Biogen (NASDAQ:BIIB) and Ionis Pharmaceuticals (NASDAQ:IONS)
announced that SPINRAZATM (nusinersen), an investigational treatment for spinal
muscular atrophy (SMA), met the primary endpoint at the interim analysis of
CHERISH, the Phase 3 study evaluating SPINRAZA in later-onset (consistent with
Type 2) SMA. The analysis found that children receiving SPINRAZA experienced a
highly statistically significant improvement in motor function compared to
those who did not receive treatment. SPINRAZA demonstrated a favorable safety
profile in the study.
“These results, along with our successful trial in
infantile-onset SMA, reinforce the potential of SPINRAZA to benefit a broad
range of SMA patients,” said Michael Ehlers, M.D., Ph.D., executive vice
president, head of Research and Development at Biogen. “We will make regulators
around the globe aware of this data and will continue working closely with them
to bring SPINRAZA to families affected by SMA as quickly as possible.”
Biogen is preparing for the potential launch of SPINRAZA in
the U.S. possibly as early as the end of 2016 or the first quarter of 2017.
Results From the CHERISH Interim Analysis
CHERISH is a fifteen-month study investigating SPINRAZA in
126 non-ambulatory patients with later-onset SMA (consistent with Type 2),
including patients with the onset of signs and symptoms at greater than 6
months and an age of 2 to 12 years at screening.
Results from the primary endpoint of the pre-specified
interim analysis demonstrated a difference of 5.9 points (p= 0.0000002) at 15
months between the treatment (n=84) and sham-controlled (n=42) study arms, as
measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). From
baseline to 15 months of treatment, patients who received SPINRAZA achieved a
mean improvement of 4.0 points in the HFMSE, while patients who were not on
treatment declined by a mean of 1.9 points. The HFMSE is a reliable and
validated tool specifically designed to assess motor function in children with
SMA, and a change of three points or greater in the HFMSE has previously been
identified as clinically meaningful. Data from the other endpoints analyzed
were consistently in favor of children who received treatment. SPINRAZA
demonstrated a favorable safety profile. The majority of the adverse events
were considered to be either related to SMA disease, common events in the
general population, or events related to the lumbar puncture procedure. No
patients discontinued the study.
With the positive interim analysis, the CHERISH study will
be stopped and participants will be able to transition into the SHINE
open-label extension study to receive SPINRAZA. Full study results will be
presented at future medical congresses.
“These data further validate the potential of SPINRAZA as a
treatment for patients with SMA,” said B. Lynne Parshall, chief operating
officer of Ionis Pharmaceuticals. “We are grateful to all the families and
clinicians who have participated in all of the SPINRAZA studies. Without their
commitment and support, this program would not have been able to progress so
quickly.”
The U.S. Food and Drug Administration (FDA) recently
accepted the company’s New Drug Application (NDA) for SPINRAZA as a treatment
for SMA and communicated they plan to act early on the NDA under an expedited
review. Additionally, the European Medicines Agency (EMA) recently validated
Biogen’s Marketing Authorization Application (MAA) in the EU. The EMA’s
Committee for Medicinal Products for Human Use (CHMP) granted Accelerated
Assessment status and the FDA granted Priority Review to SPINRAZA. Biogen is
initiating regulatory filings in other countries in the coming months.
Biogen initiated a global expanded access program (EAP) in
infantile-onset SMA earlier this year. The company will continue to explore
where and when the EAP may be broadened to include patients with later-onset
SMA (consistent with Type 2).
The SPINRAZA Clinical Trial Program
SPINRAZA has been studied in both presymptomatic and
symptomatic patients with SMA including patients likely to develop or diagnosed
with SMA Types 1, 2, and 3.
The SPINRAZA Phase 3 program is comprised of two
registrational studies, ENDEAR and CHERISH. ENDEAR is a thirteen-month study
investigating SPINRAZA in 122 patients with infantile-onset SMA, including
patients with the onset of signs and symptoms of SMA at up to six months of
age. The endpoint pre-specified for the interim analysis of the study evaluated
the proportion of motor milestone responders from the motor component of the
Hammersmith Infant Neurological Examination (HINE). Given the results of the
positive interim analysis, the ENDEAR study is being stopped and participants
are able to transition into the SHINE open-label study, in which all patients
will receive SPINRAZA.
Additionally, the SHINE open-label extension study for
patients who previously participated in ENDEAR or CHERISH is open and is
intended to evaluate the long-term safety and tolerability of SPINRAZA.
Two additional Phase 2 studies, EMBRACE and NURTURE, were
designed to collect additional data on SPINRAZA. EMBRACE is studying a small
subset of patients with infantile or later-onset SMA who do not meet the age
and other criteria of ENDEAR or CHERISH. NURTURE is an open-label, ongoing
study in pre-symptomatic infants who are up to six weeks of age at time of
first dose to determine if treatment before symptoms begin would prevent or
delay the onset of SMA symptoms. An interim analysis of NURTURE showed that
infants treated for up to one year with SPINRAZA achieved motor milestones in
timelines more consistent with normal development than what is observed in the
natural history of patients with Type 1 SMA. Three infants experienced adverse
events considered possibly related to SPINRAZA, all of which resolved. In
addition, no infants have discontinued or withdrawn from the study and no new
safety concerns have been identified. NURTURE is currently active and
enrolling. All studies are being conducted on a global scale…
About SPINRAZA (nusinersen)
SPINRAZA is an investigational, potentially
disease-modifying therapy for the treatment of SMA that was discovered and
developed by Ionis Pharmaceuticals, a leader in antisense therapeutics.
SPINRAZA is an antisense oligonucleotide (ASO) that is designed to alter the
splicing of SMN2, a gene that is nearly identical to SMN1, in order to increase
production of fully functional SMN protein.
ASOs are short synthetic strings of nucleotides designed to
selectively bind to target RNA and regulate gene expression. Through use of
this technology, SPINRAZA has the potential to increase the amount of
functional SMN protein in infants and children with SMA.
Both the U.S. and EU have granted SPINRAZA Orphan Drug
status. Additionally, both the U.S. and EU regulatory agencies have granted
special status to SPINRAZA, including Fast Track Designation and Priority
Review in the U.S. and Accelerated Assessment in the EU.
Biogen exercised its option to worldwide rights to SPINRAZA
in August 2016.
Biogen and Ionis Pharmaceuticals acknowledge support from
the following organizations for SPINRAZA: Cure SMA, Muscular Dystrophy
Association, and SMA Foundation, intellectual property licensed from Cold
Spring Harbor Laboratory and the University of Massachusetts Medical School.
Rigo F, Hua Y, Krainer AR, Bennett CF. Antisense-based therapy for the treatment of spinal muscular atrophy. J Cell Biol. 2012 Oct 1;199(1):21-5.
ReplyDeleteAbstract
One of the greatest thrills a biomedical researcher may experience is seeing the product of many years of dedicated effort finally make its way to the patient. As a team, we have worked for the past eight years to discover a drug that could treat a devastating childhood neuromuscular disease, spinal muscular atrophy (SMA). Here, we describe the journey that has led to a promising drug based on the biology underlying the disease.
Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010 Aug 1;24(15):1634-44.
Abstract
Increasing survival of motor neuron 2, centromeric (SMN2) exon 7 inclusion to express more full-length SMN protein in motor neurons is a promising approach to treat spinal muscular atrophy (SMA), a genetic neurodegenerative disease. Previously, we identified a potent 2'-O-(2-methoxyethyl) (MOE) phosphorothioate-modified antisense oligonucleotide (ASO) that blocks an SMN2 intronic splicing silencer element and efficiently promotes exon 7 inclusion in transgenic mouse peripheral tissues after systemic administration. Here we address its efficacy in the spinal cord--a prerequisite for disease treatment--and its ability to rescue a mild SMA mouse model that develops tail and ear necrosis, resembling the distal tissue necrosis reported in some SMA infants. Using a micro-osmotic pump, we directly infused the ASO into a lateral cerebral ventricle in adult mice expressing a human SMN2 transgene; the ASO gave a robust and long-lasting increase in SMN2 exon 7 inclusion measured at both the mRNA and protein levels in spinal cord motor neurons. A single embryonic or neonatal intracerebroventricular ASO injection strikingly rescued the tail and ear necrosis in SMA mice. We conclude that this MOE ASO is a promising drug candidate for SMA therapy, and, more generally, that ASOs can be used to efficiently redirect alternative splicing of target genes in the CNS.
Staropoli JF, Li H, Chun SJ, Allaire N, Cullen P, Thai A, Fleet CM, Hua Y, Bennett CF, Krainer AR, Kerr D, McCampbell A, Rigo F, Carulli JP. Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7. Genomics. 2015 Apr;105(4):220-8.
ReplyDeleteAbstract
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by disruption of the survival motor neuron 1 (SMN1) gene, partly compensated for by the paralogous gene SMN2. Exon 7 inclusion is critical for full-length SMN protein production and occurs at a much lower frequency for SMN2 than for SMN1. Antisense oligonucleotide (ASO)-mediated blockade of an intron 7 splicing silencer was previously shown to promote inclusion of SMN2 exon 7 in SMA mouse models and mediate phenotypic rescue. However, downstream molecular consequences of this ASO therapy have not been defined. Here we characterize the gene-expression changes that occur in an induced model of SMA and show substantial rescue of those changes in central nervous system tissue upon intracerebroventricular administration of an ASO that promotes inclusion of exon 7, with earlier administration promoting greater rescue. This study offers a robust reference set of preclinical pharmacodynamic gene expression effects for comparison of other investigational therapies for SMA.
Hua Y, Liu YH, Sahashi K, Rigo F, Bennett CF, Krainer AR. Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev. 2015 Feb 1;29(3):288-97.
ReplyDeleteAbstract
Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice.
The US Food and Drug Administration (FDA) has approved nusinersen (Spinraza, Biogen and Ionis Pharmaceuticals), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease…
ReplyDeleteThere is wide variability in age of onset, symptoms, and rate of progression. Nusinersen is approved for use across the range of patients with SMA, the FDA said.
Nusinersen, which is administered via injection into cerebrospinal fluid, is an antisense oligonucleotide aimed at increasing concentrations of survival motor neuron (SMN) protein, which is underexpressed in SMA.
The efficacy of nusinersen was shown in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were younger than 7 months at the time of their first dose. Patients were randomly allocated to receive an injection of nusinersen or a mock procedure without drug injection (control group).
An interim analysis performed at the request of the FDA showed that 40% of patients treated with nusinersen achieved improvement in motor milestones, as defined in the study, whereas none of the control patients did.
Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of the first dose.
"These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients," the FDA said in a news release.
"There has been a long-standing need for a treatment for [SMA], the most common genetic cause of death in infants, and a disease that can affect people at any stage of life," Billy Dunn, MD, director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research, said in the release.
"As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease," Dr Dunn said.
The most common adverse effects seen with nusinersen were upper respiratory infection, lower respiratory infection, and constipation. Warnings and precautions include low blood platelet count and renal toxicity. Neurotoxicity was observed in animal studies.
Nusinersen had fast-track designation and received priority review by the FDA. The drug also had orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
http://www.medscape.com/viewarticle/873718
Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2017 Dec 17;388(10063):3017-3026.
ReplyDeleteAbstract
BACKGROUND:
Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy.
METHODS:
This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov, number NCT01839656.
FINDINGS:
20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord.
INTERPRETATION:
Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy.