Efficacy and safety maintained in patients who switched from Humira^® to biosimilar Cyltezo^®

Ridgefield, Conn., November 6, 2017 – Boehringer Ingelheim today announced one-year data from VOLTAIRE^®-RA, a pivotal Phase III clinical trial comparing Cyltezo^® (adalimumab-adbm) and reference product Humira^®*. The 48-week data showed that Cyltezo is equivalent, with no clinically meaningful differences in efficacy, safety and immunogenicity to Humira in people with moderately-to-severely active rheumatoid arthritis (RA), including in patients who switched from Humira to Cyltezo at week 24.

“These data are an important addition to the robust body of evidence demonstrating Cyltezo is biosimilar to Humira,” said Karsten Kissel, MD, head of global medical affairs biosimilars at Boehringer Ingelheim. “Biosimilars have potential cost benefits to the healthcare system and support affordable access to important biologic medicines for patients living with chronic inflammatory diseases like RA.”

“In addition to the 48-week efficacy results, the adalimumab biosimilar Cyltezo showed equivalent safety and immunogenicity to Humira,” said Stanley B. Cohen, MD, Metroplex Clinical Research Center, Presbyterian Hospital, Dallas, Texas. “Consistent results were also demonstrated when patients were switched to Cyltezo from the reference product.”

These data will be presented at the American College of Rheumatology / Association of Rheumatology Health Professionals Annual Meeting in San Diego, California.

About the VOLTAIRE^® Clinical Trial Program
The VOLTAIRE^® clinical trial program comprises a number of studies aiming to demonstrate that Cyltezo is biosimilar to Humira across multiple indications. 

In the VOLTAIRE-RA study (NCT02137226), 645 patients aged between 18 and 80 years with moderately-to-severely active RA on stable treatment with methotrexate were randomized to receive Humira or Cyltezo at 40 mg every two weeks for 48 weeks. The primary objective of this clinical study was to assess equivalence in efficacy between Cyltezo and Humira in patients with active RA as measured by the proportion of patients meeting ACR20** (American College of Rheumatology 20) criteria at Week 12 and 24 compared to baseline.  At week 24, patients receiving Humira were re-randomized to switch to Cyltezo or continue on Humira until week 48 (n=148). Other objectives of this clinical study were to compare other efficacy parameters (DAS28), safety and immunogenicity of Cyltezo and Humira.

The VOLTAIRE clinical development program also includes studies in plaque psoriasis and Crohn’s disease:

• VOLTAIRE-X, an interchangeability study with Cyltezo and the U.S.-marketed formulation of Humira, 40mg/0.8mL.
• VOLTAIRE-PSO, a Phase IIIb study comparing the efficacy, safety and immunogenicity of Cyltezo versus Humira in patients with moderate to severe chronic plaque psoriasis.
• VOLTAIRE-CD, a Phase IIIb study comparing efficacy, endoscopic improvement, safety, and immunogenicity of Cyltezo versus Humira in patients with active Crohn’s disease.
• VOLTAIRE-AI, a study assessing an auto-injector presentation.

Cyltezo is not commercially available. Boehringer Ingelheim is currently engaged in patent litigation with AbbVie in the U.S.

About Boehringer Ingelheim in Biologics and Biosimilars
Boehringer Ingelheim is one of the largest producers of biologic medicines in the world. As a pioneer in biologics with more than 35 years of experience, the company has manufactured more than 25 biologic medicines for global markets. This includes monoclonal antibodies in immunology and oncology, interferons, and other targeted medicines that are routinely used to treat many patients across a broad range of therapeutic areas. For more information about Boehringer Ingelheim’s Biopharma and manufacturing capabilities, please click here https://www.boehringer-ingelheim.us/biopharma/biosimilars

Boehringer Ingelheim further builds on its commitment to immunology and oncology to develop biosimilars as high quality, safe, and effective treatment options to patients with autoimmune diseases and cancer. In addition to Cyltezo^® (adalimumab-adbm), Boehringer Ingelheim currently has BI 695502, a bevacizumab biosimilar candidate to Avastin^®* in late stage development.. All public information on our clinical trials is available on: http://clinicaltrials.gov/.

About Cyltezo^® (adalimumab-adbm) injection, for subcutaneous use
Rheumatoid Arthritis: Cyltezo is indicated, alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs), for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. 

Juvenile Idiopathic Arthritis: Cyltezo is indicated, alone or in combination with methotrexate, for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older. 

Psoriatic Arthritis: Cyltezo is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.

Ankylosing Spondylitis: Cyltezo is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Adult Crohn’s Disease: Cyltezo is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, and reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Ulcerative Colitis: Cyltezo is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of Cyltezo has not been established in patients who have lost response to or were intolerant to TNF blockers.

Plaque Psoriasis: Cyltezo is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. Cyltezo should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

IMPORTANT SAFETY INFORMATION FOR CYLTEZO^®
WARNING: SERIOUS INFECTIONS and MALIGNANCY

SERIOUS INFECTIONS

Patients treated with adalimumab products, including Cyltezo, are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Discontinue Cyltezo if a patient develops a serious infection or sepsis.

Reported infections include:

• Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before Cyltezo use and during therapy. Initiate treatment for latent TB prior to Cyltezo use.
• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with Cyltezo prior to initiating therapy in patients: 1. with chronic or recurrent infection, 2. who have been exposed to TB, 3. with a history of opportunistic infection, 4. who resided in or traveled in regions where mycoses are endemic, 5. with underlying conditions that may predispose them to infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with Cyltezo, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. 

• Do not start Cyltezo during an active infection, including localized infections.
• Patients older than 65 years, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants may be at greater risk of infection.
• If an infection develops, monitor carefully and initiate appropriate therapy.
• Drug interactions with biologic products: A higher rate of serious infections has been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. An increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no demonstrated added benefit in patients with RA. Concomitant administration of Cyltezo with other biologic DMARDS (e.g., anakinra or abatacept) or other TNF blockers is not recommended based on the possible increased risk for infections and other potential pharmacological interactions.

MALIGNANCY

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products. Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine (6-MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

• Consider the risks and benefits of TNF-blocker treatment prior to initiating or continuing therapy in a patient with known malignancy.
• In clinical trials of some TNF-blockers, including adalimumab products, more cases of malignancies were observed among TNF-blocker-treated patients compared to control patients.
• Non-melanoma skin cancer (NMSC) was reported during clinical trials for adalimumab-treated patients. Examine all patients, particularly those with a history of prolonged immunosuppressant or PUVA therapy, for the presence of NMSC prior to and during treatment with Cyltezo.
• In adalimumab clinical trials, there was an approximate 3-fold higher rate of lymphoma than expected in the general U.S. population. Patients with chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk of lymphoma than the general population, even in the absence of TNF blockers.
• Postmarketing cases of acute and chronic leukemia were reported with TNF blocker use. Approximately half of the postmarketing cases of malignancies in children, adolescents, and young adults receiving TNF blockers were lymphomas; other cases included rare malignancies associated with immunosuppression and malignancies not usually observed in children and adolescents.

Hypersensitivity Reactions

• Anaphylaxis and angioneurotic edema have been reported following administration of adalimumab products. If a serious allergic reaction occurs, stop Cyltezo and institute appropriate therapy.

Hepatitis B Virus Reactivation

• Use of TNF blockers, including Cyltezo, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in patients who are carriers of HBV and monitor them during and after Cyltezo treatment. Discontinue Cyltezo and begin antiviral therapy in patients who develop HBV reactivation. Exercise caution when resuming Cyltezo after HBV treatment.

Neurologic Reactions

• TNF blockers, including adalimumab products, have been associated with rare cases of new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome. Exercise caution when considering Cyltezo for patients with these disorders; discontinuation of Cyltezo should be considered if any of these disorders develop.

Hematological Reactions

• Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with adalimumab products. Consider stopping Cyltezo if significant hematologic abnormalities occur.

Congestive Heart Failure

• Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab.  Exercise caution when using Cyltezo in patients who have heart failure and monitor them carefully.

Autoimmunity

• Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

Immunizations

• Patients on Cyltezo should not receive live vaccines. Pediatric patients, if possible, should be brought up to date with all immunizations before initiating Cyltezo therapy. The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.

ADVERSE REACTIONS

• The most common adverse reactions in adalimumab clinical trials (>10%) were: infections (e.g., upper respiratory, sinusitis), injection site reactions, headache, and rash.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see full Prescribing Information, including Medication Guide.

*Humira^® is a registered trademark of AbbVie Biotechnology Ltd. and Avastin^® is a registered trademark of Genentech, Inc. (USA).

**ACR20 is a globally accepted composite measure of comparing response to treatment in Rheumatoid Arthritis clinical trials. A 55% ACR20 response means 55% of patients in the study achieved a 20% improvement in disease activity.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world’s top 20 pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with approximately 50,000 employees. Since its founding in 1885, the company has remained family-owned and today creates value through innovation for three business areas including human pharmaceuticals, animal health and biopharmaceutical contract manufacturing.

Boehringer Ingelheim is committed to improving lives and providing valuable services and support to patients and their families.  Our employees create and engage in programs that strengthen our communities. Please visit our website to learn more about how we make more health for more people through our Corporate Social Responsibility initiatives.

In 2016, Boehringer Ingelheim achieved net sales of about $17.6 billion (15.9 billion euros). R&D expenditure corresponds to 19.6 percent of its net sales.

For more information please visit www.boehringer-ingelheim.us, or follow us on Twitter @BoehringerUS.

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