Four Clinical Trials Presented at AAD Show Ligand's Targretin, Panretin Demonstrate Promising Activity in Range of Dermatologic Disorders
Monday March 24, 8:48 pm ET
Studies Indicate that Activating Retinoid X Receptors Plays Key Role in Treating Hand Dermatitis, Psoriasis, CTCL and Photoaging
SAN DIEGO--(BUSINESS WIRE)--March 24, 2003-- Ligand's approved drugs Targretin® (bexarotene) and Panretin® (alitretinoin) have beneficial effects in hand dermatitis, psoriasis, cutaneous T-cell lymphoma (CTCL) and photoaging, according to four clinical studies presented in poster form at the 61st annual meeting of the American Academy of Dermatology (AAD), underway now in San Francisco.
"These studies add to the growing body of evidence demonstrating that Targretin and Panretin may benefit patients with hard-to-treat, severe dermatologic disorders," said Andres Negro-Vilar, M.D., Ph.D., Ligand's senior vice president for research and development and chief scientific officer. "Both Targretin and Panretin bind to and activate retinoid X receptors (RXRs) inside cells, but Targretin is the only approved drug in the world that does so selectively. Activating RXRs in the skin promotes the proliferation and differentiation of epidermal keratinocytes, improves skin thickening and stratification of the epidermal layers, and promotes homeostasis of the skin and its immune system. As an RXR-selective ligand, Targretin modulates genes essential to skin health, without causing the side effects commonly observed with RAR-selective compounds."
Targretin Gel 1% Improves Symptoms of Chronic Severe Hand Dermatitis
In AAD poster 23, researchers from the Oregon Health & Science University, the University of Cincinnati and Ligand reported results from a Phase I/II dose escalation study of 55 patients with a history of chronic severe hand dermatitis for at least six months. Most patients in the 22-week, randomized, open-label study were resistant to standard treatments for hand dermatitis. Patients were randomized to Targretin gel alone; Targretin gel in combination with mometasone furoate, a medium potency topical steroid; or Targretin gel in combination with hydrocortisone, a low potency topical steroid. By study design, half of the patients were included in the Targretin monotherapy arm and the other half were equally divided into the two steroid combination arms. In order to assess tolerability, all Targretin doses were escalated every two weeks, starting every other day, then once per day, twice per day and, finally, three times per day. The investigators evaluated efficacy based on:
* Physician's Static Assessment (PSA). This primary, FDA-recommended endpoint, which calls for 90% or greater improvement in the disease, is equivalent to a clear or almost clear condition on at least two observations 14 days apart.
* Physician's Global Assessment (PGA), which calls for 50% or greater improvement in the condition on at least two observations two weeks apart.
The percentages of patients who improved in each treatment group were:
Targretin Targretin Targretin
Gel only Gel + mometasone Gel +
(28 furoate hydrocortisone
patients) (13) (14)
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PSA (at least 90% improvement) 39% 46% 21%
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PGA (at least 50% improvement) 79% 77% 50%
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"This study demonstrates that Targretin gel may effect significant improvement in severe hand dermatitis, a common, sometimes disabling condition," said lead investigator Jon Hanifin, M.D., professor, department of dermatology, Oregon Health & Science University. "Severe hand dermatitis is a difficult disease to treat, and topical steroids, the current standard of care, show progressively less effectiveness and cause troublesome side effects such as skin atrophy. New therapies are needed in this area, and Targretin gel may play an important role in filling an underserved medical need."
Despite the dose escalation nature of the study, median time to at least 50% improvement was 6.1 weeks, and median time to at least 90% improvement was 12.6 weeks. In addition, patients' responses were durable. Among patients who achieved at least 90% improvement, the median duration of response was 12 weeks, and among patients who achieved at least 50% improvement, the median duration of response was 18 weeks. Duration of response was defined as the time between a patient's first observed response and their last observed response, or the end of the study's 26-week follow-up period.
Most adverse events were mild to moderate in severity. Adverse events that occurred in more than 5% of patients, and that were thought to be at least possibly treatment-related, were:
Targretin Targretin Targretin Gel +
Gel only Gel + hydrocortisone
(28 mometasone (14)
patients) furoate
(13)
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Irritation/rash 29% 31% 29%
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Stinging/burning 7% 31% 14%
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Dermatitis flare 18% 0% 29%
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Low-Dose Targretin + Narrowband UVB Clears Psoriatic Lesions in Three Heavily Pre-Treated Patients
In AAD poster 613, a researcher from the Arlington (Texas) Center for Dermatology described three patients with moderate-to-severe plaque psoriasis who were treated with a low dose of Targretin capsules and narrowband UVB phototherapy. All patients had plaque psoriasis covering at least 70% of their body surface area (BSA), and had been treated with a median of four prior therapies. In addition, all patients had experienced an adverse event with a prior oral RAR retinoid that required them to stop using it, had failed prior topical retinoid therapy, had received prior narrowband UVB therapy without adequate response, and had failed topical steroids.
In the study, patients received a low dose of Targretin, 75 mg once daily. The recommended starting dose of Targretin in CTCL is 300 mg/m2 of body surface area per day, which for an average-size adult equates to approximately 500 mg of Targretin daily.
Following treatment with Targretin and UVB, all three patients responded, with one complete clinical response and two partial responses of at least 90% clearing. In each patient, the percent of BSA affected by psoriasis decreased dramatically:
* Patient 1: BSA 70% at baseline declined to less than 5% at week 16.
* Patient 2: BSA 75% at baseline declined to 0% at week 16.
* Patient 3: BSA 80% at baseline declined to 5% at week 20.
Signs and symptoms of psoriasis also improved significantly, with plaques being "remarkably flattened or cleared" within one to two months. In addition, pruritis (itching) improved, with no further reports of pruritis by week 16 for all patients.
"Targretin is the only retinoid that selectively binds to and activates the retinoid X receptor, and is therefore believed to offer unique therapeutic activity as well as a side effect profile distinct from RAR retinoids," said author Angela Moore, M.D., clinical assistant professor at the Baylor University Medical Center in Dallas. "Adding RAR retinoids to phototherapy has been shown to increase efficacy in patients with psoriasis, but this is the first report on the use of an RXR-selective retinoid in conjunction with narrowband UVB in plaque psoriasis. All three patients in this study had been heavily pre-treated, yet still experienced dramatic clearing of their lesions following therapy with Targretin and UVB."
In the study, one patient experienced mild triglyceride elevation, which was treated with a lipid-lowering agent. No other adverse events could be attributed to the combination therapy.
Low-Dose Targretin + PUVA Generates 88% Response Rate in Early-Stage CTCL
In AAD poster 487, researchers from Northwestern University and Ligand reported results from a Phase II study of Targretin capsules and PUVA (psoralen-UVA therapy) in patients with early-stage CTCL (stages IB-IIA). Patients were randomized to receive a low dose of Targretin, either 150 or 300 mg daily, in combination with PUVA for 24 weeks.
At the time of the analysis, 17 patients had completed at least eight weeks of therapy and were evaluated for responses. Responses were based on PGA and the percent of BSA affected by CTCL. Ten patients had a complete clinical response (defined as 100% cleared), and five had a partial response (at least 50% improvement), for an overall response rate of 88% (15 of 17 patients). In addition, two patients had stable disease (less than 50% improvement).
All responses were confirmed over at least four study weeks. Five of the patients with complete responses achieved remissions after eight weeks or less of combination treatment. Overall mean time to first response was 11 weeks, and mean time to best response was 16 weeks.
"PUVA has a good rate of response in early-stage CTCL but has significant risks for the eventual development of skin cancers," the authors wrote in their poster. "RAR retinoids have been added to PUVA therapy to increase effective clearing of CTCL lesions, with fewer PUVA sessions and a lower UVA exposure. It is accepted that this will decrease patient risk of iatrogenic skin cancers. Bexarotene, an RXR-selective retinoid, may be synergistic in combination with PUVA in CTCL patients. (In this study,) the time to response was comparable to historical PUVA alone therapy, but required fewer PUVA sessions and fewer total cumulative joules."
Elevations in triglycerides were expected in the study, and patients were treated prophylactically with lipid-lowering agents. Mild elevations in fasting triglycerides occurred in 11 patients, and all cases were controlled by reducing the dose of Targretin or increasing the dose of a lipid-lowering agent. Four patients experienced hypothyroidism, which was managed with oral thyroid supplements.
Panretin Gel 0.1% Shows Promise to Treat Photoaged Skin
In poster 92, researchers from the University of Miami (Fla.) School of Medicine reported results from a pilot study in which 20 people with photoaging on their faces and hands were treated with Panretin gel 0.1%. Photoaging is the process by which skin is damaged from exposure to ultraviolet radiation in sunlight and other sources. Symptoms include wrinkles, skin discoloration and susceptibility to cancer.
In the study, participants applied Panretin gel to their face and hands once nightly for 14 weeks. Treatment began on week two of the study, and investigators assessed safety and efficacy in weeks four, eight and 16. Efficacy assessments included physician and participant assessments of skin condition on a four-point severity scale, participant assessments of skin appearance at the beginning and end of the study based on a visual analog scale, and assessment of photographs of participants by an independent dermatologist.
Investigators found significant improvement in superficial wrinkles, deep wrinkles, skin roughness, and colored spots on the face, and significant improvement in superficial wrinkles, skin roughness and colored spots on the hands.
Similarly, participants noted significant improvements in superficial wrinkles, skin roughness and colored spots on the face and hands. In addition, participants' rating of their own skin appearance improved from week two to week 16, as measured by the visual analog scale. In terms of tolerability, the majority of participants characterized use of the gel as neutral to tolerable.
The positive physical findings observed by investigators and participants were not able to be confirmed by the independent dermatologist who evaluated color photographs of the participants, due principally to photo randomization and missing, blurry or overexposed photos.
"This pilot study found Panretin gel to be a promising treatment for photoaged skin," said lead author Leslie Baumann, M.D., chief, division of cosmetic dermatology and assistant clinical professor of dermatology and cutaneous surgery at the University of Miami. "Panretin binds to and activates both RARs and RXRs, and its RXR functions may provide added efficacy for photoaged skin. Future studies should be performed to delineate the benefits of RXR activity."
As seen in previous retinoid studies, the most common mild adverse events occurred on the face and included dryness, erythema and peeling. No serious adverse events were reported, and no patients withdrew due to adverse events.
About Targretin and Panretin
In December 1999, the U.S. Food and Drug Administration (FDA) granted marketing approval for Targretin capsules with once-daily oral administration for the treatment of cutaneous manifestations of CTCL in patients who are refractory to at least one prior systemic therapy.
In June 2000, the FDA granted marketing clearance for Targretin gel 1% for the topical treatment of cutaneous lesions in patients with early-stage (TNM Stage IA and IB) CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies.
In February 1999, the FDA granted marketing clearance for Panretin gel 0.1% for the topical treatment of cutaneous lesions of patients with AIDS-related Kaposi's sarcoma.
Full prescribing information for Ligand's products can be obtained in the United States from Ligand professional services by calling 800-964-5836, or on Ligand's internet site at www.ligand.com. |
