Sanofi : Positive topline results demonstrated by olipudase alfa,
first and only investigational therapy in late-stage development
for acid sphingomyelinase deficiency
Positive topline results demonstrated by olipudase alfa,
first and only investigational therapy in late-stage development
for acid sphingomyelinase deficiency
· Acid
sphingomyelinase deficiency (ASMD) is a rare, progressive and
potentially life-threatening disease for which no treatments are
approved PARIS – January 30, 2020 – Olipudase
alfa, an investigational recombinant human acid sphingomyelinase,
demonstrated positive results in two separate clinical trials
evaluating olipudase alfa for the treatment of acid
sphingomyelinase deficiency (ASMD) in adult and pediatric patients.
Olipudase alfa is the first and only investigational enzyme
replacement therapy in late-stage development for the treatment of
ASMD. No treatments are currently approved for ASMD.
“These significant results for olipudase alfa
mark a major scientific advancement for ASMD and an important step
toward providing a potential therapy for adult and pediatric
patients who currently have no approved treatment options for this
devastating disease,” said John Reed, M.D., Ph.D., Global Head of
Research and Development at Sanofi. “We look forward to engaging
with regulatory authorities to bring this potential new treatment
to patients.”
Trial in Adult Patients with ASMD
(ASCEND)
The randomized Phase 2/3 trial enrolled 36 adult
patients with ASMD across 24 centers in 16 countries. Patients
received either placebo or olipudase alfa intravenous infusion
every two weeks at a dose of up to 3mg/kg administered every two
weeks over 52 weeks.i
The trial contained two independent primary
efficacy endpoints to address separate critical manifestations of
ASMD, progressive lung disease and enlarged spleen, which are
prominent clinical features in patients with ASMD. The study
protocol defines the trial outcome as positive if one of the
independent primary endpoints was met.
The first independent primary endpoint measuring
improvement in lung function, using the percent predicted diffusing
capacity of carbon monoxide (DLco), was met; therefore, ASCEND is
declared positive. The relative improvement from baseline to week
52 was 22% for the olipudase alfa arm compared with 3% for the
placebo arm. The difference between the two treatment arms (19%)
was statistically significant (p=0.0004).
The other independent primary endpoint measuring
the effect of olipudase alfa on spleen size, assessed as percent
change from baseline in multiples of normal (MN) of spleen volume,
was met per the study protocol. In the olipudase alfa arm, spleen
volume was reduced by 39.5%, compared with a 0.5% increase in the
placebo arm. The difference between the two treatment arms (40%)
was statistically significant (p<0.0001).
For the U.S., the spleen volume endpoint was
further combined with a patient-reported outcome (PRO) measurement
of symptoms associated with enlarged spleen called Splenomegaly
Related Score (SRS). Compared to baseline, the SRS was reduced by
8.0 points in the olipudase alfa arm and 9.3 points in the placebo
arm (p=0.70); therefore, this combination endpoint was not met.
“These are important data in a disease with no
approved treatments available currently,” said Melissa Wasserstein,
MD, Chief, Division of Pediatric Genetic Medicine, Children's
Hospital at Montefiore; Professor of Pediatrics and Genetics,
Albert Einstein College of Medicine; and an investigator in the
ASCEND trial. “Treatment with olipudase alfa showed clinically
meaningful improvement in pulmonary function and reduction in
spleen size, critical manifestations of this progressive disease.
Both of these findings are consistent across the clinical studies
with olipudase alfa. The absence of an effect on SRS in this trial
requires exploration, in light of the significant reduction in
spleen size.”
Over the 52-week period, all patients in both
the placebo and olipudase alfa arms experienced at least one
adverse event. The number of events was lower in the olipudase alfa
arm (242 events) compared with the placebo arm (267 events). Severe
adverse events were less frequent in the olipudase alfa arm (3
events) compared with the placebo arm (13 events). There were five
serious adverse events in the olipudase alfa arm and 11 in the
placebo arm, none of which were treatment related. There were no
adverse events that led to treatment discontinuation or study
withdrawal. The most common adverse events (as defined by
percentages of events greater than or equal to 2% and number of
patients greater than or equal to two in all olipudase alfa treated
patients; occurring with higher percentages in olipudase alfa
patients compared to placebo patients) seen in this trial were
headache, nasopharyngitis, upper respiratory tract infection,
cough, and arthralgia.
Trial in Pediatric Patients with ASMD
(ASCEND-Peds)
The single arm, open label Phase 2 trial
enrolled 20 pediatric patients (birth to <18 years) with
ASMD in six countries. Children with rapidly progressive
neurological disease were excluded. The primary objective of the
trial was to evaluate the safety and tolerability of olipudase alfa
at a dose of up to 3mg/kg administered intravenously every two
weeks for 64 weeks.ii
Over the 64-week treatment period, all patients
experienced at least one adverse event. These events were mostly
mild and moderate, with one patient experiencing a severe and
serious (see below) anaphylactic reaction that was considered
related to olipudase alfa. Five treatment-related serious adverse
events were observed in three patients: two cases of transient,
asymptomatic alanine aminotransferase (ALT) increase in one
patient, one case each of urticaria and rash in one patient, and
one anaphylactic reaction in one patient. No patients had to
permanently discontinue treatment due to an adverse event. The most
common adverse events (as defined by percentages of events greater
than or equal to 2% and number of patients greater than or equal to
two in all olipudase alfa treated patients) seen in this trial were
pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache,
upper respiratory tract infection, contusion, abdominal pain, nasal
congestion, rash, urticaria, scratch, and epistaxis.
The study also explored secondary endpoints of
progressive lung disease and enlarged spleen. After one year of
treatment (52 weeks), the percent predicted DLco increased by a
mean of 33% in nine patients who were able to perform the
test at baseline (children over the age of five were assessed if
they were able to perform the test). Additionally, at 52 weeks, the
spleen volumes decreased by 49% as assessed by mean MN (individual
patient decreases ranged from 23% to 61%).
Results from these trials will be submitted to
future medical meetings and will form the basis of global
regulatory submissions expected to begin the second half of
2021.
About ASMD
Traditionally referred to as Niemann-Pick
Disease (NPD) Type A and Type B, ASMD is a rare, progressive and
potentially life-threatening lysosomal storage disorder that
results from a deficient activity of the enzyme acid
sphingomyelinase (ASM), which is found in special compartments
within cells called lysosomes and is required to breakdown lipids
called sphingomyelin. If ASM is absent or not functioning as it
should, sphingomyelin cannot be metabolized properly and
accumulates within cells, eventually causing cell death and the
malfunction of major organ systems. The deficiency of the lysosomal
enzyme ASM is due to mutations in the sphingomyelin
phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD
is approximately 2,000 patients in the U.S., Europe and Japan.
ASMD represents a spectrum of disease caused by
the same enzymatic deficiency, with two types that may represent
opposite ends of a continuum sometimes referred to as NPD Type A
and Type B. NPD Type A is a rapidly progressive neurological form
of the disease resulting in death in early childhood due to central
nervous system complications. NPD Type B is a serious and
potentially life-threatening disease that predominantly, but not
only, impacts the lungs, liver, spleen and heart. NPD Type A/B
represents an intermediate form that includes varying degrees of
neurologic involvement. Another type of NPD is NPD Type C, which is
unrelated to ASMD.
About Olipudase alfa
Olipudase alfa is an investigational enzyme
replacement therapy designed to replace deficient or defective ASM,
allowing for the breakdown of sphingomyelin. Olipudase alfa is
currently being investigated to treat ASMD Type A/B and B.
Olipudase alfa has not been studied in NPD Type A patients.
Olipudase alfa is an investigational agent and the safety and
efficacy have not been evaluated by the U.S. Food and Drug
Administration (FDA), the European Medicines Agency (EMA), or any
other regulatory authority.
The FDA has granted Breakthrough Therapy
designation to olipudase alfa. This designation is intended to
expedite the development and review of drugs intended to treat
serious or life-threatening diseases and conditions. The criteria
for granting Breakthrough Therapy designation include preliminary
clinical evidence indicating that the molecule may demonstrate
substantial improvement over available therapies on a clinically
significant endpoint.
The EMA has awarded PRIority MEdicines, also
known as PRIME, designation to olipudase alfa. This designation is
designed to aid and expedite the regulatory process for
investigational medicines that may offer a major therapeutic
advantage over existing treatments, or benefit patients without
treatment options.
Olipudase alfa was awarded the SAKIGAKE
designation in Japan. SAKIGAKE is intended to promote research and
development in Japan for innovative new medical products that
satisfy certain criteria, such as the severity of the intended
indication.
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908-981-8745 Ashleigh.Koss@sanofi.com |
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i www.clinicaltrials.gov; ClinicalTrials.gov Identifier:
NCT02004691
ii www.clinicaltrials.gov; ClinicalTrials.gov Identifier:
NCT02292654
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