Merck 2018: The $6 billion surprise
Nine years ago Keytruda was about to be out-licensed.
Now Keytruda is Merck’s top-selling medicine.
Merck & Co.
2000 Galloping Hill Road
Kenilworth, NJ 07033
|Product||2017 Sales||2016 Sales|
|Gardasil, Gardasil 9||$2,308||$2,173|
All sales are in millions of dollars.
|1H 2018||1H 2017|
All figures are in millions of dollars, except EPS.
$6 billion dollar drugs do not usually grow on trees, but they do occasionally appear under the seat cushions.
According to published reports, back in 2009 Merck’s development program for the immuno-oncologic pembrolizumab, acquired in the Schering merger, was shut down and the compound was placed on the company’s out-license list. But wiser minds prevailed, the program was restarted and eventually grew to more than 500 trials, pembrolizumab became Keytruda, and the fate of one of the world’s oldest pharmaceutical companies was transformed. Not bad for a drug that was, rumor has it, on the verge of being given away for next to nothing. And thus Merck has been able to survive a period of otherwise stagnant or falling product revenue with the company’s top line largely intact and other new products like Lynparza and Lenvima in the bullpen.
“Our inventions, including Keytruda and the hope it is providing to a growing number of patients with different cancers, show that our innovation strategy is the right one to create value for investors, patients, and other stakeholders,” says Kenneth Frazier, CEO, chairman and president of Merck. “We continue to invest significantly in research and development and believe that is the pathway to deliver urgently needed medicines and vaccines to society, which is paramount to Merck’s long-term business success.”
Merck’s top-line revenue in 2017 edged up by 0.8 percent to $40.12 billion. Net income was down 38.6 percent to $2.42 billion and EPS fell 54 cents to 87 cents, but this was impacted by one-time charges related to the formation of a joint venture with AstraZeneca and U.S. tax reform. Leaving these out of the picture, Merck executives estimate that the company’s net income would have grown by 3.8 percent. During the first half of 2018 revenue at Merck grew by 5.9 percent to $20.5 billion, though net income dropped again, by 29.9 percent to $2.46 billion, and EPS was off by 37 cents to 90 cents. Company leaders are projecting full-year 2018 EPS to fall between $2.51 and $2.59.
Sales of the type 2 diabetes drugs Januvia and Janumet fell by 3.5 percent in 2017 to a combined $5.9 billion. According to company leaders, the sales decline was driven primarily by ongoing pricing pressure partially offset by continued volume growth globally. In the first half of 2018, combined Januvia and Janumet sales rose 3.9 percent to $2.96 billion.
In June, Merck announced new data from the Comparative Trials with Sitagliptin (CompoSIT) clinical trials with Januvia. In the CompoSIT-I study, initiation of insulin therapy while continuing treatment with Januvia resulted in greater blood glucose reductions and more patients reaching A1C goal compared to those who discontinued Januvia. In the CompoSIT-R study, among patients with mild renal impairment inadequately controlled on metformin, with or without a sulfonylurea, treatment with Januvia showed non-inferiority and superiority in reducing A1C levels compared with patients treated with dapagliflozin.
In this randomized, controlled double-blind study of patients with inadequately controlled type 2 diabetes taking metformin in dual combination therapy with Januvia and initiating insulin treatment, continuing treatment with Januvia resulted in greater blood glucose reduction at week 30 compared to discontinuing Januvia, with LS mean changes from baseline A1C of -1.88 percent with Januvia and -1.42 percent with placebo, a between-group difference of -0.46 percent.
More than half of the patients (54 percent) who continued treatment with Januvia achieved the ADA target A1C goal of less than 7.0 percent, compared to 35 percent of patients who were taking insulin alone, a between-group difference of 18.8 percent. Mean change from baseline reductions in fasting plasma glucose were -84.8 mg/dL with Januvia and -78.3 mg/dL with placebo, a between-group difference of -6.5 mg/dL.
As in 2016, the most impressive performance in Merck’s portfolio in 2017 belonged to the immuno-oncologic Keytruda. Sales of Keytruda for the year were up by 171.7 percent to $3.81 billion, pushed along by volume growth in all markets, particularly in the United States, Europe, and Japan as Merck continues to launch the product with multiple new indications globally. Keytruda has supplanted the Januvia and Janumet franchise as Merck’s largest source of revenue; in the first half of 2018, sales of the anti-PD-1 immunotherapy more than doubled to $3.13 billion.
In April, Merck and the European Organization for Research and Treatment of Cancer (EORTC) announced findings from the Phase III EORTC1325/KEYNOTE-054 trial investigating Keytruda as adjuvant therapy in resected, high-risk stage III melanoma. Study results showed Keytruda significantly prolonged recurrence-free survival (RFS), reducing the risk of disease recurrence or death by 43 percent compared to placebo in the overall study population. For the primary endpoint of RFS in the overall study population, the one-year RFS rate was 75.4 percent for Keytruda compared to 61 percent for placebo. For the co-primary endpoint of RFS in patients whose tumors were considered PD-L1 positive, Keytruda demonstrated significantly prolonged RFS compared to placebo. Keytruda is the first anti-PD-1 therapy to show RFS benefit across stage IIIA (> 1 mm lymph node metastasis), IIIB and IIIC melanoma. The RFS benefit was also seen regardless of BRAF mutation status (HR=0.64 for patients with wild-type BRAF status; HR=0.57 for patients with mutant BRAF status).
Additionally in April, Merck and Incyte Corp. announced that an external Data Monitoring Committee review of the pivotal Phase III ECHO-301/KEYNOTE-252 study results evaluating Incyte’s epacadostat in combination with Keytruda in patients with unresectable or metastatic melanoma determined that the study did not meet the primary endpoint of improving progression-free survival in the overall population compared to Keytruda monotherapy. The study’s second primary endpoint of overall survival also is not expected to reach statistical significance. Based on these results, and at the recommendation of the eDMC, the study will be stopped.
In June, FDA approved Keytruda for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy. This indication was granted under the FDA’s accelerated approval regulations 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 confirmatory trials. Keytruda is the first anti-PD-1 therapy to be approved for the treatment of PMBCL, a type of non-Hodgkin lymphoma.
The approval was based on data from KEYNOTE-170, a multicenter, open-label, single-arm trial evaluating Keytruda in 53 patients with relapsed or refractory PMBCL. In KEYNOTE-170, the ORR was 45 percent, with a complete response rate (CRR) of 11 percent and a partial response rate of 34 percent. Median DOR, based on 24 patients who responded, was not reached (range, 1.1+ to 19.2+ months). For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range, 2.1 to 8.5 months). Median follow-up time was 9.7 months.
Also in June, FDA approved Keytruda for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. This indication was also approved under the FDA’s accelerated approval regulations based on tumor response rate and durability of response.
The efficacy of Keytruda was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in study KEYNOTE-158, a multi-center, non-randomized, open-label, multi-cohort trial. For the 77 patients whose tumors expressed PD-L1 with a CPS ≥1, the ORR was 14.3 percent, with a complete response rate of 2.6 percent and partial response rate of 11.7 percent.
Among the 11 responding patients, median DOR was not yet reached (range, 4.1 to 18.6+ months) and 91 percent experienced a duration of response of six months or longer. The median follow-up time was 11.7 months (range, 0.6 to 22.7 months). No responses were observed in patients whose tumors did not have PD-L1 expression.
In another June announcement, Merck reported results from KEYNOTE-042. The pivotal, Phase III study has evaluated Keytruda as monotherapy for the first-line treatment of locally advanced or metastatic nonsquamous or squamous non-small cell lung cancer (NSCLC) without EGFR or ALK genomic tumor aberrations. In this study, Keytruda monotherapy resulted in significantly longer overall survival (OS) than platinum-based chemotherapy (carboplatin plus paclitaxel or carboplatin plus pemetrexed) in patients with a PD-L1 tumor proportion score (TPS) of ≥1 percent.
For patients in the Keytruda arm of KEYNOTE-042 compared with chemotherapy, median OS was 20.0 versus 12.2 months for patients with a TPS of ≥50 percent, 17.7 versus 13.0 months for patients with a TPS of ≥20 percent, and 16.7 versus 12.1 months for the overall study population of patients with a TPS of ≥1 percent. An exploratory subgroup analysis was conducted in patients with a TPS of 1-49 percent, which showed an OS HR of 0.92. At the time of the interim analysis, Keytruda reduced disease progression or death (PFS) by 19 percent in the PD-L1 TPS ≥50 percent population, which was not statistically significant.
In another June update, Merck announced results from KEYNOTE-407, a Phase III study evaluating Keytruda in combination with carboplatin-paclitaxel or nab-paclitaxel as first-line treatment for metastatic squamous non-small cell lung cancer (sNSCLC). In this study, the Keytruda plus chemotherapy combination significantly improved OS, reducing the risk of death by 36 percent compared to chemotherapy alone. This was the first time that a combination of an anti-PD-1 therapy and chemotherapy has significantly extended overall survival in the first-line treatment of patients with squamous NSCLC.
Findings from pre-specified exploratory analyses showed an OS benefit regardless of PD-L1 expression, as follows: patients whose tumors did not express PD-L1 (HR=0.61); patients whose tumors had PD-L1 tumor proportion scores (TPS) of 1-49 percent (HR=0.57); and patients who had a TPS of greater than or equal to 50 percent (HR=0.64). The addition of Keytruda to carboplatin plus paclitaxel or nab-paclitaxel chemotherapy also significantly improved progression-free survival, with a reduction in the risk of progression or death of nearly half for patients in the Keytruda combination group, compared with chemotherapy alone (HR=0.56). A PFS improvement in the Keytruda combination group was observed in patients whose tumors did not express PD-L1 (HR=0.68); patients with a TPS of 1-49 percent (HR=0.56); and patients with a TPS greater than or equal to 50 percent (HR=0.37).
In July, Keytruda was approved by the China National Drug Administration for the treatment of adult patients with unresectable or metastatic melanoma following failure of one prior line of therapy. This was the first approval of an anti-PD-1 therapy for advanced melanoma in China. The approval of Keytruda in China was based on overall response rate (ORR) data from the Phase Ib KEYNOTE-151 study, which evaluated Keytruda monotherapy in Chinese patients with previously treated locally advanced or metastatic melanoma who received one prior line of systemic therapy. In 2018, the CNDA granted priority review status to Keytruda, which accelerated the approval process by allowing for simultaneous clinical validation for the first time – creating an industry-leading approval turnaround time for imported cancer medicine in China.
During August, FDA regulators approved an expanded label for Keytruda in combination with Eli Lilly and Co.’s Alimta (pemetrexed) and platinum chemotherapy for the first-line treatment of patients with metastatic NSCLC, with no EGFR or ALK genomic tumor aberrations, based on results of the KEYNOTE-189 trial. In the pivotal, Phase III KEYNOTE-189 study of patients regardless of PD-L1 tumor expression status, Keytruda in combination with pemetrexed and platinum chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival, reducing the risk of death by half compared to chemotherapy alone. The study additionally showed a significant improvement in progression-free survival compared to chemotherapy alone. A similar indication was approved by the European Commission during the following month.
Merck’s HPV vaccine Gardasil generated $2.31 billion in sales for the company in 2017, an improvement of 6.2 percent. According to company leaders, this result was driven primarily by higher sales in Europe resulting from the termination of the joint venture with Sanofi Pasteur that had marketed the vaccine there, as well as higher demand in Asia Pacific due in part to the launch in China, partially offset by lower sales in the United States reflecting the timing of public sector purchases. In the first half of 2018, sales of Gardasil rose 26.8 percent to $1.27 billion, with growth driven primarily by higher sales in the Asia Pacific region, particularly in China reflecting continued uptake since launch, as well as volume growth in certain European markets.
In June, FDA accepted for review a new supplemental biologics license application for Gardasil 9. The application is seeking approval for an expanded age indication for Gardasil 9 for use in women and men ages 27 to 45 for the prevention of certain cancers and diseases caused by the nine human papillomavirus (HPV) types covered by the vaccine. FDA has granted Priority Review to this sBLA and set a Prescription Drug User Fee Act date of Oct. 6, 2018.
While Zepatier’s total was not quite as impressive as Keytruda’s, the hepatitis C product actually grew faster in 2017, with sales nearly tripling to $1.66 billion. According to company leaders this performance was driven primarily by higher sales in Europe, the United States, and Japan following product launch in 2016. Competition in the hep C space caught up with Zepatier in the first half of 2018 though, with sales down 72.8 percent to $243 million.
Bridion, indicated for the reversal of two types of neuromuscular blocking agents used during surgery, enjoyed a solid year in 2017, with sales up 46.1 percent to $704 million. Growth was driven by strong global demand, particularly in the United States. This continued in the first half of 2018, with Bridion sales up another 43.2 percent to $444 million.
Collaborations and acquisitions
Merck and Viralytics Ltd. signed a definitive agreement in February under which Merck, through a subsidiary, would acquire Viralytics for AUD 1.75 cash per Viralytics share. The Australian publicly traded company has focused on oncolytic immunotherapy treatments for a range of cancers. The proposed acquisition valued the total issued shares in Viralytics at approximately AUD 502 million ($394 million). The cash consideration of AUD 1.75 per share represents a premium of 160 percent to the one month volume weighted average price of Viralytics shares.
On completion of the transaction, Viralytics will become a wholly owned subsidiary of Merck, which will gain full rights to Cavatak (CVA21). The investigational oncolytic immunotherapy is based on Viralytics’ proprietary formulation of an oncolytic virus (Coxsackievirus Type A21) that has been shown to preferentially infect and kill cancer cells.
Cavatak is being evaluated in multiple Phase I and Phase II clinical trials, both as an intratumoral and intravenous agent, including in combination with Merck’s blockbuster Keytruda. Under an agreement between Viralytics and a subsidiary of Merck, announced during November 2015, a study is investigating the use of the Cavatak and Keytruda combination in melanoma, prostate, lung, and bladder cancers.
Also in February, Merck and Ferring Pharmaceuticals announced the completion of CHAMPION (Carbetocin Hemorrhage Prevention), a global clinical trial conducted by the Human Reproduction Program (HRP) at the World Health Organization (WHO). The CHAMPION trial is studying whether Ferring’s investigational proprietary heat-stable formulation of carbetocin could offer a new solution to prevent excessive bleeding after childbirth (postpartum hemorrhage or PPH). Involving nearly 30,000 women in 10 countries, this is the largest clinical trial ever conducted in PPH. The 10 countries are Argentina, Egypt, India, Kenya, Nigeria, Singapore, South Africa, Thailand, Uganda, and the United Kingdom.
Each year, 14 million mothers are affected by PPH. As the leading direct cause of maternal mortality, 480,000 mothers died from PPH between 2003 and 2009. Even when women survive, PPH can result in the need for serious medical interventions, including surgical removal of the uterus (hysterectomy) as well as blood transfusions to address severe anemia.
The CHAMPION trial compares the effectiveness and safety of Ferring’s heat-stable carbetocin versus the current standard of care, oxytocin, for preventing PPH after vaginal birth. Oxytocin requires refrigeration during shipping and storage to prevent degradation in temperatures above 8 degrees C. Heat-stable carbetocin may remain active long-term in hot and humid climates, and in many low- and lower-middle-income countries, cold storage is difficult to achieve and maintain.
If the results of the CHAMPION trial are favorable, Ferring plans to seek registration of heat-stable carbetocin on a broad basis. If approved, Ferring would manufacture the product, which would be provided to the public sector of low- and lower-middle-income countries at an affordable and sustainable access price. Results from the study are expected to be presented and published during the second half of 2018.
In March, Merck and Eisai Co. agreed on a strategic collaboration for the worldwide joint development and joint commercialization of Lenvima (lenvatinib mesylate), an orally available tyrosine kinase inhibitor discovered by Eisai. Under the agreement, Eisai and Merck will develop and commercialize Lenvima jointly, both as monotherapy and in combination with Keytruda.
Lenvima was previously approved as monotherapy for use in the treatment of thyroid cancer, as well as in combination with everolimus for the treatment of patients with renal cell carcinoma (RCC) who have failed previous therapy.
Eisai will book Lenvima product sales globally, as monotherapy and in combination, and Merck and Eisai will share gross profits equally. Expenses incurred during co-development, including for studies evaluating Lenvima as monotherapy, will be shared equally by the two companies.
Under the agreement, Merck is responsible for a $300 million upfront payment to Eisai and up to $650 million for certain option rights through 2020, as well as $450 million as reimbursement for research and development expenses. In addition, Eisai is eligible to receive up to $385 million associated with the achievement of certain clinical and regulatory milestones and a maximum of up to $3.97 billion for the achievement of milestones associated with sales of Lenvima. Assuming the achievement of all development and commercial goals for all indications, the total amount of upfront, option and regulatory and sales milestone payments has the potential to reach up to $5.76 billion.
In May, Merck and Premier Inc., a healthcare improvement company, expanded their preventative and chronic disease care collaboration to include a new effort designed to help reduce the recurrence of Clostridium difficile infection (C. diff).
Merck and Premier will develop and test the combination of a software-based platform and a coordinator to provide surveillance, consultation, support, and education to patients with C. diff at participating Premier member health systems. The goal is to increase patient access to healthcare services, raise awareness of how to decrease patient risk of recurrence, and help patients identify if they are having a recurrence. The proposed C. diff intervention will be tested within volunteer Premier member health systems. Since 2016, Merck and Premier have been working together to co-develop and test solutions that help promote wellness and prevention for specific groups of at-risk patients.
The Centers for Disease Control and Prevention has stated that due to prolonged use of antibiotics or contact with the bacteria, C. diff infection – which causes serious and life-threatening diarrhea – has become the most common microbial cause of healthcare-associated infections in U.S. hospitals. The infection affects about half a million people and contributes to an estimated $4.8 billion in excess U.S. healthcare costs each year. Patients on antibiotics are seven to 10 times more likely to contract C. diff while on antibiotic therapy and during the month after. While the infection is treatable, one in five patients experience a recurrence.
Also in May, Merck and Moderna Inc. announced an expansion of their 2016 collaboration to develop and commercialize novel personalized messenger RNA (mRNA) cancer vaccines to include shared antigen mRNA cancer vaccines including mRNA-5671, Moderna’s mRNA KRAS cancer vaccine. Moderna developed mRNA-5671 starting in 2017. The two companies are now jointly advancing mRNA-5671 in human studies, and plan to conduct combo studies with additional immuno-oncology therapies.
Under the expanded agreement, Merck is responsible for clinical development of mRNA-5671 and associated costs while Moderna is responsible for clinical supply and associated costs. Following the completion of human proof-of-concept studies, Merck may opt-in on further development and commercialization of mRNA-5671 upon payment of an undisclosed fee to Moderna. Following opt-in, the parties will share equally the global net profits and costs associated with mRNA-5671. As part of this agreement, the parties may also initiate and collaborate on other shared antigen mRNA cancer vaccines programs. In addition, Merck will make a $125 million investment in Moderna in newly priced series H preferred equity. Moderna closed a series G round earlier this year.
This is the fourth collaboration between Merck and Moderna in the past three years. The oncology alliance builds on an initial June 2016 agreement to jointly develop personalized mRNA cancer vaccines, combining Merck’s leadership in immuno-oncology with Moderna’s mRNA vaccine platform and GMP manufacturing capabilities. Under the 2016 personal cancer vaccine agreement, Merck made an upfront cash payment to Moderna of $200 million to discover and develop individually tailored cancer vaccines for patients across a spectrum of cancers through proof of concept. In November 2017 the companies announced a key milestone with the first-in-human dosing of mRNA-4157, an mRNA PCV. The Phase I open-label, dose escalation, multicenter study in the United States (KEYNOTE-603) will assess the safety, tolerability and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with Keytruda in subjects with unresectable solid tumors.
In August, Merck and health education provider Healthy Interactions LLC announced the launch of map4health, a digital platform and mobile application in the United States designed to help facilitate and enhance communications between diabetes patients and educators. This technology was developed as an extension of the Journey for Control collaboration between Healthy Interactions and Merck and debuted at the 2018 American Association of Diabetes Educators (AADE) Annual Conference in Baltimore.
In 2007, Healthy Interactions and Merck, also in collaboration with the American Diabetes Association (ADA), launched Journey for Control – a patient-centric education initiative targeting diabetes educators and utilizing the U.S. Diabetes Conversation Map – to collaborate on developing tools focused on lifestyle and behavioral change to help healthcare providers improve diabetes management for people living with the disease.
In the pipeline
FDA regulators approved Lynparza during January for use in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor positive (HR+) breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Patients are selected for therapy based on an FDA-approved companion diagnostic from Myriad Genetics Inc.
The approval was based on data from the randomized, open-label, Phase III OlympiAD trial, which investigated Lynparza (olaparib) versus physician’s choice of chemotherapy (capecitabine, eribulin or vinorelbine). In the trial, Lynparza significantly prolonged progression-free survival compared with chemotherapy, and reduced the risk of disease progression or death by 42 percent. Patients with measurable disease taking Lynparza experienced an objective response rate of 52 percent, double the response rate for those in the chemotherapy arm, which was 23 percent. Additionally, patients experienced a confirmed complete response rate of 7.8 percent for Lynparza compared to 1.5 percent for the chemotherapy arm. This was the third U.S. approval for Lynparza, which is being developed jointly by Merck and AstraZeneca.
During February, Merck announced that the company will stop protocol 019, also known as the APECS study. The Phase III trial is evaluating verubecestat (MK-8931), an investigational small molecule inhibitor of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), in people with prodromal Alzheimer’s disease. The decision to stop the study follows a recommendation by the external Data Monitoring Committee, which assessed overall benefit/risk during a recent interim safety analysis. The eDMC concluded that it was unlikely that positive benefit/risk could be established if the trial continued.
In April, Merck announced that a pivotal Phase III study of relebactam, the company’s investigational beta-lactamase inhibitor, in combination with imipenem/cilastatin, demonstrated a favorable overall response in the treatment of certain imipenem-nonsusceptible bacterial infections, the primary endpoint, with lower treatment-emergent nephrotoxicity (kidney toxicity), a secondary endpoint, compared to a Colistin (colistimethate sodium) plus imipenem regimen. Based on these results, the company plans to submit a new drug application to FDA seeking regulatory approval of a fixed-dose combination of imipenem/cilastatin and relebactam.
RESTORE-IMI 1 was a multicenter, randomized, double-blind, comparator-controlled trial comparing the efficacy and safety of imipenem/cilastatin/relebactam (IMI/REL) versus Colistin plus imipenem/cilastatin (COL+IMI) in patients with imipenem-nonsusceptible bacterial infections. The primary endpoint of the study was favorable overall response (defined by relevant endpoints for each different infection type) in the microbiological modified intent-to-treat (mMITT) population (defined as patients having a qualifying baseline pathogen and having received at least one dose of study treatment). Secondary endpoints included favorable clinical response at Day 28, 28-day all-cause mortality, incidence of treatment-emergent nephrotoxicity, and incidence of adverse events.
In the study, 31 of 47 randomized and treated patients met mMITT criteria. Favorable overall response was comparable for the IMI/REL (71.4 percent) and COL+IMI (70 percent) treatment arms. Favorable clinical response at Day 28 was higher in the IMI/REL arm (71.4 percent) compared to the COL+IMI (40 percent) arm, and 28-day all-cause mortality was lower in the IMI/REL arm (9.5 percent) versus COL + IMI (30 percent), respectively.
Merck is conducting a second Phase III clinical study, RESTORE-IMI 2, comparing treatment with imipenem/cilastatin/relebactam, as a fixed-dose combination, versus piperacillin/tazobactam in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. The primary hypothesis of this study is that imipenem/cilastatin/relebactam is non-inferior to piperacillin/tazobactam in the incidence rate of all-cause mortality.
Also during April, Merck announced that the company is beginning two Phase III studies of PCV-15 (V114), an investigational polyvalent conjugate vaccine for the prevention of pneumococcal disease. The first study will evaluate the safety, tolerability and immunogenicity of PCV-15 followed by Pneumococcal Vaccine Polyvalent one year later in healthy adult subjects 50 years of age or older. The second study will evaluate the safety, tolerability, and immunogenicity of PCV-15 followed by Pneumococcal Vaccine Polyvalent administered eight weeks later in adults infected with human immunodeficiency virus. The decision to move PCV-15 to Phase III was based on the findings of Phase I and Phase II studies.
In May, the European Commission approved Lynparza tablets (300 milligrams twice daily) for use as a maintenance therapy for patients with platinum-sensitive relapsed high-grade, epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy, regardless of BRCA status. The EU approval was based on two randomized trials, SOLO-2 and Study 19, which showed that Lynparza reduced the risk of disease progression or death for platinum-sensitive relapsed ovarian cancer patients compared to placebo.
During June, Merck and partner developer AstraZeneca announced positive results from the randomized, double-blinded, placebo-controlled, Phase III SOLO-1 trial of Lynparza tablets.
Women with BRCA-mutated (BRCAm) advanced ovarian cancer treated first-line with Lynparza maintenance therapy had a statistically significant and clinically meaningful improvement in progression-free survival compared to placebo. The safety and tolerability profile of Lynparza was consistent with previous trials. Based upon these data, AstraZeneca and Merck plan to initiate discussions with health authorities regarding regulatory submissions. Lynparza is already indicated for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of BRCA mutation status, and for the treatment of advanced ovarian cancer patients with a gBRCA-mutation previously treated with three or more lines of chemotherapy.
That same month, Merck and AstraZeneca presented data which showed clinical improvement in median radiologic progression-free survival (rPFS) with Lynparza in combination with abiraterone compared to abiraterone monotherapy, a current standard of care, in metastatic castration-resistant prostate cancer.
Median rPFS was 13.8 months with Lynparza and abiraterone compared to 8.2 months with abiraterone alone. Median PFS2 was 23.3 months versus 18.5 months. Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone. Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients regardless of HRR status.
During August, FDA approved for marketing two new HIV-1 medicines: Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 milligrams), lamivudine (3TC, 300 milligrams), and tenofovir disoproxil fumarate (TDF, 300 milligrams); and Pifeltro (doravirine, 100 milligrams), a new non-nucleoside reverse transcriptase inhibitor to be administered in combination with other antiretroviral medicines. Both Delstrigo and Pifeltro are indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience.
The FDA approvals of Delstrigo and Pifeltro were based on findings from the pivotal, randomized, multicenter, double-blind, active controlled Phase III trials DRIVE-AHEAD and DRIVE-FORWARD, evaluating the efficacy and safety of Delstrigo and Pifeltro, respectively, in participants infected with HIV-1 with no antiretroviral treatment history.
In DRIVE-AHEAD, 728 participants with no antiretroviral treatment history were randomized and received at least one dose of either Delstrigo or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC 200 mg/TDF 300 mg) once daily. Delstrigo demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to EFV/FTC/TDF (84 percent in the Delstrigo group achieved viral suppression of HIV-1 RNA <50 copies/mL versus 81 percent in the EFV/FTC/TDF group). Of the 21 percent of study participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77 percent in the Delstrigo group and 72 percent in the EFV/FTC/TDF group achieved HIV-1 RNA <50 copies/mL at Week 48.
In DRIVE-FORWARD, 766 participants with no antiretroviral treatment history were randomized and received at least one dose of either Pifeltro once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily, each in combination with emtricitabine (FTC)/TDF or abacavir (ABC)/3TC selected by the investigator. Pifeltro demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to DRV+r, each in combination with FTC/TDF or ABC/3TC (84 percent in the Pifeltro group achieved viral suppression of HIV-1 RNA <50 copies/mL versus 80 percent in the DRV+r group). Of the 20 percent of study participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77 percent in the Pifeltro group and 74 percent in the DRV+r group achieved HIV-1 RNA <50 copies/mL at Week 48.
Also in August, FDA approved the kinase inhibitor Lenvima for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT (Study 304), where Lenvima demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival and objective response rate when compared with sorafenib in patients with previously untreated unresectable HCC.
REFLECT showed that Lenvima achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with Lenvima experienced a median OS of 13.6 months compared to 12.3 months with sorafenib. The OS analysis was conducted when 351 events had occurred in the Lenvima arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. Lenvima also showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review.
That same month, the European Commission granted a marketing authorization for Lenmiva as a single agent for the first-line treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have received no prior systemic therapy. Treatment options for this type of liver cancer are limited, and the prognosis is poor. Lenmiva is the first new, first-line treatment for advanced or unresectable HCC in a decade to show an overall survival treatment effect by statistical confirmation of non-inferiority against standard of care.
This approval was based on results from REFLECT (Study 304), an open-label, Phase III trial where Lenmiva demonstrated a treatment effect on OS by statistical confirmation of non-inferiority when compared with the standard of care, sorafenib, in 954 patients with previously untreated unresectable HCC. Lenvima also demonstrated statistically significant superiority and clinically meaningful improvements in progression-free survival and objective response rate.
In September, the China National Medical Products Administration (NMPA) approved Lenvima as a single agent for the treatment of patients with unresectable hepatocellular carcinoma who have not received prior systemic therapy. In China, the application of Lenvima was submitted in October 2017 and was designated for Priority Review by the NMPA due to Lenvima’s significant clinical benefit compared to existing treatments, leading to approval in approximately 10 months. This approval marks the first for Lenvima in China, where the incidence of HCC is high, and the only new systemic therapy approved for the first-line treatment of unresectable HCC in China in 10 years. About 780,000 new cases of liver cancer are diagnosed each year, about 80 percent of which occur in Asian regions. Lenvima is being developed jointly by Merck and Eisai.
The Lenvima marketing clearance was based on results from the REFLECT clinical study. In a subpopulation analysis of 288 patients in the study from the greater Chinese region (mainland China, Hong Kong, and Taiwan), Lenvima demonstrated efficacy based on non-inferiority of OS compared to sorafenib, with improvements also observed in PFS, TTP and ORR. About 80 percent of patients in the subpopulation were living with HCC resulting from chronic hepatitis B virus, which has high unmet medical need. For these patients, Lenvima demonstrated non-inferiority based on OS compared with sorafenib, showing the effect of Lenvima in patients with HCC resulting from HBV.
Additionally during September, Merck announced that the pivotal Phase III clinical study evaluating the company’s antibiotic Zerbaxa (ceftolozane and tazobactam) at an investigational dose for the treatment of adult patients with either ventilated hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia met the pre-specified primary endpoints, demonstrating non-inferiority to meropenem, the active comparator, in day 28 all-cause mortality and in clinical cure rate at the test-of-cure visit. In the United States, Zerbaxa is currently indicated in adult patients for the treatment of complicated urinary tract infections, including pyelonephritis, caused by certain Gram-negative microorganisms, and is indicated in combination with metronidazole in adult patients for the treatment of complicated intra-abdominal infections caused by certain Gram-negative and Gram-positive microorganisms.
Based on these results, Merck plans to submit supplemental new drug applications to FDA and the European Medicines Agency seeking regulatory approval of Zerbaxa for this potential new indication. The company plans to submit results from the study for presentation at a future scientific conference.