Aetna considers biological therapies adalimumab (Humira), alefacept (Amevive), etanercept (Enbrel), infliximab (Remicade), and ustekinumab (Stelara) medically necessary for adults aged 18 years and older with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy when the following selection criteria are met:
Ten percent or more body surface area is affected by plaque psoriasis or member has a Psoriasis Area and Severity Index (PASI) score of 10 or more*; and
Member has failed to adequately respond to or is intolerant to a 3-month trial of one of the following phototherapies (unless contraindicated):
Psoralens (methoxsalen, trioxsalen) with UVA light (PUVA); or
UVB with coal tar or dithranol; or
UVB (standard or narrow-band).
* In exceptional circumstances (e.g., disabling acral disease), individuals with severe disease may fall outside of this definition, but may be considered for treatment.
Further treatment is not considered medically necessary for persons whose psoriasis has not adequately responded after 12 weeks.
There are several brands of targeted immune modulators on the market. There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications. Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab), Simponi (golimumab) and Stelara (ustekinumab) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna. Consequently, because other brands (e.g., Amevive (alefacept), Actemra (tocilizumab), Cimzia (certolizumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab) and Xeljanz (tofacitinib)) of injectables are more costly than these least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, no other brands of targeted immune modulator will be considered medically necessary unless the member has a contraindication, intolerance or incomplete response to at least 2 of the least cost brands of targeted immune modulator: Enbrel, Humira, Remicade, Simponi or Stelara, for the same medically necessary indication. If the least costly targeted immune modulator does not have the labeled indication (see appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication.
Aetna considers alefacept experimental and investigational for all other indications (e.g., alopecia areata, pyoderma gangraenosum, and systemic sclerosis) because its effectiveness for these indications has not been established.
Aetna considers ustekinumab experimental and investigational for all other indications, including Crohn's disease, erythrodermic psoriasis, multiple sclerosis, psoriatic arthritis, and pyoderma gangrenosum because its effectiveness for these indications has not been established.
More than 2 treatments of alefacept are considered experimental and investigational. According to the Food and Drug Administration (FDA), data on the safety and efficacy of alefacept treatment beyond 2 courses are limited.
Alefacept is considered experimental and investigational in members with CD4+ T lymphocyte counts less than 250 cells/mm3 because its safety in persons with this contraindication to alefacept has not been established.
As of June 8, 2009, efalizumab (Raptiva) is no longer available in the U.S. market (FDA, 2009).
Psoriasis is a common chronic skin disease characterized by cutaneous inflammation and epidermal hyperproliferation. Lesions appear on any part of the skin, but particularly the scalp, sacral area, and over the extensor aspect of the knees and elbows.
Ultraviolet light in conjunction with systemic psoralens (PUVA) is the phototherapy treatment of first choice for psoriasis other than localized psoriasis. PUVA is a form of photochemotherapy that combines the use of a psoralens (e.g., methoxsalen) with ultraviolet A phototherapy in the range of 320 to 400 nm. PUVA is highly effective in the treatment of psoriasis with resolution of skin lesions in over 85 % of patients after 20 to 30 treatments combining drug use and ultraviolet A irradiation. UVB may be given alone or in combination with tar or dithranol.
Other systemic treatments for psoriasis include methotrexate or cyclosporine. Both are contraindicated in pregnancy and require close monitoring.
Guidelines on psoriasis from the Finnish Medical Society Duodecim (2005) stated that biologicals such as alefacept, efalizumab, etanercept and infliximab may have a role in the treament of moderate to severe psoriasis refractory to other treatments or when other treatments are contraindicated or unsuitable.
Guidelines on psoriasis from the British Association of Dermatologists (2005) stated that most patients with moderate to severe disease achieve satisfactory disease control (i.e., significant or complete clearing of disease) in the short-term with at least one of the systemic agents currently available. Long-term disease control frequently requires some form of continuous therapy and consequent, predictable risks of toxicity. The guidelines state that, at present, the risks and benefits of anti-tumor necrosis factor (anti-TNF) agents, or efalizumab, relative to standard systemic therapy, are unknown. The guidelines state that early, widespread use of these agents in uncomplicated moderate to severe psoriasis is inappropriate and is not supported by the licensed indications for etanercept or efalizumab.
The British Association of Dermatologists (2005) stated that candidates for biological therapies for psoriasis should have severe disease and fulfill at least one of the following criteria:
Are or have become intolerant to or can not receive standard therapy; or
Are or have become unresponsive to standard therapy; or
Have developed or are at higher than average risk of developing clinically important drug-related toxicity and where alternative standard therapy can not be used; or
Have disease that is only controlled by repeated inpatient management; or
Have psoriatic arthritis fulfilling the British Society for Rheumatology (BSR) eligibility criteria for treatment with anti-tumor necrosis factor [TNF] agents, in association with skin disease; or
Have severe, unstable, life-threatening disease (erythrodermic or pustular psoriasis); or
Have significant, co-existant, unrelated co-morbidity that precludes the use of systemic agents such as cyclosporine or methotrexate.
For purposes of the British Association of Dermatology guideline, standard systemic therapy was defined to include acitretin, cyclosporine, methotrexate, narrow-band UVB, and PUVA. According to these guidelines, a person is considered unresponsive to standard therapy if there is an unsatisfactory clinical response (a less than 50 %improvement in baseline PASI score or precentage body surface area, and a less than 5 % improvement in DLQI) to at least 3 months of treament in the therapeutic dose range of standard systemic therapy.
According to the British Association of Dermatology guideline, the following standard dose ranges apply:
Acitretin 25 to 50 mg daily;
Cyclosporine 2.5 to 5 mg per kg daily;
Methotrexate single weekly dose (oral, subcutaneous, intramuscular) 15 mg, max 25 to 30 mg;
Narrow band UVB or psoralen photochemotherapy (non-response, rapid relapse, or exceeding recommended maximum doses) 150 to 200 treatments for PUVA, 350 treatments for narrowband UVB.
Alefacept (Amevive; Biogen, Cambridge, MA) was evaluated in 2 randomized, double-blind, placebo-controlled studies in adults with chronic (greater than 1 year) plaque psoriasis and a minimum body surface area involvement of 10 % who were candidates for or had previously received systemic therapy or phototherapy. Each course consisted of once-weekly administration for 12 weeks of placebo or alefacept. Patients could receive concomitant low potency topical steroids. Concomitant phototherapy or systemic therapy was not allowed.
In 1 study involving 553 patients, 14 % of patients treated with 1 12-week course of intravenous alefacept achieved a 75 % or greater improvement in psoriasis, compared with 4 % of patients receiving placebo. In another study involving 173 patients, 21 % of patient treated with 1 course of intramuscular alefacept achieved a 75 % or greater improvement in psoriasis, compared to 5 % of patients assigned to placebo.
The most frequently reported side effects to alefacept included sore throat, dizziness, cough, headache, nausea, pruritus, muscle aches, chills, and pain and inflammation at the injection site. The most serious side effects were lymphopenia, malignancies, serious infections requiring hospitalization, and allergic reactions.
The recommended dose of alefacept is 7.5 mg given once-weekly as an IV bolus or 15 mg given once-weekly as an IM injection. The recommended regimen is a course of 12 weekly injections. Re-treatment with an additional 12-week course may be initiated provided that CD4+ T lymphocyte counts are within the normal range, and a minimum of a 12-week interval has passed since the previous course of treatment. Data on retreatment beyond 2 cycles are limited.
The CD4+ T lymphocyte counts of patients receiving alefacept should be monitored weekly before initiating dosing and throughout the course of the 12-week dosing regimen. Dosing should be withheld if CD4+ T lymphocyte counts are below 250 cells/µL. The drug should be discontinued if the counts remain below 250 cells/µL for one month.
A sytematic review by the Drug Evaluation Review Project (Thaler, et al., 2012) found one head-to-head trial of targeted immune modulators for plaque psoriasis, which found that ustekinumab had greater efficacy than etanercept. The assessment noted that this head-to-head trial was small and had some methodological flaws and therefore the strength of evidence for this comparison is low. The assessment found that the general efficacy of adalimumab, alefacept, etanercept, infliximab, and ustekinumab for the treatment of moderate to severe plaque psoriasis was supported by multiple good to fair randomized controlled trials. In efficacy trials 50% to 81% of patients treated with targeted immune modulators achieved a Psoriasis Area and Severity Index 75 response, compared with 2% to 20% of patients on placebo.
The Canadian Coordinating Office for Health Technology Assessment (Shukla, 2003) concluded that in clinical trials of patients with moderate to severe psoriasis, alefacept showed a modest but statistically significant increase in the number of responders compared to placebo. However, due to a lack of direct comparative data, it is difficult to predict exactly how alefacept will fit into the current rotational psoriasis therapy paradigm.
In a randomized, multi-center, double-blind, placebo-controlled clinical study, Strober et al (2009) evaluated the effectiveness of alefacept for the treatment of severe alopecia areata (AA). A total fo 45 individuals with chronic and severe AA affecting 50 % to 95 % of the scalp hair and resistant to previous therapies were included in this study. Main outcome measure was improved Severity of Alopecia Tool (SALT) score over 24 weeks. Patients receiving alefacept for 12 consecutive weeks demonstrated no statistically significant improvement in AA when compared with a well-matched placebo-receiving group (p = 0.70). The authors concluded that alefacept is ineffective for the treatment of severe AA.
Manno an Boin (2010) stated that scleroderma is a multi-system autoimmune disease characterized by an abnormal immune activation associated with the development of underlying vascular and fibrotic disease manifestations. These investigators reviewed the current use of drugs targeting the immune system in scleroderma. Non-selective immunosuppression, and in particular cyclophosphamide, remains the main treatment for progressing skin involvement and active interstitial lung disease. Mycophenolate mofetil is a promising alternative to cyclophosphamide. The use of cyclosporine has been limited by modest efficacy and serious renal toxicity. Newer T-cell (sirolimus and alefacept) and B-cell (rituximab)-targeted therapies have provided some encouraging results in small pilot studies. Hematopoietic stem cell transplantation can be effective for severe fibrotic skin disease, but toxicity remains a concern. Clinical efficacy and safety of anti-fibrotic treatments (e.g., imatinib) await confirmation. Newer biological agents targeting key molecular or cellular effectors in scleroderma pathogenesis are now available for clinical testing.
Wollina and Haroske (2011) described current progress in understanding pyoderma gangraenosum and discussed therapeutic interventions. Pyoderma gangraenosum is one of the most common extra-intestinal manifestations of chronic inflammatory bowel disease. In multi-variate analyses, pyoderma gangraenosum was significantly and independently associated with black African origin, familial history of ulcerative colitis, uninterrupted pancolitis as the initial location of inflammatory bowel disease, permanent stoma, eye involvement and erythema nodosum. The treatment of choice for idiopathic pyoderma gangraenosum is systemic corticosteroids, but cyclosporine A, mycophenolate mofetil and TNF-alpha inhibitors have been successful to control pyoderma gangraenosum as second line or adjuvant options. In addition, small studies have been published with successful therapeutic intervention using alefacept, visilizumab or anakinra, but controlled trials are needed.
Efalizumab (Raptiva), developed by Xoma Ltd. (Berkeley, CA) and Genentech Inc. (South San Francisco, CA), gained Food and Drug Administration (FDA) approval in October 2003 for the treatment of moderate-to-severe psoriasis in people at least 18 years old. Efalizumab, a once-weekly subcutaneously injected drug, is a humanized anti-CD11a monoclonal antibody.
In an open-label, multicenter, dose escalation study, Gottlieb et al (2002) examined the effects of intravenous infusions of efalizumab (Emab) in 39 patients with moderate-to-severe psoriasis. Efalizumab was administered for 7 weeks at doses of 0.1 mg/kg every other week or 0.1 mg/kg weekly (Category 1), 0.3 mg/kg weekly (Category 2), and 0.3 increasing to 0.6 or 1.0 mg/kg weekly (Category 3). Skin biopsies were performed on days 0, 28, and 56. The main outcome measures were serum Emab levels, levels of total and unoccupied T-cell CD11a, T cell counts, epidermal thickness, cutaneous intercellular adhesion molecule 1 (ICAM-1) and keratin 16 (K16) expression, Psoriasis Area and Severity Index (PASI) scores. Category 1 failed to maintain detectable serum Emab or T cell CD11a down-modulation between doses. Category 2 achieved both. Category 3 achieved both and additionally maintained sustained T-cell CD11a saturation between doses. A dose-response relationship was also observed clinically and histologically. The mean decrease in the PASI score was 47 % in Category 3, 45 % in Category 2, and 10 % in Category 1 (p < 0.001). Epidermal and dermal T-cell counts, epidermal thickness, and ICAM-1 and K16 expression decreased in Categories 2 and 3, but not in Category 1. Circulating lymphocyte counts increased in Categories 2 and 3. The authors concluded that at doses of 0.3 mg/kg or more per week, intravenous Emab produced significant clinical and histological improvement in psoriasis, which correlated with sustained serum Emab levels and T-cell CD11a saturation and down-modulation.
Data submitted to the FDA included a randomized, double-blind, placebo-controlled phase III study that showed 44 % (161/368) of patients treated continuously with 1 mg/kg of Raptiva for up to 24 weeks achieved a 75 % or greater improvement in PASI scores (PASI 75). Additional data included follow-up (84 weeks) results from a separate open-label study. In this study, patients received 2 mg/kg of Raptiva weekly for an initial 12 weeks and subsequently received a once-weekly dose of 1 mg/kg of Raptiva starting at week 13. For each successive 3-month period of treatment, drop-outs during that period were analyzed using their last available PASI assessment, but were excluded from subsequent cohorts. Among the 194 patients who remained in the trial through week-84, 67 % (130/194) of patients achieved PASI 75 and 34 % of patients (66/194) achieved PASI 90. Some side effects of Raptiva included headaches, chills, fever and nausea.
In an international consensus conference on the use of biological therapies in the systemic management of psoriasis, Sterry and colleagues (2004) stated that given the apparent lack of traditional end-organ toxicity (e.g., nephrotoxicity or hepatotoxicity), biologicals may be used for significant periods of time. The authors noted that efalizumab has shown sustained effectiveness without increased toxicity during continuous dosing of up to 24 months. They noted that data and experience suggest that biologicals promise to provide psoriasis patients with long-term control of their disease.
Gottlieb et al (2006) assessed the safety and effectiveness of long-term, continuous efalizumab therapy. Of 339 patients enrolled in an ongoing, open-label, phase III clinical trial, after 3 months 290 qualified for and entered the maintenance treatment phase. Results for the first 27 months of this 36-month continuous therapy trial were presented. At month 3, 41 % of patients achieved at least a 75 % reduction in PASI score; at month 27, 47 % achieved at least a 75 % reduction in PASI score (intent to treat, n = 339). Among patients eligible for maintenance therapy (n = 290), 56 % achieved at least a 75 % reduction in PASI score at month 27. Moreover, the at least 90 % reduction in PASI score rate increased through 18 months (33 %). The safety profile with efalizumab was sustained throughout 27 months of continuous treatment with no new common events over time. The authors concluded that these findings suggest that efalizumab maintains, and in some patients continues to improve, efficacy during long-term therapy. The major drawback of this study is that because the extended treatment period was not a randomized clinical trial, no formal comparative analyses versus placebo were conducted. Based on the findings of Gottlieb et al (2006), Menter et al (2006) stated that patients who are maintaining effectiveness and tolerating efalizumab favorably can receive efalizumab on a continuous basis.
Poulin and associates (2006) reported that phase III clinical trials for efalizumab have demonstrated its short-term and long-term (12-week, 6-month, and 3-year) safety and effectiveness for the treatment of psoriasis. The authors stated that efalizumab has emerged as an important addition to the dermatological pharmacopeia for the long-term treatment of psoriasis. Furthermore, Shear (2006) noted that efalizumab has been associated with thrombocytopenia and hemolytic anemia. Data on the safety of greater than 2.5 years' continuous treatment with efalizumab are reassuring and a valuable beginning to understanding the role and risk of harm of long-term therapy for a chronic disease. The author stated that longer follow-up studies and safety databases, for each of the biologicals used in psoriasis, are needed to ensure both prolonged effectiveness and minimal risk of harm.
Guidelines from the National Institute for Health and Clinical Excellence (NICE, 2006) stated that efalizumab is recommended for the treatment of adults with plaque psoriasis only when the following criteria are met:
The disease is severe as defined by a total Psoriasis Area Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10; and
The psoriasis has failed to respond to standard systemic therapies, including cyclosporin, methotrexate, and PUVA, or the person is intolerant to, or has a contraindication to, these treatments.
The psoriasis has failed to respond to etanercept.
According to NICE guidelines, further treatment with efalizumab is not recommended in patients unless their psoriasis has responded adequately at 12 weeks. Further treatment cycles are not recommended in these patients. According to NICE, an adequate response is defined as either: (i) a 75 % reduction in the PASI score from when treatment started (PASI 75); or (ii) a 50 % reduction in the PASI score (PASI 50) and a 5-point reduction in DLQI from when treatment started.
Guidelines from the British Association of Dermatologists (2005) stated that efalizumab should be considered first choice of biological therapy for patients with a high risk of latent tuberculosis (and therefore requiring tuberculosis prophylaxis) or with evidence of demyelinating disease.
On April 8, 2009, Genentech announced that it has begun a voluntary, phased withdrawal of efalizumab (Raptiva) from the U.S. market. Genentech took this action because of a potential risk to patients who uses efalizumab in developing progressive multifocal leukoencephalopathy (PML), a rare, serious, progressive neurological disease that affects the central nervous system. By June 8, 2009, Raptiva will no longer be available in the U.S. The risk that an individual patient taking efalizumab will develop PML is rare and is generally associated with long-term use. Generally, PML occurs in people whose immune systems have been severely weakened and often leads to an irreversible decline in neurological function and death. There is no known effective treatment for PML. On October 16, 2008, FDA updated the FDA-approved labeling for Raptiva to warn of the risk of life-threatening infections, including PML. On February 19, 2009, the FDA issued a Public Health Advisory informing patients and prescribers of the risk of PML in patients taking Raptiva, after receiving reports of 4 patients with PML, 3 of whom died. On March 13, 2009, the FDA approved a Medication Guide for Raptiva and included additional information in Raptiva's labeling regarding PML.
Etanercept (Enbrel) (Immunex Corporation, Thousand Oaks, CA) gained FDA approval for the treatment of chronic moderate-to-severe chronic plaque psoriasis in April 2004. The FDA approved a twice-weekly dose of 50 mg for the first 3 months of psoriasis treatment followed by a maintenance dose of 50 mg per week thereafter. The FDA approval was based on the results of 2 phase III clinical studies involving adults with psoriasis who were treated for up to 12 months. These studies reported nearly half (46 %) of those who received etanercept had a 75 % or greater improvement on the PASI after 3 months of treatment. That response was sustained for an additional 3 months at the lower dose (25 mg once-weekly).
According to guidelines from the National Institute for Health and Clinical Excellence (NICE, 2006), etanercept, administered at a dose not exceeding 25 mg twice-weekly is recommended for the treatment of adults with plaque psoriasis only when their disease is severe and they have failed to respond to standard systemic therapies, as described above.
According to NICE guidelines, etanercept treatment should be discontinued in patients whose psoriasis has not responded adequately at 12 weeks. Further treatment cycles are not recommended in these patients.
Guidelines from the British Association of Dermatologists (2005) stated that etanercept should be considered first choice for patients with significant, uncontrolled psoriatic arthritis, and for patients with stable psoriasis where a decision to treat with an tumor necrosis factor inhibitor has been made.
The U.S. Pharmacopeial Convention (2003) has concluded that psoriatic arthritis and psoriasis are accepted indications for infliximab. A controlled clinical study (Chaudhari et al, 2001) has demonstrated the short-term effectiveness of infliximab in plaque psoriasis. In a controlled clinical trial in which patients and investigators were blinded for the first 10 weeks, participants were assigned to either of 2 doses of infliximab (5 mg/kg or 10 mg/kg at baseline, 2 weeks, and 6 weeks) or to placebo. Nineteen of 22 patients assigned to infliximab achieved good or better physician's overall assessments, compared with 2 of 11 patients assigned to placebo. In initial studies, remissions seemed to be durable, with many patients improving for 6 months or longer. Subsequent randomized controlled clinical studies have confirmed the efficacy of infliximab for treatment of plaque psoriasis (Reich et al, 2005; Feldman et al, 2005; Gottlieb et al, 2004).
Guidelines from the British Association of Dermatologists (2005) stated that infliximab is useful in clinical circumstances requiring rapid control of psoriasis, e.g., in unstable erythrodermic or pustular psoriasis, due to its very rapid onset of action and high response rate.
Adalimumab has been approved by the FDA for the treatment for adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. According to the FDA-approved labeling, adalimumab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician. Chronic plaque psoriasis is an autoimmune disease characterized by inflammed, scaly skin lesions known as plaques, which may crack and bleed. While psoriasis can occur in people of all ages, it typically appears in patients between the ages of 15 and 35 years. Approximately 25 % of persons with chronic plaque psoriasis exhibit moderate to severe disease. Up to 30 % of psoriasis patients develop psoriatic arthritis. Treatment may include topical agents, phototherapy or oral or injectable medications.
The FDA approval of adalimumab for chronic plaque psoriasis was based on 2 pivotal trials, REVEAL and CHAMPION, showing that approximately 3 out of 4 patients achieved 75 % clearance or better at week 16 of treatment versus placebo. Both studies evaluated the efficacy and safety of HUMIRA in clearing skin in moderate to severe adult plaque psoriasis patients versus placebo. In addition, CHAMPION compared a biologic medication to methotrexate, a standard systemic treatment for psoriasis. In each trial, reduction in disease activity was determined by the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). In REVEAL, a 52-week trial, the short-term and sustained clinical efficacy and safety of adalimumab were evaluated in 1,212 patients with moderate to severe chronic plaque psoriasis. Patients experienced a significant reduction in the signs and symptoms of their disease at 16 weeks when treated with adalimumab. Specifically, 71 % of patients receiving adalimumab achieved PASI 75 compared to 7 % of patients receiving placebo at week 16. At week 16, 62 % of adalimumab-treated patients achieved a PGA score of clear or minimal compared to 4 % of placebo-treated patients. In CHAMPION, a 16-week study evaluating 271 psoriasis patients, adalimumab-treated patients experienced a significant reduction in the signs and symptoms of their disease compared with methotrexate or placebo-treated patients. Seventy-eight percent of patients treated with adalimumab (n = 99) achieved a PASI 75 response, compared to 19 % of patients treated with placebo (n = 48). Seventy-one percent of patients treated with adalimumab achieved a PGA score of clear or minimal at 16 weeks of treatment, compared with 10 % of placebo-treated patients. The safety profile of adalimumab in the plaque psoriasis clinical trials was reported to be similar to that seen in adalimumab clinical trials for rheumatoid arthritis. The most commonly reported adverse events in adalimumab psoriasis trials were upper respiratory tract infection, nasopharyngitis (inflammation of the nose and pharynx), headache, sinusitis and arthralgia. In clinical studies of plaque psoriasis, patients are treated with an initial 80 mg dose of adalimumab (2 40-mg injections) followed by 1 adalimumab injection (40 mg) 1 week later. After that, a maintenance dose of 40 mg was administered every other week.
In September 2009, the FDA approved ustekinumab (Stelara) for the treatment of adults with moderate-to-severe psoriasis. Ustekinumab is a fully human monoclonal antibody that binds with high specificity and affinity to the cytokines interleukin (IL)-12 and IL-23, thereby suppressing IL-12- and IL-23-mediated inflammation associated with psoriasis. In a review on the use of biological agents in the treatment of psoriasis, Tzu et al (2008) noted that IL-12/IL-23 inhibitors are new agents. Furthermore, Rozenblit and Lebwohl (2009) stated that new biologic therapies for psoriasis and psoriatic arthritis include antibodies to IL-12 and IL-23.
Weber and Keam (2009) noted that in 2 large, phase III trials in patients with moderate-to-severe plaque psoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients (administered as 2 injections 4 weeks apart) than placebo recipients achieved a 75 % improvement on the PASI 75 score at 12 weeks. Other efficacy measures, including the physician's global assessment of clinical response at week 12, also favored ustekinumab over placebo. Psoriatic symptom control was maintained during ustekinumab maintenance therapy (administered once every 12 weeks) for up to 76 weeks. In a phase II trial in patients with active plaque psoriasis and psoriatic arthritis, signs and symptoms of arthritis and psoriatic symptom control were improved to a greater extent with ustekinumab than with placebo at 12 weeks, based on the proportion of patients achieving a 20 % improvement in ACR response criteria (arthritis) or PASI 75 (skin symptoms). Health-related quality of life, assessed using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index, was improved to a significantly greater extent with ustekinumab than with placebo at week 12. Subcutaneous ustekinumab was generally well-tolerated in clinical trials, with most treatment-emergent adverse events being of mild severity.
In a phase III, parallel, randomized, double-blind, placebo-controlled trial (PHOENIX 1), Leonardi et al (2008) examined the safety and effectiveness of ustekinumab for the treatment of psoriasis. A total of 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n = 255) or 90 mg (n = 256) at weeks 0 and 4 and then every 12 weeks; or placebo (n = 255) at weeks 0 and 4, with subsequent cross-over to ustekinumab at week 12. Patients who were initially randomized to receive ustekinumab at week 0 who achieved long-term response (at least 75 % improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomized at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomizations were done with a minimization method via a centralized interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention-to-treat. All randomized patients were included in the efficacy analysis. Overall, 171 (67.1 %) patients receiving ustekinumab 45 mg, 170 (66.4 %) receiving ustekinumab 90 mg, and 8 (3.1 %) receiving placebo achieved PASI 75 at week 12 (difference in response rate versus placebo 63.9 %, 95 % confidence interval [CI]: 57.8 to 70.1, p < 0.0001 for 45 mg and 63.3 %, 57.1 to 69.4, p < 0.0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45-mg group and 172 patients in the 90-mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p < 0.0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54.5 %) of the 510 patients receiving ustekinumab and 123 (48.2 %) of the 255 receiving placebo. Serious adverse events occurred in 6 (1.2 %) of 510 patients receiving ustekinumab and in 2 (0.8 %) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo cross-over and randomized withdrawal phases as it was in the placebo-controlled phase. The authors concluded that ustekinumab seems to be effective for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least 1 year in most patients.
In a multi-center, phase III, double-blind, placebo-controlled trial (PHOENIX 2), Papp et al (2008) assessed the safety and effectiveness of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders. A total of 1,230 patients with moderate-to-severe psoriasis (defined by a PASI score greater than or equal to 12, and at least 10 % total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n = 409) or 90 mg (n = 411) at weeks 0 and 4, then every 12 weeks, or placebo (n = 410). Partial responders (i.e., patients achieving greater than or equal to 50 % but less than 75 % improvement from baseline in PASI) were re-randomized at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomizations were done with a minimization method via a centralized interactive voice response. The primary endpoint was the proportion of patients achieving at least PASI 75 at week 12. Analyses were by intention-to-treat. All randomized patients were included in the efficacy analysis. Overall, 273 (66.7 %) patients receiving ustekinumab 45 mg, 311 (75.7 %) receiving ustekinumab 90 mg, and 15 (3.7 %) receiving placebo achieved the primary endpoint (difference in response rate 63.1 %, 95 % CI: 58.2 to 68.0, p < 0.0001 for the 45-mg group versus placebo and 72.0 %, 67.5 to 76.5, p < 0.0001 for the 90-mg group versus placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8 %] versus 11 [33.3 %]; difference in response rate 35.4 %, 95 % CI: 12.7 to 58.1, p = 0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1 %) patients in the 45-mg group, 197 (47.9 %) in the 90-mg group, and 204 (49.8 %) in the placebo group experienced adverse events; serious adverse events were seen in 8 (2.0 %) patients in the 45-mg group, 5 (1.2 %) in the 90-mg group, and 8 (2.0 %) in the placebo group. The authors concluded that although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.
In a phase II, randomized, double-blind, placebo-controlled, cross-over study, Gottlieb et al (2009) evaluated the safety and effectiveness of ustekinumab for psoriatic arthritis. Patients with active psoriatic arthritis were randomly allocated via interactive voice response system to either ustekinumab (90 mg or 63 mg) every week for 4 weeks (weeks 0 to 3) followed by placebo at weeks 12 and 16 (n = 76; Group 1) or placebo (weeks 0 to 3) and ustekinumab (63 mg) at weeks 12 and 16 (n = 70; Group 2). The first 12 weeks of the study were placebo-controlled. Masking was maintained to week 16, and patients were followed-up to week 36 [corrected]. The primary endpoint was American College of Rheumatology 20 % improvement (ACR20) response at week 12. Analysis was by intention-to-treat. At week 12, 32 (42 %) patients in Group 1 and 10 (14 %) in Group 2 achieved the primary endpoint (difference 28 % [95 % CI: 14.0 to 41.6]; p = 0.0002). Of 124 (85 %) participants with psoriasis affecting 3 % or more body surface area, 33 of 63 (52 %) in Group 1 and 3 of 55 (5 %) in Group 2 had a 75 % or greater improvement in psoriasis area and severity index score at week 12 (47 % [33.2 to 60.6]; p < 0.0001). During the placebo-controlled period (weeks 0 to 12), adverse events arose in 46 (61 %) patients in Group 1 and 44 (63 %) in Group 2; serious adverse events were recorded in 3 (4 %) Group 2 patients (none in Group 1). The authors concluded that ustekinumab significantly reduced signs and symptoms of psoriatic arthritis and diminished skin lesions compared with placebo, and the drug was well-tolerated. They stated that larger and longer term studies are needed to further characterise ustekinumab safety and effectiveness for the treatment of psoriatic arthritis.
Ryan et al (2010) examined the safety and efectiveness of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites. Ustekinumab has shown significant effectiveness in the treatment of chronic plaque psoriasis in phase III studies, and promising results in phase II studies in psoriatic arthritis. Effectiveness has been shown in Crohn's disease only in non-responders to infliximab. Furthermore, ustekinumab did not show benefit in the treatment of multiple sclerosis.
The effectiveness of ustekinumab in treating psoriasis were reproduced in the phase III, multi-center, randomized ACCEPT trial (2008). This head-to-head study comparing ustekinumab and etanercept for the treatment of moderate-to-severe psoriasis showed ustekinumab superior to etanercept according to primary and major secondary efficacy endpoints. The primary endpoint of the trial was the percentage of participants achieving at least a 75 % reduction in psoriasis at week 12 as measured by PASI 75. At week 12, after 2 subcutaneous injections at weeks 0 and 4, 68 % and 74 % of patients receiving ustekinumab 45 mg or ustekinumab 90 mg, respectively, achieved a PASI 75 compared with 57 % of patients receiving etanercept 50 mg subcutaneous injections twice-weekly for 12 weeks (p = 0.012 for ustekinumab 45 mg; p < 0.001 for ustekinumab 90 mg, each compared with etanercept).
In a phase II clinical trial, Kavanaugh et al (2010) evaluated the effect of ustekinumab on physical disability and health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). Patients with active PsA were randomized (1:1 ratio) to receive either ustekinumab at weeks 0, 1, 2, and 3 and placebo at weeks 12 and 16 (n = 76) or placebo at weeks 0, 1, 2, and 3 and ustekinumab at weeks 12 and 16 (n = 70). Physical function was assessed using the disability index from the Health Assessment Questionnaire-Disability Index (HAQ-DI) in all randomized patients. HRQoL was evaluated using the DLQI in a subset of patients (84.9 %) with at least 3 % body surface area (BSA) psoriasis involvement at baseline. At baseline, overall mean HAQ-DI and DLQI scores were 0.9 and 11.5, respectively, indicating impaired physical function and moderate effect on HRQoL. At week 12, ustekinumab patients had significantly more improvement (decrease) in the mean HAQ-DI (-0.31) and DLQI (-8.6) scores versus placebo (-0.04 and -0.8, respectively; p < 0.001 for both comparisons). At week 12, 58.7 % (37/63) of ustekinumab-treated patients had a DLQI score of 0 or 1 (no negative effect of disease or treatment on HRQoL) versus 5.5 % (3/55) for placebo (p < 0.001). The results also indicated a positive but weak correlation between improvement in physical function and HRQoL, pain, and skin response as well as between improvement in joint and skin responses in patients receiving ustekinumab or placebo. The authors concluded that ustekinumab significantly improved physical function and HRQoL in patients with PsA and psoriasis involving at least 3 % BSA. Limitations of the study included the short duration of the placebo-controlled period and the relatively small patient population.
Kurzeja et al (2011) stated that interleukin (IL)-23 is an important regulator of T helper-17 lymphocytes, which influence the cutaneous immune system by production of IL-17 and several other pro-inflammatory cytokines. This pathway has been recently linked to the pathogenesis of psoriasis and numerous other skin diseases. A newly developed biologic drug, ustekinumab, which targets the p40 subunit of IL-12 and IL-23, was approved by the U.S. FDA and the European Medicines Agency in 2009 for the treatment of moderate to severe psoriasis. Administered as subcutaneous injections of 45 mg at weeks 0 and 4, and then every 12 weeks, ustekinumab produces a 75 % improvement in the PASI in 66.4 to 75.7 % of patients and a DLQI score of 0 or 1 in 55 to 56 % of patients after 12 weeks of therapy. A recent clinical trial also indicates the possible efficacy of ustekinumab in psoriatic arthritis. The proportion of patients who had at least 1 adverse event through 12 weeks in clinical studies was 51.6 to 57.6 % in the ustekinumab group and 50.4 % in the placebo group. Serious adverse events were observed in 1.4 to 1.6 % of patients treated with ustekinumab and in 1.4 % of patients receiving placebo. Injection-site reactions occurred in 1 to 2 % of patients and 5 % of patients developed anti-ustekinumab antibodies. The authors concluded that further studies are needed to evaluate the long-term safety and effectiveness of ustekinumab.
Guenova et al (2011) noted that IL-23 is involved in the pathogenesis of the chronic inflammatory Crohn disease. Pyoderma gangrenosum (PG) is often associated with and can even be the first manifestation of this disease and has abundant neutrophilic infiltration. Because IL-23 plays a critical role in driving inflammation associated with IL-17 production and especially neutrophil recruitment, these researches suspect that PG might be driven by a pathogenetic mechanism similar to that of inflammatory bowel diseases or psoriasis. Tissue sample analysis showed highly elevated expression of IL-23 on both transcriptional and protein level in a recalcitrant PG lesion. On the basis on these data, a treatment targeting the p40 subunit of the heterodimeric IL-23 with the monoclonal antibody ustekinumab was started. Therapy with ustekinumab resulted in a significant decrease of IL-23 expression in PG and healing after 14 weeks of treatment. No relapse occurred in a 6-month follow-up period. The authors concluded that these findings provided evidence of an IL-23-dominated inflammatory infiltrate in PG. This might specify a new concept for PG pathophysiology and suggests a possibility for using ustekinumab as a therapeutic agent in this disease.
Bailey et al (2012) summarized the current state of evidence for combination topical and systemic therapies for mild-to-severe psoriasis. These researchers performed a systematic search for all entries in PubMed, CINAHL, Cochrane Review, and EMBASE related to combination treatments for psoriasis through July 2010. They included randomized controlled trials that reported proportion of disease clearance or mean change in clinical severity score (or provided these data through communication with study authors) for efficacy of a combination treatment for psoriasis compared with 1 or more corresponding monotherapies. Study data were extracted by 3 independent investigators, with disagreement resolved by consensus. The proportion of patients who achieved clearance, definition of clearance, means and standard deviations for baseline disease symptom score and final disease symptom score, and major design characteristics were extracted for each study. Combination treatments consisting of vitamin D derivative and corticosteroid, vitamin D derivative and UV-B, vitamin A derivative and psoralen-UV-A, vitamin A derivative and corticosteroid, vitamin A derivative and UV-B, corticosteroid and hydrocolloid occlusion dressings, UV-B and alefacept, as well as vitamins A and D derivatives were more effective than 1 or more monotherapies using the likelihood of clearance as the outcome. Blinding status and potency of the corticosteroid treatment used were significant sources of heterogeneity between studies. The authors concluded that these findings demonstrated the need for additional long-term trials with standardized outcome measures to evaluate the efficacy and adverse effects of combination therapies for psoriasis and highlighted the possible effects of trial design characteristics on results.
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