Key points:
Mesoblast Limited (Nasdaq:MESO) (ASX:MSB) today announced 39-week
data from its Phase 2 trial in patients with rheumatoid arthritis
(RA) resistant to anti-Tumor Necrosis Factor (TNF) agents.
The results showed that a single intravenous infusion of the
Company's proprietary allogeneic cell therapy product candidate,
MPC-300-IV, was well tolerated and demonstrated a durable
improvement in clinical symptoms, physical function, and disease
activity relative to placebo over this period of follow-up.
Mesoblast Chief Executive Silviu Itescu commented: “The
nine-month outcomes generated from this study are highly
encouraging. The early and durable effects seen from a single
infusion of 2 million MPC/kg support the potential of our
allogeneic cell therapy to be positioned as an early treatment
option for patients resistant to anti-TNF agents.”
Major advances in the treatment of RA using biologic agents have
resulted in a $19 billion global market in 2016, the majority of
which is due to use of anti-TNF agents. The RA population resistant
to anti-TNF agents, which constitutes about one-third of patients
treated with anti-TNF agents, is the fastest growing branded market
segment within the global RA biologics market, and is set to grow
further as multiple anti-TNF biosimilars become available.
Mesoblast’s Phase 2 trial recruited a total of 48 patients with
active RA who were on a stable regimen of methotrexate and had an
inadequate prior clinical response to at least one anti-TNF agent.
Of the 48 patients, 30 (63%) had previously received 1-2 biologic
agents. Patients were randomized to a single intravenous infusion
of 1 million MPCs/kg (1M/kg, n=16), 2 million MPCs/kg (2M/kg, n=16)
or placebo (n=16). The study was comprised of a 12 week
primary study period, and a total study duration of 52
weeks.
The primary objective of the study was to evaluate safety and
tolerability of a single intravenous MPC infusion in these biologic
refractory RA patients through a 12 week primary endpoint.
Additional objectives were to evaluate clinical efficacy at the 12
week endpoint and to assess the durability of effects and safety
profile through the full 52 week study.
Pre-specified efficacy endpoints included the
following: American College of Rheumatology (ACR) composite
clinical response, which is an endpoint used in RA clinical
trials to measure improvement in signs and symptoms of the disease
in terms of 20%, 50% or 70% improvement from baseline; ACR-N which
measures the mean or median magnitude of benefit using an ACR
composite for a typical patient; the health assessment
questionnaire-disability index (HAQ-DI), a standardized measure
of functional status; and the DAS28 composite measurement of
disease activity; no adjustment for multiplicity was performed as
these efficacy endpoints were exploratory and the trial was not
powered for efficacy.
Additionally, continuous variables ACR-N, HAQ-DI and DAS-28 were
evaluated in a pre-specified manner since the use of
endpoints sensitive to change provide better discriminatory power
for dose-response assessment, in line with the FDA Guidance
For Industry Rheumatoid Arthritis: Developing Drug Products For
Treatment, May 2013.
Analyses were performed for the whole study population and for
the pre-specified exploratory subgroups based on whether the
subjects had previously received 1-2 biologic agents or more than 2
biologic agents.
Key results over nine months are shown in detail in the
tables below, and were:
- A single intravenous MPC infusion of either 1 million or 2
million MPC/kg resulted in durable responses through nine months
(39 weeks) in the 48-patient placebo-controlled, randomized
Phase 2 trial in patients who have failed one or more TNF
inhibitors
- The safety profile over 39 weeks was comparable among
the placebo and both MPC treatment groups, with no
cell-related serious adverse events
- Both MPC doses outperformed placebo at week 39 in each of
ACR20/50/70 responses
- Both MPC doses outperformed placebo at week 39 in the
proportion of patients who achieved the target of low disease
activity (DAS-28<3.2); disease remission (DAS 28 <2.6) was
seen at similar levels across all groups
- Use of continuous variables ACR-N, HAQ-DI and DAS-28, in
line with FDA guidance for dose-finding Phase 2 trials of new RA
therapies, identified the 2 million MPC/kg dose as the most
effective over 39 weeks
- While both MPC doses achieved higher median ACR-N scores
compared with placebo at 39 weeks, the 2 million MPC/kg dose
achieved the maximal ACR-N score earlier, at 12 weeks
- Over the entire 39 weeks, the 2 million MPC/kg MPC group
had a significantly greater ACR-N Area Under the Curve (AUC)
than placebo, indicating a more robust durable effect with the
higher treatment dose
- At 39 weeks, there was a dose-dependent treatment effect on
mean change from baseline in function (HAQ-DI) and disease activity
score (DAS-28), with the 2 million MPC/kg dose showing the
greatest effect
- MPC treatment effects for all parameters were greatest in
patients who had failed 1-2 biologic agents
Summary of Key Efficacy Responses at Three and Nine
Months for All Subjects:
|
Week 12 |
Week 39 |
|
Placebo |
1M/kg |
2M/kg |
Placebo |
1M/kg |
2M/kg |
|
N=16 |
N=16 |
N=16 |
N=16 |
N=16 |
N=16 |
ACR20 |
50% |
47% |
53%# |
36% |
69% |
57% |
ACR50 |
19% |
27% |
40%# |
14% |
31% |
21% |
ACR70 |
0% |
20% |
27%* |
0% |
23% |
21% |
ACR-N median |
20% |
11% |
28% |
9% |
27% |
27% |
ACR-N mean Area Under Curve (AUC) |
204.7 |
602.6 |
1476.3* |
1952.4 |
3033.4 |
8326.4* |
|
|
|
|
|
|
|
HAQ-DI <-0.22 |
38% |
53% |
93%* |
46% |
75% |
64% |
HAQ-DI (LS mean change from baseline) |
-0.2 |
-0.3 |
-0.5*# |
-0.1 |
-0.5 |
-0.5* |
|
|
|
|
|
|
|
DAS28-CRP (LS mean change from baseline) |
-1.4 |
-1.3 |
-2.0 |
-1.8 |
-1.9 |
-2.4 |
DAS28-CRP <3.2 |
19% |
27% |
36% |
29% |
54% |
50% |
|
|
|
|
|
|
|
* p<0.05 with p-values vs. placebo from Fisher’s exact test
for frequencies, from ANCOVA model using treatment as factor and
baseline value as covariate for mean change, from one-way
ANOVA on ranks for median ACR-N, and from t-test on log-transformed
geometric mean for ACR-N AUC. # week 12 results have been updated
following access to additional patient visit data.
Summary of Key Efficacy Responses at
Three and Nine Months for Subgroup with Prior Use of 1-2
Biologics:
|
Week 12 |
Week 39 |
|
Placebo |
1M/kg |
2M/kg |
Placebo |
1M/kg |
2M/kg |
|
N=9 |
N=10 |
N=11 |
N=9 |
N=10 |
N=11 |
ACR20 |
33% |
60% |
55% |
22% |
67% |
60% |
ACR50 |
11% |
30% |
55% |
0% |
33% |
30% |
ACR70 |
0% |
20% |
36% |
0% |
22% |
30% |
ACR-N median |
13% |
28% |
50% |
6% |
43% |
48%* |
ACR-N mean Area Under Curve (AUC) |
-393.0 |
1629.8 |
1713.8 |
-1567.0 |
7786.6* |
10102.9* |
|
|
|
|
|
|
|
HAQ-DI <-0.22 |
33% |
60% |
91%* |
44% |
67% |
70% |
HAQ-DI (LS mean change from baseline) |
-0.1 |
-0.4 |
-0.6# |
-0.1 |
-0.4 |
-0.6* |
|
|
|
|
|
|
|
DAS28-CRP (LS mean change from baseline) |
-1.1 |
-1.8 |
-2.4 |
-1.8 |
-2.0 |
-2.8 |
DAS28-CRP <3.2 |
22% |
30% |
40% |
33% |
56% |
67% |
|
|
|
|
|
|
|
*p<0.05 with p-values vs. placebo from Fisher’s exact test
for frequencies, from ANCOVA model using treatment as factor and
baseline value as covariate for mean change, from one-way
ANOVA on ranks for median ACR-N, and from t-test on log-transformed
geometric mean for ACR-N AUC.#week 12 results have been updated
following access to additional patient visit data.
About Rheumatoid ArthritisRA is a chronic
autoimmune disease of unknown etiology, affecting approximately one
percent of the global population. The disease is attributed to
chronic inflammation affecting the synovial membrane of multiple
joints, which eventually leads to cartilage and bone destruction.
The health-related quality of life in patients with RA is
significantly impaired by pain, fatigue, and decline in
musculoskeletal function. RA is associated with an increased risk
of cardiovascular disease and mortality.
Standard criteria established by the American College of
Rheumatology (ACR) and the European League Against Rheumatism
(EULAR) are used to assess the effectiveness of RA treatments. The
ACR20/50/70 response is a composite measure based on achieving
20%/50%/70% improvement in tender joint counts (TJC) or swollen
joint counts (SJC) plus improvement in three of the following:
- Patient global assessment
- Physician global assessment
- Patient pain assessment
- Physical function/disability questionnaire (HAQ-DI)
- Acute phase reactant (sedimentation rate or high-sensitivity
C-reactive protein)
The patient and physician global assessments and pain assessment
are measured using a visual analogue scale on a scale of
0-100. The ACR-N provides a single number that
characterizes the percentage of improvement or deterioration from
baseline that a patient has experienced in analogy to ACR20, ACR50,
and ACR70 responses. The ACR-N is defined operationally as
the lowest of 3 values (the percent change in the SJC, the percent
change in the TJC, and the median of the other 5 measures in the
ACR core data set). The ACR-N can be used to measure
improvement at specific time points in a landmark analysis and
expressed as the mean or median ACR-N achieved, or to compare the
area under the curve (AUC) by patient over time. This approach may
substantially increase the power to detect small differences
between treatment arms.
The HAQ-DI assesses physical function in performing a variety of
activities of daily living and yields a score ranging from 0-3
(lower is better). A reduction in the HAQ-DI score of -0.22 is the
minimal clinically important difference. The DAS28 is another
validated RA disease activity index based on a 28 joint count. The
derived DAS28 scores are comprised of tender joint count; swollen
joint count; acute phase reactant (hsCRP or ESR) and the subject’s
global assessment of disease but do not include measures of pain or
physical function. High disease activity is defined as DAS28 score
>5.1; moderate disease activity is defined as DAS28 scores
between 5.1-3.2; low disease activity and remission are defined as
DAS28 scores of <3.2 and <2.6, respectively.
In line with the FDA Guidance For Industry Rheumatoid Arthritis:
Developing Drug Products For Treatment, May 2013,
for dose-ranging studies the use of endpoints sensitive
to change provide better discriminatory power for dose-response
assessment. A clinical endpoint such as the ACR20 response criteria
may not be optimal for this purpose, because it is a
dichotomous endpoint, and using the proportion of responders in a
small group of patients could be unreliable. Continuous
variables such as DAS28, HAQ-DI, and ACR-N may be more
sensitive to change and provide a more suitable alternative to ACR
responder index. For continuous variables where changes from
baseline are reported, the Least Squares of the Mean (ANCOVA) is
utilized in order to adjust for baseline differences between
groups.
About Mesoblast's Product Candidate MPC-300-IV and
Potential Mechanisms of ActionMesoblast’s Tier 1 product
candidate, MPC-300-IV, comprises 1-2 million immunoselected and
culture-expanded STRO-1 positive cells/kilogram which are
intravenously delivered. These cells express receptors for
various pro-inflammatory cytokines, including TNF-alpha,
interleukin-6, or interleukin-17, and are triggered by these
cytokines to release potent immunomodulatory factors.
Mesenchymal lineage precursors and stem cells have been shown to
be capable of targeting mechanistic pathways that are central to
the process of progressive RA in humans, including by inhibiting
the joint synovial fibroblast pro-inflammatory factor NF-kappaB
that is implicated in synovial proliferation, inflammation, and
joint destruction, and by polarizing pro-inflammatory monocytes and
T cells to anti-inflammatory states. Notably, STRO-1 positive
MPCs have been shown to be at least 10-fold more potent inhibitors
of T-cell activation and proliferation than conventional
plastic-adherent mesenchymal lineage cells.1
As reported on February 13, 2016, in the current version of Stem
Cell Research & Therapy, published results in a sheep model of
early RA showed that Mesoblast’s MPCs administered intravenously
significantly ameliorated inflammatory arthritis, providing
important mechanistic and translational support for the improved
clinical outcomes seen in this ongoing Phase 2 trial in patients
resistant to anti-TNF agents.2
About Mesoblast Mesoblast Limited (Nasdaq:MESO)
(ASX:MSB) is a global leader in developing innovative cell-based
medicines. The Company has leveraged its proprietary technology
platform, which is based on specialized cells known as mesenchymal
lineage adult stem cells, to establish a broad portfolio of
late-stage product candidates. Mesoblast’s allogeneic,
‘off-the-shelf’ cell product candidates target advanced stages of
diseases with high, unmet medical needs including cardiovascular
diseases, immune-mediated and inflammatory disorders, orthopedic
disorders, and oncologic/hematologic conditions.
1 Nasef et al. Int. Jnl. Lab. Hem. (2009) 31,
9.2 NCT01851070. Additional information available at:
https://clinicaltrials.gov/show/NCT01851070
Conference Call and Webcast DetailsMesoblast
will hold a conference call beginning at 9:00 am Australian Eastern
Summer Time on Thursday February 16, 2017 / 5:00 pm Eastern
Standard Time on Wednesday February 15, 2017.
The live webcast can be accessed via:
http://webcasting.boardroom.media/broadcast/589d209414b64de6232ccb86
To access the call, please dial:
Australia
Toll Free |
1 800 558
698 |
Australia
Alternate |
1 800 809
971 |
United
States |
1 855 881
1339 |
United
Kingdom |
0800 051
8245 |
Japan |
0053 116
1281 |
Singapore |
800 101
2785 |
Hong
Kong |
800 966
806 |
International |
+61 2 9007
3187 |
|
|
The conference identification code is 957783.
Forward-Looking StatementsThis press release
includes forward-looking statements that relate to future events or
our future financial performance and involve known and unknown
risks, uncertainties and other factors that may cause our actual
results, levels of activity, performance or achievements to differ
materially from any future results, levels of activity, performance
or achievements expressed or implied by these forward-looking
statements. We make such forward-looking statements pursuant to the
safe harbor provisions of the Private Securities Litigation Reform
Act of 1995 and other federal securities laws. Forward-looking
statements should not be read as a guarantee of future performance
or results, and actual results may differ from the results
anticipated in these forward-looking statements, and the
differences may be material and adverse. You should read this press
release together with our risk factors, in our most recently filed
reports with the SEC or on our website. Uncertainties and risks
that may cause Mesoblast's actual results, performance or
achievements to be materially different from those which may be
expressed or implied by such statements, and accordingly, you
should not place undue reliance on these forward-looking
statements. We do not undertake any obligations to publicly update
or revise any forward-looking statements, whether as a result of
new information, future developments or otherwise.
For further information, please contact:
Julie Meldrum
Corporate Communications
Mesoblast
T: +61 3 9639 6036
E: julie.meldrum@mesoblast.com
Schond Greenway
Investor Relations
Mesoblast
T: +1 212 880 2060
E: schond.greenway@mesoblast.com
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