DARMSTADT, Germany, October 26, 2017 /PRNewswire/ --
- Data suggests Mavenclad may significantly increase proportion of patients exhibiting no evidence of
disease activity versus placebo
- Analysis of 10,000 patient years of safety data provides further characterization of safety
profile
- Further data suggests the relative selectivity of Mavenclad for the adaptive immune
system
Merck, a leading science and technology company, today announced positive benefit-risk data for its recently approved multiple
sclerosis (MS) therapy, MAVENCLAD® (Cladribine Tablets), at MSParis2017 (7th Joint ECTRIMS-ACTRIMS Meeting)
in Paris, France. A post hoc analysis in high disease activity subgroups from the 2-year CLARITY
study has confirmed that MAVENCLAD® significantly increased the proportion of patients with no evidence of disease
activity (NEDA) compared with placebo (43.7% vs 9.0%)[1]. This analysis is consistent with results seen in the broader
CLARITY patient population, and further supports the efficacy of MAVENCLAD® for the treatment of relapsing MS.
Late-breaking safety analysis including patients with up to 8-years follow-up from the (3.5 mg/kg) cohorts of CLARITY, CLARITY
Extension, ORACLE-MS studies and the PREMIERE registry also confirmed that despite the imbalance of malignancy cases in
placebo-controlled trials, the overall incidence of malignancy in patients treated with MAVENCLAD® (3.5 mg/kg) was not
significantly different to the incidence in a matched population based on GLOBOCAN (0.97, 95% CI 0.44-1.85). Within the pooled
safety analyses the incidence per 100 patient-years of malignancy was 0.293 (95% CI 0.158-0.544) for MAVENCLAD®
compared with 0.148 (95% CI 0.048-0.460) for placebo. The incidence of malignancies in the MAVENCLAD® arm was shown to
be constant and did not increase over time, in contrast to placebo.[2]
"MAVENCLAD® shows a positive benefit-risk profile from the safety and efficacy analyses," said Professor
Olaf Stuve, Department of Neurology and Neurotherapeutics at UT Southwestern Medical Center in
Dallas. "The data presented across several posters show that the effect of the drug on
lymphocytes is moderate, with a highly nuanced effect on different lymphocyte subsets. Whilst we need to further understand the
qualitative effect of MAVENCLAD® on the adaptive response in MS, these results point to its selective mode of action
which may contribute to its unique posology."
Additional MAVENCLAD® data presented at MSParis2017 showed:
- A detailed safety analysis from CLARITY, CLARITY Extension, ORACLE-MS studies and the PREMIERE registry was consistent with
findings of previous integrated safety analyses and showed that during periods of severe (Grade 3/4) lymphopenia vs outside
these periods the incidence of infection was increased. However, all but two of the infections were mild to moderate and
non-serious, and the types of infections were generally similar during these periods.[3]
- An analysis of T lymphocyte (T cells) subpopulations from the ORACLE-MS study provided a detailed assessment of the changes
that occur in the adaptive immune system following MAVENCLAD® treatment. Specifically, levels of CD4+ T cells were
shown to be moderately and selectively reduced by up to 63% from baseline, and the greatest reductions in absolute cell numbers
occurred at week 13 post-treatment for effector memory cells (54% reduction) and week 24 for central memory cells (63%
reduction), with similar or slightly increased levels of these CD4+ cell subtypes at week 48.[4]
- An analysis of neutrophils and monocytes from patients in CLARITY or CLARITY Extension, including time spent in the
PREMIERE registry, demonstrated that the effect of MAVENCLAD® treatment on these innate immune cell subsets was
relatively minor, compared to patients treated with placebo.[5]
"The data demonstrated a reduction of the B and T cells, thought to be important in the pathogenesis of MS, followed by the
gradual reconstitution of adaptive immune function, with only a relatively small effect on innate immune function throughout,"
said Dr. Andrew Galazka, Senior Vice President and Global Program Leader for MAVENCLAD®
at Merck. "These important data provide further insights on how MAVENCLAD® targets the immune system in patients with
MS. With a clinical program comprising over 10,000 patient-years in MS, unprecedented at time of launch, the
MAVENCLAD® database provides key data in support of safety, efficacy and mode of action to physicians and patients
considering this therapy."
In addition to MAVENCLAD® presentations, Merck also presented data on its well-established relapsing MS product,
Rebif® (interferon beta-1a), focused on predicting long-term outcomes. A post-hoc analysis of patient data from the
PRISMS study investigated the association between the MAGNIMS (Magnetic Resonance Imaging in MS) score at Year 1 and long-term
clinical disease activity free (CDAF) status and disability progression. The score, when calculated in Year 1 of treatment with
Rebif®, was shown to accurately predict the risk of a CDA (clinical disease activity) event or disability progression
in patients with MS.[6] Further data on NEDA and real-world evidence will be presented.
For up-to-date information and activities during MSParis2017, follow Merck on Twitter (@MerckHealthcare) or #AddressMS or visit MerckNeurology.com (intended for Healthcare
Professionals).
About MAVENCLAD ®
In August 2017, the European Commission (EC) granted marketing authorization for
MAVENCLAD® (cladribine tablets) for the treatment of relapsing forms of multiple sclerosis (RMS) in the 28 countries
of the European Union (EU) in addition to Norway, Liechtenstein
and Iceland. MAVENCLAD® is a short-course oral therapy that selectively and
periodically targets lymphocytes thought to be integral to the pathological process of relapsing MS (RMS). MAVENCLAD®
is currently under clinical investigation and not yet approved for the treatment for any use in the
United States or Canada.
The clinical development program for MAVENCLAD® includes:
- The CLARITY (Cladribine Tablets Treating MS Orally) study: a two-year Phase III placebo-controlled study designed to
evaluate the efficacy and safety of MAVENCLAD® as a monotherapy in patients with RRMS.
- The CLARITY extension study: a two-year Phase III placebo-controlled study following on from the CLARITY study, designed to
evaluate the safety and efficacy of MAVENCLAD® over an extended administration for four years.
- The ORACLE MS (Oral Cladribine in Early MS) study: a two-year Phase III placebo-controlled study designed to evaluate the
efficacy and safety of MAVENCLAD® as a monotherapy in patients at risk of developing MS (patients who have
experienced a first clinical event suggestive of MS).
- The ONWARD (Oral Cladribine Added ON To Interferon beta-1a in Patients With Active Relapsing Disease) study: a Phase II
placebo-controlled study designed primarily to evaluate the safety and tolerability of adding MAVENCLAD® treatment
to patients with relapsing forms of MS, who have experienced breakthrough disease while on established interferon-beta
therapy.
- PREMIERE (Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in
Cladribine Clinical Studies) study: interim long-term follow-up data from the prospective registry, PREMIERE, to evaluate the
safety and efficacy of MAVENCLAD®
The clinical development program of Cladribine in MS comprises more than 10,000 patient years of data with over 2,700 patients
included in the clinical trial program, and more than 10 years of observation in some patients.
EU Indication
MAVENCLAD® (cladribine tablets) is indicated for the treatment of adult patients with highly active relapsing multiple
sclerosis (RMS) as defined by clinical or imaging features.
Important EU Safety Information
Contraindications:
MAVENCLAD® is contraindicated in patients with hypersensitivity to the active substance, human immunodeficiency virus
(HIV), active chronic infection (tuberculosis or hepatitis), active malignancy, moderate to severe renal impairment (creatinine
clearance <60 mL/min), and those who are pregnant and breast-feeding. MAVENCLAD® is also contraindicated in
immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy.
Special warnings and precautions for use:
The most clinically relevant adverse reactions were lymphopenia and herpes zoster.
Haematology
Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count compared to baseline values have
been observed in clinical studies, although these parameters usually remain within normal limits.
Additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other
substances that affect the haematological profile
Lymphocyte counts must be determined
- before initiating MAVENCLAD® in year 1,
- before initiating MAVENCLAD® in year 2,
- 2 and 6 months after start of treatment in each treatment year. If the lymphocyte count is below 500 cells/mm³, it should
be actively monitored until values increase again.
Infections
Cladribine can reduce the body's immune defence and may increase the likelihood of infections. HIV infection, active tuberculosis
and active hepatitis must be excluded before initiation of cladribine.
The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts drop below 200 cells/mm³,
anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia.
Interruption or delay of MAVENCLAD® may be considered until proper resolution of the infection.
Cases of progressive multifocal leukoencephalopathy (PML) have been reported for parenteral cladribine in patients treated for
hairy cell leukaemia with a different treatment regimen.
In the clinical study data base of cladribine in MS (1,976 patients, 8,650 patient years) no case of PML has been reported.
However, a baseline magnetic resonance imaging (MRI) should be performed before initiating MAVENCLAD® (usually within
3 months).
About Rebif®
Rebif® (interferon beta-1a) is a disease-modifying drug used to treat relapsing forms of multiple sclerosis (MS) and is similar
to the interferon beta protein produced by the human body. The efficacy of Rebif® in chronic progressive MS has not been
established. Interferon ß is thought to help reduce inflammation. The exact mechanism is unknown.
Rebif®, which was approved in Europe in 1998 and in the US in 2002, is registered in more
than 90 countries worldwide. Rebif® has been proven to delay the progression of disability, reduce the frequency of relapses and
reduce MRI lesion activity and area+.
Rebif® can be administrated with the RebiSmart® electronic auto-injection device (not approved in the US), or with the
RebiDose® single-use disposable pen, or the manual multidose injection pen RebiSlide™. Rebif® can also be administered with the
autoinjector Rebiject II® or by manual injection using ready-to-use pre-filled syringes. These injection devices are not approved
in all countries.
In January 2012, the European commission approved the extension of the indication of Rebif® in
early multiple sclerosis. The extension of the indication of Rebif® has not been submitted in the
United States.
Rebif® should be used with caution in patients with a history of depression, liver disease, thyroid abnormalities and
seizures. Most commonly reported side effects are flu-like symptoms, injection site disorders, elevation of liver enzymes and
blood cell abnormalities. Patients, especially those with depression, seizure disorders, or liver problems, should discuss
treatment with Rebif® with their doctors.
Rebif® (interferon beta-1a) is approved in the United States for relapsing forms of MS.
RebiSmart®, an electronic device for self-injection of Rebif®, is also not approved in the United
States. Cladribine Tablets is an investigational product and not approved for use in any indication in the United States.
+The exact correlation between MRI findings and the current or future clinical status of patients, including disability
progression, is unknown.
About Multiple Sclerosis
Multiple sclerosis (MS) is a chronic, inflammatory condition of the central nervous system and is the most common, non-traumatic,
disabling neurological disease in young adults. It is estimated that approximately 2.3 million people have MS worldwide. While
symptoms can vary, the most common symptoms of MS include blurred vision, numbness or tingling in the limbs and problems with
strength and coordination. The relapsing forms of MS are the most common.
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About Merck
Merck is a leading science and technology company in healthcare, life science and performance materials. Around 50,000 employees
work to further develop technologies that improve and enhance life - from biopharmaceutical therapies to treat cancer or multiple
sclerosis, cutting-edge systems for scientific research and production, to liquid crystals for smartphones and LCD televisions.
In 2016, Merck generated sales of € 15.0 billion in 66 countries.
Founded in 1668, Merck is the world's oldest pharmaceutical and chemical company. The founding family remains the majority
owner of the publicly listed corporate group. Merck holds the global rights to the Merck name and brand. The only exceptions are
the United States and Canada, where the company operates as EMD
Serono, MilliporeSigma and EMD Performance Materials.
1. Giovannoni G. ECTRIMS ACTRIMS 2017 [Abstract No. P1143] Proportions of Patients with Highly Active RMS Achieving No
Evidence of Disease Activity (NEDA) in Response to Cladribine Tablets in CLARITY
2. Galazka A. ECTRIMS ACTRIMS 2017 [Abstract No. P1878] An Analysis of Malignancy Risk in the Clinical Development Programme of
Cladribine Tablets in Patients With Relapsing Multiple Sclerosis (RMS).
3. Cook S. ECTRIMS ACTRIMS 2017 [Abstract No. P1142] Infections During Periods of Grade 3 or 4 Lymphopenia in Patients Taking
Cladribine Tablets 3.5 mg/kg: Data from an Integrated Safety Analysis
4. Stuve O. ECTRIMS ACTRIMS 2017 [Abstract No. P667] Effects of Cladribine Tablets on CD4+ T Cell Subsets in the ORACLE-MS Study:
Results from an Analysis of Lymphocyte Surface Markers
5. Soelberg-Sorensen P. ECTRIMS ACTRIMS 2017 [Abstract No. P1141] Innate Immune Cell Counts in Patients With Relapsing-Remitting
Multiple Sclerosis (RRMS) Treated With Clabribine Tablets 3.5mg/kg in CLARITY and CLARITY Extension
6. Sormani MP. ECTRIMS ACTRIMS 2017 [Abstract No. P770] Disease Activity as Assessed by the MAGNIMS Score Predicts Long-Term
Clinical Disease Activity Free Status and Disability Progression in Patients Treated with Subcutaneous Interferon Beta-1a
Contact: Erin-Marie Beals, +49 151 1454 2694
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