-
In the dose-finding Part 1 of
FIREFISH, infants with Type 1 spinal muscular atrophy survive and
achieve key milestones beyond those expected in the natural history
of the disease
-
New data from the dose-finding
Part 1 of SUNFISH reinforce risdiplam as a promising
investigational therapy for people with Type 2 or 3 spinal muscular
atrophy
-
No treatment-related safety
findings leading to withdrawal seen to date in risdiplam
trials
Basel, 7 May 2019 - Roche (SIX: RO, ROG; OTCQX:
RHHBY) today announced new data from the dose-finding Part 1 of the
pivotal FIREFISH trial showing infants with Type 1 spinal muscular
atrophy (SMA) achieved key motor milestones after one year of
treatment with investigational risdiplam.[1] Among the
infants who received the dose selected for the confirmatory Part 2
of the study (n=17), 7 (41.2%) were able to sit without support for
at least 5 seconds, assessed by the Gross Motor Scale of the Bayley
Scales of Infant and Toddler Development - Third Edition
(BSID-III). In addition, 11 (64.7%) infants were able to sit (with
or without support) while 9 (52.9%) achieved upright head control
after 12 months of treatment as assessed by the Hammersmith Infant
Neurological Examination Module 2 (HINE-2). Finally, 1 infant
(5.9%) achieved the milestone of standing (supports weight) by this
12-month time point.
The data were presented at the 71st American
Academy of Neurology (AAN) Annual Meeting from 4-10 May in
Philadelphia, Pennsylvania. Roche leads the clinical development of
risdiplam, an investigational, orally administered survival motor
neuron-2 (SMN2) splicing modifier for SMA, as part of a
collaboration with the SMA Foundation and PTC
Therapeutics.
"The continued improvements in motor milestones and function in the
FIREFISH study to date are meaningful for this typical SMA Type 1
population where the majority of babies started treatment at nearly
seven months old," said FIREFISH study lead investigator Giovanni
Baranello, MD, Carlo Besta Neurological Research Institute
Foundation, Developmental Neurology Unit, Milan, Italy.* "These
encouraging findings further validate a treatment approach that
increases survival motor neuron protein in both the central nervous
system and throughout the body."
Part 1 of FIREFISH also assessed motor function with the Children's
Hospital of Philadelphia Infant Test of Neuromuscular Disorders
(CHOP-INTEND), a scale used for infants with Type 1 SMA.[1] Results
showed that 10 out of 17 infants (58.8%) in the therapeutically
dosed group achieved a CHOP-INTEND total score of 40 points or
more.[1] Median
change from baseline to month 12 in CHOP-INTEND was 17.5
points. The maximum CHOP-INTEND score was 57 points after 12
months treatment, increasing from a maximum of 49 points after 8
months.[1]
Among all 21 infants enrolled in Part 1 of the FIREFISH study, the
median duration of treatment is 14.8 months, with 19 infants
treated for more than 12 months.[2] Three
infants experienced fatal complications of their disease after
approximately 1, 8, and 13 months of treatment. None of these has
been attributed by the investigator as related to risdiplam. No
infant has lost the ability to swallow during the study, and no
infant has required tracheostomy or permanent ventilation.
[2] The
event-free survival was 18 out of 21 (85.7%) overall and 15 out of
17 (88.2%) in the therapeutically dosed group. The most
common adverse events included fever (pyrexia; 52.4%), upper
respiratory tract infections (42.9%), diarrhea (28.6%), vomiting
(23.8%), cough (23.8%) pneumonia (19.0%) and constipation
(19.0%).[2]
"We are highly encouraged by our latest findings for risdiplam,
which take us one step closer to potentially bringing the first
oral treatment option to the SMA community," said Sandra Horning,
MD, Roche's Chief Medical Officer and head of Global Product
Development. "While SMA has seen important advances over the past
few years, significant medical need remains for people living with
all types of SMA across multiple age groups. We look forward to
sharing additional data from our broad development programme for
risdiplam as it emerges."
Roche also presented new data from Part 1 of its pivotal SUNFISH
trial in people aged 2 -25 years with Type 2 or 3 SMA. The
dose-finding SUNFISH Part 1 includes a particularly broad patient
population. Baseline functional status ranged
from individuals unable to sit to those capable of walking.
Scoliosis ranged from none to severe. As previously reported,
a sustained median increase from baseline in SMN protein of greater
than two-fold, as measured in blood, was seen after 12 months of
treatment with risdiplam.
The most common adverse events in Part 1 of the SUNFISH study were
fever (pyrexia; 41%), cough (33%), vomiting (29%), upper
respiratory tract infections (26%), persistent sore throat
(oropharyngeal pain; 22%) and cold (nasopharyngitis;
20%).[3] The most
common serious adverse event that occurred in two of the 51
patients exposed to risdiplam was pneumonia.[3] To
date there have been no treatment-related safety findings leading
to withdrawal from any study.[2],[3]
An exploratory efficacy analysis of Part 1 (n=51) of the SUNFISH
study assessed motor function, using the Motor Function Measure-32
(MFM32) scale. This scale is designed to detect motor function
changes in a broad range of patients, from weak Type 2 to strong
Type 3 SMA, and is therefore more appropriate for the SUNFISH
population. One patient withdrew from the trial during the
open-label extension.[3] Among
the patients for which the MFM32 scale has been completed at
all visits up to month 12 (n=43), 58% saw an improvement of at
least 3 points on the scale from baseline, including 71% among
patients 2-11 years old and 42% aged 12-25 years.[3] While
Part 1 of the SUNFISH study was not designed or powered to detect
efficacy, the change from baseline in total MFM32 score is the
primary efficacy endpoint in the ongoing Part 2 (n=180) of the
trial.
The confirmatory Part 2 portions of the SUNFISH and FIREFISH
studies have completed enrollment and will conduct their primary
efficacy analyses in Q4 2019 and Q1 2020, respectively.
Roche is planning to include the new data presented at the AAN
Annual Meeting in regulatory filings with the U.S. Food and Drug
Administration and European Medicines Agency during the second half
of 2019.
About SMA
Spinal muscular atrophy (SMA) is a severe, inherited, progressive
neuromuscular disease that causes devastating muscle atrophy and
disease-related complications.[4] It is the
most common genetic cause of infant mortality and one of the most
common rare diseases, affecting approximately one in 11,000
babies.[5] SMA leads
to the progressive loss of nerve cells in the spinal cord that
control muscle movement.[6] Depending
on the type of SMA, an individual's physical strength and their
ability to walk, eat or breathe can be significantly diminished or
lost.[7]
SMA is caused by a mutation in the survival motor neuron 1 (SMN1)
gene that results in a deficiency of SMN protein.[6] SMN
protein is found throughout the body and increasing evidence
suggests SMA is a multi-system disorder and the loss of SMN protein
may affect many tissues and cells, which can stop the body from
functioning.[8]
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About risdiplam
Risdiplam is an investigational orally-administered medicine being
studied in a broad range of patients with SMA from 1 month to 60
years of age. It is designed to provide sustained increases in SMN
protein centrally and peripherally through daily dosing and is
being evaluated for its potential ability to help the SMN2 gene
produce more functional SMN protein throughout the body.[9]
Roche leads the clinical development of risdiplam as part of a
collaboration with the SMA Foundation and PTC Therapeutics.
Risdiplam is currently being evaluated in four multicentre trials
in people with SMA:
-
FIREFISH (NCT02913482) - an open-label, two-part
seamless pivotal clinical trial in infants with Type 1 SMA. Part 1
was a dose-escalation study in 21 infants. The primary objective of
Part 1 was to assess the safety profile of risdiplam in infants and
determine the dose for Part 2. Per protocol, four infants
enrolled ("Cohort A") were required to remain at their low dose for
over 12 months in order to evaluate longer term safety at multiple
doses. The remaining patients ("Cohort B"; n=17) were allowed by
the protocol to more quickly escalate to the expected therapeutic
dose selected in Part 2. Part 2 is a pivotal, single-arm study of
risdiplam in 41 infants with Type 1 SMA for 24 months, followed by
an open-label extension. Enrolment for Part 2 was completed in
November 2018. The primary objective of Part 2 is to assess
efficacy as measured by the proportion of infants sitting without
support after 12 months of treatment, as assessed in the Gross
Motor Scale of the Bayley Scales of Infant and Toddler Development
- Third Edition (BSID-III) (defined as sitting without support for
5 seconds). Part 2 is ongoing.
-
SUNFISH (NCT02908685) - a two-part,
double-blind, placebo-controlled pivotal clinical trial in children
and young adults (2-25 years old) with Type 2 and 3 SMA. Part 1
determined the dose for the confirmatory Part 2. The primary
objective of Part 2 is to evaluate motor function using total score
of Motor Function Measure 32 (MFM-32) at 12 months. Enrolment for
Part 2 was completed in September 2018 with 180 patients randomised
and the study is ongoing.
-
JEWELFISH (NCT03032172) - an open-label
exploratory trial in people with all types of SMA aged 6 months-60
years who have been previously treated with SMN-targeting therapy
or olesoxime. The study is currently recruiting.
-
RAINBOWFISH (NCT03779334) - a new trial in
pre-symptomatic SMA initiated earlier this year.
About Roche in neuroscience
Neuroscience is a major focus of research and development at Roche.
The company's goal is to develop treatment options based on the
biology of the nervous system to help improve the lives of people
with chronic and potentially devastating diseases. Roche has more
than a dozen investigational medicines in clinical development for
diseases that include multiple sclerosis, spinal muscular atrophy,
neuromyelitis optica spectrum disorder, Alzheimer's disease,
Huntington's disease, Parkinson's disease, Duchenne muscular
dystrophy and autism.
About Roche
Roche is a
global pioneer in pharmaceuticals and diagnostics focused on
advancing science to improve people's lives. The combined strengths
of pharmaceuticals and diagnostics under one roof have made Roche
the leader in personalised healthcare - a strategy that aims to fit
the right treatment to each patient in the best way
possible.
Roche is the world's largest biotech company, with truly
differentiated medicines in oncology, immunology, infectious
diseases, ophthalmology and diseases of the central nervous system.
Roche is also the world leader in in vitro diagnostics and
tissue-based cancer diagnostics, and a frontrunner in diabetes
management.
Founded in 1896, Roche continues to search for better ways to
prevent, diagnose and treat diseases and make a sustainable
contribution to society. The company also aims to
improve patient access to medical innovations by working with
all relevant stakeholders. Thirty medicines developed by Roche are
included in the World Health Organization Model Lists of Essential
Medicines, among them life-saving antibiotics, antimalarials and
cancer medicines. Moreover, for the tenth consecutive year, Roche
has been recognised as the most sustainable company in the
Pharmaceuticals Industry by the Dow Jones Sustainability Indices
(DJSI).
The Roche Group, headquartered in Basel, Switzerland, is active in
over 100 countries and in 2018 employed about 94,000 people
worldwide. In 2018, Roche invested CHF 11 billion in R&D and
posted sales of CHF 56.8 billion. Genentech, in the United
States, is a wholly owned member of the Roche Group. Roche is the
majority shareholder in Chugai Pharmaceutical, Japan. For more
information, please visit www.roche.com.
All trademarks used or mentioned in this release are protected by
law.
References
* Current
location of Investigator: Dubowitz Neuromuscular Centre, UCL,
Institute of Child Health, Great Ormond Street Hospital, London,
UK
[1] Baranello G et al.FIREFISH Part 1: 1-Year Results on Motor
Function in Babies with Type 1 SMA. S25.003. Presented at 71st
American Academy of Neurology Annual Meeting, Philadelphia,
Pennsylvania, 4-10 May 2019.
[2] Servais L et al. FIREFISH Part 1: Survival, Ventilation and
Swallowing Ability in Babies with Type 1 SMA Receiving Risdiplam
(RG7916). S25.008. Presented at 71st American Academy of Neurology
Annual Meeting, Philadelphia, Pennsylvania, 4-10 May
2019.
[3] Mercuri E. Update from SUNFISH Part 1: Safety, Tolerability and
PK/PD from the Dose-Finding Study, Including Exploratory Efficacy
Data in Patients with Type 2 or 3 Spinal Muscular Atrophy (SMA)
Treated with Risdiplam (RG7916). S25.007. Presented at 71st
American Academy of Neurology Annual Meeting, Philadelphia,
Pennsylvania, 4-10 May 2019.
[4] Farrar MA and Kiernan MC. The genetics of spinal muscular
atrophy: progress and challenges. Neurotherapeutics. 2015;12:290-
302.
[5] Cure SMA. About SMA. 2018. Available from:
http://www.curesma.org/sma/about-sma/. Accessed March
2019.
[6] Kolb SJ and Kissel JT. Spinal muscular atrophy. Neurol Clin.
2015;33:831-46
[7] Spinal Muscular Atrophy UK. What is spinal muscular atrophy?
Available from:
http://www.smasupportuk.org.uk/what-is-spinal-muscular-atrophy.
Accessed March 2019.
[8] Hamilton G and Gillingwater TH. Spinal muscular atrophy: going
beyond the motor neuron. Trends Mol Med. 2013;19:40-50.
[9] Ratni H et al. Discovery of risdiplam, a selective survival
motor neuron-2 (SMN2) gene splicing modifier for the treatment of
spinal muscular atrophy (SMA). J Med Chem.
2018;61:6501-17.
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