Author 丨Ji Yuanyuan Editor 丨 Xu Xu Image source 丨 Figure Worm
With the inclusion of the Bojian spinal muscular atrophy (SMA) treatment drug Nocinasin sodium in the new 2021 medicare drug list, Novartis has also accelerated the pace of introducing innovative SMA drugs in China.
Recently, according to the Drug Evaluation Center (CDE) of the State Food and Drug Administration of China, the clinical trial application submitted by Novartis' AAV gene therapy drug Zolgensma (OAV101 injection) for the treatment of SMA has been implicitly approved for clinical trials in China. Previously, on October 21, 2021, the clinical trial application for the drug was accepted.
According to public information, Novartis Zolgensma is the world's first gene therapy for the treatment of spinal muscular atrophy, priced at $2.125 million (about 13.58 million yuan) abroad, also known as "the most expensive drug in history", but Zolgensma only needs to be injected once. At present, Zolgensma has been approved in nearly 40 countries and regions around the world. Among them, Zolgensma was included in Japan's medical insurance in 2020, and patients only need to pay 30% of the cost; later, in March 2021, it was included in the national health service system in the United Kingdom.
At present, only three SMA treatment drugs have been approved worldwide: Bojian, Novartis and Roche. In addition to Novartis Zolgensma, which has just been approved for clinical trials in China, Roche's Evrysdi was also approved for marketing in China in June 2021, becoming the first oral therapeutic drug approved to treat SMA in China. In addition, there are more than a dozen related drugs in the field of SMA in the global scope that are in different clinical stages.
Rare disease SMA is difficult to diagnose and treat
Spinal muscular atrophy (SMA) is a rare autosomal recessive hereditary neuromuscular disorder characterized by progressive, debilitating muscle atrophy and weakness. Children with SMA are predominantly infants and may present with hypotonia, poor head control, "frog leg" posture, dyspnea, developmental delay, scoliosis, or joint contractures. As the disease progresses, motor function gradually decreases.
SMA is the leading genetic factor in the death of infants under two years of age, severely affecting the quality of life of patients and caregivers, and patients have previously faced the dilemma of not having access to drugs.
Jenny from Zhejiang is an SMA patient who was born without prenatal screening. When Jenny was more than 1 year old, her family found that she never walked on the ground. After being examined by the hospital, she was diagnosed with the rare disease SMA. "Your daughter will live to be four years old at most, so go home and take good care of her." The doctor's words made Jenny's father, Bao Zongfeng, suddenly blinded. He took Jenny throughout the major hospitals in Zhejiang and traveled all over the country to seek medical treatment, and was told the same result again and again.
In the end, Bao Zongfeng spent all his savings and even carried more than 400,000 yuan in debt. But the daughter not only did not get better at all, but even the lower limbs gradually lost their ability to move, the upper limbs were also weakening, and the spine was deformed.
In his long career in treatment, Bao Zongfeng knew that it was impossible to make his daughter better, and after consulting with local doctors, they learned that if they had another child, the chance of getting the disease was only 25%. If this child is healthy, they will be able to take care of Jenny after a hundred years. The couple decided to gamble for Jenny.
So, in 2008, his son Bao Aojian was born, and unfortunately, the tragedy recurred: in 2009, Xiao Aojian was still diagnosed with SMA.
After giving birth to their son, the couple learned that about 50 people had an SMA pathogenic gene carrier, and the second-child obstetric examination and the screening of carriers in high-risk groups with family medical history could effectively block new cases. But the couple were farmers, and they had no idea that prenatal genetic testing could be done for the disease, not to mention that there was no corresponding testing agency in the local area at that time.
Peng Jing, chief physician of the Department of Pediatrics at Xiangya Hospital of Central South University, previously said in an interview with the media that the incidence of SMA is about one in 6,000 to 10,000. Based on this estimate, there may be between 20,000 and 30,000 patients in China.
"The misdiagnosis rate of this rare disease is extremely high. Newborn children may be misdiagnosed as ischemic hypoxic encephalopathy due to lack of muscle strength, or for cerebral palsy or movement disorders due to lack of strength throughout the body. In addition, the rare disease may be diagnosed with severe pneumonia until death due to often lung disease and lack of strength in the respiratory muscles. But the disease also has its own characteristics, although the child is weak, but the eyes are very good, if you think of this disease, diagnosis is not difficult. Knocking on the knee tendon reflex can not lead out, and doing an electromyography, or genetic testing, can quickly help the patient make a definitive diagnosis. Professor Peng Jing said.
In 1991, the International Spinal Muscular Atrophy Consortium confirmed the SMA classification. According to the highest level of motor function and the age of onset, it is mainly divided into I, II and III types. There are also adult-onset type IV, and type 0, which occurs prenatal and dies within a few weeks.
Type I is also known as Werdnig-Hoffman disease, that is, infant type, accounting for about 45% of all SMA cases, the child onset of illness within 6 months after birth, the rapid development of progressive, symmetrical limb weakness, maximum motor capacity can not reach sitting alone; type II also known as Dubnowitz disease, that is, intermediate type, accounting for about 30% to 40%, patients mostly onset in the first 6 to 18 months after birth, the progression is slower than type I, the maximum motor ability can reach sitting alone, but the age of sitting alone may lag behind normal children of the same age, Can not stand alone or walk alone; type III is also known as Kugelberg-Welander disease, that is, juvenile type, accounting for about 20%, patients mostly onset the disease after 18 months of birth, early motor development is normal, can walk alone, part of the solo time delay, with age the emergence of proximal muscle weakness, lower limbs heavier than the upper limbs, and eventually partial loss of the ability to walk alone, gradually dependent on wheelchairs; type IV is adult type, early motor development is normal, adult onset, proximal limb weakness, slow progression, Life expectancy is not shortened.
Only three SMA treatments have been approved worldwide
Currently, only three SMA treatments have been approved worldwide, namely Bojian's Nocinasson sodium, Novartis' Zolgensma and Roche's Evrysdi.
Nocinasin sodium is the world's first approved SMA treatment drug, approved by the FDA in December 2016 for the treatment of pediatric and adult 5q spinal muscular atrophy (5q-SMA), a drug is an antisense oligonucleotide (ASO) that binds to mRNA through base pairing, thereby regulating protein expression, acting on spinal cord motor neurons, making SMA treatment possible for the first time. At the beginning of this year, the new version of the national medical insurance drug catalog landed, Beijing, Shanghai, Guangdong, Zhejiang Sichuan, Shandong, Hunan, Hubei, Fujian, Jiangxi, Henan and other 11 provinces and cities of the hospital nearly 20 SMA patients received Bojian Nosinasin sodium injection, treatment, the drug from more than 700,000 to more than 30,000, greatly reducing the economic burden of the corresponding groups.
Zolgensma is a gene therapy that addresses the genetic roots of SMA by providing a functional copy of the human SMN gene to stop the progression of the disease through a single intravenous injection of sustained SMN protein expression. The drug was developed by AveXis (acquired by Novartis for $8.7 billion in 2018) and approved by the FDA in May 2019 for the treatment of children aged 2 years with bialpalum mutations in the SMN1 gene.
Evrysdi is the world's first approved oral SMA therapy and was approved in August 2020 for the treatment of children aged 2 months and older and adultSMA patients. Evrysdi is a motor neuron survival gene II (SMN2) mRNA splicing modifier that treats SMA by increasing the production of motor neuron survival protein (SMN). It is a liquid formulation that can be administered at home orally or by feeding tube once a day and can be used to treat infants, children, adolescents, adults of all types (type I, II, III) SMA.
In China, Evrysdi was approved by the State Food and Drug Administration in June 2021 for the treatment of SMA in patients aged 2 months and above, which is also the first oral disease modification treatment drug approved for the treatment of SMA in China. It is reported that the annual treatment cost of patients in the United States is about 2.37 million yuan.
"Rare disease patients are not easy, the first is the difficulty of diagnosis, because of the rarity, many people do not understand. The second is difficulty in treatment, because sometimes there is no medicine available when the diagnosis is confirmed. Third, there are many social factors, and there are many rare diseases, even if there is a cure, it is impossible to afford to use, and you have to go abroad to buy drugs. In addition, the availability of drugs is not an easy solution to the problem, but also requires the cooperation of multidisciplinary management teams in the medical field. Professor Peng Jing said.
Even if there is a drug available, family income has become a major problem in the face of rare diseases, only a cup of water, and "sky-high drugs" have become helpless for many patients and their families. How to make "sky-high drugs" become "life-saving medicines" has also become a social problem that needs to be solved urgently in front of Chinese medical experts.