Block-buster Small Molecule Pharmaceuticals Approved by the NMPA in 2023

In last year, according to data collated from the National Medical Products Administration (NMPA) official website, a total of more than 80 new drugs were granted inaugural approval within the domestic market. Observing the molecular categorization of these approved entities, small molecule therapeutics constituted the majority, representing an overwhelming 75%. Among these, which compounds are considered significant breakthroughs, and what ramifications have their approvals engendered? 

Mobocertinib (Brand Name: Exkivity) 

Approval Date: January 13, 2023 

Pharmaceutical Company: Takeda 

Indications: Indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) exhibiting progression during or subsequent to platinum-containing chemotherapy, who harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations (EGFR ex20ins) 

Within the domestic landscape, the incidence of EGFR ex20ins mutations constitutes approximately 2.3% of all NSCLC cases in China, positioning it as the third most common EGFR mutation. Compared to more prevalent EGFR mutations, patients with advanced NSCLC harboring the EGFR ex20ins mutation exhibit inferior survival outcomes, with a 5-year survival rate mere at 8%. Currently, there exists a significant void in effective targeted therapeutic strategies for this mutation in clinical settings. 

The market introduction of Mobocertinib provides a novel therapeutic option for patients with advanced NSCLC harboring the EGFR ex20ins mutation in China. Specifically engineered for EGFR ex20ins, Mobocertinib incorporates an innovative isopropyl ester structure, forming a flexible monocyclic core, enabling more efficacious binding with EGFR ex20ins, thereby offering precise selectivity and heightened affinity. 

Mobocertinib received accelerated approval from the FDA (September 15, 2021) and conditional approval from the NMPA, predicated on the outcomes of the EXKIVITY I/II phase single-arm trial. 

This trial encompassed 114 patients with EGFR ex20ins mutation NSCLC who had previously undergone platinum-based treatment. The data revealed that the median Overall Survival (OS) in the platinum-based chemotherapy cohort (PPP) achieved an impressive 24 months. Despite its remarkable efficacy, the necessity for phase III confirmatory trials remains, due to its single-arm trial design. 

However, the phase III confirmatory trial, Exclaim-2, was terminated due to Mobocertinib's lack of efficacy. Consequently, on October 2 of this year, Takeda announced its intention to collaborate with the FDA to voluntarily withdraw Mobocertinib in the United States. Its potential withdrawal from the Chinese market remains uncertain. 

Keverprazan Hydrochloride (Brand Name: Beiwen) 

Approval Date: February 15, 2023 

Pharmaceutical Company: Jiangsu Carephar Medicine/Fosun Pharma 

Indications: For the treatment of duodenal ulcers and reflux esophagitis 

Acid-related disorders (ARDs) denote gastrointestinal diseases arising from excessive gastric acid secretion or abnormal sensitivity to gastric acid, including gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD). The suppression of gastric acid secretion stands as the cornerstone of current ARD therapeutic strategies. 

Since the market debut of the first proton pump inhibitor (PPI), Omeprazole, in 1988, the treatment paradigm for ARDs such as reflux esophagitis has witnessed a milestone breakthrough. Nevertheless, PPIs exhibit limitations such as slow onset of action, elevated incidence of nocturnal acid breakthrough, and stringent preparation requirements, hence the pressing demand for the introduction of next-generation acid-suppressive medications. 

Keverprazan Hydrochloride represents a pioneering class of potassium-competitive acid blockers (P-CABs), inhibiting gastric acid secretion by binding to the potassium binding site on the H+-K+-ATPase. Owing to its ability to bind both active and resting proton pumps, Keverprazan Hydrochloride demonstrates rapid onset of action and potent acid-suppressive effects. Moreover, it accumulates in high concentrations within gastric parietal cells and dissociates slowly, ensuring sustained and potent anti-secretory activity, unaffected by food intake. 

To date, three P-CAB medications have been approved for marketing domestically, including Keverprazan Hydrochloride, Takeda's Vonoprazan and Luoxin Pharmaceuticals's Tegoprazan. In the arena of P-CAB new drug development, domestic endeavors also include Yangtze River Pharmaceutical Group and Shanghai Pharmaceuticals. 

Selumetinib (Brand Name: Koselugo) 

Approval Date: May 8, 2023 

Pharmaceutical Company: AstraZeneca/ Merck 

Indications: Indicated for the treatment of symptomatic, inoperable plexiform neurofibromas in pediatric patients with PN type 1 (NF1), aged 3 years and above 

Neurofibromatosis type 1 (NF1) is a multisystemic genetic disorder elicited by mutations in the nf1 gene, with a morbidity rate of approximately 1/3000. About 30%-50% of individuals with NF1 develop plexiform neurofibromas (PNs), which proliferate diffusely along the nerve axis, potentially involving multiple nerve trunks, branches, and plexuses, invading surrounding tissues, causing pain, neurological dysfunction, skeletal deformities, disfigurement, vision impairment, and bladder or bowel dysfunction. Furthermore, PNs may transform into malignant peripheral nerve sheath tumors (MPNSTs), which exhibit poor response to conventional therapies and high mortality rates post-malignant transformation. 

Historically, the primary modality for neurofibroma management has been surgical intervention, yet the efficacy of surgical treatment is often limited, along with complete resection challenging, and high recurrence rate. 

Selumetinib, a mitogen-activated protein kinase (MEK) inhibitor, curtails tumor proliferation by inhibiting the activity of MEK, an upstream regulator within the extracellular signal-regulated kinase (ERK) pathway, part of the RAS-RAF-MEK-ERK (MAPK) pathway. 

In the SPRINT clinical research, the Objective Response Rate (ORR) for pediatric patients with NF1 treated with selumetinib administered twice daily was 68%. The 3-year disease progression-free survival rate for patients undergoing selumetinib treatment was an impressive 84%, in stark contrast to just 15% for patients with the natural history of the disease. 

Selumetinib is the first and only pharmacological therapy approved in China for the treatment of symptomatic, inoperable PN in pediatric patients with NF1 aged 3 years and older, addressing a previously unmet medical need. 

Ritlecitinib (Brand Name: Litfulo) 

Approval Date: October 19, 2023 

Pharmaceutical Company: Pfizer 

Indications: Indicated for adolescents and adults aged 12 years and older with severe alopecia areata who are candidates for systemic therapy 

Alopecia areata is an autoimmune disease characterized by patchy hair loss, predominantly on the scalp, yet potentially affecting eyebrows, eyelashes, facial hair, and other body areas. This condition significantly impacts patient health and quality of life, potentially leading to severe psychological distress, including depression and anxiety. An estimated 6.8 million individuals in the United States and 147 million globally suffer from alopecia areata. 

Toluenesulfonic acid ritlecitinib, a kinase inhibitor, irreversibly inhibits JAK3 and the tyrosine kinase family. Research has demonstrated that ritlecitinib impedes signal molecules and immune cell activity. In the pivotal global multicenter, randomized, double-blind, placebo-controlled Phase IIb/III ALLEGRO study, ritlecitinib's efficacy and safety in treating patients aged 12 years and older with alopecia areata (n=718) were assessed. The findings indicated that patients administered 30mg and 50mg doses of ritlecitinib daily exhibited a significantly higher proportion of scalp hair coverage ≥80% at 24 weeks compared to the placebo group. 

In comparison to first-generation pan-JAK inhibitors, ritlecitinib presents advantages in toxicity reduction. 

Despite the burgeoning R&D of Antibody-Drug Conjugates (ADCs) and bispecific antibodies in recent years, which has, to some extent, impacted the development of small molecule therapeutics, the technology underlying the development of small molecule drugs is relatively mature, and the associated risks comparatively lower. Small molecule drugs continue to offer unique advantages and play a pivotal role in pharmaceutical development. The anticipation for the emergence of more innovative small molecule therapeutics in 2024 remains high. 

Reference:

1.https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.9014.

2.Chen, Songfeng et al. "The efficacy and safety of keverprazan, a novel potassium-competitive acid blocker, in treating erosive oesophagitis: a phase III, randomised, double-blind multicentre study." Alimentary pharmacology & therapeutics vol. 55,12 (2022): 1524-1533. doi:10.1111/apt.16959.

3.Anderson MK, Johnson M, Thornburg L, et al. A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. Ann Pharmacother. 2022 Jun;56(6):716-726.

About the Author:

Yefenghong

Ye Fenghong, a medical editor specializing in oncology at a healthcare internet company, has conducted in-depth research on the pathogenesis and clinical treatment of lung cancer and breast cancer. She has previously been involved in the design and synthesis of anti-tumor drugs and has some experience in computer-aided drug design. She is currently devoted to introducing cutting-edge cancer treatment drugs to a wide range of readers, aiming to help more people avoid cancer pain and embrace good health.