CIMZIA® (certolizumab pegol) is the First Therapy to Demonstrate Positive Results in a 52-week, Placebo Controlled Non-Radiographic Axial Spondyloarthritis Study

BRUSSELS, May 16, 2018 /PRNewswire/ -- 

• Positive top line results from Phase 3 C-AXSPAND study underscore the potential of CIMZIA^® (certolizumab pegol) for non-radiographic axial spondyloarthritis (nr-axSpA), and provide concrete evidence for the high burden of the disease and limitations of current standard of care to provide adequate disease control¹
• The study met the primary objective, with 47.2% of CIMZIA patients demonstrating major improvement response in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) at Week 52 versus 7% of placebo patients²
• UCB looks forward to quickly submitting this data to the US Food & Drug Administration (FDA), as there are currently no approved biologic treatment options in the US for nr-axSpA

UCB today announced positive topline results from C-AXSPAND, a Phase 3 placebo controlled study to investigate the efficacy of CIMZIA^® (certolizumab pegol) on the signs and symptoms of active axSpA in patients without x-ray evidence of ankylosing spondylitis (AS). The study met the primary objective of achieving a major improvement, or ASDAS-MI, defined as a two-point improvement on the ASDAS at week 52 for CIMZIA-treated patients compared to placebo.³ The study also met Assessment of SpondyloArthritis International Society 40% (ASAS40) response at week 12, a key secondary objective.⁴

"People living with nr-axSpA frequently face delayed or incorrect diagnosis, and currently, in the US, there are no FDA approved options to treat this condition. The C-AXSPAND study results provide important insights into the potential of CIMZIA as an effective and durable treatment option for these patients. Additionally, the study is unique in that it used ASDAS-MI, a rigorous response threshold, and assessed the long-term efficacy of CIMZIA in a one-year, placebo-controlled trial. The study included nr-axSpA patients with objective signs of inflammation, an extended placebo phase, and allowed for modification of background medications to help gain a deeper understanding of the natural history of axSpA and to demonstrate the need for biologic treatment for this disease," said Atul Deodhar, MD, MRCP, FACP, FACR, Professor of Medicine, OHSU, and a lead investigator for the study.

"Axial spondyloarthritis is a painful, chronic inflammatory disease that starts in the sacroiliac joints and progresses to the spine, ultimately causing spinal fusion over time in many patients. People with nr-axSpA face a significant disease burden, similar to people with ankylosing spondylitis, and are in need of effective treatment options. The positive topline results of the C-AXSPAND study show the significant value that CIMZIA may provide to people living with nr-axSpA. The study also reinforces UCB's leadership in this disease area and our commitment to connecting science to unmet patient needs and ultimately providing valuable solutions. We look forward to quickly submitting this data to the FDA for review," said Emmanuel Caeymaex, Head of Immunology and Executive Vice President at UCB.

Axial spondyloarthritis, or axSpA, is a spectrum of disease which comprises both non-radiographic axSpA and radiographic axSpA, also known as ankylosing spondylitis (AS). nr-axSpA and AS share similar symptomology and burden of disease. However, in AS there is a definitive structural change of the sacroiliac joints detectable by x-ray; while in nr-axSpA there is no definitive radiographic sacroiliitis, though there may be magnetic resonance imaging (MRI) evidence of sacroiliitis.⁵

The primary efficacy variable assessed in C-AXSPAND was ASDAS-MI response at week 52. The ASDAS is a composite index to assess patient disease activity. It is comprised of objective evidence of systemic inflammation, such as C-reactive protein, and patient-reported outcomes, such as back pain, duration of morning stiffness, patient global assessment of the disease, and peripheral pain/swelling. The ASDAS is a validated, highly discriminatory instrument for assessing disease activity in axSpA.⁶ In the C-AXSPAND study, the primary outcome was defined as a composite endpoint that was achieved if a patient remained on study treatment through 52 weeks and achieved ASDAS-MI response at week 52.⁷ Patients in both the treatment and placebo groups remained on their background therapy for the duration of the study. No new safety signals were observed in the study.⁸

CIMZIA is approved by the FDA for adults with active AS, but not for nr-axSpA.

About Axial Spondyloarthrits (axSpA)
Axial Spondyloarthritis (axSpA) is a chronic inflammatory disease that typically starts in patients under 45 years of age, normally in their late teens and twenties. These relatively young patients face a significant disease burden whether they have AS (i.e., definitive evidence of sacroiliitis on x-ray) or nr-axSpA (i.e., no definitive evidence of sacroiliitis on x-ray). They often experience substantial back pain, prolonged and severe stiffness, sleep disturbances, reduced mobility and overall function, impaired quality of life, and impaired work and home productivity and social participation.⁹

Limited evidence exists regarding the exact prevalence of axSpA, though it is thought to impact a substantial proportion of the population. Recent data suggest that 0.5% to 1.4% of the adult population have axSpA, similar to the prevalence of rheumatoid arthritis, which is 0.5% to 1.0%.^10,11,12

About C-AXSPAND¹³
C-AXSPAND is a multi-center, randomized, double-blind, parallel-group, placebo controlled study of certolizumab pegol (CZP) compared to placebo. The study randomized 317 adult patients with active axSpA without x-ray evidence of ankylosing spondylitis (AS). Patients needed to have evidence of inflammatory disease, defined as sacroiliitis on magnetic resonance imaging (MRI) and/or elevated C-reactive protein (CRP) levels. Patients must have had an inadequate response to, have a contraindication to, or have been intolerant to at least two non-steroidal anti-inflammatory drugs (NSAIDs). Inadequate response to an NSAID is defined as lack of response to at least 14 days of continuous NSAID therapy at the highest tolerated dose of the administered NSAID.

Patients whose disease activity could not be controlled by study medication and changes in background therapy (including but not limited to analgesics, NSAIDs, and slow-acting antirheumatic drugs) were permitted to withdraw from the study. Patients could either transition to open-label CZP treatment offered by UCB or to other treatment, including biologics, at the discretion of the investigator until the end of the trial.

The study includes a 52-week treatment period, an ongoing 2-year safety follow up extension, and an 8-week follow-up period after treatment is stopped. During the 52-week treatment period, patients received either placebo or a 400mg dose of CZP subcutaneously at weeks zero, two, and four, followed by 200mg of CZP every two weeks starting at week six.

The primary objective assessed in C-AXSPAND was the efficacy of CZP on the signs and symptoms of active axSpA in patients without x-ray evidence of AS. The primary efficacy variable assessed was ASDAS-MI response at week 52.

The secondary objectives of the study were to assess efficacy, safety, and tolerability, and to demonstrate the effect of CZP on health outcomes, disease activity, sacroiliac (SI) joint inflammation through MRI, and changes in concomitant and background medications.  

The key secondary efficacy variables at weeks 12 and 52 included ASAS40 response, change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI), change from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), change from Baseline in SI joint Spondyloarthritis Research Consortium of Canada (SPARCC) score (week 12 only), and the number of patients without relevant changes to background medication. Additional variables assessed at week 52 only were change from baseline in Ankylosing Spondylitis Quality of Life (ASQoL), the number of patients with anterior uveitis (AU) or new AU flares, and change from baseline in total and nocturnal spinal pain.

Safety variables assessed in the study were adverse events, vital signs, physical examination, and measurements of laboratory parameters.

About CIMZIA^® in the US
CIMZIA^® is the only Fc-free, PEGylated anti-TNF (Tumor Necrosis Factor). CIMZIA^® has a high affinity for human TNF-alpha, selectively neutralizing the pathophysiological effects of TNF-alpha.

CIMZIA^® is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis, adults with active psoriatic arthritis (PsA), and adults with active ankylosing spondylitis (AS). 

In addition, it is indicated for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. See important safety information including risk of serious bacterial, viral and fungal infections and tuberculosis below.

Important Safety Information about CIMZIA^® in the US

Risk of Serious Infections and Malignancy

Patients treated with CIMZIA^® are at an 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. CIMZIA^® should be discontinued if a patient develops a serious infection or sepsis. Reported infections include:

• Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before CIMZIA^® use and during therapy. Treatment for latent infection should be initiated prior to CIMZIA^® 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. Empiric anti-fungal therapy should be considered 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.

The risks and benefits of treatment with CIMZIA^® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIMZIA^®, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA^® is a member. CIMZIA^® is not indicated for use in pediatric patients.

Patients treated with CIMZIA^® are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.

Treatment with CIMZIA^® should not be initiated in patients with an active infection, including clinically important localized infections. CIMZIA^® should be discontinued if a patient develops a serious infection or sepsis. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (e.g., corticosteroids or methotrexate) may be at a greater risk of infection. Patients who develop a new infection during treatment with CIMZIA^® should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for immunocompromised patients, and appropriate antimicrobial therapy should be initiated. Appropriate empiric antifungal therapy should also be considered while a diagnostic workup is performed for patients who develop a serious systemic illness and reside or travel in regions where mycoses are endemic.

Malignancies

During controlled and open-labeled portions of CIMZIA^® studies of Crohn's disease and other diseases, malignancies (excluding non-melanoma skin cancer) were observed at a rate of 0.5 per 100 patient-years among 4,650 CIMZIA^®-treated patients versus a rate of 0.6 per 100 patient-years among 1,319 placebo-treated patients. In studies of CIMZIA^® for Crohn's disease and other investigational uses, there was one case of lymphoma among 2,657 CIMZIA^®-treated patients and one case of Hodgkin's lymphoma among 1,319 placebo-treated patients. In CIMZIA^® RA clinical trials (placebo-controlled and open label), a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of TNF blocker therapy in the development of malignancies is not known.

Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤18 years of age), of which CIMZIA^® is a member. Approximately half of the cases were lymphoma (including Hodgkin's and non-Hodgkin's lymphoma), while the other cases represented a variety of different malignancies and included rare malignancies associated with immunosuppression and malignancies not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.

Cases of acute and chronic leukemia have been reported with TNF-blocker use. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for developing leukemia.

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma that has a very aggressive disease course and is usually fatal, have been reported in patients treated with TNF blockers, including CIMZIA^®. The majority of reported TNF blocker cases occurred in adolescent and young adult males with Crohn's disease or ulcerative colitis. Almost all of these patients had received treatment with the immunosuppressants azathioprine and/or 6-mercaptopurine (6-MP) concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treatment with CIMZIA^®, especially in these patient types.

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-antagonists, including CIMZIA^®. Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer.

Heart Failure

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. CIMZIA^® has not been formally studied in patients with CHF. Exercise caution when using CIMZIA^® in patients who have heart failure and monitor them carefully.

Hypersensitivity

Symptoms compatible with hypersensitivity reactions, including angioedema, dyspnea, hypotension, rash, serum sickness, and urticaria, have been reported rarely following CIMZIA^® administration. Some of these reactions occurred after the first administration of CIMZIA^®. If such reactions occur, discontinue further administration of CIMZIA^® and institute appropriate therapy.

Hepatitis B Reactivation

Use of TNF blockers, including CIMZIA^®, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. Some cases have been fatal. Test patients for HBV infection before initiating treatment with CIMZIA^®. Exercise caution in prescribing CIMZIA^® for patients identified as carriers of HBV, with careful evaluation and monitoring prior to and during treatment. In patients who develop HBV reactivation, discontinue CIMZIA^® and initiate effective anti-viral therapy with appropriate supportive treatment.

Neurologic Reactions

Use of TNF blockers, including CIMZIA^®, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis, and with peripheral demyelinating disease, including Guillain-Barré syndrome. Rare cases of neurological disorders, including seizure disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with CIMZIA^®. Exercise caution in considering the use of CIMZIA^® in patients with these disorders.

Hematologic Reactions

Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) has been infrequently reported with CIMZIA^®. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CIMZIA^®. Consider discontinuation of CIMZIA^® therapy in patients with confirmed significant hematologic abnormalities.

Drug Interactions

An increased risk of serious infections has been seen in clinical trials of other TNF blocking agents used in combination with anakinra or abatacept. Formal drug interaction studies have not been performed with rituximab or natalizumab; however, because of the nature of the adverse events seen with these combinations with TNF blocker therapy, similar toxicities may also result from the use of CIMZIA^® in these combinations. Therefore, the combination of CIMZIA^® with anakinra, abatacept, rituximab, or natalizumab is not recommended. Interference with certain coagulation assays has been detected in patients treated with CIMZIA^®. There is no evidence that CIMZIA^® therapy has an effect on in vivo coagulation. CIMZIA^® may cause erroneously elevated aPTT assay results in patients without coagulation abnormalities.

Autoimmunity

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

Immunizations

Do not administer live vaccines or live-attenuated vaccines concurrently with CIMZIA^®.

Adverse Reactions

In controlled Crohn's clinical trials, the most common adverse events that occurred in ≥5% of CIMZIA^® patients (n=620) and more frequently than with placebo (n=614) were upper respiratory infection (20% CIMZIA^®, 13% placebo), urinary tract infection (7% CIMZIA^®, 6% placebo), and arthralgia (6% CIMZIA^®, 4% placebo). The proportion of patients who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA^® and 7% for placebo.

In controlled RA clinical trials, the most common adverse events that occurred in ≥3% of patients taking CIMZIA^® 200 mg every other week with concomitant methotrexate (n=640) and more frequently than with placebo with concomitant methotrexate (n=324) were upper respiratory tract infection (6% CIMZIA^®, 2% placebo), headache (5% CIMZIA^®, 4% placebo), hypertension (5% CIMZIA^®, 2% placebo), nasopharyngitis (5% CIMZIA^®, 1% placebo), back pain (4% CIMZIA^®, 1% placebo), pyrexia (3% CIMZIA^®, 2% placebo), pharyngitis (3% CIMZIA^®, 1% placebo), rash (3% CIMZIA^®, 1% placebo), acute bronchitis (3% CIMZIA^®, 1% placebo)and fatigue (3% CIMZIA^®, 2% placebo). Hypertensive adverse reactions were observed more frequently in patients receiving CIMZIA^® than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs. Patients receiving CIMZIA^® 400 mg as monotherapy every 4 weeks in RA controlled clinical trials had similar adverse reactions to those patients receiving CIMZIA^® 200 mg every other week. The proportion of patients who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for CIMZIA^® and 2.5% for placebo.

The safety profile for patients with psoriatic arthritis (PsA) treated with CIMZIA^® was similar to the safety profile seen in patients with RA and previous experience with CIMZIA^®.

The safety profile for AS patients treated with CIMZIA^® was similar to the safety profile seen in patients with RA.

For full prescribing information, please visit www.ucb.com

CIMZIA^® is a registered trademark of the UCB Group of Companies.

For further information, UCB:

About UCB
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases in immunology or neurology. With more than 7 500 people in approximately 40 countries, the company generated revenue of € 4.5 billion in 2017. UCB is listed on Euronext Brussels (symbol: UCB). Follow us on Twitter: @UCB_news

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REFERENCES

¹ UCB Clinical Study Protocol. PROTOCOL AS0006 (C-AXSPAND) AMENDMENT 4. Data on File.
² UCB Data on File. May 2018.
³ UCB Data on File. May 2018.
⁴ UCB Data on File. May 2018.
⁵ UCB Clinical Study Protocol. PROTOCOL AS0006 (C-AXSPAND) AMENDMENT 4. Data on File.
⁶ UCB Clinical Study Protocol. PROTOCOL AS0006 (C-AXSPAND) AMENDMENT 4. Data on File.
⁷ UCB Clinical Study Protocol. PROTOCOL AS0006 (C-AXSPAND) AMENDMENT 4. Data on File.
⁸ UCB Data on File. May 2018.
⁹ UCB Clinical Study Protocol. PROTOCOL AS0006 (C-AXSPAND) AMENDMENT 4. Data on File.
¹⁰ Reveille JD (2012): Prevalence of axial spondylarthritis in the United States: estimates from a cross-sectional survey. Arthritis Care Res (Hoboken). 2012 Jun;64(6):905-10. doi: 10.1002/acr.21621. Epub 2012 Jan 24. Accessed at: https://www.ncbi.nlm.nih.gov/pubmed/22275150  
¹¹ Reveille JD, Weisman MH. (2013): The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States. Am J Med Sci. 2013 Jun;345(6):431-6. Accessed at: https://www.ncbi.nlm.nih.gov/pubmed/23841117 
¹² Strand et al paper (2013) : Prevalence of axial spondyloarthritis in United States rheumatology practices: Assessment of SpondyloArthritis International Society criteria versus rheumatology expert clinical diagnosis. Arthritis Care Res (Hoboken).2013 Aug;65(8):1299-306. Accessed at: https://www.ncbi.nlm.nih.gov/pubmed/23436774 
¹³ UCB Clinical Study Protocol. PROTOCOL AS0006 (C-AXSPAND) AMENDMENT 4. Data on File.

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