The Science and Business of Biotechnology

15.480x

Professor Harvey Lodish

Departments of Biology and Biological Engineering

Professor Andrew W. Lo
Sloan School of Management
Although I have helped start several successful biotechnology companies, at heart I
am a cell and developmental biologist focused on understanding basic life
processes
• 1979 Damon Biotech
• 1979 BioInformation Associates
• 1981 Genzyme
Sold to Sanofi for $20.2 billion
• 1983 Arris (now Axys) Pharmaceuticals
• 1993 Millennium Pharmaceuticals
Sold to Takeda for $9 billion
• 2005 Allozyne
• 2014 Rubius
Initial public stock offering July 2018
• 2017 Tevard
• 2019 Carmine

From 2007 to 2016 I was the Founding Chair of the Scientific Advisory Board of the Massachusetts Life
Sciences Center, the group charged with oversight of the state’s 10-year $1 billion investment in
the life sciences.

Since 2007 I have served on the Board of Trustees of Boston Children’s Hospital and have been the
Chair of the Board Research Committee
New types of therapeutics are entering clinical practice and form the basis of
successful companies

• Small molecule drugs

• Proteins as therapeutics (~1980)
Recombinant therapeutic proteins
Monoclonal antibodies
• Cell therapies (~2010)
Replacement cells (e.g. pancreatic islets)
Engineered cells (e.g. red blood cells expressing new proteins; anti-cancer T cells)
• Nucleic acid therapies (~2010)
• Gene therapies (~2010)
• Gene editing (~2020?)
U0b: Introduction to drug development;
U1a: Therapeutic recombinant proteins
U2a: Gene therapy: Adeno Associated Viral (AAV) vectors
U3a: Gene therapy: Retroviral and lentiviral vectors;
Disorders of the blood-forming system
U4a: Nucleic acid therapies
U5a: Gene editing
U7a: Basic immunology – antibody properties and generation
U8a: Therapeutic monoclonal antibodies
U9a: Cancer immunotherapies
U10a: New types of cell therapies
 Unit 0
Introduction to Drug Development

• Building the Cambridge biotechnology ecosystem

• Developing therapeutics for rare diseases
• Small molecule drugs
 Unit 0
Introduction to Drug Development;

• Building the Cambridge biotechnology ecosystem

• Developing therapeutics for rare diseases
• Small molecule drugs
 Developing cures for many diseases requires
intense collaborations:
Not for profit:
• Academic laboratories researching the underlying basic cellular and molecular biology
• Medical centers and research hospitals studying the disease or condition
• Government support of research and development
• Patient or disease based national or international organizations
• Philanthropic support of research and development
GOAL: One or more candidate drugs that work in cell cultures and/or experimental animals

For profit:
• Venture capital
• Patient or disease based organizations
• Small to medium sized biotech companies
• Multinational biopharmaceutical companies
GOAL: An FDA- approved drug that is available to all patients
 Developing cures for most diseases requires intense
collaborations and costs a considerable amount of money.
Universities,
Institutes,
Medical Companies
Centers

Patent Filing Launch

1250 Drug Discovery Drug Development and Clinical trials

1000
Annual Net Cash Flow

Initial Research and Preclinical Phase I Phase II Phase III FDA/510k

Development, Drug and safety Review
750 Identification tests Approval
(in millions)

Public
Equities
500 Corporate & Debt
Grants Venture Venture Mezzanine
and Funding Funding Financing
250 Angels Public
Equities &IPO
Time in Market
0 Funding Gap Funding Gap
Highest Risk Medium Risk Medium Risk Lowest Risk &
-250 & Lowest & Low or & Medium Highest
Valuation Medium Valuation Valuation
Valuation
-500
New types of therapeutics are entering clinical practice and form the basis of
successful companies

• Small molecule drugs

• Proteins as therapeutics (~1980)
Recombinant therapeutic proteins
Monoclonal antibodies
• Cell therapies (~2010)
Replacement cells (e.g. pancreatic islets)
Engineered cells (e.g. red blood cells expressing new proteins; anti-cancer T cells)
• Nucleic acid therapies (~2010)
• Gene therapies (~2010)
• Gene editing (~2020?)
The basics of starting a successful biotechnology
company
• Entrepreneurial faculty and a collaborative entrepreneurial environment.
• A top Scientific Advisory Board and Board of Directors
• Experienced biopharmaceutical leaders and workers
• Proprietary and protected intellectual property
• A solid business plan
• Solid financial backing, usually by venture capital
• Supportive infrastructure including a helpful government and regulatory
environment
Policies of most U.S. research universities encourage faculty
members to become entrepreneurs

• One day per week “Outside Professional Activity”

– For - profit companies
– Not - for - profit organizations
• Faculty can consult for and own stock in companies but
cannot be an operating officer
• Clear conflict of interest rules
Entrepreneurial MIT faculty generate a collaborative entrepreneurial
and teaching environment.
• A culture of faculty entrepreneurs
• Experienced serial entrepreneurs
• Mentors of young faculty
• Entrepreneurship courses for faculty and students
• Finance
• Marketing
• Intellectual property
• Human resources
• New graduate course “Science and Business of Biotechnology”
• Business and Economics
• Biological and Chemical Engineering
• Biology
Geography is important. MIT, the Whitehead Institute, and the Broad Institute are at the
epicenter of Kendall Square and its several hundred biotechnology and pharmaceutical
companies

Courtesy of Biomed Realty Trust

2012
Kendall Square 1975 – just across Main Street from MIT – a polluted
industrial wasteland.
The Whitehead Institute was the pioneer in Kendall Square
The Whitehead Institute at MIT 1983
Over half of the faculty members of the Whitehead Institute started
publicly traded biotech companies during the past 10 years

• FoldRx- acquired by Pfizer (Susan Lindquist)

• Computational Biology Company - acquired by Agilent (Rick Young)
• Alnylam Pharmaceuticals (David Bartel)
• Verastem (Bob Weinberg, Piyush Gupta)
• Syros Pharmaceuticals (Rick Young)
• Fate Therapeutics (Rudolf Jaenisch)
• Ironwood Pharmaceuticals (Gerry Fink)
• Rubius (Harvey Lodish and Hidde Ploegh)

Whitehead Institute for Biomedical Research

Eric Lander at the Whitehead led the Human
Genome Project
In turn the Whitehead Human Genome Project gave
birth to the Broad Institute
 Geography is important:
MIT and the Whitehead and Broad Institutes form the epicenter of an ecosystem of
biotech, pharmaceutical, and venture capital firms
Whitehead Institute for
Biomedical Research

Rubius Lab Central Flagship

Incubator Ventures
The basics of starting a successful biotechnology
company
• Entrepreneurial faculty and a collaborative entrepreneurial environment.
• A top Scientific Advisory Board and Board of Directors
• Experienced biopharmaceutical leaders and workers
• Proprietary and protected intellectual property
• A solid business plan
• Solid financial backing, usually by venture capital
• Supportive infrastructure including a helpful government and regulatory
environment
 Incubator space supports the growth of new life sciences companies across
Massachusetts

Tufts University
Biotechnology Transfer
Center

UMass Boston

Massachusetts
Cape Ann Business
Biomedical Initiatives
Incubator
 Lab Central – supported by the Massachusetts Life Sciences Center

A model incubator for start-up biotechnology companies including Rubius and Tevard:
Shared open laboratory space
Lab Central – a model incubator for start-up biotechnology
companies:
Private laboratories for ~10 researchers
 Unit 0
Introduction to Drug Development

• Building the Cambridge biotechnology ecosystem

• Developing therapeutics for rare diseases
• Small molecule drugs
 A major unmet medical need:
In aggregate rare diseases affect an estimated 25 to 30 million
people in the United States

• Definition: Any disease or condition that affects fewer than 200,000 people in the
United States or 500,000 in China

• There are more than 6,800 rare diseases

• Similar to the United States, Europe has approximately 30 million people living
with rare diseases.

• It is estimated that 350 million people worldwide suffer from rare diseases

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 Some examples of rare diseases:
Most have been identifiedin Caucasians
• CysticFibrosis
• Phenylketonuria (PKU)
• MuscularDystrophy
• Tay-Sachs
• GaucherDisease
• Beta Thalassemia
• SickleCell Disease
• Familial Hypercholesterolemia
• Progeria
• TouretteSyndrome
• SevereCombinedImmuneDeficiency(Bubbleboy disease)
• Dravet’sSyndrome
• KleefstraSyndrome
 Most rare diseases are of genetic origin and
appear early in life
• 80% of rare diseases are genetic in origin, and thus are
present throughout a person’s life, even if symptoms do not
immediately appear

• Approximately 50% of the people affected by rare diseases

are children

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 Because of consanguineous marriages, every ethnic group has its own
constellation of rare genetic diseases.
Iceland:
Population 300,000; founded 1,100 years ago by between 8,000 and 20,000 people mainly from
Scandinavia, Ireland and Scotland.
• Recessive frameshift mutation in MYL4 (myosin essential light chain) causing early-onset atrial
fibrillation.
• Mutation in ABD B4 (Multidrug resistance protein 3) increasing risk of gallstones

D. Gudbjartsson et.al., Nature Genetics 47, 435 – 444 (2015)

Finland:
• Mutation in SLC26A2 (Sulfate transporter) causing recessive multiple epiphyseal dysplasia
(ED M4/rMED)

J. Hästbacka et. al., Cell 78: 1073 – 1087 (1994)

Many rare diseases can be prevented by
prenatal screening of members of at- risk
ethnic groups

• They test for common, incurable recessive diseases that present serious health
issues or risk of fatality and for which there exists reliable testing methods with
definitive carrier status results.
• They test for 16 diseases affecting Ashkenazic (Eastern European) Jews and 16
diseases common in Sephardic (Western European) Jews.
• Tay-Sachs and other genetic diseases have been virtually eliminated in these
ethnic groups.
 Unit 0
Introduction to Drug Development

• Building the Cambridge biotechnology ecosystem

• Developing therapeutics for rare diseases
• Small molecule drugs
 Proteins - The Working Molecules of Cells and
Organisms

• Enzymes
• Antibodies (Bind foreign objects, such as bacteria)
• Binding (Hemoglobin in red blood cells)
• Transporters (Proteins in cell membranes that enable sugars, salts, and other
molecules to cross)
• Structural (Form the internal cytoskeleton and the extracellular matrix)
• Movement (Contractile fibers in muscle)
 Of Particular Interest To Biotechnology:

Proteins as drug targets:

• Transporters for ions, small molecules
• Hormone, growth factor, and cell adhesion receptors
• Enzymes
• Cytokines and other extracellular signaling proteins
Proteins as drugs
• Monoclonal antibodies
• Hormones
• Modified hormone receptors
A Typical "Small Molecule" Drug:

Aspirin
(Acetyl- Salicylate)
C9 H7 O4
 Aspirin and otherNSAIDs inhibittwocyclooxygenase
(Cox) enzymes
• Prostaglandins
Importantroles in gastricmucosal protection
Majorrole in theinflammatory and immuneresponse

• Cyclooxygenase(Cox), alsoknownasProstaglandinHsynthase.
Rate-limiting enzymein prostaglandin biosynthesis.
Catalyzes theconversionof arachidonic acid toprostaglandins and thromboxane.

• Nonsteroidal anti inflammatory drugs(NSAIDs)

Widely used forthetreatmentof inflammatorydiseases
All irreversibly inhibitCOXs
Significant sideeffects such as gastrointestinal erosion and kidneydamage.
Aspirin
Indomethacin
Ibuprofen
Meclofenamate
Relafen
 Examples of small molecule drugs
All inhibit the function of specific proteins

Enzyme inhibitors:

• Angiotensin converting enzyme (hypertension)

• HIV protease (AIDS)
• Bcr- Abl protein tyrosine kinase (leukemia)
• Prostaglandin synthesis (inflammation)
• cAMP phosphodiesterase (asthma)
• cGMP phosphodiesterase (erectile disfunction)
• HMG CoA reductase (statins, atherosclerosis)
 Examples of small molecule drugs

• Hormone receptor antagonists (inhibitors)

• H2 histamine receptor (ulcer)
• ß1- adrenergic receptor (cardiac)

• Hormone receptor agonists (stimulators)

• ß2- adrenergic receptor (asthma)
• Inhibitors of bacterial enzymes
• Cell wall biosynthetic enzymes (antibiotics)
• DNA topoisomerases (antibiotics)
• Ribosomes (antibiotics)
 Unit 0
Introduction to Drug Development

• Building the Cambridge biotechnology ecosystem

• Developing therapeutics for rare diseases
• Small molecule drugs