracks >917 Regenerative Medicines companies (502 US, 233 Europe and 145 Asia, 47 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 / Regulation

AAV

AdV

Lenti-

Retro

Plasmid

Other

Partners

https://alliancerm.org/event/sotibriefing

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://en.wikipedia.org/wiki/File:Sanofi.svg&ei=aDNKVfneOqPasASH9YCQBg&bvm=bv.92765956,d.cWc&psig=AFQjCNFMPXuD7ZKXF-T5RmOT5lwZWzbiHw&ust=1431012576738297

http://lentigen.com/

http://www.pfizer.com/

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwi-oIij_6LLAhXJmR4KHccRCf4QjRwIBw&url=http://medcitynews.com/2015/09/baxalta-shire-google-in-healthcare/&bvm=bv.115339255,d.amc&psig=AFQjCNEOoGKWnDbWqQBulFjkC-xI_jWIHQ&ust=1457042183112868


VCs Continue to Invest In Early Stage ADVTX Platforms to Add to The Increasingly Versatile Toolkit of Vectors, Payloads and Cell Systems

2014 2015 2016 2017 2018 2019

Undisclosed $1M $4M $14M

Marketed

Phase III $73M $22M $29M

Phase II $185M $64M $92M $81M $92M $100M

Phase I/II $161M $108M $35M $50M $143M

Phase I $75M $125M $74M $114M $529M

IND $17M $50M

Preclinical $86M $343M $412M $313M $287M $50M

# of Financings 16 16 23 21 18 5

0

5

10

15

20

25

0

200

400

600

800

1,000

To

tal F

ina

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alu

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$M

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Status of Lead Asset at Time of Funding by Year

BCIQ; Cell & Gene Therapy VC Finances From 2014 to 2019

Round Avg.

Raised

(2014-2019)

Seed $4.05 M

Series A $36.3 M

Series B $47.1 M

Most Frequent Players in Early ADVTX VC Financing

(>4 Financings)

Atlas VentureWellington

ManagementSofinnova

Deerfield

ManagementFidelity Arch Venture

Alexandria Venture New Ent. Assoc. Cowen

5AM Ventures Third Rock Ventures Access Industries

68

13

642 6

USA UK France

China Switzerland RoW

Adv Tx Seed – Series B Financing by Country


… Giving Rise to an Increasingly Capable and Precise Toolkit With Improved Therapeutic Index and Durability

Near-Term Growth of ADVTX Sector is Anticipated With Dozens of Potential Market Authorizations of Oncology Therapies Coming in Next Few Years!

CHBC Analysis, Clarivate Analytics Cortellis, EvaluatePharma

2018 & Earlier 2019 2020 2021 ALONE

AUTO1 (Autolus) - ALL

AUTO3 (Autolus) - ALL

FATE-NK100 (Fate Tpx) - AML

UCART123 (Cellectis) - AML

Liso-cel (Celgene) - B-cell lymphoma

Avelumab-haNK (NantKwest) - Bladder

Cancer

GSK3377794 (GSK) - Bladder Cancer

MAGE-A10 (Adaptimmune) - Bladder Cancer

MAGE-A4 (Adaptimmune) - Bladder Cancer

LN-145 (Iovance) - Bone Cancer

Avelumab-haNK (NantKwest) - Breast

Cancer

Pexa-Vec (Transgene) - Breast Cancer

LN-145 (Iovance) - Cervical Cancer

Avelumab-haNK (NantKwest) - CRC

Pexa-Vec (Transgene) - CRC

Liso-cel (Celgene) - DLBCL

GSK3377794 (GSK) - H&N Cancer

MAGE-A4 (Adaptimmune) - H&N Cancer

FATE-NK100 (Fate Tpx) - Fallopian Tube

Cancer

Liso-cel (Celgene) - FCL

UCART123 (Cellectis) - General heme

malignancies

Avelumab-haNK (NantKwest) - H&N

Cancer

LN-145 (Iovance) - H&N Cancer



AFP TCR (Adaptimmune) - Hepatoma

Avelumab-haNK (NantKwest) - Hepatoma

Pexa-Vec (Transgene) - Hepatoma

Tabelecleucel (Atara) - Lymphoproliferative

disease

Avelumab-haNK (NantKwest) - Melanoma

GSK3377794 (GSK) - Melanoma

LN-145 (Iovance) - Melanoma

Kymriah (Novartis) - ALL

Yescarta (Gilead) - DLBCL

JCAR-014 (Celgene) - ALL

JCAR-015 (Celgene) - ALL

Yescarta (Gilead) - ALL

JCAR-014 (Celgene) - CLL

JCAR-014 (Celgene) - NHL

JCAR-015 (Celgene) - NHL

AXAL (Advaxis) - Uterine

cervix tumor

Rivogenlecleucel (Bellicum) - ALL

Rivogenlecleucel (Bellicum) - AML

Yescarta (Gilead) - CLL

ProTmune (Fate Tpx) - General

heme malignancies

Rivogenlecleucel (Bellicum) -

General heme malignancies

Toca 511 & Toca FC (Tocagen) -

GBM

Toca 511 & Toca FC (Tocagen) -

Glioma

LN-144 (Iovance) - H&N Cancer

LN-144 (Iovance) - Melanoma

bb2121 (bluebird bio) - MM

Liso-cel (Celgene) - NHL

LN-144 (Iovance) - NSCLC

Eltrapuldencel-T (Neostem) -

Melanoma

Approximate WW Approval Timeline Estimates – Oncology

ADVTX Development Activity Moving

Towards Solid Tumors from Early Wins in

Heme Malignancies

MAGE-A10 (Adaptimmune) - Melanoma

MAGE-A4 (Adaptimmune) - Melanoma

Pexa-Vec (Transgene) - Melanoma

AUTO2 (Autolus) - MM

GSK3377794 (GSK) - MM

JCARH125 (Celgene) - MM

Avelumab-haNK (NantKwest) -

Neuroendocrine Tumor

AUTO1 (Autolus) - NHL

AUTO3 (Autolus) - NHL

Avelumab-haNK (NantKwest) - NHL

Avelumab-haNK (NantKwest) - NSCLC

GSK3377794 (GSK) - NSCLC

LN-145 (Iovance) - NSCLC

MAGE-A10 (Adaptimmune) - NSCLC

MAGE-A4 (Adaptimmune) - NSCLC

Avelumab-haNK (NantKwest) - Ovarian

Cancer

FATE-NK100 (Fate Tpx) - Ovarian Cancer

GSK3377794 (GSK) - Ovarian Cancer

LN-145 (Iovance) - Ovarian Cancer

MAGE-A4 (Adaptimmune) - Ovarian

Cancer

Avelumab-haNK (NantKwest) -

Pancreatic Cancer

Tabelecleucel (Atara) -

Lymphoproliferative disease

GSK3377794 (GSK) - STS

LN-145 (Iovance) - STS

MAGE-A4 (Adaptimmune) - STS

Pexa-Vec (Transgene) - STS

AUTO2 (Autolus) - Solid tumor

FATE-NK100 (Fate Tpx) - Solid tumor

Pexa-Vec (Transgene) - Solid tumor

Avelumab-haNK (NantKwest) - SCC

MAGE-A4 (Adaptimmune) - Stomach

tumor


Outside Oncology, Rare Disease Focused Biopharmas Are Increasingly Dependent on Sourcing ADVTXs

47%

19%

12%

8%

5%

4%3%

WW Clinical-Stage Rare Disease Pipeline by Therapeutic Modality*

Small molecule Protein/Peptide

Antibody Viral gene therapy

Oligonucleotide Gene modified stem cell therapy

Gene unmodified stem cell therapy Gene modified adoptive cell therapy

Gene unmodified adoptive cell therapy Other**

CHBC Analysis, Cortellis Clarivate Analytics

*Exclusive of infectious disease and cancer indications

**Other includes microbiome/bacterial replacement agents

0

5

10

15

20

25

30

35

40

Clinical Stage ADVTX Delivery Technology & Payload by TA (n=207)

Non-viral Other / UndefinedViral Other / UndefinedNon-viral Gene Knockdown / SilencingViral Gene Knockdown / SilencingNon-viral Gene EditingViral Gene EditingNon-viral Gene Addition / AugmentationViral Gene Addition / Augmentation

Wide Array of ATVTXs for Regenerative Medicine and Rare Monogenetic Diseases Are Expected to be Commercialized in Next Few Years

CHBC Analysis, Clarivate Analytics Cortellis, EvaluatePharma

2018 & Earlier 2019 2020 2021 & 2022 ALONE

DCCI-10 (Cytori) - Burns

NSR-REP1 (NightstaRx) - Choroideremia

AT342 (Audentes) - Criggler-Najjar

ATA230 (Atara) - CMV infections

Donaperminogene seltoplasmid (ViroMed) - DFU

OpRegen (BioTime) - Dry AMD

KB103 (Krystal Biotech) - EB

QRX-313 (ProQR Therapeutics) - EB

RGX-501 (REGENXBIO) - FH

SPK-8011 (Spark) - Hemophilia A

AMT-061 (uniQure) - Hemophilia B

Fidanacogene elaparvovec (Spark) - Hemophilia B

MYO-102 (Sarepta) - LGMD


Donaperminogene seltoplasmid (ViroMed) - PAD

AGN-151597 (Allergan) - RP

QRX-421 (ProQR Therapeutics) - RP

Habeo (Cytori) - Scleroderma

DTX301 (Dimension) - UCDs

ABO-201 (Abeona) - Batten's Disease

SGT-001 (SolidBio) - DMD

FCX-007 (Fibrocell Science) - EB

DTX401 (Dimension) - GSD

RGX-121 (REGENXBIO) - Hunter Syndrome

SB-913 (Sangamo) - Hunter Syndrome

Sepofarsen (ProQR Therapeutics) - LCA




ATA188 (Atara) - MS

CAP-1002 (Capricor Inc) - MI

AlloJoin (Cellular Biomedicine) - OA

CLBS12 (Caladrius) - PVD

MULTISTEM (Athersys) - RDS

ReN003 (ReNeuron) - RP

FCX-007 (Fibrocell Science) - Scleroderma

CTX001 (CRISPR Tpx) - SCD

AST-OPC1 (BioTime) - Spinal Cord Injury

RGX-314 (REGENXBIO) - Wet AMD

Epicel (Vericel) - Wounds

BIO4 (Osiris Therapeutics) -

Bone repair

Grafix (Osiris Therapeutics) –

DFU, Wound Healing

Cartiform (Osiris Therapeutics)

- Musculoskeletal Disorders

Remestemcel-L (Mesoblast) -

GvHD

MACI (Vericel) - Bone repair

Luxturna (Spark) - LCA

Alofisel (Takeda) - Crohn's

Lenti-D (bluebird bio) - ALD

Zynteglo (bluebird bio) - Beta

Thalassemia

RVT-802 (Enzyvant) - DiGeorge

syndrome

EB-101 (Abeona) - EB

ECCI-50 (Cytori) - ED

ECCO-50 (Cytori) - OA

Zolgensma (Novartis) - SMA

ECCI-50 (Cytori) - UI

AGIL-AADC (PTC) - AADC Deficiency

NurOwn (BrainStorm) - ALS

Rivogenlecleucel (Bellicum) - Bone

marrow transplant

StrataGraft (Mallinckrodt) - Burns

SPK-7001 (Spark) - Choroideremia

MPC-06-ID (Mesoblast) - Back Pain

MPC-150-IM (Mesoblast) - CHF

Rexlemestrocel-L (Mesoblast) - CHF

Rexmyelocel-T (Rexgenero) - Diabetic

complication

ATIR-101 (Kiadis Pharma) - GvHD

ProTmune (Fate Tpx) - GvHD

Rivogenlecleucel (Bellicum) - GvHD

Valoctocogene roxaparvovec

(BioMarin) - Hemophilia A

RGX-111 (REGENXBIO) - Hurler

GS-010 (GenSight) - LCA

AT132 (Audentes) - Myotubular

Myopathy

PLX-PAD (Pluristem) - PAD

Rexmyelocel-T (Rexgenero) - PAD

ABO-102 (Abeona) - Sanfillipo

StrataGraft (Mallinckrodt) - Wounds

MULTISTEM (Athersys) - Stroke

SB623 (SanBio) - TBI

Approximate WW Approval Timeline Estimates – Non-Malignant Indications

ADVTX Development Activity Spreads

Across Multitude of Therapeutic Areas


Beyond Large M&A Activities Most Rare Disease Focused Companies Have Already Invested in ADVTX Platforms

Company Mkt Cap Asset : Indication Modality Phase Partners

Biogen $64.5B

Spinraza : SMA Antisense Mkt Ionis

BIIB087 : X-linked Retinoschisis AAV P2 AGTC

BIIB080 : Alzheimer’s Antisense P1 Ionis

Shire/Takeda $61B SHP654 : Hemophilia A AAV8 P1/2 Chatham Therapeutics

Vertex $44.8BCTX001 : Beta-thalassemia Edited HSC P1

CRISPR TherapeuticsCFTR-mRNA : Cystic Fibrosis mRNA PC

Biomarin $17.2BBMN270 : Hemophilia A AAV P3 -

BMN307 : PKU AAV PC -

Ultragenyx $2.7BDTX301 : OTC Deficiency AAV P1 Dimension

TherapeuticsDTX401 : GSD Type 1a AAV P1

PTC $2.4B GT-AADC : Aromatic L-Amino Acid Decarboxylase Deficiency AAV P3 Agilis

Amicus $2.1B

CLN6 Gene therapy : Batten AAV P2

CelenexAAV Gene therapy : Niemann-Pick C AAV PC

AAV Gene therapy : Wolman AAV PC

Ipsen $8.9B

Recordati $7.0B - - - -

Horizon Pharma $4.5B - - - -

Retrophin $0.9B


Favorable US/EU Regulatory Environments Are Compressing Regulatory Review Timelines – Necessitating Rapid Scientific to Commercial Transition

1990 1995 2000 2005 2010 2015 2020 2025

Strimvelis (Orchard)

Luxturna (Spark)

Spinraza (Biogen)

Onpattro (Alnylam)

Lentiglobin (bluebird)

AVXS-101 (AveXis)

jCell (jCyte)

NSR-REP1 (NightstaRx)

ABO-102 (Abeona)

DTX301 (Ultragenyx)

EB-101 (Abeona)

OTL-101 (Orchard)

RVT-802 (Roivant)

AT132 (Audentes)

Sample ADVTX Asset Development Timeline

IND to PoC PoC to Approval / Expected Approval

CHBC Analysis; Adis R&D Insight; Clarivate Analytics Cortellis

Approved Products

In Development

RMAT Designation


ADVTX Business Models Encounter Unique Risks in Healthcare Delivery Compared to Conventional Therapeutics

• Clinical Development: Need for novel development paths (endpoints)

• Regulatory: History of stringent agency scrutiny, Now RMAT expedites development timeline

• Manufacturing / Scalability: Complex manufacturing processes, lack of standardization (Individualized vs. Off-the-Shelf), high COGS, issues with delivery, stability and batch purity

• Traditional Biopharma Commercial Model Does Not Apply: revenue sustainability concerns for curative therapy, value-based pricing approaches now emerging

• Complex Business Development Issues: Intricate IP and royalties ownership

CHBC Insight


At the forefront is Significant Payer Value Uncertainty of ADVTXs

Therapeutic Challenges Analysis, 2016, Compass Strategic Consultants

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

• Pharma and biotech companies suggest annuity programs – may be practically impossible today in most health systems


Industry Explores Novel Reimbursement Models For Curative TherapiesBrand Company Indication Price Pricing Strategy & Current Status

Glyberra

(2012)

Lipoprotein lipase

deficiency patients who

have acute and chronic

pancreatitis attacks

$1M+• High upfront payment, no durability data

• Product withdrawn, with <5 patients treated

Strimvelis

(2016)

ADA-SCID or “bubble boy

syndrome”

$714,000

(£594,000)

• Money back guarantee and pay-for-performance

• Reimbursement and payment hurdles limit use

• Divested to Orchard in April 2018, despite # of treated

patients in line with projections

Kymriah

(2017)

B-cell precursor ALL for

patients <25 years

$475,000 ALL

$373,000 DLBCL

• R/R ALL outcomes-based reimbursement model - full

payment with response 30 days post-Tx

• No outcomes-based concessions in R/R DLBCL

Yescarta

(2018)

Relapsed/refractory large

B-cell lymphoma, including

DLBCL

$373,000 DLBCL

• On par w/competitor’s price, but not value-based

• Despite 2nd CAR-T approved in US, CMS & some

private insurers still lack billing codes for CAR-Ts

Luxturna

(2018)

Confirmed biallelic RPE65

mutation-associated retinal

dystrophy

$850,000 or

$425,000/eye

• Outcomes-based rebate linked to DoR

• Installment payment negotiated with CMS with greater

rebates tied to clinical outcomes;

• “Buy and Bill” contracting with commercial payers

LentiGlobin(est. 2019 EU,

2020 US)

Beta thalassemiaestimated at

$900K-$1.2M

• 20% up front, with subsequent annual 20%

installments paid by insurer if efficacious


ADVTX Becoming Essential To Rare Disease, But Diversification is Imperative For Sustainability

• 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 only from few very small number of newly diagnosed patients entering treatment eligibility • Continued speed of innovation and aggressive BD/M&A needed to support pipeline that delivers new “curative” products

to new rare disease populations every 4-5 years or less

EvaluatePharma

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1200

1400

1600

1800

2017 2018 2019 2020 2021 2022 2023 2024Wo

rld

wid

e P

rod

uct

Sale

s:

US

$ (

mln

)

Luxturna (Spark)

NVS SPTX

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

30%

40%

50%

0

200

400

600

800

1000

1200

1400

1600

1800

2017 2018 2019 2020 2021 2022 2023 2024

Sale

s G

row

th (

%)

WW

Pro

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ct

Sale

s:

US

$ (

mln

)

Zolgensma (AveXis)

Sales (New molecular entity)

Ann. Growth (New molecular entity)

0

200

400

600

800

1,000

1,200

1,400

1,600

1,800

2018 2019 2020 2021 2022 2023 2024

(US

$ (

mln

))

Zinteglo (bluebird)

Zynteglo (bluebird bio (Sickle cell disease))

Zynteglo (bluebird bio (Thalassaemia))


Questions for Panel

1. Why is ADVTX such a hot sector for VC financing, IPOs and Biopharma acquisitions/partnerships? What is driving valuations?

2. What has changed with regulatory agencies to facilitate accelerated review and approval based on data from limited patient exposure? What opportunities and challenges does this present?

3. How are the risks associated with developing and commercializing ADVTXs different than conventional therapeutic?

4. What are scientifically focused biotechs doing upon establishing PoC to prepare for healthcare delivery and commercializing their ADVTX?

5. How are ADVTX business models emerging to mitigate the unique risks of manufacturing, logistics and reimbursement?


Implementing Strategic Development and Innovating Disruptive Business Models for Transformative Cell and Gene Therapies

Moderator: Michael C. Rice, Principal, Cello Health BioConsulting

Panelists:• Sam Hall, Partner, Apple Tree Partners• RA Session, Chief Business Officer, BridgeBio-Gene Therapy• Jean-Philippe Combal, Co-Founder & CEO, Vivet Therapeutics• Chip Baird, Chief Financial Officer, bluebird bio

Implementing Strategic Development and Innovating ... · •High upfront payment, no durability...

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