Merck Accelerates Global Phase III ADC Trials Amid Intensifying Biosimilar Threat to Keytruda

Mar 28, 2024 21:27 CST Updated 21:27

Amgen

Developer of Treatment Drugs for Serious Diseases

MSD

Pharmaceutical R&D and Manufacturer

Facing the步步紧逼of pembrolizumab (hereinafter referred to as K药) biosimilars from Amgen, Sandoz and others, as well as the accelerating pursuit of Novo Nordisk's star weight-loss and blood-sugar-lowering drug semaglutide, MSD's "blockbuster drug" defense battle cannot afford any slack.

Recently, Amgen registered a Phase III clinical trial for ABP 234, a biosimilar of Keytruda (K药), on the Clinicaltrials.gov website. The trial plans to enroll 927 patients with advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). It will conduct a head-to-head comparison of the efficacy, pharmacokinetics, safety, and immunogenicity of ABP 234 and Keytruda in the participants. The trial is expected to be completed in October 2027.

Coincidentally, MSD also registered two global Phase III clinical trials for its TROP2-targeted ADC MK-2870 (SKB264) on the same day on the aforementioned website. These trials aim to evaluate the efficacy of MK-2870 as a monotherapy or in combination with Keytruda in specific types of breast cancer and NSCLC patients, with planned enrollments of 1,200 and 780 participants respectively. Preliminary results are expected...Completion dates are July 2027 and February 2034.Notably, in less than half a year, MSD has initiated six global Phase III clinical trials for MK-2870.

Industry insiders point out that AbbVie's Humira, once the world's most profitable blockbuster drug, topped the charts for over a decade. In contrast, MSD’s Keytruda (K药), which faces near-term market concerns and even greater long-term challenges, is surrounded by uncertainty and variables in its ability to defend this year's "top drug" throne. Unlike AbbVie’s strategy of building a "patent thicket," MSD has chosen a multi-faceted approach to expand Keytruda’s indications, with combination therapies being a crucial dimension. Could MK-2870, introduced from Kelun-Biotech, become MSD’s new bridgehead in the oncology field?

Patent expiration in 2028

Biosimilars Launch Pursuit

In 2023, Keytruda contributed $25.011 billion in sales for MSD, successfully claiming the throne as the "King of Drugs" as expected. However, behind this glory, the patent cliff for Keytruda is looming. In 2028, the core patent compound amino acid sequence of Keytruda will expire in the U.S. and Chinese markets, losing its protection; in the EU and Japanese markets, the expiration will occur later, extending beyond 2030.

This means that the time left for Keytruda to reach its sales peak is running out, and its market share may soon be eroded by biosimilars. According to incomplete statistics, so far, nearly 10 pharmaceutical companies have entered the clinical trial stage with their Keytruda biosimilars. Based on the information disclosed on the Clinicaltrials.gov website, six pharmaceutical companies — Amgen, Sandoz, Bio-Thera Solutions, R-Pharm, Biocad, and Laboratorio ELEA — have successively registered or initiated Phase III clinical trials for their Keytruda biosimilars.

Amgen is a key player in the biosimilar field, with total biosimilar product sales reaching approximately $1.6 billion in 2023. Among these, the adalimumab biosimilar generated $626 million in revenue, marking a 36% year-over-year increase. In the Phase III clinical trial of Amgen's registered Keytruda biosimilar ABP 234, the company will enroll 927 patients with non-small cell lung cancer (NSCLC), significantly more than its competitors, with preliminary completion expected by October 2027. Notably, in September 2023, Amgen also registered a Phase III clinical trial for its Opdivo biosimilar ABP 206, making it one of the few companies simultaneously developing biosimilars for two major PD-1 inhibitors.

In the development team of Keytruda biosimilars, Sandoz, the generic drug giant with 10 commercialized biosimilars in hand, is an undeniable presence. In 2023, the biosimilar business contributed $2.215 billion to Sandoz’s revenue, marking a 15% year-on-year increase. For the development of GME751, a Keytruda biosimilar, Sandoz registered a Phase III clinical trial in December 2023, planning to officially launch it in April this year. The trial will enroll 720 patients with NSCLC and is expected to be preliminarily completed by August 2026.

Moreover, the presence of Bio-Thera Solutions, a domestic innovative pharmaceutical company, is particularly striking. In February this year, Bio-Thera Solutions also registered a Phase III clinical trial for BAT3306, a biosimilar of K药 (Keytruda), as a first-line treatment for non-squamous NSCLC, planning to enroll 676 patients, with an expected preliminary completion date in July 2027. Bio-Thera Solutions is a major player in China's biosimilar field. Its developed biosimilars, bevacizumab and tocilizumab, have been approved for marketing in both China and the United States. Additionally, several other biosimilars, including BAT2206 (ustekinumab), BAT2306 (secukinumab), and BAT2506 (golimumab), are undergoing global Phase III clinical trials.

It can be seen that, at the current pace of development, these products are expected to obtain primary endpoint data around 2027. Afterward, they can submit marketing applications and likely receive approval for market launch around 2028, rushing towards the expiration of Keytruda's (K药) patent. Overall, most pharmaceutical companies have focused on MSD's Keytruda advantage in the NSCLC field. In terms of clinical progress, the two Russian pharmaceutical companies that chose to enter via the melanoma indication are evidently moving faster.

Founded in 2001, R-Pharm is a leading pharmaceutical company in Russia, with 70 branches established across 30 countries worldwide. R-Pharm maintains close ties with Chinese pharmaceutical companies. In 2021, it successively partnered with KangLeWeiShi Bio and Frontier Biotechnologies to collaborate on the research, development, and commercialization of a nine-valent human papillomavirus vaccine and a new anti-HIV drug. The biosimilar RPH-75 of Keytruda, developed by R-Pharm, initiated a global multi-center Phase III clinical trial targeting melanoma patients in September 2023, enrolling 266 participants, with preliminary completion expected by June this year.

Biocad is the largest biopharmaceutical company in Russia. In 2019, it established a joint venture, Shanghai Pharma Biocad, with Shanghai Pharmaceuticals and licensed six collaborative products to the latter, including the anti-PD-1 monoclonal antibody drug BCD-100 (Prolgolimab). BCD-201, a biosimilar of Keytruda developed by Biocad, entered Phase III clinical trials as early as July 2022. Similar to R-Pharm's strategy, it chose the indication of cutaneous melanoma, with an actual enrollment of 366 participants. The anticipated preliminary completion date was December 2023, with the final completion date set for December this year.

Industry insiders believe that the first-generation heavyweight antibody Adalimumab and Roche's "troika" have led to numerous Chinese and international pharmaceutical companies developing biosimilars. The competition for Keytruda biosimilars will only become more intense. In addition to the aforementioned companies that have advanced Keytruda biosimilars to late-stage clinical trials, products from a group of pharmaceutical companies such as Samsung Bioepis, Qilu Pharmaceutical, and Henlius have also successively entered the early clinical trial stage. It can be foreseen that the further entry of these powerful players will accelerate the encirclement of MSD's Keytruda.

Launching 6 Major Clinical Trials

PD-1+ADC Invincible?

According to Evaluate's forecast, Keytruda will remain the top-selling branded drug globally in 2024. However, if the sales of Novo Nordisk's three brands of semaglutide (the antidiabetic injectable Ozempic, the oral antidiabetic Rybelsus, and the weight-loss injectable Wegovy) are combined, the total revenue will exceed $28 billion, surpassing Keytruda to become the new "blockbuster drug." In 2023, semaglutide generated revenue of 145.811 billion Danish kroner, approximately $21.2 billion, rapidly closing the gap with Keytruda.

According to the annual report, Keytruda accounted for approximately 46% of MSD's pharmaceutical revenue in 2023, making it the undisputed pillar product. The most urgent challenge facing MSD is how to accelerate the development of successor products while mitigating the sales impact of biosimilars on Keytruda. A key strategy for MSD is to expedite the advancement of the "PD-1 + chemotherapy" or the upgraded "Keytruda + ADC" targeted therapies from later-line to front-line treatment, solidify the confirmed efficacy of this combination therapy across various cancer types, and further increase the difficulty for competitors to follow.

MK-2870, introduced from Kelun Botai, is the vanguard先锋 of MSD's implementation of the aforementioned strategy. As an ADC targeting TROP2, it consists of a humanized anti-TROP2 monoclonal antibody linked via a stability-optimized CL2A linker (with the antibody end of the linker achieving irreversible conjugation to the antibody through a methanesulfonyl pyrimidine group) and the small-molecule toxin T030 (a topoisomerase I inhibitor). The drug-to-antibody ratio (DAR) averages 7.4.

It is reported that MK-2870 is the first domestically produced TROP2 ADC drug in China to enter Phase III clinical trials and the NDA registration stage. Its proposed indications for development, including first-line treatment of locally advanced, recurrent, or metastatic PD-L1-negative triple-negative breast cancer (TNBC) that is inoperable, treatment of locally advanced or metastatic HR+/HER2- breast cancer that has undergone at least two prior lines of systemic chemotherapy, and treatment of locally advanced or metastatic EGFR-mutant non-small cell lung cancer (NSCLC) that has failed EGFR-TKI therapy, have all received Breakthrough Therapy Designation (BTD) from the National Medical Products Administration (NMPA).

The increasingly clear clinical application potential is an important reason why MSD has placed MK-2870 at the most prominent position in its ADC pipeline. To this end, MSD is accelerating the global clinical development of MK-2870. Since October 2023, MSD has launched six global large-scale Phase III clinical trials around MK-2870, covering disease areas such as NSCLC, breast cancer, and endometrial cancer, with a total planned enrollment of 4,380 patients.

Among them, based on Keytruda's established first-line treatment position in NSCLC, this field will remain an important track for MSD to defend. There are up to four clinical trials related to MK-2870. In the recently registered MK-2870-019 study, MSD is conducting a head-to-head comparison of MK-2870 combined with Keytruda versus Keytruda alone as adjuvant therapy for NSCLC patients (resectable stage II to stage IIIB (N2)) who previously received neoadjuvant Keytruda and platinum-based doublet chemotherapy but did not achieve pathological complete response after surgery. The trial plans to enroll 780 patients and is expected to preliminarily complete by February 2034.

Previously, MSD had initiated three global Phase III clinical trials for MK-2870 in NSCLC. These are for EGFR mutation-positive NSCLC that has progressed after immunotherapy and chemotherapy (MK-2870-004 study, planned to enroll 556 patients), PD-L1 high expression (TPS≥50%) metastatic NSCLC (MK-2870-007 study, planned to enroll 614 patients), and EGFR mutation-positive NSCLC that has progressed after immunotherapy (MK-2870-009 study, planned to enroll 520 patients). In the industry's view, the registration of this Phase III clinical trial also marks MSD's expansion of MK-2870 to the frontline adjuvant treatment.

Another MK-2870-010 study registered this time is a global Phase III clinical trial evaluating MK-2870 as monotherapy or in combination with Keytruda (K药) for the treatment of locally advanced or metastatic HR+/HER2- breast cancer. The trial plans to enroll 1,200 patients, making it the largest of the six studies, with an expected preliminary completion date in July 2027. Results from a Phase I/II single-arm basket trial of MK-2870 in previously treated HR+/HER2- metastatic breast cancer, presented at the 2023 ESMO Annual Meeting, showed that among 38 evaluable patients, the objective response rate (ORR) was 36.8%, the disease control rate (DCR) was 89.5%, the 6-month duration of response (DoR) rate was 80%, and the median progression-free survival (PFS) was 11.1 months.

Industry insiders believe that as the core patent periods of blockbuster drugs enter the countdown, the speed of global generic drug development is bound to accelerate, and it is only a matter of time before they further seize the market share of original products. However, the commercial operation after a drug's market launch determines its lifecycle length. AbbVie's Humira is a prime example. Will Merck & Co., Inc., which is fully committed to PD-1+ADC, be equally fortunate? Currently, the combination therapy of Keytruda (K-drug) + Nectin-4 ADC drug Padcev (enfortumab vedotin) has already gained approval from the U.S. FDA. Whether subsequent PD-1+ADC combination therapies will follow suit remains to be answered over time.

Editor: Zheng Miao