Merck’s extraordinary success with the immuno-oncologic Keytruda has pushed the company back to the pinnacle of the pharma industry.
Merck & Co.
2000 Galloping Hill Road
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|Product||2018 Sales||2017 Sales|
|Gardasil, Gardasil 9||$3,151||$2,308|
|Zetia and Vytorin||$1,355||$2,095|
All sales are in millions of dollars.
|1H 2019||1H 2018|
All figures are in millions of dollars, except EPS.
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The list of medicines that have generated more than $10 billion in sales in a single year is not long. Lipitor. Humira. Sovaldi. Harvoni. Revlimid, almost. And that is about it.
Merck may soon be adding another entry to that list, though: Keytruda. Since earning the drug’s first approval in 2014, the world’s best-selling immuno-oncologic has, so far, earned indications in melanoma, NSCLC, HNSCC, Hodgkin lymphoma, B-cell lymphoma, urothelial carcinoma, microsatellite instability-high solid tumors, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, and renal cell carcinoma … and that is just in the United States, where Keytruda has added no less than 11 new approvals in the last two years.
Sales of Keytruda nearly doubled worldwide in 2018, and with $4.9 billion banked in the first half of 2019 behind a growth rate of more than 50 percent, the drug seems a good bet to cross the $10 billion mark in time for Christmas. Beyond that, the analysts at EvaluatePharma are projecting that Keytruda will pass Humira and become the world’s top-selling pharmaceutical product by 2024.
For the wisdom Merck – a company with little previous experience in oncology – showed in rescuing Keytruda from the out-licensing scrap heap after the acquisition of Schering-Plough, the persistence the company displayed in building up a vast development program across dozens of indications, and the extraordinary success it has enjoyed in bringing this life-saving compound to patients around the world, Med Ad News is pleased to name Merck as Company of the Year.
“When I came to this job, some pharmaceutical companies were taking resources away from R&D,” said Merck CEO Kenneth Frazier in an interview with the Harvard Business Review last year. “Merck is a science-based, R&D-based company, and I wanted to reinforce that from the very beginning. We’ve even begun to insource things that we outsourced 10 years ago, because we realize that they are critical to our long-term success. At the end of the day, the quality of this company largely comes down to the quality of the science and of the scientists.”
Merck’s top-line revenue in 2018 was $42.29 billion, a 5.4 percent improvement over 2017; this was the first time Merck exceeded $42 billion in revenue since 2014, back when Nasonex and Singulair were still billion-dollar brands. Net income in 2018 attributable to Merck was up by more than two and a half times from $2.39 billion to $6.22 billion, and earnings per share rose by $1.45 to $2.32. In the first half of 2019, top-line revenue was up another 10.1 percent to $22.58 billion while net income attributable to Merck more than doubled – again – from $2.44 billion to $5.59 billion and earnings per share rose by $1.25 to $2.15. Merck executives are projecting that full-year EPS for 2019 will fall between $3.78 and $3.88, which would be easily the company’s highest amount since 2014.
2018 was the year that the oncology drug Keytruda went from contender to champion. Sales for the year were $7.17 billion, an improvement of 88 percent over 2017 and the fourth-highest total for any prescription drug in the world. During the course of the year, Keytruda earned no less than six new approvals from FDA, plus three more from the European Commission along with approvals in China and Japan. The rush of approvals continued into 2019, with five new approvals and a label extension from FDA, two approvals in Europe, and five in Japan. Sales of Keytruda during first-half 2019 amounted to $4.9 billion, up 56.6 percent compared with first-half 2018.
In January, Keytruda received five new approvals from Japan’s Pharmaceuticals and Medical Devices Agency: in combination with pemetrexed and platinum-based chemotherapy (cisplatin or carboplatin) for the first-line treatment of unresectable, advanced/recurrent nonsquamous NSCLC regardless of PD-L1 expression (based on results of the Phase III trial KEYNOTE-189); in combination with carboplatin and paclitaxel or nab-paclitaxel for the first-line treatment of unresectable, advanced/recurrent squamous NSCLC regardless of PD-L1 expression (based on results of the Phase III trial KEYNOTE-407); monotherapy in the first-line treatment of PD-L1-positive (Tumor Proportion Score [TPS] ≥1%) unresectable, advanced/recurrent NSCLC (based on results of the Phase III trial KEYNOTE-042); monotherapy as adjuvant therapy for melanoma (based on results of the Phase III trial EORTC1325/KEYNOTE-054; and monotherapy for treating advanced/recurrent MSI-H solid tumors that have progressed after chemotherapy (only if refractory or intolerant to standard therapies), based on results of two Phase II trials, KEYNOTE- 164 and KEYNOTE-158. A companion diagnostic to detect MSI-H, the MSI test kit Falco by Falco Biosystems Ltd., was also approved.
In addition to the adjuvant therapy approval, dosage and administration for all patients with melanoma has been changed from intravenous infusion of 2 mg/kg (body weight) over 30 minutes at a three-week interval to intravenous infusion of the fixed dose of 200 milligrams over 30 minutes at a three-week interval. Previously, Keytruda was approved in Japan for the treatment of curatively unresectable melanoma; PD-L1-positive unresectable, advanced or recurrent NSCLC (TPS≥1% in second-line setting; TPS≥50% in first-line setting); relapsed or refractory classical Hodgkin lymphoma; and curatively unresectable urothelial carcinoma that progressed after chemotherapy. Keytruda is copromoted in Japan with Taiho Pharmaceutical Co.
In February, FDA approved Keytruda for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection based on results from the EORTC1325/KEYNOTE-054 trial. This pivotal Phase III trial, which was conducted in collaboration with the European Organisation for Research and Treatment of Cancer, demonstrated that Keytruda significantly prolonged recurrence-free survival, reducing the risk of disease recurrence or death by 43 percent compared to placebo in patients with resected, high-risk stage III melanoma. Keytruda is the first anti-PD-1 therapy studied in the adjuvant setting across patients with stage IIIA (>1 mm lymph node metastasis), IIIB, and IIIC melanoma.
Also in February, Merck announced that the pivotal Phase III KEYNOTE-240 trial evaluating Keytruda plus best supportive care for the treatment of patients with advanced hepatocellular carcinoma who were previously treated with systemic therapy, did not meet its co-primary endpoints of overall survival and progression-free survival compared with placebo plus best supportive care. In the final analysis of the study, there was an improvement in OS for patients treated with Keytruda compared to placebo; however, these OS results did not meet statistical significance per the pre-specified statistical plan. Results for PFS were also directionally favorable in the Keytruda arm compared with placebo but did not reach statistical significance. The key secondary endpoint of objective response rate was not formally tested, since superiority was not reached for OS or PFS.
Also in February, Merck announced the presentation of interim data from the Phase Ib/II KEYNOTE-365 umbrella trial investigating Keytruda in combination with various agents for the treatment of patients with metastatic castration-resistant prostate cancer. These early findings show anti-tumor activity across three cohorts of the study, which investigated Keytruda in combination with Lynparza (Cohort A, Abstract #145); docetaxel and prednisone (Cohort B, Abstract #170); and enzalutamide (Cohort C, Abstract #171) – with a safety profile consistent with each therapy alone. Based on the findings, Merck is initiating three new pivotal Phase III trials with Keytruda in combination with Lynparza (KEYLYNK-010, NCT03834519), docetaxel and prednisone (KEYNOTE-921, NCT03834506), and enzalutamide (KEYNOTE-641, NCT03834493). With the initiation of KEYLYNK-010, KEYNOTE-921, and KEYNOTE-641, Merck now has the largest clinical program with an anti-PD-1 therapy in prostate cancer and the only program to evaluate overall survival as a co-primary endpoint across three Phase III trials.
In March, the European Commission approved Keytruda in combination with carboplatin and either paclitaxel or nab-paclitaxel for the first-line treatment of adults with metastatic squamous non-small cell lung cancer. This approval was based on data from the Phase III KEYNOTE-407 trial, which demonstrated that Keytruda in combination with chemotherapy significantly improved overall survival in adults with metastatic squamous NSCLC regardless of PD-L1 tumor expression status, reducing the risk of death by 36 percent compared to chemotherapy alone.
In April, Keytruda was approved by the Chinese National Medical Products Administration in combination with pemetrexed and platinum chemotherapy for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. This new indication was granted conditional approval based on overall survival and progression-free survival data from the pivotal Phase III KEYNOTE-189 trial in patients regardless of PD-L1 tumor expression status. With this approval, Keytruda became the first anti-PD-1 therapy approved for more than one tumor type in China, following its initial approval in July 2018 for advanced melanoma, and the first anti-PD-1 therapy approved in the first-line treatment setting for metastatic nonsquamous NSCLC. Each year, more than 782,000 new cases of lung cancer are diagnosed in China and more than 626,000 deaths result from the disease.
Also in April, FDA approved an expanded label for Keytruda as monotherapy for the first-line treatment of patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. The approval was based on results from the Phase III KEYNOTE-042 trial, in which overall survival was sequentially tested as part of a pre-specified analysis plan. In the trial, Keytruda monotherapy demonstrated a statistically significant improvement in OS compared with chemotherapy alone in patients whose tumors expressed PD-L1 with a TPS ≥50%, with a TPS ≥20%, and then in the entire study population (TPS ≥1%).
Also in April, FDA approved Keytruda in combination with Inlyta (axitinib), a tyrosine kinase inhibitor, for the first-line treatment of patients with advanced renal cell carcinoma (RCC). The approval was based on findings from the pivotal Phase III KEYNOTE-426 trial, which demonstrated significant improvements in overall survival, progression-free survival and objective response rate for Keytruda in combination with axitinib compared to sunitinib. Consistent results were observed across pre-specified subgroups, IMDC risk categories, and PD-L1 tumor expression status. For the main efficacy outcome measures of OS and PFS, the Keytruda-axitinib combination reduced the risk of death by 47 percent compared with sunitinib; for PFS, the Keytruda-axitinib combination showed a reduction in the risk of progression of disease or death of 31 percent compared to sunitinib. The ORR, an additional efficacy outcome measure, was 59 percent for patients who received the Keytruda-axitinib combination and 36 percent for those who received sunitinib. This is the first indication for Keytruda in advanced RCC, the most common type of kidney cancer, and the first anti-PD-1 therapy FDA-approved as part of a combination regimen that significantly improved OS, PFS, and ORR versus sunitinib in patients with advanced RCC. The European Commission subsequently approved a similar indication in September.
In May, Merck announced that the Phase III KEYNOTE-119 trial evaluating Keytruda as monotherapy for the second-line or third-line treatment of patients with metastatic triple-negative breast cancer did not meet its prespecified primary endpoint of superior overall survival compared to chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Other endpoints were not formally tested per the study protocol because the primary endpoint of OS was not met.
In June, FDA approved Keytruda as monotherapy 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. This accelerated approval was based on tumor response rate and durability of response. This marked the first indication for Keytruda in SCLC.
The approval was based on pooled data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1), two multicenter, multicohort, non-randomized, open-label trials evaluating Keytruda in patients with SCLC who had disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. The trials excluded patients with autoimmune disease or a medical condition that required immunosuppression. Among the 83 patients enrolled in the trials and who were evaluated for efficacy, 64 percent received two prior lines of therapy and 36 percent received three or more lines of therapy; 60 percent received prior thoracic radiation therapy; 51 percent received prior radiation therapy to the brain. Keytruda demonstrated an ORR of 19 percent, with a complete response rate of 2 percent and a partial response rate of 17 percent. Among the 16 responding patients, 94 percent had a DOR of six months or longer, 63 percent had a DOR of 12 months or longer and 56 percent had a DOR of 18 months or longer. Responses ranged from 4.1 to 35.8-plus months.
Also in June, FDA approved Keytruda as monotherapy in patients whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) or in combination with platinum and fluorouracil, a commonly used chemotherapy regimen, for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). The approval was based on results from the pivotal Phase III KEYNOTE-048 trial, where Keytruda demonstrated a significant improvement in overall survival compared with the EXTREME regimen (cetuximab with carboplatin or cisplatin plus FU), a standard treatment, as monotherapy in patients whose tumors expressed PD-L1 (CPS ≥1) and in combination with chemotherapy in the total study population. With these new indications, Keytruda became the first anti-PD-1 therapy approved in the first-line setting as monotherapy in patients whose tumors express PD-L1 (CPS ≥1) or in combination with chemotherapy regardless of PD-L1 expression for patients with metastatic or with unresectable, recurrent HNSCC and the first anti-PD-1 therapy to demonstrate a statistically significant improvement in OS in these patients.
Also in June, Merck announced full results from the pivotal Phase III KEYNOTE-062 trial evaluating Keytruda as monotherapy and in combination with chemotherapy (cisplatin and either 5-fluorouracil or capecitabine) for the first-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma. In KEYNOTE-062, 763 patients with advanced gastric or GEJ adenocarcinoma whose tumors expressed PD-L1 and who were human epidermal growth factor receptor 2 (HER2) negative were randomized to receive either Keytruda as monotherapy, Keytruda in combination with chemotherapy or chemotherapy alone. In the study, Keytruda monotherapy was noninferior to chemotherapy for OS in the ITT population of patients whose tumors expressed PD-L1 (CPS≥1). The median OS for Keytruda monotherapy was 10.6 months compared with 11.1 months for chemotherapy alone, and the estimated two year survival rate was 27 percent for Keytruda monotherapy and 19 percent for chemotherapy alone. In a pre-specified subgroup of patients whose tumors expressed high levels of PD-L1 (CPS ≥10), Keytruda monotherapy demonstrated an improvement in OS compared with chemotherapy alone; however, this was not formally tested per the statistical analysis plan. In this subgroup, the median OS for Keytruda monotherapy was 17.4 months versus 10.8 months for chemotherapy alone, and the estimated two-year survival rate was 39 percent for Keytruda monotherapy, compared with 22 percent for chemotherapy alone.
In the combination arm of KEYNOTE-062, Keytruda plus chemotherapy was not found to be statistically superior for OS at CPS ≥1, OS at CPS ≥10, or progression-free survival at CPS ≥1 compared with chemotherapy alone. The median OS for Keytruda plus chemotherapy was 12.5 months compared with 11.1 months for chemotherapy alone, and the estimated two-year survival rate was 24 percent for Keytruda in combination with chemotherapy, and 19 percent for chemotherapy alone. In patients whose tumors had a CPS ≥10, the median OS for Keytruda in combination with chemotherapy was 12.3 months versus 10.8 months for chemotherapy alone; the estimated two-year survival rate was 28 percent for Keytruda plus chemotherapy, compared with 22 percent for chemotherapy alone.
In July, FDA approved Keytruda as monotherapy for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. The approval was based on data from KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. In this pivotal study, Keytruda met a primary endpoint by significantly improving overall survival in patients with squamous cell carcinoma or adenocarcinoma who progressed after standard therapy and whose tumors expressed PDL1 (Combined Positive Score [CPS] ≥10), with a 31 percent reduction in the risk of death compared to chemotherapy (paclitaxel, docetaxel or irinotecan). This was the first time an anti-PD-1 therapy demonstrated a survival benefit for this patient population. The new indication was also based on data from KEYNOTE-180 (NCT02559687), a multicenter, non-randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least two prior systemic treatments for advanced disease.
Also in July, Merck announced that the Phase III KEYNOTE-522 trial investigating Keytruda in combination with chemotherapy met one of the dual-primary endpoints of pathological complete response following the neoadjuvant part of the neoadjuvant/adjuvant study regimen in patients with triple-negative breast cancer. Based on an interim analysis conducted by the independent Data Monitoring Committee, Keytruda in combination with chemotherapy demonstrated a statistically significant improvement in pCR rates compared with chemotherapy alone, regardless of PD-L1 status. A pathological complete response or pCR is defined as a lack of all signs of cancer in tissue samples analyzed following completion of neoadjuvant therapy and definitive surgery. Based on the recommendation of the DMC, the trial will continue without changes to evaluate the other dual-primary endpoint of event-free survival, per the trial design.
Also in July, FDA accepted for review six supplemental Biologics License Applications to update the dosing frequency for Keytruda to include an every-six-weeks (Q6W) dosing schedule option. Merck is seeking FDA approval of a 400 milligram Q6W dose infused over 30 minutes for Keytruda indications in melanoma, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, gastric cancer, hepatocellular carcinoma, and Merkel cell carcinoma. If approved by FDA, the Q6W dose would be available for use in adults in addition to the currently approved dose of Keytruda 200 milligrams every three weeks (Q3W) infused over 30 minutes. FDA has set a Prescription Drug User Fee Act date of Feb. 18, 2020. The European Commission approved 400 milligram Q6W dosing for Keytruda monotherapy in March 2019.
In September, Merck announced that first-line treatment with Keytruda in combination with chemotherapy demonstrated improvements in overall survival, progression-free survival, and objective response rate in a pooled analysis of a subgroup of patients with advanced nonsquamous and squamous non-small cell lung cancer whose tumors do not express PD-L1 (tumor proportion score [TPS] <1%) from three randomized trials. Patients with nonsquamous NSCLC with EGFR or ALK genomic tumor aberrations were ineligible. Results – from KEYNOTE-189, KEYNOTE-407, and KEYNOTE-021 (Cohort G) – were consistent with those observed in the overall study populations across all three trials.
This data was from a pooled subgroup of 428 previously untreated patients whose tumors do not express PD-L1 (TPS <1%) from the KEYNOTE-189 (nonsquamous NSCLC), KEYNOTE-407 (squamous NSCLC), and KEYNOTE-021 (nonsquamous NSCLC [Cohort G]) trials. Patients were randomized to receive Keytruda 200 milligrams every three weeks plus chemotherapy or chemotherapy alone. Patients with nonsquamous NSCLC received pemetrexed (Alimta) and platinum chemotherapy; patients with squamous NSCLC received carboplatin and either paclitaxel or nab-paclitaxel. Patients with nonsquamous NSCLC with EGFR or ALK genomic tumor aberrations were ineligible. Key efficacy outcome measures included OS, PFS, and ORR.
With a median follow-up of 10.2 months, Keytruda in combination with chemotherapy reduced the risk of death by 44 percent compared to chemotherapy alone. Estimated 12-month OS rates were 66 percent with the Keytruda-chemotherapy combinations compared to 47 percent with chemotherapy alone; the 18-month OS rates were 52 percent and 29 percent, respectively. Median OS was 19.0 months with the Keytruda-chemotherapy combinations compared to 11.0 months with chemotherapy alone.
The Keytruda-chemotherapy combinations also reduced the risk of disease progression or death by 33 percent compared to chemotherapy alone. Estimated 12-month PFS rates were 29 percent with the Keytruda-chemotherapy combinations compared to 17 percent with chemotherapy alone; the 18-month PFS rates were 22 percent and 9 percent, respectively. Median PFS was 6.5 months with the Keytruda-chemotherapy combinations compared to 5.4 months with chemotherapy alone.
The ORR was 46.9 percent for patients who received the Keytruda-chemotherapy combinations and 28.6 percent for those who received chemotherapy alone. Median DOR was 7.9 months (range, 1.1+ to 28.4+) with the Keytruda-chemotherapy combinations and 6.7 months (range, 1.4+ to 30.1+) with chemotherapy alone. For patients receiving the Keytruda-chemotherapy combinations, 42.4 percent experienced a response lasting 12 months or longer compared to 35.3 percent of those receiving chemotherapy alone.
Also in September, FDA approved the combination of Keytruda plus Eisai’s Lenvima for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This was the first U.S. approval for the combination of Keytruda plus Lenvima and the first time an anti-PD-1 therapy was approved in combination with a kinase inhibitor for advanced endometrial carcinoma in the United States. Following submission on June 17, this was an accelerated approval reviewed under the FDA’s Real-Time Oncology Review pilot program, which aims to improve the efficiency of the review process for applications to ensure that treatments are available to patients as early as possible.
The approval was based on data from KEYNOTE-146/Study 111, a Phase II, multi-cohort, multicenter, open-label, single-arm trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with Keytruda 200 milligrams intravenously every three weeks in combination with Lenvima 20 milligrams orally once daily until unacceptable toxicity or disease progression as determined by the investigator.
Administration of Keytruda plus Lenvima was permitted beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Keytruda dosing was continued for a maximum of 24 months; however, treatment with Lenvima could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every six weeks until week 24, followed by every nine weeks thereafter. The major efficacy outcome measures were objective response rate and duration of response by independent radiologic review committee using RECIST 1.1.
Among the 108 patients, 87 percent had tumors that were not MSI-H or dMMR, 10 percent had tumors that were MSI-H or dMMR, and 3 percent had tumors that had unknown status. The baseline characteristics of the 94 patients with tumors that were not MSI-H or dMMR were: median age of 66 years, with 62 percent age 65 or older; 86 percent White, 6 percent Black, 4 percent Asian, and 3 percent other races; and Eastern Cooperative Oncology Group (ECOG) performance status of 0 (52 percent) or 1 (48 percent). All 94 patients had received prior systemic therapy for endometrial carcinoma; 51 percent had one, 38 percent had two, and 11 percent had three or more prior systemic therapies.
In the 94 patients with tumors that were not MSI-H or dMMR, the Keytruda-Lenvima combination demonstrated an ORR of 38.3 percent, with a complete response rate of 10.6 percent and a partial response rate of 27.7 percent. The median follow-up time was 18.7 months. In the patients who had a response as determined by independent review, at the time of data cutoff, the median DOR was not reached (range: 1.2+ to 33.1+ months), and 69 percent of these patients experienced responses lasting six months or greater.
Other Leading products
Merck’s type 2 diabetes medicines Januvia and Janumet generated combined sales of $5.91 billion for 2018, edging up by 0.3 percent compared to 2017. According to company leaders, this was driven primarily by ongoing pricing pressure, particularly in the United States, partially offset by higher demand in most international markets. Individually, Januvia sales for 2018 totaled nearly $3.69 billion and Janumet sales came in at almost $2.23 billion. Combined sales of Januvia and Janumet in the first half of 2019 reached about $2.8 billion, a decline of 5.5 percent compared with the first six months of 2018. Januvia generated $1.73 billion in the 2019 first half while Janumet accounted for $1.06 billion.
The HPV vaccines Gardasil and Gardasil 9 enjoyed a solid revenue bounce in 2018, with sales up 36.5 percent to $3.15 billion. Sales growth was driven primarily by higher sales in the Asia Pacific region, particularly in China reflecting continued uptake since launch, as well as higher demand in certain European markets. The sales increase was also attributable to the replenishment in 2018 of doses borrowed from the CDC Pediatric Vaccine Stockpile in 2017. In April 2018, China’s Food and Drug Administration approved Gardasil 9 for use in girls and women ages 16 to 26; in October 2018, FDA approved an expanded age indication for use in women and men ages 27 to 45 for the prevention of certain cancers and diseases caused by the nine HPV types covered by the vaccine. In the first half of 2019, Gardasil sales totaled $1.72 billion, an improvement of 35.9 percent over first-half 2018.
The ProQuad, M-M-R II and Varivax vaccine franchise earned about $1.8 billion in sales in 2018, up 7.3 percent compared with 2017. According to company leaders, ProQuad (a pediatric combination vaccine to help protect against measles, mumps, rubella and varicella) growth was driven primarily by higher volumes and pricing in the United States and volume growth in certain European markets. M-M-R II (a vaccine to help protect against measles, mumps, and rubella) growth was driven primarily by volume growth in Latin America. Varivax (a vaccine to help prevent chickenpox) sales in 2018 were flat compared with the previous year, reflecting volume growth in Latin America and the Asia Pacific region along with higher pricing in the United States offset by volume declines in Turkey from the loss of a government tender due to competition. In the first half of 2019 sales of ProQuad, M-M-R II and Varivax rose an impressive 43.2 percent to $1.17 billion.
Global sales of Bridion – for the reversal of two types of neuromuscular blocking agents used during surgery – were $917 million in 2018, representing growth of 30.3 percent, driven primarily by volume growth in the United States and certain European markets. Bridion looks to cross the $1 billion barrier in 2019 with first-half sales of $533 million, an improvement of 20 percent over the first six months of 2018.
Sales of the vaginal contraceptive product NuvaRing amounted to $902 million in 2018, an increase of 18.5 percent compared with 2017. Sales growth was driven primarily by higher U.S. pricing. The patent that provided U.S. market exclusivity for NuvaRing expired in April 2018, so Merck executives are anticipating a significant decline in U.S. NuvaRing sales as a result of generic competition. In the first half of 2019, NuvaRing sales edged up 1.5 percent to $459 million.
Acquisitions and partnerships
In February, Merck announced an agreement to acquire Immune Design for $5.85 per share in cash for a total of about $300 million. The deal duly closed in April. Immune Design is a late-stage immunotherapy company employing next-generation in vivo approaches to enable the body’s immune system to fight disease. The company’s proprietary technologies, GLAAS and ZVex, are engineered to activate the immune system’s natural ability to generate and/or expand antigen-specific cytotoxic immune cells to fight cancer and other chronic diseases.
“Scientists at Immune Design have established a unique portfolio of approaches to cancer immunization and adjuvant systems designed to enhance the ability of a vaccine to protect against infection, which could meaningfully improve vaccine development,” says Roger M. Perlmutter, M.D., Ph.D., executive VP and president, Merck Research Laboratories. “This acquisition builds upon Merck’s industry-leading programs that harness the power of the immune system to prevent and treat disease.”
In March, Merck and NGM BioPharmaceuticals Inc. announced that Merck had exercised its option to extend the research phase of the companies’ broad, strategic collaboration for an additional two-year period from March 2020 to March 2022. The collaboration, originally announced in February 2015, is focused on discovering, developing and commercializing novel biologic therapeutics across a wide range of therapeutic areas. Under the terms of the original agreement, Merck had the option to extend the initial five-year research and early development phase of the collaboration for an additional two-year period and retains one additional two-year extension option that is exercisable in 2021.
During the two-year extension period, Merck will continue to fund NGM’s research and development efforts at similar levels to the original collaboration terms and, in lieu of the $20 million extension fee payable to NGM, Merck will make additional payments totaling up to $20 million in support of NGM’s research and development activities during the two-year extension period in 2021 and 2022.
As part of the collaboration, the companies had previously announced in January that Merck had exercised its option to license NGM313, an investigational monoclonal antibody agonist of the β-Klotho/FGFR1c receptor complex for the treatment of nonalcoholic steatohepatitis (NASH) discovered by NGM. Merck’s one-time option to license NGM313 (now renamed MK-3655) was triggered by NGM’s completion of a proof-of-concept clinical study of NGM313. Merck intends to advance MK-3655 into a Phase IIb study to evaluate the effect of MK-3655 on liver histology and glucose control in NASH patients with or without diabetes.
NGM’s fibroblast growth factor 19 (FGF19) program, including its lead clinical asset NGM282 – in Phase II studies for treating NASH – is excluded from the agreement and remains wholly owned by NGM.
Merck and NGM also announced that Merck would terminate its license to NGM’s growth differentiation factor 15 (GDF15) receptor agonist program, which is being developed for the treatment of obesity, effective May 31, 2019. As part of the original collaboration agreement, Merck received an exclusive worldwide license to NGM’s GDF15 analogs, including NGM386 and NGM395, protein variants of GDF15 with potential for once-daily and once-weekly or less frequent dosing, respectively.
In 2018, Merck completed dosing of a Phase I multiple ascending dose clinical trial evaluating NGM386 in otherwise healthy overweight/obese subjects. Preliminary data from this study indicate that while NGM386 was generally well tolerated, treatment with the drug for 28 days did not result in body weight loss relative to placebo.
Upon license termination, Merck will grant to NGM an exclusive license under Merck’s intellectual property related to the GDF15 receptor agonist program for further development and commercialization of products, subject to the payment of a low single digit royalty on any future product sales back to Merck. Merck’s decision to terminate the GDF15 program, a right stipulated in the deal, does not impact the remainder of the collaboration arrangement.
In May, Merck agreed to acquire Peloton, a clinical-stage biopharmaceutical company focused on the development of novel small molecule therapeutic candidates targeting hypoxia-inducible factor-2α (HIF-2α) for the treatment of patients with cancer and other non-oncology diseases. Peloton’s lead candidate is PT2977, a novel oral HIF-2α inhibitor in late-stage development for renal cell carcinoma. Under terms of the agreement, Merck – through a subsidiary – will acquire all outstanding shares of Peloton in exchange for an upfront payment of $1.05 billion in cash. In addition, Peloton shareholders will be eligible to receive a further $1.15 billion contingent upon successful achievement of future regulatory and sales milestones for certain candidates.
PT2977 is a potent, selective, investigational oral HIF-2α inhibitor currently being evaluated in multiple clinical studies. Specifically, PT2977 is being evaluated in a Phase II clinical trial in von Hippel-Lindau (VHL) disease-associated RCC, a Phase II clinical trial in combination with cabozantinib, a VEGFR-targeting agent, in metastatic RCC, a Phase I/II dose-escalation and dose-expansion clinical trial in patients with metastatic RCC, and an expansion arm of its Phase I/II clinical trial in glioblastoma multiforme (GBM). In cancer, HIF-2α is aberrantly activated in these diseases as a result of the inactivity of the VHL tumor suppressor. This inactivation of the VHL tumor suppressor is observed in more than 90 percent of clear cell RCC, the most common form of kidney cancer. Results from a Phase I/II study of PT2977 demonstrated favorable safety and early signs of anti-tumor activity as a monotherapy for the treatment of patients with advanced or metastatic RCC.
“This acquisition exemplifies Merck’s strategy to pursue novel therapeutic candidates based on exceptionally promising and innovative research,” Dr. Perlmutter says. “Peloton scientists have applied their unique expertise in HIF-2α biology to develop PT2977, which has already shown intriguing activity in the treatment of renal cell carcinoma. We look forward to advancing this late-stage asset as part of our broad oncology R&D program.”
In June, Merck, IBM, KPMG, and Walmart announced that the four companies had been selected by FDA to be included in a program in support of the U.S. Drug Supply Chain Security Act (DSCSA) that addresses requirements to identify, track and trace prescription medicines and vaccines distributed within the United States. The program is intended to assist drug supply chain stakeholders, including FDA, in developing the electronic, interoperable system that will identify and trace certain prescription drugs as they are distributed within the United States.
“Our supply chain strategy, planning, and logistics are built around the customers and patients we serve,” says Craig Kennedy, senior VP, Supply Chain, Merck. “Reliable and verifiable supply helps improve confidence among all the stakeholders – especially patients – while also strengthening the foundation of our business.”
The project will create a shared permissioned blockchain network that allows real-time monitoring of products. The proposed network is intended to help reduce the time needed to track and trace inventory; allow timely retrieval of reliable distribution information; increase accuracy of data shared among network members; and help determine the integrity of products in the distribution chain, including whether products are kept at the correct temperature. Blockchain is designed to establish a permanent record and may be integrated with existing supply chain and traceability systems. The pilot project is scheduled to be completed in fourth-quarter 2019, and results are expected to be published in an FDA DSCSA program report. At that time, the project’s participants will evaluate next steps.
Also in June, Merck entered into a definitive agreement to acquire Tilos Therapeutics, a privately held biopharmaceutical company developing therapeutics targeting the latent TGFβ complex for the treatment of cancer, fibrosis and autoimmune diseases. Under the terms of the agreement, Merck – through a subsidiary – will acquire all outstanding shares of Tilos for total potential consideration of up to $773 million, including an upfront payment as well as contingent milestone payments.
TGFβ is a potent cytokine believed to play an important role in the development of cancer and fibrotic diseases. TGFβ is secreted as a complex with the protein, latency-associated peptide (LAP). LAP forms a cage around TGFβ, holding the cytokine in an inactive state until it is deployed. Evidence has shown that anti-LAP antibodies block the release of TGFβ from the TGFβ-LAP complex with the potential to provide a novel therapeutic mechanism to reduce TGFβ activity.
“At Merck we continue to enhance our robust pipeline through active execution of our business development strategy,” says Dr. Dean Li, senior VP, discovery and translational medicine, Merck Research Laboratories. “Tilos has developed a compelling portfolio of candidates that employ a novel approach to modulating the potent signaling molecule TGFβ by binding to latency-associated peptide, with potential applications across a range of disease indications.”
In the pipeline
In January, FDA granted Breakthrough Therapy Designation to V114, Merck’s investigational 15-valent pneumococcal conjugate vaccine, for the prevention of invasive pneumococcal disease (IPD) caused by the vaccine serotypes in pediatric patients 6 weeks to 18 years of age.
V114 is also under development for the prevention of IPD in adults. Both indications are currently being studied in Phase III clinical trials.
FDA’s decision was informed in part by immunogenicity data from two studies. Study 005 was a Phase I/II, multicenter, randomized, double-blind study to evaluate the safety, tolerability and immunogenicity profiles of four different lots of a new formulation of V114 in healthy adults and infants. Study 008 was a proof of concept, Phase II, pediatric trial to confirm the results from Study 005 in a larger population of infants. In both studies, V114 induced an immune response in infants for two disease-causing serotypes (22F and 33F) not contained in the currently available 13-valent pneumococcal conjugate vaccine, while demonstrating non-inferiority for the serotypes contained in both vaccines.
In April, FDA granted Breakthrough Therapy Designation to Merck and AstraZeneca’s investigational MEK 1/2 inhibitor selumetinib. This designation is for the treatment of pediatric patients aged 3 years and older with neurofibromatosis type 1 (NF1) symptomatic and/or progressive, inoperable plexiform neurofibromas, a rare, incurable genetic condition. The BTD is based on Phase II data from the SPRINT trial, evaluating selumetinib as an oral monotherapy in pediatric patients, aged 3 years or older with inoperable NF1-related plexiform neurofibromas.
Selumetinib is an investigational MEK 1/2 inhibitor and potential new medicine licensed by AstraZeneca from Array BioPharma Inc. in 2003. AstraZeneca and Merck entered a co-development and co-commercialization agreement for selumetinib in 2017.
The NF1 gene provides instructions for making a protein called neurofibromin, which negatively regulates the RAS/MAPK pathway, helping to control cell growth, differentiation and survival. Mutations in the NF1 gene may result in dysregulations in RAS/RAF/MEK/ERK signaling, which can cause cells to grow, divide and copy themselves in an uncontrolled manner, and may result in tumor growth. Selumetinib inhibits the MEK enzyme in this pathway, potentially leading to inhibition of tumor growth. Selumetinib is being assessed as a monotherapy and in combination with other treatments in ongoing trials. The compound was granted Orphan Drug Designation for the treatment of NF1 by FDA in February 2018 and by the European Medicines Agency in August 2018.
In July, Merck announced results from a Phase IIb clinical trial evaluating the efficacy, tolerability and safety of islatravir (MK-8591), the company’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), for the treatment of HIV-1. The study evaluated three oral, once-daily doses of islatravir initially for 24 weeks in combination with Merck’s doravirine (a nonnucleoside reverse transcriptase inhibitor [NNRTI]) plus lamivudine (3TC, 300 milligrams), and then for a further 24 weeks in combination with doravirine, compared to Delstrigo (doravirine 100 milligrams/3TC 300 milligrams/tenofovir disoproxil fumarate 300 milligrams) in adults with HIV-1 infection who had not previously received antiretroviral treatment. At all dose levels, the combination of islatravir and doravirine maintained antiviral activity as measured by the number of study participants achieving HIV-1 RNA levels <50 copies/mL, similar to Delstrigo at Week 48 of the study.
In this international, multicenter clinical trial, adult participants with HIV-1 infection who had not previously received antiretroviral therapy were randomly assigned (1:1:1:1) to one of four once-daily treatment groups: islatravir 0.25 milligrams, 0.75 milligrams, or 2.25 milligrams in combination with doravirine (100 milligrams) and 3TC (300 milligrams) compared to Delstrigo. After a minimum of 24 weeks of treatment, participants in the islatravir treatment groups with HIV-1 RNA levels less than 50 copies/mL who had not met any protocol defined virologic failure (PDVF) criteria were transitioned to a two-drug regimen consisting of the same dose of islatravir plus doravirine (100 milligrams), without 3TC.
Results showed that the participants who received islatravir in combination with doravirine plus 3TC for 24 weeks, and switched to islatravir in combination with doravirine, demonstrated efficacy at Week 48 as measured by HIV-1 RNA <50 copies/mL, similar to Delstrigo (FDA snapshot approach). The antiretroviral activity observed at Week 48 was consistent with study findings at Week 24, showing comparable antiviral activity for all islatravir treatment groups versus Delstrigo, regardless of HIV-1 RNA level at baseline. The Phase IIb study continues with additional measures to be taken at Week 96 and beyond. Based on these data, Merck plans to initiate a Phase III program evaluating islatravir in combination with doravirine across diverse patient populations to address the evolving needs of people living with HIV-1.
Also in July, FDA approved Merck’s Recarbrio (imipenem, cilastatin, and relebactam) for injection, 1.25 grams, a new combination antibacterial. Recarbrio is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
Recarbrio is also indicated in patients 18 years of age or older who have limited or no alternative treatment options, for treating complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis, and Pseudomonas aeruginosa.
Recarbrio is a combination of imipenem/cilastatin and relebactam. Imipenem is a penem antibacterial drug, cilastatin sodium is a renal dehydropeptidase inhibitor, and relebactam is a beta lactamase inhibitor. Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity.
The bactericidal activity of imipenem results from binding to PBP 2 and PBP 1B in Enterobacteriaceae and Pseudomonas aeruginosa and the subsequent inhibition of penicillin binding proteins (PBPs). Inhibition of PBPs leads to the disruption of bacterial cell wall synthesis.
Imipenem is stable in the presence of some beta lactamases. Relebactam has no intrinsic antibacterial activity. Relebactam protects imipenem from degradation by certain serine beta lactamases such as Sulhydryl Variable (SHV), Temoneira (TEM), Cefotaximase-Munich (CTX-M), Enterobacter cloacae P99 (P99), Pseudomonas -derived cephalosporinase (PDC), and Klebsiella-pneumoniae carbapenemase (KPC).
In September, FDA accepted the Biologics License Application and granted priority review for Merck’s investigational Ebola vaccine V920, under review for the prevention of disease caused by the Ebola Zaire virus. The Prescription Drug User Fee Act date is set for March 14, 2020. In July 2016, FDA granted Breakthrough Therapy Designation to V920.
In parallel to its regulatory efforts, Merck has continued to scale up the number of investigational V920 Ebola vaccine doses being produced to help international public health officials and government authorities meet ongoing, unpredictable, and evolving outbreak response needs in the Democratic Republic of the Congo and neighboring countries.
Since May 2018, Merck has donated and shipped more than 245,000 1.0mL investigational V920 Ebola vaccine doses to the World Health Organization in response to requests by the WHO. Beyond doses already delivered, more than 190,000 additional 1.0mL investigational doses are available and ready to ship to the outbreak region at WHO’s request.
In addition, in June 2019, Merck started executing an updated replenishment strategy to increase investigational V920 Ebola vaccine supply, based on ongoing consultations with the U.S. Department of Health and Human Services, WHO and Gavi (the Vaccine Alliance).
The strategy targets production of an additional estimated 650,000 1.0mL investigational doses, to be released and made available in a phased manner over the next 6-to-18 months. In total, Merck executives project that past, current and upcoming production will amount to more than 900,000 1.0mL investigational doses of V920.
Also in September, FDA approved supplemental New Drug Applications for Pifeltro (in combination with other antiretroviral agents) and Delstrigo (as a complete regimen) that expand their indications to include adult patients with HIV-1 infection who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to Pifeltro or the individual components of Delstrigo.
Pifeltro (doravirine, 100 milligrams) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral agents.
The once-daily, fixed-dose tablet Delstrigo combines doravirine (100 milligrams), lamivudine (3TC, 300 milligrams) and tenofovir disoproxil fumarate (TDF, 300 milligrams). Pifeltro and Delstrigo were approved by FDA in August 2018 for treating HIV-1 infection in adults with no prior antiretroviral treatment history.
FDA’s approval of the sNDAs of Pifeltro and Delstrigo was based on findings from the Phase III DRIVE-SHIFT trial evaluating a switch to Delstrigo in virologically suppressed participants (HIV-1 RNA <50 copies/mL) on a baseline regimen for at least six months prior to trial entry with no history of virologic failure.
The baseline regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI.
In DRIVE-SHIFT, 670 participants were randomized to begin treatment with DELSTRIGO immediately on Day 1 (immediate switch group, ISG) or after 24 weeks (delayed switch group, DSG). In the trial, the primary efficacy comparison was between the Delstrigo ISG at Week 48 and the baseline regimen DSG at Week 24. Two percent in the Delstrigo ISG had HIV-1 RNA ≥50 copies/mL at Week 48 compared to 1 percent in the baseline regimen DSG at Week 24.
In addition, 91 percent of participants who switched to Delstrigo on Day 1 (ISG) had HIV-1 RNA <50 copies/mL at Week 48. Ninety-five percent of participants who continued on their baseline regimen (DSG) had HIV-1 RNA <50 copies/mL at Week 24. At Week 24, participants who switched to Delstrigo on Day 1 showed statistically significant differences in changes from baseline in fasting LDL-cholesterol and non-HDL-cholesterol compared to those who continued on a boosted protease inhibitor regimen.