Multidimensional thinking on factors influencing therapeutic efficacy of spinal muscular dystrophy disease correction

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Myopathy spinosa (SMA) is a rare and serious inherited neuromuscular disease

The advent of new drugs is changing the course of the disease and the way patients are managed by SMA

SMA has fully entered the era of DMT treatment ^[2], and the survival status of patients has been effectively improved

SMA is an autosomal recessive neuromuscular disease that results in a homozygous deletion or mutation of the motor neuron survival gene 1 (SMN1) on chromosome 5q11.

In 2016, the world's first SMA therapeutic drug, noxenacin sodium injection, was approved by the US Food and Drug Administration (FDA) for the treatment of 5q SMA, marking the official entry of SMA into the DMT era ^[6

Noxenacon is a precisely designed antisense oligonucleotide (ASO) that acts on the SMN2 gene precursor mRNA, targeting and promoting the retention of SMN2 mRNA exon 7 and promoting the production of full-length functional SMN proteins, thereby improving motor function in SMA patients ^[8].

Fig.

The response to modified treatment for SMA disease is affected by many factors, and it is necessary to comprehensively consider the patient's initial age of administration, body weight, and baseline motor function

Nosinacon has shown good benefit-risk characteristics in a wide range of SMA ^{populations [12]} and has shown significant and clinically significant efficacy

Baseline growth metrics
.

The results of an analysis based on data from the ENDEAR/SHINE study ^[12] showed that first administration at a higher age was significantly associated
with a decrease in baseline weight-age percentile (ρ=–0.
25; p=0.
02) and a decrease in baseline pNF-H levels (ρ=–0.
29; p=0.
01).

In the corrected multivariate model, patients with a higher baseline weight-age percentile (<5%) had a 4.
5-fold increase in the probability of sitting alone (p=0.
004) compared with a lower baseline weight-age percentile (≥5%); For every 1 point increase in the baseline CHOP-INTEND score, the probability of sitting alone increases by a factor
of 1.
1.

Postmortem analysis of the ENDEAR/SHINE study showed that the younger the first dose of type 1 SMA, the higher the age-weight percentile, and the better the baseline motor function (CHOP INTEND), the better the prognosis ^[14].


The results highlight the value of baseline motor function, growth indicators, etc.
in terms of prediction, while emphasizing that for SMA, the earlier treatment is started, the greater the benefit
.

Age
of initiation of treatment.

Multiple centers have published in the Expanded Access Plan (EAP) the experience of using Nosinacon in patients with SMA type 1 in different age groups and have yielded similar results that the age of initiation of treatment is an important factor in determining improvement in motor function ^[15].


In the Hungarian real-world study [16] and an international multicenter study ^[17], it was also found that the age of initiation of treatment in patients with type 2 SMA was correlated with the degree of improvement in motor function
.

A systematic review of 31 studies ^[18] showed that the duration of SMA course before DMT was highly predictable and that age at first treatment was also a factor influencing prognosis
.

Together, this underscores the need to start treatment for SMA as early as possible, especially for patients aged 6 to 15 years who
are susceptible to complications such as scoliosis.

In addition to treatment, factors influencing the prognosis of SMA include SMN2 copy number, baseline exercise, age and severity of disease onset, and supportive care ^[18].


A retrospective, observational study of 55 patients with SMA showed that the use of noxenazon in combination with rehabilitation produced better exercise outcomes, including postural correction, reduction of stiffness, increased range of motion, and muscle enhancement than treatment with noxenacon ^{alone [19].}

Figure 2: A systematic review exploring prognostic factors for the efficacy of SMA ^[18].

Patient baseline and clinical features may influence treatment outcomes and may be used to predict response
to specific treatments.

Determining reliable predictors of the response to SMA disease modification therapy is critical to optimizing patient management and supporting personalized care ^[12].

In recent years, the use of biomarkers to predict the therapeutic effect of nocinazom has become a hot topic
in the field of SMA.

Non-SMN-related markers such as plasma phosphorylated neurofilament heavy strands (pNF-H), blood creatine kinase (CK) and creatinine (Cr), proteomics, muscle-specific miRNAs (myomiRs), etc.
may predict nocinazonian treatment response
.

Neurofilamentin (NF) is thought to be a potential biomarker for diseases characterized by axonal damage and degeneration ^[20].


Studies have found that lower baseline plasma pNF-H is associated with greater improvement in motor function (CHOP INTEND and HINE-2) ^[21
].

In three clinical trials of nosinacin, the magnitude of the decrease in plasma pNF-H levels in treated patients predicted motor function responses, suggesting that changes in neurofilamentin (NF) levels could serve as markers of response to SMA therapy ^[22].


In response to adult SMA therapy, a retrospective, multicenter observational study of 206 adult patients with SMA ^[23] showed that improvements in motor function were observed in patients receiving noxenazon for 18 months (68 of type 2, 85 of type 3), accompanied by decreased CK and slightly elevated
Cr.

Suggests that blood CK and Cr may be valuable biomarkers
for predicting the response to treatment with SMA nosinacon in adults.

The treatment of SMA in China is just getting started, and as the availability of drug therapy increases, more and more patients will be treated, and the clinical application value of these biomarkers will also be evaluated in domestic SMA patients ^[20].

Real-world evidence with RCT consistency issues

As a complement to traditional clinical trials^[24], the impact of real-world data on treatment is gaining international attention
.

At this year's European Congress of Neurology (EAN), some scholars noted that real-world evidence is critical in determining treatment effectiveness, long-term drug safety, quality of life improvements, and the impact of clinical interventions on treatment management ^[25].


For SMA, real-world data on the long-term efficacy and safety of DMT are increasingly needed in patient cohorts reflecting age and severity throughout age ^[26].

As the first SMA DMT drug to be marketed in the world and China, Noxenacon has demonstrated the efficacy of changing the course of SMA in high-evidence randomized controlled clinical trials (RCTs), and has also accumulated rich experience and data in the real world, making it the most evidenced DMT drug
in real-world research.

Its improvements in SMA motor function, respiratory function, and improved patient-reported outcomes (PRO) in children and adults reflect evidence
of real-world consistency between key clinical studies and the real world.

For example, the Expanded Access Plan (EAP) for Noxenacon therapy in the patient population type 1 ^{SMA [27}], and real-world studies of the EP cohort [^28-30] in Italy, Germany, and France showed that treatment with Noxenacon improved CHOP-INTEND and HINE-2 scores in children with type 1 SMA1 for 6 months, and its efficacy was the same as that of ENDEAR ^[10].
The findings were consistent; Real-world data from Asian populations, including Hong Kong, China and Taiwan, show that Noxenazon treatment significantly improves CHOP-INTEND and HINE-2 scores in children with SMA type 1 and stabilizes or improves respiratory function
.

Real-world research evidence similarly supports effectiveness in motor function in patients with late-onset (type 2/3) SMA
.

A meta-analysis of 30 real-world studies^[31] showed significant improvements
in motor function in all SMA patients treated with noxenacon regardless of their type and age, compared with patients not receiving nosthenazon.

In addition, there is currently increasing
real-world evidence for the use of nosinison in adult patients.

Although these patients were much older than those treated in clinical trials and had a multi-year course of the disease, Nosinacon treatment improved or stabilized their motor function
.

Figure 3: Hammersmith Motor Function Rating Scale (HFMSE) score for children ^[31].

Evidence from real-world studies is an important manifestation of randomized controlled studies in clinical practice ^[24].


So far, the real-world research data on the treatment of SMA at home and abroad has been increasing, which to a certain extent complements and reflects the therapeutic benefits of key clinical research, and at the same time accumulates and answers various problems encountered in clinical practice and guides better clinical application ^[6
].

There is a lack of head-to-head comparative studies in the field of SMA therapy, and indirect comparison conclusions need to be viewed with caution

At present, three DMT drugs have been approved for SMA worldwide, and if different clinical treatments are to be scientifically and rigorously compared, a rigorous randomized controlled trial direct comparison or head-to-head comparison of systematic reviews ^[32] is currently lacking
.

It has been suggested that in the absence of direct head-to-head comparison, indirect comparison (ITC) may be possible to achieve a comparison of differences in efficacy between different treatment measures ^[33].


However, some scholars have questioned the differences between different clinical trials in terms of inclusion and exclusion criteria, and the conclusions drawn by indirect comparison methods must be interpreted
with caution.

Recently, the efficacy and safety of Noxenacon^, listebolan and Onasemnogene abeparvovec in the treatment of SMA type 1-3 were compared
by systematic literature review using the methods of match-adjusted indirect comparison (MAIC) and analogue therapy comparison (STC).

From a methodological point of view, indirect comparison methods, especially non-anchored MAIC methods, have certain limitations^[35], including problems such
as the inability to completely eliminate biases, the susceptibility of comparative results to effect correction factors, and the potential bias of results.

Most of the results of the MAIC analysis were not adopted by the mainstream European Health Technology Assessment (HTA) institutions when evaluating the study, concluding that "at least one important dimension of the model, such as ventilator support, was not considered" or that "there was a large bias in the comparative approach" ^[36-39].

The consistency of drug efficacy is reflected in many key clinical studies and real-world studies of Nosinacen, and confirms the role of nosinozom in different subtypes, different ages, and different disease stages, which is of more practical significance
for SMA patients.

Currently, more than 11,000 infants, children and adults with SMA have received Nocinacanazon worldwide
.

brief summary

SMA is a severe, disabling, fatal disease
.

The approval of disease modification therapy drugs in China has changed the quality of life of SMA patients and made the treatment of SMA in China enter a new stage
.

Nosinacon's critical clinical research and a range of real-world research evidence support practical clinical applications
.

Looking forward to the release of more research data for China's SMA population in the future, to guide the clinical practice of domestic doctors, improve the quality of life of SMA patients, and benefit more SMA patients and families!

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