NSR-RPGR data presented at EURETINA 2018 Congress
demonstrated proof of concept with durable dose-related
improvements seen as early as month 1 across multiple
microperimetry analyses
Nightstar Therapeutics plc (NASDAQ:NITE), a clinical-stage gene
therapy company developing treatments for rare inherited retinal
diseases, today announced that positive preliminary safety and
efficacy data of NSR-RPGR from the dose escalation study in the
Phase 1/2 XIRIUS trial were presented today at the EURETINA 2018
Congress.
“We initiated this study last year, with the
anticipation of demonstrating safety and stabilization of disease
with NSR-RPGR, our codon-optimized gene therapy for XLRP,” said
Tuyen Ong, M.D., chief development officer of Nightstar. “Based on
the preliminary findings of improved visual function as measured by
microperimetry, we have established early proof of concept in XLRP,
our second clinical program. As we move forward with the expansion
study, we look forward to continuing to execute our clinical
programs and sharing additional data on our XLRP program at future
medical meetings.”
XIRIUS is a Phase 1/2, open-label, dose-ranging,
single-eye clinical trial consisting of a dose escalation study and
an expansion study with sites in both the United States and the
United Kingdom. The XIRIUS trial is intended to evaluate the
safety, tolerability and efficacy of NSR-RPGR for the treatment of
XLRP in patients with the RPGR mutation.
Enrollment of the dose escalation study in the
XIRIUS trial was completed in August 2018, consisting of six
cohorts of three patients each for a total of 18 adult patients.
Each patient in the trial received a single sub-retinal injection
of NSR-RPGR. Doses ranged from 5x10^9 genome particles (gp) in
cohort 1 up to 5x10^11gp in cohort 6. One-year follow-up data
on all 18 patients in the dose escalation study is expected to be
available in the second half of 2019.
Preliminary NSR-RPGR Data from the Dose
Escalation Study of XIRIUS Trial in XLRP
Safety and efficacy data were presented from the
one-month follow-up for the first five cohorts. As of September 4,
2018, data through varying timepoints up to 12 months was available
for the earlier cohorts. However, the one-month follow-up was the
common timepoint for which the complete set of safety and efficacy
data was available for all patients in cohorts 1-5. One-month
follow-up data were not yet available for cohort 6 as not all
patients had completed their one-month visit. In addition to the
one-month data for the first five cohorts, microperimetry data were
presented for cohort 3 through the six-month follow-up visit.
Efficacy Summary: At the
one-month follow-up after treatment with NSR-RPGR, all three
patients in cohort 3 (5x10^10 gp), one of three patients in cohort
4 (1x10^11 gp) and one of three patients in cohort 5 (2.5x10^11 gp)
experienced an improvement in microperimetry, as discussed further
below. Among the patients in cohorts 4 and 5, improvements in
microperimetry in the treated eyes were observed in those patients
receiving a second course of steroids. The safety data and efficacy
signals observed in the higher dose groups provided the basis for
an early clinical proof of concept for the XIRIUS trial to progress
to the expansion study.
All patients in cohort 3 (5x10^10 gp) showed an
improvement in microperimetry endpoints at one, three and six
months of follow-up after treatment with NSR-RPGR with general
concordance across the various analyses described below. Efficacy
signals were generally observed within one month and maintained
through the six-month follow-up visit for patients in this
cohort.
Microperimetry (MP):
Microperimetry measures changes in visual function by gauging the
ability to detect varying levels of light stimulus projected across
the macula, the central part of the retina responsible for visual
acuity. In the XIRIUS trial, microperimetry was measured on a
grid of 68 points across the macula. Comparisons are made to
baseline measurements in the treated eye as well as in comparison
to the untreated eye.
- Overall Macula Sensitivity: Change in the average retinal
sensitivity (in dB) of all 68 test loci. A responder analysis
was also completed with a threshold of at least 2dB.
- Central 16 Sensitivity: Change in the average retinal
sensitivity (in dB) from the 16 test loci closest to the center of
the macula.
- Number of Improved Loci: The number of patients with at least a
5dB improvement in over 10% of loci (>= 7 loci).
The following table provides a summary of the
microperimetry data observed in cohorts 1-5 at the one-month
follow-up visit. Microperimetry data from the latest available
timepoints for cohorts 1-5 (ranging from one month in cohort 5
through 12 months in cohort 1) were generally consistent with the
one-month data presented below.
|
Overall Macula Sensitivity (Mean
Change (dB) / # of Patients with ≥2dB Increase) |
Central 16 Sensitivity (Mean Change
(dB)) |
Improved Loci (# of Patients with ≥5dB
Increase at ≥ 7 loci) |
|
Treated
Eye |
Untreated Eye |
Treated
Eye |
Untreated Eye |
Treated
Eye |
Untreated Eye |
Cohort 1 (n=3) |
+0.1
dB / 0 pts |
+0.2
dB / 0 pts |
+0.5
dB |
+0.4
dB |
0
pts |
0
pts |
Cohort 2* (n=2) |
+0.2
dB / 0 pts |
-0.8
dB / 0 pts |
-0.1
dB |
-0.8
dB |
1
pts |
0
pts |
Cohort 3 (n=3) |
+2.4
dB / 3 pts |
-0.1
dB / 0 pts |
+6.1
dB |
-1.0
dB |
3
pts |
0
pts |
Cohort 4 (n=3) |
+0.1
dB / 1 pts |
-0.1
dB / 0 pts |
+1.2
dB |
-0.2
dB |
1
pts |
0
pts |
Cohort 5 (n=3) |
+0.6
dB / 1 pts |
+1.2
dB / 1 pts |
-0.6
dB |
+1.4
dB |
1
pts |
1
pts |
* One patient in cohort 2 was excluded from the
analysis because triplicate testing was not performed at
baseline.
The following table summarizes the changes in
microperimetry observed from baseline through the six-month
follow-up visit for cohort 3 using the three microperimetry
analyses described above:
|
Overall Macula Sensitivity (Mean
Change (dB) from Baseline) |
Central 16 Sensitivity (Mean Change
(dB)) |
Improved Loci (# of Patients with ≥5dB
Increase at ≥ 7 loci) |
|
Treated
Eye |
Untreated Eye |
Treated
Eye |
Untreated Eye |
Treated
Eye |
Untreated Eye |
|
|
|
|
|
|
|
Month 1 |
+2.4
dB |
-0.1
dB |
+6.1
dB |
-1.0
dB |
3
pts |
0
pts |
Month 3 |
+2.4
dB |
-0.3
dB |
+5.6
dB |
-1.1
dB |
3
pts |
0
pts |
Month 6 |
+2.3
dB |
-0.5
dB |
+5.1
dB |
-1.2
dB |
3
pts |
0
pts |
|
|
|
|
|
|
|
The efficacy data for cohort 3 was further
analyzed using a histogram analysis, which revealed that the mean
number of loci with retinal sensitivity improvements was
consistently greater in the treated eyes as compared to the
untreated eyes. Conversely, the mean number of loci with
worsening retinal sensitivity was consistently greater in the
untreated eyes as compared to the treated eyes for cohort 3.
Ellipsoid Zone (EZ): Ellipsoid
zone measurements use optical coherence tomography to quantify the
extent of undamaged photoreceptors remaining in the retina.
No significant decreases in EZ from baseline were observed through
the last follow-up visit for which data were available (ranging
from one month in cohort 5 to 12 months in cohort 1). Due to
the advanced stage of disease of patients enrolled in this dose
escalation study, only two patients (one in cohort 2 and one in
cohort 5) had a measurable baseline EZ that extended beyond the
central 5 degrees of the macula. Prior natural history studies have
shown that significant changes in EZ may require at least 1 year to
1.5 years to be detected, with follow-up visits on an annual basis
being sufficient to detect progression. One-year follow-up
data on all 18 patients in the dose escalation study is expected to
be available in the second half of 2019. Nightstar plans to enroll
patients into the expansion study with higher measurable baseline
EZ to allow assessment and correlation of this anatomical endpoint
with functional improvements in microperimetry.
Visual acuity (VA): Best
corrected visual acuity was assessed using the clinically validated
vision test chart developed for the Early Treatment of Diabetic
Retinopathy Study (ETDRS). The mean baseline VA for treated
eyes in patients in cohorts 1-5 ranged from 22 letters to 77
letters, while the mean baseline VA for untreated eyes ranged from
37 letters to 78 letters, respectively. At the latest
follow-up timepoints for which data were available (ranging from
three months in cohort 5 to 12 months in cohort 1), the visual
acuity of 93% of patients in cohorts 1-5 was maintained within five
ETDRS letters, or one line, of baseline in both the treated and
untreated eyes.
Safety Summary: Available
safety data (ranging from three months in cohort 5 to 12 months in
cohort 1) from the 15 treated patients in cohorts 1-5 indicates
that NSR-RPGR was well-tolerated. The safety profile in the dose
escalation study is generally consistent with that of surgical
vitrectomy procedures and what has been observed in clinical trials
of other ocular gene therapies. No serious adverse events related
to treatment were reported and no early discontinuations or dose
limiting toxicity were observed. Mild drug-related
inflammation that potentially dampened efficacy was seen in the
treated eyes of cohorts 4-5, with treatment efficacy observed to
have been rescued in patients who received additional steroid
treatment.
Adverse events of varying severity and duration
related to the vitrectomy procedure or drug have been observed in
the dose escalation study such as retinal changes, intraocular
inflammation and visual disturbances.
The Data Monitoring Committee (DMC) reviewed
preliminary safety data for cohorts 1-5 and recommended escalation
to cohort 6. The DMC also has not restricted pediatric enrollment
in either the dose escalation study or expansion study.
XIRIUS Expansion Study
Based on the totality of results to date,
Nightstar expects to initiate enrollment of the expansion study in
the XIRIUS trial in the fourth quarter of 2018. The expansion study
is intended to enroll approximately 30 adult and pediatric patients
at a therapeutic dose informed by the dose escalation study and a
low-dose control group of approximately 15 patients. Preliminary
efficacy data from the expansion study is expected to be available
in mid-2019, with one-year follow-up data expected to be available
in 2020.
R&D Webcast and Conference Call
Information
Nightstar will host an R&D Day on Monday,
September 24, with presentations beginning at 8:00 a.m., Eastern
Time. The R&D Day will feature presentations on the preliminary
NSR-RPGR data presented at EURETINA 2018 and Nightstar’s other
pipeline programs.
The R&D Day event will be webcast live under
the investor relations section of Nightstar’s website at
ir.nightstartx.com. The dial-in details for the call are
+1-877-491-5960 or +1-786 815-8441 (international), Conference ID:
1565326. To access the live webcast, please visit
ir.nightstartx.com. A replay of the webcast will be available on
the Nightstar website for two weeks following the conference.
About NSR-RPGR
NSR-RPGR is comprised of a standard AAV8 vector
containing codon-optimized cDNA that is designed to produce human
RPGR inside the eye. Nightstar has developed a codon-optimized gene
that features RPGR protein expression levels up to four times
higher than with a wild-type RPGR coding sequence. In addition,
codon optimization provides greater sequence stability, which
results in the consistent production of an identical protein
product. NSR-RPGR is designed to produce RPGR-ORF15, the form of
RPGR preferentially expressed in the retina.
About X-Linked Retinitis Pigmentosa
(XLRP)
XLRP, a form of retinitis pigmentosa, is a rare
inherited X-linked recessive genetic retinal disorder primarily
affecting males. Approximately 70% of XLRP cases are due to
variants in the genes responsible for the production of RPGR. RPGR
is involved in the transport of proteins necessary for the
maintenance of photoreceptor cells. Loss of RPGR function in the
retinal cells causes the progressive loss of rod and cone
photoreceptors, leading to the loss of vision experienced by
patients. The estimated worldwide prevalence of XLRP due to RPGR
variants is approximately one in 40,000 people, which translates to
approximately 17,000 patients in the United States and the five
major European markets. There are no treatments currently available
for XLRP. Nightstar is conducting a prospective, natural
history observational study, referred to as the XOLARIS study, to
better understand the progression of untreated XLRP in up to
approximately 100 patients enrolled from approximately 23 centers
in North America and Europe.
About Nightstar
Nightstar is a leading clinical-stage gene
therapy company focused on developing and commercializing novel
one-time treatments for patients suffering from rare inherited
retinal diseases that would otherwise progress to blindness.
Nightstar’s lead product candidate, NSR-REP1, is currently in Phase
3 development for the treatment of patients with choroideremia, a
rare, degenerative, genetic retinal disorder that has no treatments
currently available and affects approximately one in every 50,000
people. Positive results from a Phase 1/2 trials of NSR-REP1 were
published in The Lancet in 2014 and
in The New England Journal of
Medicine in 2016.
For more information about Nightstar or its
clinical trials, please
visit www.nightstartx.com.
Cautionary Language Concerning
Forward-Looking Statements
This press release contains “forward-looking
statements” within the meaning of the Private Securities Litigation
Reform Act of 1995. The words “believe,” “anticipate,” “could,”
“intend,” “estimate,” “will,” “would,” “may,” “should,” “project,”
“target,” “track,” “expect” or other similar expressions are
intended to identify forward-looking statements, although not all
forward-looking statements contain these identifying words. All
statements contained in this press release other than statements of
historical facts are forward-looking statements, including, without
limitation: our planned and ongoing clinical trials for NSR-REP1
and NSR-RPGR, including our Phase 3 STAR trial in choroideremia and
Phase 1/2 XIRIUS trial in X-linked retinitis pigmentosa; potential
results and timelines relating to the dose escalation study in the
XIRIUS trial and the planned expansion study in the XIRIUS trial;
the potential utility of prior preclinical and clinical data and
the data and endpoints presented herein in predicting future
clinical results for our product candidates and any results of
assessments to be conducted by regulatory agencies; the doses of
NSR-RPGR to be used in the expansion study in the XIRIUS trial and
future trials of NSR-RPGR; the continued clinical development of
our pipeline; the timelines associated with our research and
development programs including the timing of patient enrollment and
the release of data from ongoing clinical trials and studies; the
prevalence of patient populations for our targeted indications; and
statements about our cash position and sufficiency of capital
resources to fund our operating requirements, trends and other
factors that may affect our financial results. These
forward-looking statements are based on management's current
expectations of future events as of the date of this release and
are subject to a number of substantial known and unknown risks,
uncertainties and other factors that may cause our actual results,
levels of activity, performance or achievements to be materially
different from the information expressed or implied by these
forward-looking statements, including those related to the timing
and costs involved in commercializing any product candidate that
receives regulatory approval; the initiation, timing and conduct of
clinical trials; the availability of data from clinical trials and
expectations for regulatory submissions and approvals; whether
interim results of a clinical trial will be predictive of the final
results of the trial; whether results of small or early stage
clinical trials will be predictive of the results of later-stage
trials; our scientific approach and general development progress;
the availability or commercial potential of the our product
candidates; the sufficiency of our cash resources; and other risks
and uncertainties set forth in Item 3.D. "Risk Factors" section of
our Annual Report on Form 20-F for the year ended December 31, 2017
and subsequent reports that we file with the U.S. Securities and
Exchange Commission. We may not actually achieve the plans,
intentions, estimates or expectations disclosed in our
forward-looking statements, and you should not place undue reliance
on our forward-looking statements. Actual results or events could
differ materially from the plans, intentions, estimates and
expectations disclosed in the forward-looking statements we make.
We anticipate that subsequent events and developments will cause
our views to change. We are under no duty to update any of these
forward-looking statements after the date of this press release to
conform these statements to actual results or revised expectations,
except as required by law. You should, therefore, not rely on these
forward-looking statements as representing our views as of any date
subsequent to the date of this press release. Any reference to our
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Contact:Senthil Sundaram, Chief
Financial OfficerBrian Luque, Sr. Manager, Investor
Relationsinvestors@nightstartx.com
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