Mereo BioPharma Group plc (NASDAQ: MREO, AIM: MPH), "Mereo" or the
"Company" or the "Group," today announces 12-month topline data
from the Company's Phase 2b dose-ranging "ASTEROID" clinical study
of setrusumab (BPS-804), an anti-sclerostin antibody, in
adults with Type I, III or IV osteogenesis imperfecta (OI), a rare
bone disease with no approved treatments. ASTEROID was the largest,
prospectively-designed, interventional clinical study to be
performed in this patient group.
The primary endpoint of the ASTEROID study was
change in Trabecular Volumetric Bone Mineral Density (Tr vBMD) of
the radius (wrist) over baseline after 12 months of treatment as
measured by High Resolution peripheral Quantitative Computed
Tomography (HR-pQCT). As a result of the unexpected high
heterogeneity of the study patients’ trabecular bone baseline
values at the wrist (including both very low and very high
trabecular bone at baseline as compared to the literature1), the
primary endpoint was not met at any of the three setrusumab dose
levels. HR-pQCT is a relatively new imaging technique that has not
been used widely in clinical studies and was chosen in order to
improve the understanding of the effect of setrusumab on the bone
biology in OI patients, given it can measure both trabecular and
cortical vBMD separately. Importantly, an increase in total vBMD at
the wrist as measured by HR-pQCT (measuring cortical and trabecular
together), a secondary endpoint of the study, was observed and
reached statistical significance in the medium and high dose
cohorts. Mean increases in total vBMD were 4.11% (p=0.004), 4.5%
(p=0.028), and 0.58% (p=0.97) in the high, medium, and low dose
cohorts, respectively. This suggests total vBMD increases were
driven by the ability of setrusumab to increase cortical vBMD.
The study achieved its important secondary
endpoint of increase in areal Bone Mineral Density (BMD) at the
lumbar spine at 6 and 12 months over baseline using two-dimensional
dual-energy X-ray absorptiometry (DXA), a well-established
measurement tool of BMD (cortical + trabecular bone), reaching
statistical significance in the high and medium doses cohorts at
both 6 and 12 months with a clear dose-dependent response. Mean
increases in areal BMD at the lumbar spine were 8.8% (p<0.001),
6.8 % (p<0.001), and 2.6% (p=0.057) in the high, medium, and low
dose cohorts at 12 months, respectively. Moreover, increases in
areal BMD were consistent across all OI subtypes (I, III or IV)
represented in the study and improved with duration of treatment.
Statistically significant changes in areal BMD were also observed
by DXA at the femoral neck and total hip with mean increases of
3.1% (p=0.022) and 2.2% (P=0.011), respectively, at 12 months in
the high dose cohort.
Although the ASTEROID study was not powered to
show a difference in fracture rates, a trend of reduction in
fractures was observed in the high dose cohort. Setrusumab was safe
and well-tolerated in the study. There were no cardiac-related
safety concerns observed in the study.
“These topline 12-month results from the
ASTEROID study demonstrate a clear, dose-dependent, statistically
significant bone building effect of setrusumab at multiple
anatomical sites in adult OI patients irrespective of OI subtype,”
said Dr. Denise Scots-Knight, Chief Executive Officer of Mereo.
“The DXA data clearly differentiate setrusumab from other
therapeutic agents in OI types I, III and IV, such as teriparatide,
where a 4.7% increase was observed at the lumbar spine at 12 months
and where the effect was significantly lower in types III & IV
versus type I OI patients2. Further, the DXA data also show a
consistent improvement at 12 months in areal BMD at the lumbar
spine compared to the open-label data set from the study that we
first reported in May 2019 where a 3.5% change from baseline was
observed seen at 6 months in the highest dose cohort.”
Dr. Scots-Knight continued, “The trend of
decrease in fractures observed in the high dose cohort is also
particularly encouraging. Based on these data, we are excited to
move forward with the preparations for our pivotal pediatric study
in children with OI as originally planned, which will be based on a
primary endpoint of fracture rate over a 12-month period. We
believe setrusumab has the potential to become the first approved
pharmacologic treatment for the OI patient community and would like
to thank the investigators and patients for participating in the
ASTEROID study, the largest ever completed interventional trial in
adult OI."
“The technique of HR-pQCT is a relatively new
and cutting-edge technology in bone research. We believe the
HR-pQCT data from the ASTEROID study indicate a significant
improvement in total vBMD that is driven by cortical changes, which
differentiates setrusumab from existing bone-building agents,” said
Dr. Alastair MacKinnon, Chief Medical Officer of Mereo. “It is
important to emphasize that it is not possible to build bone that
does not already exist, which may be the case with some patients’
trabecular bone at the wrist in this study given the variable
HR-pQCT measurements of Tr vBMD. The total vBMD data together with
the statistically significant and dose dependent improvement in
areal BMD as measured by DXA, a well-established bone measurement
technique, support the further development of setrusumab in
pediatric patients, where the unmet medical need is most
apparent.”
“Taken in totality, the results from the
ASTEROID study underscore the ability of setrusumab to function as
a strong bone-building agent and potentially serve as a new
therapeutic option for patients living with OI,” said Jay R.
Shapiro, MD, F.A.C.E, F.A.C.P, Former Director of the Bone and
Osteogenesis Imperfecta Department at the Kennedy Krieger
Institute. “The fracture rate reduction seen in the highest dose
cohort with setrusumab is particularly encouraging and bodes well
for future development in pediatric OI patients.”
Phase 2b ASTEROID Study
DesignASTEROID was a 12-month, randomized, double-blind,
Phase 2b dose-finding study in 112 adults diagnosed with type I,
III or IV Osteogenesis Imperfecta and a confirmed COL1A1/COL1A2
mutation who have fractured over the previous 5 years. The primary
endpoint of the study was the change over baseline in Tr vBMD of
the wrist at 12 months, assessed using HR-pQCT. Change from
baseline at 6 and 12 months for areal BMD at the lumbar spine, as
measured by DXA, was an important secondary endpoint. Additional
secondary endpoints included HR-pQCT parameters (such as total
vBMD), bone biomarkers, patient reported outcomes (PRO) and quality
of life measures. Fracture data were also collected throughout the
duration of the study, although the trial was not statistically
powered for fractures.
Patient Baseline
DemographicsThe study enrolled 112 adults (69 with type I,
28 with type IV and 15 with type III OI) at 27 clinical sites
across the U.S. and Europe and randomized patients originally to
one of four different blinded monthly dosing regimens of
setrusumab: high, medium, low and placebo. The study was
subsequently revised to convert the placebo arm into an open-label
arm where patients received the high dose regimen of setrusumab.
6-month results from this open-label arm were reported in May 2019
and presented at the American Society of Bone Mineral Research
(ASBMR) Annual Meeting in September 2019. Patients in the
open-label arm of the study have not yet completed 12 months of
treatment with setrusumab, therefore the topline 12-month results
reported today are from the three-arm blinded portion of the
study.
Patients in the trial had not been treated with
bisphosphonates in the previous 3 months or other anabolic or
anti-resorptive medications in the previous 6 months. 10 patients
discontinued treatment with setrusumab in the blinded portion of
the study.
Efficacy Endpoint
ResultsPatient baseline Tr vBMD HR-pQCT values ranged
widely from 18.2 to 279 and changes did not show a dose response.
As such, the study demonstrated mean changes in Tr vBMD of the
wrist over baseline of 0.7% (±5.1), -0.8% (±4.2), and 0.61% (±2.8)
in the high (n=27), medium (n=20), and low dose (n=22) cohorts,
respectively. When combined with the change in cortical vBMD of the
wrist, a dose-dependent percentage increase in total vBMD was
observed (a secondary endpoint of the study), reaching statistical
significance in the medium and high dose cohorts. Mean increases in
total vBMD were 4.11% (p=0.004), 4.5% (p=0.028), and 0.58% (p=0.97)
in the high, medium, and low dose cohorts, respectively, suggesting
total BMD increases may be driven by the ability of setrusumab to
increase cortical vBMD. The total vBMD increase in the high dose
cohort was in-line with the open-label data reported in May 2019
and presented at ASBMR in September 2019, where an increase of 3.0%
was observed at 6 months at the high dose.
The study achieved its important secondary
endpoint of increase in areal BMD at the lumbar spine at 6 and 12
months over baseline using two-dimensional dual-energy X-ray
absorptiometry (DXA) measurement, reaching statistical significance
in the high and medium doses cohorts at both 6 and 12 months, with
a clear dose-dependent response. The magnitude of areal BMD changes
over baseline at the lumbar spine at 6 months in the blinded
high-dose cohort was consistent with the previously reported
6-month data from the open-label arm of the study.
Table 1: Increase in
areal BMD at the lumbar spine as measured by DXA by dose
cohort |
Dose Cohort |
Mean % Change in Areal BMD at 6 months |
P value at 6 months |
Mean % Change in Areal BMD at 12 months |
P value at 12 months |
High (n=23) |
+4.2% |
p<0.001 |
+8.8% |
p<0.001 |
Medium (n=17) |
+3.61% |
p=0.003 |
+6.8% |
p<0.001 |
Low (n=21) |
+1.52% |
p=0.153 |
+2.6% |
P=0.057 |
Increases in areal BMD as measured by DXA were
also consistent across all OI subtypes represented in the study
(types I, III & IV).
Table 2: Increase in
areal BMD at the lumbar spine as measured by DXA by OI subtype in
high dose group |
OI Type in High Dose Cohort |
Mean % Change in Areal BMD at 6 months |
Mean % Change in Areal BMD at 12 months |
Type I (n=17) |
+4.1% |
+8.6% |
Type III & IV (n=6) |
+5.4% |
+9.8% |
Statistically significant changes in areal BMD
were also observed by DXA at the femoral neck and total hip with
mean increases of 3.2% (p=0.022) and 2.3% (P=0.009), respectively,
at 12 months in the high dose cohort.
Although the ASTEROID study was not
statistically powered to show a difference in fracture rates, a
trend of reduction in fractures was observed in the high dose
cohort. Fractures in the study included both X-ray confirmed as
well as those confirmed by a local radiologist dependant on the
nature of the fracture.
Table 3: Percentage
of patients with at least one fracture and occurrence rate per
patient year |
Dose Cohort |
Percentage of patients experience >= 1 new
fracture |
Fractures per subject year |
High (n=27) |
15% |
0.16 |
Medium (n=20) |
35% |
0.49 |
Low (n=22) |
23% |
0.39 |
Topline Safety ResultsTopline
12-month safety results suggest setrusumab was safe and well
tolerated in the ASTEROID study. The adverse event (AE) profile was
balanced across the arms. There were 5, 8 and 4 serious treatment
emergent adverse events (STEAEs) in the high, medium and low dose
cohorts, respectively, three of which were initially recorded as
treatment-related. Two events occurred in one patient, these were
headache and hydrocephalus. The patient had a history of basilar
invagination, subdural haematoma and subdural haemorrhage; the
Neurologist and Data Monitoring Committee (DMC) concluded that the
events were unlikely related to study drug. There was a temporary
interruption to study drug but the patient restarted treatment and
continued on study with no complications. The other SAE that was
initially recorded as related was of anaphylactic reaction, which
occurred 2 days following setrusumab infusion. This was the
patient’s 6th infusion. As the reaction was 2 days following the
infusion and the patient had had 5 previous doses, it was
determined that it was unlikely to be a drug reaction and the
patient continued on therapy, without symptoms or signs with
subsequent infusions. There were 9 AEs that were reported as
potentially cardiac related, all were discussed with the DMC
(including cardiology review), and none were concluded to represent
a cardiovascular (CV) safety concern.
Next StepsThe Company plans to
present detailed study results from ASTEROID, including additional
secondary endpoint data, at an upcoming medical meeting or in a
peer-reviewed publication.
81 patients who have completed 12-months of
treatment in ASTEROID study have opted to continue into a 12-month
extension “off therapy” portion to examine the off effect of
setrusumab. Patients who continue in the extension portion have the
option to receive 12 months of treatment with the bisphosphonate
zoledronic acid (given at months 6 and/or 12). Patients will
receive both DXA and HR-pQCT scans at 6 and 12 months after
entering the extension portion.
In addition to evaluating setrusumab in adult OI
patients, Mereo's Paediatric Investigation Plan (PIP) has been
approved by the European Medicines Agency (EMA) and a study design
has been agreed for a pivotal study in children with OI, based on a
primary endpoint of fracture rate over a 12-month period. The
pivotal study will be conducted in approximately 165 children aged
5 to <18 years old, with OI, initially in EU and Canada, with
potential expansion into the U.S. following planned discussions
with the U.S. Food and Drug Administration (FDA).
Conference Call
InformationMereo will host a live conference call and
webcast today at 8:00 a.m. EST / 1:00 p.m. GMT. To participate in
the conference call, please dial (866) 688-2942 (U.S.) or (561)
569-9224 (U.K./International). The conference ID number is 7187418.
A live and archived webcast may be accessed by visiting the
Investors sections of the Company’s website at
https://www.mereobiopharma.com/investors/results-reports-and-presentations/.
The archived webcast will remain available on the Company's website
for fourteen (14) days following the live call.
About Osteogenesis
ImperfectaOsteogenesis Imperfects (OI) is a rare genetic
disorder that is characterized by fragile bones and reduced bone
mass resulting in bones that break easily, loose joints and
weakened teeth. In severe cases patients may experience hundreds of
fractures in a lifetime. In addition, people with OI often suffer
muscle weakness, early hearing loss, fatigue, curved bones,
scoliosis, respiratory problems and short stature, leading to
significant impacts on overall health and quality of life. The
majority of cases of OI (estimated at approximately 90.0%) are
caused by a dominant mutation in a gene coding for type I collagen,
a key component of healthy bone. Current treatment of OI is
supportive, focusing on minimizing fractures and maximizing
mobility, but to date, there are no EMA or FDA approved
treatments.
About SetrusumabSetrusumab is a
fully humanized monoclonal antibody that inhibits sclerostin, a
protein which inhibits the activity of bone-forming cells. The
mechanism of action of setrusumab could be particularly well suited
for the treatment of OI and has the potential to become the first
approved treatment option that could reduce fractures and improve
OI patients' quality of life. In addition to evaluating setrusumab
in adult OI patients, Mereo's Paediatric Investigation Plan (PIP)
has been approved by the European Medicines Agency (EMA) and a
study design has been agreed for a Phase 3 registration trial in
children, based on a primary endpoint of fracture rate over a
12-month period. The pivotal study will be conducted in
approximately 165 children aged 5 to <18 years old with OI,
initially in EU and Canada.
Mereo has obtained orphan drug designation in OI
for setrusumab in both the United States and the EU, in February
2017 setrusumab was accepted into the EMA’s adaptive pathways
program in the EU and, in November 2017 it was accepted into the
EMA’s Priority Medicines scheme (PRIME).
About Mereo BioPharmaMereo
BioPharma is a biopharmaceutical company focused on the development
and commercialization of innovative therapeutics that aim to
improve outcomes for patients with rare diseases. Mereo's strategy
is to selectively acquire product candidates for rare diseases that
have already received significant investment from pharmaceutical
and large biotechnology companies and that have substantial
preclinical, clinical and manufacturing data packages. Mereo’s lead
rare disease product candidate, setrusumab, has completed a Phase
2b dose ranging study in adult patients with osteogenesis
imperfecta (“OI”). Mereo’s second lead product candidate,
alvelestat, is being investigated in a Phase 2 proof-of-concept
clinical trial in patients with alpha-1 antitrypsin deficiency
(“AATD”) with topline data expected in mid-2020.
Mereo’s broader pipeline consists of four
additional clinical-stage product candidates; acumapimod for the
treatment of acute exacerbations of chronic obstructive pulmonary
disease (“AECOPD”), leflutrozole for the treatment of
hypogonadotropic hypogonadism (“HH”) in obese men, navicixizumab
for the treatment of platinum-resistant ovarian cancer, and
etigilimab for patients with advanced or metastatic solid
tumors.
Forward-Looking StatementsThis
document contains “forward-looking statements.” All statements
other than statements of historical fact contained in this
presentation are forward-looking statements within the meaning of
Section 27A of the United States Securities Act of 1933, as amended
(the “Securities Act”), and Section 21E of the United States
Securities Exchange Act of 1934, as amended (the “Exchange Act”).
Forward-looking statements usually relate to future events and
anticipated revenues, earnings, cash flows or other aspects of our
operations or operating results. Forward-looking statements are
often identified by the words “believe,” “expect,” “anticipate,”
“plan,” “intend,” “foresee,” “should,” “would,” “could,” “may,”
“estimate,” “outlook” and similar expressions, including the
negative thereof. The absence of these words, however, does not
mean that the statements are not forward-looking. These
forward-looking statements are based on the Company’s current
expectations, beliefs and assumptions concerning future
developments and business conditions and their potential effect on
the Company. While management believes that these forward-looking
statements are reasonable as and when made, there can be no
assurance that future developments affecting the Company will be
those that it anticipates.
Factors that could cause actual results to
differ materially from those in the forward-looking statements
include risks relating to unanticipated costs, liabilities or
delays; failure or delays in research and development programs; the
safety and efficacy of the Company’s product candidates and the
likelihood of clinical data to be positive and of such product
candidates to be approved by the applicable regulatory authorities;
unanticipated changes relating to competitive factors in the
Company’s industry; risks relating to the Company’s capitalization,
resources and ownership structure, including as a result of
circumstances affecting the Company’s former principal shareholder;
the availability of sufficient resources for company operations and
to conduct or continue planned clinical development programs,
including the Company’s ability to continue as a going concern; the
outcome of any legal proceedings; risks related to the ability to
correctly estimate operating expenses; risks related to the ability
to project future cash utilization and reserves needed for
contingent future liabilities and business operations; risks
related to the changes in market prices of the Company’s ordinary
shares; the Company’s ability to hire and retain key personnel;
changes in law or regulations affecting the Company; international,
national or local economic, social or political conditions that
could adversely affect the Company and its business; conditions in
the credit markets; risks associated with assumptions the Company
makes in connection with its critical accounting estimates and
other judgments.
All of the Company’s forward-looking statements
involve risks and uncertainties (some of which are significant or
beyond its control) and assumptions that could cause actual results
to differ materially from the Company’s historical experience and
its present expectations or projections. The foregoing factors and
the other risks and uncertainties that affect the Company’s
business, including those described in its Annual Report on Form
20-F, Reports on Form 6-K and other documents filed from time to
time by the Company with the United States Securities and Exchange
Commission (the “SEC”) and those described in other documents the
Company may publish from time to time should be carefully
considered. The Company wishes to caution you not to place undue
reliance on any forward-looking statements, which speak only as of
the date hereof. The Company undertakes no obligation to publicly
update or revise any of our forward-looking statements after the
date they are made, whether as a result of new information, future
events or otherwise, except to the extent required by law.
1Kocijan et al Osteoporos Int. Oct 2015; 2431-402Tsai et al
JBMR Jan 2015; 39-45
Further Enquiries
Mereo |
+44 (0)333 023
7300 |
Denise Scots-Knight, Chief
Executive Officer |
|
Richard Jones, Chief Financial
Officer |
|
|
|
Cantor Fitzgerald Europe
(Nominated Adviser and Broker to
Mereo) |
+44 (0)20 7894
7000 |
Phil Davies |
|
Will Goode |
|
|
|
Burns McClellan (US
Public Relations Adviser to Mereo) |
|
Lisa Burns |
+01 (0) 212 213
0006 |
Steve Klass |
|
|
|
FTI Consulting (UK Public
Relations Adviser to
Mereo) |
|
Simon Conway |
|
Brett Pollard |
+44 (0)20 3727
1000 |
Ciara Martin |
|
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