Sandoz Delivers Positive Results For Proposed Biosimilars Adalimumab And Etanercept

• Sandoz proposed biosimilar adalimumab matched reference biologic for safety, efficacy, and immunogenicity in patients with moderate-to-severe rheumatoid arthritis at 24 weeks
• Switching from reference medicine to Erelzi (biosimilar etanercept) did not impact efficacy and safety in patients with moderate to severe rheumatoid arthritis at 48 weeks
• Sandoz is the pioneer and global leader in biosimilars, with seven approved biosimilars worldwide – more than any other company

Sandoz, a Novartis division and the pioneer and global leader in biosimilars, announced Phase III data confirming that Sandoz proposed biosimilar adalimumab matched the reference biologic in terms of safety, efficacy and immunogenicity in patients with moderate-to-severe rheumatoid arthritis at 24 weeks.

The study met the primary endpoint of change in Disease Activity Score-28 including high-sensitivity C-reactive protein (DAS28-CRP) from baseline at week 12, and confirmed the therapeutic equivalence of Sandoz proposed biosimilar adalimumab. Sandoz presented the results at the American College of Rheumatology (ACR) Annual Meeting in Chicago, IL^[1].

Rheumatoid arthritis is among the most common types of arthritis, affecting nearly 1.3 million adults in the United States (US),^[2],[3]. This is a severe, long-lasting inflammatory disease that not only affects a person’s joints, but can also damage the heart, lungs and blood vessels^[4].

“We are passionate about developing biosimilar medicines that help patients overcome the most frustrating aspects of autoimmune conditions like rheumatoid arthritis,” said Carlos Sattler, Vice President, Clinical Development and Medical Affairs, North America. “Data from the ADMYRA and EQUIRA trials support the value of our research efforts, because these studies confirm that our proposed biosimilar adalimumab and Erelzi have the potential to help US patients get back to living their lives.”

In addition to the ADMYRA trial, data for biosimilar Erelzi (etanercept) was presented at ACR in a poster titled, “Phase 3 EQUIRA 48 Week Study Results Demonstrated no impact on Efficacy and Safety when Patients with Moderate-to-Severe Rheumatoid Arthritis were Switched between Reference Etanercept (ETN) and GP2015, an Etanercept Biosimilar.” The efficacy of Sandoz biosimilar etanercept over 48 weeks was comparable to that of reference etanercept and switching to Sandoz etanercept did not impact efficacy and safety in patients with moderate-to-severe rheumatoid arthritis^[5].

Sandoz has been producing high-quality biologic medicines for more than 30 years, with nearly two decades of developing biosimilars. Sandoz believes that biosimilars have the potential to save resources for over-burdened healthcare systems, while delivering the same efficacy and safety that patients and physicians trust and rely upon from reference biologics.

About The Biosimilar Adalimumab Research: “A Randomized, Double-Blind, Parallel-Group, Multicenter Study To Compare The Efficacy, Safety And Immunogenicity Of A Proposed Adalimumab Biosimilar (GP2017) With Reference Adalimumab In Patients With Moderate-To-Severe Active Rheumatoid Arthritis”

The Phase III ADMYRA trial compared the efficacy and safety of Sandoz proposed biosimilar adalimumab and reference adalimumab in patients with inadequate response to disease modifying anti-rheumatic drugs (DMARDs), including methotrexate up to Week 48.^[6],[7].

Three-hundred and fifty-three eligible patients were randomized 1:1 to receive 40mg subcutaneous Sandoz proposed biosimilar adalimumab or reference adalimumab biweekly until Week 22. Researchers confirmed therapeutic equivalence if the 95% confidence intervals for the difference in DAS28-CRP change from baseline at Week 12 between Sandoz proposed biosimilar adalimumab and reference adalimumab (∆=0.02; 95% CI: -0.24, 0.27) were completely contained within the predefined equivalence margin of [-0.6,0.6]. Mean change from baseline at Week 12 in DAS28-CRP was -2.16 for Sandoz proposed biosimilar adalimumab (n=140) and -2.18 for reference adalimumab (n=144). Key secondary endpoints included time-weighted averaged change in DAS28-CRP from baseline to Week 24, other efficacy secondary endpoints included ACR 20/50/70 response rates, quality of life as well as safety and immunogenicity¹.

Most treatment emergent adverse events (TEAEs) were mild or moderate in severity. Infections and infestations were the most common TEAEs, reported by 35.6% and 36.9% of patients in the Sandoz proposed biosimilar adalimumab and reference adalimumab groups, respectively^1,2.

Mild viral upper respiratory tract infections were reported by 14.7% and 9.1% of patients in the Sandoz proposed biosimilar adalimumab and reference adalimumab groups, respectively. Injection site reactions occurred in 7 (4.0%) and 11 (6.3%) patients receiving Sandoz biosimilar adalimumab and reference adalimumab groups. From baseline to Week 24, antidrug antibodies were detected in 21.8% and 24.4% of patients treated with Sandoz proposed biosimilar adalimumab and reference adalimumab, of which >70% in both groups were neutralizing.

About The Erelzi (Etanercept) Research: “Phase 3 EQUIRA 48 Week Study Results Demonstrated no Impact on Efficacy and Safety When Patients with Moderate-to-Severe Rheumatoid Arthritis Were Switched between Reference Etanercept (ETN) and GP2015, an Etanercept Biosimilar”

The objective of this 48-week, randomized, Phase III, double-blind, dual-treatment period confirmatory study was to compare the efficacy and safety of Sandoz etanercept and reference etanercept, evaluating the effects of switching to Sandoz etanercept in patients with moderate-to-severe rheumatoid arthritis. The study met the primary endpoint of equivalent change from baseline in DAS28-CRP at Week 24.

Adult patients with active rheumatoid arthritis (ACR 1987 or ACR/EULAR 2010 criteria for ≥ 6 months before baseline and active disease defined as DAS28-CRP ≥3.2 and CRP >5 mg/L or ESR ≥28 mm/h) and inadequate response to methotrexate were randomized 1:1 to 50mg Sandoz etanercept or reference etanercept, subcutaneously and once weekly, for 24 weeks. Patients with at least moderate EULAR response at Week 24 either continued treatment with Sandoz etanercept or, in the reference etanercept group, were switched to receive 50mg of Sandoz etanercept up to 48 weeks – these patients formed part of the second treatment period.

Baseline characteristics were comparable between the Sandoz etanercept (n=186) and reference etanercept (n=190) groups. The primary endpoint for equivalence during the first treatment period was met. At Week 48, ACR 20 response rates were comparable between patients who continued on or switched to Sandoz etanercept. In the second treatment phase, TEAS were observed in in 42.9% versus 38.0% patients, and 13.1 vs. 11.2 were classified as drug related in patients treated with Sandoz etanercept (n=175) compared to the switched (n=166) groups. Serious adverse events (AEs) occurred in 2.3% versus 2.4% patients^[8].

About Biosimilar Adalimumab
The active ingredient, adalimumab, is an inhibitor of tumor necrosis factor (TNF), a protein that is overproduced in certain autoimmune conditions-including rheumatoid arthritis, plaque psoriasis, Crohn's disease and ulcerative colitis-causing inflammation and tissue destruction in joints, mucosa or skin. In some cases of autoimmune disease, the immune system damages the body's own tissues. Adalimumab can be a potentially appropriate treatment option for certain patients across a variety of indications. Adalimumab works by targeting and blocking the protein that contributes to disease symptoms.

The US Food and Drug Administration accepted the Biologics License Application submitted under the 351(k) pathway for Sandoz proposed biosimilar adalimumab. The European Commission granted marketing authorization to biosimilar adalimumab under the brand name Hyrimoz on July 26, 2018. The EC granted approval for use in all indications of the reference medicine, including rheumatoid arthritis, plaque psoriasis, Crohn's disease, uveitis and ulcerative colitis.

About Erelzi
Erelzi is the Sandoz biosimilar of the reference medicine, Enbrel. Erelzi has been studied in a global development program, which included a comprehensive comparison of Erelzi and Enbrel at the analytical, preclinical, and clinical levels.

Erelzi Important Safety Information
What is the most important information I should know about ERELZI? ERELZI is a medicine that affects your immune system. ERELZI can lower the ability of your immune system to fight infections. Serious infections have happened in patients taking ERELZI. These infections include tuberculosis (TB) and infections caused by viruses, bacteria or other opportunistic pathogens that have spread throughout the body. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Some patients have died from these infections. Your doctor should test you for TB before you take ERELZI and monitor you closely for TB before, during, and after ERELZI treatment, even if you have tested negative for TB.

Treatment with ERELZI should not be initiated in patients with an active infection, including clinically important localized infections. Patients have frequently presented with disseminated rather than localized disease. There have been some cases of unusual cancers reported in children and teenage patients who started using tumor necrosis factor (TNF) blockers before 18 years of age. Also, for children, teenagers, and adults taking TNF blockers, including ERELZI, the chances of getting lymphoma, leukemia, melanoma, non-melanoma skin cancer or other cancers may increase. Patients with RA may be more likely to get lymphoma.

Before Starting ERELZI, Tell Your Doctor If You:

• Have any existing medical conditions
• Are taking any medicines, including herbals
• Think you have, are being treated for, have signs of, or are prone to infection. You should not start taking ERELZI if you have any kind of infection, unless your doctor says it is okay
• Have any open cuts or sores
• Have diabetes, HIV, or a weak immune system
• Have TB or have been in close contact with someone who has had TB
• Were born in, lived in, or traveled to countries where there is more risk for getting TB. Ask your doctor if you are not sure
• Live, have lived in, or traveled to certain parts of the country (such as, the Ohio and Mississippi River valleys, or the Southwest) where there is a greater risk for certain kinds of fungal infections, such as histoplasmosis. These infections may develop or become more severe if you take ERELZI. If you don't know if these infections are common in the areas you've been to, ask your doctor
• Have or have had hepatitis B
• Have or have had heart failure
• Develop symptoms such as persistent fever, bruising, bleeding, or paleness while taking ERELZI
• Use the medicine Kineret (anakinra), Orencia (abatacept), or Cytoxan (cyclophosphamide)
• Are taking anti-diabetic medicines
• Have, have had, or develop a serious nervous disorder, seizures, any numbness or tingling, or a disease that affects your nervous system such as multiple sclerosis or Guillain-Barré syndrome
• Are scheduled to have surgery
• Have recently received or are scheduled for any vaccines.
• Are allergic to rubber or latex
• Are pregnant, planning to become pregnant, or breastfeeding
• Have been around someone with chicken pox
• Have moderate to severe alcoholic hepatitis

What are the possible side effects of ERELZI?
ERELZI can cause serious side effects including: New infections or worsening of infections you already have; hepatitis B can become active if you already have had it; nervous system problems, such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes; blood problems (some fatal); new or worsening heart failure; new or worsening psoriasis; allergic reactions; autoimmune reactions, including a lupus-like syndrome and autoimmune hepatitis. Live vaccines should not be given concurrently with ERELZI. It is recommended that pediatric patients, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating ERELZI therapy.

Common side effects include: Injection site reactions, upper respiratory infections (sinus infections), and headache. In a medical study of patients with JIA, side effects were generally similar in frequency and type as those seen in adult patients. The kinds of infections reported were generally mild and similar to those usually seen in children. These are not all the side effects with ERELZI. Tell your doctor about any side effect that bothers you or does not go away. If you have any questions about this information, be sure to discuss them with your doctor. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch (link is external), or call 1-800-FDA-1088. Please see Prescribing Information (link is external) and Medication Guide (link is external).

Indications
Moderate to Severe Rheumatoid Arthritis (RA): ERELZI is indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function in patients with moderately to severely active rheumatoid arthritis. ERELZI can be taken with methotrexate or used alone.

Moderately to Severely Active Polyarticular Juvenile Idiopathic Arthritis (JIA): ERELZI is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in children ages 2 years and older.

Ankylosing Spondylitis (AS): ERELZI is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

For more information,visit https://www.ERELZI.com

About Sandoz
Sandoz is a global leader in generic pharmaceuticals and biosimilars. As a division of the Novartis Group, our purpose is to discover new ways to improve and extend people’s lives. We contribute to society’s ability to support growing healthcare needs by pioneering novel approaches to help people around the world access high-quality medicine. Our portfolio of approximately 1,000 molecules, covering all major therapeutic areas, accounted for 2017 sales of USD 10.1 billion. In 2017, our products reached well over 500 million patients. Sandoz is headquartered in Holzkirchen, in Germany’s Greater Munich area.

References
^[1]A Randomized, Double-Blind, Parallel-Group, Multicenter Study To Compare The Efficacy, Safety And Immunogenicity Of A Proposed Adalimumab Biosimilar (GP2017) With Reference Adalimumab In Patients With Moderate-To-Severe Active Rheumatoid Arthritis. Presented at the American College of Rheumatology Annual Congress 2018.

^[2]American College of Rheumatology. Prevalence Statistics. Available at: https://www.rheumatology.org/Learning-Center/Statistics/Prevalence-Statistics. Accessed August 9, 2018.

^[3]Barbour KE, Helmick CG, Boring M, Brady TJ. Vital Signs: Prevalence of Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation - United States, 2013–2015. MMWR 2017; 66:246–253. DOI.

^[4]Mayo Clinic. Rheumatoid Arthritis. Available at: https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648. Accessed August 9, 2018.

^[5]Kavanaugh, A. Phase 3 Equira 48 Week Study Results Demonstrated No Impact on Efficacy and Safety When Patients with Moderate-to-Severe Rheumatoid Arthritis Were Switched between Reference Etanercept (ETN) and GP2015, an Etanercept Biosimilar. Presented at the American College of Rheumatology Annual Congress 2018.

^[6]Wiland, P. Jeka, S. Dokoupilova, E. Limón, JM. Jauch-Lembach, J. Haliduola, H. et al. A Randomized, Double-Blind, Parallel-Group, Multicenter Study To Compare The Efficacy, Safety And Immunogenicity Of A Proposed Adalimumab Biosimilar (GP2017) With Reference Adalimumab In Patients With Moderate-To-Severe Active Rheumatoid Arthritis. Abstract presented at ACR/AHRP Annual Meeting 2018.

^[7]ClinicalTrials.gov. Clinical Trial to Compare Treatment With GP2017 and Humira in Patients With Rheumatoid Arthritis (ADMYRA). Available at: https://clinicaltrials.gov/ct2/show/NCT02744755?term=ADMYRA&rank=1. Accessed September 10, 2018.

^[8]Cerinic, M. Phase 3 EQUIRA 48 week confirmatory study demonstrated no impact on efficacy and safety when patients with moderate-to-severe rheumatoid arthritis were switched between reference etanercept (ETN) and GP2015, an etanercept biosimilar. Abstract presented at ACR/AHRP Annual Meeting 2018.