Bexarotene ligand pharmaceuticals

Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the treatment of cutaneous T-cell lymphoma (CTCL), as Targretin capsules, in the US in January 2000 [359023]. The company filed an NDA for Targretin capsules in June 1999, and for topical gel in December 1999 [329011], [349982] specifically for once-daily oral administration for the treatment of patients with early-stage CTCL who have not tolerated other therapies, patients with refractory or persistent early stage CTCL and patients with refractory advanced stage CTCL. The FDA approved Targretin capsules at the end of December 1999 for once-daily oral treatment of all stages of CTCL in patients refractory to at least one prior systemic therapy, at an initial dose of 300 mg/m2/day. After an NDA was submitted in December 1999 for Targretin gel, the drug received Priority Review status for use as a treatment of cutaneous lesions in patients with stage IA, IB or IIA CTCL [354836]. The FDA issued an approvable letter in June 2000, and granted marketing clearance for CTCL in the same month [370687], [372768], [372769], [373279]. Ligand had received Orphan Drug designation for this indication [329011]. At the request of the FDA, Ligand agreed to carry out certain post-approval phase IV and pharmacokinetic studies [351604]. The company filed an MAA with the EMEA for Targretin Capsules to treat lymphoma in November 1999 [348944]. The NDA for Targretin gel is based on a multicenter phase III trial that was conducted in the US, Canada, Europe and Australia involving 50 patients and a multicenter phase I/II clinical program involving 67 patients. Targretin gel was evaluated for the treatment of patients with early stage CTCL (IA-IIA) who were refractory to, intolerant to, or reached a response plateau for at least 6 months on at least two prior therapies. Efficacy results exceeded the protocol-defined response target rates; side effects were primarily limited to local skin reactions [349982]. Ligand has worldwide rights to market bexarotene capsules, and will market the drug in the US, Canada and selected European markets. In Spain, Portugal, Greece and Central and South America, Ferrer Internacional will market and distribute the drug. As of December 1999, Ligand was seeking additional distribution partners for select European and Asian markets [351604]. In January 2000, Alfa Wassermann signed an agreement with Ligand to exclusively market and distribute Targretin gel and capsules in Italy. Alfa paid US $0.75 million on signing with additional amounts up to an aggregate total of US $1.0 million on achievement of certain registration milestones, which are expected to be met in 2000 [351882].     

A brief primer on treatments of cutaneous T cell lymphoma, newly approved or late in development

Dermatologists use a variety of treatments for cutaneous T cell lymphoma (CTCL) or mycosis fungoides, in particular topical corticosteroids, psoralen and ultraviolet A phototherapy (PUVA) or ultraviolet B (UVB) phototherapy. Metastatic disease has been treated with radiotherapy, extracorporeal photophoresis, and old line chemotherapy agents such as methotrexate, chlorambucil, purine analogues, cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone (CHOP), and interferon-alpha-2a. This feature will review these new agents including zanolimumab, denileukin diftitox, bexarotene, and vorinostat. Zanolimumab is a human monoclonal antibody that acts as a CD4 antagonist and has been granted orphan drug status in the US and Europe. Vorinostat (suberoylanilide hydroxamic acid) is a histone deacetylases inhibitor that has recently been approved by the FDA for the treatment of progressive, persistent, or recurrent CTCL on or after 2 systemic therapies have failed. Bexarotene is indicated in CTCL patients who are refractory to at least one prior systemic therapy. Denileukin diftitox is indicated for the treatment of patients with persistent or recurrent CTCL whose malignant cells express the CD25 component of the interleukin-2 receptor.     

Bexarotene in the treatment of cutaneous T-cell lymphoma

Primary cutaneous T-cell lymphomas encompass a spectrum of non-Hodgkin's lymphomas that are characterised by clonal proliferation of skin-homing malignant T lymphocytes. Mycosis fungoides and the leukaemic variant Sézary syndrome, collectively referred to as cutaneous T-cell lymphomas, are the most common entities. No curative therapy exists and patients ultimately develop advanced or relapsed disease that is refractory to standard treatment options. Therefore, there is a great need for the development of novel emerging therapies. Bexarotene is the first synthetic nuclear retinoid X receptor-selective retinoid approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma in all stages, as both an oral capsule and a topical gel formulation. Bexarotene was found to induce apoptosis in a variety of preclinical in vitro and in vivo models including cutaneous T-cell lymphoma cells, and has shown efficacy in two multi-centre, open-label Phase II - III clinical trials for early and advanced stages of cutaneous T-cell lymphoma in patients who have failed or were refractory to standard therapies. New insights into the immunomodulatory function of bexarotene have indicated opportunities for combined treatment with IFN-alpha, denileukin diftitox or phototherapy. This article reviews the biological properties, pharmacokinetics, clinical efficacy, safety and role of bexarotene in the treatment of cutaneous T-cell lymphoma.     

Bexarotene in the treatment of cutaneous T-cell lymphoma

Primary cutaneous T-cell lymphomas encompass a spectrum of non-Hodgkin’s lymphomas that are characterised by clonal proliferation of skin-homing malignant T lymphocytes. Mycosis fungoides and the leukaemic variant Sézary syndrome, collectively referred to as cutaneous T-cell lymphomas, are the most common entities. No curative therapy exists and patients ultimately develop advanced or relapsed disease that is refractory to standard treatment options. Therefore, there is a great need for the development of novel emerging therapies. Bexarotene is the first synthetic nuclear retinoid X receptor-selective retinoid approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma in all stages, as both an oral capsule and a topical gel formulation. Bexarotene was found to induce apoptosis in a variety of preclinical in vitro and in vivo models including cutaneous T-cell lymphoma cells, and has shown efficacy in two multi-centre, open-label Phase II – III clinical trials for early and advanced stages of cutaneous T-cell lymphoma in patients who have failed or were refractory to standard therapies. New insights into the immunomodulatory function of bexarotene have indicated opportunities for combined treatment with IFN-α, denileukin diftitox or phototherapy. This article reviews the biological properties, pharmacokinetics, clinical efficacy, safety and role of bexarotene in the treatment of cutaneous T-cell lymphoma.     

Bexarotene: new preparation. Cutaneous lymphoma: too many adverse effects

(1) Existing treatments for cutaneous T cell lymphoma (topical agents, chemotherapy, photopheresis, interferon alfa) have cosmetic benefits but no impact on survival. (2) Bexarotene, a synthetic retinoid, is approved for the treatment of adults with advanced-stage cutaneous lymphoma refractory to at least one systemic treatment. (3) Two non comparative trials included patients who were refractory or in relapse after various systemic treatments: one included 58 patients at an early stage of the disease, and the other 94 patients at an advanced stage. The evidence from these trials is weak for several reasons such as the lack of a standard endpoint for efficacy and numerous protocol modifications. The optimal dose of bexarotene is unknown. No comparative trials are available, and indirect comparisons are often misleading. (4) Nearly all patients treated with bexarotene suffer adverse effects, which can include hyperlipidemia (risk of pancreatitis), hypothyroidism, and haematological reactions (leukopenia, anemia). There is also an unconfirmed risk of cataract. (5) In practice, bexarotene is a highly toxic drug with uncertain efficacy, and there is no reason to prescribe it. Bexarotene should never have been authorised on the basis of such a bad evaluation.     

Successful treatment of patch type mycosis fungoides with tacrolimus ointment 0.1%

Cutaneous T cell lymphomas (CTCLs) are a heterogenous group of lymphoproliferative disorders caused by clonally-derived, skin-invasive T cells. A variety of skin-directed and systemic therapies are available to treat mycosis fungoides/Sézary syndrome (MF/SS), the therapeutic choices of which are guided by the stage of disease. A 29-year-old man presented at our clinic with pruritic, erythematous macules located on the sternum and the lower back. Histological findings and immunohistochemistry studies showed patch stage MF. The patient was treated with tacrolimus ointment 0.1% twice daily for one month, achieving complete remission. Three months after the first episode a relapse was successfully treated with the same therapeutic regimen. Tacrolimus is an immunomodulatory macrolide that reduces the stimulatory capacity toward T cells and is therefore worth investigating as a treatment of CTCL. Topical tacrolimus has been related to an unknown effect with the risk for secondary malignancies including CTCL. Also, black box warnings have been proposed by the FDA for the topical calcineurin inhibitors. Nevertheless, our results in the treatment of early stage MF are in agreement with other unpublished data that have observed its efficacy. To our knowledge, there is no other case of patch type mycosis fungoides treated with tacrolimus ointment 0.1% in the medical literature.     

Investigative drugs for the treatment of cutaneous T-cell lymphomas (CTCL): an update

Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Mycosis fungoides and Sézary syndrome are the most common CTCL. Early stage disease follows a protracted course, carries a 5-year disease specific survival of 97% and can be treated with skin-directed therapies. Widespread, advanced disease has a 5-year OS of less than 25% and necessitates systemic treatment. Allogeneic stem cell transplantation is a potentially curative treatment option for advanced CTCL, however, transplant-related morbidity and mortality must be considered and a risk-benefit assessment performed on individual basis.

Areas covered: Herein, we provide a review of investigative drugs in early-stage trials for the treatment of cutaneous CTCL, including topically applied immunomodulators such as replicating herpes virus or toll-like receptor 7/8 agonist resiquimod and systemic therapies with monoclonal antibodies, such as anti-CD47, recombinant cytotoxic interleukin 2 fusion protein anti-KIR3DL2 antibody and anti-miR-155 antibody.

Expert Opinion: Among the reviewed drugs, resiquimod shows promising clinical efficacy with good tolerability in early CTCL. In refractory or relapsed disease, intratumoral anti-CD47-, anti-CCR4- and anti-KIR3DL2-antibodies show high response rates, however, latter two also show considerable toxicity. Larger trials are needed to better evaluate the discussed therapies.     

Use of retinoids in the treatment of psoriasis

The limitations of conventional therapy for psoriasis are reviewed, and the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosing and therapeutic monitoring of etretinate and other retinoids are described. Traditional treatments for psoriasis include topical application of anthralin and coal tar ointments; systemic therapy with corticosteroids or methotrexate; and systemic or methotrexate; and systemic psoralens combined with exposure to ultraviolet light (PUVA). The topical therapies are beneficial but aesthetically displeasing to patients; the systemic treatments are associated with severe adverse reactions. Etretinate provides another option in the treatment of psoriasis. Etretinate and acitretin, an investigational retinoid, appear to be effective oral therapies for severe variants of psoriasis, especially pustular psoriasis. Retinoids generally do not offer substantial therapeutic advantages over other treatments for chronic-plaque psoriasis. The most common adverse effects of etretinate are cheilitis, alopecia, desquamation of the skin, drying of mucous membranes, and pruritus. Use of low-dose etretinae in combination with other forms of therapy, such as corticosteroids or PUVA, may minimize the frequency of adverse effects. Etretinate is a known teratogen. Its elimination half-life is prolonged to 100-120 days with long-term use. Acitretin, the carboxylic acid derivative of etretinate, has a much shorter elimination half-life than etretinate (50 hours after multiple doses). Its adverse-effect profile is similar to that of etretinate. Etretinate and acitretin appear to be clinically effective for therapy of severe variants of psoriasis. Etretinate should not be used to treat mild psoriasis because of the high incidence of serious adverse effects.     

Bexarotene in cutaneous T-cell lymphoma: third retrospective study of long-term cohort and review of the literature

Background: Bexarotene was approved for cutaneous T-cell lymphoma (CTCL) in 1999. Apart from the two first clinical trials published ten years ago, very few data were published on the long-term use of bexarotene in CTCL patients.

Objectives: We performed a retrospective review of CTCL patients treated with bexarotene at a single skin Cancer department between 2002 and 2012. We aimed to determine retrospectively the long-term tolerability and outcome of bexarotene in a cohort of CTCL patients and to compare these results with data from the literature.

Results: Thirty-two patients were included (18 men/14 women); 20 patients had a mycosis fungoïdes and 12 a Sézary syndrome. The longest bexarotene treatment duration observed was 65.2 months and 10 patients were treated for more than 24 months. A clinical response was reported in 60% of all patients and in 75% of patients with Sézary syndrome. Most common drug-related adverse events were hypothyroidism (94%), hypertriglyceridemia (78%) and hypercholesterolemia (44%). Most events (84%) were mild to moderate.

Conclusions: This study with a very long observation time confirms that bexarotene is well tolerated by CTCL patients during long-term use. It is effective in early and advanced stages of CTCL.     

The economics of topical immunomodulators for the treatment of atopic dermatitis

Atopic dermatitis is a common, chronic, relapsing inflammatory skin disease frequently affecting infants and children. The worldwide prevalence of atopic dermatitis is estimated to be 5--20% of the paediatric population. First-line therapy has generally consisted of dry skin care, avoidance of triggers, application of topical corticosteroids, and administration of antihistamines and oral antibacterials. Topical corticosteroids improve the lesions of atopic dermatitis; however, concern on the part of physicians and patients regarding adverse effects has led to reluctance to utilise topical corticosteroids early and especially for prolonged periods. Topical immunomodulators (TIMs), including tacrolimus ointment and pimecrolimus cream, were recently introduced for the treatment of atopic dermatitis.Clinical data show that TIMs are effective in atopic dermatitis, yet do not cause the significant adverse effects associated with topical corticosteroids. Questions remain regarding the place of TIMs as a treatment for atopic dermatitis and how to use them most effectively, from both therapeutic and pharmacoeconomic standpoints. Specifically, two major issues remain unresolved: (i) how TIMs measure up to other therapies, especially topical corticosteroids; and (ii) how members of the TIM drug class compare against each other.Previous research has established that atopic dermatitis has a significant impact on quality of life (QOL) and carries a substantial economic burden. Some studies have also measured the utility of various atopic dermatitis disease states. While there is a need for further research, early economic studies provide evidence that TIMs positively affect the QOL of patients and families. In certain patients, TIMs may be cost effective and have an acceptable incremental cost utility compared with topical corticosteroids.Making cost-effectiveness comparisons between tacrolimus and pimecrolimus is challenging because there are limited head-to-head comparative data. Given currently available efficacy data, the results of one study suggest that tacrolimus may be more cost effective than pimecrolimus in paediatric patients with moderate atopic dermatitis.The full economic and QOL benefits of both agents are yet to be completely understood. The studies reviewed herein are the first to delineate the pharmacoeconomic benefits of TIMs in atopic dermatitis, and lay the foundation for future analyses. TIMs represent an exciting advance in the treatment of atopic dermatitis. Additional research will help determine the proper place of TIMs among the current array of therapeutic options for atopic dermatitis.     

Evidence-based review: fixed-combination therapy and topical retinoids in the treatment of acne

Topical fixed-combination products and topical retinoid monotherapy are established first-line treatments for mild-to-moderate acne vulgaris, yet adequate comparative data are lacking. The following evidence-based review addresses the question: "In patients with mild-to-moderate acne, are topical fixed-combination products or topical retinoids a more efficacious choice in reducing noninflammatory, inflammatory and total lesions after 12 weeks of treatment?" To identify relevant studies, a PubMed search was performed using "acne" and search terms for adapalene, tretinoin, tazarotene, benzoyl peroxide, clindamycin, or erythromycin. Forty-two studies from January 1991 to November 2009 were included. The studies were evaluated using the Strength of Recommendation Taxonomy, and all but seven received the highest level of evidence grade. To evaluate efficacy, a side-by-side comparison was made using reduction in acne lesion counts at week 12 for study groups treated with fixed-combination therapy or retinoid monotherapy. Twenty-nine studies containing relevant efficacy data for fixed-combination therapy and retinoid monotherapy are summarized here. Nine studies compared fixed-combination therapy with retinoid monotherapy; in eight of these studies, fixed-combination therapy was significantly more efficacious in reducing acne lesion counts. This evidence-based review analyzes clinical evidence to date for these therapies to provide guidance in determining appropriate treatment for patients with mild-to-moderate acne.     

Treatment of mycosis fungoides with oral bexarotene combined with PUVA

Bexarotene has recently been approved in the United States and Europe as a single orally administered retinoid for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. We describe a 47-year old female with a 4-year history of mycosis fungoides (MF) who developed debilitating side effects from acitretin and PUVA, and subsequently responded to bexarotene 75 mg orally once daily combined with PUVA. Bexarotene has been approved at an optimal starting dose of 300 mg/m2/d but has not yet been approved for use in combination with PUVA. We used a low dose (75 mg) combined with PUVA in an attempt to minimize side effects while maintaining treatment efficacy. Our patient's response to a novel regimen of low dose bexarotene combined with PUVA has been excellent and suggests that this regimen may be a useful method for treatment of MF.     

Ascomycins: promising agents for the treatment of inflammatory skin diseases

Ascomycin derivatives represent a novel class of anti-inflammatory macrolactams currently under development for the treatment of skin diseases. The main biological effect of ascomycins is an inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells. Several compounds are being developed with SDZ ASM 981 being at the most advanced stage. It has high anti-inflammatory activity in animal models of skin inflammation and does not induce skin atrophy. Topical application of SDZ ASM 981 was shown to be effective in atopic dermatitis (AD), allergic contact dermatitis and also in psoriasis under semi-occlusive conditions. In patients with AD, SDZ ASM 981 cream led to consistently low systemic exposure even when applied on large areas of skin. SDZ ASM 981 overcomes the drawbacks of current topical therapies of inflammatory skin diseases as its safety profile is better than that of topical corticosteroids. Studies continue to investigate its efficacy and safety in the treatment of inflammatory skin diseases.     

A novel hydrogel vehicle formulated for the treatment of atopic dermatitis

Atopic dermatitis (AD) is a chronic cyclical inflammatory skin disease that is increasing in incidence. Twenty percent of those affected with AD are infants and young children. Despite the development of newer nonsteroidal topical therapies, such as calcineurin inhibitors, topical corticosteroids remain the gold standard for the treatment of active eczematous disease and management of exacerbation due to established efficacy and safety with appropriate use. The xerotic, sensitive skin of AD patients mandates the use of nonirritating and nondrying topical vehicles. Recently, phase III clinical studies have demonstrated the safety and efficacy of a novel aqueous hydrogel vehicle for desonide delivery in mild to moderate AD, which is free of fragrances and surfactants. Corneometry and transepidermal water loss studies have demonstrated that this patented hydrogel vehicle alone offers advantages including moisturization and skin barrier enhancement, both of which are significant when treating eczematous and xerotic skin. Patient and physician preference surveys suggest that the novel properties of this vehicle may aid in patient compliance with AD therapy.     

Clobetasol propionate foam in the treatment of psoriasis

Psoriasis is a common, chronic, distressing skin disorder that frequently affects the scalp, skin, nails and joints. Despite treatment, many patients suffer from unremitting disease and decreased quality of life. Scalp-type psoriasis is particularly difficult to treat. Although topical corticosteroids are the mainstay of therapy for moderate-to-severe disease, patients frequently object to the messiness and unfavourable cosmetic appearance of topical treatments. In this context, foam vehicles, which have the advantage of minimal residue and increased ease of application, have emerged as novel alternatives to traditional creams, ointments and solutions. Clobetasol propionate foam 0.05% (OLUX^?, Connetics Corporation), a high potency topical steroid, has been shown to alleviate symptoms of several dermatological conditions, including scalp and body psoriasis, improve disease severity and increase quality of life. Dose should be limited to 50 g/week, given the risk of adrenal suppression. Because patient preference is an important determinant of medication efficacy in clinical practice, clobetasol foam is a useful new formulation in the treatment of psoriasis and other skin conditions.     

Successful treatment of Hailey-Hailey disease with acitretin

Hailey-Hailey disease is an autosomal dominant skin condition characterized by waxing and waning painful and pruritic vesicles and plaques affecting the intertriginous areas. Its pathogenesis involves inherited abnormalities in a cutaneous calcium pump. Most patients are managed conservatively with topical corticosteroids as well as topical and oral anti-infective agents. Scarce reports in the literature describe the use of oral retinoid therapy to manage refractory cases. We present a case of Hailey-Hailey disease in a 64-year-old man who was refractory to conservative management but improved dramatically over 6 months of oral therapy with 25 mg of acitretin daily. The mechanism by which such therapy improves disease manifestations is unknown. A potential mechanism is based on the influence of retinoids on epidermal differentiation and may involve cutaneous calcium homeostasis. Hailey-Hailey disease is discussed and the use of oral retinoid treatment for Hailey-Hailey disease is reviewed.     

Novel immunomodulators for topical skin disease therapy

The use of topical corticosteroids has revolutionised the treatment of inflammatory skin diseases. However, problems including pharmacological resistance, as well as the side effect profile of potent topical corticosteroids, has prompted studies to investigate into other topical non-corticosteroidal agents in inflammatory skin diseases. This review outlines the major types of inflammatory skin diseases and discusses emerging therapies based on topical immunosuppressive macrolide antibiotics. In particular, tacrolimus and ascomycin derivatives have been shown to be effective for treating atopic dermatitis with a surprising lack of side effects. It is expected that these agents will play an important role in future dermatological therapy. Accumulating evidence suggests the importance of lipid-derived mediators of inflammation (eicosanoids and platelet-activating factor) in cutaneous inflammatory diseases. The role of these mediators in skin inflammation is also addressed in this review. Though there appears to be a large amount of redundancy in the activities of these lipid mediators, this family of agents could potentially serve as targets for anti-inflammatory therapy. Inasmuch as the phospholipase A(2) family of enzymes serve to synthesise both eicosanoids and platelet-activating factor, inhibition at this step could have important therapeutic benefits in designing therapy for inflammatory skin diseases.     

Folliculotropic mycosis fungoides responding to bexarotene gel

Folliculotropic mycosis fungoides (FMF) is an uncommon and potentially aggressive form of cutaneous T cell lymphoma (CTCL). Phototherapy, radiotherapy, and systemic chemotherapy are the most commonly employed treatment options, but may have limited success and common adverse reactions. Bexarotene gel is a topical retinoid X receptor (RXR) agonist with activity on the follicular unit that has not been previously reported in the management of FME The case of a 73-year-old male with FMF that responded to bexarotene gel is presented.