A few days ago, American biopharmaceutical company Scholar Rock announced that its research drug apitegromab has been granted fast track qualification for the treatment of spinal muscular atrophy (SMA) by the FDA. If the relevant requirements are met, Scholar Rock will submit a rolling listing application for apitegromab to the FDA.

apitegromab is one of Scholar Rock's leading product candidates

Scholar Rock is a clinical-stage biotechnology company headquartered in Cambridge, Massachusetts, USA. It focuses on the development of new inhibitor drugs around the biological mechanism of growth factors and has developed a series of drug candidates.

As one of the leading product candidates of Scholar Rock, apitegromab (SRK-015) is a pioneering and selective inhibitor of myostatin activation. Myostatin is a member of the growth factor TGF-β superfamily. It is mainly expressed in skeletal muscle cells. It is a negative regulator of skeletal muscle. It regulates and breaks down muscles and participates in mediating various wasting diseases that restrict muscle growth. , Leading to muscular dystrophy.

It is worth mentioning that apitegromab has been awarded the title of orphan drug for the treatment of SMA and the title of rare pediatric disease by the FDA, and was awarded the title of priority drug for the treatment of SMA and the title of orphan drug by the EMA.

At the MDA Clinical and Scientific Conference held in March this year, the TOPAZ Phase 2 clinical study of apitegromab for the treatment of SMA was successfully shortlisted. The study is a 52-week phase 2 study, enrolling 58 patients with type 2 and type 3 SMA from 16 research centers in the United States and the European Union. The patients in the study were administered intravenously every 4 weeks.

The study was divided into three cohorts. Cohort 1 compared the effects of apitegromab 20 mg/kg monotherapy and Nusinersen treatment, cohort 2 evaluated the effects of apitegromab 20 mg/kg combined with Nusinersen, and cohort 3 compared apitegromab high-dose 20 mg/kg. kg and low-dose 2 mg/kg treatment. The primary endpoints were safety and tolerability in patients with type 2 and type 3 SMA, and changes in motor function as measured by the Hammersmith total score. The secondary endpoint is to evaluate the pharmacokinetic and pharmacodynamic effects of apitegromab, the onset time and immunogenicity of apitegromab (SRK-015) in cohort 3 at low and high doses.

The results showed that at 6 months, improvements in motor function were observed in all three treatment cohorts, with 67% of patients achieving an increase of ≥1 point in Hammersmith's total score; 35% of patients achieving an increase of ≥3 points in Hammersmith's total score. In cohort 3, compared with the average improvement of 2.4 points in the low-dose group, the overall Hammersmith score of the high-dose group improved by an average of 5.6 points.

Three pillars of the SMA market, Spinraza sales began to decline

Spinal muscular atrophy (SMA) is a common autosomal recessive genetic disease. It is a type of disease in which muscle weakness and muscle atrophy are caused by the degeneration of motor neurons in the anterior horn of the spinal cord. The clinical manifestations are progressive, symmetry, and limbs. Generalized flaccid paralysis and muscle atrophy mainly proximal. SMA is the first genetic disease that causes death in children under the age of 2, and the prevalence in newborns is 1:6000-1:10000. There are approximately 30-35,000 SMA patients in the United States and Europe.

The underlying pathology of SMA is caused by insufficient production of SMN protein necessary for motor neuron survival, which is encoded by two genes SMN1 and SMN2. Currently, only three SMA treatment drugs are approved globally, namely Bojian/Ionis' Spinraza (nusinersen), Novartis' Zolgensma (onasemnogene abeparvovec) and Roche's Evrysdi (risdiplam).

1. Spinraza

Spinraza is the world's first SMA treatment drug approved by the FDA in December 2016 for the treatment of pediatric and adult 5q spinal muscular atrophy (5q-SMA) patients. 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 gene on chromosome 5. The drug is an antisense oligonucleotide, which is administered by intrathecal injection, which delivers the drug directly to the cerebrospinal fluid (CSF) around the spinal cord, changes the splicing of SMN2 pre-messenger RNA (pre-mRNA), and increases full functionality Production of SMN protein. Clinical studies have shown that Spinraza treatment can significantly improve the motor function of patients with SMA.

2. Zolgensma

Zolgensma is a kind of gene therapy, by providing a functional copy of human SMN gene, through a single intravenous injection of continuous SMN protein expression to prevent the progression of the disease, thereby solving the genetic root of SMA. The drug was developed by AveXis (acquired by Novartis for US$8.7 billion in 2018) and was approved by the FDA in May 2019 for the treatment of children with SMA who are 2 years old and older with biallelic SMN1 gene mutations.

3. Evrysdi

Evrysdi is the world's first oral SMA therapy approved in the world. It was approved in August 2020 for the treatment of children and adults with SMA for 2 months and older. 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). The drug is a liquid preparation that can be administered orally or via a feeding tube at home, once a day, and can be used to treat infants, children, adolescents, and adults with all types (type 1, type 2, and type 3) of SMA.

In terms of market performance, according to the company's financial report, the above three approved SMA drugs all show strong market potential. Among them, Spinraza has the highest sales due to its first-mover advantage. However, due to competition from competing products, sales will begin to decline in 2020. . Novartis’s Zolgens grew strongly, with sales reaching US$920 million in its second year of listing. Evrysdi was approved late, with sales of only 55 million Swiss francs in its first year of listing.

It is worth mentioning that these drugs are expensive. It is reported that Spinraza is priced at US$125,000 per injection abroad. It requires 6 injections in the first year. The treatment cost is US$750,000. The cost in the second year is reduced by half to US$375,000. Zolgensma is priced at US$2.125 million, which is currently the most expensive drug in the world. Evrysdi is priced at a maximum of US$340,000 per year and is expected to compete for a certain SMA market share with its oral advantage and price advantage.

However, in China, there is only one SMA drug currently approved, namely Spinraza (nusinersen) of Bojian Pharmaceutical. However, Roche's risdiplam was made in China in April 2020, and its listing application (relevant acceptance number is JXHS2000042) has completed the first round of supplementary information, and it is expected to be approved this year.

In addition, there are more than a dozen drugs under research in the SMA field around the world that are in different clinical stages. I believe that as more and more drugs are approved, SMA patients will have more treatment options in the future.