Paris, 25 November 2019, 8.15am
Summary of webcast with Key Opinion
Leaders on Indolent Systemic
Mastocytosis
AB Science SA (NYSE Euronext -
FR0010557264 - AB) is providing a summary of the live webcast on
November 20 with key opinion leaders on indolent systemic
mastocytosis (ISM) and the role that masitinib may play in treating
this disorder.
The presentation of the webcast is available on
the company’s website.A replay of the webcast is available at the
following address:
https://viavid.webcasts.com/starthere.jsp?ei=1269879&tp_key=e0397d61a9
The webcast provides:
- An overview of mastocytosis.
- Current treatment options and new treatments in development for
the disease.
- An overview of the masitinib profile and prior Phase 3 results
in indolent systemic mastocytosis (published in The Lancet in
2017).
Experts opinion on
mastocytosis
Mastocytosis can be categorized into cutaneous
mastocytosis and systemic mastocytosis. Systemic mastocytosis (SM)
can be further categorized into indolent SM, smouldering SM and
aggressive SM (ASM, SM-AHN, MCL). Patients with indolent SM or
smouldering SM have a (nearly) normal life expectancy, while
patients with aggressive SM have a median overall survival of
approximately four years. About 90% of patients express a specific
mutation of c-kit (D816V), which is activating mast cells.
The planned indication for masitinib is indolent
systemic mastocytosis (ISM) and smouldering systemic mastocytosis
(SSM), which are the most prevalent forms of mastocytosis,
accounting for approximately 60% of patients.
Patient with ISM or SSMS experience multiple
symptoms, which can be severe and considered for some patients as
not tolerable. The quality of life of patients with mastocytosis is
overall severally affected. Patients suffer from itching, flushing,
nausea, diarrhea, brain fog, anxiety, depression, and acute
episodes of anaphylaxis among other debilitating symptoms Cognitive
impairment and depression are prominent features of the
disease.
While aggressive SM therapy is based on
registered cytoreductive treatments (cladribine, midostaurin),
treatment of ISM and SSM remains a challenge as conventional
symptomatic therapies fail to improve severe symptoms.
There is a high unmet need in ISM/SSM for new
therapeutic options with demonstrated activity on severe symptoms
and adequate safety profile for a life-long treatment.
Masitinib is the leading program in ISM and a
viable approach to this goal. It is currently the only drug in
phase 3 for a claim on indolent systemic mastocytosis. The key
differentiating factors of masitinib are:
- Safety profile: Most frequent AEs occurring at treatment start
(rash, diarrhea, nausea) can be managed by judicious
dose-escalation in the first two months of treatment. Based on
available data, there is no apparent long-term cumulative toxicity
with masitinib and no vascular toxicity. Midostaurin and
Avapritinib, two tyrosine kinase inhibitors active in aggressive
forms of SM, have demonstrated numerous side effects, sometimes
life-threatening, challenging their use in classical
therapy-resistant ISM/SSM patients. Numerous patients remain on
masitinib for years without exhibiting significant adverse
effects
- Efficacy on neurology symptoms: Patients complain first about
neurological symptoms, and masitinib has proven efficacy on these
neurology symptoms, namely depression and asthenia.
- Masitinib has already been proved as highly efficacious on
severely handicapped ISM/SSM patients in two well-conducted proof
of concept studies and one Phase 3.
- Favorable long-term safety profile is key as patient need
life-long treatment, and masitinib fulfill this requirement based
on currently available data, unlike other drugs.
In the opinion of certain experts, there is
enough evidence to support the use of masitinib in the treatment of
ISM/SSM with severe symptoms, and the GCP findings raised during
the inspection of the first study AB0006 do not affect the overall
positive benefit risk assessment in favor of masitinib.
The European Competence Network (ECNM), the
largest network of experts working in the field of mastocytosis,
considers that masitinib, thanks to its selectivity on mast cell
activation and safety profile, is very adequate to control severe
handicaps in symptomatic ISM/SSM patients.
Masitinib clinical program in
mastocytosis
Masitinib is a selective kinase inhibitor that
targets mast cells and macrophages/microglia. Masitinib inhibits
mast cells, regardless of c-Kit mutation status, through inhibition
of c-Kit, Lyn and Fyn kinases. The safety profile of masitinib is
sufficiently understood with over 6,000 patients enrolled in
clinical studies.
The clinical program in mastocytosis is
comprised of two proof of concept studies, one Phase 3 study
(published in the Lancet), and one Phase 3 confirmatory study.
- Clinical proof of concept has been established both in patients
with and without D816V c-Kit mutation. In these two proof of
concept studies, masitinib showed a significant reduction of
symptoms associated with flush (range from -60% to -74%), pruritus
(range from -36% to -45%), fatigue (range from -30% to -38%), and
depression (range from –43% to -49%). The majority of patients in
phase 2 chose to remain on masitinib over the long term, and some
have been treated for more than 7 years. Masitinib also had an
effect on mast cells in the skin, as shown by the reduction in
urticaria pigmentosa. In addition, imaging showed that masitinib
may be able to reverse cerebral hypoperfusion in mastocytosis
patient, correlating with improved cognitive function.
- In the first phase 3 study (AB06006) evaluating masitinib
versus placebo in 135 patients with ISM and severe symptoms at
baseline, the pre-specified primary and secondary analyses on
symptoms were positive and supported efficacy based on odds ratio.
Study results showed that masitinib administered at 6.0 mg/kg/day
was superior to the comparator, as measured by the cumulative 75%
response rate until week 24 on the handicaps of pruritus or flushes
or depression or fatigue (4H75% response). The 4H75% response was
18.7% for the masitinib treatment-arm versus 7.4% for the placebo
treatment-arm (p=0.0076, Odd ratio=3.63) in the mITT population
(primary analysis). Masitinib also demonstrated significant
activity on objective markers of mast cell activation and burden
(i.e. level of tryptase, body surface area with urticaria
pigmentosa, and presence of Darier’s sign). The most frequent
severe adverse events were related to gastrointestinal disorders
and skin cutaneous disorders. No life-threatening toxicities
occurred.
A phase 3 confirmatory study (AB15003) is
planned in order to request a marketing authorization. Three
optimizations of the phase 3 confirmatory study have been
implemented based on the first phase 3 and are increasing the
probability of success of the study.
- Dose titration: In the first phase 3 study, the starting dose
of treatment was 6 mg/kg/day. This led to 20% treatment
discontinuation, with discontinuation being counted as treatment
failure in the analysis, hence penalizing masitinib. With dose
titration from 3.0 to 4.5 and then 6.0 mg over two months period,
marginal discontinuation rate is expected, which will favor
efficacy assessment of masitinib.
- Recording of rescue therapy: In the first phase 3 study,
patients could take rescue treatment in case of worsening of
symptoms, which favored the placebo arm. In the new study, rescue
treatment will be counted as treatment failure in the
analysis.
- Run-in period: In the first phase 3 study, there was no run-in
to ensure that patients were taking optimal symptomatic treatment
at screening. In new study, one-month run-in period to control
failure to symptomatic treatment.
This phase 3 confirmatory study is being
initiated and patient enrolment is expected to be initiated in Q1
2020. The design benefited from scientific advices and
recommendation from health authorities, and from the previous
registration procedure of AB06006 study. The study is expected to
enroll its first patients in Q1 2020 and plans to enroll 140
patients from around 30 specialized centers.
Masitinib IP rights are secured up to 2031 in
the US and potentially 2036 in Europe in ISM.
KOL Biography
The following key opinion leaders participated
in the webcast:
Cem AKIN, MD, PhD: Dr. Akin is
currently a Professor of Allergy and Immunology in the Department
of Internal Medicine at the University of Michigan. He is co-chair
of the steering committee of the American Initiative in Mast Cell
Diseases (AIM) and a member of the Medical Advisory Board of The
Mastocytosis Society (TMS).
Michel AROCK, PharmD, PhD: Dr.
Arock is professor of physiology and hematology at the Ecole
Normale Supérieure of Paris-Saclay and is currently heading the
Functional Unit for Biological Emergencies within the Hospital
Pitié-Salpêtrière Charles-Foix in Paris. He has conducted
researches on the physiology of mast cells and on the
pathophysiology and treatment of mastocytosis for many years. He
has also co-authored more than 180 publications referenced in
Medline and is currently the Chair (2015-2020) of the European
Competence Network on Mastocytosis (ECNM).
Mariana CASTELLS, MD, PhD:
Mariana Castells is a Professor at Harvard Medical School. She is a
clinician/teacher/researcher at the Brigham and Women’s Hospital
Rheumatology, Immunology and Allergy Division serving as Director
of Drug Hypersensitivity and Rapid Desensitization Center and the
Director of the Mastocytosis Center. In 2005, Dr. Castells was the
founding Chair of the Task Force on Mast Cell Disorders of the
American Academy of Allergy, Asthma and Immunology. Dr. Castells is
a member of the American Initiative in Mast Cell Diseases (AIM)
Organizing Committee and a member of the Medical Advisory Board of
The Mastocytosis Society (TMS).
Olivier HERMINE, MD, PhD:
Olivier Hermine is Professor of Hematology at Paris V-René
Descartes University, Chief of adults Hematology staff at Hospital
Necker (Paris), member of the French Académie des Sciences and
author of 365 international publications. He is founder and
coordinator of the reference center of mastocytosis (CEREMAST). He
is member of the Medical Advisory Board of The Mastocytosis Society
(TMS), a US non-profit organization dedicated to supporting
patients affected by Mastocytosis or Mast Cell Activation Diseases.
Olivier Hermine is also co-founder of AB Science and Head of its
scientific committee.
About masitinibMasitinib is a
new orally administered tyrosine kinase inhibitor that targets mast
cells and macrophages, important cells for immunity, through
inhibiting a limited number of kinases. Based on its unique
mechanism of action, masitinib can be developed in a large number
of conditions in oncology, in inflammatory diseases, and in certain
diseases of the central nervous system. In oncology due to its
immunotherapy effect, masitinib can have an effect on survival,
alone or in combination with chemotherapy. Through its activity on
mast cells and microglia and consequently the inhibition of the
activation of the inflammatory process, masitinib can have an
effect on the symptoms associated with some inflammatory and
central nervous system diseases and the degeneration of these
diseases.
About AB ScienceFounded in
2001, AB Science is a pharmaceutical company specializing in the
research, development and commercialization of protein kinase
inhibitors (PKIs), a class of targeted proteins whose action are
key in signaling pathways within cells. Our programs target only
diseases with high unmet medical needs, often lethal with short
term survival or rare or refractory to previous line of treatment.
AB Science has developed a proprietary portfolio of molecules and
the Company’s lead compound, masitinib, has already been registered
for veterinary medicine and is developed in human medicine in
oncology, neurological diseases, and inflammatory diseases. The
company is headquartered in Paris, France, and listed on Euronext
Paris (ticker: AB).
Further information is available on AB Science’s website:
www.ab-science.com.
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