Merck & Co. 2021: Passing the Keytruda torch

New CEO Richard Davis inherits a company for whom oncology was once an afterthought, but now depends on one oncology drug for 30 percent of its revenue.

By Joshua Slatko • [email protected]

 

 

 

 

Merck & Co.

2000 Galloping Hill Road

Kenilworth, NJ 07033

Telephone: 908-740-4000

Website: merck.com

 

 

OUTCOMES CREATIVITY INDEX SCORE: 12

Manny Awards — 2

Cannes Lions — N/A

Clio Health — N/A

Creative Floor Awards — 4 

MM+M Awards — 6 

One Show — N/A 

 

Financial Performance

(All figures are in millions of dollars, except EPS.)

2020  

Revenue $47,994  

Net income $7,082  

Diluted EPS $2.78 

R&D expense $13,558 

1H 2021 

Revenue $22,029 

Net income $4,724  

Diluted EPS $1.86  

R&D expense $6,732  

Best-Selling Products

(All sales are in millions of dollars.)

2020

Keytruda $14,380  

Gardasil, Gardasil 9 $3,938  

Januvia $3,306  

Janumet $1,971  

ProQuad/MMR II/Varivax $1,878  

Bridion $1,198  

Pneumovax 23 $1,087  

Isentress, Isentress HD $857  

Simponi $838 

RotaTeq $797  

Lynparza $725*  

Implanon, Nexplanon $680  

Lenvima $580*  

1H 2021  

Keytruda $8,076 

Gardasil, Gardasil 9 $2,151  

Januvia $1,593 

ProQuad/MMR II/Varivax $965  

Janumet $962  

Bridion $727  

Lynparza $475* 

Simponi $416 

Isentress, Isentress HD $401   

RotaTeq $366  

Pneumovax 23 $323  

Lenvima $310*  

 

Note: * Alliance revenue

 

 

When Kenneth Frazier took over as CEO of Merck on January 1, 2011, the company was coming off its first year with legacy Schering-Plough products in house and top-line revenue of just under $46 billion. The company’s leading product was the asthma drug Singulair, its diabetes brands Januvia and Janumet were rolling up the charts, and Merck’s oncology portfolio was barely noticeable. 

Ten years later – practically a lifetime in pharma years – Frazier has just passed the reins of an entirely different company along to new incumbent CEO Richard Davis. The top-line revenue is not much more than it was 10 years ago – just short of $48 billion now – but Singulair has long gone generic, Januvia and Janumet have moved into the “mature” phase, and nearly 30 percent of the company’s sales comes from a single drug that Merck pulled off the out-licensing rubbish pile right around the time Frazier took over. Merck’s enormous bet on an immuno-oncologic called Key­truda has paid off in the form of tens of billions in revenue, more than 30 U.S. approvals along with many more around the world, and countless cancer patients living longer lives. If Keytruda ends up being Frazier’s primary legacy at Merck, well, one suspects he would take it gladly. 

“It has been a privilege to serve as Merck’s CEO for the past decade and to work with the most dedicated and talented employees and management team in the industry,” Frazier said in the announcement of his retirement in February. “As executive chairman, I look forward to collaborating with Rob and our board of directors to help Merck achieve even higher levels of success.” 

Merck’s top-line sales in 2020 were $47.99 billion, up 2.5 percent compared with the previous year. Net income, however, declined by 27.6 percent to $7.08 billion and earnings per share declined $1.03 to $2.78. This was in large part due to a substantial jump in R&D expense, which rose by 37.3 percent to $13.56 billion. In first-half 2021, top-line sales were up another 12.2 percent to $22.03 billion but net income declined 24.1 percent to $4.72 billion and earnings per share were down 59 cents to $1.86. This was again largely due to increased investment in research, as R&D expense rose 58 percent to $6.73 billion. Merck executives are projecting that full-year 2021 earnings per share will fall between $4.24 and $4.34. 

New CEO

In February, Merck announced that Kenneth C. Frazier would retire as CEO, effective June 30, 2021. Frazier continues to serve on Merck’s board of directors as executive chairman, for a transition period to be determined by the board. The Merck board of directors unanimously elected Robert M. Davis, Merck’s executive VP, global services and chief financial officer, as CEO, as well as a member of the board, effective July 1, 2021. Davis became president of Merck, effective April 1, at which time the company’s operating divisions – Human Health, Animal Health, Manufacturing, and Merck Research Laboratories – began reporting to him.

“The board and I are delighted that Rob will serve as Merck’s next CEO,” Frazier said. “He has deep knowledge of our company and industry and has been a valued strategic thought partner to me and the Merck senior management team as well as a highly capable finance leader. Rob has been instrumental in helping Merck take the right actions to adapt to the changing healthcare environment while remaining committed to investing in the scientific innovation that we expect will drive our future growth. Rob personifies the values and integrity that are essential for a leader of Merck. I am confident that he has the strategic and leadership skills necessary to ensure that the company remains fully committed to its core mission of translating cutting-edge science into products and services that save and improve lives while simultaneously adopting new business and operating models that will unlock future value through innovation, digital transformation, and efficiency.”

Davis joined Merck as chief financial officer in 2014. In 2016 his role was expanded to include the company’s global support functions, which encompass corporate business development, investor relations, information technology, procurement, real estate operations, and corporate strategy.

“I am honored to be appointed the next chief executive officer of Merck,” Davis stated in the announcement. “I thank the board and Ken for their confidence in me. I plan to continue Ken’s focus on innovation as we aspire to be the premier research-intensive biopharmaceutical company. This will be a year of great change both for the company and for our industry. 

“As we work through the pandemic, we will continue to focus on the important work of bringing our medicines and vaccines to those who need them. Merck will not waver in its role of searching for and developing medically necessary products to improve people’s lives throughout the world.” 

Partnerships & Acquisitions

In February, Merck and Pandion Therapeutics Inc. announced a definitive agreement, under which Merck, through a subsidiary, would acquire Pandion, a clinical stage biotechnology company developing novel therapeutics designed to address the unmet needs of patients living with autoimmune diseases, for $60 per share in cash. This represents an approximate total equity value of $1.85 billion.

Pandion is advancing a pipeline of precision immune modulators targeting critical immune control nodes. The company’s lead candidate, PT101, is an engineered IL-2 mutein fused to a protein backbone designed to selectively activate and expand regulatory T cells (Tregs) for the potential treatment of ulcerative colitis and other autoimmune diseases. Earlier this year, Pandion announced that PT101 had completed a Phase Ia clinical trial, which achieved its primary objective of safety and tolerability. The company’s pipeline also includes PD-1 agonists in development for numerous autoimmune diseases.

In March, Merck and Gilead Sciences entered into an agreement to co-develop and co-commercialize long-acting treatments in HIV that combine Gilead’s investigational capsid inhibitor lenacapavir and Merck’s investigational nucleoside reverse transcriptase translocation inhibitor islatravir into a two-drug regimen with the potential to provide new, meaningful treatment options for people living with HIV.

Islatravir and lenacapavir are both potentially first-in-class medicines in late-stage clinical trials, with significant clinical data generated to date. Both medicines have long half-lives and have demonstrated activity at low dosages in clinical studies, which support development as an investigational combination regimen with long-acting formulations, both oral and injectable.

The first clinical studies of the oral combination were expected to begin in the second half of 2021. Under the terms of the agreement, Gilead and Merck will work as partners, sharing operational responsibilities, as well as development, commercialization and marketing costs, and any future revenue.

Also in March, Merck and Alydia Health entered into a definitive agreement pursuant to which, after the intended Merck spinoff of Organon, Organon would acquire Alydia Health. Alydia Health is a commercial-stage medical device company focused on preventing maternal morbidity and mortality caused by postpartum hemorrhage (PPH) or abnormal postpartum uterine bleeding. PPH is one of the most common complications of birth, resulting in pharmacologic treatment in up to 10 percent of mothers and potentially resulting in emergency intervention such as hysterectomy and blood transfusions, and, in some cases, maternal death. The transaction was expected to close after Organon was spun off from Merck as a standalone publicly traded company in early June 2021. 

Product Performance

Leading the way once again for Merck in 2020 was the oncologic Keytruda, in both sales and R&D activity. The prolific drug earned $14.38 billion in sales for the company last year, an improvement of 29.7 percent compared with 2019 and more than double its sales in 2018, as the checkpoint inhibitor continues to roll out new indications around the world. Keytruda has now been the world’s best-selling oncologic and second-best selling prescription brand for back to back years. In the first half of 2021, sales of Keytruda rose another 21 percent to $8.08 billion. 

In January, the European Commission approved Keytruda as a monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. This approval was based on results from the pivotal Phase III KEYNOTE-177 trial, in which Keytruda monotherapy significantly reduced the risk of disease progression or death by 40 percent compared with chemotherapy (investigator’s choice: mFOLFOX6 [oxaliplatin, leucovorin and fluorouracil (FU)] with or without bevacizumab or cetuximab; or FOLFIRI [irinotecan, leucovorin and FU] with or without bevacizumab or cetuximab). In the trial, treatment with Keytruda also more than doubled median progression-free survival compared with chemotherapy (16.5 months versus 8.2 months). This approval marks the first gastrointestinal indication for Keytruda in Europe and makes Keytruda the first anti-PD-1/L1 therapy approved in Europe for these patients.

During February, Merck announced first-time data from the Phase III KEYNOTE-598 study evaluating Keytruda in combination with ipilimumab (Yervoy) compared with Keytruda monotherapy as first-line treatment for patients with metastatic non-small cell lung cancer without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1. Results of the study showed that the addition of ipilimumab to Keytruda did not improve overall survival or progression-free survival but added toxicity compared with Keytruda monotherapy in these patients. The median OS was 21.4 months for patients randomized to Keytruda in combination with ipilimumab versus 21.9 months for those randomized to Keytruda monotherapy. Additionally, the median PFS was 8.2 months for patients in the combination arm versus 8.4 months for those in the Keytruda monotherapy arm.

In March, FDA approved Keytruda for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation in combination with platinum- and fluoropyrimidine-based chemotherapy. The approval was based on results from the Phase III KEYNOTE-590 trial, which demonstrated significant improvements in overall survival, progression-free survival, and objective response rate for Keytruda plus fluorouracil (FU) and cisplatin versus FU and cisplatin alone, regardless of histology or PD-L1 expression status. For OS and PFS, Keytruda plus FU and cisplatin reduced the risk of death by 27 percent and reduced the risk of disease progression or death by 35 percent versus FU and cisplatin alone. The ORR, an additional efficacy outcome measure, was 45 percent for patients who received Keytruda plus FU and cisplatin and 29 percent for those who received FU and cisplatin alone.

That same month, the European Commission approved an expanded label for Keytruda as monotherapy for the treatment of adult and pediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant or following at least two prior therapies when ASCT is not a treatment option. This approval was based on results from the pivotal Phase III KEYNOTE-204 trial, in which Keytruda monotherapy demonstrated a significant improvement in progression-free survival compared with brentuximab vedotin, a commonly used treatment. Keytruda reduced the risk of disease progression or death by 35 percent and showed a median PFS of 13.2 months versus 8.3 months for patients treated with BV. The approval was also based on supportive data from an updated analysis of the KEYNOTE-087 trial; KEYNOTE-087 was the basis for the 2017 EC approval of Keytruda for the treatment of adult patients with relapsed or refractory cHL who have failed ASCT and BV or who are transplant ineligible and have failed BV. This was the first pediatric approval for Keytruda in the European Union.

Also during March, Merck and Eisai announced the first presentation of investigational data from the pivotal Phase III KEYNOTE-775/Study 309 trial evaluating the combination of Keytruda plus Lenvima for the treatment of certain patients with advanced, metastatic or recurrent endometrial cancer following one prior platinum-based regimen in any setting.

The study met the dual primary endpoints of progression-free survival, as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and overall survival as well as the secondary efficacy endpoint of objective response rate, as assessed by BICR per RECIST v1.1, in the all-comer population (mismatch repair proficient and mismatch repair deficient) and in the pMMR subgroup. Median follow-up was 11.4 months for both the all-comer population and the pMMR subgroup. A statistically significant and clinically meaningful improvement in PFS was seen in the all-comer population, in which Keytruda plus Lenvima reduced the risk of disease progression or death by 44 percent, with a median PFS of 7.2 months versus 3.8 months for patients who received chemotherapy (treatment of physician’s choice of doxorubicin or paclitaxel). Additionally, a statistically significant and clinically meaningful improvement in OS was seen in the all-comer population, in which Keytruda plus Lenvima reduced the risk of death by 38 percent, with a median OS of 18.3 months versus 11.4 months for patients who received TPC.

Additionally in March, Merck announced that the company would voluntarily withdraw the U.S. indication for Keytruda for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. The withdrawal of this indication was done in consultation with FDA.

This accelerated approval was granted in June 2019 based on tumor response rate and durability of response data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1). Continued approval for this indication was contingent upon completion of the post-marketing requirement establishing superiority of Keytruda as determined by overall survival. KEYNOTE-604, the confirmatory Phase III trial for this indication, met one of its dual primary endpoints of progression-free survival but did not reach statistical significance for the other primary endpoint of OS.

In May, FDA approved Keytruda in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. This indication was approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The approval was based on data from the ongoing Phase III KEYNOTE-811 trial, in which Keytruda in combination with trastuzumab and either 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin demonstrated a statistically significant objective response rate of 74 percent for patients who received the regimen with Keytruda versus 52 percent for those who received trastuzumab and chemotherapy alone. For patients who received the regimen with Keytruda, the complete response rate was 11 percent and the partial response rate was 63 percent. For patients who received trastuzumab and chemotherapy alone, the complete response rate was 3.1 percent and the partial response rate was 49 percent.

In June, the European Commission approved Keytruda in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction adenocarcinoma in adults whose tumors express PD-L1.

This approval was based on results from the Phase III KEYNOTE-590 trial, in which Keytruda plus 5-fluorouracil (5-FU) and cisplatin showed statistically significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in all pre-specified study populations. In a pre-specified analysis of patients whose tumors expressed PD-L1, Keytruda plus 5-FU and cisplatin reduced the risk of death by 38 percent and reduced the risk of disease progression or death by 49 percent versus 5-FU and cisplatin alone. For patients treated with Keytruda plus 5-FU and cisplatin, the objective response rate was 51.1 percent, with a complete response rate of 5.9 percent and a partial response rate of 45.2 percent versus 26.9 percent, with a CR rate of 2.5 percent and a PR rate of 24.4 percent, for patients treated with 5-FU and cisplatin alone.

Also in June, Merck announced first-time results from the pivotal Phase III KEYNOTE-564 trial evaluating Keytruda for the potential adjuvant treatment of patients with renal cell carcinoma at intermediate-high or high risk of recurrence following nephrectomy (surgical removal of a kidney) or following nephrectomy and resection of metastatic lesions. After a median follow-up of 24.1 months, Keytruda demonstrated a statistically significant and clinically meaningful reduction in the risk of disease recurrence or death by 32 percent compared to placebo. Additionally, a favorable trend in overall survival was observed with a 46 percent reduction in the risk of death with Keytruda as compared to placebo. The trial will continue to evaluate OS, a key secondary endpoint.

In July, FDA approved Keytruda for the treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery, based on the Phase III KEYNOTE-522 trial. TNBC is an aggressive type of breast cancer with an increased risk for disease recurrence. KEYNOTE-522 showed that Keytruda in combination with chemotherapy (carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide) before surgery and continued as a single agent after surgery significantly prolonged event-free survival versus the same neoadjuvant chemotherapy regimens alone in patients with previously untreated stage II or stage III TNBC – there was a 37 percent reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause. This approval brought Keytruda to 30 approved indications in the United States. 

Also in July, FDA approved the combination of Keytruda plus Lenvima for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. The approval for this population was based on results from the pivotal Phase III KEYNOTE-775/Study 309 trial, in which Keytruda plus Lenvima demonstrated statistically significant improvements in overall survival, reducing the risk of death by 32 percent, and progression-free survival, reducing the risk of disease progression or death by 40 percent, versus chemotherapy (investigator’s choice of doxorubicin or paclitaxel). Key­truda plus Lenvima showed a statistically significant improvement in objective response rate, with an ORR of 30 percent versus 15 percent for patients who received investigator’s choice of doxorubicin or paclitaxel, in addition to a complete response rate of 5 percent for Keytruda plus Lenvima versus 3 percent for doxorubicin or paclitaxel and a partial response rate of 25 percent versus 13 percent.

That same month, FDA approved an expanded label for Keytruda as monotherapy for the treatment of patients with locally advanced cutaneous squamous cell carcinoma that is not curable by surgery or radiation. This approval was based on data from the second interim analysis of the Phase II KEYNOTE-629 trial, in which Keytruda demonstrated an objective response rate of 50 percent, including a complete response rate of 17 percent and a partial response rate of 33 percent in the cohort of patients with locally advanced disease. Among the 27 responding patients, 81 percent had a duration of response of six months or longer, and 37 percent had a DOR of 12 months or longer.

Also in July, Merck announced that the company would voluntarily withdraw the U.S. accelerated approval indication for Keytruda for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted therapy.

The decision was made in consultation with FDA following the April 29 Oncologic Drugs Advisory Committee evaluation of this third-line gastric cancer indication for Keytruda as a monotherapy because it failed to meet the post-marketing requirement of demonstrating an overall survival benefit in a Phase III study. As agreed with FDA, Merck planned to initiate the withdrawal six months after the announcement.

In August, FDA approved the combination of Keytruda plus Lenvima for the first-line treatment of adult patients with advanced renal cell carcinoma. The approval was based on results from the pivotal Phase III CLEAR (Study 307)/KEYNOTE-581 trial, in which Keytruda plus Lenvima demonstrated statistically significant improvements versus sunitinib in the efficacy outcome measures of progression-free survival, overall survival, and confirmed objective response rate.

For PFS, Keytruda plus Lenvima reduced the risk of disease progression or death by 61 percent with a median PFS of 23.9 months versus 9.2 months for sunitinib. For OS, Keytruda plus Lenvima reduced the risk of death by 34 percent versus sunitinib. Additionally, the confirmed ORR was 71 percent for patients who received Keytruda plus Lenvima versus 36 percent with sunitinib. Keytruda plus Lenvima achieved a complete response rate of 16 percent and partial response rate of 55 percent versus a CR rate of 4 percent and a PR rate of 32 percent for those who received sunitinib.

Also during August, Merck announced a label update for Keytruda for its indication in first-line advanced urothelial carcinoma (bladder cancer) in the United States. FDA has converted this indication from an accelerated to a full (regular) approval. In addition, as part of the label update, this indication has been revised to be for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy.

Previously, Keytruda was indicated for the treatment of patients with locally advanced or mUC who were not eligible for cisplatin-containing chemotherapy and whose tumors expressed PD-L1, as determined by an FDA-approved test, or in patients who were not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication was approved under accelerated approval based on tumor response rate and duration of response. Continued approval was contingent upon verification and description of clinical benefit in confirmatory trials. The subsequent Phase III trial KEYNOTE-361, evaluating Keytruda as monotherapy and in combination with chemotherapy for the first-line treatment of patients with advanced or mUC who were eligible for platinum-containing chemotherapy, did not meet its pre-specified dual primary endpoints of overall survival or progression-free survival, compared with standard of care chemotherapy.

This label update followed the FDA’s Oncologic Drugs Advisory Committee meetings held earlier this year as part of an industry-wide evaluation of indications based on accelerated approvals that have not met their post-marketing requirements. Members voted 5-3 in favor of maintaining the accelerated approval of Keytruda for its first-line bladder indication.

In September, Merck announced that the Phase III KEYNOTE-394 trial investigating Keytruda in Asian patients with advanced hepatocellular carcinoma previously treated with sorafenib met its primary endpoint of overall survival. The study found that treatment with Keytruda plus best supportive care resulted in a statistically significant improvement in OS compared with placebo plus best supportive care. KEYNOTE-394 also met its key secondary endpoints of progression-free survival and objective response rate, with statistically significant improvements for Keytruda compared with placebo. 

Also in September, Merck announced the final overall survival results from the pivotal Phase III KEYNOTE-355 trial investigating Keytruda in combination with chemotherapy (paclitaxel, nab-paclitaxel or gemcitabine/carboplatin) for the first-line treatment of patients with metastatic triple-negative breast cancer. Keytruda is the first anti-PD-1 therapy in combination with chemotherapy to demonstrate a statistically significant and clinically meaningful improvement in OS for these patients.

In this study, Keytruda plus chemotherapy reduced the risk of death by 27 percent in patients with mTNBC whose tumors expressed PD-L1, as compared to chemotherapy alone. There was an increase of 6.9 months in median OS with Keytruda plus chemotherapy compared to chemotherapy alone (23.0 months versus 16.1 months). Although the trial was not powered to compare efficacy between treatment groups by different chemotherapy regimens, the increase in OS was observed for Keytruda plus chemotherapy across the three chemotherapy choices.

That same month, Merck announced the first results from the Phase III KEYNOTE-716 trial, in which adjuvant treatment with Keytruda showed a statistically significant and clinically meaningful improvement in recurrence-free survival, the trial’s primary endpoint, compared to placebo in patients with resected high-risk stage II melanoma; Key­truda is the first anti-PD-1 therapy to demonstrate this.

At the first interim analysis, Keytruda reduced the risk of disease recurrence or death by 35 percent compared to placebo. Median RFS had not been reached for either group at the time of this analysis. After 14.4 months follow-up, 11.1 percent of patients on Keytruda had recurrence or died compared with 16.8 percent of patients on placebo, with fewer distant recurrences with Keytruda (4.7 percent) versus placebo (7.8 percent).

Also in September, Merck announced the presentation of the full results from the pivotal Phase III KEYNOTE-826 trial investigating Keytruda in combination with chemotherapy with or without bevacizumab for the first-line treatment of persistent, recurrent or metastatic cervical cancer. This is the first combination regimen with an anti-PD-1/PD-L1 therapy to improve overall survival, progression-free survival, and objective response rate compared to chemotherapy with or without bevacizumab as a first-line treatment of persistent, recurrent, or metastatic cervical cancer.

Keytruda plus chemotherapy (paclitaxel plus cisplatin or paclitaxel plus carboplatin) with or without bevacizumab (Keytruda plus chemo ± bev) reduced the risk of death by one-third, or 33 percent, versus chemotherapy with or without bevacizumab (chemo ± bev). Median OS for Keytruda plus chemo ± bev was 24.4 months compared to 16.5 months for chemo ± bev. For the dual primary endpoint of PFS, median PFS was 10.4 months in those treated with Keytruda plus chemo ± bev and 8.2 months among those treated with chemo ± bev. In the trial, Keytruda plus chemo ± bev showed an ORR of 65.9 percent, and chemo ± bev showed an ORR of 50.8 percent. Median duration of response was 18.0 months in the Keytruda plus chemo ± bev arm and 10.4 months in the chemo ± bev arm. The results were consistent with or without bevacizumab use.

Second in sales in Merck’s portfolio in 2020 were the company’s HPV vaccines Gardasil and Gardasil 9. The Gardasil line generated $3.94 billion in sales for the company last year, an improvement of 5.4 percent. According to company leaders, this was primarily due to higher volumes in China and the replenishment in 2020 of doses borrowed from the U.S. Centers for Disease Control and Prevention Pediatric Vaccine Stockpile in 2019. In first-half 2021, sales of the Gardasil line were up another 22.7 percent to $2.15 billion.

Sales of Merck’s diabetes products Januvia and Janumet both declined in 2020, with Januvia down 5.1 percent to $3.31 billion and Janumet declining 3.4 percent to $1.97 billion. This was a result of continued pricing pressure in the United States, partially offset by higher demand in certain international markets, particularly in China. Januvia and Janumet will lose market exclusivity in the United States in January 2023; The supplementary patent certificates that provide market exclusivity for Januvia and Janumet in the EU expire in September 2022 and April 2023, respectively. In the first half of 2021, sales of Januvia declined another 2.1 percent to $1.59 billion, while sales of Janumet were down 3.1 percent to $962 million.

A product of a collaboration with AstraZeneca, the oncologic Lynparza generated $725 million in alliance revenue for Merck in 2020, a jump of 63.3 percent compared with 2019. This was due to continued uptake across the multiple approved indications in the United States, the EU, China, and Japan. In the first half of 2021, Lynparza alliance revenue grew another 47.1 percent to $475 million. 

In June, AstraZeneca and Merck announced the first presentation of data from the Phase III OlympiA trial, in which Lynparza demonstrated a statistically significant improvement in its primary endpoint of invasive disease-free survival versus placebo in the adjuvant treatment of patients with germline BRCA1/2 mutations and high-risk human epidermal growth factor receptor 2 (HER2)-negative early breast cancer following definitive local treatment and neoadjuvant or adjuvant chemotherapy.

In the overall trial population of 1,836 patients, results showed Lynparza reduced the risk of invasive breast cancer recurrences, second cancers or death by 42 percent versus placebo based on a pre-specified event-driven interim analysis with a median follow-up of 2.5 years. At three years following trial initiation, 85.9 percent of patients treated with Lynparza were alive and free of invasive breast cancer and second cancers versus 77.1 percent of patients treated with placebo.

Results also showed an improvement in the key secondary endpoint of distant disease-free survival in the overall trial population. Lynparza reduced the risk of distant disease recurrence or death by 43 percent. At the time of data cut-off, overall survival data, while directionally encouraging, did not reach statistical significance and were not mature. The trial will continue to assess OS as a secondary endpoint.

In September, AstraZeneca and Merck announced positive results from the Phase III PROpel trial, in which Lynparza in combination with abiraterone and prednisone demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of radiographic progression-free survival versus abiraterone plus prednisone as a first-line treatment for men with metastatic castration-resistant prostate cancer with or without homologous recombination repair gene mutations.

At a planned interim analysis, the Independent Data Monitoring Committee concluded that the trial met the primary endpoint of rPFS in men with mCRPC who had not received treatment in the first-line setting, including new hormonal agents or chemotherapy. The trial also showed a trend at this interim analysis towards improved overall survival. However, the OS data are still immature, and the trial will continue to assess OS as a key secondary endpoint.

Another oncologic outcome of a partnership – Lenvima, developed with Eisai – produced an alliance revenue bump of 43.6 percent to $580 million in 2020 for Merck due to higher demand in the United States, China, and the EU. In the first half of 2021, alliance revenue of Lenvima rose 11.1 percent to $310 million.

In The Pipeline

In January, FDA approved Verquvo, a soluble guanylate cyclase stimulator, to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient intravenous diuretics in adults with symptomatic chronic heart failure and ejection fraction less than 45 percent. The approval of Verquvo by FDA, which is the first treatment for chronic heart failure approved specifically for patients following a hospitalization for heart failure or need for outpatient IV diuretics, was based on the results of the pivotal Phase III VICTORIA trial in which Verquvo was superior to placebo in reducing the risk of cardiovascular death or heart failure hospitalization based on a time-to-event analysis, and follows a priority regulatory review. Verquvo (vericiguat) 2.5 mg, 5 mg, and 10 mg tablets is being jointly developed with Bayer AG.

In March, FDA accepted for review Merck’s New Drug Application for gefapixant, an investigational, orally administered, selective P2X3 receptor antagonist, for the treatment of refractory chronic cough or unexplained chronic cough in adults. The NDA was based on results from the COUGH-1 and COUGH-2 clinical trials, which are the first companion Phase III studies ever conducted in patients with RCC, a cough that persists despite appropriate treatment of underlying conditions, or UCC, a cough where the underlying cause cannot be identified despite a thorough evaluation.

In April, Merck announced the discontinuation of development of MK-7110 for the treatment of hospitalized patients with COVID-19. Merck acquired MK-7110 in December 2020 through its acquisition of OncoImmune, a privately held clinical-stage biopharmaceutical company. Merck subsequently received feedback from FDA that additional data, beyond the study conducted by OncoImmune, would be needed to support a potential Emergency Use Authorization application. Based on the additional research that would be required – new clinical trials as well as research related to manufacturing at scale – MK-7110 would not be expected to become available until the first half of 2022. Given this timeline and these technical, clinical and regulatory uncertainties, the availability of a number of medicines for patients hospitalized with COVID-19, and the need to concentrate Merck’s resources on accelerating the development and manufacture of the most viable therapeutics and vaccines, Merck decided to discontinue development of MK-7110 for COVID-19 and to focus its pandemic efforts on advancing molnupiravir and on producing Johnson & Johnson’s COVID-19 vaccine.

In June, Vaxelis (Diphtheria and Tetanus Toxoids and Acellular Pertussis, Inactivated Poliovirus, Haemophilus b Conjugate, and Hepatitis B Vaccine), developed as part of a U.S.-based partnership between Merck and Sanofi Pasteur, the global vaccines business unit of Sanofi, became available in the United States. Vaxelis is the first hexavalent (six-in-one) combo vaccine available in the United States indicated for active immunization to help prevent diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae type b. Vaxelis is approved for use as a 3-dose series in children 6 weeks through 4 years of age (prior to the 5th birthday).

In July, FDA approved Vaxneuvance (Pneumococcal 15-valent Conjugate Vaccine) for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F in adults 18 years of age and older. Vaxneuvance was approved based on data from seven randomized, double-blind clinical studies assessing safety, tolerability, and immunogenicity in adults. Clinical data showed that immune responses elicited by Vaxneuvance were non-inferior to the currently available 13-valent pneumococcal conjugate vaccine (PCV13) for the 13 shared serotypes, as assessed by opsonophagocytic activity Geometric Mean Titers.

Also in July, Merck announced results from a Phase IIa trial evaluating the safety, tolerability, and pharmacokinetics of six monthly oral doses, over 24 weeks, of islatravir, the company’s investigational nucleoside reverse transcriptase translocation inhibitor, versus placebo for pre-exposure prophylaxis of HIV-1 infection in adults at low-risk of contracting HIV-1. After 24 weeks, once-monthly oral islatravir was generally well tolerated versus placebo. The levels of islatravir in peripheral blood mononuclear cells also remained above the pre-specified efficacy PK threshold for PrEP at both doses studied (60 mg and 120 mg) eight weeks after the last study dose.

In August, FDA approved Welireg, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery. The approval was based on results from the open-label Study 004 trial, where the major efficacy endpoint was overall response rate in patients with VHL-associated RCC. In Study 004, Welireg showed a confirmed overall response rate of 36.1 percent in patients with VHL disease-associated RCC.

Welireg is the first HIF-2α inhibitor therapy approved in the United States. As an inhibitor of HIF-2α, Welireg reduces transcription and expression of HIF-2α target genes associated with cellular proliferation, angiogenesis, and tumor growth.

Also in August, Merck announced topline results from the pivotal PNEU-PED (V114-029) study evaluating the immunogenicity, safety and tolerability of Vaxneuvance in healthy infants enrolled between 42-90 days of age. In the trial, infants were given a four-dose regimen of either Vaxneuvance or the licensed 13-valent pneumococcal conjugate vaccine (PCV13) at 2, 4, 6, and 12-15 months of age. 

In the PNEU-PED study, primary endpoints demonstrated that Vaxneuvance had a safety profile generally comparable to PCV13 following receipt of any vaccine dose. At 30 days following the third dose in the series (PD3), Vaxneuvance was non-inferior to PCV13 for all 13 shared serotypes based on serotype-specific response rates and for 12 of the 13 shared serotypes based on serotype-specific IgG geometric mean concentrations (GMCs). The lower bounds of the two-sided 95 percent confidence intervals (CI) for the serotype-specific IgG GMC ratios were greater than 0.5 for 12 shared serotypes; the lower bound was 0.48 for serotype 6A, narrowly missing non-inferiority criteria. At 30 days following the fourth (toddler) dose (PD4), Vaxneuvance was non-inferior to PCV13 for all 13 shared serotypes based on serotype-specific IgG GMCs.

In September, Merck and partner developer Ridgeback Biotherapeutics announced the initiation of the Phase III MOVe-AHEAD trial to evaluate molnupiravir for the prevention of COVID-19 infection. The global study is enrolling individuals at least 18 years old who reside in the same household as someone with lab-confirmed SARS-CoV-2 infection with symptoms.

Molnupiravir (MK-4482/EIDD-2801) is an investigational, orally administered form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19. Molnupiravir has been shown to be active in several preclinical models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission, as well as SARS-CoV-1 and MERS.