The first oral medicine for spinal muscular atrophy (SMA)! Roche's Evrysdi treatment has continued to improve motor function and survival rate for 2 years. It has been under review in China!

News on April 15, 2021 // --Roche recently announced the new two-year data for the second part of the global phase 2/3 FIREFISH study of the oral drug Evrysdi (risdiplam) for spinal muscular atrophy (SMA).
The study was carried out in infants with symptomatic type 1 SMA who were 1-7 months old at the time of enrollment.
The data shows that between 12 months and 24 months, Evrysdi continued to improve motor function, including the ability to sit without support.
Research also shows that Evrysdi continues to improve survival rates, improve oral feeding capabilities, and reduce the need for permanent ventilation.
Exploratory data show that compared with the natural course of type 1 SMA, Evrysdi continues to improve swallowing ability and reduce hospitalization rates.
Evrysdi’s safety complies with its established safety status.
These long-term data are based on the one-year key findings of Part 2 of the FIREFISH study and will be released at the 73rd American Academy of Neurology (AAN) Annual Meeting to be held from April 17 to 22, 2021.

SMA is the primary genetic factor leading to death in infants and young children , and 5q-SMA is the most common type.
The disease can lead to muscle weakness and progressive loss of motor function, and there are significant unmet medical needs.
Evrysdi was approved by the US FDA in August 2020 for the treatment of children and adults with SMA ≥ 2 months of age.
In March 2021, Evrysdi was approved by the European Union to treat patients with SMA ≥ 2 months of age and clinically diagnosed as type 1/2 type/3 SMA or 5q type SMA with 1-4 copies of SMN2.
So far, Evrysdi has been approved in 39 countries and has submitted listing applications in 33 other countries, including China.

Evrysdi is the first oral therapy for SMA and the first SMA therapy that can be administered at home.
The drug is a liquid preparation that can be administered orally or via a feeding tube at home, once a day.
The drug can be used to treat infants, children, adolescents, and adults with all types (type 1, type 2, and type 3) of SMA .

Evrysdi is a motor neuron survival gene 2 (SMN2) mRNA splicing modifier, which treats SMA by increasing the production of motor neuron survival protein (SMN).
SMN protein is distributed throughout the body and is essential for maintaining healthy motor neurons and exercise.
Data from two key clinical trials confirm that Evrysdi is effective for infants, children, and adults aged 2 months and older, and is used in SMA patients of different ages and disease severity (including type 1, type 2, and type 3).
Motor function has been improved clinically.
Infants treated with Evrysdi can sit for at least 5 seconds without support, which is a key movement milestone that cannot be achieved in the natural course of SMA disease.
In addition, compared with natural medical history, Evrysdi also improved survival without permanent ventilation.

Dr.
Basil Darras, FIREFISH research investigator, professor of neurology at Harvard Medical School, and director of the SMA program at Boston Children’s Hospital, said: “The natural course of type 1 SMA tells us that, sadly, if left untreated, children will always sit without support.
No, it usually cannot survive after the age of 2.
It is encouraging that the baby's condition continues to improve after receiving Evrysdi treatment for 12 months.
Among the babies treated with Evrysdi in the past two years, twice as many babies are able to survive.
Sit and stand for at least 5 seconds without support.
Infants treated with Evrysdi also have a series of improvements in motor function, usually due to the reduction of serious events caused by disease progression, such as the need for permanent ventilation or hospitalization, and improved survival.
"

SMA boy (picture from: drpgx.
com)

The primary endpoint of the FIREFISH study is the percentage of infants able to sit for at least 5 seconds without support at 12 months.
Data shows that at 12 months of treatment, infants treated with Evrysdi can sit for at least 5-30 seconds without support.
The data at 24 months showed continuous improvement compared with the 12th month: as measured by the Bailey Infant and Toddler Development Inventory Third Edition (BSID-III) Great Exercise Scale, 61% (25/41 ), 29% (12/41) were able to sit for at least 5 seconds without support at 12 months, 44% (18/41) at 24 months, and 17% (7/41) at 12 months ) Able to sit for at least 30 seconds without support.
Importantly, infants treated with Evrysdi were able to maintain oral feeding ability at 24 months (92%; 35/38).
In addition, exploratory data showed that the ability to swallow remained similar (95%; 36/38).
In the natural course of the disease, infants with type 1 SMA who are older than 12 months usually require feeding support.

After 24 months of treatment, 93% of infants (38/41) survived.
83% of infants (34/41) survived after 24 months and were out of permanent ventilation, and their performance improved compared with the natural course of the disease.
There were no new deaths between 12 months and 24 months.
Without treatment, the median age of infant death or permanent ventilation is 13.
5 months.
In addition, compared with the natural course of the disease, the number of hospitalizations in the second year of treatment with Evrysdi was smaller, and 34% of infants (14/41) did not need to be hospitalized during the 24-month treatment period.
Other research results showed that Evrysdi continued to improve at the 24th and 12th months.
According to the Hammersmith Infant Neurological Examination Scale 2 (HINE-2), including the ability to stand upright (63% vs 44%), from supine Switch to prone (44% vs 10%), support standing (15% vs 5%), and walking (4% vs 2%).
The total score of CHOP-INTEND also continued to improve, and the proportion of patients who reached 40 points or more by the 24th month (76%; 31/41) was higher than that at the 12th month (56%; 23/41).
In the natural course of the disease, children with type 1 SMA rarely achieve a total score of 40 points.

In the study, the observed adverse events and serious adverse events are consistent with previous studies.
The most common adverse reactions were upper respiratory tract infection (54%), pneumonia (46%), fever (44%), constipation (29%), nasopharyngitis (17%), bronchitis (15%), diarrhea (15%) ) And rhinitis (12%).
During the first and second 12-month period of Part 2 of the FIREFISH study, the incidence of severe pneumonia dropped by approximately three times.
The most common serious adverse events were pneumonia (39%) and respiratory distress (7%).
No drug-related adverse events led to withdrawal or discontinuation of treatment.

Levi Garraway, MD, Roche’s chief medical officer and head of global product development, said: “These data highlight the real impact of this revolutionary drug on infants with the most severe SMA.
For example, after 24 months of treatment, all surviving infants have Being able to swallow, this helps them eat by mouth rather than via a feeding tube.
These results increase our understanding of how this first-of-its-kind treatment can extend the lifespan of infants with type 1 SMA, providing much-needed hope for their families.
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The chemical structure of risdiplam (picture source: medchemexpress.
cn)

Evrysdi is an oral liquid.
Its active pharmaceutical ingredient, risdiplam, is a survival motor neuron gene 2 (SMN2) splicing modifier designed to continuously increase and maintain the level of SMN protein in the central nervous system and peripheral tissues.
More and more clinical evidences show that SMA is a multi-system disease, and the loss of SMA protein may affect many tissues and cells outside the central nervous system.
After oral administration, risdiplam presents a systemic distribution and can continuously increase the level of SMN protein in the central nervous system and peripheral tissues.
It has been shown to improve the motor function of patients with type 1, type 2, and type 3 SMA.

As part of the collaboration with the SMA Foundation and PTC Therapeutics, Roche led the clinical development of Evrysdi.
Currently, more than 3,000 patients have received Evrysdi treatment in clinical trials , compassionate use, and real-world settings.

As part of a large-scale, extensive and robust clinical trial project in the SMA field, Evrysdi is conducting research in more than 450 people.
The project covers infants from 2 months old to 60-year-olds who have different symptoms and motor functions, such as scoliosis or joint contractures, as well as patients who have previously received other SMA therapies.
The drug's clinical trial population is intended to represent a broad, real-world population of SMA disease, with the goal of ensuring that all suitable patients can receive treatment.

Currently, Roche is carrying out 4 global multicenter clinical studies (SUNFISH[NCT02908685], FIREFISH[NCT02913482], JEWELFISH[NCT03032172], RAINBOWFISH[NCT03779334]) to evaluate all types of Evrysdi treatment (type 1, type 2, type 3) The efficacy and safety of SMA and presymptomatic SMA in neonates.

Spinraza: The world's first SMA treatment drug, approved in China

SMA is a motor neuron disease that can cause muscle weakness and atrophy.
The disease is an autosomal recessive genetic disease caused by genetic defects.
It can cause damage to the muscles around the patient’s body.
The patient’s main manifestation is systemic muscle atrophy and weakness.
The body gradually loses various motor functions, even breathing and swallowing.
SMA is the number one genetic disease killer in infants under 2 years of age .
The disease is a relatively common "rare disease" with a prevalence of 1:6000-1:10000 in newborns.
According to related reports, the current number of SMA patients in China is about 3-5 million.

In December 2016, Spinraza (nusinersen), a drug developed by Biogen and its partner Ionis, was approved and became the world's first drug for the treatment of SMA.
The drug is an antisense oligonucleotide (ASO).
It is administered by intrathecal injection and delivers the drug directly to the cerebrospinal fluid (CSF) around the spinal cord.
It changes the splicing of SMN2 pre-messenger RNA (pre-mRNA) and increases Production of fully functional SMN protein.
In SMA patients, insufficient levels of SMN protein lead to degeneration of spinal cord motor neuron function.
In clinical studies, Spinraza treatment significantly improved the motor function of SMA patients.

In May 2019, the gene therapy Zolgensma (onasemnogene abeparvovec) from Novartis was approved, becoming the world's first gene therapy to treat SMA.
The drug prevents the progression of the disease by continuously expressing SMN protein after a single, one-time intravenous infusion, can solve the underlying cause of SMA, and is expected to improve the quality of life of patients in the long term.

In the Chinese market, Spinraza was approved at the end of February 2019 for the treatment of patients with 5q spinal muscular atrophy (5q-SMA).
This approval makes Spinraza the first drug to treat SMA in the Chinese market.
5q-SMA is the most common type of SMA, accounting for about 95% of all SMA cases.
This type of SMA is caused by a mutation in the SMN1 (survival motor neuron protein 1) gene on chromosome 5, hence the name 5q-SMA .
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Original source: Roche's Evrysdi continues to improve motor function and survival in babies with Type 1 Spinal Muscular Atrophy (SMA)