The autoimmune diseases represent a growing therapeutic catagory in specialty pharmacy, as the pipeline for biologics that treat inflammatory conditions remains strong.
Inflammatory conditions, sometimes referred to as autoimmune diseases, represent a growing therapeutic category in specialty pharmacy. Prior to 2010, there were biologic therapies available to treat rheumatoid arthritis (RA), anklyosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis, and psoriatic arthritis.
With the recent approval of 2 new molecular entities (Savient Pharmaceuticals’ Krystexxa and GlaxoSmithKline’s Benlysta), gout and lupus can now be added to the list of inflammatory conditions that are treated with a biologic therapy approved by the FDA. In addition to the expanding list of autoimmune diseases that are treated with a biologic, the pipeline for biologics that treat inflammatory conditions currently being investigated in Phase III remains strong.
Crohn’s Disease and Ulcerative Colitis1-4
Prochymal is an infusion of adult human mesenchymal stem cells from healthy volunteer donors. The cells do not require any donor–recipient matching and may have both immunosuppressive and healing benefits in CD. The cells appear to migrate specifically to sites of inflammation, so the effects are believed to be local and self limiting rather than systemic. Phase III trials are currently active to evaluate whether or not the adult human mesenchymal stem cells can induce remission in patients with moderate to severe CD.
Patients in the active comparator arms are receiving either the low-dose protocol, the high-dose protocol, or placebo. Those in the low-dose arm are receiving 600 million cells total over 4 infusions given in 2 weeks and those in the high-dose arm are receiving 1200 million cells total delivered in 4 infusions over 2 weeks. Osiris Therapeutics estimates that the primary completion date of the study will be December 2011.
Vedolizumab is an anti-47 Integrin therapeutic antibody currently in Phase III testing for both CD and UC. Millennium and its parent company Takeda are calling the Phase III program GEMINI and plan to enroll nearly 2000 patients. GEMINI-I consists of a placebo-controlled induction and maintenance study in patients with UC which is expected to be complete April 2012; GEMINI-II and GEMINI-III are placebo-controlled induction and maintenance studies in patients with CD expected to collect the final data in July 2012; and GEMINI LTS, an open label long-term safety study in patients with either UC or CD, is expected to be complete in December 2016. Vedolizumab is given as an intravenous (IV) infusion at weeks 0, 2, 6, and then at 4- or 8-week intervals.
GSK1605786A (formerly CCX282-B) targets chemokine receptor CCR9, which is expressed selectively on intestinal lymphocytes and dendritic cells. CCR9 mediates migration of immune cells to the intestine, and blockade of the receptor inhibits migration. GSK1605786A is being studied in CD at a dose of 500 mg by mouth once daily or 500 mg by mouth twice daily versus placebo. Final data is anticipated to be collected mid-2012 for a study evaluating efficacy over a 12-week treatment period. A study reviewing maintenance of remission is expected to be complete in July 2014 and a long-term safety study is scheduled for completion in July 2015.
Orencia (abatacept), already approved in the United States for RA and juvenile idiopathic arthritis, has gone through Phase III trials to evaluate its use in UC. Stelara (ustekinumab), already approved in the United States for moderate to severe plaque psoriasis, is being investigated for use in CD. Simponi (golimumab), approved in the United States for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylits, is being researched for its use in ulcerative colitis. Humira (adalimumab) is approved in the United States for rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, CD, and plaque psoriasis; it was announced in May 2011 that Abbott met the primary end point for the Phase III UC study and filed an application with the FDA for the additional UC indication.
Forigerimod, also known as Lupuzor or CEP-33457, is a CD4 T-cell modulator being investigated for the treatment of systemic lupus erythematosus (SLE). In the Phase II trials, Lupuzor was administered subcutaneously at a dose of 200 mcg once a month for 3 months. The Phase III study is anticipated to be complete in September 2012 and will measure the proportion of patients achieving a combined clinical response using the SLE responder index.
LY2127399, a human monoclonal antibody that neutralizes B-cell activating factor (BAFF), is currently in Phase III trials for evaluation as a treatment for SLE as well as RA. The drug is being studied with a loading dose of 240 mg given 1 time, then 120 mg given subcutaneously every 2 weeks or every 4 weeks. The primary outcome measure is the proportion of patients achieving an SLE responder index response at week 52. The final data collection for the primary outcome measure is anticipated to take place in February 2013.
Epratuzumab is a humanized IgG1 antibody that acts as an antagonist of the CD22 receptor present on B cells. UCB is currently enrolling patients for the 2 Phase III trials, EMBODY-1 and EMBODY-2. The primary objective of both studies is to measure the percent of subjects meeting treatment response criteria at week 48 among those patients with moderate to severe SLE. Epratuzumab is dosed at either 600 mg per week or 1200 mg every other week administered over four 12-week treatment cycles. The cumulative dose for both treatment arms is 2400 mg for each of the 4-week dosing periods. The estimated primary completion date is January 2014 for both EMBODY-1 and EMBODY-2.
Secukinumab is an anti-IL17A drug being investigated for a number of inflammatory conditions. For AS, Novartis is planning to evaluate a dose of 75 mg subcutaneously or 150 mg subcutaneously compared with placebo. The primary outcome measure of the planned Phase III trial is to evaluate the efficacy of each secukinumab regimen in patients with active AS based on the proportion of patients obtaining an ASAS 20 response. The final data collection for the primary outcome measure is anticipated by July 2014.
Ilaris (canakinumab), already approved in the United States for cryopyrin-associated periodic syndromes (CAPS), is also being studied for use in acute gout flares. It is a fully humanized monoclonal antibody that provides selective inhibition of IL-1 beta. The 2 Phase III trials enrolled 228 and 226 patients, respectively. Enrolled patients were required to have experienced 3 or more gouty arthritis attacks in the previous 12 months and were required to have been unresponsive or intolerant to NSAIDs or colchicines. Patients were randomized to receive a single dose of canakinu-mab 150 mg subcutaneously or triamcinolone acetate 40 mg given via intramuscular injection.
Both studies had primary end points of pain intensity at 72 hours post dose and time to the first subsequent gouty arthritis attack. In both studies, pain intensity met statistical significance in favor of canakinumab and the number of patients with new attacks was significantly reduced with canakinumab compared with triamcinolone acetate. In the first study, 40 triamcinolone acetate patients experienced a subsequent attack during the study compared with 21 canakinumab patients. In the second study, 42 trimacinolone acetate patients experienced a subsequent attack during the study compared with 15 canakinumab patients. There were more adverse events seen in the canakinumab group compared with the triamcinolone acetate group (55.8% vs 38.3% in the first study and 54.5% vs 50.9% in the second study). Novartis filed for FDA approval in the first half of 2011.
In June 2011, an FDA advisory committee voted 11-1 against recommending approval of the drug for treating attacks of gout. The panel also unanimously voted against Ilaris for delaying and reducing the frequency of future attacks. A final FDA decision is pending.
Arcalyst (rilonacept) is an IL-1 inhibitor and is also already approved in the United States for CAPS. The Phase III trials of rilonacept were designed to study prevention of gout flares rather than reduction of pain in acute flares. In the PRE-SURGE 1 Phase III study, patients who received 80 mg of rilonacept saw a 73% reduction in flares compared with placebo and patients who received 160 mg of rilonacept saw an 80% reduction in flares compared with placebo. The PRESURGE 2 trial showed a 72% reduction of flares per patient both for patients treated with rilonacept 80 mg and rilonacept 160 mg compared with placebo. Regeneron also conducted a Phase III safety study, entitled RE-SURGE, in which treatment-emergent adverse events were generally well balanced between those taking the study drug and those on placebo. Injection site reactions were more prevalent with the treatment group than with placebo (15.2% vs 3.3%) but were generally considered mild. Regeneron is expected to file for FDA approval in mid-2011.
Psoriasis and Psoriatic Arthritis1,14-16
Apremilast (CC-10004) is an oral agent that modulates multiple inflammatory pathways through targeted phosphodiesterase type 4 (PDE4) enzyme inhibition including suppression of TNF-alpha, interleukins 6, 17, & 23, and interferongamma. The Phase III trials that are looking at apremilast’s efficacy in psoriatic arthritis are named the PALACE studies, and those looking into efficacy in plaque psoriasis are called ESTEEM. The PALACE studies to review psoriatic arthritis are reviewing a dose of 20 mg by mouth twice daily or 30 mg by mouth twice daily versus placebo. The final data collection for the PALACE 1, 2, and 3 studies is anticipated in the first half of 2012, with the final data from PALACE 4 to be collected in the second half of 2012. The ESTEEM studies are reviewing a dose of apremilast 30 mg by mouth twice daily versus placebo. ESTEEM-1 is expected to collect final data in October 2011 and ESTEEM-2 is expected to complete data collection in June 2012.
Tofacitinib (CP-690,550) is an oral Janus kinase (JAK) inhibitor. It is being studied versus placebo at a dose of 5 mg orally twice daily or 10 mg orally twice daily. Phase III trials for plaque psoriasis with tofacitinib compared with placebo are expected to collect final data for analysis in the first half of 2013 with a long-term safety study being completed in May 2017. Tofacitinib is also being evaluated at a dose of 5 mg orally twice daily or 10 mg orally twice daily compared with Enbrel (enterecept) 50 mg subcutaneously twice weekly for plaque psoriasis. Final data from that trial are anticipated to be completed in July 2012.
Secukinumab is an anti-IL17A drug being investigated for a number of inflammatory conditions. For plaque psoriasis, Novartis is planning to evaluate a dose of 150 mg subcutaneously compared with placebo. The primary outcome measure of the planned Phase III trial named ERASURE is to evaluate the efficacy in patients with moderate to severe chronic plaque-type psoriasis. Novartis is also planning to evaluate secukinumab dosed at either 150 or 300 mg versus Enbrel (enterecept) 50 mg in a Phase III trial entitled FIXTURE. Final data collection for the primary outcome measures in both ERASURE and FIXTURE are anticipated by March 2013.
Briakinumab (ABT-874) targets IL-12 and IL-23. Phase III studies were completed, but following feedback from regulatory authorities indicating the need for further safety analysis and the potential for additional studies, Abbott withdrew its application from the FDA in January 2011.
Stelara (ustekinumab), already approved in the United States for moderate to severe plaque psoriasis, is being investigated for use in psoriatic arthritis. Cimzia (certolizumab pegol) is approved in the United States for use in CD and RA and is being investigated for use in psoriatic arthritis. The estimated final data collection for the primary outcome measure of the American College of Rheumatology 20 (ACR20) response is expected to occur around August 2011. Rheumatoid Arthritis 1,17-22 LY2127399, a human monoclonal antibody that neutralizes BAFF, is currently in Phase III trials for evaluation as a treatment for SLE as well as RA. The drug is being studied in RA with a loading dose of 240 mg given 1 time, then 120 mg given subcutaneously every 4 weeks for 24 weeks or a loading dose of 180 mg given 1 time, then 90 mg subcutaneously every 2 weeks for 24 weeks. The primary outcome measure is the proportion of patients achieving an ACR20 response. The final data collection for the primary outcome measure is anticipated to take place mid-2013. A long-term safety study is scheduled for completion in 2018.
Tofacitinib (CP-690,550) is an oral JAK inhibitor. It is being studied for treatment of RA versus placebo at a dose of 5 mg orally twice daily or 10 mg orally twice daily. Tofacitinib is also being evaluated against the active comparators methotrexate and Humira (adalimumab) at a dose of 40 mg subcutaneously every 2 weeks. The Phase III program, named ORAL, consists of 5 pivotal studies and 1 long-term safety study. The pivotal studies were completed in the first half of 2011, with results from the long-term safety study expected in 2015. It is expected to be submitted for FDA approval mid to second half 2011 and may become the first oral disease modifying anti-rheumatic drug approved in more than 10 years.
Fostamatinib (R788) is a spleen tyrosine kinase (Syk) inhibitor. Syk is a key mediator of Fc and B-cell receptor signaling in inflammatory cells, such as B cells, mast cells, macrophages, and neutrophils. The Phase III program to investigate fostamatinib use in RA is referred to as the OSKIRA trials. The regimen being studied is fostamatinib 100 mg by mouth twice daily or 150 mg by mouth once daily. The pivotal trials are expected to wrap up in early 2013, with a long-term safety study planned for completion in 2015.
SAR153191 (REGN88) is a fully human IgG1 monoclonal antibody directed against the interleukin-6 receptor alpha (IL-6R a). An ongoing Phase III study is evaluating several dosing regimens of SAR153191 (REGN88) in addition to methotrexate compared with placebo plus methotrexate. SAR153191 (REGN88) is being studied at doses of 100 mg subcutaneously every week, 150 mg subcutaneously every week, 100 mg subcutaneously every other week, 150 mg subcutaneously every other week, or 200 mg subcutaneously every other week (all in addition to methotrexate). Data collection is expected to be complete in the second half of 2013 with a longer duration safety study planned for 2015.
Arzerra (ofatumumab) is a CD20 directed cytolytic monoclonal antibody marketed by GlaxoSmithKline already approved in the United States for treatment of patients with chronic lymphocytic leukemia. For use in RA, the dose being studied is two 700-mg IV infusions given 14 days apart with a total of 8 infusion cycles given over a 144-week period. Data from the Phase III program was presented at EULAR in late May 2011, but the filing timeline is unknown. GlaxoSmithKline is also in Phase II for development of a subcutaneous version of ofatumumab for use in RA.
Bristol-Myers Squibb’s Orencia (abatacept) is currently approved by the FDA as an IV infusion for adult patients with moderate to severe RA. On July 29, 2011, a subcutaneous formulation of Orencia was approved for the treatment of adults with moderate to severe RA. After a single IV infusion as a loading dose (dosed per body weight), 125 mg administered by subcutaneous injection should be given within 24 hours, followed by 125 mg subcutaneously once a week. The subcutaneous formulation of Orencia is expected to be commercially available in the United States in September 2011.
Stacey Ness, PharmD, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence and persistency programs, and chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is currently associate director of specialty services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, NJ.
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