The Curtain Has Risen on the Competition for the First Generic Drug, so What Other Innovative Drugs in the Rare Disease Field Can We Look Forward to?

Recently, CDE official website revealed that Qilu Pharmaceutical has declared for marketing of nusinersen (brand name: Spinraza) injection, making it the second generics of nusinersen to apply for marketing application in China.

Nusinersen Faces the Controversy over First Generic Drugs

In 2021, news of a "4-day medical bill of RMB 550,000 for an infant in Xi'an" went viral. The child was diagnosed with spinal muscular atrophy (SMA), and the protagonist of the "exorbitant medical bill", as netizens called it, was nusinersen, which was priced at RMB 550,000 per injection in China at that time.

The high price of nusinersen is related to the small patient population with SMA. SMA is a rare genetic disease caused by gene mutations, with a morbidity rate of 1/6,000-1/10,000 in newborns, and it is a major genetic cause of infant mortality.

The specific pathogenesis 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). When the SMN1 gene is mutated, the body cannot produce normal SMN protein, leading to the loss and progressive degeneration of motor neurons. Although the SMN2 gene can also encode SMN protein, its transcript is unstable and cannot exert the normal physiological function of full-length SMN protein.

Clinically, SMA is divided into 5 types: Type 0 (often fatal within 1 month of birth) and Types I-IV, with Types I-III onset in childhood and Type IV onset in adulthood. Generally, Type I patients cannot sit independently; Type II patients can sit independently but cannot stand or walk independently; Type III and IV patients may be able to walk independently but may 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 that target the cause of SMA by producing more SMN protein have entered the market, with nusinersen being one of them.

Nusinersen is an antisense oligonucleotide (ASO) drug developed by Biogen that selectively binds to mRNA, thereby affecting RNA translation initiation or altering exon splicing. Nusinersen upregulates the expression of full-length SMN protein by increasing the translational splicing of exon 7 of the SMN2 gene.

In a clinical trial involving 121 patients, 40% of patients receiving nusinersen treatment showed significant improvement, compared with 0% in the untreated control group. Based on these research results, nusinersen was approved by the FDA in 2016 as the world's first drug for the treatment of SMA. In April 2019, nusinersen was approved for marketing in China, with a price of up to RMB 700,000 per dose. Although the price has since decreased, it is still above RMB 500,000.

In 2021, through the "soul-bargaining" negotiations conducted by the National Healthcare Security Administration, nusinersen was reduced to RMB 33,000 per dose and successfully included in the catalog of medicines covered by national medical insurance system, greatly improving the accessibility and affordability for SMA patients. After being included in the catalog, nusinersen achieved significant growth, with sales volume in Chinese public medical institutions reaching nearly RMB 600 million in 2022.

To improve patient access to the drug, in October 2022, NMPA issued a notice on the Reference Preparation Catalog for Generic Drugs (61st Batch), listing nusinersen injection in the catalog. Under this policy guidance, in September 2024, Chongqing YAOPHARMA submitted a marketing application of a generic nusinersen injection under the registration category 4. In the future, Qilu Pharmaceutical will compete with it for the first generic drug in China.

Multiple Breakthroughs: SMA Treatment Enters a Harvest Period

Currently, there are three drugs approved for marketing in the SMA treatment field. In addition to nusinersen, there are also Roche's Evrysdi and Novartis's Zolgensma.

Evrysdi is a splicing modifier targeting the SMN2 gene, which increases the expression of functional SMN protein by dually and specifically regulating the mRNA splicing of the SMN2 gene.

In 2020, Evrysdi was approved by FDA, becoming the first small molecule targeting RNA. In 2021, Evrysdi was approved for marketing in China for the treatment of SMA patients aged 2 months and older. In June 2023, Evrysdi was again approved by NMPA, expanding its use to SMA patients aged 16 days and older. Evrysdi was included in the national medical insurance in March 2023, with its price reduced from RMB 63,800 per bottle to RMB 3,780 per bottle.

Novartis's Zolgensma is an adeno-associated virus (AAV) gene therapy targeting the underlying cause of SMA. In May 2019, Zolgensma was approved by FDA, becoming the world's first gene therapeutic drug for the treatment of SMA.

Zolgensma uses AAV9 as a vector, which can bind to galactose on the cell surface through its viral capsid, allowing AAV9 to cross the blood-brain barrier and deliver the AAV9 vector containing the SMN gene to motor neurons in the central nervous system. By replacing the missing or non-functional SMN1 gene, it directly addresses the genetic root of the disease. Through a single intravenous infusion, Zolgensma can achieve sustained expression of SMN protein, providing long-term relief or even cure for SMA patients.

Due to its one-time treatment, Zolgensma is priced high, currently at USD 2.125 million per dose. Zolgensma has been approved in over 50 countries/regions, but not yet in China.

Despite significant breakthroughs in SMA treatment, there is still a tremendous unmet need. Multiple pharmaceutical companies in China have entered this field, with notable progress being made by Romics' EXG001-307 and Skyline Therapeutics' SKG0201, among others.

Both of these drugs are AAV gene therapeutic drugs, but they have different designs. EXG001-307 is the first SMA gene therapy in China approved to enter pivotal clinical trials. Its mechanism of action and administration are similar to those of Zolgensma. On this basis, Romics has adopted an innovative design aimed at reducing the side effects on the heart and liver in pediatric patients caused by AAV-vectored gene therapy.

The innovative design of SKG0201 is composed of a fully codon-optimized human SMN1 cDNA regulated by a unique central nervous system-specific promoter. This innovative design enables better tissue targeting, allowing the normal SMN1 gene, once introduced into the body, to achieve maximal therapeutic effect in the central nervous system region, thereby rapidly restoring normal SMN protein expression in motor neurons even at low doses. SKG0201 was approved by NMPA in December 2023 to proceed with clinical trials.

Currently, the treatment options for SMA have included the intrathecal injection drug nusinersen, the one-time gene therapeutic drug Zolgensma, and the oral small molecule drug Evrysdi. We eagerly anticipate the next innovative therapeutic drug to emerge.

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