The Race for First Generic Nusinersen Heats Up: What Innovative SMA Therapies Are on the Horizon?
Qilu Pharmaceutical
Specialty Formulations and Active Pharmaceutical Ingredients (API) Developer
Recently, the CDE official website showed that Qilu Pharmaceutical's nusinersen (trade name: Spinraza) injection has applied for marketing, becoming the second nusinersen generic drug to submit a marketing application in China.
In 2021, the news of "A 550,000-yuan Medical Bill for a Xi'an Toddler in 4 Days" went viral online. The disease the child suffered from was Spinal Muscular Atrophy (SMA). The main subject referred to by netizens as the "astronomical medical cost" was Nusinersen, which was priced at 550,000 yuan per injection in China at that time.
The reason why Nusinersen is so expensive is related to the relatively small size of the SMA patient population. SMA is a rare genetic disease caused by gene mutations, with an incidence rate of 1/6000-1/10000 in newborns, and it is the leading genetic cause of infant mortality.
The specific pathogenic mechanism of SMA is related to mutations in the SMN1 and SMN2 genes in the body. The normal SMN1 gene encodes the survival motor neuron protein (SMN protein). When the SMN1 gene mutates, the body cannot produce normal SMN protein, leading to the loss and progressive degeneration of motor neurons. Although the SMN2 gene can also encode the SMN protein, its transcription product is unstable and cannot perform the normal physiological function of the full-length SMN protein.
Clinically, SMA is divided into five types: type 0 (usually fatal within one month of birth) and types I to IV. Types I to III onset during childhood, while type IV is SMA that begins in adulthood. Generally speaking, type I patients cannot sit independently; type II patients can sit independently but are unable to stand or walk alone; type III and IV patients may be able to walk independently, but they might gradually lose these abilities over time.
For a long time, the treatment of SMA has mainly relied on supportive care, with a bleak prognosis. In recent years, therapies targeting the underlying cause of SMA by producing more SMN protein have begun to enter the market, and Nusinersen is one of them.
Nusinersen is an antisense oligonucleotide (ASO) drug developed by Biogen that selectively binds to mRNA, thereby affecting the initiation of RNA translation or altering exon splicing. Nusinersen increases the translation and splicing of exon 7 of the SMN2 gene, upregulating the expression of full-length SMN protein.
In a clinical trial involving 121 patients, 40% of those treated with nusinersen showed significant improvement, compared to 0% in the untreated control group. Based on these results, nusinersen was approved by the FDA in 2016, becoming the world’s first drug for the treatment of SMA. In April 2019, nusinersen was approved for use in China, with a price tag as high as 700,000 RMB per injection. Although the price has since decreased, it remains above 500,000 RMB.
In 2021, the "soul-cutting price" negotiation conducted by the National Healthcare Security Administration reduced the price of Nusinersen to 33,000 yuan per injection, successfully including it in the national medical insurance catalog, which greatly improved the accessibility and affordability for SMA patients. After entering the medical insurance catalog, Nusinersen achieved significant growth. In China's public medical institutions, the sales of this drug rose to nearly 600 million yuan in 2022.
In order to improve the accessibility of medications for patients, in October 2022, the National Medical Products Administration issued an announcement regarding the "List of Reference Preparations for Generic Drugs (61st Batch)," which included Nusinersen Injection in the list of reference preparations. Guided by this policy, in September 2024, Chongqing PharmaFriend Pharmaceutical Co., Ltd. submitted a market application for a generic version of Nusinersen Injection under Registration Category 4. In the future, Qilu Pharmaceutical will compete with it for the first domestically produced generic drug in China.
Currently, there are three approved drugs available in the SMA treatment field. Apart from Nusinersen, there are also Roche's Risdiplam (Evrysdi) and Novartis' Zolgensma.
Risdiplam is a splicing modulator targeting the SMN2 gene, which increases the expression of functional SMN protein by regulating the mRNA splicing of the SMN2 gene at two specific sites.
In 2020, Risdiplam was approved by the FDA for marketing, becoming the first small molecule targeting RNA. In 2021, Risdiplam was approved for marketing in China for the treatment of SMA patients aged 2 months and above. In June 2023, Risdiplam was again approved by the NMPA, expanding its applicable population to SMA patients aged 16 days and above. In March 2023, Risdiplam was included in the national medical insurance, with the price dropping from 63,800 yuan per bottle to 3,780 yuan per bottle.
Novartis' Zolgensma is an adeno-associated virus (AAV) vector gene therapy targeting the cause of SMA. In May 2019, Zolgensma received FDA approval and became the world’s first gene therapy drug for the treatment of SMA.
Zolgensma uses AAV9 as a vector, leveraging the viral capsid's ability to bind to galactose on the cell surface, allowing AAV9 to cross the blood-brain barrier. It delivers the AAV9 vector containing the SMN gene to motor neurons in the central nervous system through the blood-brain barrier. By replacing the function of the missing or non-functional SMN1 gene, it directly addresses the genetic root cause of the disease. A single one-time intravenous infusion can continuously express the SMN protein, providing long-term relief or even a cure for patients with SMA.
Priced at $2.125 million per dose, Zolgensma is expensive due to its one-time treatment. It has been approved in over 50 countries/regions but has not yet been approved in China.
Despite significant breakthroughs in SMA treatment, there remains a huge unmet need. Several pharmaceutical companies in China have already positioned themselves in this field, with relatively rapid progress seen in EXG001-307 by Jia Yin Bio and SKG0201 by Nine Skies Bio, among others.
Both of these drugs are AAV gene therapies, but they have different designs. EXG001-307 is the first SMA gene therapy in China to be approved for a registrational clinical trial. Its mechanism of action and usage are similar to Zolgensma. On this basis, Jia Ying Bio has adopted an innovative design aimed at reducing the side effects on the heart and liver of children caused by AAV-based gene therapy.
SKG0201: The innovative design consists of a vector regulated by a unique central nervous system-specific promoter and a fully codon-optimized human SMN1 cDNA. This innovative design achieves better tissue targeting, allowing the normal SMN1 gene to reach maximum therapeutic effect in the central nervous system after being introduced into the body. It aims to rapidly restore the expression of normal SMN protein in motor neurons at a low dose. SKG0201 was approved by the National Medical Products Administration (NMPA) for clinical trials in December 2023.
Currently, SMA treatment has gathered intrathecal injection drug Nusinersen, one-time gene therapy drug Zolgensma, and oral small molecule drug Risdiplam. Who will be the next innovative treatment drug? We wait and see.
Main References:
1.https://www.mdaconference.org/abstracts/2024-abstract-library/?_title=%20Zolgensma
2.https://www.zolgensma-hcp.com/clinical-experiences/start-trial-efficacy/
3.https://www.researchandmarkets.com/reports/4808538/global-gene-therapy-market-size-share-and-trends#src-pos-5
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