Pelabresib and ruxolitinib combination
significantly reduced spleen size, with an SVR35 response rate
nearly double that of placebo plus ruxolitinib
Showed a strong positive trend in reducing
symptom burden and a twofold increase in patients achieving both
SVR35 and TSS50 versus placebo plus ruxolitinib
Improved measures of anemia, including higher
hemoglobin response rates, fewer patients requiring transfusions
and fewer anemia adverse events versus placebo plus ruxolitinib
Improved bone marrow fibrosis by at least one
grade in more patients versus placebo plus ruxolitinib
Demonstrated safety results consistent with
prior clinical trials, with fewer grade ≥3 adverse events compared
with placebo plus ruxolitinib
MorphoSys will host an investor event to review
findings on Monday, December 11
MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announced
comprehensive results from the Phase 3 MANIFEST-2 study
investigating pelabresib, an investigational BET inhibitor, in
combination with the JAK inhibitor ruxolitinib in JAK
inhibitor-naïve patients with myelofibrosis. These findings were
presented in an oral presentation at the 65th American Society of
Hematology (ASH) Annual Meeting and Exposition in San Diego,
California.
Myelofibrosis is characterized by four hallmarks: an enlarged
spleen, anemia, bone marrow fibrosis and disease-associated
symptoms. In MANIFEST-2, all hallmarks were improved with the
pelabresib and ruxolitinib combination versus placebo plus
ruxolitinib, which is the standard of care in myelofibrosis.
Ruxolitinib dosing was similar in both arms of the study and was
determined based on its approved myelofibrosis indication.
“The MANIFEST-2 results demonstrated clear benefits across the
four hallmarks of myelofibrosis, including a significant reduction
in spleen size – a key finding given the known association between
spleen volume reduction and patient survival,” said Raajit K.
Rampal, M.D., Ph.D., Director, Center for Hematologic Malignancies,
and Director, Myeloproliferative Neoplasms Program, Memorial Sloan
Kettering Cancer Center. “The comprehensive results presented at
ASH also show that the pelabresib combination improves anemia,
disease-associated symptoms and bone marrow fibrosis, and that it
is well-tolerated. These findings point to pelabresib and
ruxolitinib as a potential paradigm-shifting first-line treatment
of this debilitating disease.”
MANIFEST-2 Comprehensive Findings
MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study
of 430 JAK inhibitor-naïve adults with myelofibrosis, randomized
1:1 to receive the pelabresib and ruxolitinib combination or
placebo plus ruxolitinib. MANIFEST-2 is one of the largest studies
in this disease to date.
Strong Reductions in Spleen Size and Symptoms
In the MANIFEST-2 study, pelabresib and ruxolitinib demonstrated
a near doubling in the proportion of patients achieving a ≥35%
reduction in spleen volume (SVR35) at 24 weeks, the primary
endpoint, versus placebo plus ruxolitinib (p<0.001).
For the first key secondary endpoint assessing symptom
reduction, absolute change in total symptom score (TSS) at 24
weeks, there was a strong numerical improvement for patients
receiving pelabresib and ruxolitinib versus placebo plus
ruxolitinib. The response rate for the second key secondary
endpoint, proportion of patients achieving ≥50% reduction in
symptom score (TSS50) at 24 weeks, was also numerically greater for
patients receiving pelabresib and ruxolitinib. Significant
improvements in both key secondary endpoints were observed with the
pelabresib combination for patients classified as intermediate-risk
(Dynamic International Prognostic Scoring System [DIPSS] Int-1 and
Int-2), who account for over 90% of the MANIFEST-2 population.
The proportion of patients achieving both SVR35 and TSS50 at 24
weeks was doubled with pelabresib and ruxolitinib versus placebo
plus ruxolitinib (40.2% vs. 18.5%, respectively).
Details are included in the table below.
Endpoint
Pelabresib + Ruxolitinib
(N=214)
Placebo +
Ruxolitinib
(N=216)
Difference
SVR35
65.9%
35.2%
30.4%*
P-value: p<0.001
Absolute Change in TSS
-15.99
(Mean Baseline: 28.26)
-14.05
(Mean Baseline: 27.36)
-1.94**
P-value: 0.0545
TSS50
52.3%
46.3%
6.0%*
P-value: 0.216
*Difference calculated using
Cochran–Mantel–Haenszel (CMH) common risk difference
**Least square mean estimate
Improvement in Anemia
Patients receiving pelabresib in combination with ruxolitinib
reported fewer anemia adverse events (43.9%, grade ≥3: 23.1%)
compared with placebo plus ruxolitinib (55.6%, grade ≥3: 36.4%).
Additionally, by week 24, fewer patients in the pelabresib and
ruxolitinib arm required red blood cell transfusions compared with
the placebo arm (30.8% vs. 41.2%, respectively).
A greater proportion of patients achieved a hemoglobin response
— defined as a ≥1.5 g/dL mean increase in hemoglobin levels over
baseline in the absence of transfusions during the previous 12
weeks — with pelabresib and ruxolitinib versus placebo plus
ruxolitinib (9.3% vs. 5.6%, respectively). Average hemoglobin
levels were greater in patients receiving pelabresib and
ruxolitinib than in those receiving placebo plus ruxolitinib,
starting at week 9 and continuing to week 24. Anemia benefits were
observed across all studied patient risk groups.
“Anemia can reduce patients’ quality of life by causing severe
fatigue and necessitating blood transfusions,” said Professor
Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust,
London, United Kingdom. “In MANIFEST-2, patients receiving the
combination therapy showed clear benefits on anemia, including
greater hemoglobin levels, fewer red blood cell transfusions and
fewer anemia and fatigue adverse events. Given its strong efficacy,
safety profile and signs of disease modification, the pelabresib
and ruxolitinib combination has the potential to become the new
standard of care in the first-line treatment of myelofibrosis.”
Improvement in Bone Marrow Fibrosis
Bone marrow fibrosis, or the replacement of bone marrow with
fibrous scar tissue, is a central pathological feature of
myelofibrosis. In MANIFEST-2, fibrosis was improved by at least one
grade in a greater proportion of patients receiving pelabresib and
ruxolitinib (38.5% vs. 24.2% with placebo plus ruxolitinib) and
worsened by at least one grade in a smaller proportion of patients
receiving pelabresib and ruxolitinib (16.3% vs. 28.3% with placebo
plus ruxolitinib) at 24 weeks. Bone marrow fibrosis is graded on a
scale from 0 (normal) to 3 (most severe) based on fiber density;
studies suggest a correlation between the grade of bone marrow
fibrosis and patient prognosis.
Biomarker Analysis Suggests Disease Modification
In a biomarker analysis, average plasma levels of inflammatory
cytokines (IL-8, IL-6, TNF-α and NF-κB-regulated cytokines) were
reduced in patients receiving pelabresib and ruxolitinib compared
with placebo plus ruxolitinib at 24 weeks. Increased cytokine
levels are associated with all four disease hallmarks; increased
IL-8 levels are also associated with worse survival outcomes. These
biomolecular improvements suggest early evidence of a
disease-modifying effect.
Well-Tolerated Safety Profile
Overall, grade ≥3 treatment-emergent adverse events (TEAEs) were
reported less frequently with pelabresib and ruxolitinib than with
placebo plus ruxolitinib (49.1% vs. 57.5%, respectively).
In the pelabresib and ruxolitinib arm, the most common (≥10%)
hematologic TEAEs were anemia (43.9%; grade ≥3: 23.1%),
thrombocytopenia (32.1%; grade ≥3: 9.0%) and platelet count
decrease (20.8%; grade ≥3: 4.2%). In the placebo plus ruxolitinib
arm, the most common hematologic TEAEs were anemia (55.6%; grade
≥3: 36.4%), thrombocytopenia (23.4%; grade ≥3: 5.6%) and platelet
count decrease (15.9%; grade ≥3: 0.9%).
The most common (≥10%) nonhematologic TEAEs in the pelabresib
and ruxolitinib arm were diarrhea (23.1%; grade ≥3: 0.5%),
dysgeusia (18.4%; grade ≥3: 0.5%), constipation (18.4%; grade ≥3:
0%), nausea (14.2%; grade ≥3: 0.5%), cough (12.7% grade ≥3: 0),
asthenia (11.8% grade ≥3: 0.5%), fatigue (11.8%; grade ≥3: 0.5%),
dizziness (11.3%; grade ≥3: 0%), headache (11.3% grade ≥3: 0.5%)
and COVID-19 (11.3%; grade ≥3: 0%). The most common nonhematologic
TEAEs in the placebo plus ruxolitinib arm were constipation (24.3%;
grade ≥3: 0%), diarrhea (18.7%; grade ≥3: 1.4%), fatigue (16.8%;
grade ≥3: 0.9%), COVID-19 (15.9%; grade ≥3: 1.9%), nausea (15.0%;
grade ≥3: 0%), asthenia (13.6%; grade ≥3: 0%), dyspnea (13.1%;
grade ≥3: 0.9%), cough (11.2%; grade ≥3: 0%) and headache (10.7%;
grade ≥3: 0%). Discontinuation rates due to adverse events were
10.7% with pelabresib and ruxolitinib and 6.5% with placebo plus
ruxolitinib.
The safety profile of the pelabresib and ruxolitinib combination
therapy was consistent with previous clinical studies. No new
safety signals were observed.
“The four hallmarks of myelofibrosis – enlarged spleen, anemia,
bone marrow fibrosis and disease-associated symptoms – have a
strong impact on a patient’s life. In MANIFEST-2, the combination
of JAK and BET inhibition addressed all four of these hallmarks
with the potential to modify the course of the disease,” said Tim
Demuth, M.D., Ph.D., MorphoSys Chief Research and Development
Officer. “We are confident that the comprehensive data package will
provide impactful insights into the promising and well-tolerated
combination of pelabresib and ruxolitinib. Our goal now is to bring
this first-line therapy to patients with intermediate- and
high-risk myelofibrosis as quickly as possible. We look forward to
meeting with regulatory agencies regarding these data and are
diligently preparing regulatory filings with the intention of
submitting applications to the U.S. Food and Drug Administration
and the European Medicines Agency in the middle of 2024.”
Investor Event at ASH 2023
MorphoSys will host an in-person investor event to review these
detailed findings and address questions with the company’s
management team and medical experts, including Professor Claire
Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London,
United Kingdom, and Ruben Mesa, M.D., FACP, President and Executive
Director, Atrium Health Levine Cancer Center and Atrium Health Wake
Forest Baptist Comprehensive Cancer Center.
The event, taking place on Monday, December 11 at the Hilton San
Diego Bayfront Hotel, will start with a networking breakfast at
6:30 a.m. PST and continue with a formal presentation at 7:00 a.m.
PST (4:00 p.m. CET / 3:00 p.m. GMT / 10:00 a.m. EST). A webcast
will also be available for those not attending ASH 2023 in
person.
Webcast participants may pre-register and will receive dial-in
details to access the call easily and quickly:
https://services.choruscall.it/DiamondPassRegistration/register?confirmationNumber=5982651&linkSecurityString=c1a71840b.
Please dial in 10 minutes before the beginning of the
conference.
The live webcast (audio and presentation) can be directly
accessed via
https://media.choruscall.eu/mediaframe/webcast.html?webcastid=q3lG25n3
or via the Investors section under "Events & Conferences" on
the MorphoSys website, www.morphosys.com; after the call, a
slide-synchronized audio replay of the conference call will be
available at the same location.
About MorphoSys
At MorphoSys, we are driven by our mission: More life for people
with cancer. As a global commercial-stage biopharmaceutical
company, we develop and deliver innovative medicines, aspiring to
redefine how cancer is treated. MorphoSys is headquartered in
Planegg, Germany, and has its U.S. operations anchored in Boston,
Massachusetts. To learn more, visit us at www.morphosys.com and
follow us on Twitter at X and LinkedIn.
About Pelabresib
Pelabresib (CPI-0610) is an investigational selective small
molecule designed to promote anti-tumor activity by inhibiting the
function of bromodomain and extra-terminal domain (BET) proteins to
decrease the expression of abnormally expressed genes in cancer.
Pelabresib is being investigated as a treatment for myelofibrosis
and has not yet been approved by any regulatory authorities.
The development of pelabresib was funded in part by The Leukemia
and Lymphoma Society®.
About MANIFEST-2
MANIFEST-2 (NCT04603495) is a global, double-blind, Phase 3
clinical trial that randomized 430 JAK inhibitor-naïve adult
patients with myelofibrosis 1:1 to receive pelabresib in
combination with ruxolitinib or placebo plus ruxolitinib. The
primary endpoint of the study is a 35% or greater reduction in
spleen volume (SVR35) from baseline at 24 weeks. The key secondary
endpoints of the study are the absolute change in total symptom
score (TSS) from baseline at 24 weeks and the proportion of
patients achieving a 50% or greater improvement in total symptom
score (TSS50) from baseline at 24 weeks. TSS is measured using the
myelofibrosis self-assessment form (MFSAF) v4.0, which asks
patients to report the severity of seven common symptoms, rating
each of them on a scale from 0 (absent) to 10 (worst
imaginable).
The new key secondary endpoint, absolute change in TSS, was
added to directly measure change in the average TSS from baseline
to week 24 of treatment and is listed as the first key secondary
endpoint in the MANIFEST-2 hierarchical testing scheme. The
decision to update the MANIFEST-2 clinical trial protocol was made
following a Type C meeting with the U.S. Food and Drug
Administration (FDA) in September 2023. The final clinical protocol
amendment is subject to approvals by health authorities outside of
the U.S.
Additional secondary endpoints include progression-free
survival, overall survival, duration of the splenic and total
symptom score response, hemoglobin response rate and improvement in
bone marrow fibrosis, among others.
Constellation Pharmaceuticals, Inc., a MorphoSys company, is the
MANIFEST-2 trial sponsor.
About Myelofibrosis
Myelofibrosis is a blood cancer – belonging to a group of
diseases called myeloproliferative neoplasms – caused by genetic
abnormalities in bone marrow stem cells and characterized by four
hallmarks: enlarged spleen, anemia, impaired bone marrow
microenvironment causing fibrosis, and debilitating
disease-associated symptoms, including severe fatigue, night
sweats, itching, increased bleeding and significant pain caused by
their enlarged spleen. For many living with myelofibrosis, the
combination of symptoms often severely impacts their quality of
life. At diagnosis, several factors, such as age, genetics and
bloodwork, help determine a patient’s long-term prognosis. About
90% of newly diagnosed patients have intermediate- to high-risk
disease, which has a worse prognosis and a higher likelihood of
disease-associated symptoms. While JAK inhibitors, the current
standard of care, address some aspects of the disease, no agent
provides broad disease control. There is an urgent need for novel,
well-tolerated therapeutic options capable of changing the natural
course of myelofibrosis to provide patients with deep and durable
responses across its four hallmarks.
Forward-Looking Statements
This communication contains certain forward-looking statements
concerning the MorphoSys group of companies. The forward-looking
statements contained herein represent the judgment of MorphoSys as
of the date of this release and involve known and unknown risks and
uncertainties, which might cause the actual results, financial
condition and liquidity, performance or achievements of MorphoSys,
or industry results, to be materially different from any historic
or future results, financial conditions and liquidity, performance
or achievements expressed or implied by such forward-looking
statements. In addition, even if MorphoSys' results, performance,
financial condition and liquidity, and the development of the
industry in which it operates are consistent with such
forward-looking statements, they may not be predictive of results
or developments in future periods. Among the factors that may
result in differences are that MorphoSys' expectations may be
incorrect, the inherent uncertainties associated with competitive
developments, clinical trial and product development activities and
regulatory approval requirements, MorphoSys' reliance on
collaborations with third parties, estimating the commercial
potential of its development programs and other risks indicated in
the risk factors included in MorphoSys' Annual Report on Form 20-F
and other filings with the U.S. Securities and Exchange Commission.
Given these uncertainties, the reader is advised not to place any
undue reliance on such forward-looking statements. These
forward-looking statements speak only as of the date of publication
of this document. MorphoSys expressly disclaims any obligation to
update any such forward-looking statements in this document to
reflect any change in its expectations with regard thereto or any
change in events, conditions or circumstances on which any such
statement is based or that may affect the likelihood that actual
results will differ from those set forth in the forward-looking
statements, unless specifically required by law or regulation.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20231210152441/en/
Media Contacts: Thomas Biegi Vice President Tel: +49
(0)151 / 74612318 thomas.biegi@morphosys.com
Eamonn Nolan Director Tel: +1 617-548-9271
eamonn.nolan@morphosys.com
Investor Contact: Dr. Julia Neugebauer Head of Investor
Relations Tel: +49 (0)89 / 899 27 179
julia.neugebauer@morphosys.com
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