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Analisten , rapporten etc

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Frenky_Tornado
0
Uit andere degelijke bron (geeft in 'Jip & Janneke taal' weer waar het over gaat)

What happened:
• ProQR released positive interim results from its Phase 1/2 trial of QR-110 for Leber congenital amaurosis type 10 (LCA10). While the trial was not powered for any statistical significance, QR-110 demonstrated a remarkable improvement in vision for the majority of subjects such that these results have prompted ProQR to announce its intent to start a Phase 2/3 pivotal trial in 1H19 despite only having results from 10 patients dosed at relatively low doses for 3 months.
• The ongoing Phase 1/2 trial is a safety and proof of concept trial, with multiple exploratory efficacy outcomes. Though the minimum treatment period is 12 months, ProQR moved up the interim analysis to 3 months due to positive emerging data from just the first two dose cohorts. 62.5% (5 of 8) of patients showed improvement in best corrected visual acuity (BCVA) (improvement of greater than -0.3 LogMAR from baseline) and in the ability to navigate a customized mobility course. There was a meaningful improvement in full field stimulus test (FST) and nystagmus tracking (ocular instability; OCI).
• At this point in the trial, QR-110 has proven to be safe and well-tolerated, with no serious adverse events (SAEs) related to the treatment or injection procedure. There were some mild local adverse events at the injection site, but there was no evidence of inflammation and no patients have discontinued treatment early.
Our take:
• BCVA as measured by logarithm of the minimum angle of resolution (logMAR) is the most important registrational endpoint for ophthalmic therapies, with the traditional clinically meaningful threshold being -0.3 logMAR (3 lines on an eye chart). At interim analysis, patients experienced an improvement of -0.67 logMAR in their treated eye versus 0.02 logMAR in their untreated eye. Though the sample size was small (n=8) and the trial was not powered for statistical significance, the improvement in mean logMAR was nevertheless statistically significant (p=0.011).
• The data included results from 3 pediatric patients and 5 adults. There was a clear correlation between baseline visual acuity and likelihood to respond to therapy, and the two non-responders were adults that started with very low baseline visual acuity. ProQR has not confirmed what patient population will be used for the pivotal trial, but since younger patients are more likely to be significant responders, we expect to see this reflected in the enrollment of the Phase 2/3 trial.
• ProQR’s drug candidates are unified by the fact that they are all RNA-based molecules that exert their effects on mutated mRNA such that a wild-type or at least functionally correct protein can be made from the corrected mRNA. ProQR’s drugs have either been shown clinically, or are expected, to have a highly favorable safety profile. ProQR circumvents the historical problem of RNA-based drugs being difficult to usefully give systemically by focusing solely on diseases that can be addressed with local drug administration. This is exemplified by ProQR’s focus on ophthalmic diseases that can be treated with injections directly into the eye, which delivers the drug to the target area and minimizes the chances for systemic toxicity. We believe that today’s results will further increase ProQR’s focus on its ophthalmic franchise.
ivet
4
PROQR THERAPEUTICS N.V.
PRQR | $21.60
OUTPERFORM | TARGET PRICE: $35.00
Initiating Coverage
Josh Schimmer
310-473-2942
josh.schimmer@evercoreisi.com
Maneka Mirchandaney
212-497-0881
maneka.mirchandaney@evercoreisi.com
Shenstone Huang
212-446-9436
shenstone.huang@evercoreisi.com
Amy Liu
212-497-0825
amy.liu@evercoreisi.com

Initiating Coverage At Outperform With
$35PT
And At Last I See The Light
We are initiating coverage on PRQR with an OP rating and $35 price
target. The company's recent clinical data for QR-110 for treatment of
LCA-10 (congenital cause of blindness) has transformed the outlook for
the company. The striking results not only appear to establish proof of
concept for the lead program, it also helps de-risk the company's broader
platform.
¦ A whole new PRQR world: Some still associate PRQR with its
initial mRNA targeting program for cystic fibrosis, which has failed to
resonate with the investor community. But the company has steadily
re-positioned its platform to focus on other topical indications such
as ophthalmology and dermatology. With QR-110 off to the races
and validating its strategy, we can turn our attention to the rest of its
pipeline.
¦ Eye to eye: Clinical data for QR-110 far surpassed our
expectations with a number of LCA-10 patients experiencing dramatic
improvements in vision. Given ONCE's Luxturna's ability to navigate
development/regulatory hurdles to reach commercialization for LCARPE65,
we believe the trail has been blazed for QR-110 to advance
rapidly to market. The price of '110 will depend on whether or not the
rest of the pipeline bears fruit, so we believe peak (2024) sales could
range from $150-$225M. As such, this program alone could justify
upside to the current valuation (assuming 4-5x peak revenue).
¦ More to potentially come: QR-110 validated mRNA targeting
therapeutics for retina diseases, and so did Vitravene back in the
day for CMV retinitis. Other RNAi/ASO companies have pursued
target organs like liver and CNS, leaving PRQR a niche in eye
and skin, where local delivery obviates need for systemic exposure/
risks. Watch for clinical results from QR-313 (Exon 73 skipper) for
Dystrophic Epidermolysis Bullosa in 2H18 (a potential $100M+ oppy)
and QR-421a (Exon 13 skipper) for Usher Syndrome in mid-2019
(potential $400M+ oppy).
¦ So much more than a dream: We are in the midst of a wave of
DNA/mRNA targeting therapies. One of the most exciting aspects of
these is their modularity. Once proof of concept in a target organ is
established for one genetic disease, the targeting sequence can be
swapped out to address another disease while keeping everything
else the same. Initial success with QR-110 bodes extremely well
for the rest of PRQR's locally administered pipeline-- both disclosed
programs as well as undisclosed ones in even earlier pre-clinical
stages.
¦ Key risks: Traditional development, regulatory, commercial (inc
pricing) and competitive (from other platforms/companies inc EDIT
and WVE) risks for an emerging platform in the gene targeting field
apply to PRQR's portfolio.

zie verder!: evercore.na.bdvision.ipreo.com/NSight...
Tom3
0
AB ivet. Het enige wat we moeten doen is het nauwkeurig volgen van Editas en WVE , zoals aangegeven door Evercore.

www.bloomberg.com/quote/WVE:US
ivet
0
cantor2.bluematrix.com/sellside/Email...

(hier is 2e oogprogramma mee in opgenomen)

ProQR Therapeutics N.V. (PRQR- $18.51)
Rating: Overweight
Price Target: $40.00
Usher-ing in upside with data in Usher Syndrome in 2019; Initiate at Overweight, $40 PT
REV
1Q
2Q
3Q
4Q
2017A
0.0A
0.0A
0.0A
1.0A
2018E
0.0A
1.0A
3.0A
0.0E
2019E
0.0E
0.0E
0.0E
0.0E
EPS
1Q
2Q
3Q
4Q
2017A
(0.45)A
(0.47)A
(0.42)A
(0.39)A
2018E
(0.34)A
(0.23)A
(0.18)A
(0.24)E
2019E
(0.25)E
(0.27)E
(0.28)E
(0.29)E
FY
2017A
2018E
2019E
REV
1.0A
4.4E
0.0E
EPS
(1.72)A
(0.96)E
(1.09)E
REV?in?€M;?EPS?in?€/sh
Investment Summary. Initiating at OW and $40 12-month PT.
ProQR is
a European RNA-based platform technology company focused on developing
therapeutics for inherited blindness. Although shares are up close to 500% YTD (vs.
XBI down 9%) after positive proof of concept in first ophthalmology drug QR-110,
we think this could be just the beginning of a major turning point for the company’s
platform. In September, ProQR established the first proof of concept for its RNA
platform in inherited ophthalmology with lead asset QR-110. We think QR-110 could
be just the tip of the iceberg in terms of PRQR’s platform potential in inherited forms
of blindness. In this report, we are focused on the company’s next clinical program in
Usher’s Syndrome which represents a larger opportunity than QR-110 (we estimate
$1.1B peak vs. $300M peak) and is guided to have clinical data in 2019.
n
We think LCA10 data provided not only positive data but also gives us
increased confidence in platform capability and the next drug in clinic,
QR-421a.
Lead asset, QR-110, is targeting an ultra-rare genetic eye disease
called Leber’s congenital amaurosis type-10 (LCA10). We believe that QR-110's
proof-of-concept study provided compelling evidence of efficacy and we
estimate peak sales of $300M. Almost as important as the compelling LCA10
data, we think that this proof-of-concept data gave us reason to believe that
Usher’s Syndrome and other ophthalmology indications may be successful using
this platform technology. Key reasons we discuss in this report: 1) same delivery,
chemistry, safety and PK/PD profile as QR-110, 2) both programs target proteins
in the cilia in the retina, 3) USH2A patients have more retinal cells intact than
LCA10 patients.
n
USH2A clinical data in '19 could be a major value driver. We think it
is underappreciated by investors making risk/reward attractive into the
readout:
Shares could trade +150-225% (to ~$47-$62) vs. -30-60% ($8-$13/sh).
Mutations in the USH2A gene lead to blindness due to lack of a protein called
usherin. QR-421a is an exon skipping approach that could lead to increased
truncated usherin. QR-421a is moving into patients by early '19 and we expect
initial data in mid to 2H2019. If QR-421a is successful, we think it could sell
$1.1B+ at peak which is a nearly a ~4x larger opportunity than QR-110 ($300M).
n
Inherited ophthalmology diseases where PRQR’s platform is focused
represent a very large opportunity.
We estimate $4.5B+ in peak unadjusted
sales across PRQR’s disclosed clinical and preclinical targets. ProQR will have
two programs in clinical development by early '19 and is guiding for more to
enter the clinic over the next 12-18 months. At ~$750M in cap, we think current
levels give credit for the LCA10 opportunity, but not the platform’s potential
including QR-421a which is guided to have proof of concept data in 2019.
Current Statistics
Market Cap ($Mil)
$714
Avg. Daily Trading Volume (3 mo.) :
482,576
Shares Out (Mil) :
38.5
52 Wk. Range
$24.00 - $2.75
The Disclosure Section may be found on pages 96 - 99.
ivet
0
See Appendix A-1 for Analyst Certification, Important Disclosures and non-US research analyst disclosures.
Citi Research is a division of Citigroup Global Markets Inc. (the "Firm"), which does and seeks to do business with companies covered in its research reports. As a
result, investors should be aware that the Firm may have a conflict of interest that could affect the objectivity of this report. Investors should consider this report as only
a single factor in making their investment decision. Certain products (not inconsistent with the author's published research) are available only on Citi's portals.
15 Nov 2018 00:05:00 ET
¦
49 pages
Biotechnology
North America
¦
United States
ProQR Therapeutics (PRQR)
RNA Therapeutics Platform for Rare Disease; Init w/ Buy, TP $32
?
Initiating coverage of ProQR with Buy/High Risk, $32 TP.
ProQR is developing
RNA-based therapeutics for severe rare diseases lacking approved therapies, with
a focus on ophthalmologic disorders.
?
Lead program for Leber Congenital Amaurosis 10 (LCA10), a severe eye
disease leading to childhood blindness with ~2,000 addressable pts (p.C998X
mutation) in US/EU, has achieved proof-of-concept.
There are no available
therapies for LCA10 and ~1/3 of children have no light perception. ProQR’s drug
QR-110 is an intraocular injection that works by correcting a mutation (extra RNA
splice site) in the CEP290 gene in a component of our retinas (photoreceptors)
critical to vision. ~85% of LCA10 pts have the mutation QR-110 targets. Recent
interim Ph1/2 data (Sept. ‘18) have demonstrated very good proof-of-concept in
restoring vision to patients who entered the trial with only light perception (stock up
~130% on this). We think the QR-110 data reflected a degree of visual benefit
arguably better than what Spark’s Luxturna showed in the related disease LCA2.
ProQR will start a Ph2/3 in 1H19 with data 2H20. We assume a ~50% prob. of
success (PoS) with peak WW risk-adj. revs of ~$240M. The key competitor is
Editas’ gene-editing drug EDIT-101 (IND filed last month).
?
Next in the pipeline is Usher Syndrome Type 2A, another disease of blindness
with ~14K addressable pts (exon 13 mutations) in US/EU, also with no
approved therapies.
ProQR’s drug QR-421a is another intra-ocular injection
targeting defective photoreceptors. QR-421a works by forcing cells to skip the
defect (exon 13) in the USH2A gene that causes the disease. A Ph1/2 trial is
expected to start by 4Q18/1Q19 with initial data mid-19. Ahead of the data, we
believe that achieving proof-of-concept using a similar delivery approach for LCA10
provides some risk-mitigation. We assume a ~20% PoS with peak WW risk-adj.
revs of ~$550M.
?
Recently acquired QR-1123 (in-licensed WW rights from Ionis) for autosomal
dominant Retinitis Pigmentosa (adRP) with ~6k US/EU addressable pts (P23H
mutation).
RP typically leads to blindness by middle age, and there are no
approved therapies. A Ph1/2 is starting 2019. We assume ~15% PoS with risk-
adjusted revs of ~$185M.

ProQR Investment Thesis
We rate PRQR Buy/High Risk with a $32 target price.
ProQR is a Leiden, Netherlands based clinical staged biotechnology company
focused on developing novel RNA therapeutics for rare diseases. ProQR expects to
advance its lead clinical candidate, QR-110 for Leber Congenital Amaurosis 10
(LCA10), into a Ph2/3 (IILUMINATE) trial in 1H19. Recently reported (September
2018) topline Ph1/2 data for QR-110 in LCA10 demonstrated very good proof-of-
concept for vision restoration in a small number of patients. The company expects
to advance their second clinical ophthalmology asset QR-421a for Usher Syndrome
Type 2A (USH2A) into a Ph1/2 (STELLAR) trial by 4Q18/1Q19. In October 2018,
ProQR, in-licensed worldwide rights to QR-1123 (from Ionis Pharmaceuticals) for
autosomal dominant retinitis pigmentosa (adRP), which is expected to enter a Ph1/2
clinical trial in 2019. ProQR's dermatologic clinical asset, QR-313 for Dystrophic
Epidermolysis Bullosa (DEB), is currently enrolling pts in a Ph1/2 (WINGS) trial with
topline data expected in 4Q18/1Q19.
Key Aspects of Our Thesis
?
Solid rationale for targeting rare ophthalmologic and skin diseases with no
approved therapies
– LCA10 (a severe eye disease leading to childhood
blindness), USH2A (leading cause of combined deafness and blindness), RP
(leading to blindness in middle age), and DEB (severe blistering from birth) are
diseases with very high unmet needs and no approved therapies. Importantly,
the ophthalmological indications are not crowded (although Editas is developing
an intravitreal gene editing therapies for LCA10 and USH2A). DEB is more
crowded market with several different approaches being taken, but notably none
have been successful thus far.
?
Good proof-of-concept established in LCA10
– In September 2018, ProQR
presented interim data from their Ph1/2 trial. QR-110 treatment resulted in
clinically meaningful improvements in two clinical endpoints at three months: best
corrected visual acuity (BCVA) and a mobility test. Both of these endpoints could
be used as primary endpoints in the pivotal Ph2/3 (ILLUMINATE) trial for LCA10
which ProQR plans on initiating in 1H19, although the trial design has not yet
been finalized.
?
ProQR has three additional assets in the clinic or entering the clinic within
the next year
– A Ph1/2 (WINGS) trial for QR-313 in DEB is currently enrolling
patients, with initial data expected in 4Q18/1Q19. A Ph1/2 (STELLAR) trial for
QR-421a in USH2A is expected to initiate in 4Q18/1Q19. A Ph1/2 for QR-1123 in
adRP is expected to initiate in 2019.
ivet
0
RNA Therapeutics – A Novel Class of Drugs
Designed to Function At The RNA Level

The central dogma of molecular biology states that the flow of genetic information
begins with DNA, is transcribed into RNA, and is ultimately translated into proteins
that carry out most cellular functions. This provides multiple different points upon
which therapeutics could impinge, although to date development efforts have largely
focused on drugs designed to function at the protein level. However, recent
advances have allowed drug development to shift towards targeting DNA via gene
therapy/editing and RNA via splice correction, exon skipping, and mRNA
degradation (
Figure 3).
ProQR is developing RNA therapies that function by modulating endogenous pre-
mRNA transcripts that carry a pathogenic mutation. The therapies are designed to
correct extra splice sites introduced by mutations (i.e. splice correction;
Figure 4) or
to remove entire exons that harbor pathogenic mutations (i.e. exon skipping;
Figure
5). Through these mechanisms, ProQR's therapies are designed to produce a
corrected mRNA transcript that can be translated into an operational (although
smaller in the case of exon skipping) protein that is able to function normally. In
contrast, other types of antisense oligonucleotides and RNAi function by mediating
mRNA degradation through the recruitment of endogenous protein machinery
(RNase H and RISC, respectively).
ProQR's RNA therapies are also differentiated from mRNA therapies, which
function by delivering an exogenous
in vitro
transcribed mRNA into target cells,
rather than corrected the mutated endogenous pre-mRNA.
ProQR's lead clinical candidate, QR-110, is designed to function through a splice
correction mechanism for patients with LCA10 that harbor the Cys998X mutation
(
Figure 4). The Cys998X mutation results in an aberrant (i.e. extra) splice site prior
to exon 27 in the
CEP290
gene, which results in the inclusion of a pseudo-exon in
the
CEP290
mRNA. Unfortunately, the pseudo-exon carries a stop codon, which
results in the premature truncation and loss-of-function of the CEP290 protein.
Treatment with QR-110 is able to block the aberrant splice site, which results in the
correct removal of the pseudo-exon and allows the translation of a full-length,
function CEP290 protein.
ProQR's QR-421a and QR-313, both antisense oligonucleotides, are designed to
function through an exon skipping mechanism for patients with USH2A who harbor
a mutation in exon 13 in the
USH2A
gene and patients with DEB that harbor a
mutation in exon 73 of the
COL7A1
gene, respectively (
Figure 5). Both drugs block
splicing factors, which results in the removal of the exon carrying the pathogenic
mutations.
ProQR’s QR-1123, licensed from Ionis Pharmaceuticals, is a gapmer (a type of
oligonucleotide) with an allele–specific knockdown mechanism. This means that
QR-1123 specifically knocks-down the mutant allele (in this case a P23H mutation
in the
RHO
gene causing adRP) while sparing the wild-type allele.
ProQR has also developed an RNA editing platform called Axiomer. The technology
functions by having a specially designed RNA editing oligonucleotide bind to a
target RNA, which then recruits a protein called ADAR (adenosine deaminase
acting on RNA). ADAR then facilitates an A-to-G conversion at the target location.
Given that there are more than ~20,000 disease caused by G-to-A mutations, this
platform has the potential to become a useful therapeutic approach. While none of
ProQR's lead assets were developed utilizing the Axiomer platform, ProQR has
partnered with Galapagos to work on targets in fibrosis using this technology.
ivet
0
RNA Therapeutics Have Several Benefits
Over Gene Therapy

Genetic diseases caused by mutations in a single gene that result in loss-of-function
recessive phenotypes (such as LCA10, recessive DEB, and USH2A), are often
good candidates for gene therapy. However, an RNA therapy approach provides
several benefits over gene therapy, including:
1.
Not limited by the size of the gene being targeted –
Gene therapy is
currently limited by the size of the gene product that can be delivered.
For
example, some genes (such as CEP290, which harbors mutations that cause
LCA10) are too large to be enclosed within currently used viral vectors. In
contrast, RNA therapy does not require the delivery of an exogenous genomic
sequence, and therefore is into limited by the size of the target mRNA.
2.
Unlikely to result in target protein overexpression –
RNA therapies function
by repairing endogenously expressed RNA transcripts. Even if the therapy
were 100% efficient, it is unlikely to result in target protein expression greater
than physiological levels. On the other hand, gene therapy introduces an
exogenous DNA sequence which runs the risk of inducing target protein
expression at levels higher than normal. This risk becomes especially important
when considering proteins associated with cellular toxicity when
overexpressed.
3.
Lower risk of permanent off-target effects –
RNA therapies require patients
to be dosed repeatedly in order to maintain a therapeutic benefit. Therefore,
RNA treatment can be halted if complications arise, which could potentially
allow for a reversal of adverse effects. In contrast, the goal of gene therapy is a
permanent genetic change after a single administration, which carries the
potential for not only harmful on-target effects, but also potentially serious off-
target effects that cannot be reversed.


Leber Congenital Amaurosis
Leber Congenital Amaurosis (LCA) is a genetic disease characterized by
progressive vision loss typically beginning early in life. Vision loss is mediated by a
disruption of a process called phototransduction, which occurs in specialized retinal
cells called photoreceptors. For most types of LCA, both types of photoreceptors,
rods (responsible for low-light & black-and-white vision) and cones (responsible for
color perception) are affected, which results in progressive blindness. The
prevalence of LCA is estimated to be about 1 in 60,000 worldwide.
Leber Congenital Amaurosis 10
There are at least 16 different subtypes of LCA. One of the most common is LCA10,
which is caused by autosomal recessive loss-of-function mutations in the
CEP290
gene. This protein plays a role in cilium function (cilia are cellular organelles that
protrude outside of the cell and play an important role interacting with the
extracellular environment), which is particularly important for photoreceptor cell
function. LCA10 is considered one of the more severe forms of LCA and is
generally characterized by preserved cone vision and severely impaired rod vision
(although both types of photoreceptor cells are affected at later stages of the
disease). This subtype is estimated to affect about 15-20% of LCA patients (
Figure
6).

Diagnosis and Management of LCA10
LCA10 diagnosis can typically be made on clinical examination: patients first
present by failing a vision screening test at an early age, with additional symptoms
such as eye rubbing and involuntary eye movements providing diagnostic clues.
While an LCA10 diagnosis is confirmable through genetic testing, not all patients
are provided this option given the lack of disease modifying therapies available for treatment. In other words, there has historically been no benefit for clinicians or
insurance companies knowing a patient's specific genotype. Importantly, there has
been a recent push for LCA genotyping since the approval of Luxturna (gene
therapy; Spark Therapeutics) for LCA2, as well as the increased interest in
development of therapies for other LCA subtypes, such as QR-110 (ProQR's lead
clinical candidate) and EDIT-101 (gene therapy in preclinical development; Editas)
for LCA10.
Currently, there are no approved therapies for LCA10. Most patients receive only
supportive care, which is primarily focused on visual aids such as glasses and
magnifying glasses. Unfortunately, many of these patients are unable to work and
maintain careers given their profound loss of vision.
QR-110 Is Being Developed for Most Common
LCA10 Mutation
ProQR is developing their lead therapeutic, QR-110, for the treatment of LCA10.
QR-110 is designed to target a specific mutation in
CEP290
: p.Cys998X (meaning
the insertion of a premature stop codon at position 998). This mutation results from
the genetic change c.2991+1655A>G (meaning that an A was changed to a G at
1655bp from the 5

end of the intron immediately downstream of the
CEP290
exon
ending at position 2991). This genetic change creates a novel cryptic splice site

a
splice site which is not normally present

that gives rise to a truncated protein that
is not functional. While minimal amounts of wild-type protein (i.e. functional) are still
occasionally produced in some patients, it is often not sufficient to compensate for
the loss-of-function resulting from the truncated protein. QR-110 is designed to
"mask" this cryptic splice site, thereby preventing truncation of the CEP290 protein
and shifting the ratio of mutant to wild-type transcript in favor of the wild-type
transcript. Although there have been a number of other CEP290 mutations that
have been implicated in LCA10, Cys998X is the most common.
~2,000 LCA10 Patients Could Benefit from QR-
110
QR-110 is designed to only treat LCA10 patients carrying a p.Cys998X mutation.
The p.Cys998X mutation is relatively common with about 85% of LCA10 patients
carrying at least one allele (~10-20% of these patients are homozygotes and
=
75%
are heterozygotes). We estimate the addressable market for QR-110 is about 2,000
LCA10 Cys998X patients in the Western World (US and EU).
Preclinical Data Demonstrates QR-110 Can
Modulate CEP290 Cys998X Mutations
ProQR has shown that QR-110 corrects disease-causing RNA in patient cells
in-
vitro
, resulting in increased CEP290 protein levels and improvements in cilia
function.
In-vivo
, the company has shown that QR-110 makes it to the outer nuclear
layer which houses the photoreceptor cells underlying LCA10 pathophysiology.
QR-110
In-Vitro
Proof-of-Concept Demonstrates Molecular
Mechanism Is Working
In patient-derived fibroblasts, ProQR has shown that treatment with QR-110 (25
µM)
is sufficient to correct
CEP290
transcripts and increase CEP290 protein levels
ivet
0
This provides evidence that the QR-110 is working as
expected and is converting mutant transcripts into wild-type (i.e. functional)
transcripts. However, this model has its limitations given that fibroblast cells, even
though they carry disease-causing patient mutations, are not directly linked to
LCA10 disease progression
ProQR has used an optic cup model in which patient-derived fibroblasts are
reprogrammed to iPS cells, which are then differentiated to retinal pigmented
epithelium cells and neural retinal cells. This organoid model is highly relevant since
it contains not only patient-derived mutations, but also utilizes cells resembling
those involved in LCA10. Using this model, ProQR has demonstrated that treatment
with QR-110 (10
µM)
is sufficient to significantly increase CEP290 wild-type
transcript levels and decrease CEP290 mutant transcript levels (
Figure 7, right
panel). Furthermore, there an improvement in cilium function was observed, as
indicated by an increase in the percentage of ciliated cells and the length of cilia,
which suggests the drug is exerting an on-target effect.

etc. etc. het is een wat te lijvig rapport om helemaal hier neer te zetten..zal kijken of ik iets van highlights tegenkom.
ivet
0
Prevalence of Patients Who Might Benefit from
QR-313
The subset of DEB patients who have mutations in exon 73 is about 15%. We
calculate an addressable patient population of about 400 patients in the Western
World.
QR-313 Preclinical Data Is Positive
In patient-derived fibroblasts, ProQR has shown that treatment with QR-313 (100
µM)
is sufficient to increase COL7A1 protein levels (
Figure 16, left panel). These
cells carry disease-causing patient mutations making them a relevant model. This
work is an important proof-of-concept demonstrating that QR-313 is having the
desired molecular effect.
QR-313 is formulated as a topical cream which will be applied to patient skin
wounds. ProQR has demonstrated that QR-313 reaches the relevant cells of the
epidermis and dermis in a minipig wounded skin model (
Figure 16, right panel). In
contrast, QR-313 does not penetrate intact skin.

Upcoming Milestones for QR-313
The upcoming milestones for QR-313 in DEB with mutations in exon 73 are:
1)
interim data from Phase 1/2 (WINGS; NCT03605069) in 4Q18/1Q19 and
2)
complete readout of the trial in 2019.
Competition in DEB
A number of different companies are working on DEB, taking approaches such as
topical peptides, gene therapy, and autologous cell therapy combined with gene
therapy. In 2017, Amicus Therapeutics stopped development of SD-101, an anti-
inflammatory for EB, when it failed to meet primary and secondary endpoints in a
Ph3 trial.

Probability of Success
We model QR-110 with a 50% probability of success (PoS), QR-421a with a 20%
PoS, QR-1123 with a 15% PoS, and QR-313 with a 15% PoS. We assign a 50%
PoS for QR-110 given the recent positive Ph1/2 proof-of-concept data. We assign a
slightly higher PoS for QR-421a in USH2A based on the positive read-through from
clinical data in LCA10. A recent publication that analyzed over 400K clinical trials
found the probability of a Ph1 asset gaining regulatory approval was 13.8%.
1
Based
on this we assign a 15% PoS for QR-313 and QR-1123.
Our bull case assumes an 80% PoS for QR-110 in LCA10, a 30% PoS for QR-421a
in USH2A, and a 25% PoS for QR-313 in DEB. Our bear case assumes ProQR
trades at cash.
Assumptions for QR-110 in LCA10
We assume QR-110 will be approved for use in LCA10. We estimate a peak
addressable population of 900/1,300 in the US/EU in 2032. We assume a peak
market share of 60%/50% in 2032, which implies a peak population of LCA10
patients treated with QR-110 of 460/540 in the US/EU.

etc. etc. uiteraard met bijbehorende disclaimers, grafieken, cijfers, modellen, foto´s etc.
jan941
0
Beste Flosz,, dank voor dit bericht, leuke herinneringen aan datgene wat je altijd plaatste bij Crucell.
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