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Biotech Boot Camp
Session 5 – Life sciences
Presenter: Nick Weston
Melbourne, Brisbane, Sydney
28 May – 18 June, 2014
This session provides an overview of the global life
sciences sector
Analysis includes key trends in market size & growth,
demand drivers, adoption & scope trends, emerging
themes, key areas of investment, and implications for key
stakeholders
The session also provides specific insights on what is
driving key strategic initiatives in the sector
Session 5 Overview
2
Agenda
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Future trends
• Case Studies and examples
3
Session 5 Overview
Life sciences
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Future trends
• Case Studies and examples
4
Session 5 Overview
Life sciences
The term “life sciences" is used to connote sciences
concerned with the study of living organisms (as opposed
to physical sciences), including biology, botany, zoology,
microbiology, medicine, human therapeutics, veterinary
therapeutics, physiology, the ‘omics’ (eg: proteomics,
genomics), biochemistry, biotechnology, and related
subjects
Basic overview of the life sciences
5
Definition
Basic overview of the life sciences
6
State of play
2003 2014
• Biotechs that wanted to emulate
bigpharma (a build model)
• Bigpharma wants to emulate
biotech (a buy model)
• Small molecule blockbusters • Antibody drug conjugates
• Cell based therapies
• Treatments that regulate or
alter genes
• Trial and error drug projects • Therapies designed to precisely
target molecular drivers
• Treatment of symptoms • Treatment of causes
• Move to curative medicine
• Human Genome Project
completed at cost of $3billion
• Illumina can sequence genome
for <$1,000
Basic overview of the life sciences
7
State of play
¹ Source: Tufts Center for the Study of Drug Development 2013
² Source: Analysis Group, 2013
• Biotech sales have grown from 36B in 2001 to 163B in 2013¹
• 1800 projects with orphan disease designation in development @
Oct 2011
• >5,000 drugs in clinical development (78% in Phase I, 69% in PhII
and 45% in Ph II I are potentially first-in-class)² (Note: by
definition, only one can be ‘first-in-class’)
• FDA approved 27 new drugs in 2013 (see handouts) including
Gilead’s Solvadi, a therapy for hepatitis C virus infection (HCV)
with peak sales forecast by some as much as $12B³ and a sticker
price of $84,000 per course
³ Source: http://www.forbes.com/sites/johnlamattina/2014/03/24/will-the-hep-c-drug-sovaldi-drive-gilead-to-the-top-of-the-
biopharm-industry/
Basic overview of the life sciences
8
State of play
¹ Source: Medecines Sans Frontieres/The Lancet Global Health See http://globalhealth.thelancet.com/2014/04/01/neglected-
tropical-diseases-and-access-medicines-time-think-beyond-drug-donations
• Of 850 new drugs and vaccines approved between 2000 and
2011, just 37 (4%) were for malaria, TB, tropical diseases,
diarrhoeal diseases and diseases of poverty¹
• Industry has moved past the steepest part of the patent cliff –
increased competition from generics and biosimilars
• Trend is outsourced or ‘open’ innovation (eg: GSK $465M +
Avalon Ventures $30M = 10 startups, Celgene $45M + Versant
Ventures = Quanticel, Sanofi + Third Rock Ventures = Warp Drive
Bio $125M)
• Improved clinical trial designs, increased use of biomarkers and
adoption of sophisticated statistical analyses to reduce costs and
streamline development of new medicines
• Biotech is no longer just transforming pharma
• Transforming healthcare as a whole
• Changing demographics, aging population, rise of
chronic conditions, escalating cost of care
• Changes to the way care is accessed, delivered,
funded
• Payers are demanding evidence therapies are cost-
effective relative to other choices available to patients
• Companies are redesigning R&D strategies to save
money and shorten time-to-market (eg: In April 2013 Sanofi
announced it will not pursue clinical trials for Alzheimers indication
until better understanding of the disease’s mechanism exists)
Basic overview of the life sciences
9
State of play
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Future trends
• Case Studies and examples
10
Session 5 Overview
Life sciences
Life sciences
11
State of the art – elements of an antibody drug conjugate
Life sciences
12
State of the art – the computer will see you now
• AI (eg: Indiana University has developed and is testing
prototype artificial intelligence decision support systems
in three clinical settings: cardiology, clinical depression
and emergency room readmission)
• Next-generation sequencing is moving from research to
clinical use as doctors will increasingly be able to
consider a patient’s genetic information in their diagnoses
and treatment decisions
Life sciences
13
State of the art – the rise of immunotherapies
• Immunotherapies harness the body’s immune system to
target cancer
• Recent attention on drugs that make use of two new
targets
• The two targets are both proteins that regulate the
immune system but instead of boosting immunity, the
new drugs targeting these proteins block inhibitory
immune responses that allow tumour cells to escape
detection and subsequent destruction by T cells
• Inhibiting the immune system’s tolerance to tumours may
prove a useful immunotherapeutic strategy for cancer
patients
Life sciences
14
State of the art – the rise of immunotherapies
• One of the new target proteins, CTLA-4, is present on the
surface of the immune system’s T cells
• CTLA-4 sends an inhibitory signal to T cells, acting as an
of switch for immune responses
• This helps avoid autoimmune disease but tumour cells’
ability to turn off this recognition function is one
mechanism that allows them to escape detection and
subsequent destruction by T cell and natural killer cell
responses
• Antibodies that block CTLA-4 can flip the of switch to on,
and push the equilibrium of the T cell response towards a
greater recognition of cancer cells as non-self
Life sciences
15
State of the art – the rise of immunotherapies
• PD-1 is the other protein targeting this aspect of immune
surveillance
• PD-1 helps ensure that unhealthy cells get rid of
themselves through a process known as programmed
cell death, or apoptosis
• PD-1 drugs target the programmed cell death-1 signal
transduction pathway
• Drugs against these individual targets, as well as drugs
aimed at a combination of the targets, are showing
promise in clinical trials
Life sciences
16
State of the art – gene therapies
Life sciences
17
State of the art – gene therapies
• Gene therapy also enlists the immune system against
cancer
• The approach is to genetically engineer a patient’s own T
cells to kill cancer cells
• These modified ‘hunter’ cells work with the immune
system to attack tumours in an entirely new way
• The approach is also expected to reduce longer-term
toxicities associated with current chemotherapies
Life sciences
18
State of the art – stem cell therapies
• Stem cell therapies are also advancing through clinical
development
• Indications include heart failure and progressive
neurodegenerative diseases
• Players include Aastrom, Aldagen, Amorcyte, Athersys,
Baxter, BrainStorm, Mesoblast, Celgene, Neuralstem,
Geron, Pluristem, ReNeuron and SanBio
Life sciences
19
State of the art – data driven decision making
• Big-data-driven decision-making is transforming the ways in which
healthcare payers and providers are approaching intervention and
clinical care and impacting decisions on which drug development
projects biotechs pursue
• Biotechs can access cross referenced cancer drug data across solid
tumour disease states, giving them a nuanced understanding of the
reimbursement and regulatory environment for these cancers
• Using sophisticated statistical techniques and a large body of
reimbursement data, modelling can now predict whether or not a
reimbursement agency will add a drug to its recommended drugs list
and inform whether a project is viable to pursue
Life sciences
20
State of the art – the metabolome
• Metabolomics is a newborn cousin to genomics and proteomics that
interfaces chemistry, biology, statistics and computer science
• This research involves the rapid, high throughput characterisation of
the small molecule metabolites found in an organism in a systematic
study of the structures, movements, concentrations, biochemical
transformations and biological functions of the thousands of small
molecule natural products that are absorbed, synthesised,
metabolised and excreted by biological systems
• It presents unique informatic challenges
Life sciences
21
State of the art – the metabolome
• Chemical diversity demands that an ever wider variety of analytical
technologies are employed to gain comprehensive coverage of the
metabolome so researchers are faced with new types of raw data
requiring specialised algorithms for data handling and processing
• the literature is laden with examples of software offering new
capabilities
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Future trends
• Case Studies and examples
22
Session 5 Overview
Life sciences
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Typical life sciences development process
• Biosimilars
• Generics
• Future trends
• Case Studies and examples
23
Session 5 Overview
Life sciences
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Typical life sciences development process
• Biosimilars
• Generics
• Future trends
• Case Studies and examples
24
Session 5 Overview
Life sciences
Typical life sciences development process
2
5
Graphic: Aptuit 2014
A life sciences biotech project starts with high throughput
screening identification of promising drug targets in the lab
(hits) that undergo in vitro testing for safety, specificity and
efficacy (candidate), proceeds to testing in animals and then
humans and ends in regulatory approval for marketing. The
focus of regulatory approval is on the safety and efficacy of the
drug in humans. Most countries have a government agency to
regulate and oversee the path to drug approval (approval).
Typical life sciences development process
2
6
Time 4 days* – 9 months
Test
population
Computational studies, discovery analytical sciences, assays
development and in vitro profiling, pre-clinical in vivo
pharmacology, microbiology, pharmacokinetics
Purpose Testing whether it is specific, whether there a concentration
range where it is effective and safe (therapeutic window)
Success
rate
Thousands of hits evaluated
Hit to lead, lead to candidate
*Affinity Bio www.affinitybio.com.au
Typical life sciences development process
2
7
File IND at TGA/EMA/FDA/CFDA
Typical life sciences development process
2
8
*Source: Calvert Research Institute
Years 1 - 5 years
Test
population
Laboratory and animal studies
Purpose Assess safety and biological activity, bioanalysis, toxicity,
pathology, safety pharmacology, CMC development and
manufacture
Success
rate
5,000 compounds evaluated*
Pre-clinical development and testing
Typical life sciences development process
2
9
*Source: Calvert Research Institute
Years 1
Test
population
20 – 80 healthy volunteers
Purpose Determine safety and dosage, typically using single ascending
dosage (SAD) or multiple ascending dosage (MAD) statistical
designs to establish the maximum tolerated dose (MTD)
Success
rate
5 enter trials*
Phase 1
Typical life sciences development process
30 *Source: Calvert Research Institute
Years 2
Test
population
100 – 300 patient volunteers
Purpose Evaluate effectiveness, look for side-effects
Success
rate
5 enter trials*
Phase 2
Typical life sciences development process
31 *Source: Calvert Research Institute
Years 3
Test
population
1,000 – 3,000 patient volunteers
Purpose Verify effectiveness, monitor adverse reactions from long-term
use
Success
rate
5 enter trials*
Phase 3
Typical life sciences development process
32
File NDA at TGA/EMA/FDA/CFDA
Typical life sciences development process
33 *Source: Calvert Research Institute
Years 2.5
Test
population
Purpose Review process / Approval
Success
rate
1 approved*
EMA/FDA/EMA/CFDA
Typical life sciences development process
34
Typically, 9 - 12 years
Typical life sciences development process
35
Phase IV - Pharmacovigilance
36
FDA’s expedited programs for serious conditions
Designation Qualifying criteria When to submit
Fast track • A drug that is intended to
treat a serious condition AND
nonclinical or clinical data to
demonstrate the potential to
address unmet medical need
OR
• A drug that has been
designated as a qualifed
infectious disease product
• With IND or
after
• Ideally, no
later than the
pre-BLA or pre-
NDA meeting
Regulatory nuances
37
FDA’s expedited programs for serious conditions
Designation Qualifying criteria When to submit
Breakthrough
therapy
• A drug that is intended to treat
a serious condition AND
preliminary clinical evidence
indicates that the drug may
demonstrate substantial
improvement on a clinically
significant endpoint(s) over
available therapies
• With IND or
after
• Ideally, no
later than the
end-of-phase 2
meeting
Regulatory nuances
38
FDA’s expedited programs for serious conditions
Designation Qualifying criteria When to submit
Accellerated
approval
A drug that treats a serious condition AND
generally provides meaningful advantage
over available therapies AND
demonstrates an effect on a surrogate
endpoint that is reasonably likely to
predict clinical benefit, or on a clinical
endpoint that can be measured earlier
than an effect on irreversible morbidity or
mortality that is reasonably likely to
predict an effect on irreversible morbidity
or mortality or other clinical benefit (i.e.,
an intermediate clinical endpoint)
The sponsor should
ordinarily discuss the
possibility of
accelerated approval
with the review
division during
development,
supporting, for
example, the use of
the planned
endpoint as a basis
for approval and
discussing the
confirmatory trials
Regulatory nuances
39
FDA’s expedited programs for serious conditions
Designation Qualifying criteria When to submit
Priority review • An application (original or efficacy
supplement) for a drug that treats a
serious condition AND if approved,
would provide a significant
improvement in safety or effectiveness
OR
• Any supplement that proposes a
labelling change pursuant to a report on
a paediatric study under 505A OR
• An application for a drug that has been
designated as a qualified infectious
disease product OR
• Any application or supplement for a
drug submitted with a priority review
voucher
With original BLA,
NDA, or efficacy
supplement
Regulatory nuances
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Typical life sciences development process
• Biosimilars
• Generics
• Future trends
• Case Studies and examples
40
Session 5 Overview
Life sciences
Life sciences
41
Regulatory nuances – biosimilars
• Biosimilars or ‘similar biological medicinal product’ (SBMP) (Australia
and Europe) or ‘follow-on’ biologics (USA) are biological products
that are similar, but not identical, to an innovator product that is
already marketed and whose patent has typically expired
• Biosimilars cannot be considered ‘generic’ equivalents of innovator
products as they are not necessarily clinically interchangeable and in
some cases may exhibit different therapeutic effects
• The TGA defines a biosimilar as imitating an already registered
biological medicine that “has a demonstrable similarity in
physicochemical, biological and immunological characteristics,
efficacy and safety, based on comprehensive comparability studies”,
and “has been evaluated by the TGA according to this guideline and
other relevant EU guidelines adopted by the TGA”
Life sciences
42
Regulatory nuances – biosimilars
• The reference product must be registered in Australia and marketed
for a “suitable duration and have a volume of marketed use so that
there is likely to be a substantial body of acceptable data regarding
the safety and efficacy”
• For reference products registered in Australia but manufactured
overseas, a bridging comparability study between the Australian-
sourced product and all batches of the reference product is required
• The data requirements for comparability studies follow EU and
International Conference on Harmonization (ICH) guidelines
verbatim
• Where a registration fails to prove comparability, the application can
be withdrawn, or re-filed as a novel biologic entity
Life sciences
43
Regulatory nuances – biosimilars
Where the reference product is approved for more than one
indication, the biosimilar must prove safety and efficacy in
each of those indications
Extrapolation of therapeutic similarity across indications is
allowed “in certain cases” depending on “clinical
experience, available literature data, whether or not the
same mechanisms of action or the same receptor(s) are
involved in all indications”
Life sciences
44
Regulatory nuances – biosimilars
Biological drugs, such as
with long-chain or heavily
glycosylated proteins and
monoclonal antibodies, tend
to be recombinant three-
dimensional proteins with
structural complexity and a
high molecular weight which
makes them more difficult to
characterise than small
molecule drugs
Life sciences
45
Regulatory nuances – biosimilars
In other words, biological medicines are not composed of a
single, pure substance, but are invariably complex, micro-
heterogeneous mixtures of isoforms of the desired
substance and each isoform may exhibit differences in:
• potency
• half life
• immunogenicity.
These differences mean that biosimilar medicines cannot
be shown to be sufficiently similar to the original medicine
(the reference product) to be considered bioequivalent
Life sciences
46
Regulatory nuances – biosimilars
For that reason, the therapeutic equivalence of biosimilars
and innovator drugs is required to be assessed in a
switching study where patients are switched between the
two products
There is a clearly defined registration pathway for SBMPs
(biosimilars)
This determines whether the biosimilar induces an
immunological response (using assays to detect
neutralising antibodies), and whether efficacy and safety
are affected when products are switched
Life sciences
47
Regulatory nuances – biosimilars
The results of such a trial determine if the sponsor of a
biosimilar can claim for interchangeable use with the
innovator product
These studies are costly and time-consuming as the
guidelines call for far more rigorous testing than would be
needed for a chemical generic product, including
pharmaco-toxicology, pharmacokinetic, pharmacodynamic,
immunological, efficacy and clinical safety studies drawing
on TGA (and EMA) guidelines to inform that assessment
Life sciences
48
Regulatory nuances – biosimilars
The TGA post-registration regulations require the
manufacturer to establish a comprehensive
pharmacovigilance Risk Management Plan with a focus on
monitoring immunogenicity after the product receives
marketing approval, including reporting of safety updates
and adverse events to the TGA
Biosimilars are placed on batch release as a condition of
registration, meaning that all batches are tested by the TGA
until consistency has been demonstrated
Life sciences
49
Regulatory nuances – biosimilars
• Biosimilars have their own naming conventions including an Australia
Biological Name (ABN) with the reference product’s active ingredient,
along with a biosimilar identifier: the prefix “sim-” plus a three-letter
code issued by the World Health Organization (WHO) International
Non-proprietary Name (INN) Committee
• Unlike generic medicines, which must demonstrate bioequivalence to
the reference product, biosimilars are not bioequivalent to the
products they follow and as such pharmacists may not substitute a
biosimilar for the original medicine and the prescribing physician is
required to specify the specific biosimilar of choice on the
prescription because of minor differences in clinical effects (eg:
immunogenicity)
Life sciences
50
Product
name
Australian
Biological
Name
Sponsor Indications
Tevagrastim filgrastim Aspen Treatment of neutropenia in patients receiving
myelosuppressive or myeloablative chemotherapy, patients
infected with HIV or to mobilise peripheral blood progenitor
cells in normal volunteers for allogenic cell therapy
Nivestim filgrastim
(rbe)
Hospira Treatment of neutropenia in patients receiving
myelosuppressive or myeloablative chemotherapy, patients
infected with HIV or to mobilise peripheral blood progenitor
cells in normal volunteers for allogenic cell therapy
Zarzio filgrastim
(rbe)
Sandoz Treatment of neutropenia in patients receiving
myelosuppressive or myeloablative chemotherapy, patients
infected with HIV or to mobilise peripheral blood progenitor
cells in normal volunteers for allogenic cell therapy
Novicrit epoetin
lambda (rch)
Novartis Treatment of anaemia in chronic renal failure, nonmyeloid
malignancies or enable/augment pre-elective surgery blood
donations to minimise allogenic blood transfusions
Regulatory nuances – biosimilars registered in Australia
@ November 2013*
*Source: TGA URL http://www.tga.gov.au/hp/hp-information-biosimilars.htm Accessed 25/05/2013
• Basic overview of the life sciences
• The state of the art
• Regulatory nuances
• Typical life sciences development process
• Biosimilars
• Generics
• Future trends
• Case Studies and examples
51
Session 5 Overview
Life sciences
Life sciences
52
Regulatory nuances – generics
A ‘generic’ medicine (also known as ‘over-the-counter’
or OTC medicine) has all of the following characteristics:
• the same quantitative composition of therapeutically active
substances, being substances of similar quality to those in the
equivalent originator product (eg: same small molecule)
• the same pharmaceutical form (the various immediate-release
oral dosage forms such as tablets, capsules, oral liquids or
suspensions can be considered to be one and the same
pharmaceutical form)
• bioequivalence (or for topical products, is considered to be
therapeutically equivalent)
• the same safety and efficacy properties
Life sciences
53
Regulatory nuances – generics
• Generally, an application to register an OTC product does not require
a full dossier of chemical, biological, pharmaceutical,
pharmacological-toxicological and clinical safety and efficacy data
where the proposed indications and dosage regimen are the same as
those of the originator product
• TGA may require bioequivalence (or therapeutic equivalence) studies
depending on the product’s formulation
• Topical OTC products are treated differently as many have a long
history of use in many different formulations and their efficacy is well
accepted (e.g. salicylic acid for treatment of warts)*
• Efficacy and safety data are generally not required to support the
registration of such generic products
*Source: TGA URL http://www.tga.gov.au/industry/otc-argom-app1-06-generic.htm Accessed 25/05/2013
• Basic overview of Medical Devices and Diagnostics
• The State of the Art
• Regulatory nuances
• Future trends
• Case Studies and examples
54
Session 5 Overview
Life sciences
Life sciences
55
Future trends – systems biology
Quantitative approaches at multiple scales, from single
molecules and cells to whole tissues and organisms, wrt
• stem cell therapies will continue to be developed
• quantitative cell and developmental biology
• functional genomics and therapies that regulate genes
involved in specific diseases (gene therapies)
• systems genetics and medicine, technologies that alter
genes, technologies that enlist the body’s own defences
against disease (immuno-therapies)
• theoretical and biophysical modelling
• quantitative single-cell approaches (systems nanobiology)
Life sciences
56
Future trends – systems biology
Expect to see software-aided biological interpretation of
metabolic profiles (ie metabolomics) continue to develop:
• visual overlay of metabolite profile data onto biochemical
network diagrams
• detection of statistical evidence for perturbation of
particular pathways (e.g. over-representation analysis)
• identifying metabolite profile patterns that reliably indicate
specific biological states (identifying biomarkers)
• using these patterns to diagnose the states of biological
systems (detecting biomarkers)
• analysis of correlation networks between metabolites and
other types of biomolecules
Life sciences
57
Future trends – ‘next generation’ sequencing
• 2013 saw new companies launch to deploy rapid
advances in gene sequencing and analytics with big
ideas like gene editing and harnessing the microbiome to
develop new therapies for intractable diseases
• Expect to see breakthrough designations for drugs meant
to treat global chronic conditions that are the major cause
of death and disability, diabetes, heart disease and
dementia
Source: Burrill Predictions for 2014
Life sciences
58
Future trends – Human Brain Project
EC is providing €1 billion over ten years to construct the
most detailed model of the human brain ever
The project will reconstruct the brain, piece by piece, in
digital supercomputer-based models and simulations with
the ultimate goal of allowing neuroscientists to understand
the role of genes, molecules, and cells in human cognition
and behaviour
Life sciences
59
Future trends – Brain Research through Advancing
Innovative Neurotechnologies Initiative (BRAIN)
NIH, DARPA and NSF are providing $100 million launch
contribution ($40M in 2014) to
• develop new tools to look at the brain with better spatial and temporal
resolution
• analyse the data generated by the tools
The project will also map neural circuits, first in invertebrates
then in mammals
Life sciences
60
Future trends – National Cancer Institute (USA) Initiative
The NCI has begun to make available a database of the
genetic variation of cancer to help researchers understand
how to better tailor drugs to treat specific cancers
By studying the correlations between key cancer-related
genes and 103 cancer drugs approved by the FDA and an
additional 207 INDs, the researchers were able to identify
new determinants of response and mechanisms of
resistance to drugs, and offer opportunities to target
genomic defects and overcome acquired resistance
• Basic overview of Medical Devices and Diagnostics
• The State of the Art
• Regulatory nuances
• Future trends
• Case Studies and examples
61
Session 5 Overview
Life sciences
Life sciences
62
Case Studies and Examples
Antibody drug conjugates
Genentech’s Kadcycla
• Approved by FDA in 2013, Kadcyla is the first
antibody-drug conjugate approved for a solid tumour
• It treats HER2-positive breast cancers, a particularly
aggressive form of the disease
• Pairs Genentech’s Herceptin with a powerful
chemotherapy agent
• The combination delivers the therapy directly to
tumour cells, bypassing healthy cells
Life sciences
63
Case Studies and Examples
Antibody drug conjugates
Genentech’s Kadcycla
• In a clinical study of 991 patients randomly assigned to
receive Kadcyla or another chemotherapy drug,
patients treated with Kadcyla had a median
progression-free survival of 9.6 months compared to
6.4 months in patients treated with lapatinib plus
capecitabine
• The median overall survival was 30.9 months in the
Kadcyla group and 25.1 months in the lapatinib plus
capecitabine group
Life sciences
64
Case Studies and Examples
The rise of immunotherapies
PD-1 experimental therapies
• Bristol-Myers Squibb, Merck, and Roche all have
experimental therapeutics directed against the PD-1
pathway
• Nivolumab (BMS) is in multiple early-to-mid-stage
trials
• BMS reports¹ positive responses in a study of more
than 250 patients with melanoma, non-small cell lung
cancer, or renal cell carcinoma and some patients in
long-term remissions
¹ Source: ASCO Conference June 2013
Life sciences
65
Case Studies and Examples
The rise of immunotherapies
PD-1 experimental therapies
• Lambrolizumab (Merck) is in Phase III studies with a
Phase II trial completed
• 135 participants with advanced metastatic melanoma,
across all dose levels given in the trial, 38 percent had
improvement of their cancer after 12 weeks of treatment
• Improvement ranged from 25% in patients who got the
lowest dose to 52% in those who got the highest dose
• 13% suffered severe side effects with inflammation of
the lung or kidney and thyroid problems
¹ Source: Burrill Biotech Report 2014
Life sciences
66
Case Studies and Examples
The rise of immunotherapies
PD-L1 experimental therapies
• MPDL3280A (Roche) has an antibody targeting the PD-
1 ligand (rather than the pathway thus PD-L1) that has
completed a Phase II study
• 21% response rate across various tumour types
• In addition to non-small cell lung cancer and renal
cancer, the antibody therapy showed activity against
colon, gastric, and head and neck cancers
¹ Source: Burrill Biotech Report 2014
Life sciences
67
Case Studies and Examples
The rise of immunotherapies
PD-L1 experimental therapies
• MDX-1105 (BMS) also targets the PDS-1 ligand
• This antibody demonstrated lower response rates than
either nivolumab (BMS) or MPDL3280A (Roche) for
reasons that are yet to be determined
• BMS is also testing a combination of the two therapy
groups, attacking tumours by stimulating immune
system recognition through CTLA-4 blockade and
promoting apoptosis through PD-1 receptor blockade
¹ Source: Burrill Biotech Report 2014
Life sciences
68
Case Studies and Examples
Gene therapies
Some companies playing in this space
• Glybera (UniQure) is a gene therapy for the rare metabolic
disorder familial lipoprotein lipase deficiency and the first
Western approved gene therapy (EMA 2012)
• Perelman School of Medicine at the University of
Pennsylvania and the Children’s Hospital of Philadelphia
(evidence of leukaemia remissions)
• Penn U’s Abramson Cancer Center
• Novartis Oncology
• Juno Therapeutics
• Bluebird Bio
¹ Source: Burrill Biotech Report 2014
Life sciences
69
Case Studies and Examples
Metabolomics
Metabolomics analysis project
flow
Step 1 - Project idea
To start a project, there must be some sort of
question to be addressed, such as a drug,
food or environment-related question (for
example, "why is this drug toxic, or why does
this food show antihypertensive action"), or a
disease-related question, or a genome /
proteomics-related question (for example,
"what is the function of this gene, or protein").
This question then becomes the project idea.
¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
Life sciences
70
Case Studies and Examples
Metabolomics
Metabolomics analysis project flow
Step 2 – Experiment design
A variety of approaches are possible in metabolomics, so it is important that
the experiment be designed so that when the project is analysed,
meaningful results will have been obtained. For example, should cultured
cells be used for the pre-clinical sample or should an animal disease model
be used, and for the clinical sample, should a healthy human sample
(Phase I) be used or a disease sample (Phase II and later), and should the
sample itself consist of tissue and cells or a biological fluid such as plasma,
serum or urine. In addition, it is necessary to decide the number of samples
taking into consideration the biological variability of the system.
¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
Life sciences
71
Case Studies and Examples
Metabolomics
Metabolomics analysis project flow
Step 3 – Discovery of changed metabolites
The approaches for discovering changed metabolites can be broadly
divided into two categories.
• Non-targeted metabolomics - This refers to the search for changed
metabolites among all of the compounds, and the emphasis is on in-
depth search techniques that usually involve relative quantitative
analysis
• Targeted metabolomics - In this approach, known metabolites are
selectively analysed, relative quantitative analysis is taken into
consideration, and multiple sample concentration profile analysis is
possible
¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
Life sciences
72
Case Studies and Examples
Metabolomics
Metabolomics analysis project flow
Step 3 – Discovery of changed metabolites
• There are various technology-related approaches in metabolomics, including
the use of chromatography - mass spectrometry, and so on
• When chromatography-mass spectrometry is used, the measurement data
advances the analysis starting with retention time and mass. If retention time
calibration and alignment are required, iterative measurement using the same
sample is conducted (eg: finding the changed metabolites in the case of a
drug, will necessarily involve the generation of large quantities of data due to
the production of multiple data sets associated with acquisition at timed
intervals after the drug is administered, as well as the possibility of biological
variability and parent population variability)
¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
Life sciences
73
Case Studies and Examples
Metabolomics
Metabolomics analysis project flow
Step 3 – Discovery of changed metabolites
• Because of the huge volume of data generated from so many samples
submitted to analysis, analytical software becomes virtually
indispensable
• Metabolite discovery is normally conducted using specialised software
applications to handle processing of acquired data, such as calibration
of retention time and mass, alignment and normalisation, as well as to
perform such operations as statistical analysis and data mining
¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
Life sciences
74
Case Studies and Examples
Metabolomics
Metabolomics analysis project flow
Step 4 – Identification of changed metabolites
• To identify the metabolites discovered in step 3, the compounds are
cross-checked with those registered in databases, and their structures
are determined through compound information analysis. Various
databases are in development both domestically and internationally,
which contain MS/MS and other reference spectra, as well as
compounds associated with metabolic maps
• Since it will take some time to identify all metabolites through
database referencing, structural identification is attempted based on
the information obtained on changed metabolites in addition to that
obtained from analytical instrumentation like the MS and NMR
¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
Life sciences
75
Case Studies and Examples
Metabolomics
Metabolomics analysis project flow
Step 5 – Hypothesis, verification and conclusion
• After the changed metabolites are discovered and identified, the
project idea is revisited, a hypothesis is framed and verified, and a
conclusion is drawn
• The framing of a meaningful hypothesis and drawing conclusions
requires reproducible data, a means of separating each of the
metabolites from complex samples (normally, a combination of mass
resolution and chromatographic resolution), abundant data for ID
verification (a combination of mass accuracy and mass spectrometry
(MSn) information), and software that can extract from huge amounts
of data the information required to fulfil the research objective
¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
Life sciences
76
Case Studies and Examples
R&D Tax Incentive Biotechnology Guidance example in context
Encapsulate - Zinc metal protein attenuating powder for amyloid
plaques*
• 10 Feb 2014: Summer Street Analyst Bart Classen on Prana
Biotechnology Limited (Nasdaq: PRAN)
“We are not enthusiastic about the drug's proposed mechanism,
allowing zinc and copper ions into the cell, because there is only a
limited amount of ions that can enter the cell before they would
precipitate and cause toxic deposits”
• Sangamo Biosciences early stage data shows gene therapy
approach slowed Alzheimer’s related deterioration in brain
* Fictitious example from AusIndustry R&D Tax Incentive Biotechnology Guidance product, April 2013
Life sciences
77
Case Studies and Examples
R&D Tax Incentive Biotechnology Guidance example in context
Encapsulate*
• April 2013 - Sanofi announced it will not pursue clinical trials for
Alzheimers indication until better understanding of the disease’s
mechanism exists
• March 2014 - Otsuka licenses Lundbeck’s Alzheimer’s disease
drug for up to $825M
• July 2013 - Biogen Idec in-licenses mouse model for
demyelinating diseases, another approach to Alzheimer’s, from
Myelin Research Foundation
• Dec 2013 - Eisai, Lilly form dementia consortium with
Alzheimer’s Research UK, MRC Technology
* Fictitious example from AusIndustry R&D Tax Incentive Biotechnology Guidance product, April 2013

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Nw biotech fundamentals day 1 session 5 life sciences

  • 1. Biotech Boot Camp Session 5 – Life sciences Presenter: Nick Weston Melbourne, Brisbane, Sydney 28 May – 18 June, 2014
  • 2. This session provides an overview of the global life sciences sector Analysis includes key trends in market size & growth, demand drivers, adoption & scope trends, emerging themes, key areas of investment, and implications for key stakeholders The session also provides specific insights on what is driving key strategic initiatives in the sector Session 5 Overview 2 Agenda
  • 3. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Future trends • Case Studies and examples 3 Session 5 Overview Life sciences
  • 4. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Future trends • Case Studies and examples 4 Session 5 Overview Life sciences
  • 5. The term “life sciences" is used to connote sciences concerned with the study of living organisms (as opposed to physical sciences), including biology, botany, zoology, microbiology, medicine, human therapeutics, veterinary therapeutics, physiology, the ‘omics’ (eg: proteomics, genomics), biochemistry, biotechnology, and related subjects Basic overview of the life sciences 5 Definition
  • 6. Basic overview of the life sciences 6 State of play 2003 2014 • Biotechs that wanted to emulate bigpharma (a build model) • Bigpharma wants to emulate biotech (a buy model) • Small molecule blockbusters • Antibody drug conjugates • Cell based therapies • Treatments that regulate or alter genes • Trial and error drug projects • Therapies designed to precisely target molecular drivers • Treatment of symptoms • Treatment of causes • Move to curative medicine • Human Genome Project completed at cost of $3billion • Illumina can sequence genome for <$1,000
  • 7. Basic overview of the life sciences 7 State of play ¹ Source: Tufts Center for the Study of Drug Development 2013 ² Source: Analysis Group, 2013 • Biotech sales have grown from 36B in 2001 to 163B in 2013¹ • 1800 projects with orphan disease designation in development @ Oct 2011 • >5,000 drugs in clinical development (78% in Phase I, 69% in PhII and 45% in Ph II I are potentially first-in-class)² (Note: by definition, only one can be ‘first-in-class’) • FDA approved 27 new drugs in 2013 (see handouts) including Gilead’s Solvadi, a therapy for hepatitis C virus infection (HCV) with peak sales forecast by some as much as $12B³ and a sticker price of $84,000 per course ³ Source: http://www.forbes.com/sites/johnlamattina/2014/03/24/will-the-hep-c-drug-sovaldi-drive-gilead-to-the-top-of-the- biopharm-industry/
  • 8. Basic overview of the life sciences 8 State of play ¹ Source: Medecines Sans Frontieres/The Lancet Global Health See http://globalhealth.thelancet.com/2014/04/01/neglected- tropical-diseases-and-access-medicines-time-think-beyond-drug-donations • Of 850 new drugs and vaccines approved between 2000 and 2011, just 37 (4%) were for malaria, TB, tropical diseases, diarrhoeal diseases and diseases of poverty¹ • Industry has moved past the steepest part of the patent cliff – increased competition from generics and biosimilars • Trend is outsourced or ‘open’ innovation (eg: GSK $465M + Avalon Ventures $30M = 10 startups, Celgene $45M + Versant Ventures = Quanticel, Sanofi + Third Rock Ventures = Warp Drive Bio $125M) • Improved clinical trial designs, increased use of biomarkers and adoption of sophisticated statistical analyses to reduce costs and streamline development of new medicines
  • 9. • Biotech is no longer just transforming pharma • Transforming healthcare as a whole • Changing demographics, aging population, rise of chronic conditions, escalating cost of care • Changes to the way care is accessed, delivered, funded • Payers are demanding evidence therapies are cost- effective relative to other choices available to patients • Companies are redesigning R&D strategies to save money and shorten time-to-market (eg: In April 2013 Sanofi announced it will not pursue clinical trials for Alzheimers indication until better understanding of the disease’s mechanism exists) Basic overview of the life sciences 9 State of play
  • 10. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Future trends • Case Studies and examples 10 Session 5 Overview Life sciences
  • 11. Life sciences 11 State of the art – elements of an antibody drug conjugate
  • 12. Life sciences 12 State of the art – the computer will see you now • AI (eg: Indiana University has developed and is testing prototype artificial intelligence decision support systems in three clinical settings: cardiology, clinical depression and emergency room readmission) • Next-generation sequencing is moving from research to clinical use as doctors will increasingly be able to consider a patient’s genetic information in their diagnoses and treatment decisions
  • 13. Life sciences 13 State of the art – the rise of immunotherapies • Immunotherapies harness the body’s immune system to target cancer • Recent attention on drugs that make use of two new targets • The two targets are both proteins that regulate the immune system but instead of boosting immunity, the new drugs targeting these proteins block inhibitory immune responses that allow tumour cells to escape detection and subsequent destruction by T cells • Inhibiting the immune system’s tolerance to tumours may prove a useful immunotherapeutic strategy for cancer patients
  • 14. Life sciences 14 State of the art – the rise of immunotherapies • One of the new target proteins, CTLA-4, is present on the surface of the immune system’s T cells • CTLA-4 sends an inhibitory signal to T cells, acting as an of switch for immune responses • This helps avoid autoimmune disease but tumour cells’ ability to turn off this recognition function is one mechanism that allows them to escape detection and subsequent destruction by T cell and natural killer cell responses • Antibodies that block CTLA-4 can flip the of switch to on, and push the equilibrium of the T cell response towards a greater recognition of cancer cells as non-self
  • 15. Life sciences 15 State of the art – the rise of immunotherapies • PD-1 is the other protein targeting this aspect of immune surveillance • PD-1 helps ensure that unhealthy cells get rid of themselves through a process known as programmed cell death, or apoptosis • PD-1 drugs target the programmed cell death-1 signal transduction pathway • Drugs against these individual targets, as well as drugs aimed at a combination of the targets, are showing promise in clinical trials
  • 16. Life sciences 16 State of the art – gene therapies
  • 17. Life sciences 17 State of the art – gene therapies • Gene therapy also enlists the immune system against cancer • The approach is to genetically engineer a patient’s own T cells to kill cancer cells • These modified ‘hunter’ cells work with the immune system to attack tumours in an entirely new way • The approach is also expected to reduce longer-term toxicities associated with current chemotherapies
  • 18. Life sciences 18 State of the art – stem cell therapies • Stem cell therapies are also advancing through clinical development • Indications include heart failure and progressive neurodegenerative diseases • Players include Aastrom, Aldagen, Amorcyte, Athersys, Baxter, BrainStorm, Mesoblast, Celgene, Neuralstem, Geron, Pluristem, ReNeuron and SanBio
  • 19. Life sciences 19 State of the art – data driven decision making • Big-data-driven decision-making is transforming the ways in which healthcare payers and providers are approaching intervention and clinical care and impacting decisions on which drug development projects biotechs pursue • Biotechs can access cross referenced cancer drug data across solid tumour disease states, giving them a nuanced understanding of the reimbursement and regulatory environment for these cancers • Using sophisticated statistical techniques and a large body of reimbursement data, modelling can now predict whether or not a reimbursement agency will add a drug to its recommended drugs list and inform whether a project is viable to pursue
  • 20. Life sciences 20 State of the art – the metabolome • Metabolomics is a newborn cousin to genomics and proteomics that interfaces chemistry, biology, statistics and computer science • This research involves the rapid, high throughput characterisation of the small molecule metabolites found in an organism in a systematic study of the structures, movements, concentrations, biochemical transformations and biological functions of the thousands of small molecule natural products that are absorbed, synthesised, metabolised and excreted by biological systems • It presents unique informatic challenges
  • 21. Life sciences 21 State of the art – the metabolome • Chemical diversity demands that an ever wider variety of analytical technologies are employed to gain comprehensive coverage of the metabolome so researchers are faced with new types of raw data requiring specialised algorithms for data handling and processing • the literature is laden with examples of software offering new capabilities
  • 22. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Future trends • Case Studies and examples 22 Session 5 Overview Life sciences
  • 23. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Typical life sciences development process • Biosimilars • Generics • Future trends • Case Studies and examples 23 Session 5 Overview Life sciences
  • 24. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Typical life sciences development process • Biosimilars • Generics • Future trends • Case Studies and examples 24 Session 5 Overview Life sciences
  • 25. Typical life sciences development process 2 5 Graphic: Aptuit 2014 A life sciences biotech project starts with high throughput screening identification of promising drug targets in the lab (hits) that undergo in vitro testing for safety, specificity and efficacy (candidate), proceeds to testing in animals and then humans and ends in regulatory approval for marketing. The focus of regulatory approval is on the safety and efficacy of the drug in humans. Most countries have a government agency to regulate and oversee the path to drug approval (approval).
  • 26. Typical life sciences development process 2 6 Time 4 days* – 9 months Test population Computational studies, discovery analytical sciences, assays development and in vitro profiling, pre-clinical in vivo pharmacology, microbiology, pharmacokinetics Purpose Testing whether it is specific, whether there a concentration range where it is effective and safe (therapeutic window) Success rate Thousands of hits evaluated Hit to lead, lead to candidate *Affinity Bio www.affinitybio.com.au
  • 27. Typical life sciences development process 2 7 File IND at TGA/EMA/FDA/CFDA
  • 28. Typical life sciences development process 2 8 *Source: Calvert Research Institute Years 1 - 5 years Test population Laboratory and animal studies Purpose Assess safety and biological activity, bioanalysis, toxicity, pathology, safety pharmacology, CMC development and manufacture Success rate 5,000 compounds evaluated* Pre-clinical development and testing
  • 29. Typical life sciences development process 2 9 *Source: Calvert Research Institute Years 1 Test population 20 – 80 healthy volunteers Purpose Determine safety and dosage, typically using single ascending dosage (SAD) or multiple ascending dosage (MAD) statistical designs to establish the maximum tolerated dose (MTD) Success rate 5 enter trials* Phase 1
  • 30. Typical life sciences development process 30 *Source: Calvert Research Institute Years 2 Test population 100 – 300 patient volunteers Purpose Evaluate effectiveness, look for side-effects Success rate 5 enter trials* Phase 2
  • 31. Typical life sciences development process 31 *Source: Calvert Research Institute Years 3 Test population 1,000 – 3,000 patient volunteers Purpose Verify effectiveness, monitor adverse reactions from long-term use Success rate 5 enter trials* Phase 3
  • 32. Typical life sciences development process 32 File NDA at TGA/EMA/FDA/CFDA
  • 33. Typical life sciences development process 33 *Source: Calvert Research Institute Years 2.5 Test population Purpose Review process / Approval Success rate 1 approved* EMA/FDA/EMA/CFDA
  • 34. Typical life sciences development process 34 Typically, 9 - 12 years
  • 35. Typical life sciences development process 35 Phase IV - Pharmacovigilance
  • 36. 36 FDA’s expedited programs for serious conditions Designation Qualifying criteria When to submit Fast track • A drug that is intended to treat a serious condition AND nonclinical or clinical data to demonstrate the potential to address unmet medical need OR • A drug that has been designated as a qualifed infectious disease product • With IND or after • Ideally, no later than the pre-BLA or pre- NDA meeting Regulatory nuances
  • 37. 37 FDA’s expedited programs for serious conditions Designation Qualifying criteria When to submit Breakthrough therapy • A drug that is intended to treat a serious condition AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies • With IND or after • Ideally, no later than the end-of-phase 2 meeting Regulatory nuances
  • 38. 38 FDA’s expedited programs for serious conditions Designation Qualifying criteria When to submit Accellerated approval A drug that treats a serious condition AND generally provides meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit (i.e., an intermediate clinical endpoint) The sponsor should ordinarily discuss the possibility of accelerated approval with the review division during development, supporting, for example, the use of the planned endpoint as a basis for approval and discussing the confirmatory trials Regulatory nuances
  • 39. 39 FDA’s expedited programs for serious conditions Designation Qualifying criteria When to submit Priority review • An application (original or efficacy supplement) for a drug that treats a serious condition AND if approved, would provide a significant improvement in safety or effectiveness OR • Any supplement that proposes a labelling change pursuant to a report on a paediatric study under 505A OR • An application for a drug that has been designated as a qualified infectious disease product OR • Any application or supplement for a drug submitted with a priority review voucher With original BLA, NDA, or efficacy supplement Regulatory nuances
  • 40. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Typical life sciences development process • Biosimilars • Generics • Future trends • Case Studies and examples 40 Session 5 Overview Life sciences
  • 41. Life sciences 41 Regulatory nuances – biosimilars • Biosimilars or ‘similar biological medicinal product’ (SBMP) (Australia and Europe) or ‘follow-on’ biologics (USA) are biological products that are similar, but not identical, to an innovator product that is already marketed and whose patent has typically expired • Biosimilars cannot be considered ‘generic’ equivalents of innovator products as they are not necessarily clinically interchangeable and in some cases may exhibit different therapeutic effects • The TGA defines a biosimilar as imitating an already registered biological medicine that “has a demonstrable similarity in physicochemical, biological and immunological characteristics, efficacy and safety, based on comprehensive comparability studies”, and “has been evaluated by the TGA according to this guideline and other relevant EU guidelines adopted by the TGA”
  • 42. Life sciences 42 Regulatory nuances – biosimilars • The reference product must be registered in Australia and marketed for a “suitable duration and have a volume of marketed use so that there is likely to be a substantial body of acceptable data regarding the safety and efficacy” • For reference products registered in Australia but manufactured overseas, a bridging comparability study between the Australian- sourced product and all batches of the reference product is required • The data requirements for comparability studies follow EU and International Conference on Harmonization (ICH) guidelines verbatim • Where a registration fails to prove comparability, the application can be withdrawn, or re-filed as a novel biologic entity
  • 43. Life sciences 43 Regulatory nuances – biosimilars Where the reference product is approved for more than one indication, the biosimilar must prove safety and efficacy in each of those indications Extrapolation of therapeutic similarity across indications is allowed “in certain cases” depending on “clinical experience, available literature data, whether or not the same mechanisms of action or the same receptor(s) are involved in all indications”
  • 44. Life sciences 44 Regulatory nuances – biosimilars Biological drugs, such as with long-chain or heavily glycosylated proteins and monoclonal antibodies, tend to be recombinant three- dimensional proteins with structural complexity and a high molecular weight which makes them more difficult to characterise than small molecule drugs
  • 45. Life sciences 45 Regulatory nuances – biosimilars In other words, biological medicines are not composed of a single, pure substance, but are invariably complex, micro- heterogeneous mixtures of isoforms of the desired substance and each isoform may exhibit differences in: • potency • half life • immunogenicity. These differences mean that biosimilar medicines cannot be shown to be sufficiently similar to the original medicine (the reference product) to be considered bioequivalent
  • 46. Life sciences 46 Regulatory nuances – biosimilars For that reason, the therapeutic equivalence of biosimilars and innovator drugs is required to be assessed in a switching study where patients are switched between the two products There is a clearly defined registration pathway for SBMPs (biosimilars) This determines whether the biosimilar induces an immunological response (using assays to detect neutralising antibodies), and whether efficacy and safety are affected when products are switched
  • 47. Life sciences 47 Regulatory nuances – biosimilars The results of such a trial determine if the sponsor of a biosimilar can claim for interchangeable use with the innovator product These studies are costly and time-consuming as the guidelines call for far more rigorous testing than would be needed for a chemical generic product, including pharmaco-toxicology, pharmacokinetic, pharmacodynamic, immunological, efficacy and clinical safety studies drawing on TGA (and EMA) guidelines to inform that assessment
  • 48. Life sciences 48 Regulatory nuances – biosimilars The TGA post-registration regulations require the manufacturer to establish a comprehensive pharmacovigilance Risk Management Plan with a focus on monitoring immunogenicity after the product receives marketing approval, including reporting of safety updates and adverse events to the TGA Biosimilars are placed on batch release as a condition of registration, meaning that all batches are tested by the TGA until consistency has been demonstrated
  • 49. Life sciences 49 Regulatory nuances – biosimilars • Biosimilars have their own naming conventions including an Australia Biological Name (ABN) with the reference product’s active ingredient, along with a biosimilar identifier: the prefix “sim-” plus a three-letter code issued by the World Health Organization (WHO) International Non-proprietary Name (INN) Committee • Unlike generic medicines, which must demonstrate bioequivalence to the reference product, biosimilars are not bioequivalent to the products they follow and as such pharmacists may not substitute a biosimilar for the original medicine and the prescribing physician is required to specify the specific biosimilar of choice on the prescription because of minor differences in clinical effects (eg: immunogenicity)
  • 50. Life sciences 50 Product name Australian Biological Name Sponsor Indications Tevagrastim filgrastim Aspen Treatment of neutropenia in patients receiving myelosuppressive or myeloablative chemotherapy, patients infected with HIV or to mobilise peripheral blood progenitor cells in normal volunteers for allogenic cell therapy Nivestim filgrastim (rbe) Hospira Treatment of neutropenia in patients receiving myelosuppressive or myeloablative chemotherapy, patients infected with HIV or to mobilise peripheral blood progenitor cells in normal volunteers for allogenic cell therapy Zarzio filgrastim (rbe) Sandoz Treatment of neutropenia in patients receiving myelosuppressive or myeloablative chemotherapy, patients infected with HIV or to mobilise peripheral blood progenitor cells in normal volunteers for allogenic cell therapy Novicrit epoetin lambda (rch) Novartis Treatment of anaemia in chronic renal failure, nonmyeloid malignancies or enable/augment pre-elective surgery blood donations to minimise allogenic blood transfusions Regulatory nuances – biosimilars registered in Australia @ November 2013* *Source: TGA URL http://www.tga.gov.au/hp/hp-information-biosimilars.htm Accessed 25/05/2013
  • 51. • Basic overview of the life sciences • The state of the art • Regulatory nuances • Typical life sciences development process • Biosimilars • Generics • Future trends • Case Studies and examples 51 Session 5 Overview Life sciences
  • 52. Life sciences 52 Regulatory nuances – generics A ‘generic’ medicine (also known as ‘over-the-counter’ or OTC medicine) has all of the following characteristics: • the same quantitative composition of therapeutically active substances, being substances of similar quality to those in the equivalent originator product (eg: same small molecule) • the same pharmaceutical form (the various immediate-release oral dosage forms such as tablets, capsules, oral liquids or suspensions can be considered to be one and the same pharmaceutical form) • bioequivalence (or for topical products, is considered to be therapeutically equivalent) • the same safety and efficacy properties
  • 53. Life sciences 53 Regulatory nuances – generics • Generally, an application to register an OTC product does not require a full dossier of chemical, biological, pharmaceutical, pharmacological-toxicological and clinical safety and efficacy data where the proposed indications and dosage regimen are the same as those of the originator product • TGA may require bioequivalence (or therapeutic equivalence) studies depending on the product’s formulation • Topical OTC products are treated differently as many have a long history of use in many different formulations and their efficacy is well accepted (e.g. salicylic acid for treatment of warts)* • Efficacy and safety data are generally not required to support the registration of such generic products *Source: TGA URL http://www.tga.gov.au/industry/otc-argom-app1-06-generic.htm Accessed 25/05/2013
  • 54. • Basic overview of Medical Devices and Diagnostics • The State of the Art • Regulatory nuances • Future trends • Case Studies and examples 54 Session 5 Overview Life sciences
  • 55. Life sciences 55 Future trends – systems biology Quantitative approaches at multiple scales, from single molecules and cells to whole tissues and organisms, wrt • stem cell therapies will continue to be developed • quantitative cell and developmental biology • functional genomics and therapies that regulate genes involved in specific diseases (gene therapies) • systems genetics and medicine, technologies that alter genes, technologies that enlist the body’s own defences against disease (immuno-therapies) • theoretical and biophysical modelling • quantitative single-cell approaches (systems nanobiology)
  • 56. Life sciences 56 Future trends – systems biology Expect to see software-aided biological interpretation of metabolic profiles (ie metabolomics) continue to develop: • visual overlay of metabolite profile data onto biochemical network diagrams • detection of statistical evidence for perturbation of particular pathways (e.g. over-representation analysis) • identifying metabolite profile patterns that reliably indicate specific biological states (identifying biomarkers) • using these patterns to diagnose the states of biological systems (detecting biomarkers) • analysis of correlation networks between metabolites and other types of biomolecules
  • 57. Life sciences 57 Future trends – ‘next generation’ sequencing • 2013 saw new companies launch to deploy rapid advances in gene sequencing and analytics with big ideas like gene editing and harnessing the microbiome to develop new therapies for intractable diseases • Expect to see breakthrough designations for drugs meant to treat global chronic conditions that are the major cause of death and disability, diabetes, heart disease and dementia Source: Burrill Predictions for 2014
  • 58. Life sciences 58 Future trends – Human Brain Project EC is providing €1 billion over ten years to construct the most detailed model of the human brain ever The project will reconstruct the brain, piece by piece, in digital supercomputer-based models and simulations with the ultimate goal of allowing neuroscientists to understand the role of genes, molecules, and cells in human cognition and behaviour
  • 59. Life sciences 59 Future trends – Brain Research through Advancing Innovative Neurotechnologies Initiative (BRAIN) NIH, DARPA and NSF are providing $100 million launch contribution ($40M in 2014) to • develop new tools to look at the brain with better spatial and temporal resolution • analyse the data generated by the tools The project will also map neural circuits, first in invertebrates then in mammals
  • 60. Life sciences 60 Future trends – National Cancer Institute (USA) Initiative The NCI has begun to make available a database of the genetic variation of cancer to help researchers understand how to better tailor drugs to treat specific cancers By studying the correlations between key cancer-related genes and 103 cancer drugs approved by the FDA and an additional 207 INDs, the researchers were able to identify new determinants of response and mechanisms of resistance to drugs, and offer opportunities to target genomic defects and overcome acquired resistance
  • 61. • Basic overview of Medical Devices and Diagnostics • The State of the Art • Regulatory nuances • Future trends • Case Studies and examples 61 Session 5 Overview Life sciences
  • 62. Life sciences 62 Case Studies and Examples Antibody drug conjugates Genentech’s Kadcycla • Approved by FDA in 2013, Kadcyla is the first antibody-drug conjugate approved for a solid tumour • It treats HER2-positive breast cancers, a particularly aggressive form of the disease • Pairs Genentech’s Herceptin with a powerful chemotherapy agent • The combination delivers the therapy directly to tumour cells, bypassing healthy cells
  • 63. Life sciences 63 Case Studies and Examples Antibody drug conjugates Genentech’s Kadcycla • In a clinical study of 991 patients randomly assigned to receive Kadcyla or another chemotherapy drug, patients treated with Kadcyla had a median progression-free survival of 9.6 months compared to 6.4 months in patients treated with lapatinib plus capecitabine • The median overall survival was 30.9 months in the Kadcyla group and 25.1 months in the lapatinib plus capecitabine group
  • 64. Life sciences 64 Case Studies and Examples The rise of immunotherapies PD-1 experimental therapies • Bristol-Myers Squibb, Merck, and Roche all have experimental therapeutics directed against the PD-1 pathway • Nivolumab (BMS) is in multiple early-to-mid-stage trials • BMS reports¹ positive responses in a study of more than 250 patients with melanoma, non-small cell lung cancer, or renal cell carcinoma and some patients in long-term remissions ¹ Source: ASCO Conference June 2013
  • 65. Life sciences 65 Case Studies and Examples The rise of immunotherapies PD-1 experimental therapies • Lambrolizumab (Merck) is in Phase III studies with a Phase II trial completed • 135 participants with advanced metastatic melanoma, across all dose levels given in the trial, 38 percent had improvement of their cancer after 12 weeks of treatment • Improvement ranged from 25% in patients who got the lowest dose to 52% in those who got the highest dose • 13% suffered severe side effects with inflammation of the lung or kidney and thyroid problems ¹ Source: Burrill Biotech Report 2014
  • 66. Life sciences 66 Case Studies and Examples The rise of immunotherapies PD-L1 experimental therapies • MPDL3280A (Roche) has an antibody targeting the PD- 1 ligand (rather than the pathway thus PD-L1) that has completed a Phase II study • 21% response rate across various tumour types • In addition to non-small cell lung cancer and renal cancer, the antibody therapy showed activity against colon, gastric, and head and neck cancers ¹ Source: Burrill Biotech Report 2014
  • 67. Life sciences 67 Case Studies and Examples The rise of immunotherapies PD-L1 experimental therapies • MDX-1105 (BMS) also targets the PDS-1 ligand • This antibody demonstrated lower response rates than either nivolumab (BMS) or MPDL3280A (Roche) for reasons that are yet to be determined • BMS is also testing a combination of the two therapy groups, attacking tumours by stimulating immune system recognition through CTLA-4 blockade and promoting apoptosis through PD-1 receptor blockade ¹ Source: Burrill Biotech Report 2014
  • 68. Life sciences 68 Case Studies and Examples Gene therapies Some companies playing in this space • Glybera (UniQure) is a gene therapy for the rare metabolic disorder familial lipoprotein lipase deficiency and the first Western approved gene therapy (EMA 2012) • Perelman School of Medicine at the University of Pennsylvania and the Children’s Hospital of Philadelphia (evidence of leukaemia remissions) • Penn U’s Abramson Cancer Center • Novartis Oncology • Juno Therapeutics • Bluebird Bio ¹ Source: Burrill Biotech Report 2014
  • 69. Life sciences 69 Case Studies and Examples Metabolomics Metabolomics analysis project flow Step 1 - Project idea To start a project, there must be some sort of question to be addressed, such as a drug, food or environment-related question (for example, "why is this drug toxic, or why does this food show antihypertensive action"), or a disease-related question, or a genome / proteomics-related question (for example, "what is the function of this gene, or protein"). This question then becomes the project idea. ¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
  • 70. Life sciences 70 Case Studies and Examples Metabolomics Metabolomics analysis project flow Step 2 – Experiment design A variety of approaches are possible in metabolomics, so it is important that the experiment be designed so that when the project is analysed, meaningful results will have been obtained. For example, should cultured cells be used for the pre-clinical sample or should an animal disease model be used, and for the clinical sample, should a healthy human sample (Phase I) be used or a disease sample (Phase II and later), and should the sample itself consist of tissue and cells or a biological fluid such as plasma, serum or urine. In addition, it is necessary to decide the number of samples taking into consideration the biological variability of the system. ¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
  • 71. Life sciences 71 Case Studies and Examples Metabolomics Metabolomics analysis project flow Step 3 – Discovery of changed metabolites The approaches for discovering changed metabolites can be broadly divided into two categories. • Non-targeted metabolomics - This refers to the search for changed metabolites among all of the compounds, and the emphasis is on in- depth search techniques that usually involve relative quantitative analysis • Targeted metabolomics - In this approach, known metabolites are selectively analysed, relative quantitative analysis is taken into consideration, and multiple sample concentration profile analysis is possible ¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
  • 72. Life sciences 72 Case Studies and Examples Metabolomics Metabolomics analysis project flow Step 3 – Discovery of changed metabolites • There are various technology-related approaches in metabolomics, including the use of chromatography - mass spectrometry, and so on • When chromatography-mass spectrometry is used, the measurement data advances the analysis starting with retention time and mass. If retention time calibration and alignment are required, iterative measurement using the same sample is conducted (eg: finding the changed metabolites in the case of a drug, will necessarily involve the generation of large quantities of data due to the production of multiple data sets associated with acquisition at timed intervals after the drug is administered, as well as the possibility of biological variability and parent population variability) ¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
  • 73. Life sciences 73 Case Studies and Examples Metabolomics Metabolomics analysis project flow Step 3 – Discovery of changed metabolites • Because of the huge volume of data generated from so many samples submitted to analysis, analytical software becomes virtually indispensable • Metabolite discovery is normally conducted using specialised software applications to handle processing of acquired data, such as calibration of retention time and mass, alignment and normalisation, as well as to perform such operations as statistical analysis and data mining ¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
  • 74. Life sciences 74 Case Studies and Examples Metabolomics Metabolomics analysis project flow Step 4 – Identification of changed metabolites • To identify the metabolites discovered in step 3, the compounds are cross-checked with those registered in databases, and their structures are determined through compound information analysis. Various databases are in development both domestically and internationally, which contain MS/MS and other reference spectra, as well as compounds associated with metabolic maps • Since it will take some time to identify all metabolites through database referencing, structural identification is attempted based on the information obtained on changed metabolites in addition to that obtained from analytical instrumentation like the MS and NMR ¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
  • 75. Life sciences 75 Case Studies and Examples Metabolomics Metabolomics analysis project flow Step 5 – Hypothesis, verification and conclusion • After the changed metabolites are discovered and identified, the project idea is revisited, a hypothesis is framed and verified, and a conclusion is drawn • The framing of a meaningful hypothesis and drawing conclusions requires reproducible data, a means of separating each of the metabolites from complex samples (normally, a combination of mass resolution and chromatographic resolution), abundant data for ID verification (a combination of mass accuracy and mass spectrometry (MSn) information), and software that can extract from huge amounts of data the information required to fulfil the research objective ¹ Source: Shimadzu http://www.shimadzu.com/an/lcms/lcmsittof/metabolo.html
  • 76. Life sciences 76 Case Studies and Examples R&D Tax Incentive Biotechnology Guidance example in context Encapsulate - Zinc metal protein attenuating powder for amyloid plaques* • 10 Feb 2014: Summer Street Analyst Bart Classen on Prana Biotechnology Limited (Nasdaq: PRAN) “We are not enthusiastic about the drug's proposed mechanism, allowing zinc and copper ions into the cell, because there is only a limited amount of ions that can enter the cell before they would precipitate and cause toxic deposits” • Sangamo Biosciences early stage data shows gene therapy approach slowed Alzheimer’s related deterioration in brain * Fictitious example from AusIndustry R&D Tax Incentive Biotechnology Guidance product, April 2013
  • 77. Life sciences 77 Case Studies and Examples R&D Tax Incentive Biotechnology Guidance example in context Encapsulate* • April 2013 - Sanofi announced it will not pursue clinical trials for Alzheimers indication until better understanding of the disease’s mechanism exists • March 2014 - Otsuka licenses Lundbeck’s Alzheimer’s disease drug for up to $825M • July 2013 - Biogen Idec in-licenses mouse model for demyelinating diseases, another approach to Alzheimer’s, from Myelin Research Foundation • Dec 2013 - Eisai, Lilly form dementia consortium with Alzheimer’s Research UK, MRC Technology * Fictitious example from AusIndustry R&D Tax Incentive Biotechnology Guidance product, April 2013