Pfizer's Abrocitinib Looks Competitive In Atopic Dermatitis
Executive Summary
The first detailed Phase III results for the company's next-generation oral JAK inhibitor abrocitinib appear to show efficacy on par or better than data from Sanofi/Regeneron's Dupixent and may give Lilly's Olumiant a run for its money in AD.
Pfizer Inc. has expanded on the long lead it had with Xeljanz (tofacitinib) over competing Janus kinase (JAK) inhibitors by engineering more selective next-generation drugs in this class, including abrocitinib, for which the company presented the first detailed Phase III atopic dermatitis (AD) data on 12 October in a late-breakers session at the European Academy of Dermatology and Venereology (EADV) meeting in Madrid.
Positive top-line results already have been reported for abrocitinib, a selective inhibitor of JAK1, in two out of three Phase III clinical trials meant to support a US Food and Drug Administration filing in the second half of 2020 for the treatment of moderate-to-severe AD. Detailed data from the JADE MONO-1 study at EADV show an efficacy profile for the oral small molecule abrocitinib that may compare well with competitors in this itchy skin disease, including the blockbuster biologic Dupixent (dupilumab) from Sanofi and Regeneron Pharmaceuticals Inc.
Pfizer is submitting results from the JADE MONO-2 study for abrocitinib for possible presentation at the American Academy of Dermatology (AAD) meeting in March. Results from a third trial, JADE Compare, also tests abrocitinib versus placebo, but with a separate active comparator arm in which patients will be treated with Dupixent, with results expected in the first half of 2020. (Also see "Pfizer Continues Positive Data Readouts For JAK Inhibitor Abrocitinib In Eczema" - Scrip, 27 Sep, 2019.)
Michael Corbo, senior vice president and chief development officer for Pfizer's Inflammation & Immunology (I&I) unit, stressed in an interview with Scrip that there is need for new options, particularly for an oral therapy, which is not currently available. "There is a subset of patients who always will prefer oral therapy," Corbo said. "But also not every mechanism works for every patient. While dupilumab is a very good drug and it works well for patients, not all patients respond, so having an alternative mechanism is very important for patients with moderate to severe disease."
He said Pfizer also believes the rapid onset of action observed in Phase III trials for abrocitinib to date is going to be a differentiating factor for the drug versus other AD options. Most approved agents are topical treatments, including the company's phosphodiesterase-4 (PDE-4) inhibitor Eucrisa (crisaborole). (Also see "Atopic Dermatitis Market Snapshot: The Next Multi-Billion Dollar Opportunity" - Scrip, 20 Oct, 2016.)
Data At EADV Show Significance Across Doses
One of the co-primary endpoints in JADE MONO-1 was the proportion of patients who at 12 weeks achieved an Investigator Global Assessment (IGA) score of 0 or 1 – clear or almost clear skin – and a two-point or greater improvement from baseline, which Corbo noted is the US FDA's standard for drug approvals in AD. The other co-primary endpoint was the proportion of patients with at least a 75% change from baseline in their Eczema Area and Severity Index (EASI) score.
Key secondary endpoints included the proportion of patients with a four-point or greater reduction in itch severity measured with the pruritus numerical rating scale (NRS) and the magnitude of decrease in the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) – a patient-reported measurement scale developed by Pfizer. Among other secondary endpoints were the proportion of patients with at least a 90% change in EASI score (EASI 90) and the percentage change from baseline in SCORing Atopic Dermatitis (SCORAD) response at all scheduled time points.
Both once-daily abrocitinib doses – 100 mg and 200 mg – met the co-primary endpoints with statistical significance, however, Pfizer did not report the p-values. The company said the percentage changes in SCORAD were statistically significant for both doses of abrocitinib versus placebo at all time points.
JADE MONO-1 enrolled 387 AD patients aged 12 and up, including 154 patients in the 200 mg arm, 156 in the 100 mg arm and 77 in the placebo arm of the study.
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Abrocitinib Vs. Placebo Response Rates In JADE MONO-1 |
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|
|
Abrocitinib 200 mg |
Abrocitinib 100 mg |
Placebo |
|
IGA |
43.8% |
23.7% |
7.9% |
|
EASI 75 |
62.7% |
39.7% |
11.8% |
|
NRS Four-Point Improvement |
57.2% |
37.7% |
15.3% |
|
EASI 90 |
38.6% |
18.6% |
5.3% |
In addition to abrocitinib's oral administration and selective JAK1 inhibition, Pfizer believes that its rapid onset of action will be a differentiating factor for its drug. Corbo said 50% of the patients treated with 200 mg of abrocitinib in JADE MONO-1 had a meaningful improvement in pruritis starting at two weeks on the drug.
"This is the thing keeping them up at night, preventing them from doing daily activities and it's really all-consuming when you have such intense itching," he noted. "We also do see rapid improvement in inflammation as well, but itching is a hallmark of the disease, and being able to see rapid responses in that is important."
The US FDA granted a breakthrough therapy designation for abrocitinib in the treatment of moderate to severe AD in February 2018.
Data Look Competitive Vs. Dupixent And Lilly's Olumiant
Corbo admitted it's difficult to compare drugs across different clinical trials, but the JADE Compare trial with Dupixent as an active comparator should shed some light on abrocitinib's potentially differentiating features.
However, the Dupixent label notes that in two studies testing the interleukin-4 (IL-4)/IL-13 inhibitor as a monotherapy IGA response rates were 38% and 36% at 16 weeks, which is less than the 43.8% IGA response rate for abrocitinib 200 mg in JADE MONO-1 at 12 weeks. EASI 75 responses were 51% and 44% for Dupixent, also lower than the 62.7% EASI 75 response rate for abrocitinib 200 mg.
EASI 90 responses for Dupixent monotherapy were 36% and 30%, closer to abrocitinib 200 mg's 38.6%. Improvements in pruritis of four NRS points or more were 41% and 36% for Dupixent at 16 weeks versus 57.2% for abrocitinib 200 mg at 12 weeks.
Eli Lilly & Co.'s JAK1 and JAK2 inhibitor Olumiant (baricitinib) also is in Phase III for AD. EASI 75 rates at week 16 for Olumiant in the BREEZE-AD7 trial were 43.1% for the 2 mg dose and 47.7% for the 4 mg dose. NRS response rates were 38.1% for Olumiant 2 mg and 44% for the 4 mg dose. (Also see "Lilly's Latest Olumiant Data Raise Question Of JAK Inhibitor Role In Atopic Dermatitis" - Scrip, 27 Aug, 2019.)
Abrocitinib Safety May Stand Out In JAK Class
BREEZE-AD7 was the third of five Phase III studies for Olumiant in AD to report and it raised an already concerning safety flag. One patient in the study, which studied Olumiant in combination with topical corticosteroids, had a pulmonary embolism. Cardiovascular concerns due to pulmonary emboli reported in a few patients treated with Olumiant in rheumatoid arthritis (RA) clinical trials are why the drug is approved in the US only at the lower 2 mg dose. (Also see "Lilly Prices Olumiant For JAK Battle, But Misses Approval For Higher Dose" - Scrip, 2 Jun, 2018.)
No patients treated with abrocitinib in JADE MONO-1 had any cardiovascular events.
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Rates Of Serious Adverse Events (SAEs) And Treatment Discontinuations Due To AEs |
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|
|
Abrocitinib 200 mg |
Abrocitinib 100 mg |
Placebo |
|
SAEs |
3.2% |
3.2% |
1.9% |
|
Discontinuations |
5.8% |
5.8% |
9.1% |
"The adverse event rate was similar in both MONO-1 and MONO-2," Corbo said.
Short-lasting nausea (20.1% in the 200 mg arm, 9% in the 100 mg arm), headache (9.7%, 7.7%) and nasopharyngitis (11.7%, 14.7%) were the most common treatment-emergent adverse events (TEAEs) for abrocitinib, while the most common TEAE in the placebo group was dermatitis (16.9%).
Serious adverse events (SAEs) in the abrocitinib 200 mg group were inflammatory bowel disease (IBD), peritonsillitis, dehydration and two cases of asthma, while SAEs in the 100 mg group were retinal detachment, acute pancreatitis, dizziness and seizures. Aggravated dermatitis, meniscal degeneration and atopic dermatitis were SAEs in the placebo group.
"Of all of the serious adverse events, there was one in the 100 mg arm of acute pancreatitis in an alcoholic and there was one case of inflammatory bowel disease reported in the 200 mg arm" that were deemed by the JADE MONO-1 investigators to be related to treatment with abrocitinib, Corbo said.
Safety And Efficacy By Design
Corbo noted that Pfizer has been working for several years now to design kinase inhibitors with more specificity to improve both efficacy and safety.
"We're really seeing the maturation of the investment that we've made in the science of the JAK pathway, both in biology and chemistry, which has led up to abrocitinib," he said.
Michael Vincent, senior vice president and chief scientific officer in Pfizer's I&I unit, said abrocitinib is the most advanced of the five assets in the company's immuno-kinase inhibitor portfolio, which are being tested across nine immune-mediated diseases in the I&I group's three main areas of focus – dermatology, gastroenterology and rheumatology.
The other four immuno-kinase inhibitors are: PF-06651600, a JAK3/TEC family kinase inhibitor in Phase III for alopecia areata (AA) and Phase II for vitiligo, Crohn’s disease (CD) and ulcerative colitis (UC); PF-06700841, a tyrosine kinase 2 (TYK2)/JAK1 inhibitor with a topical formulation in Phase II for psoriasis and AD, and an oral formulation in Phase II for psoriatic arthritis, CD, UC, vitiligo, systemic lupus erythematosus (SLE) and AA; PF-06826647, a TYK2 inhibitor in Phase II for psoriasis; and PF-06650833, an IL-1 receptor-associated kinase 4 (IRAK4) in Phase II for RA.
"Our interest and our expertise in this area is really driven by tofacitinib, Xeljanz, which was approved six years ahead of any agent for rheumatoid arthritis," Vincent said. "That's given us really great capabilities in the biology of JAK inhibition as well as the chemistry required to come up with those unique assets."
"In addition, having a suite of molecules to choose from has enabled us to take a different approach than I think some others have taken with their JAK programs," he continued. "Rather than studying one inhibitor across a range of indications and hoping it works well in all of those, we've actually tried to target our particular unique kinase inhibitors to the pathophysiology of the underlying disease, so that we're matching the cytokines that are inhibited by that particular kinase with the pathology that's driven by cytokines in a particular disease."
For example, Dupixent inhibits the cytokines IL-4 and IL-13, but IL-31 also is an important cytokine in AD, because it stimulates nerve cells to drive the pruritis, or itching, that's a hallmark of the disease. Inhibition of JAK1 by drugs like abrocitinib modulates IL-4, IL-13 and IL-31 as well as interferon gamma.
"We think that's probably one of the reasons why, since JAK1 inhibits IL-31, that we have such a rapid and marked effect on itch in our patients," Vincent said.
Pfizer's next selective immuno-kinase inhibitor to report data will be the JAK3/TEC inhibitor PF-06651600. Two late-stage trials in alopecia are under way and a US FDA filing based on those studies is expected in 2021. Pfizer believes that the JAK3/TEC inhibitor and abrocitinib have the potential to exceed $1bn each in peak revenues across their targeted indications, Vincent said.
In addition to the three Phase III JADE studies for abrocitinib in adults and adolescents with AD, the company also plans to test the drug in pediatric patients – first in children aged 6-12 and then in 2- to 6-year-olds – after reviewing the adult and adolescent data with regulators. Dupixent was approved first in adults and more recently in adolescents, but Sanofi and Regeneron also now have positive results in children aged 6-11. (Also see "Getting A Good Start: Sanofi Extends Dupixent's Potential To Younger Patients" - Scrip, 6 Aug, 2019.)