Developing drugs and building companies to treat rare diseases���

Professor Harvey Lodish Whitehead Institute for Biomedical Research Departments of Biology and Biological Engineering, MIT

My involvement with start-up companies

•  1961 Carl Djerassi and Syntex SA •  1979 Damon Biotech •  1979 BioInformation Associates •  1981 Genzyme •  1993 Milennium Pharmaceuticals •  2005 Allozyne •  2013 Rubius

•  2006 - Founding Chair, Scientific Advisory Board of the Massachusetts Life Sciences Center, the group charged with oversight of the state’s 10- year $1 billion investment in life sciences.

• Genzyme: Gaucher Disease���• Rubius: Harvey’s new company ���

• The Massachusetts biotech ecosystem���• The Massachusetts Life Sciences Center���

• Genzyme: Gaucher Disease���• Rubius: Harvey’s new company ���

• The Massachusetts biotech ecosystem���• The Massachusetts Life Sciences Center���

Genzyme’s Initial Products

•  Products in the Koch-Light catalog •  Hyaluronic acid •  Ceredase and Cerezyme – Enzyme

replacement therapies for Gaucher Disease

Hyaluronic acid, Nature’s lubricant

Applications of Hyaluronic Acid (HA)-based biomaterials

• Pain relief for of knee osteoarthritis

• Cataract surgeries

• Abdominal and pelvic surgeries

• Dermal filler to erase facial wrinkles.

Captique Injectable gel���A dermal filler product based on Genzyme's hyaluronic

acid (HA) technology.

Captique, a clear gel containing a purified form of hyaluronic acid, adds volume lost during the aging process by temporarily smoothing out facial lines and wrinkles.

Captique is injected just under the skin’s surface in order to temporarily correct wrinkles.

It is indicated for the correction of moderate to severe facial wrinkles and is manufactured by Genzyme.

Gaucher Disease – Symptoms

•  Gaucher is a progressive, debilitating and sometimes life-threatening disease.

•  Symptoms can include:���easy bleeding and bruising, fatigue, anemia, weak bones, bone and joint pain, and enlargement of the spleen ���or liver.

•  Symptoms can appear at any age.

Gaucher Disease

Gaucher Disease

Enzyme Replacement Therapy for Gaucher Disease

• Replacement enzyme is targeted to

macrophages via the macrophage

mannose receptor, internalized by

receptor- mediated endocytosis, and

delivered to lysosomes

Lodish Figure 2

Lodish, H.F. Post-translational modification of proteins. Enzyme and Microbial Technology 3: 178-188 (1981).

Structure of asparagine- linked oligosaccharides attached to yeast cell surface proteins

ClcNAc = N Acetyl glucosamine

M = Mannose

Phagocytosis of yeast cells by macrophages and transfer of the endocytosed particles to lysosomes utilizes macrophage cell

surface mannose receptors

ASCB Image & Video Library

Enzymic formation of the modified mannose- terminal N-linked oligosaccharides on Ceredase™ and Cerezyme™ that target injected

glucocerebrosidase protein to the macrophage mannose receptor, where it is internalized by endocytosis and transported to lysosomes

1) Neuraminidase 2) ß- Galactosidase 3) ß- N-acetylglucosaminidase

• Genzyme: Gaucher Disease���• Rubius: Harvey’s new company ���

• The Massachusetts biotech ecosystem���• The Massachusetts Life Sciences Center���

Rubius: Genetically and chemically modified red blood cells: ���

Novel therapeutics and immunomodulatory agents

20

•  Lack nucleus and mitochondria: no remnants of exogenous genes •  Long lifespan: 120 days in blood stream •  Hemoglobin, cytosolic, membrane, cytoskeletal proteins, and

metabolism well- characterized •  Large cell surface area and excellent biocompatibility •  Genes can be ectopically expressed or knocked out at will in

cultured erythroid progenitor cells •  Blood transfusion is a widely used therapeutic

Red cells are an attractive vehicle introducing therapeutics & diagnostics into the human body

1.  Equip erythrocytes with single- chain antibodies that neutralize foreign pathogens or toxins

2.  Equip erythrocytes with receptors that bind and remove pathological macromolecules (LDL, immune complexes)

3.  Equip erythrocytes with protein or nonprotein sensors that serve as targeting devices

Adding unique functional modalities to red cells:

Nova Pishesha, Nai-Jia Huang Jiahai Shi, and Sherry Lee, in collaboration with members of Hidde Ploegh’s lab

We developed a 21- day culture system for human peripheral blood CD34+ stem/progenitor cells that generates normal enucleated red blood cells

1

10

100

1000

10000

100000

0 5 10 15 20 25

Expt 1 Expt 2

Fold

Exp

ansi

on

Days in Culture

Cultured Reticulocytes

Normal hRBCs

HbA 92.81% 95.24%

HbF 4.97% 2.58%

HbA2 2.23% 2.17%

Sortase as a labeling tool

R1 and R2 can be: •  proteins

•  peptides

•  lipids •  small molecules/functional probes

Cell surface C-terminal labeling of Kell, a Type-II red cell membrane protein

Single-domain antibodies- VHHs

VHH

Schematic of conventional Ab Schematic of camelid hcAb

Tagged VHH (14 KDa)

Conventional antibody (Ab)

http://www.structuralbiology.be/chaperones

Heavy-chain only antibody (HcAb)

Botulinum neurotoxin (BoNT)

•  Cleaves SNARE proteins and inactivates exocytosis of neurotransmitters

•  Causes botulism, a potentially lethal flaccid paralysis

•  Seven different BoNT serotypes (A to G) •  Polyclonal antitoxin sera are available to treat

infants (BabyBIG) or adults (HBAT) •  Co-administration of several monoclonal

antibodies (mAbs) are needed for clearance

A chimera of two BoNT/A VNAs with the extracellular domain of human glycophorin A is functionally expressed on the red cell surface

Signal  pep*de  

Myc     Linker   VHH1:  H7     Spacer  (36  a.a.)  

VHH  2:  B5     Linker    Glycophorin  A    

Install on the surface of red blood cells:

•  Butyrylcholinesterase (BCA): Inactivate nerve gas

•  LDL-binding domain of the LDL receptor: remove cholesterol- filled lipoprotein particles

•  Urokinase Plasminogen Activator (UPA): dissolve blood clots in acute care settings ���

29

30  

September 13, 2014 – Whitehead Scientific Retreat Waterville Valley NH

• Genzyme: Gaucher Disease���• Rubius: Harvey’s new company ���

• The Massachusetts biotech ecosystem���• The Massachusetts Life Sciences Center���

There are over 150 biotech/pharma companies located in Cambridge and Boston – an incredible concentration.

There are nearly 400 biotech/pharma establishments located outside of Boston and Cambridge in Massachusetts.

Massachusetts has over 550 biopharmaceutical companies

Source: MassBio Industry Trade Association 2012

Massachusetts has 400 medical device companies

–  Medical devices are the state’s #1 export (13% of all MA exports)

Source: “The Medical Device Industry in Massachusetts” by Deloitte, 2011 Massachusetts Export Center

Massachusetts employs the second highest number of medical technology workers in the U.S.

  24,268 employees in 2008

  82,500 jobs in related Massachusetts industries.

2006 2010

Massachusetts’ venture capital dollars encourage company start-ups

Massachusetts consistently receives a high percentage of all U.S. venture capital biotech investment

Investments in start-up and seed-stage companies have increased dramatically

Source: 2013 PricewaterhouseCoopers, National Venture Capital Association, MoneyTreeTM Report, Historical Trend Data, MassBio analysis “The Medical Device Industry in Massachusetts” by Deloitte, 2011 Massachusetts Export Center

2002

4.8% 21.9% 5.4%

12.0%  

15.9%  

19.5%  16.9%  

20.8%  23.1%  

21.0%  

0%  

5%  

10%  

15%  

20%  

25%  

2000   2002   2004   2006   2008   2010   2012  

Massachusetts has abundant laboratory space….���

…. Since 2007, 2.6 million square feet of commercial lab space has been added to the state’s inventory, and the pace of growth is accelerating.

Source: Colliers Meredith & Grew, Life Science Review, 2007-2013 Courtesy of MassBio Industry Trade Association 2013

16,064,000 17,021,000

18,437,000

2007 2009 2011 2013

18,687,000

…and incubator space to support the growth of new life sciences companies across the state

Cape Ann Business Incubator

Massachusetts Biomedical Initiatives

Tufts University Biotechnology Transfer

Center

UMass  Boston  

Barry  Bluestone  Director,  Dukakis  Center  for  Urban  And  Regional  Policy  

Alan  Clayton-­‐Ma5hews  Senior  Research  Associate,  Dukakis  Center  

May  29,  2013  

The  “BoTom  Line”  Life  Sciences  Center’s  Impact:    Crea*ng  Economic  Opportunity  

Sources: B. Bluestone and A. Clayton-Matthews, Life Sciences Innovation as a Catalyst for Economic Development: The Role of the Massachusetts Life Sciences Center (March 2013)

Es*mated  Annual  Earnings  for  Life  Sciences  Workers  (2006-­‐2010)  

The proliferation of small mainly start-up firms in biopharmaceuticals, medical devices, and diagnostics has helped attract 10 of the top 10 global leaders in pharmaceutical research and development to establish major research units in Massachusetts:

Pfizer, Novartis, Johnson & Johnson, Sanofi, AstraZeneca, Abbott Laboratories, Merck, Bristol-Myers Squibb, Roche, and Baxter

The Massachusetts Life Sciences Center���

•  A quasi- state agency •  Supporting and expanding the Life Sciences

industry in Massachusetts

•  Workforce development •  Creation of well- paying jobs •  Development of new drugs, diagnostic tests,

medical devices for the benefit of all

•  $100,000,000 per year for 10 years

Life Sciences Initiative Investments

•  10 years •  $1 billion investment

$250m Investment Fund ���(subject to appropriation)

Sources: B. Bluestone and A. Clayton-Matthews, Life Sciences Innovation as a Catalyst for Economic Development: The Role of the Massachusetts Life Sciences Center (March 2013)

The  “BoTom  Line”  Life  Sciences  Center’s  Impact:  Return  on  the  MLSC  Tax  Incen*ves  

Program  

Does not include any “Multiplier Effects”

The MLSC is a Public-Private Partnership, Governed by a Multi-Disciplinary Board of Directors

•  Secretary of Housing and Economic Development –  Gregory Bialecki

•  Secretary of Administration and Finance

–  Glen Shor •  President of University of Massachusetts System

–  Robert Caret, Ph.D.

•  A researcher involved in the commercialization of biotechnology, pharmaceuticals or medical diagnostic products –  Adeline Perkins, President and CEO, Infinity Pharmaceuticals

•  A physician licensed to practice medicine in the Commonwealth and affiliated with an academic medical center –  Edward Benz, M.D., President & CEO, Dana-Farber Cancer Institute

•  A person with financial expertise in the life sciences

–  Joshua Boger, Ph.D., Founder & CEO (Retired), Vertex

The MLSC Scientific Advisory Board FY ‘13 CHAIR: Harvey Lodish, Ph.D., ���

Whitehead Institute and Massachusetts Institute of Technology (MIT)

•  James J. Collins, Ph.D., Boston University

•  John M. Collins, Ph.D., Center for Integration of Medicine & Innovative Technology (CIMIT)

•  Robert D’Amato, M.D., Ph.D., Center for Macular Degeneration Research , Harvard Medical School and Boston Children’s Hospital

•  Rainer Fuchs, Ph.D., ���Harvard Medical School

•  Glenn R. Gaudette, Ph.D., ���Worcester Polytechnic Institute (WPI)

•  Judith Lieberman, Ph.D., ���Immune Disease Institute, Boston Children’s Hospital and Harvard Medical School

•  Lita L. Nelsen, ���Massachusetts Institute ���of Technology (MIT)

•  Barbara Osborne, Ph.D., ���UMass Amherst

•  Guillermo Tearney, M.D., Ph.D., ���Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology (HST) and Massachusetts General Hospital

•  David Walt, Ph.D., ���Tufts University School of Medicine

•  Philip Zamore, Ph.D., ���UMass Medical School

Academia •  Kevin Bitterman, Ph.D.,���

Polaris Venture Partners

•  T. (Teo) Dagi, M.D., M.B.A.,���HLM Venture Partners

•  Jonathan Fleming, M.P.A.,���Oxford Bioscience Partners

•  Henry Kay, ���Boston Harbor Angels

•  Carmichael Roberts, Ph.D., M.B.A., ���North Bridge Venture Partners

•  Lauren Silverman, Ph.D., Novartis Option Fund

Venture Capital

•  James Barry, Ph.D., ���Arsenal Medical

•  Dalia Cohen, Ph.D.,���ALN Associates

•  José-Carlos Gutiérrez-Ramos, Ph.D., ���Pfizer

•  Dale Larson,���Draper Laboratory

•  Alan Smith, Ph.D., ���Formerly of Genzyme, a Sanofi Company

Industry

•  Alison Taunton-Rigby, Ph.D. ���RiboNovix, Inc.

Entrepreneurs

•  Business Plan Competitions: –  Funded $545,000 in sponsorships

•  Accelerator Program: –  Working capital for early-stage life

sciences companies –  $17.7 million in loans awarded to 27

early-stage companies

•  SBMG Program: –  Funding to match federal small

business grants (SBIR & STTR)

–  $4 million awarded to eight life sciences companies

•  Tax Incentive Program: –  Incentives for companies to locate

and grow jobs in MA

–  MLSC can commit up to ���$25 million/year

–  103 active awards totaling ���$93 million to companies that have created or are promising to create more than 3,800 jobs

Objective: Provide funding and incentives to accelerate the formation and growth of life sciences companies in Massachusetts

Helping Life Sciences Companies Grow

  Center for Salivary Diagnostics at the Forsyth Institute

  Children’s Center for Cell Therapy at Children’s Hospital

  Emerging Technologies and Innovation Center at UMass Lowell

  Gateway Park in Worcester

  “Hall of Human Life” at Boston Museum of Science

  Holyoke Community College: Clean Room

  Joint Center for Personalized Cancer Therapy at UMass Boston

  LabCentral in Kendall Square

  Loeb Lab at the Marine Biological Laboratory (Renovation)

  Massachusetts Accelerator for Biomanufacturing (MAB) at UMass Dartmouth

  Molecular Cancer Imaging Center at Dana-Farber

  New England Regional Biosafety Laboratory at Tufts’ Cummings School of Veterinary Medicine

  Albert Sherman Center at UMass Medical School

  Systems Pharmacology Lab at Harvard Medical School

  Translational Center for the Cure of Diabetes at Joslin Diabetes Institute

Capital projects: Investments in infrastructure

  New MLSC program for:   Vocational technical schools   Community colleges   Workforce training organizations

  Awards grants of up to $250,000 per institution for equipment and supplies that support life sciences training

  Industry match is required for funding above $100,000

  First round of awards made on Feb 23rd 2011

  Awards made to 32 institutions across Massachusetts; $3.4 million investment

 Over $600k in additional “matching” funds provided by industry sponsors

Supporting workforce development in classrooms

Equipment & Supplies Program for Skills Training and Education

Banafsheh Salamat, head of the Science Department at Lynn Vocational Technical Institute, after receiving a shipment of lab equipment and supplies from Vertex Pharmaceuticals. Vertex matched with an in-kind contribution the Center’s recently announced Equipment and Supply Grant for LVTI.

Supporting Workforce Development in the Real World:���

Internship Challenge Program���Funds interns working at Massachusetts companies with fewer than 100 employees Over 1,306 internships placed

145 different colleges and universities represented

356 companies have participated Over $9 million committed to the program to date More than 160 participating interns have been offered full or part-time jobs at the conclusion of their internships