Bristol-myers Squibb (BMS) reported Q3 sales of its blockbuster Revlimid product of $2.47 billion for the third quarter of 2022, beating analysts' expectations of $2.17 billion and indicating that sales of the drug are holding up in an increasingly competitive market amid patent expirations.
The drug, which brought BMS $12.821 billion in 2021 and topped $10 billion in sales for the third year in a row, is one of the world's best-selling small-molecule therapeutics but has a "demon" past life.
As you can see, the FDA's black box warnings on lenalidomide include fetal toxicity, hematologic toxicity (including significant neutropenia and thrombocytopenia), and serious risk of venous and arterial thromboembolism. The story starts with its predecessor thalidomide.
In 1953, CIBA Pharmaceuticals, the predecessor of Novartis, synthesized thalidomide in the process of developing antibacterial drugs, but it was abandoned due to its poor antibacterial effect. It was developed and marketed over the counter as a new sedative hypnosis drug by Grantz, but was pulled from the market after a notorious "reaction stop" incident. After it was removed from the market, researchers also found that thalidomide may have a therapeutic effect on erythema nodosum leprosy and cancer. In 1997, the FDA reapproved thalidomide for the treatment of leprosy.
But Shinkei's research doesn't stop there.
They hypothesized that thalidomide was only a prodrug and set out to modify its structure in hopes of enhancing its TNF-α inhibitory activity. Finally, the researchers introduced an amino group into the 4-position of thalidomide o-benzoylimide to obtain the pemalidomide, which directly increased the activity by 15,000 times. Because the o-benzoylimide of thalidomide (the protective group of amino in organic synthesis) was unstable, they replaced it with isoindolinone (reducing an amide, Improved stability) and the introduction of an amino group at the 4-position gives the famous lenalidomide.
Lenalidomide was first approved by the FDA in 2005 for the treatment of anemia due to myelodysplastic syndrome associated with chromosome 5Q deletion, and has since been approved for multiple myeloma patients, follicular lymphoma, myelodysplastic syndrome, mantle cell lymphoma, and more.
In order to get rid of the dark history of thalidomide, Shingroup designed a clear indication range and strict drug safety measures for lenalidomide, which clearly prohibited the use of pregnant women and women who may become pregnant, and strengthened the training of doctors and patient education. These measures have won a good market reputation for lenalidomide, quickly seized the market, and achieved a spectacular turn into a blockbuster drug.
Since its launch in 2015, the sales performance of lenalidomide has maintained a high growth rate. In 2018, nalidomide became the world's largest small-molecule drug with sales of $9.685 billion, second only to the king of the drug Sultamide. In 2019, the sales volume exceeded 10 billion dollars and reached 11.11 billion dollars. In 2020 and 2021, the sales volume reached 12.15 billion dollars and 12.821 billion dollars respectively, which is the third consecutive year that the sales volume exceeded 10 billion dollars.
On the flip side of that growth, lenalidomide has been facing patent challenges and competition from copycats.
Lenalidomide was spared a major blow in the past two years when the United States Patent and Trademark Office rejected three of Dr. Reddy's patent invalidations. A settlement with Natco, Alvogen, Dr. Reddy and others to try to delay the launch of generics will allow lenalidomide to take its final dance in 2020 and 2021. This year, however, lenalidomide sold only $5.3 billion in the first half of the year as generic versions of the patent cliff entered the American market. BMS revised down its full-year sales to $9 billion to $9.5 billion.
Lenalidomide's compound patents in China (CN97180299.8) and Europe (EP0925294B3) expired in July 2017, and its patent in the United States (US5635517B1) expired in October 2019. After the core patent expired in 2019, most other patents expired this year. Nalidomide will only become more competitive in the U.S. market.
The situation of lenalidomide in China is even worse. In 2013, Shinji obtained the marketing license of lenalidomide in China, but because its price is similar to that of the United States, few patients in China can accept its price, so the volume of lenalidomide has not been realized in China, which also leads to the phenomenon of "unable to afford medicine" in the clinical treatment of multiple myeloma in China. What is more difficult for Xinji to accept is that the patent was invalidated by Nanjing Cavendish Bioengineering Technology Co., Ltd. through patent challenge before the expiration, and it was rated as one of the top ten cases of invalidation in patent review in 2016 by China Intellectual Property News.
In 2017, the first imitation of lenalidomide "Lishen" of Shuanglu Pharmaceutical was launched, and the pricing was almost the same as that of New Kiluifomide. The average intermediate price in each province was 1017 yuan (25mg/ pill) and 1031 yuan (25mg/ pill) respectively. Subsequently, Lenalidomide capsule "Anxian" was launched, which opened the prelude of the drug price war. In 2019, Lisheng's online price dropped to 265 yuan (25mg/ pill) in Shandong Province, followed by the approval of Qilu's lenalidomide capsule "Qipu Yi" in May, which also joined the chaos of generics of Lenalidomide. That year, the price of Lisheng further dropped to less than 200 yuan (25mg/ pill).
According to the data of pharmacizhi.com, there are 12 companies listed lenalidomide in China at present, with 7 kinds of drug products, the number has exceeded 30.
There is a famous saying in new drug discovery research that lives on today: "The best way to discover a new drug is to start with an old one". Aspirin, a century-old drug, and thalidomide, which brings people back from the dead, are classic examples of old drugs being reinvented. Lenalidomide evolved from thalidomide to become the most lucrative small-molecule drug, allowing the new group and thalidomide to interact. Although its core patent has expired, Shingroup has not given up the research of lenalidomide, and its clinical trials for indication expansion are also in full swing. It is not clear that nalidomide will have a good performance in new disease fields in the future!
