The competition in the generic drug market is not intense, and the barriers to entry are usually high...

Breakthrough in Two Major Domestic First Generic Painkillers

On July 5th, according to official information from Luye Pharma and approval documents received, the painkiller Mimeixin? (oxycodone/naloxone extended-release tablets) received market approval from the CDE on June 28, 2024. It is indicated for adults who require opioid analgesics for adequate control of severe pain (both cancer and non-cancer related).

It is understood that the domestic first generic Mimeixin?, through the combined action of the strong opioid receptor agonist oxycodone and the opioid receptor antagonist naloxone, helps patients control pain while effectively reducing opioid-induced constipation. A single dose can maintain pain relief for up to 12 hours. Additionally, Mimeixin?'s unique "lock-drug" technology effectively prevents drug abuse.

Luye Pharma has applied for four specifications. Based on the dosage and administration information in the instructions, it is expected that the two lower-dose specifications have been approved: each tablet containing 5mg oxycodone hydrochloride and 2.5mg naloxone hydrochloride, and each tablet containing 10mg oxycodone hydrochloride and 5mg naloxone hydrochloride.

Currently, most sustained-release and controlled-release formulations in clinical use in China are still monopolized by imported or joint venture pharmaceutical companies. On September 28, 2022, the domestic oxycodone hydrochloride extended-release tablets (first generic) from Renfu Pharma were approved for market, and the recent approval of Luye Pharma's oxycodone/naloxone extended-release tablets (first generic) marks two significant breakthroughs in domestic generic painkillers, providing alternatives to imported oxycodone extended-release tablets.

Original Research Accumulated Domestic Sales Nearly 9 Billion

Pain is the fifth vital sign of human life and a common issue among cancer patients. In 2022, there were nearly 20 million new cancer cases globally, with 9.7 million deaths. China accounted for 4.8 million new cases and 2.6 million deaths. Approximately 25% of newly diagnosed cancer patients experience pain, with 60%-80% of late-stage patients affected. Among these, one-third suffer from severe pain. If pain is not effectively controlled, patients experience extreme discomfort, affecting daily activities and quality of life. Therefore, pain management is crucial in cancer treatment.

Oxycodone is a strong opioid analgesic, recommended by the World Health Organization (WHO) as one of the ideal drugs in its three-step cancer pain relief ladder. Clinically, it is mainly used to alleviate persistent moderate to severe pain. In China, oxycodone is classified as a narcotic drug and a controlled substance under national regulations, requiring strict prescription and distribution oversight. Similarly, the UK classifies it as a controlled substance.

However, in the United States, the drug was once falsely marketed as non-addictive by pharmaceutical companies, and doctors were incentivized to over-prescribe it, leading to nearly 500,000 opioid overdose deaths since the 1990s. In response to the escalating opioid crisis, U.S. authorities have implemented measures such as encouraging the use of abuse-deterrent formulations and developing addiction treatment medications.

Regarding its therapeutic effect, oxycodone has a methoxy group that protects it from the first-pass effect in the liver, resulting in higher bioavailability compared to morphine. Consequently, the oral analgesic effect of oxycodone is 1.5-2 times that of oral morphine at equivalent doses. The extended-release formulation of oral oxycodone has a dual absorption phase, with 38% of the drug released quickly for rapid onset and 62% released slowly to maintain steady blood concentration. It reaches peak blood concentration approximately three hours after oral administration, with a duration of action of 12 hours, providing prolonged pain relief and reducing the frequency of administration, thereby improving patient compliance.

The original oxycodone hydrochloride drug was first marketed in the UK by Napp Pharmaceuticals in 2003. China approved the introduction of oxycodone hydrochloride in 2009, but it was only used to relieve pain in late-stage cancer patients. The approved formulations in China include oxycodone hydrochloride injection, capsules, and extended-release tablets.

Market-wise, the original research company has maintained a dominant position. In 2022, oxycodone sales in urban public hospitals in China exceeded 800 million yuan, with extended-release tablets accounting for approximately 74% of this figure. In recent years, terminal sales have consistently remained around 600 million yuan, with cumulative domestic sales nearing 9 billion yuan. In 2023, sales grew by 5.53% year-on-year, ranking among the top 8 pain relief products. It is anticipated that the domestic market for oxycodone will soon surpass 1 billion yuan in annual sales.

Image source: American TV series "Dose of Addiction"

Compared to single-agent extended-release oxycodone formulations, the recently approved oxycodone/naloxone extended-release tablets from Luye Pharma represent a combination formulation. At equivalent doses, they provide comparable analgesic efficacy while significantly improving bowel function and reducing the incidence and severity of opioid-induced constipation (OIC). Additionally, the inclusion of naloxone, an antagonist, helps prevent abuse, and the approved low dose makes it suitable for managing severe non-cancer pain in adults requiring opioid analgesics.

The market for cancer pain treatment drugs is relatively niche, and domestic investment in new drug and generic drug development in this field has been insufficient. According to Luye Pharma's announcement, Mimeixin? is currently the only approved domestic extended-release oxycodone/naloxone tablet with high technical barriers.

High Barriers and Few Competitors in the Generic Drug Market

In December 2020, Northeast Pharmaceuticals secured the first generic approval for oxycodone hydrochloride injection, followed closely by Enhua Pharmaceuticals and Huasu Pharmaceuticals. As of now, only three domestic companies have received approval for this formulation. No generics have been approved for oxycodone hydrochloride capsules. Luye Pharma is the first to secure approval for the combination oxycodone/naloxone extended-release tablets.

Regarding extended-release tablets, information from the National Medical Products Administration (NMPA) indicates that only two companies, Yichang Renfu and Hefei Lanfang Pharmaceuticals, hold production approvals for oxycodone hydrochloride extended-release tablets. Yichang Renfu obtained the first generic approval in September 2022 for the 40mg dosage, achieving sales revenue of 2.7 million yuan that year. In the first half of 2023, sales revenue grew to approximately 15 million yuan. In May this year, Renfu Pharmaceuticals announced that its subsidiary, Yichang Renfu Pharmaceuticals, received approval for a new 10mg dosage. Currently, Southwest Pharmaceuticals is the only company with a type 4 generic application for oxycodone hydrochloride extended-release tablets under review, and approval will be considered equivalent to a quality evaluation.

The competition in the generic oxycodone market is not intense, possibly due to high barriers to entry. As a special drug, it requires high standards in both technology and production management. For instance, Luye Pharma has developed a unique lock-drug technology, producing tablets with high hardness that cannot be easily crushed or ground. These tablets also possess sustained-release characteristics in various pH buffer solutions, preventing the extraction and purification of oxycodone for abuse. Additionally, naloxone antagonizes the effects of oxycodone, preventing the user from experiencing euphoria and inducing withdrawal symptoms in abusers, thus significantly reducing the attractiveness of the drug for misuse.

Regarding active pharmaceutical ingredients (APIs), only four companies have registered with the CDE for oxycodone hydrochloride APIs, all receiving an "A" approval rating.

For the antagonist naloxone hydrochloride APIs, 25 companies have registered with the CDE, with 23 receiving an "A" approval rating.