Merck Bets Big on ADC Combinations to Extend Keytruda's Reign Amid Patent Cliff

Dec 25, 2023 21:09 CST Updated 21:09

MSD

Pharmaceutical R&D and Manufacturer

Pembrolizumab (hereinafter referred to as K drug) is almost certain to ascend to the top as the global "blockbuster drug" this year. However, faced with the increasingly approaching core patent cliff and the gradual slowdown in market sales growth, Merck Sharp & Dohme AG is attempting to deeply integrate it with ADC drugs in order to secure the "throne" of this blockbuster drug.

Recently, the U.S. FDA fully approved MSD's Keytruda (Pembrolizumab) in combination with Nectin-4 ADC Padcev (Enfortumab Vedotin) as a first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC), nearly five months ahead of the original PDUFA target date. In April this year, the U.S. FDA granted accelerated approval to this drug combination as a first-line treatment for la/mUC patients unsuitable for cisplatin-based chemotherapy, making it the world’s first approved "PD-1 + ADC" combination therapy.

Combining ADC to Open Up New Battlefields: Just a Part of Merck's Clinical Development Strategy for KeytrudaThe combination of ADC to open up new battlefields is only a part of MSD's clinical development strategy for Keytruda (K-drug). The company’s bigger ambition is to continue disrupting the benchmarks already set by Keytruda through the "Keytruda + ADC" regimen, further solidifying its market position. Just one day before the aforementioned indication received full approval, MSD also registered a Phase III clinical trial (NCT06170788) on Clinicaltrials.gov, testing Keytruda in combination with TROP2 ADC MK-2870 (SKB264) as a first-line treatment for metastatic non-small cell lung cancer (NSCLC). Notably, this time MSD has chosen to conduct a head-to-head comparison with Keytruda monotherapy.

At that time, the sudden rise of K drug and O drug allowed the industry to see the immense clinical potential of PD-(L)1 inhibitors, sparking vigorous global development of this platform technology. Today, the focus of research and development in the field of new cancer drugs has long shifted from PD-1s to the increasingly mature ADC drugs. After missing the acquisition of Seagen, MSD's three collaborations with Kelun Biotech and its massive investment in Daiichi Sankyo reveal obvious urgency. By deeply "tying" itself to ADC, can MSD, unwilling to fall behind, recreate the legendary success of K drug?

Combining ADC to Launch the Defense Battle for K Medicine

With the largest immuno-oncology clinical research program in the industry, MSD's Keytruda has secured nearly 40 indications to date, driving its annual sales to continuously rise. In its eighth year on the market, in 2022, Keytruda’s annual sales surpassed the $20 billion mark—taking only half the time it took AbbVie’s former "blockbuster drug" Humira.

However, throughout history, the "blockbuster" drugs have ultimately been unable to escape the fate of slowing market growth and the erosion of market share by generic drugs after the expiration of core patents. According to the year-over-year percentage change (YOY) for each quarter compiled by Guosheng Securities, after an initial rapid increase in sales volume, the growth curve of Keytruda (K药) has steadily declined, with figures hovering around 20%. Meanwhile, the impending expiration of the core patent compound's amino acid sequence in 2028 also indicates that Keytruda’s peak sales may not last much longer.

Despite the continuous expansion of Keytruda’s indications, the average single-agent response rate is only around 25%, representing an objective bottleneck for immune checkpoint inhibitors. Therefore, exhaustive explorations of combination therapy clinical trials have become MSD's "key strategy" to break through this limitation. Overall, unlike the relatively limited outcomes of other combination therapies, the combination of Keytruda and chemotherapy has shown positive efficacy across a range of indications, becoming MSD’s most effective and widely applicable option. This also lays the foundation for its combination with ADC drugs, which are considered an upgraded version of chemotherapy.

At the ESMO Investor Event held in October this year, MSD provided a comprehensive overview of the layout and latest developments in its oncology pipeline. MSD summarized its ongoing oncology strategy into three key areas: immuno-oncology, which aims to enhance anti-tumor immune responses; precision molecular targeting, which focuses on influencing pathways that drive cancer growth; and tissue targeting, which involves increasing the sensitivity of tumor cells through ADC drugs and immune stimulants. Recent actions indicate that MSD is channeling resources and concentrating efforts heavily on this third area.

This timely expansion of the first-line treatment for la/mUC with "K drug + Vedimlimumab" marks the initial success of MSD's combination strategy in the ADC field. Vedimlimumab is an innovative ADC drug targeting Nectin-4, jointly developed by Seagen and Astellas. Previously, MSD reached a clinical cooperation agreement with both companies to evaluate the efficacy of this drug combined with K drug in treating patients with previously untreated metastatic urothelial carcinoma.

Nectin-4, as a membrane protein, is overexpressed in various tumor cells, such as urothelial carcinoma, breast cancer, pancreatic cancer, and bladder cancer. Enfortumab vedotin can bind to tumor cells expressing Nectin-4, after which the antineoplastic agent monomethyl auristatin E (MMAE) is internalized and released into the cells, leading to cell cycle arrest and apoptosis. At the end of 2019, enfortumab vedotin received accelerated approval from the U.S. FDA for single-agent treatment of adult patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who have been previously treated with platinum-containing chemotherapy. In March this year, the new drug application for enfortumab vedotin in China has been accepted by the CDE.

The approval by the U.S. FDA this time is based on data from the pivotal Phase III KEYNOTE-A39 study (also known as the EV-302 trial), with the control group receiving platinum-based chemotherapy combined with gemcitabine. The results showed that the KEYNOTE-A39 study met the dual primary endpoints of OS and PFS: the median OS in the experimental group and the control group were 31.5 months vs 16.1 months, respectively, and the median PFS were 12.5 months vs 6.3 months, both achieving a doubling of benefits; additionally, the ORR also showed a statistically significant improvement, at 68% vs 44%, respectively.

Outside the field of urothelial carcinoma, Keytruda (K药) and Vinblastine (维恩妥尤单抗) are also undergoing two additional Phase III clinical trials: the EV-303 trial (NCT03924895) and the EV-304 trial (NCT04700124). These trials aim to evaluate the efficacy of this combination therapy compared to standard treatments in patients with muscle-invasive bladder cancer (MIBC). The former focuses on perioperative MIBC patients who cannot tolerate cisplatin treatment, while the latter targets adjuvant/neoadjuvant treatment for cisplatin-tolerant MIBC patients.

In addition to the leading combination with Seagen's vedotin, MSD is also exploring the combination of Keytruda with ADC drugs from Daiichi Sankyo and Kelun-Biotech, further enhancing its influence in the ADC field. It is reported that the three ADCs introduced by MSD from Kelun-Biotech are Trop2 ADC MK-2870 (SKB264), Claudin18.2 ADC MK-1200 (SKB315), and the third one remains undisclosed; the three ADCs introduced from Daiichi Sankyo are HER3 ADC U3-1402 (HER3-DXd), B7-H3 ADC DS-7300 (I-DXd), and CDH6 ADC DS-6000 (R-DXd).

Currently, these six ADC drugs have all been incorporated into MSD's oncology R&D pipeline. It remains to be seen what kind of synergy they will create with Keytruda in the future.

Aiming to Rewrite the Landscape of Targeted Lung Cancer Treatment Once Again

At the 41st J.P. Morgan Healthcare Conference held earlier this year, Dr. Dean Li, President of MSD Research Laboratories, revealed the company's "pyramid" strategy in immuno-oncology. On one hand, MSD is building a wide "high wall" around Keytruda, its pillar product, to continuously strengthen the "pyramid" base of oncology products. On the other hand, by exploring potential drugs through extensive collaborations and expanding combination therapies, MSD aims to form a diversified "pyramid" top.

Nowadays, MSD's continuously expanding clinical development program for Keytruda combination therapies has extended to a direct competition with Keytruda monotherapy in niche treatment areas. Specifically, this newly registered Phase III clinical trial plans to enroll 614 patients with metastatic NSCLC having a PD-L1 Tumor Proportion Score (TPS) ≥50%. The aim is to compare whether the combination therapy of Keytruda + SKB264 offers advantages over Keytruda monotherapy, with preliminary completion expected by January 2028. The primary endpoint of the study is OS, while secondary endpoints include key metrics such as PFS, OR, and DoR.

SKB264 is an innovative TROP2 ADC independently developed by Kelun-Biotech, utilizing a proprietary toxin-linker strategy (Kthiol design strategy) and incorporating a fully differentiated design. The toxin in SKB264 is a belotecan-derived topoisomerase I (TOPO1) inhibitor with moderate cytotoxicity. Additionally, SKB264 employs a carbonate linker that enables specific toxin release in the acidic tumor microenvironment while exerting a bystander effect. This linker is conjugated via cysteine, with a DAR value as high as 7.4, demonstrating excellent stability in circulation and effectively enhancing safety.

Earlier this month, Kelun-Biotech announced that the CDE has accepted the new drug application for SKB264, intended for adult patients with locally advanced or metastatic triple-negative breast cancer (TNBC) that is unresectable and who have previously received at least two systemic treatments (at least one of which targets the advanced or metastatic stage). This application is based on a multicenter, randomized, controlled Phase III clinical study (OptiTROP-Breast01) evaluating SKB264 monotherapy for second-line and above treatment in locally advanced or metastatic TNBC.

In fact, Trop2, as a popular target for ADC drug development, is involved in multiple intracellular signaling pathways, including the MAPK/PI3K/AKT pathway that mediates cancer cell proliferation, migration, and invasion. Studies have confirmed that the overexpression of TROP2 in various cancers such as breast cancer, gastric cancer, and ovarian cancer is associated with accelerated tumor growth and poor prognosis. In recent years, Trop2 ADCs have been highly favored by pharmaceutical companies both in and outside China, with significant investments made by companies like Everest Medicines, AstraZeneca, and Gilead.

MSD also seems to favor exploring the combination of Keytruda with Trop2 ADC. According to statistics from Minsheng Securities, the number of clinical trials in China combining Keytruda with ADC drugs has exceeded 10, half of which are partnered with Trop2 ADC. As early as 2021, MSD reached a cooperation agreement with Gilead to jointly advance the first-line treatment of TNBC and NSCLC using Keytruda and Trodelvy (sacituzumab govitecan), the first Trop2 ADC to receive FDA approval for marketing.

A Review of K Drug Combined with ADC Drugs in Clinical Trials in China (Source: Minsheng Securities)

In September 2022, building on their previous collaboration to develop the PD-L1 high expression (TPS≥50%) NSCLC indication, MSD's Keytruda once again joined forces with AstraZeneca/Daiichi Sankyo's Trop2 ADC DS-1062 (Dato-DXd) to target PD-L1 low-expression NSCLC. The first patient in this study was dosed in January this year. Notably, the control group in these studies is Keytruda monotherapy, identical to the aforementioned clinical trial design of Kelun-Biotech's SKB264.

After acquiring SKB264, MSD launched two international multicenter Phase III clinical trials for it, including EGFR-mutated NSCLC and endometrial cancer. The combination therapy with K drug for metastatic NSCLC patients with TPS≥50% marks the third trial. Based on the data from the KEYNOTE-024 study, K drug monotherapy has already reshaped the first-line treatment landscape for PD-L1 TPS≥50% metastatic NSCLC patients, achieving an impressive 5-year overall survival rate of up to 31.9%. Faced with such remarkable past achievements, whether K drug in collaboration with SKB264, DS-1062, Trodelvy, and other Trop2 ADC products can unleash a "1+1＞2" potential effect and continue to revolutionize the clinical treatment options for this specific patient population remains to be seen.

Attacking is easy, defending is hard. As MSD's Keytruda (K药) is about to reach the top, the market growth of GLP-1 drugs from Novo Nordisk and Eli Lilly is also becoming increasingly fierce. Whether these drugs can take the throne of "best-selling drug" and how long they can maintain it remains uncertain. On the other hand, MSD’s former rival, BMS, has placed a heavy year-end bet on Baili Tianheng's bispecific antibody ADC product BL-B01D1. In addition to recognizing the drug's excellent efficacy and its first-in-class clinical potential globally, BMS is also considering combining BL-B01D1 with its cornerstone product Opdivo (O药), which will undoubtedly launch a new round of attacks against Keytruda. It is foreseeable that MSD’s path to defending its crown will be fraught with challenges.

Editor: Zheng Miao