Download FINAL Orphan drugs – Pharma foundlings or wellsprings of wealth

Orphan drugs: Pharma foundlings or
wellsprings of future wealth?
Prescient Healthcare Group - Market Access
Marcus J. Healey, PhD, MBA, MSc [email protected]
Krithika Venkataraman, PhD [email protected]
February 22, 2016
Introduction
Rare diseases are not rare collectively as 1 in 17 people worldwide will be affected
by a rare disease in their lifetime. A synonym for rare diseases is “orphan
diseases”; unsurprisingly, therefore, the drugs developed to treat rare disease are
called “orphan drugs”, an important subset of specialty drugs. The definition of a
rare disease is variable, as shown in Table 1. Given that rare diseases have small
populations and that it would be difficult to commercially develop treatments for
diseases with small populations, incentives have been granted. The
World Health Organization, the US, the EU and Japan each have
Collectively, rare
diseases are not
different prevalence-based definitions. There is no legal definition of an
rare. It is
ultra-rare disease, though the National Institute for Health and Clinical
estimated that
Excellence in the UK has developed such a sub-category.
as many as 1
out of 17 people
worldwide will
be affected by a
rare disease in
their lifetime.
However, given
that individual
rare diseases
have small
populations,
incentives for
drug
development
have been
granted.
Table 1: Definitions of rare disease and ultra-rare disease, worldwide
WHO
US
EU
Rare
disease
prevalence
Afflicts 0.65–
1.0:1,000
Afflicts <250,000
patients or
<5:10,000,
based on an EU
population of
506 million (5)
Ultra-rare
disease
prevalence
No definition
Afflicts <200,000
patients or
<6.4:10,000,
based on a US
population of
314 million
(4,5)†
No legal
definition
No legal
definition;
subcategory
defined as
<1,000 cases in
England and
Wales or
<1:50,000 (6)
Japan
Afflicts <50,000
patients or
<4:10,000,
based on a
Japanese
population of
128 million (5)
No legal
definition
Abbreviations: EU, European Union; WHO, World Health Organization
†
1983 US Orphan Drug Act (USC 360 Title 21)
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The objective of this white paper is to delineate rare and ultra-rare diseases and to
describe, in brief, the external and internal drivers for pharmaceutical
manufacturers to develop therapies for orphan diseases. This paper attempts to
group and characterize the different types of orphan drug manufacturers and
describes, in broad strokes, some of the strategies, therapeutic foci, market
products, competitive advantages, manufacturing, sales and marketing, mergers
and acquisitions, partnerships, and notable strategic investments that serve to
distinguish different firms. Since there are many excellent articles on orphan drugs
in the literature (see, for example, Tordrup et al., 2014 and Gammie et al., 2015;
Premier Research, 2015 (1-3)), we will not attempt to provide a comprehensive
overview of orphan drugs in this paper.
External drivers of orphan drug development
Fundamentally, the cost of developing an orphan drug is the same as the average
cost of developing a non-orphan drug; however, the potential treatable population
is significantly smaller with orphan drugs. In response to this price-volume
conundrum, the US Congress passed the Orphan Drug Act in 1983 and the EU
passed similar legislation in 2000 in order to entice pharmaceutical manufacturers
to develop drugs for smaller populations of patients with rare diseases. Table 2
summarizes the regulatory, research and development, and commercial drivers for
orphan drug development in the US.
Table 2: Regulatory, research and development, and commercial drivers in rare diseases
Regulatory
Increased scientific advice
Waived or reduced FDA fees
Fewer approval hurdles
Research and development
Tax credits equal to 50% of
expenditures during the clinical
testing phase
Direct funding (grants)
Shorter development timelines
Elevated chances for regulatory
success
Commercial
Favorable reimbursement
Longer market exclusivity
Reduced marketing costs
Possibility for premium pricing
Acceptance of lower levels of
evidence for licensing
Source: (3,7)
In the EU, an orphan drug designation application can be filed at any clinical
development stage prior to the submission of the application for marketing
authorization. Once a product receives an orphan designation from the EMA, this
information is made public, which is not always advantageous to the product
manufacturer (3). Table 3 more specifically outlines some of the competitive and
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procedural advantages in the US versus the EU. Many firms submit joint FDA/EMA
applications when seeking orphan drug designation.
Table 3: Competitive and procedural advantages for orphan drugs in the US and EU
US
Incentives
Exclusivity review
Timeline
Procedural
7 years’ market exclusivity in
addition to current patent
protections
None
No timelines (1–3 months)
Not applicable
EU
10 years’ market exclusivity
After 5 years, if prevalence changes
90 days (COMP) + 30 days (EC)
Centralized procedure and EU-wide
approval
Abbreviations: COMP, Committee of Orphan Medicinal Products; EC, European Commission; EU,
European Union
Source: (3)
Internal drivers of orphan drug development
Innovation in research and development, translational research,
endpoint development, manufacturing, regulatory and reimbursement
With the advent
strategies, and market access strategies form the core internal drivers
of enhanced
targeting via the
in many pharmaceutical firms that have undertaken the challenge of
use of
developing orphan drugs. For example, orphan drug research in
companion
neurodegenerative disorders such as Duchenne’s muscular dystrophy
diagnostics,
(DMD) and spinal muscular atrophy (SMA) has provided opportunities
many diseases,
to develop disease models for research that can be applied elsewhere
particularly in
within an organization (for example, gene expression studies and
oncology, are
systems biology). A common thread is that many diseases are now
now considered
moving toward the “rare” category due to the impact of personalized
“rare”.
medicine and the enhanced targeting options available through
companion diagnostics, particularly in oncology. In the end, orphan drug
development has benefitted greatly from the advent of genomics technologies.
Another prominent internal driver of orphan drug development is more from a
strategic perspective. Orphan drug research, development and commercialization
may lead to the validation of new technologies (e.g., gene therapy, exon skipping
and meganucleases) and therapeutic strategies (e.g., cell or gene therapy for
central nervous system diseases) that can be applied to other disease states.
Outcomes researchers may be called upon to craft a new endpoint (e.g., the sixminute walk test in DMD), in concert with internal and external experts, to validate
and defend the new technologies and/or therapeutic strategies all the way through
to final regulatory approval. This in turn helps the company successfully navigate
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tortuous clinical and regulatory pathways and establishes a validated clinical
endpoint that becomes a standard and can be used in other similar disease states.
Yet another strategic internal driver is the pursuit of a multiple-indication strategy.
For example, in oncology, most drugs receive their highest price point when they
are first reimbursed. As new indications for a particular drug are added, the price of
the drug rarely, if ever, rises. In oncology, companies have employed the strategy
of obtaining approval in multiple indications in order to expand overall orphan drug
revenue. In this realm, Novartis is noteworthy as it has successfully used Gleevec in
multiple oncology indications, and Celgene has also used this strategy successfully
with Revlimid (8). Interestingly, Alexion’s Soliris is unique in that it is the only
marketed product with multiple indications for ultra-rare diseases (e.g., hemolytic
uremic syndrome [aHUS] and paroxysmal nocturnal hemoglobinuria [PNH]).
One need not be prescient to understand the allure of orphan drug development, as
pharmaceutical firms in rare and ultra-rare disease drug development face less
competition from branded drugs and generic rivals. In addition, there are
advantages that are conferred upon orphan drug developers in the commercial
(i.e., statutory market exclusivity), research and development (i.e., tax incentives
and direct funding), national (i.e., grants and tax reductions), licensing (i.e.,
acceptance of lower levels of evidence), pricing (i.e., recognition that firms have to
recoup an investment in a disease with lower patient numbers), strategic (i.e.,
gaining familiarity with new platforms, drug mechanisms of action and
manufacturing techniques), and regulatory (i.e., increased scientific advice and
reduced fees) processes, and these advantages are difficult to ignore (3).
Because of small population sizes in rare diseases, manufacturers seek premium
pricing, if at all possible. Special efforts are undertaken to connect with patient
advocacy groups that can provide political pressure for reimbursement and access
to patients, as well as rare disease foundations that can provide funding and
interaction with key opinion leaders and the physicians who must diagnose and
treat patients with rare disease. In the rare disease community, networking with
providers, patient organizations, foundations, and patients has replaced more
traditional detailing or one-to-one sales and marketing which sought to educate
providers about a firm’s products. On the other hand, payers worry about
affordability and whether many new patients with the rare disease will be identified
in the future.
Orphan drug players
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There appear to
be at least
seven different
types of
pharmaceutical
firms in the
orphan drug
development
industry.
Any attempted classification of companies (see Figure 1) in the rare
disease space is likely to be woefully incomplete when trying to
compare and contrast the wide range of companies in this domain, as
there are mature and newer players with differing levels of funding and
focus. Though it is fraught with risk, we will attempt to broadly
characterize the different types of firms that are seeking to
commercialize products in this space.
Table 4 in the Appendix summarizes orphan drug manufacturer
characteristics. There appear to be at least seven different types of
pharmaceutical firms in the orphan drug development industry. Shire
typifies the grouping termed “acquisitors” based on its past mergers and inlicensing deals, as well as the recently proposed acquisition of Baxalta (a
biopharmaceutical spinoff from Baxter). Shire has become the largest biotechnology
firm exclusively focused on rare diseases, with six commercialized orphan drugs.
With the purchase of Baxalta’s Advate, Shire has acquired a top-ten orphan drug,
based on 2014 US sales (5).
The original orphan disease “pioneer” is Genzyme, which was acquired by Sanofi in
2006 and has become a rare disease grownup with ten commercialized orphan
drugs. Both Shire and Genzyme/Sanofi appear to be almost exclusively focused on
rare diseases.
Figure 1: Different types of firms in the orphan drug development industry
Ultra-rare
disease pure
plays
(Alexion)
Acquisitors
(Shire)
Laser-like
antisense focus
(IONIS)
Pioneers
(Genzyme/
Sanofi)
Small
company/big
strategy (PTC
Therapeutics)
Repurposers
(Novartis,
Roche,
Celgene)
Organic
growers
(BioMarin)
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Novartis and Roche are classic “big pharma” companies with long histories in
pharmaceutical drug development that also can be categorized as “Repurposers”.
These firms have important orphan drugs in their respective portfolios, not as a
result of focus on orphan drug development but as a byproduct of their deep
understanding of molecular pathways and drug development for cancer, and the
translation of these oncology drugs to rarer tumors. Celgene is both an in-licensor
and a translational specialist and has succeeded in the orphan drug arena by
recognizing opportunity, further developing that opportunity, and capitalizing on it.
Novartis has ten commercialized rare-disease drugs; Roche has three marketed
orphan drugs and Celgene has two. Celgene acquired the rights to thalidomide and
then further developed next-generation analogs (Revlimid [lenalidomide] and
Pomalyst [pomalidomide]), which are used as backbone therapy drugs in a number
of different, rarer cancers, and are big moneymakers. Novartis, Roche, and Celgene
are global and sophisticated, insofar as sales and marketing, mergers and
acquisitions, and the formation of strategic partnerships are concerned. Thus, all
three firms are rare disease opportunists or translational specialists and represent
the current and near-future (in the next five years) leaders in orphan drug sales.
BMS is likely to climb into this pack as a result of sales of Opdivo (nivolumab) in
many different tumor types. Some of the anti-PD-1 manufacturers (like Merck with
Keytruda [pembrolizumab]) and other oncology small-molecule manufacturers (like
BMS [Sprycel, dasatinib; CML, Ph+ ALL], J&J/AbbVie [Imbruvica, ibrutinib; CLL]
and Pfizer [with 22 molecules classified as orphan]) are also predicted to remain in
the top five in orphan drug sales in 2020 (5).
As traditional
pharmaceutical
firms struggle
for
differentiation
(in order to
justify price),
the orphan drug
arena has
continued to be
a dynamic
cauldron of
innovation.
BioMarin is a company that has grown organically in the rare-disease
area and may be an acquisition target, despite already having five
commercialized rare-disease products. BioMarin is seeking approval for
drisapersen (exon skipping) in DMD, which was acquired from Prosensa
in November 2014. Its product line is diverse, though it has yet to turn
a profit (Some analysts are predicting 2017 as BioMarin’s year to turn a
profit.).
PTC Therapeutics is an interesting smaller company with a big strategy
– post-transcriptional control – but no commercialized products, as yet.
PTC Therapeutic’s strategy is to focus on the discovery of agents that
promote premature termination codon (i.e., nonsense mutation) readthrough. Many diseases, including neuromuscular disorders (e.g., cystic
fibrosis or DMD), hemoglobinopathies (e.g., β-thalassemia) and many
types of cancers, are caused by the presence of premature termination
mutations in mRNAs. Approximately 10–15% of an estimated 2,000 monogenetic
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diseases are caused by a nonsense mutation, so PTC Therapeutics’ strategy is a
bold play, though it has not yet met with commercial success (9,10).
IONIS Pharmaceuticals, which recently (January 2016) changed its name from ISIS
Pharmaceuticals, is an antisense oligonucleotide (ASO) specialist company with two
commercialized products and more than thirty products in the pipeline. IONIS
possesses an antisense drug discovery and ASO oligonucleotide manufacturing
platform. The company is interesting because it is at the vanguard of new RNAbased technologies that are starting to emerge.
Alexion Pharmaceuticals has a sharp focus on the development of transformative
(not incremental) therapies in the ultra-rare disease arena. Its strategy is to focus
on being the science leader in complement inhibitors and ultra-rare metabolic
diseases, and to focus on regulatory and reimbursement pathways to
commercialization over its 50-country platform. To date, Alexion has
commercialized three products and has been spectacularly successful in
commanding a high price for its lead drug, Soliris, in aHUS and PNH. Achievement
of the company’s commercial goals was grounded in superior clinical performance
within two ultra-rare disease states where there were inferior standards of care,
and its willingness to slog through the necessary regulatory and country-specific
reimbursement hurdles without sacrificing too much in terms of price. Many
traditional pharmaceutical firms have struggled to differentiate their products in
order to justify price in an industry that is becoming heavily commoditized. The
orphan drug arena has continued to be a dynamic cauldron of innovation for
pharmaceutical and biotechnology firms.
Which firms are the winners in the near term?
Drug value is
often measured
by efficacy,
safety, unmet
medical need
and magnitude
of benefit. Some
firms struggle to
master this
metric, while
others have
flourished.
Drug value is oftentimes measured by efficacy, safety, unmet medical
need and magnitude of benefit of a therapeutic over current standard of
care. Some firms struggle to master this metric, while others have
flourished. Since oncology products are so well represented in the rare
disease/ orphan drug arena, repurposers like Novartis, Roche, and
Celgene are well positioned for revenue growth now and in the future.
Alexion has demonstrated an ability to develop a product (Soliris) in
ultra-rare disease states (aHUS and PNH) with such superior efficacy
and safety characteristics compared to standard of care that it was
clear to virtually all reviewers that there were sufficient cost offsets
from reduced spending in other healthcare settings (e.g., reduced
transfusions and hospitalizations for patients with aHUS or PNH) to
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make it well worth its high cost. In addition ‒ and perhaps more importantly ‒
Alexion has pursued a regulatory and reimbursement strategy across 50 markets
that have permitted it to not sacrifice price at the altar of reimbursement and
market access.
Genzyme has the scale, marketing muscle and backing of Sanofi, so its survival in
the orphan drug area seems to be certain for now.
Shire has 28 pipeline assets in development for rare disease and appears to be well
positioned in the orphan drug area through acquisitions, though only Advate (from
the recently acquired Baxalta) is a top revenue producer.
BioMarin has grown more organically and, as it has yet to be commercially
successful, it may well be acquired. Acquiring a company with assets, or being
acquired, appears to be part and parcel of the pharmaceutical and orphan drug
industries, so it is possible that BioMarin will be an acquisition target in the not-toodistant future. Insofar as revenue is concerned, BioMarin’s organic growth appears
to be less fruitful than that of repurposers as exemplified by big pharma. This may
be due to the ability of repurposers to develop multiple indications for the same
drug.
There are three different camps in the pharmaceutical industry that are beginning
to emerge: small-molecule drug makers, specialty pharmaceutical companies, and
the RNA-based technology creators. Sarepta and Moderna are examples of the third
camp with specific technologies like antisense, RNA interference and microRNA
therapy, which seek to precisely alter disease processes at the molecular level (11).
IONIS is interesting because it is at the vanguard of this third camp and already
has two commercialized products, with 30 others in the pipeline. It is doubtful that
in the near term IONIS will supplant the oncology orphan drug producers as
revenue leader, though it might well be successful in providing meaningful
treatments for diseases like DMD and SMA. PTC Therapeutics is also interesting in
that it focuses on the discovery of small molecules as treatments for diseases that
are caused by nonsense mutations. Both IONIS and PTC Therapeutics are eager to
partner with other players and may well be attractive acquisition targets as their
product lines mature.
Summary
In this paper we have outlined some of the external (i.e., regulatory, research and
development, and commercial) and internal (i.e., the pursuit of innovation, new
technologies, therapeutic modalities and multiple indications) drivers in the orphan
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disease world. We have focused on mainline pharmaceutical firms that have
entered the orphan drug market as a result of a deep understanding of molecular
pathways in oncology. These molecular pathways have been naturally extended to
rare tumor types as cancer has become more personalized in the last two decades.
To some payers, this approach constituted a form of “salami slicing”, but to the
cognoscenti in oncology, cancer is not a monolithic disorder and personalized care
within cancer subtypes addresses our unique genomes, which have different
susceptibilities to different cancers. We have also included some of the older orphan
drug pioneers and younger firms that have yet to turn a profit in the orphan drug
space. Other firms that we could easily have included are Vertex (Orkambi
[lumacaftor; ivacaftor] in cystic fibrosis), Teva Pharmaceuticals (Copaxone
[glatiramer acetate] in multiple sclerosis), and Merck KGaA (Rebif [interferon beta1a]) in multiple sclerosis.
Interestingly, according to Evaluate Pharma’s Orphan Drug Report, the
preponderance of the predicted global top-twenty medicines in sales in the year
2020 will be oncology drugs (18 of 20 drugs). Therefore, the orphan drug area is a
natural destination for mainline science-driven specialty-pharmaceutical firms,
which entered oncology because differentiation from the competition appeared to
have a higher probability of commercial success. The orphan drug world is also
considered a safe haven - with lower costs and reduced competition - which in turn
might serve as a driver of research and development and a wellspring of sustained
revenue. The orphan drug world also provides fertile grounds for more established
pharmaceutical firms to partner with, or in-license compounds from, smaller
biotechnology firms with fresh ideas about new mechanisms of action, druggable
targets and development platforms, thereby offering several beneficial commercial
opportunities.
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Appendix
Table 4: Summary of drug manufacturer categories’ characteristics
Category
nickname:
Acquisitors
Pioneers
Repurposers
Organic
growers
Small
company/big
strategy
Laser
antisense
focus
Ultra-rare
disease pure
plays
Company
Shire
Genzyme/Sano
fi
Novartis, Roche,
Celgene
BioMarin
PTC
Therapeutics
IONIS
Alexion
Strategy
Largest biotech
focused on RD;
acquisitive
RD grownup
with ability to
uncover niche
opportunities
due to savvy
borne of
experience
RD opportunists;
translational
specialists
(reposition/
repurpose
oncology drugs;
further develop
older drugs)
Organically
develop new
products;
with diverse
product line
in RD;
merger/
acquisition
target?
Specialize in
disease states
due to
nonsense
mutations
(>2,000
diseases)
ASO leaders
with >30
compounds in
pipeline
Scientific
leaders in
ultra-rare
diseases
involving the
complement
system and
metabolic
disorders
Tx focus
6 commerciallized RD
products
10 commercialized RD
products
Commercialized
RD products:
Novartis - 10
Roche - 3
Celgene - 2
5 commercialized RD
products
0 commercialized RD
products
2 commercialized RD
products
3 commercialized RD
products
10
Marketed
products
Replagal,
Elaprase,
VPRIV, Firazyr,
Gattex, Advate
Aldurazyme,
Cerdelga,
Cerezyme,
Cholestagel,
Elaprase,
Fabrazyme,
Kynamro,
Lumizyme,
Myozyme,
Thyrogen
Novartis:
Tasigna, Afinitor,
Exjade/Jadenu,
Gleevec,
Sandostatin
SC/Sandostatin
LAR, Zykadia,
Signifor, Farydak,
Jakavi, Arzerra;
Roche: Rituxan,
Gazyva, Esbriet;
Celgene:
Revlimid,
Pomalyst
VIMIZIM,
KUVAN,
Naglazyme;
Aldurazyme
(codeveloped
with
Genzyme),
Firdapse
None
KYNAMRO,
oligo-TCS
(partnered
with Atlantic
Pharmaceutical
s)
Soliris,
Kanuma,
Strensiq
Competitive
advantage
Sophisticated,
purposeful;
skillful at inlicensing and
identifying
targets for
acquisition
Sophisticated,
RD pioneer;
scale and
market muscle
of Sanofi
Sophisticated,
with scale and
market muscle
Diversity of
products;
may not
turn a profit
until 2017
Laser focus on
nonsense
mutations;
Alternative
Splicing
Technology
program
ASO drug
discovery with
mfg platform;
large pipeline
Sophisticated
regulatory and
reimbursement
strategy; 50country
platform; highpriced
products in
high UMN
areas
Manufacturing
In-house, CMO
In-house, CMO
In-house, CMO
CMO; mfg
difficult for
MPS
products
Mostly CMO
Mostly inhouse
In-house, CMO
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Sales and
marketing
Both intensive
detailing and
patient
advocacy
(form of DTC?)
Clinicianphysician
network and
direct to
patients
Clinicianphysician
network and
direct to patients
Patient
advocacy
(form of
DTC?)
Patient
advocacy
(form of DTC?)
Patient
advocacy
(form of DTC?)
Patient
advocacy
(form of DTC?)
Mergers and
acquisitions
Jerini, New
River
Pharmaceutical
s, NPS
Pharma, TKT,
ViroPharma;
recently
acquired
Baxalta
Sanofi
acquired
Genzyme in
2006
2015 swap with
GSK (vaccines to
GSK; oncology to
Novartis)
Acquisition
of
Prosensa’s
drisapersen,
Nov 2014
None reported
to date
IONIS was
formerly ISIS
Pharmaceutical
s
Synageva,
Moderna,
Enobia,
Blueprint, XChem,
Ensemble,
Genomics
England,
Selventa
Partnerships
Many
partnerships;
examples
include
Sangamo and
UPMC
Alnylam
Alexion and
Novartis
partnered with
Ensemble Tx in
2013. Roche
partnered with
PTC; Roche also
with >150
partnerships
worldwide;
Celgene with
large number of
partnerships
Myriad
Genetics
(Dx)
Consortium
with Roche and
SMA Fdn in
SMA
Alnylam; Also
partnering with
AZ on CV,
metabolic, and
renal drugs
(Aug 2015)
Moderna
Therapeutics
(Sep 2014); XChem
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Strategic
investment
Voyager Tx, a
gene therapy
company, Feb
2015
Voyager
Therapeutics
(Feb 2015), a
gene therapy
company
seeking to
commercialize
novel gene
therapies for
severe CNS
disorders
Roche purchased
Trophos
(olesoxime for
SMA); Celgene
repurposed
thalidomide for
multiple myeloma
and other
oncology
indications, and
also developed
2nd- and 3rdgeneration
analogs
lenalidomide
(Revlimid) and
pomalidomide
(Pomalyst)
BioMarin is
in patent
litigation
with Sarepta
over exon
51 skipping
oligonucleoti
des
RG7800 and
RG7916 are
being jointly
developed by a
consortium of
Roche, PTC,
and SMA
Foundation
Roche and
IONIS (HD)
Alexion and
Moderna
announced an
agreement to
develop
messenger
RNA
therapeutics
(Mar 3, 2015)
Abbreviations: ASO, antisense oligonucleotide; AZ, AstraZeneca; CMO, contract manufacturing organization; CNS, central nervous system;
CV, cardiovascular; DTC, direct to consumer; Dx, diagnostics; HD, Huntingdon’s disease; M&A, mergers and acquisitions; mfg,
manufacturing; MPS, mucopolysaccharidosis; RD, rare disease; S&M, sales and marketing; SMA, spinal muscular atrophy; Tx, therapeutics;
UMN, unmet medical need; UPMC, University of Pittsburgh Medical Center; URD, ultra-rare disease
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