Two New Topical Field Therapies for Actinic Keratoses

WAILEA, HAWAII – Physicians will likely gain a novel short-course field therapy for multiple actinic keratoses next year.

Ingenol mebutate (Leo Pharmaceuticals) hit all of its end points in two phase III clinical trials. One trial was conducted in patients treated for fields of multiple actinic keratoses (AKs) on the head and neck, the other in patients with clusters of AKs anywhere else, Dr. Theodore Rosen said at a seminar sponsored by Skin Disease Education Foundation (SDEF).

Median reductions in AKs in these pivotal trials were comparable to results reported with other field therapies, such as imiquimod and 5-fluorouracil. What is remarkable about ingenol mebutate, however, is these outcomes were achieved with only 2 days of once-daily therapy for non–head and neck AKs and 3 days of therapy at a lower concentration for AKs on the head and neck, noted Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

In contrast, the original regimen for the 5% imiquimod dermatologists have been using since its 2004 marketing approval for AKs entails a full 16 weeks of twice-weekly therapy. That being said, last year, the FDA approved a new, shorter-duration formulation of imiquimod which Dr. Rosen said was a better product than the traditional 5% version.

Ingenol mebutate is a diterpene ester derived from the sap of a plant, Euphorbia peplus, traditionally used by Australian aborigines for topical treatment of various skin ailments. Ingenol mebutate’s mechanism of action is not fully understood, but involves initial cell necrosis because of mitochondrial disruption followed by granulocyte-dependent cytotoxicity. Immune upregulation also appears to be involved, Dr. Rosen explained.

Non–Head and Neck AK Study. The phase III non–head and neck AK study involved 256 patients randomized to 2 consecutive days of once-daily ingenol mebutate 0.05% gel or placebo applied to up to a 25-cm² area of skin with four to eight visible AKs. The ingenol mebutate group showed a complete clearance rate at day 57 of 27.8%, compared with 4.7% for placebo, and a median 67% reduction in AKs.

The 27.8% complete clearance rate is nothing to write home about, but the 67% reduction in AKs is quite impressive, particularly for a 2-day therapy, according to Dr. Rosen, who was an investigator in these and other AK clinical trials.

“That 67% median reduction is very nice, and it’s really the most accurate measurement because it tells you how many of these things are going to go away by treating the field,” Dr. Rosen said.

The complete clearance rate was highest on the chest, followed by the arms, legs, back of hand, and back.

Side effect rates were low at 1%-2%, and consisted of burning, irritation, pain, and other symptoms that are associated with most field therapies for AKs. Interestingly, the peak incidence of the skin side effects was not until day 8.

“You’ll have to prepare patients for the fact that almost a week after they’re done with therapy, they may suddenly look worse,” he noted.

The product labeling will limit treatment to areas of 25 cm² or less because that is how the pivotal trials were done. “If you want to treat more than 25 cm², you’ll probably be off-label, but we do that all the time,” he said.

In an exploratory trial in which investigators treated AK fields of 25, 50, 75, and 100 cm² on the dorsal arms using 0.05% ingenol mebutate applied once daily for 2 days, cumulative local skin reaction scores correlated with the size of the area treated. Even in patients who underwent treatment of 100 cm² of involved skin, side-effect scores returned to baseline by 2 months. Most patients tolerated even the most severe reactions, he noted.

Head and Neck AK Study. The phase III head and neck AK trial involved treatment of areas up to 25 cm² in 264 patients. This trial featured several drug concentrations and durations; the one that produced the best outcomes and will move forward to the marketplace is 0.015% once daily for 3 days. It yielded a complete clearance rate of 50% on day 57, and an 85% median reduction in AKs, according to Dr. Rosen.

With two different concentrations of ingenol mebutate likely to be approved for application at different sites, physicians will need to remain vigilant regarding possible dispensing errors or patient misuse, he said.

Imiquimod. While ingenol mebutate’s duration of efficacy remains unknown, that is not the case with imiquimod.

The new imiquimod 3.75% cream (Zyclara), approved last year for treatment of AKs, provides clear benefits over the older 5% formulation in terms of convenience, and with comparable efficacy.

Instead of the traditional 16 weeks of therapy, the 3.75% cream is used daily for 2 weeks, followed by a 2-week rest, then another 2 weeks of therapy, for a total 6-week treatment course. And the imiquimod 3.75% cream is approved for treatment of the full face or balding scalp, unlike imiquimod 5%, whose approved indication is limited to a much smaller area of 25 cm², Dr. Rosen said.

In the pivotal trial for imiquimod 3.75%, 160 treated patients showed a complete clearance rate of 35.6% and a median 81.8% reduction in AKs 8 weeks after the final treatment. That is near-identical to the 83.3% reduction noted in an earlier trial of 215 patients treated with imiquimod 5%.

Dr. Rosen said field therapy makes sound sense in patients with multiple AKs in the same area of the skin.

“When you have a patient with [a lot of] AKs, then all the skin in between those AKs is no more normal than the AK skin; it just hasn’t manifest yet. That’s where field therapy comes in,” he explained.

As much as he likes field therapy, though, Dr. Rosen stressed that the emerging new paradigm for treatment of patients with multiple AKs is combination therapy. This can take the form of either a field therapy followed by individual lesion-directed therapy such as cryotherapy, or lesion-directed therapy followed by a field therapy. There are numerous possible combinations. Insurance reimbursement can be a problem for now, but payers will eventually have to come around to the new paradigm.

“The bottom line is for every study where field therapy is combined with lesion-directed therapy or with another field therapy, the combination proved superior to monotherapy,” Dr. Rosen said. “It’s a little more work, but in the end I think it’s probably the best thing for your patient.”

Other Agents in the AK Pipeline. AK remains an active target for new drug development. Among the wide range of drugs in the developmental pipeline, albeit still years away from the marketplace, are:

P Resiquimod and sotirimod. These are the most promising of the more than 1,000 known analogues of imiquimod. Like the parent compound, they work via immune upregulation, said Dr. Rosen.

P Betulin. A triterpene isolated from the extract of birch bark. It eliminates actinic keratoses through cytotoxicity.

P Perillyl alcohol. A monoterpene isolated from essential oils of peppermint, spearmint, lavender, and other plants. Its mechanism of action involves induction of apoptosis in rapidly dividing cells without affecting normal cells.

P Difluoromethylornithine. Irreversibly inhibits ornithine decarboxylase, which regulates cell division. DFMO is already marketed in a topical formulation for the treatment of facial hirsutism, and as an injectable drug for treatment of African trypanosomiasis.

P Afamelanotide. This synthetic analogue of melanocyte-stimulating hormone is under development as a treatment for a diverse collection of skin diseases, including polymorphous light eruption, solar urticaria, and squamous cell carcinoma, as well as AKs.

P T4 endonuclease V. This drug enhances repair of UV-induced DNA damage. “It might help prevent future AKs, but not existing ones,” Dr. Rosen said.

Why does AK therapy remain such a busy area of new drug development? Simple: A substantial portion of the public continues to be casual about sun protection or disregards it altogether, and with the graying of the baby boomer generation, AKs are more common than ever, he said.

“Everybody in Texas has AKs, including me. I just found one on my hand, and now I need to go treat it,” he said.

Dr. Rosen is on the speaker’s bureau for Graceway and is a consultant to Graceway and Leo Pharmaceuticals. SDEF and this news organization are owned by Elsevier.

WAILEA, HAWAII – Physicians will likely gain a novel short-course field therapy for multiple actinic keratoses next year.

Ingenol mebutate (Leo Pharmaceuticals) hit all of its end points in two phase III clinical trials. One trial was conducted in patients treated for fields of multiple actinic keratoses (AKs) on the head and neck, the other in patients with clusters of AKs anywhere else, Dr. Theodore Rosen said at a seminar sponsored by Skin Disease Education Foundation (SDEF).

Median reductions in AKs in these pivotal trials were comparable to results reported with other field therapies, such as imiquimod and 5-fluorouracil. What is remarkable about ingenol mebutate, however, is these outcomes were achieved with only 2 days of once-daily therapy for non–head and neck AKs and 3 days of therapy at a lower concentration for AKs on the head and neck, noted Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

In contrast, the original regimen for the 5% imiquimod dermatologists have been using since its 2004 marketing approval for AKs entails a full 16 weeks of twice-weekly therapy. That being said, last year, the FDA approved a new, shorter-duration formulation of imiquimod which Dr. Rosen said was a better product than the traditional 5% version.

Ingenol mebutate is a diterpene ester derived from the sap of a plant, Euphorbia peplus, traditionally used by Australian aborigines for topical treatment of various skin ailments. Ingenol mebutate’s mechanism of action is not fully understood, but involves initial cell necrosis because of mitochondrial disruption followed by granulocyte-dependent cytotoxicity. Immune upregulation also appears to be involved, Dr. Rosen explained.

Non–Head and Neck AK Study. The phase III non–head and neck AK study involved 256 patients randomized to 2 consecutive days of once-daily ingenol mebutate 0.05% gel or placebo applied to up to a 25-cm² area of skin with four to eight visible AKs. The ingenol mebutate group showed a complete clearance rate at day 57 of 27.8%, compared with 4.7% for placebo, and a median 67% reduction in AKs.

The 27.8% complete clearance rate is nothing to write home about, but the 67% reduction in AKs is quite impressive, particularly for a 2-day therapy, according to Dr. Rosen, who was an investigator in these and other AK clinical trials.

“That 67% median reduction is very nice, and it’s really the most accurate measurement because it tells you how many of these things are going to go away by treating the field,” Dr. Rosen said.

The complete clearance rate was highest on the chest, followed by the arms, legs, back of hand, and back.

Side effect rates were low at 1%-2%, and consisted of burning, irritation, pain, and other symptoms that are associated with most field therapies for AKs. Interestingly, the peak incidence of the skin side effects was not until day 8.

“You’ll have to prepare patients for the fact that almost a week after they’re done with therapy, they may suddenly look worse,” he noted.

The product labeling will limit treatment to areas of 25 cm² or less because that is how the pivotal trials were done. “If you want to treat more than 25 cm², you’ll probably be off-label, but we do that all the time,” he said.

In an exploratory trial in which investigators treated AK fields of 25, 50, 75, and 100 cm² on the dorsal arms using 0.05% ingenol mebutate applied once daily for 2 days, cumulative local skin reaction scores correlated with the size of the area treated. Even in patients who underwent treatment of 100 cm² of involved skin, side-effect scores returned to baseline by 2 months. Most patients tolerated even the most severe reactions, he noted.

Head and Neck AK Study. The phase III head and neck AK trial involved treatment of areas up to 25 cm² in 264 patients. This trial featured several drug concentrations and durations; the one that produced the best outcomes and will move forward to the marketplace is 0.015% once daily for 3 days. It yielded a complete clearance rate of 50% on day 57, and an 85% median reduction in AKs, according to Dr. Rosen.

With two different concentrations of ingenol mebutate likely to be approved for application at different sites, physicians will need to remain vigilant regarding possible dispensing errors or patient misuse, he said.

Imiquimod. While ingenol mebutate’s duration of efficacy remains unknown, that is not the case with imiquimod.

The new imiquimod 3.75% cream (Zyclara), approved last year for treatment of AKs, provides clear benefits over the older 5% formulation in terms of convenience, and with comparable efficacy.

Instead of the traditional 16 weeks of therapy, the 3.75% cream is used daily for 2 weeks, followed by a 2-week rest, then another 2 weeks of therapy, for a total 6-week treatment course. And the imiquimod 3.75% cream is approved for treatment of the full face or balding scalp, unlike imiquimod 5%, whose approved indication is limited to a much smaller area of 25 cm², Dr. Rosen said.

In the pivotal trial for imiquimod 3.75%, 160 treated patients showed a complete clearance rate of 35.6% and a median 81.8% reduction in AKs 8 weeks after the final treatment. That is near-identical to the 83.3% reduction noted in an earlier trial of 215 patients treated with imiquimod 5%.

Dr. Rosen said field therapy makes sound sense in patients with multiple AKs in the same area of the skin.

“When you have a patient with [a lot of] AKs, then all the skin in between those AKs is no more normal than the AK skin; it just hasn’t manifest yet. That’s where field therapy comes in,” he explained.

As much as he likes field therapy, though, Dr. Rosen stressed that the emerging new paradigm for treatment of patients with multiple AKs is combination therapy. This can take the form of either a field therapy followed by individual lesion-directed therapy such as cryotherapy, or lesion-directed therapy followed by a field therapy. There are numerous possible combinations. Insurance reimbursement can be a problem for now, but payers will eventually have to come around to the new paradigm.

“The bottom line is for every study where field therapy is combined with lesion-directed therapy or with another field therapy, the combination proved superior to monotherapy,” Dr. Rosen said. “It’s a little more work, but in the end I think it’s probably the best thing for your patient.”

Other Agents in the AK Pipeline. AK remains an active target for new drug development. Among the wide range of drugs in the developmental pipeline, albeit still years away from the marketplace, are:

P Resiquimod and sotirimod. These are the most promising of the more than 1,000 known analogues of imiquimod. Like the parent compound, they work via immune upregulation, said Dr. Rosen.

P Betulin. A triterpene isolated from the extract of birch bark. It eliminates actinic keratoses through cytotoxicity.

P Perillyl alcohol. A monoterpene isolated from essential oils of peppermint, spearmint, lavender, and other plants. Its mechanism of action involves induction of apoptosis in rapidly dividing cells without affecting normal cells.

P Difluoromethylornithine. Irreversibly inhibits ornithine decarboxylase, which regulates cell division. DFMO is already marketed in a topical formulation for the treatment of facial hirsutism, and as an injectable drug for treatment of African trypanosomiasis.

P Afamelanotide. This synthetic analogue of melanocyte-stimulating hormone is under development as a treatment for a diverse collection of skin diseases, including polymorphous light eruption, solar urticaria, and squamous cell carcinoma, as well as AKs.

P T4 endonuclease V. This drug enhances repair of UV-induced DNA damage. “It might help prevent future AKs, but not existing ones,” Dr. Rosen said.

Why does AK therapy remain such a busy area of new drug development? Simple: A substantial portion of the public continues to be casual about sun protection or disregards it altogether, and with the graying of the baby boomer generation, AKs are more common than ever, he said.

“Everybody in Texas has AKs, including me. I just found one on my hand, and now I need to go treat it,” he said.

Dr. Rosen is on the speaker’s bureau for Graceway and is a consultant to Graceway and Leo Pharmaceuticals. SDEF and this news organization are owned by Elsevier.

WAILEA, HAWAII – Physicians will likely gain a novel short-course field therapy for multiple actinic keratoses next year.

Ingenol mebutate (Leo Pharmaceuticals) hit all of its end points in two phase III clinical trials. One trial was conducted in patients treated for fields of multiple actinic keratoses (AKs) on the head and neck, the other in patients with clusters of AKs anywhere else, Dr. Theodore Rosen said at a seminar sponsored by Skin Disease Education Foundation (SDEF).

Median reductions in AKs in these pivotal trials were comparable to results reported with other field therapies, such as imiquimod and 5-fluorouracil. What is remarkable about ingenol mebutate, however, is these outcomes were achieved with only 2 days of once-daily therapy for non–head and neck AKs and 3 days of therapy at a lower concentration for AKs on the head and neck, noted Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

In contrast, the original regimen for the 5% imiquimod dermatologists have been using since its 2004 marketing approval for AKs entails a full 16 weeks of twice-weekly therapy. That being said, last year, the FDA approved a new, shorter-duration formulation of imiquimod which Dr. Rosen said was a better product than the traditional 5% version.

Ingenol mebutate is a diterpene ester derived from the sap of a plant, Euphorbia peplus, traditionally used by Australian aborigines for topical treatment of various skin ailments. Ingenol mebutate’s mechanism of action is not fully understood, but involves initial cell necrosis because of mitochondrial disruption followed by granulocyte-dependent cytotoxicity. Immune upregulation also appears to be involved, Dr. Rosen explained.

Non–Head and Neck AK Study. The phase III non–head and neck AK study involved 256 patients randomized to 2 consecutive days of once-daily ingenol mebutate 0.05% gel or placebo applied to up to a 25-cm² area of skin with four to eight visible AKs. The ingenol mebutate group showed a complete clearance rate at day 57 of 27.8%, compared with 4.7% for placebo, and a median 67% reduction in AKs.

The 27.8% complete clearance rate is nothing to write home about, but the 67% reduction in AKs is quite impressive, particularly for a 2-day therapy, according to Dr. Rosen, who was an investigator in these and other AK clinical trials.

“That 67% median reduction is very nice, and it’s really the most accurate measurement because it tells you how many of these things are going to go away by treating the field,” Dr. Rosen said.

The complete clearance rate was highest on the chest, followed by the arms, legs, back of hand, and back.

Side effect rates were low at 1%-2%, and consisted of burning, irritation, pain, and other symptoms that are associated with most field therapies for AKs. Interestingly, the peak incidence of the skin side effects was not until day 8.

“You’ll have to prepare patients for the fact that almost a week after they’re done with therapy, they may suddenly look worse,” he noted.

The product labeling will limit treatment to areas of 25 cm² or less because that is how the pivotal trials were done. “If you want to treat more than 25 cm², you’ll probably be off-label, but we do that all the time,” he said.

In an exploratory trial in which investigators treated AK fields of 25, 50, 75, and 100 cm² on the dorsal arms using 0.05% ingenol mebutate applied once daily for 2 days, cumulative local skin reaction scores correlated with the size of the area treated. Even in patients who underwent treatment of 100 cm² of involved skin, side-effect scores returned to baseline by 2 months. Most patients tolerated even the most severe reactions, he noted.

Head and Neck AK Study. The phase III head and neck AK trial involved treatment of areas up to 25 cm² in 264 patients. This trial featured several drug concentrations and durations; the one that produced the best outcomes and will move forward to the marketplace is 0.015% once daily for 3 days. It yielded a complete clearance rate of 50% on day 57, and an 85% median reduction in AKs, according to Dr. Rosen.

With two different concentrations of ingenol mebutate likely to be approved for application at different sites, physicians will need to remain vigilant regarding possible dispensing errors or patient misuse, he said.

Imiquimod. While ingenol mebutate’s duration of efficacy remains unknown, that is not the case with imiquimod.

The new imiquimod 3.75% cream (Zyclara), approved last year for treatment of AKs, provides clear benefits over the older 5% formulation in terms of convenience, and with comparable efficacy.

Instead of the traditional 16 weeks of therapy, the 3.75% cream is used daily for 2 weeks, followed by a 2-week rest, then another 2 weeks of therapy, for a total 6-week treatment course. And the imiquimod 3.75% cream is approved for treatment of the full face or balding scalp, unlike imiquimod 5%, whose approved indication is limited to a much smaller area of 25 cm², Dr. Rosen said.

In the pivotal trial for imiquimod 3.75%, 160 treated patients showed a complete clearance rate of 35.6% and a median 81.8% reduction in AKs 8 weeks after the final treatment. That is near-identical to the 83.3% reduction noted in an earlier trial of 215 patients treated with imiquimod 5%.

Dr. Rosen said field therapy makes sound sense in patients with multiple AKs in the same area of the skin.

“When you have a patient with [a lot of] AKs, then all the skin in between those AKs is no more normal than the AK skin; it just hasn’t manifest yet. That’s where field therapy comes in,” he explained.

As much as he likes field therapy, though, Dr. Rosen stressed that the emerging new paradigm for treatment of patients with multiple AKs is combination therapy. This can take the form of either a field therapy followed by individual lesion-directed therapy such as cryotherapy, or lesion-directed therapy followed by a field therapy. There are numerous possible combinations. Insurance reimbursement can be a problem for now, but payers will eventually have to come around to the new paradigm.

“The bottom line is for every study where field therapy is combined with lesion-directed therapy or with another field therapy, the combination proved superior to monotherapy,” Dr. Rosen said. “It’s a little more work, but in the end I think it’s probably the best thing for your patient.”

Other Agents in the AK Pipeline. AK remains an active target for new drug development. Among the wide range of drugs in the developmental pipeline, albeit still years away from the marketplace, are:

P Resiquimod and sotirimod. These are the most promising of the more than 1,000 known analogues of imiquimod. Like the parent compound, they work via immune upregulation, said Dr. Rosen.

P Betulin. A triterpene isolated from the extract of birch bark. It eliminates actinic keratoses through cytotoxicity.

P Perillyl alcohol. A monoterpene isolated from essential oils of peppermint, spearmint, lavender, and other plants. Its mechanism of action involves induction of apoptosis in rapidly dividing cells without affecting normal cells.

P Difluoromethylornithine. Irreversibly inhibits ornithine decarboxylase, which regulates cell division. DFMO is already marketed in a topical formulation for the treatment of facial hirsutism, and as an injectable drug for treatment of African trypanosomiasis.

P Afamelanotide. This synthetic analogue of melanocyte-stimulating hormone is under development as a treatment for a diverse collection of skin diseases, including polymorphous light eruption, solar urticaria, and squamous cell carcinoma, as well as AKs.

P T4 endonuclease V. This drug enhances repair of UV-induced DNA damage. “It might help prevent future AKs, but not existing ones,” Dr. Rosen said.

Why does AK therapy remain such a busy area of new drug development? Simple: A substantial portion of the public continues to be casual about sun protection or disregards it altogether, and with the graying of the baby boomer generation, AKs are more common than ever, he said.

“Everybody in Texas has AKs, including me. I just found one on my hand, and now I need to go treat it,” he said.

Dr. Rosen is on the speaker’s bureau for Graceway and is a consultant to Graceway and Leo Pharmaceuticals. SDEF and this news organization are owned by Elsevier.