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Genentech Presents Data from the Risdiplam Pivotal FIREFISH and SUNFISH Studies in Spinal Muscular Atrophy at the 2019 AAN Annual Meeting

May 7, 2019 Off By BusinessWire

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

SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Genentech, a member of the Roche Group (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. Among the infants who received the dose
selected for the confirmatory Part 2 of the study (n=17), seven (41.2
percent) 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
percent) infants were able to sit (with or without support) while nine
(52.9 percent) achieved upright head control after 12 months of
treatment as assessed by the Hammersmith Infant Neurological Examination
Module 2 (HINE-2). Finally, one infant (5.9 percent) achieved the
milestone of standing (supports weight) by this 12-month time point.

The data were presented at the 71^st American Academy of
Neurology (AAN) Annual Meeting from May 4-10 in Philadelphia,
Pennsylvania. Roche and Genentech lead 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, M.D., 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. Results showed
that 10 out of 17 infants (58.8 percent) in the therapeutically dosed
group achieved a CHOP-INTEND total score of 40 points or more. 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 of treatment,
increasing from a maximum of 49 points after eight months.

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. Three infants experienced fatal complications of
their disease after approximately one, eight and 13 months of treatment.
None of these have 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. The
event-free survival was 18 out of 21 (85.7 percent) overall and 15 out
of 17 (88.2 percent) in the therapeutically dosed group. The most common
adverse events included fever (pyrexia; 52.4 percent), upper respiratory
tract infections (42.9 percent), diarrhea (28.6 percent), vomiting (23.8
percent), cough (23.8 percent), pneumonia (19.0 percent) and
constipation (19.0 percent).

“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, M.D., 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 program for risdiplam as it emerges.”

Genentech 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 percent), cough (33 percent), vomiting (29 percent), upper
respiratory tract infections (26 percent), persistent sore throat
(oropharyngeal pain; 22 percent) and cold (nasopharyngitis; 20 percent).
The most common serious adverse event that occurred in two of the 51
patients exposed to risdiplam was pneumonia. To date there have been no
treatment-related safety findings leading to withdrawal from any study.

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. Among the
patients for which the MFM32 scale has been completed at all visits up
to month 12 (n=43), 58 percent saw an improvement of at least three
points on the scale from baseline, including 71 percent among patients
2-11 years old and 42 percent aged 12-25 years. 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 and Genentech are 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.

Full session details and data presentation listings for the 2019 AAN
Annual Meeting can be found at the meeting website: https://www.aan.com/conferences-community/annual-meeting/.

Follow Genentech on Twitter via @Genentech and keep up to date with AAN
2019 Annual Meeting news and updates by using the hashtag #AANAM.

*Current location of investigator: Dubowitz Neuromuscular Centre, UCL,
Institute of Child Health, Great Ormond Street Hospital, London, U.K.

About spinal muscular atrophy

Spinal muscular atrophy (SMA) is a severe, inherited, progressive
neuromuscular disease that causes devastating muscle atrophy and
disease-related complications. 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. SMA leads to the progressive loss of
nerve cells in the spinal cord that control muscle movement. 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.

SMA is caused by a mutation in the survival motor neuron 1 (SMN1) gene
that results in a deficiency of SMN protein. 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.

About risdiplam

Risdiplam is an investigational orally-administered medicine being
studied in a broad range of patients with SMA from one 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.

Roche and Genentech lead the clinical development of risdiplam as part
of a collaboration with the SMA Foundation and PTC Therapeutics.
Risdiplam is currently being evaluated in four multicenter 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.
Enrollment 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 or 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 (MFM32) at 12 months.
Enrollment for Part 2 was completed in September 2018 with 180
patients randomized 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 Genentech in neuroscience

Neuroscience is a major focus of research and development at Genentech
and 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. Genentech and Roche
have 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 Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology
company that discovers, develops, manufactures and commercializes
medicines to treat patients with serious and life-threatening medical
conditions. The company, a member of the Roche Group, has headquarters
in South San Francisco, California. For additional information about the
company, please visit http://www.gene.com.