Insights from Leading CNS Players By Michael Davitian and David Dopfel, PhD This is the fourth and final installment of our ongoing 2022 CNS year in review. See below for our the other blogs in the series: CNS Year in Review: Introduction and Large CNS Diseases https://healthadvancesblog.com/2023/03/29/introduction-and-large-cns-diseases/ CNS Year in Review: Going Digital https://healthadvancesblog.com/2023/04/06/cns-year-in-review-going-digital/ CNS Year in Review: Novel Modalities https://healthadvancesblog.com/2023/04/13/cns-year-in-review-novel-modalities/ Johnson and Johnson (Janssen), Roche, Biogen, Novartis and AbbVie are the leading biopharma players in the CNS space, with collective CNS sales in excess of $30B and active pipelines spanning neurodegeneration, psychiatry, and neurodevelopmental disorders. We identified several key themes in observing these players’ activities, investments and stated priorities: * Sustained interest in neurodegenerative diseases with high unmet needs despite challenging historical development track records. This is motivated by the large commercial opportunity as well as improving basic neuroscience to understand disease pathways and patient segments * Growing emphasis on, and investments in, basic research to improve disease understanding, identify better targets and therapeutics, and leverage precision medicine approaches (e.g., Janssen, Novartis, AbbVie) * Increasing interest in deal-making among larger players as a means of bolstering portfolios In our final 2022 CNS year in review blog, we provide a brief summary of these companies’ CNS strategy, approach, and recent activities. ### Michael Davitian is a Vice President in our biopharma practice, where he focuses on building the firm’s expertise within neurology and ophthalmology. David Dopfel, PhD is a senior analyst and member of Health Advances’ neurology and ophthalmology committee.

1. By Michael Davitian and David Dopfel, PhD
Insights from Leading CNS Players

2. 2
CNS
Overview
• Novartis’s updated strategy focuses on delivering high-value medicines through across three
neuroscience pillars
– Neurodevelopmental: Brain development and early life disease or disorders
– Neuropsychiatry: Brain function in adulthood post development
– Neurodegenerative & Neuroinflammation: Healthy brain aging and response to injury
• Novartis continued streamlining in 2022 by simplifying its operational model. The broader goal of the
yearslong effort is to focus the company on innovation and growth. This has led to new leadership in
neuroscience who will drive this strategy
– Includes the new President of Novartis Institute for Biomedical Research (NIBR), Fiona Marshall who holds a PhD in
Neuroscience and a new Head of Neuroscience at NIBR Robert Baloh
Approach Recent Highlights
Neuroscience has emerged as a key focus area for Novartis. In CNS, the
company is applying advanced discovery techniques to develop high-value assets.
Asset Selection
Methodologies
Disease Models
in R&D
Brain Organoids
Biomarker Driven
Gene Therapies Pruned Pipeline
Optogenetics High Value Assets
Dec
Jan Aug
Apr
• License option agreement with
Voyager Therapeutics for evaluation
and potential exclusive use of AAV
platform, TRACER
 Zolgensma, first one-time
treatment for SMA, in phase III
for intrathecal administration in
patients up to 18 years of age.
Filing planned for 2025
▲ Announced intention to separate Sandoz, its generics and
biosimilars business, in 100% spin-off to focus Novartis on
innovative medicines
3 Pillars
Restructuring
Source: Health Advances analysis, company website, analyst reports.
Deal Pipeline Other

3. 3
CNS
Overview
• AbbVie’s portfolio and pipeline is focused in 3 therapeutic areas
– Migraine: In both acute treatment and prevention
– Neuropsychiatry: Therapies for mood, thought, and anxiety disorders
– Neurodegeneration: Focus on Parkinson’s and Alzheimer’s
• Building on and maintaining Abbvie’s existing investment and footprint in neuroscience
– Removing the $2B annual M&A cap provides options for inorganic growth to supplement internal neuroscience
pipeline
Approach Recent Highlights
AbbVie is poised to be an active deal-maker after lifting its self-
imposed M&A cap.
Dec
Jan Aug
Apr
• Acquisition of Syndesi Therapeutics synaptic
vesicle protein 2A modulators for cognitive
impairment, and other symptoms associated with
neuropsychiatric and neurodegenerative
disorders
 FDA approval of Vraylar
as an adjunctive
therapeutic for major
depressive disorder
 Expanded collaboration with Sosei Hetare for
G protein coupled receptor development to
treat neurological disorders
Focus Areas
Investment
Organic and
Inorganic
Investment
Disease
Modification and
Management
MOA Insight
Genetic
Symptomatic
Disease Modifying
Physiological
Robust Pipeline
Molecular M&A
Source: Health Advances analysis, company website, analyst reports.
Deal Pipeline Other

4. 4
CNS
Overview
• Janssen is broadening its CNS focus to include the full range of disorders in existing segments
(mainly neuropsychiatry with schizophrenia treatments) as well as additional segments within CNS
– Neurological & Neuromuscular: Brain development and early life disease or disorders
– Neuropsychiatry: Leveraging Janssen’s existing presence and expertise in schizophrenia
– Neurodegenerative: Early development using biomarker driven discovery to build on the recent launch of Ponvory for MS
• Janssen’s goal is to reduce the burden of nervous system disease through pursuit of precision medicine
– Facilitated by partnership with the broader neuroscience community working with patient and care organizations like
National Alliance on Mental Health and Mental Health America
– Increasing scientific understanding of CNS disorders and disease as a critical first step to drive a new era of innovation
Approach Recent Highlights
Targeted
Therapeutics
Subpopulation
Definition
Mechanism
Discovery
Janssen CNS innovation strategy is to leverage and grow their expertise in
biomarkers and CNS disease pathways/etiology to facilitate a precision medicine approach.
* J&J has a network of Innovation locations for early innovation, incubator labs, venture investing and late-stage partnerships. Collaborations are then built within the broader neuroscience community including academic and industry partners.
Source: Health Advances analysis, company website, analyst reports, Buntz 2022 Drug Discovery and Development.
Innovation
Centers and Labs*
Patient
Stratification
Plasma
Biomarkers
Antibody
Neuroscience
Collaboration
Pathway Based
Dec
Jan Aug
Apr
 Drug discovery collaboration
with Evotec for use of
TargetAlloMod platform for
cell surface targets
▲ Reported growth in paliperidone
long-acting injectables used to
treat schizophrenia, fueled by the
launch of Invega Hafyera
• Acquisition of Yumanity Therapeutics lead program,
which has clinical data in Parkinson’s, and unpartnered
discovery-stage neuroscience candidates
“It starts with deep insights
into unmet medical needs
[and] aligns these market
insights with our deep
understanding of immune
pathway science to focus on
the highest impact assets and
programs,” – Tom
Cavanaugh, Janssen,
May 2022
Focus Areas
Precision
Medicine
Deal Pipeline Other

5. 5
CNS
Overview
• Roche’s neuroscience efforts are focused on two areas
– Neurodevelopmental: spinal muscular atrophy, Duchenne muscular dystrophy, and autism
– Neurodegenerative: Alzheimer’s, Parkinson’s, and multiple sclerosis
• Focused on creating collaborations between Roche and academia or corporate partners
– Recent partnership with Shape Therapeutics for RNA-editing candidates that includes CNS targets
Approach Recent Highlights
Roche plans to bridge the translational gap in neuroscience by committing to
building collaboration across academia and industry to drive therapeutic innovation.
Innovative
Treatments
Improved Targets
Improved Biomarkers
Alliance for Therapies*
Molecular Targets
Gene Therapies
Tissue Specific
Diagnostics Innovation RNA Modulators
Dec
Jan Aug
Apr
 FDA approves
Evrysdi for use in
SMA patients
under 2 months
 Gantenerumab failed to meet clinical
endpoints in Alzheimer’s, however an
alternate formulation designed for better
uptake, trontinemab, is still in testing
▲ FDA clearance of Elecsys beta-
Amyloid CSF II and Phospho-
Tau CSF assays for improved
AD diagnostics
Partnerships
* Alliance for Therapies is a long-term research partnership between Roche/Genentech, UCSF, and UC Berkeley to speed up therapeutic development through advances in academic neuroscience.
Note: SMA = spinal muscular atrophy, DMD = Duchenne muscular dystrophy
Source: Health Advances analysis, company website, analyst reports.
• Entered collaboration with Recursion for
drug discovery platform combining
single-cell data generation and machine
learning capabilities
Focus Areas
Deal Pipeline Other

6. 6
CNS
Overview
• Biogen almost entirely focused on neuroscience. Priority indications include Alzheimer’s, Parkinson’s,
MS, SMA, ALS, MDD, PPD, and Lupus
• Biogen has put an emphasis on reprioritizing its portfolio by focusing on pipeline value vs. operational
milestones
– Improving allocation of resources to programs with attractive risk/reward profiles
– Focus on pre-proof-of-concept programs to increase probability of success by emphasizing a deeper understanding
of the MOA and running early exploratory trials
– Enhance translational science capabilities
Approach Recent Highlights
Biogen rapidly advanced its Alzheimer's treatment Leqembi to market and is
pursing a broad CNS pipeline.
Growth Focused
Asset Selection
Early R&D Capabilities
Translational Capabilities Risk/Reward Balance Global Market
R&D Prioritization External Opportunities
(e.g., Licensing and M&A)
Dec
Jan Aug
Apr
• Collaborations with Happify Health to
support MS patients with a digital
platform for care management
 FDA approved Leqembi
under accelerated approval
pathway for AD
▲ CMS finalizes national coverage
determination that limts access to
Alzheimer’s therapeutics approved
by accelerated pathway
Indication
Focus
Prioritize
Note: MS = multiple sclerosis, ALS = amyotrophic lateral sclerosis, SMA = spinal muscular atrophy, MDD = Major depressive disorder, PPD = Post-partum depression.
Source: Health Advances analysis, company website, analyst reports.
• License agreement with MedRythms to
develop and commercialize, a digital
therapeutic for treatment of gait deficits in MS
High Value Assets
Deal Pipeline Other