Company sees a filing pathway for approval in acute medically ill

MUNICH, Germany I August 27, 2018 I The Janssen Pharmaceutical Companies of Johnson & Johnson today announced the results of the Phase 3 MARINER and COMMANDER HF (heart failure) studies, which were presented this week at the European Society of Cardiology (ESC) Congress 2018 and simultaneously published in The New England Journal of Medicine. In both studies, there was no significant difference found between XARELTO® (rivaroxaban) and placebo for the primary efficacy endpoints. XARELTO® did, however, demonstrate a consistent safety profile.

MARINER demonstrated that XARELTO® did not reduce the composite endpoint of venous thromboembolism (VTE), or blood clots, and VTE-related death in acute medically ill patients following hospital discharge. However, XARELTO® did significantly reduce VTE with consistent safety, reinforcing the medicine’s positive benefit-risk profile. An earlier clinical trial (MAGELLAN) evaluated the use of XARELTO® in the same population of acute medically ill patients as in MARINER.

“Beyond the three already approved VTE indications for XARELTO®, the combination of results from MARINER and MAGELLAN tell a more complete story about its role in preventing VTE in appropriate acute medically ill patients, both in-hospital and post-discharge,” said James List, M.D., Ph.D., Global Therapeutic Area Head, Cardiovascular & Metabolism, Janssen Research & Development, LLC. “We see a filing pathway towards approval with these combined findings and look forward to discussing them with the U.S. Food and Drug Administration (FDA).”

In COMMANDER HF, XARELTO® did not impact overall mortality outcomes compared to standard of care. However, there were numerically fewer heart attacks and strokes with XARELTO® in sick patients with significant coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF) who experienced a recent episode of acute decompensated heart failure (ADHF). These results suggest that the high death rate in these patients is primarily driven by poor heart function, and not thrombotic events.

The MARINER and COMMANDER HF studies are part of XARELTO®’s differentiated and industry-leading clinical development program EXPLORER, which evaluates the potential role of XARELTO® in treating a wide range of critical medical needs.

“We initiated the EXPLORER program to understand the full potential of XARELTO®. We’ve already filed an application to the FDA for two new indications based on the COMPASS trial, which stopped a year early for efficacy, and we look forward to sharing data from the upcoming CASSINI and VOYAGER PAD studies,” said Dr. List. “XARELTO® has been approved for a variety of indications and prescribed more than 42 million times worldwide since its launch. Building off this strong foundation, these findings from the COMMANDER HF and MARINER trials will help the scientific community better understand the underlying role of thrombosis in morbidity and mortality across many different disease states.”

Johnson & Johnson will conduct a conference call with investors to discuss this news release today, August 27, 2018 at 8 a.m. Eastern Time.

MARINER Results
In the study, researchers found no significant difference between XARELTO® and placebo for the primary efficacy endpoint, which was a composite of VTE and VTE-related death (0.83% for XARELTO® vs. 1.1% for placebo; HR=0.76; 95% CI, 0.52-1.09; p=0.136). However, when examining VTE only, fewer VTE events were observed with XARELTO® (0.18% vs. 0.42%; HR=0.44; 95% CI, 0.22-0.89; p=0.023). Fewer events were also observed with XARELTO® in the exploratory secondary composite endpoint of symptomatic VTE and all-cause mortality (1.3% vs. 1.78%; HR=0.73; 95% CI, 0.54-0.97; p=0.033). Major bleeding occurred infrequently and was not significantly different between XARELTO® and placebo (0.28% vs. 0.15%; HR=1.88; 95% CI, 0.84-4.23; p=0.124), though the study was not powered to detect differences in this measure; however, non-major clinically relevant bleeding was higher in the XARELTO® group (1.42% vs. 0.85%; HR=1.66; 95% CI, 1.17-2.35; p=0.004).

“Acute medically ill patients discharged from the hospital are at risk of VTE up to six weeks after hospital discharge, even though these events are largely preventable,” said Alex C. Spyropoulos[i], M.D., Professor of Medicine, The Donald and Barbara Zucker School of Medicine, Northwell Health at Lenox Hill Hospital, New York, NY. “Exploratory analyses of symptomatic VTE in the MARINER study, which included non-fatal pulmonary embolism (PE), suggest a benefit with rivaroxaban. Given the very low rates of major bleeding with rivaroxaban, these overall findings give us important insight into the optimization of treatment strategies for preventing VTE in acute medically ill people once they leave the monitored care of a hospital.”

COMMANDER HF Results

The COMMANDER HF study evaluated XARELTO® in reducing the risk of heart attack, stroke and death after an episode of ADHF in patients who have had symptomatic HF for at least three months. In the study, researchers found no significant difference in the primary efficacy endpoint, which was a composite of heart attack, stroke and all-cause death, between XARELTO® plus standard of care compared to standard of care alone (25% vs. 26.2%; HR=0.94; 95% CI, 0.84-1.05; p=0.270). However, patients taking XARELTO® were observed to have numerically fewer heart attacks (3.9% vs. 4.7%; HR=0.83; 95% CI, 0.63-1.08; p=0.165) and strokes (2.0% vs. 3.0%; HR=0.66; 95% CI, 0.47-0.95; p=0.023) compared to standard of care alone.

Importantly, the composite endpoint was driven primarily by all-cause death, which comprised 80 percent of the primary endpoint in both groups. In addition, fatal bleeding or bleeding into a critical space (like an organ) was similar between the two groups (0.7% vs. 0.9%; HR=0.80; 95% CI, 0.43-1.49; p=0.484), but non-major clinically relevant bleeding was higher in the XARELTO® group (3.3% vs. 2.0%; HR=1.68; 95% CI, 1.18-2.39; p=0.003).

“Given the high mortality rates after an episode of worsening heart failure, we explored whether reducing thrombotic events through anticoagulation would lead to better overall outcomes for patients compared to standard of care alone,” said Faiez Zannadii, M.D., Ph.D., FESC, Professor of Therapeutics and Cardiology, Inserm Clinical investigation center, CHU and University de Lorraine, Nancy, France. “COMMANDER HF demonstrated that rivaroxaban did not impact overall mortality outcomes, suggesting the high death rate in these very sick patients is primarily driven by poor heart function and not thrombotic events.”

About MARINER
Sponsored by Janssen, MARINER was a randomized, double-blind, placebo-controlled study in acute medically ill patients. “Acute medically ill” is a broad term that describes people who are hospitalized for serious yet common medical conditions, such as HF, infectious diseases or ischemic stroke. These patients are at increased risk for VTE, both during their hospital stay and for up to three months after discharge. In fact, 67 percent of recently hospitalized patients who develop a VTE do so within one month of discharge.[ii] Evidence-based guidelines currently recommend that people at risk of VTE receive anticoagulants in the hospital, but advise against routine anticoagulant use beyond the hospital stay.

The study was conducted at 671 centers in 36 countries. A total of 12,019 patients were randomized in a 1:1 ratio, with one group receiving XARELTO® (n=6,007) and the other group receiving placebo (n=6,012), beginning at the time of hospital discharge and continuing for 45 days. For patients receiving XARELTO®, those with normal or mildly impaired renal function (CrCl ≥50 ml/min) received 10 mg once daily; those with moderate renal impairment (CrCl ≥30 ml/min and <50 ml/min) received 7.5 mg once daily. Patients with moderate renal impairment comprised 18 percent of the total population.

To be eligible, patients had to be 40 years of age or older and hospitalized between three and 10 days for serious medical conditions, including HF, chronic obstructive pulmonary disease (COPD), acute ischemic stroke, acute infectious diseases, or inflammatory diseases, including rheumatic disease. Patients also needed to be at increased risk of VTE, as determined by an IMPROVE VTE (International Medical Prevention Registry On Venous Thromboembolism) risk score of four or more, or by an IMPROVE VTE risk score of two or three plus a plasma D-dimer level of more than twice the upper limit of normal. Patients with medical conditions requiring anticoagulants, or a history of recent bleeding or high risk of bleeding due to concomitant conditions, drugs or procedures, were excluded from the study.

Mean age of study participants was 69.7 years. Randomization occurred on the same day or the day after hospital discharge. All participants were seen in person on days 21 and 45, and contact also was made on day seven with a final contact on day 75. The primary efficacy endpoint was the composite of all symptomatic VTE events, including lower extremity deep vein thrombosis (DVT), non-fatal PE, and VTE-related death. The primary safety endpoint was major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) bleeding criteria.

Since superiority was not established in the primary composite efficacy analysis, the prespecified secondary efficacy outcomes were assessed as exploratory analyses. Secondary efficacy endpoints included: VTE-related death; symptomatic VTE; composite of symptomatic VTE and all-cause death; composite of symptomatic VTE, heart attack, non-hemorrhagic stroke and cardiovascular (CV) death; and all-cause mortality. Other safety outcomes were non-major clinically relevant bleeding and other bleeding.

About MAGELLAN
Prior to MARINER, Janssen evaluated the use of XARELTO® 10 mg in preventing VTE in a similar population of acute medically ill patients, starting with their hospital stay and continuing through post-hospital discharge. This earlier Phase 3 trial met its two co-primary endpoints, with XARELTO® demonstrating non-inferiority to enoxaparin in short-term use (10 ± 4 days) and superiority in long-term use (35 ± 4 days) compared to short-term use of enoxaparin followed by placebo. The combined rates of major and non-major clinically relevant bleeding were higher in those treated with XARELTO®.

About COMMANDER HF
Sponsored by Janssen, COMMANDER HF was an international, prospective, multi-center, randomized, double-blind, placebo-controlled, event-driven study. Conducted at 628 sites in 32 countries, this study is the first randomized trial to explore the role of a Factor Xa inhibitor in patients with HF. Patients with significant valvular heart disease or atrial fibrillation before randomization were excluded.

Approximately 6.5 million Americans have HF, and this number is expected to increase. Hospitalization is very common after HF diagnosis, with research showing 83 percent of patients hospitalized at least once and 43 percent hospitalized at least four times. Mortality rates after hospitalization for HF are 10.4 percent, 22 percent and 42.3 percent at 30 days, one year and five years, respectively.[iii]

The study enrolled 5,022 patients after they were hospitalized for ADHF. Patients were randomized in a 1:1 ratio, with one group (n=2,507) receiving XARELTO® 2.5 mg twice daily plus standard of care and the other group (n=2,515) receiving placebo plus standard of care. Standard of care was at the treating physician’s discretion and could include aspirin or dual antiplatelet therapy.

To be eligible, participants over the age of 18 had to be treated for an episode of ADHF – also known as worsening heart failure – requiring intravenous diuretics or hospitalization within the previous 21 days. They also had to have symptomatic HF for at least three months, significant CAD and a LVEF of less than 40 percent. LVEF measures the amount of blood that is pumped out of the left ventricle with each heartbeat, with normal levels ranging from 55-70 percent. Patients receiving anticoagulation for other chronic conditions were also excluded.

The mean age of study participants was 66.4 years. The majority of patients had concomitant conditions, with approximately 75.7 percent having a history of heart attack, 75.3 percent having hypertension and 40.9 percent having a history of diabetes. All patients were seen at randomization (day 1), weeks four and 12, and every 12 weeks after that, with a final visit within 30 days before the end of the trial.

The primary efficacy endpoint was the composite of heart attack, stroke and all-cause death. The primary safety endpoint was the composite of fatal bleeding or bleeding into a critical space with potential for permanent disability. Secondary efficacy endpoints included the composite of CV death and rehospitalization for ADHF, as well as the separate outcomes of CV death, rehospitalization for ADHF, and rehospitalization for CV events. Additional safety endpoints included bleeding events requiring hospitalization and major bleeding events according to ISTH bleeding criteria.
About EXPLORER

MARINER and COMMANDER HF are both part of the EXPLORER clinical research program for XARELTO®. A collaborative effort between Janssen and its development partner Bayer, EXPLORER generates important clinical evidence on the safety and efficacy of XARELTO®. Many studies in the program are designed to seek additional indications or expand the label for XARELTO® to benefit more patients in need of therapies for their CV disease. By the time of its completion, more than 275,000 patients will have participated in the EXPLORER program, other completed and ongoing clinical trials, investigative registries and non-interventional studies.

Johnson & Johnson to Host Investor Conference Call
A conference call and simultaneous webcast for investors and other interested parties may be accessed by visiting the Johnson & Johnson website at www.investor.jnj.com. A replay and podcast will be available approximately three hours after the live webcast by visiting www.investor.jnj.com.

WHAT IS XARELTO®?

XARELTO® (rivaroxaban) is a prescription medicine used to reduce the risk of stroke and blood clots in people with atrial fibrillation not caused by a heart valve problem. For patients currently well managed on warfarin, there is limited information on how XARELTO® and warfarin compare in reducing the risk of stroke.

XARELTO® is also a prescription medicine used to treat deep vein thrombosis (DVT) and pulmonary embolism (PE), and to reduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE after receiving treatment for blood clots for at least 6 months.

XARELTO® is also a prescription medicine used to reduce the risk of forming a blood clot in the legs and lungs of people who have just had knee or hip replacement surgery.

Please click here for full Prescribing Information, including Boxed Warnings, and Medication Guide.

Trademarks are those of their respective owners. Janssen and Bayer together are developing rivaroxaban.

For more information about XARELTO®, visit www.xarelto.com.

About the Janssen Pharmaceutical Companies

At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science.

We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com. Follow us on Twitter at @JanssenUS and @JanssenGlobal. Janssen Research & Development, LLC is part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

[i] Dr. Alex C. Spyropoulos and Dr. Faiez Zannad worked directly with Janssen R&D and were compensated for their work on the MARINER and COMMANDER HF studies, respectively.
[ii] Spencer FA, Lessard D, et al. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007;167(14):1471-75.

[iii] Benjamin EJ, Virani SS, et al. Heart disease and stroke statistics—2018 update: a report from the American Heart Association. Circulation. 2018;137:e67-e492.

SOURCE: Janssen