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NEW ORLEANS – according to results of a phase 2 clinical trial presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
The phase 2b data, which are prompting a phase 3 trial, suggest that the drug, called orismilast, “is a potential new addition to the psoriasis armamentarium,” reported Lars E. French, MD, professor and chair, department of dermatology, Ludwig Maximilian University of Munich (Germany).
At the same session, findings from another study supported off-label use of oral roflumilast (Daliresp and generic), a PDE4 inhibitor approved for severe chronic obstructive pulmonary disease (COPD). The only PDE4 inhibitors with an indication for psoriasis are roflumilast, approved as a cream (Zoryve), and apremilast (Otezla), approved as an oral therapy.
Phase 2 study of orismilast
In the orismilast trial, Dr. French attributed the efficacy observed to the potency of orismilast on the B and D subtypes of PDE4 associated with inflammation. One clue is that these specific subtypes are overly expressed in the skin of patients with either psoriasis or atopic dermatitis.
“When compared to apremilast, orismilast is at least two to fivefold more potent on all PDE4 isoforms and up to 39 times more potent on some of the PDE4 B and D isoforms,” said Dr. French, referring to preclinical findings in human whole blood and blood cells and in a mouse model of chronic inflammation.
The efficacy of orismilast in an immediate-release oral formulation was previously demonstrated in a recently published phase 2a trial, but the newest study tested a modified-release formulation of orismilast to test its potential to improve tolerability.
In the study, 202 adult patients with moderate to severe psoriasis (Psoriasis Area Severity Index [PASI] score ≥ 12) were randomly assigned to one of three doses of orismilast or to placebo. Each of the three doses – 20 mg, 30 mg, or 40 mg – were administered twice daily. The primary endpoint was change in PASI score at 16 weeks. Secondary endpoints included PASI 75 responses (signifying 75% clearance) and safety.
Relative to placebo, which was associated with a PASI improvement of 17%, all three of the tested orismilast doses were superior in a dose-dependent manner. The rates of response were 53%, 61%, and 64% for the 20-mg, 30-mg, and 40-mg twice-daily doses, respectively.
The PASI improvements were rapid, Dr. French said. At 4 weeks, PASI scores climbed from baseline by nearly 40% for those on all orismilast doses, which was more than double the improvement in the placebo group.
In the intention-to-treat analysis with missing data counted as nonresponders, the proportion of patients reaching PASI-75 scores at 16 weeks were 39%, 49%, 45%, and 17%, in the 20-mg, 30-mg, 40-mg, and placebo groups, respectively. The proportion of patients experiencing complete or near-complete skin clearance defined by a PASI 90 were 24%, 22%, 28%, and 8%, respectively.
The side-effect profile was consistent with other PDE4 inhibitors. The most common adverse events included gastrointestinal complaints, such as diarrhea and nausea, as well as headache and dizziness. But the majority of these events were of low grade, and they were largely confined to the first 4 weeks of treatment, which is a pattern reported with other PDE4 inhibitors in psoriasis and other chronic inflammatory diseases, such as COPD, according to Dr. French.
“There were no discontinuations for a treatment-related adverse event in the arms receiving either the 20-mg or the 30-mg doses,” Dr. French reported. There were only two serious adverse events, and neither were considered by trial investigators to be related to orismilast.
Based on the limited therapeutic gain but greater risk for adverse events on the 40-mg twice-daily dose, “the question is now whether to move forward with the 20-mg or the 30-mg dose,” said Dr. French, who said planning of a phase 3 trial is underway.
Phase 2 study of roflumilast
However, this was not the only set of data on an oral PDE4 inhibitor presented as a late-breaker at the AAD meeting. For clinicians looking for a more immediate and less expensive alternative to apremilast, another study indicated that off-label use of oral roflumilast is an option.
In an investigator-initiated, multicenter, double-blind, placebo-controlled trial conducted in Denmark, the rate of response to oral roflumilast at 24 weeks, including the clear or almost clear response, was on the same general order of magnitude as that seen in the orismilast study, reported Alexander Egeberg, MD, PhD, professor of dermatology, University of Copenhagen.
“At 24 weeks, 21.7% had achieved a PASI 90, and 8.7% achieved a PASI 100,” Dr. Egeberg said.
Oral roflumilast has been available for the treatment of COPD for more than 10 years and is now available in a generic formulation. This study was conducted independent of any pharmaceutical company involvement, and the high rate of response and low risk of adverse events suggests that patients can benefit from a PDE4 inhibitor in a very low-cost form.
“Generic oral roflumilast is cheaper than a Starbucks coffee,” Dr. Egeberg said.
In this trial, 46 patients were randomly assigned to placebo or to the COPD-approved roflumilast dose of 500 mcg once daily. The primary endpoint was change in PASI scores from baseline to week 12, which Dr. Egeberg pointed out is a shorter time frame than the 16 weeks more typical of psoriasis treatment studies.
At week 12, the median improvement in PASI was 34.8% in the roflumilast group versus 0% in the placebo group. Patients were then followed for an additional 12 weeks, but those randomized to placebo were switched to the active treatment. By week 24, the switch patients had largely caught up to those initiated on roflumilast for median PASI improvement (39.1% vs. 43.5%).
Similar to orismilast, roflumilast “was generally well tolerated,” Dr. Egeberg said. The adverse events were consistent with those associated with PDE4 inhibitors in previous trials, whether in psoriasis or COPD. There was only one serious adverse event, and it was not considered treatment related. Discontinuations for adverse events “were very low.”
In a population with a relatively high rate of smoking, Dr. Egeberg further reported, lung function was improved, a remark initially interpreted as a joke by some attending the presentation. However, Dr. Egeberg confirmed that lung function was monitored, and objective improvements were recorded.
By Danish law, the investigators were required to inform the manufacturers of roflumilast. Despite the results of this study, he is not aware of any plans to seek an indication for roflumilast in psoriasis, but he noted that the drug is readily available at a low price.
For those willing to offer this therapy off label, “you can start using it tomorrow if you’d like,” he said.
Dr. French reports financial relationships with Almirall, Amgen, Biotest, Galderma, Janssen Cilag, Leo Pharma, Pincell, Regeneron, UCB, and UNION Therapeutics, which provided funding for this trial. Dr. Egeberg reports financial relationships with Eli Lilly, Galderma, Janssen-Cilag, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – according to results of a phase 2 clinical trial presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
The phase 2b data, which are prompting a phase 3 trial, suggest that the drug, called orismilast, “is a potential new addition to the psoriasis armamentarium,” reported Lars E. French, MD, professor and chair, department of dermatology, Ludwig Maximilian University of Munich (Germany).
At the same session, findings from another study supported off-label use of oral roflumilast (Daliresp and generic), a PDE4 inhibitor approved for severe chronic obstructive pulmonary disease (COPD). The only PDE4 inhibitors with an indication for psoriasis are roflumilast, approved as a cream (Zoryve), and apremilast (Otezla), approved as an oral therapy.
Phase 2 study of orismilast
In the orismilast trial, Dr. French attributed the efficacy observed to the potency of orismilast on the B and D subtypes of PDE4 associated with inflammation. One clue is that these specific subtypes are overly expressed in the skin of patients with either psoriasis or atopic dermatitis.
“When compared to apremilast, orismilast is at least two to fivefold more potent on all PDE4 isoforms and up to 39 times more potent on some of the PDE4 B and D isoforms,” said Dr. French, referring to preclinical findings in human whole blood and blood cells and in a mouse model of chronic inflammation.
The efficacy of orismilast in an immediate-release oral formulation was previously demonstrated in a recently published phase 2a trial, but the newest study tested a modified-release formulation of orismilast to test its potential to improve tolerability.
In the study, 202 adult patients with moderate to severe psoriasis (Psoriasis Area Severity Index [PASI] score ≥ 12) were randomly assigned to one of three doses of orismilast or to placebo. Each of the three doses – 20 mg, 30 mg, or 40 mg – were administered twice daily. The primary endpoint was change in PASI score at 16 weeks. Secondary endpoints included PASI 75 responses (signifying 75% clearance) and safety.
Relative to placebo, which was associated with a PASI improvement of 17%, all three of the tested orismilast doses were superior in a dose-dependent manner. The rates of response were 53%, 61%, and 64% for the 20-mg, 30-mg, and 40-mg twice-daily doses, respectively.
The PASI improvements were rapid, Dr. French said. At 4 weeks, PASI scores climbed from baseline by nearly 40% for those on all orismilast doses, which was more than double the improvement in the placebo group.
In the intention-to-treat analysis with missing data counted as nonresponders, the proportion of patients reaching PASI-75 scores at 16 weeks were 39%, 49%, 45%, and 17%, in the 20-mg, 30-mg, 40-mg, and placebo groups, respectively. The proportion of patients experiencing complete or near-complete skin clearance defined by a PASI 90 were 24%, 22%, 28%, and 8%, respectively.
The side-effect profile was consistent with other PDE4 inhibitors. The most common adverse events included gastrointestinal complaints, such as diarrhea and nausea, as well as headache and dizziness. But the majority of these events were of low grade, and they were largely confined to the first 4 weeks of treatment, which is a pattern reported with other PDE4 inhibitors in psoriasis and other chronic inflammatory diseases, such as COPD, according to Dr. French.
“There were no discontinuations for a treatment-related adverse event in the arms receiving either the 20-mg or the 30-mg doses,” Dr. French reported. There were only two serious adverse events, and neither were considered by trial investigators to be related to orismilast.
Based on the limited therapeutic gain but greater risk for adverse events on the 40-mg twice-daily dose, “the question is now whether to move forward with the 20-mg or the 30-mg dose,” said Dr. French, who said planning of a phase 3 trial is underway.
Phase 2 study of roflumilast
However, this was not the only set of data on an oral PDE4 inhibitor presented as a late-breaker at the AAD meeting. For clinicians looking for a more immediate and less expensive alternative to apremilast, another study indicated that off-label use of oral roflumilast is an option.
In an investigator-initiated, multicenter, double-blind, placebo-controlled trial conducted in Denmark, the rate of response to oral roflumilast at 24 weeks, including the clear or almost clear response, was on the same general order of magnitude as that seen in the orismilast study, reported Alexander Egeberg, MD, PhD, professor of dermatology, University of Copenhagen.
“At 24 weeks, 21.7% had achieved a PASI 90, and 8.7% achieved a PASI 100,” Dr. Egeberg said.
Oral roflumilast has been available for the treatment of COPD for more than 10 years and is now available in a generic formulation. This study was conducted independent of any pharmaceutical company involvement, and the high rate of response and low risk of adverse events suggests that patients can benefit from a PDE4 inhibitor in a very low-cost form.
“Generic oral roflumilast is cheaper than a Starbucks coffee,” Dr. Egeberg said.
In this trial, 46 patients were randomly assigned to placebo or to the COPD-approved roflumilast dose of 500 mcg once daily. The primary endpoint was change in PASI scores from baseline to week 12, which Dr. Egeberg pointed out is a shorter time frame than the 16 weeks more typical of psoriasis treatment studies.
At week 12, the median improvement in PASI was 34.8% in the roflumilast group versus 0% in the placebo group. Patients were then followed for an additional 12 weeks, but those randomized to placebo were switched to the active treatment. By week 24, the switch patients had largely caught up to those initiated on roflumilast for median PASI improvement (39.1% vs. 43.5%).
Similar to orismilast, roflumilast “was generally well tolerated,” Dr. Egeberg said. The adverse events were consistent with those associated with PDE4 inhibitors in previous trials, whether in psoriasis or COPD. There was only one serious adverse event, and it was not considered treatment related. Discontinuations for adverse events “were very low.”
In a population with a relatively high rate of smoking, Dr. Egeberg further reported, lung function was improved, a remark initially interpreted as a joke by some attending the presentation. However, Dr. Egeberg confirmed that lung function was monitored, and objective improvements were recorded.
By Danish law, the investigators were required to inform the manufacturers of roflumilast. Despite the results of this study, he is not aware of any plans to seek an indication for roflumilast in psoriasis, but he noted that the drug is readily available at a low price.
For those willing to offer this therapy off label, “you can start using it tomorrow if you’d like,” he said.
Dr. French reports financial relationships with Almirall, Amgen, Biotest, Galderma, Janssen Cilag, Leo Pharma, Pincell, Regeneron, UCB, and UNION Therapeutics, which provided funding for this trial. Dr. Egeberg reports financial relationships with Eli Lilly, Galderma, Janssen-Cilag, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – according to results of a phase 2 clinical trial presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
The phase 2b data, which are prompting a phase 3 trial, suggest that the drug, called orismilast, “is a potential new addition to the psoriasis armamentarium,” reported Lars E. French, MD, professor and chair, department of dermatology, Ludwig Maximilian University of Munich (Germany).
At the same session, findings from another study supported off-label use of oral roflumilast (Daliresp and generic), a PDE4 inhibitor approved for severe chronic obstructive pulmonary disease (COPD). The only PDE4 inhibitors with an indication for psoriasis are roflumilast, approved as a cream (Zoryve), and apremilast (Otezla), approved as an oral therapy.
Phase 2 study of orismilast
In the orismilast trial, Dr. French attributed the efficacy observed to the potency of orismilast on the B and D subtypes of PDE4 associated with inflammation. One clue is that these specific subtypes are overly expressed in the skin of patients with either psoriasis or atopic dermatitis.
“When compared to apremilast, orismilast is at least two to fivefold more potent on all PDE4 isoforms and up to 39 times more potent on some of the PDE4 B and D isoforms,” said Dr. French, referring to preclinical findings in human whole blood and blood cells and in a mouse model of chronic inflammation.
The efficacy of orismilast in an immediate-release oral formulation was previously demonstrated in a recently published phase 2a trial, but the newest study tested a modified-release formulation of orismilast to test its potential to improve tolerability.
In the study, 202 adult patients with moderate to severe psoriasis (Psoriasis Area Severity Index [PASI] score ≥ 12) were randomly assigned to one of three doses of orismilast or to placebo. Each of the three doses – 20 mg, 30 mg, or 40 mg – were administered twice daily. The primary endpoint was change in PASI score at 16 weeks. Secondary endpoints included PASI 75 responses (signifying 75% clearance) and safety.
Relative to placebo, which was associated with a PASI improvement of 17%, all three of the tested orismilast doses were superior in a dose-dependent manner. The rates of response were 53%, 61%, and 64% for the 20-mg, 30-mg, and 40-mg twice-daily doses, respectively.
The PASI improvements were rapid, Dr. French said. At 4 weeks, PASI scores climbed from baseline by nearly 40% for those on all orismilast doses, which was more than double the improvement in the placebo group.
In the intention-to-treat analysis with missing data counted as nonresponders, the proportion of patients reaching PASI-75 scores at 16 weeks were 39%, 49%, 45%, and 17%, in the 20-mg, 30-mg, 40-mg, and placebo groups, respectively. The proportion of patients experiencing complete or near-complete skin clearance defined by a PASI 90 were 24%, 22%, 28%, and 8%, respectively.
The side-effect profile was consistent with other PDE4 inhibitors. The most common adverse events included gastrointestinal complaints, such as diarrhea and nausea, as well as headache and dizziness. But the majority of these events were of low grade, and they were largely confined to the first 4 weeks of treatment, which is a pattern reported with other PDE4 inhibitors in psoriasis and other chronic inflammatory diseases, such as COPD, according to Dr. French.
“There were no discontinuations for a treatment-related adverse event in the arms receiving either the 20-mg or the 30-mg doses,” Dr. French reported. There were only two serious adverse events, and neither were considered by trial investigators to be related to orismilast.
Based on the limited therapeutic gain but greater risk for adverse events on the 40-mg twice-daily dose, “the question is now whether to move forward with the 20-mg or the 30-mg dose,” said Dr. French, who said planning of a phase 3 trial is underway.
Phase 2 study of roflumilast
However, this was not the only set of data on an oral PDE4 inhibitor presented as a late-breaker at the AAD meeting. For clinicians looking for a more immediate and less expensive alternative to apremilast, another study indicated that off-label use of oral roflumilast is an option.
In an investigator-initiated, multicenter, double-blind, placebo-controlled trial conducted in Denmark, the rate of response to oral roflumilast at 24 weeks, including the clear or almost clear response, was on the same general order of magnitude as that seen in the orismilast study, reported Alexander Egeberg, MD, PhD, professor of dermatology, University of Copenhagen.
“At 24 weeks, 21.7% had achieved a PASI 90, and 8.7% achieved a PASI 100,” Dr. Egeberg said.
Oral roflumilast has been available for the treatment of COPD for more than 10 years and is now available in a generic formulation. This study was conducted independent of any pharmaceutical company involvement, and the high rate of response and low risk of adverse events suggests that patients can benefit from a PDE4 inhibitor in a very low-cost form.
“Generic oral roflumilast is cheaper than a Starbucks coffee,” Dr. Egeberg said.
In this trial, 46 patients were randomly assigned to placebo or to the COPD-approved roflumilast dose of 500 mcg once daily. The primary endpoint was change in PASI scores from baseline to week 12, which Dr. Egeberg pointed out is a shorter time frame than the 16 weeks more typical of psoriasis treatment studies.
At week 12, the median improvement in PASI was 34.8% in the roflumilast group versus 0% in the placebo group. Patients were then followed for an additional 12 weeks, but those randomized to placebo were switched to the active treatment. By week 24, the switch patients had largely caught up to those initiated on roflumilast for median PASI improvement (39.1% vs. 43.5%).
Similar to orismilast, roflumilast “was generally well tolerated,” Dr. Egeberg said. The adverse events were consistent with those associated with PDE4 inhibitors in previous trials, whether in psoriasis or COPD. There was only one serious adverse event, and it was not considered treatment related. Discontinuations for adverse events “were very low.”
In a population with a relatively high rate of smoking, Dr. Egeberg further reported, lung function was improved, a remark initially interpreted as a joke by some attending the presentation. However, Dr. Egeberg confirmed that lung function was monitored, and objective improvements were recorded.
By Danish law, the investigators were required to inform the manufacturers of roflumilast. Despite the results of this study, he is not aware of any plans to seek an indication for roflumilast in psoriasis, but he noted that the drug is readily available at a low price.
For those willing to offer this therapy off label, “you can start using it tomorrow if you’d like,” he said.
Dr. French reports financial relationships with Almirall, Amgen, Biotest, Galderma, Janssen Cilag, Leo Pharma, Pincell, Regeneron, UCB, and UNION Therapeutics, which provided funding for this trial. Dr. Egeberg reports financial relationships with Eli Lilly, Galderma, Janssen-Cilag, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
AT AAD 2023