Avapritinib Under Normal NMPA Review in China as CStone Pharmaceuticals Accelerates Commercialization Transition

In response to recent controversies surrounding the “unexpected clinical underperformance of a new drug,” CStone Pharmaceuticals has confirmed that avapritinib, for which the company has submitted a marketing application, is undergoing routine review by the National Medical Products Administration. The VOYAGER clinical trial results released by its partner will neither affect the commercialization of avapritinib in the United States nor impact its regulatory approval process in China.

On April 28, 2020, Blueprint Medicines Corporation (NASDAQ: BPMC), a partner of CStone Pharmaceuticals, announced the global Phase III VOYAGER clinical trial results for avapritinib, a precision targeted inhibitor of KIT/PDGFRA gene mutations in gastrointestinal stromal tumors (GIST). The results showed that avapritinib did not demonstrate superior efficacy over regorafenib and failed to improve progression-free survival (PFS) in patients with locally advanced, unresectable, or metastatic third-/fourth-line advanced GIST. However, there was no statistically significant difference between avapritinib and regorafenib regarding the primary endpoint of PFS. This indicates that avapritinib and regorafenib have comparable efficacy in improving PFS for GIST patients.

On April 23, the National Medical Products Administration (NMPA) formally accepted CStone Pharmaceuticals’ new drug application for avapritinib. The indications sought include unresectable or metastatic gastrointestinal stromal tumors (GIST) with PDGFRA exon 18 mutations (including PDGFRA D842V mutation), as well as fourth-line advanced GIST that is progressive, unresectable, or metastatic. This marks the first new drug application submitted by CStone Pharmaceuticals for market approval in China.

News of the clinical trial’s failure to meet expectations immediately sparked widespread attention within the industry. Will CStone Pharmaceuticals’ inaugural commercialization effort suffer a setback? The company has provided an authoritative response.

The indication for avapritinib submitted for marketing approval in China is not the same as the indication involved in the VOYAGER clinical study.

The two indications for which CStone Pharmaceuticals has submitted New Drug Applications (NDAs) in China are: patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including the PDGFRA D842V mutation), and patients with advanced GIST in the fourth-line setting who have experienced disease progression and whose tumors are unresectable or metastatic. Notably, the indication for patients with unresectable or metastatic GIST harboring PDGFRA exon 18 mutations (including the PDGFRA D842V mutation) was approved for marketing by the U.S. FDA on January 9 this year.It is currently the first and only approved drug worldwide for the precise targeted treatment of GIST with PDGFRA exon 18 mutations.Patients with unresectable or metastatic GIST harboring PDGFRA exon 18 mutations (including the PDGFRA D842V mutation) are currently resistant to all conventionally approved therapeutic agents, leaving no available treatment options. Thus, the indication submitted by CStone Pharmaceuticals to the National Medical Products Administration represents an exclusive therapy for this condition.

Furthermore, it is understood that avapritinib achieved robust sales in the U.S. market during the first quarter of this year, significantly exceeding expectations.

Blueprint’s VOYAGER study demonstrated that avapritinib achieved a higher objective response rate than regorafenib. Although it did not show a statistically significant advantage in progression-free survival (PFS) over regorafenib, the lack of statistical difference indicates that avapritinib has comparable efficacy to regorafenib, the standard third-line therapy, in patients with gastrointestinal stromal tumors (GIST) receiving third- and fourth-line treatment. Currently, there is no standard treatment regimen in China for GIST patients undergoing fourth-line therapy.

As can be seen, of the two indications submitted by CStone Pharmaceuticals to the National Medical Products Administration (NMPA), one is an exclusive drug for treating the disease and has already been approved for marketing in the United States; the other has also demonstrated efficacy in a therapeutic area lacking effective treatment options.

This may well be the “cornerstone” of CStone Pharmaceuticals’ confidence.

From the product pipeline perspective, CStone Pharmaceuticals has 15 assets with precision medicine and immuno-oncology as its dual cores, including 5 assets in late-stage clinical development. It is expected that within this year, 5 marketing applications will be submitted, 1 marketing application will be approved, and clinical trial data for 7 items will be announced; covering 4 assets such as CS1001 (PD-L1), ivosidenib (IDH1 inhibitor), pralsetinib (RET inhibitor), and avapritinib (KIT/PDGFRA inhibitor).

Since June 2018, CStone Pharmaceuticals has entered into an agreement with Blueprint Medicines Corporation to obtain the rights for clinical development and commercialization in China of three drugs, including avapritinib, as monotherapy or combination therapy.

CStone Pharmaceuticals shares the medical community’s high expectations for avapritinib, a precision-targeted, highly selective KIT/PDGFRA inhibitor. On one hand, avapritinib is the first drug globally approved for patients with gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations. Furthermore, since approximately 60% of patients who develop secondary resistance have KIT exon 11, 17, or combined 11/17 mutations, avapritinib is theoretically effective in treating this subset of patients with secondary resistance due to these specific genetic alterations. On the other hand, owing to its unique targets, avapritinib demonstrates therapeutic potential across more than 10 indications, including systemic mastocytosis (SM), non-small cell lung cancer, liver cancer, colorectal cancer, esophageal cancer, head and neck squamous cell carcinoma, acute myeloid leukemia, melanoma, and low-grade glioma.

Among them, SM, as a rare disease, has an estimated patient population of approximately 17,000 in China, representing a substantial market size. The median age of onset is between 20 and 50 years; patients require long-term, nearly lifelong treatment, primarily aimed at symptom control.

When the disease involves other organs of the body, including the gastrointestinal tract, bone marrow, liver, spleen, and lymph nodes, failure to diagnose and treat it in a timely manner may be life-threatening in severe cases. Avapritinib can potently and precisely inhibit the KIT D816V mutation; systemic mastocytosis (SM) is a rare disease driven by the KIT D816V mutation. In Phase II clinical trials of avapritinib for patients with indolent SM,In the treatment group, the mean total symptom score decreased by approximately 30%, a 10-fold greater reduction than that observed in the placebo group. The mean quality-of-life score improved by 34%, representing a fivefold greater improvement compared with the placebo group. Results from the EXPLORE clinical study in patients with advanced systemic mastocytosis (SM) demonstrated that avapritinib achieved an overall response rate (ORR) of 83%, with 76% of patients maintaining a durable response for one year.Blueprint is preparing to submit a marketing application to the FDA for this indication within the year. CStone Pharmaceuticals is also actively preparing its regulatory submission pathway for this indication in mainland China.

It is evident that robust R&D capabilities and strong commercialization prowess are both indispensable for translating laboratory innovations into market success.

CStone Pharmaceuticals is a typical biopharmaceutical company operating under the VIC model; once its products are approved and launched, scaled-up production and market promotion become the key to realizing their value.

In August 2019, CStone Pharmaceuticals officially established its global R&D headquarters and manufacturing base in the Suzhou Industrial Park. The facility is designed with a production capacity of 26,000 liters for biopharmaceuticals and 1 billion tablets for small-molecule chemical drugs, and construction has already commenced. Meanwhile, CStone Pharmaceuticals has rapidly assembled a commercialization team with a strong core leadership. As product launches accelerate in the future, the company’s commercial capabilities will be swiftly enhanced.

Furthermore, CStone Pharmaceuticals is continuously exploring additional strategic collaborations to maximize the value of its drugs in the Chinese market. Unlike some companies whose external partnerships and business development efforts have repeatedly encountered obstacles, CStone Pharmaceuticals has established a solid foundation for comprehensive commercialization by adopting a dual-engine model driven by both “partnered products” and “in-house products.”

Successful commercialization also relies on capital support. CStone Pharmaceuticals’ 2019 initial public offering (IPO) in Hong Kong set multiple records in the then capital market environment, and the funds raised successfully enhanced the company’s operational capabilities, propelling CStone Pharmaceuticals onto a path of rapid growth.

2020 will be a year of breakthrough for CStone Pharmaceuticals after years of accumulation; let us wait and see.