Phase 3 Study Results Supporting U.S. FDA and European Commission Approvals of STELARA® in the Treatment of Moderately to Severely Active Crohn's Disease Published in The New England Journal of Medicine

SPRING HOUSE, Pa., Nov. 16, 2016 /PRNewswire/ -- Results from three pivotal Janssen Research & Development, LLC (Janssen)-sponsored Phase 3 studies published today in The New England Journal of Medicine show that treatment with STELARA^® (ustekinumab) induced and maintained both clinical response and remission in a significantly greater proportion of adult patients with moderately to severely active Crohn's disease compared to placebo.  These results were demonstrated in two separate induction studies as well as in a maintenance study which assessed treatment effect one year after initiation of STELARA^® treatment.  The UNITI Phase 3 development program consisted of two eight-week induction studies, one in patients who had previously failed or were intolerant to treatment with one or more anti-tumor necrosis factor (TNF)-alpha therapies (UNITI-1) and the other in patients who had previously failed conventional therapy, the majority of whom were naïve to treatment with anti-TNF-alpha therapy (UNITI-2). Patients then continued into a 44-week maintenance study (IM-UNITI). These pivotal studies supported the recent approval by the U.S. Food and Drug Administration and the recent approval by the European Commission of STELARA^® for the treatment of moderately to severely active Crohn's disease in adults. STELARA^® is a monoclonal antibody that targets interleukin (IL)-12 and IL-23 cytokines, which play a role in immune-mediated diseases, including psoriasis, psoriatic arthritis and Crohn's disease.

"Findings from the UNITI Phase 3 Crohn's disease studies, as published today in The New England Journal of Medicine, show the significant benefit of STELARA^® in the treatment of this debilitating inflammatory bowel disease," said Brian Feagan, M.D., Professor of Medicine, Senior Scientific Officer, Robarts Research Institute, University of Western Ontario, and study investigator.  "It is especially gratifying for the UNITI study investigators who contributed to defining the efficacy and safety profile of STELARA^®, an anti-IL-12/23 monoclonal antibody recently approved in the U.S. and the European Union for the treatment of moderately to severely active Crohn's disease."

A single intravenous (I.V.) infusion of STELARA^® 130 mg or STELARA^® ~6 mg/kg (weight-tiered dosing: patients weighing less than or equal to 55 kg received 260 mg; patients weighing more than 55 kg and less than or equal to 85 kg received 390 mg; and patients weighing more than 85 kg received 520 mg) or placebo was administered at week 0 in both the UNITI-1 and UNITI-2 induction studies.  The benefits of STELARA^® ~6 mg/kg in inducing clinical response and remission were observed as early as week 3 in both Crohn's disease populations studied.  Patients responding to a single I.V. dose of STELARA^® in the induction studies were re-randomized in the IM-UNITI maintenance study to receive STELARA^® 90 mg subcutaneous (SC) injections every eight weeks (Q8W), STELARA^® 90 mg SC injections every 12 weeks (Q12W) or placebo (withdrawal from therapy) and were followed for a total of one year of treatment.  All patients randomized in the IM-UNITI maintenance study had achieved clinical response to STELARA^® at week 8 of the induction studies, and approximately 60 percent of these patients were in clinical remission at entry into the IM-UNITI study.  Clinical remission was defined by a Crohn's Disease Activity Index (CDAI) score of less than 150 points and clinical response was defined by a reduction from baseline in the CDAI score of at least 100 points or being in clinical remission.  CDAI is a symptom-based disease assessment tool commonly used in clinical trials to quantify Crohn's disease activity. 

Each of the three UNITI Phase 3 studies achieved their study primary endpoint as follows.

• The UNITI-1 induction study included 741 patients who had received TNF-antagonist(s) at approved doses and had met primary non-response, secondary non-response, and/or intolerance criteria. The primary endpoint was achieved as 34 percent of patients receiving STELARA^® 130 mg and 34 percent of patients receiving STELARA^® ~6 mg/kg achieved clinical response at week 6 compared with 22 percent of patients receiving placebo (P = 0.002 for STELARA^® 130 mg; P = 0.003 for STELARA^® ~6 mg/kg). All four pre-specified major secondary endpoints were attained, at both induction doses, including clinical response and clinical remission at week 8, meaning these were significantly higher among patients receiving STELARA^® compared with patients receiving placebo.
• The UNITI-2 induction study included 628 patients who had failed conventional therapy (immunomodulators and /or oral corticosteroids), and could have previously received TNF-antagonist(s) provided they had not demonstrated an intolerance or inadequate response. The primary endpoint was achieved as 52 percent of patients receiving STELARA^® 130 mg and 56 percent of patients receiving STELARA^® ~6 mg/kg achieved clinical response at week 6 compared with 29 percent of patients receiving placebo (P < 0.001 for both doses). All four pre-specified major secondary endpoints were attained with both I.V. induction doses studied including clinical response and clinical remission at week 8, meaning these were both significantly higher among patients receiving STELARA^® compared with patients receiving placebo.
• In the IM-UNITI maintenance study, 388 patients were included in the primary randomized population who had responded to a single I.V. dose of STELARA^® in either the UNITI-1 or UNITI-2 induction studies. This study showed that 53 percent of patients who received STELARA^® 90 mg SC Q8W and 49 percent of patients who received STELARA^® 90 mg SC Q12W were in clinical remission at week 44, the study's primary endpoint, compared with 36 percent of patients receiving placebo (P = 0.005 and P = 0.040, respectively). Patients maintained response at week 44 (59 percent for Q8W, 58 percent for Q12W, and 44 percent for placebo (P =0.018 and P = 0.033, respectively). Major secondary endpoints achieved included clinical response with both Q8W and Q12W as well as clinical remission among patients in remission after induction and corticosteroid-free remission for the Q8W regimen, all at week 44.

"Inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis, is a disease area where we are committed to bringing forward novel therapeutic approaches to benefit patients and support health care professionals," said Newman Yeilding, M.D., Head of Immunology Development, Janssen Research & Development, LLC.  "STELARA^® is an important new therapeutic option for patients living with Crohn's disease who may be candidates for biologic therapy.  We are proud to publish the pivotal Phase 3 study findings and make this treatment available in the United States and the European Union."

The safety profile observed in these trials was consistent with five years of cumulative experience acquired in patients with psoriasis (with SC doses up to 90 mg) and in the two years of safety experience observed in patients with psoriatic arthritis.  In UNITI-1, Adverse events (AEs) were reported in 65 percent, 66 percent and 65 percent of patients in the STELARA^® 130 mg, STELARA^® ~6 mg/kg and placebo groups, respectively.  The proportions of patients with a serious AE in UNITI-1 were 5 percent, 7 percent, and 6 percent, respectively.  In UNITI-2, AEs were reported in 50 percent, 56 percent, and 54 percent, of patients in the STELARA^® 130 mg, STELARA^® ~6 mg/kg and placebo groups, respectively.  The proportions of patients with a serious AE in UNITI-2 were 5 percent, 3 percent and 6 percent, respectively.  Through 44 weeks of IM-UNITI, 82 percent, 80 percent, and 84 percent of patients receiving STELARA^® 90 mg Q8W, STELARA^® 90 mg Q12W, or placebo, respectively, experienced at least one AE.  The proportions of patients with a serious AE in IM-UNITI were 10 percent, 12 percent, and 15 percent, respectively. 

In the combined studies, through one year of therapy, there were a total of three opportunistic infections: one case of Listeria meningitis in a patient treated with STELARA^®, and two non-serious cases of esophageal candidiasis, one in a placebo-treated patient, and the other in a STELARA^®-treated patient.  Additionally, there was one case of active pulmonary tuberculosis reported in a STELARA^® -treated patient.  Malignancies were reported in two STELARA^®-treated patients (multiple myeloma in one patient and metastatic small bowel adenocarcinoma and an incidentally discovered carcinoid tumor in the other) and in one placebo-treated patient (basal cell carcinoma). 

About the UNITI-1 Induction Study
UNITI-1, a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group study, evaluated the efficacy and safety of STELARA^® induction therapy in adult patients with moderate to severe Crohn's disease.  Patients were randomized equally to receive a single I.V. infusion of placebo, STELARA^® 130 mg or STELARA^® ~6 mg/kg (weight-tiered dosing: patients weighing less than or equal to 55 kg received 260 mg; patients weighing more than 55 kg and less than or equal to 85 kg received 390 mg; and patients weighing more than 85 kg received 520 mg) at week 0.  All participating patients had previously failed or were intolerant to treatment with at least one anti-TNF-alpha therapy.  The primary endpoint was clinical response at week 6, measured by the proportion of patients who achieved at least a 100-point reduction from baseline CDAI scores or being in clinical remission.  Major secondary endpoints at week 8 included clinical response and clinical remission (defined by CDAI scores less than 150 points).  At week 8, patients either transitioned to the IM-UNITI maintenance study or were to complete a safety follow-up period through week 20. 

About the UNITI-2 Induction Study
UNITI-2, a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group study, evaluated the efficacy and safety of STELARA^® induction therapy in adult patients with moderate to severe Crohn's disease.  Patients were randomized equally to receive a single I.V. infusion of placebo, STELARA^® 130 mg or STELARA^® ~6 mg/kg (weight-tiered dosing: patients weighing less than or equal to 55 kg received 260 mg; patients weighing more than 55 kg and less than or equal to 85 kg received 390 mg; and patients weighing more than 85 kg received 520 mg) at week 0.  All participating patients had previously failed steroids and/or immunomodulators and were either naïve to or had been exposed to anti-TNF-alpha therapy, but had not failed such biologic therapy.  The primary endpoint was clinical response at week 6, measured by the proportion of patients who achieved at least a 100-point reduction from baseline CDAI scores or being in clinical remission.  Major secondary endpoints at week 8 included clinical response and clinical remission (defined by CDAI scores less than 150 points).  At week 8, patients either transitioned to the IM-UNITI maintenance study or participated in safety follow-up through week 20. 

About the IM-UNITI Maintenance Study
IM-UNITI, a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group study, evaluated the efficacy and safety of STELARA^® maintenance therapy in adult patients with moderate to severe Crohn's disease. Patients who completed UNITI-1 or -2 could enroll in the IM-UNITI maintenance trial.  Patients who had responded to a single intravenous dose of STELARA^® in the UNITI-1 or UNITI-2 induction studies were the primary population in IM-UNITI.  These patients were randomized equally to receive maintenance SC injections of STELARA^® 90 mg SC Q8W or Q12W, or placebo.  Together, the UNITI-1 and UNITI-2 induction studies and the IM-UNITI maintenance study represent one year of therapy.  The primary endpoint was clinical remission at week 44, defined by CDAI scores less than 150 points.  Major secondary endpoints at week 44 included clinical response, measured by the proportion of patients who achieved at least a 100-point reduction from baseline CDAI scores or being in clinical remission, corticosteroid-free clinical remission, clinical remission among patients in remission at the start of the IM-UNITI study, and clinical remission in the subgroup of patients refractory or intolerant to treatment with one or more anti-TNF-alpha therapies. 

About Crohn's Disease
More than five million people worldwide are living with Crohn's disease and ulcerative colitis—collectively known as inflammatory bowel disease (IBD).¹  Crohn's disease is a chronic inflammatory condition of the gastrointestinal tract that affects approximately 700,000 Americans.  The cause of Crohn's disease is not known, but the disease is associated with abnormalities of the immune system that could be triggered by a genetic predisposition or diet and other environmental factors.  Symptoms of Crohn's disease can vary but often include abdominal pain and tenderness, frequent diarrhea, rectal bleeding, weight loss and fever.  There is currently no cure for Crohn's disease.²

About STELARA^® (ustekinumab)
STELARA ^®, a human IL-12 and IL-23 antagonist, is approved in the United States for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, as well as for the treatment of adult patients (18 years or older) with active psoriatic arthritis and can be used alone or in combination with methotrexate (MTX).  In September 2016, STELARA^® received approval for the treatment of adult patients (18 years or older) with moderately to severely active Crohn's disease who failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed a tumor necrosis factor (TNF) blocker, or failed or were intolerant to treatment with one or more TNF blockers.

In the European Union, STELARA^® is approved for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, MTX or psoralen plus ultraviolet A (PUVA), and is a also indicated for the treatment of moderate to severe plaque psoriasis in adolescent patients from the age of 12 years and older who are inadequately controlled by or are intolerant to other systemic therapies or phototherapies.  In addition, STELARA^® is approved alone or in combination with MTX for the treatment of active psoriatic arthritis in adult patients when the response to previous non-biological disease-modifying antirheumatic drug (DMARD) therapy has been inadequate.  In November 2016, the European Commission approved STELARA^® for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF-alpha antagonist or have medical contraindications to such therapies.

The Janssen Pharmaceutical Companies of Johnson & Johnson maintain exclusive worldwide marketing rights to STELARA^®, which is currently approved for the treatment of moderate to severe plaque psoriasis in 87 countries and psoriatic arthritis in 71 countries.

IMPORTANT SAFETY INFORMATION (U.S.)

STELARA^® is a prescription medicine that affects your immune system. STELARA^® can increase your chance of having serious side effects including:

Serious Infections

STELARA^® may lower your ability to fight infections and may increase your risk of infections. While taking STELARA^®, some people have serious infections, which may require hospitalization, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses.

• Your doctor should check you for TB before starting STELARA^® and watch you closely for signs and symptoms of TB during treatment with STELARA^®.
• If your doctor feels that you are at risk for TB, you may be treated for TB before and during treatment with STELARA^®.

You should not start taking STELARA^® if you have any kind of infection unless your doctor says it is okay.

Before starting STELARA^®, tell your doctor if you:

• think you have an infection or have symptoms of an infection such as:
  • fever, sweats, or chills
  • muscle aches
  • cough
  • shortness of breath
  • blood in your phlegm
  • weight loss
  • warm, red, or painful skin or sores on your body
  • diarrhea or stomach pain
  • burning when you urinate or urinate more often than normal
  • feel very tired
• are being treated for an infection
• get a lot of infections or have infections that keep coming back
• have TB, or have been in close contact with someone who has TB

After starting STELARA^®, call your doctor right away if you have any symptoms of an infection
(see above).

STELARA^® can make you more likely to get infections or make an infection that you have worse. People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL‐12) and interleukin 23 (IL‐23) are at a higher risk for certain serious infections that can spread throughout the body and cause death. People who take STELARA^® may also be more likely to get these infections.

Cancers

STELARA^® may decrease the activity of your immune system and increase your risk for certain types of cancer. Tell your doctor if you have ever had any type of cancer. Some people who had risk factors for skin cancer developed certain types of skin cancers while receiving STELARA^®. Tell your doctor if you have any new skin growths.

Reversible posterior leukoencephalopathy syndrome (RPLS)

RPLS is a rare condition that affects the brain and can cause death. The cause of RPLS is not known. If RPLS is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including: headache, seizures, confusion, and vision problems.

Serious Allergic Reactions

Serious allergic reactions can occur. Stop using STELARA^® and get medical help right away if you have any symptoms such as: feeling faint, swelling of your face, eyelids, tongue, or throat, chest tightness, or skin rash.

Before receiving STELARA^®, tell your doctor if you:

• have any of the conditions or symptoms listed above for serious infections, cancers, or RPLS.
• ever had an allergic reaction to STELARA^® or any of its ingredients. Ask your doctor if you are not sure.
• are allergic to latex. The needle cover on the prefilled syringe contains latex.
• have recently received or are scheduled to receive an immunization (vaccine). People who take STELARA^® should not receive live vaccines. Tell your doctor if anyone in your house needs a vaccine. The viruses used in some types of vaccines can spread to people with a weakened immune system, and can cause serious problems. You should not receive the BCG vaccine during the one year before taking STELARA^® or one year after you stop taking STELARA^®.
• have any new or changing lesions within psoriasis areas or on normal skin.
• are receiving or have received allergy shots, especially for serious allergic reactions.
• receive or have received phototherapy for your psoriasis.
• have any other medical conditions.
• are pregnant or plan to become pregnant. It is not known if STELARA^® will harm your unborn baby. You and your doctor should decide if you will take STELARA^®.
• are breast‐feeding or plan to breast‐feed. It is thought that STELARA^® passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take STELARA^®.

Tell your doctor about all the medicines you take, including prescription and over‐the‐counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

When prescribed STELARA^®:

• Use STELARA^® exactly as prescribed by your doctor.
• If your doctor decides that you or a caregiver may give your injections of STELARA^® at home, you should receive training on the right way to prepare and inject STELARA^®. Do not try to inject STELARA^® yourself until you or your caregiver has been shown how to inject STELARA^® by your doctor or nurse.

Common side effects of STELARA^® include: upper respiratory infections, headache, tiredness, joint pain, nausea, itching, vomiting, vaginal yeast infections, urinary tract infections, and redness at the injection site. These are not all of the possible side effects with STELARA^®. Tell your doctor about any side effect that you experience. Ask your doctor or pharmacist for more information.

Please read the full Prescribing Information and Medication Guide for STELARA^® and discuss any questions you have with your doctor.

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

060386-160920

IMPORTANT SAFETY INFORMATION (EU)
Special Warnings & Precautions

Infections: Potential to increase risk of infections and reactivate latent infections. Exercise caution in patients with a chronic infection or history of recurrent infection, particularly TB. Patients should be evaluated for tuberculosis and treated for latent TB prior to initiation of STELARA^®. Also, consider anti-tuberculosis therapy prior to initiation of STELARA^® in patients with past history of latent or active tuberculosis. Patients should seek medical advice if signs or symptoms suggestive of an infection occur. If a serious infection develops, they should be closely monitored and STELARA^® should not be administered until infection resolves.

Malignancies: Potential to increase the risk of malignancy. No studies have been conducted in patients with a history of malignancy or in those who continue to receive STELARA^® after being diagnosed with a malignancy. Exercise caution when considering STELARA^® in these patients. Monitoring for the appearance of non-melanoma skin cancer recommended, in particular for patients greater than 60 years of age, or with a medical history of prolonged immunosuppressant therapy or a history of PUVA treatment.

Hypersensitivity reactions: Serious hypersensitivity reactions (anaphylaxis and angioedema) reported, in some cases several days after treatment. If these occur, institute appropriate therapy and discontinue use of STELARA^®.

Vaccinations: Patients receiving STELARA^® should not receive concurrent live viral or live bacterial vaccines such as BCG. Before live viral or live bacterial vaccination, treatment with STELARA^® should be withheld for at least 15 weeks after the last dose and can be resumed at least 2 weeks after vaccination. Patients receiving STELARA^® may receive concurrent inactivated or non-live vaccinations.

Concomitant immunosuppressive therapy: Exercise caution, including when changing immunosuppressive biologic agents. In psoriasis studies, the safety and efficacy of STELARA^® in combination with other immunosuppressants, including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA^®. In Crohn's disease studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of STELARA^®.

Immunotherapy: Not known whether STELARA^® affects allergy immunotherapy.

Serious skin conditions: In patients with psoriasis, exfoliative dermatitis has been reported following STELARA^® treatment. Patients with plaque psoriasis may develop erythrodermic psoriasis, with symptoms that may be clinically indistinguishable from exfoliative dermatitis, as part of the natural course of their disease. If these symptoms occur, appropriate therapy should be instituted. STELARA^® should be discontinued if a drug reaction is suspected.

Latex sensitivity: Needle cover contains natural rubber (latex), may cause allergic reactions.

Elderly Patients > 65 years: Use caution when treating elderly patients.

For complete European Union (EU) prescribing information, please visit: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000958/human_med_001065.jsp&mid=WC0b01ac058001d124

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 https://twitter.com/JanssenGlobal.

Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding development, availability and regulatory approval of a product. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in product research and development, including uncertainty of clinical success and obtaining regulatory approvals; uncertainty of commercial success for products; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 3, 2016, including in Exhibit 99 thereto, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

References

1. World IBD Day. Home. Available at http://www.worldibdday.org/index.html. Accessed May 10, 2016.
2. Crohn's & Colitis Foundation of America. What is Crohn's Disease? Available at http://www.ccfa.org/what-are-crohns-and-colitis/what-is-crohns-disease/. Accessed May 10, 2016.

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