TREATMENT OF ATOPIC DERMATITIS EMPLOYING ANTI-IL-13Ra1 ANTIBODY OR BINDING FRAGMENT THEREOF

Abstract

An antibody, antigen binding fragment thereof or a pharmaceutical formulation, which is an inhibitor of signalling through IL-13Rα1 by binding said receptor and compositions comprising the same for use in the treatment of atopic dermatitis (for example moderate to severe atopic dermatitis, in particular poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range 200 mg to 600 mg, (such as 400 to 600 mg), wherein the disease is modified by a percentage reduction in EASI score in the range −20 to −100% from the baseline.

Claims

1. A method of treating a patient to reduce EASI score in the range −20 to −100% from the baseline in a patient with atopic dermatitis, for example moderate to severe atopic dermatitis (in particular poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range 200 mg to 600 mg of an antibody, antigen binding fragment thereof or a pharmaceutical formulation thereof , which is an inhibitor of signalling through of the IL-13Rα1 by binding the said receptor.

2. A method according to claim 1, wherein reduction in EASI is present after about two weeks from administration of the first dose (such as day 15).

3. A method according to claim 1, wherein reduction in EASI is present after about four weeks from administration of the first dose (day 29).

4. A method according to claim 1, wherein reduction in EASI is present after about six weeks from administration of the first dose (such as day 43).

5. A method according to claim 1, wherein reduction in EASI is present after about eight weeks from administration of the first dose (such as day 57).

6. A method according to claim 1, wherein multiple doses are administered in a treatment cycle.

7. A method according to claim 1, wherein multiple treatment cycles are administered, for example 2, 3, 4 or more treatment cycles are administered.

8. A method according to claim 1, wherein following the treatment cycle or cycles and disease modification, maintenance therapy is administered, for example the same dose administered less frequently (for example monthly), or a lower dose (such as 200 mg) administered the same frequency or less frequently (such as about 2 weekly, about 3 weekly, or about 4 weekly.

9. A method according to claim 1, wherein said antibody or binding fragment thereof is administered approximately weekly, once approx. every 2 weeks, once approximately every 3 weeks, or once approximately every 4 weeks (for example monthly), (in particular a single treatment cycle, especially 8 weeks).

10. A method according to claim 1, wherein a loading dose in the range 400 to 900 mg, for example 400, 500, 600, 700, 800 or 900 mg is employed before administration of the treatment cycle.

11. A method according to claim 1, wherein the treatment does not comprise a loading dose.

12. A method according to claim 1, wherein the dose is 200 mg.

13. A method according to claim 12, wherein the reduction in EASI is in the range −15 to −60% (for example at about day 15).

14. A method according to claim 12, wherein the reduction in EASI score is in the range −40 to −85% (eg at about day 29).

15. A method according to claim 12, wherein the reduction in EASI score is in the range −25 to −85% (eg at about day 43 or 57)

16. A method according to claim 12, wherein the dose is in the range 350 to 450 mg, such as 400 mg, for example wherein 80% of the patient population has an EASI 50 at about day 29 and/or day 57.

17. A method according to claim 1, wherein the dose is 600 mg.

18. A method according to claim 17, wherein the reduction in EASI score is in the range −25 to −60% (eg −39 to −59, such as −40 to −59, in particular −47, −48, −49, −50, −51, −52, −53, −54, −55, −56, −57, −58 or −59%) for example at about day 15.

19. A method according to claim 17, wherein the reduction in EASI is in the range −50 to −100% (eg −55 to −97%) such as at about day 29.

20. A method according to claim 17, wherein the reduction in EASI is in the range −60 to −100% (eg −70 to −97%) in particular at about day 43.

21. A method according to claim 17, wherein the reduction in EASI score is in the range −65 to −100% (for example −70 to −100, such as −90 to −100, in particular 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%) in particular at about day 57.

22. A method according to claim 17, wherein 90% of the patient population has an EASI 50 at about day 57.

23. A method according to claim 1, wherein the treatment cycles comprises a first dose at 600 mg, followed by three weekly doses of 400 mg, e.g. wherein the treatment cycle is repeated twice i.e. two treatment cycles lasting 8 weeks, in particular day 1 600 mg, approx. day 8 400 mg, approx. day 15 400 mg, approx. day 22 400 mg, approx. day 29 600 mg, approx. day 36 400 mg, approx. day 43 400 mg, and approx. day 50 400 mg are administered.

24. A method according to claim 1, wherein disease modification, occurs by day 4, wherein day 1 is the first administration of the antibody or binding fragment thereof, for example wherein the disease modification is a reduction in EASI score, such as wherein the reduction is a percentage from base line in the range −10 to 55%.

25. A method according to claim 1, wherein the disease modification in the range −40 to −100% is achieved by about day 57 following first administration on day 1, e.g. maximum disease modification is achieved by about day 57.

Description

BRIEF DESCRIPTION OF FIGURES

[0123] FIG. 1A Table showing demographics of full analysis set

[0124] FIG. 1B Table showing baseline disease characteristics of full analysis set

[0125] FIG. 1C Table showing baseline disease characteristics of Evaluable for Efficacy set (EES)

[0126] FIG. 2A Table showing % change from baseline in EASI score at Day 57 for EES

[0127] FIG. 2B Graph showing % change from baseline in EASI score at Day 57 for EES (ASLAN004 200 mg, 400 mg and 600 mg)

[0128] FIG. 2C Graph showing % change from baseline in EASI score at Day 57 for EES (ASLAN004 low dose and high doses)

[0129] FIG. 3A Table showing % change from baseline in EASI score at Day 29 for EES.

[0130] FIG. 3B Graph showing % change from baseline in EASI score at Day 29 for EES (ASLAN004 200 mg, 400 mg and 600 mg)

[0131] FIG. 4A Graph showing % change in EASI score over time for EES (ASLAN004 200 mg, 400 mg and 600 mg)

[0132] FIG. 4B Graph showing % change in EASI score over time for EES (ASLAN004 low and high dose)

[0133] FIG. 5A Graph showing % change in baseline in EASI score over time for EES (Placebo)

[0134] FIG. 5B Graph showing % change in baseline in EASI score over time for EES (ASLAN004 200 mg)

[0135] FIG. 5C Graph showing % change in baseline in EASI score over time for EES (ASLAN004 400 mg)

[0136] FIG. 5D Graph showing % change in baseline in EASI score over time for EES (ASLAN004 600 mg)

[0137] FIG. 6A Table showing Day 57 sensitivity analysis in the modified intention to treat (mITT)

[0138] FIG. 6B Graph showing Day 57 sensitivity analysis in the mITT (ASLAN004 200 mg, 400 mg and 600 mg)

[0139] FIG. 6C Graph showing Day 57 sensitivity analysis in the mITT (ASLAN004 low and high dose)

[0140] FIG. 7A Summary table showing EASI 50, EASI 75, EASI 90 at Day 57 for EES

[0141] FIG. 7B Graph showing EASI 50 at Day 57 for EES (ASLAN004 200 mg, 400 mg and 600 mg)

[0142] FIG. 7C Graph showing EASI 50 at Day 57 for EES (ASLAN004 low and high dose)

[0143] FIG. 7D Graph showing EASI 75 at Day 57 for EES (ASLAN004 200 mg, 400 mg and 600 mg)

[0144] FIG. 7E Graph showing EASI 75 at Day 57 for EES (ASLAN004 low and high dose)

[0145] FIG. 7F Graph showing EASI 90 at Day 57 for EES (ASLAN004 200 mg, 400 mg and 600 mg)

[0146] FIG. 7G Graph showing EASI 90 at Day 57 for EES (ASLAN004 low and high dose)

[0147] FIG. 8A Graph showing proportion of patients achieving EASI 50

[0148] FIG. 8B Graph showing proportion of patients achieving EASI 75

[0149] FIG. 8C Graph showing proportion of patients achieving EASI 90

[0150] FIG. 9 Summary table showing proportion of patients achieving EAS ISO, 75, 90 for EES and mITT

[0151] FIG. 10A Summary table showing proportion of patients with IGA score of 0 or 1 at Day 57 for ESS

[0152] FIG. 10B Graph showing proportion of patients with IGA score of 0 or 1 at Day 57 for ESS

[0153] FIG. 10C Graph showing proportion of patients with IGA score of 0 or 1 over time for ESS

[0154] FIG. 11 Table showing baseline TARC and IgE levels of patients

[0155] FIG. 12A Graph showing average % change from baseline TARC (ASLAN004 200 mg and 400 mg)

[0156] FIG. 12B Graph showing average % change from baseline TARC (ASLAN004 400 mg and placebo)

[0157] FIG. 12C Graph showing % change from baseline TARC for individual patients (ASLAN004 400 mg)

[0158] FIG. 13A Graph showing IgE % change from baseline for ASLAN004 200 mg and 400 mg

[0159] FIG. 13B Graph showing average IgE% change from baseline for ASLAN004 200 mg and 400 mg

[0160] FIG. 13C Graph showing IgE % change from baseline for individual patients for placebo

[0161] FIG. 13D Graph showing IgE % change from baseline for individual patients for ASLAN004 200 mg

[0162] FIG. 13E Graph showing IgE % CFB for individual patients for ASLAN004 400 mg

[0163] FIG. 14 Graph showing comparison between ASLAN004 exposure, EASI, TARC and IgE over time for patients receiving ASLAN004 400 mg

[0164] FIG. 15 Table showing comparison in activity between ASLAN004 and Duplilumab

[0165] FIG. 16 Flow chart showing number of subjects in each test group

[0166] FIG. 17 Table showing baseline demographics and disease characteristics of Intention-to-treat (ITT), modified Intention-to-treat (mITT) and Excluded site groups

[0167] FIG. 18 Table showing adverse events (AEs) for mITT vs Excluded site groups

[0168] FIG. 19 Graph showing EASI, mean % change from baseline (%CFBL) for mITT group

[0169] FIG. 20 Graph showing EASI, mean % change from baseline (%CFBL) at week 8 for mITT vs Excluded site groups

[0170] FIG. 21 Graph showing placebo adjusted means (EASI) for mITT vs Excluded site groups

[0171] FIG. 22 Graph showing % of patients achieving EASI-50, EASI-75 and EAS-90 at week 8 for mITT group

[0172] FIG. 23 Graph showing % of patients achieving IGA 0/1 at week 8 for mITT group

[0173] FIG. 24 Graph showing mean % CFBL in % BSA affected for mITT group

EXAMPLES

Example 1 Study Protocol (Initial MAD Escalation)

[0174] Patients enrolled in ascending dose cohorts of ASLAN004 (SEQ ID NO: 51, 53 and 59 herein): 200 mg 400 mg, 600 mg. ASLAN low dose=ASLAN004 200 mg ASLAN high dose=ASLAN004 400 mg+ASLAN004 600 mg.
Details of patients are shown in FIG. 1. Initially the doses were given weekly (QW). Within each cohort, patients were randomized in a 3:1 ratio of ASLAN004: Placebo

Results

[0175] Table 1 shows the % change in baseline in EASI score at Day 57 (8 weeks).

TABLE-US-00006 TABLE 1 % change in baseline in EASI score at Day 57 (8 weeks) Diff (vs. Treatment Arm N Mean Placebo) Placebo 5 −42.4% — ASLAN004 200 mg QW 4 −49.5%  −7.1% ASLAN004 400 mg QW 6 −73.6% −31.2% ASLAN004 600 mg QW 3 −75.8% −33.4% ASLAN004 High Doses 9 −74.3% −31.9%
FIGS. 2B to 2C shows the %change in baseline in EASI score in graph form.
Table 2 shows the % change in baseline in EASI score at Day 29 (4 weeks).

TABLE-US-00007 TABLE 2 % change in baseline in EASI score at Day 29 (4 weeks) Diff (vs. Treatment Arm N Mean Placebo) Placebo 5 −30.5% — ASLAN004 200 mg 4 −51.2% −20.7% ASLAN004 400 mg 6 −63.7% −33.2% ASLAN004 600 mg 3 −53.6% −23.1% ASLAN004 High Doses 9 −60.4% −29.8%
FIG. 3B shows the %change in baseline in EASI score in graph form.
FIGS. 4 and 5 show the % change in baseline in EASI score over time.
Table 3 shows the sensitivity analysis in the mITT (modified intention to treat) set at Day 57

TABLE-US-00008 TABLE 3 Sensitivity analysis in the mITT at Day 57 Diff (vs. Analysis Set Treatment Arm N Mean Placebo) EES Placebo 5 −42.9% — (Primary) ASLAN004 200 mg 4 −49.5%  −7.1% ASLAN004 400 mg 6 −73.6% −31.2% ASLAN004 600 mg 3 −75.8% −33.4% mITT Placebo 6 −31.4% — (sensitivity) ASLAN004 200 mg 4 −49.5% −18.9% ASLAN004 400 mg 7 −63.1% −31.6% ASLAN004 600 mg 5 −47.1% −15.7%
FIG. 6B to C shows the sensitivity analysis in graph form.
Table 4 shows a summary of the proportion of patients achieving EASI 50, EASI 75 and EASI 90 at Day 57.

TABLE-US-00009 TABLE 4 EASI 50, EASI 75 and EASI 90 at Day 57 EASI 50 EASI 75 EASI 90 Treatment Group N (%) N (%) N (%) Placebo (n = 5) 2 0 0 (40.0%) ASLAN004 200 2 2 0 mg (n = 4) (50.0%) (50.0%) ASLAN004 400 5 4 4 mg (n = 6) (83.3%) (66.7%) (66.7%) ASLAN004 600 3 2 1 mg (n = 3) (100%) (66.7%) (33.3%) ASLAN004 High 8 6 1 Doses (n = 9) (88.9%) (66.7%) (55.6%)
FIGS. 7B to 8C shows the same data in graph form.
FIG. 9 shows the proportion of miTT sensitivity analysis set achieving EASI 50, EASI 75 and EASI 90 at Day 57.
Finally, FIG. 15 shows a comparison between the proportion of patients achieving EASI 50, EASI 75 and EASI 90 at Day 57 when treated with ASLAN004 vs dupilumab.
The results indicate that ASLAN004 results in a significant improvement in EASI score compared to placebo. In particular, at week 8, the average reduction in EASI from baseline at therapeutic doses (400 mg and 600 mg cohorts) was 74% (n=9) compared to 42% (n=5) for patients on placebo. [0176] 89% achieved EASI-50 versus 40% on placebo; [0177] 67% achieved EASI-75 versus 0% on placebo; [0178] 56% achieved EASI-90 versus 0% on placebo
The results further suggest that ASLAN004 has a comparable or in some cases a higher efficacy compared to Dupilumab, thus demonstrating the potential of ASLAN004 as an alternative therapy for the treatment and management of atopic dermatitis.

Example 2

[0179] In the 32 patients that completed at least 29 days of dosing across all sites, defined in the protocol as the efficacy evaluable data set, the average reduction from baseline in EASI at 8 weeks was 73% (n=19) compared to 44% (n=13) for patients on placebo (p=0.007.sup.1).

[0180] The proportion of patients with adverse events and treatment-related adverse events were similar across treatment and placebo arms. There were no incidences of conjunctivitis in the expansion cohort.

TABLE-US-00010 TABLE 5 EASI score for RITT and ITT groups RITT (n = 29) ITT (n = 38) 600 mg Placebo 600 mg Placebo Endpoint (n = 16) (n = 13) p-value.sup.1 (n = 22) (n = 16) p-value.sup.1 Mean % change from −64.9 −27.2 0.021 −61.3 −31.9 0.023 baseline in EASI EASI-50 (%) 81.3 30.8 0.008 77.3 37.5 0.016 EASI-75 (%) 68.8 15.4 0.005 50.0 12.5 0.018 EASI-90 (%) 37.5 15.4 0.183 27.3 12.5 0.245 IGA 0/1 (%) 43.8 15.4 0.107 31.8 18.8 0.301 Mean % change from −38.6 −15.3 0.051 −37.1 −15.7 0.032 baseline in peak pruritis Numerical Rating Scale Mean change from −9.8 −2.5 0.007 −9.0 −3.5 0.014 baseline in POEM .sup.1One-sided p-value

[0181] ASLAN004 achieved a statistically significant improvement (p<0.025) versus placebo in the primary efficacy endpoint of percent change from baseline in the Eczema Area Severity Index (EASI), and also showed significant improvements (p<0.05) in other key efficacy endpoints: EASI-50, EASI-75, peak pruritis and the Patient-Oriented Eczema Measure (POEM).

[0182] Following discussions with the Data Monitoring Committee prior to unblinding, a Revised ITT population (RITT, n=29) was defined to exclude one study site at which all patients enrolled in the study appeared atypical of moderate-to-severe AD patients based on biomarkers, such as TARC, and patient medical history. In the RITT population, which is more comparable to other published studies in moderate-to-severe AD, ASLAN004 also achieved a statistically significant improvement (p<0.025) versus placebo in percent change from baseline in EASI and showed a greater improvement over placebo in the key efficacy endpoints versus the ITT population.

Example 3

[0183] The objective of this study was to further analyze secondary endpoints of clinical relevance and post hoc subgroup analyses.

Methods

[0184] Three patient cohorts were randomized to receive either 200, 400 or 600 mg eblasakimab or placebo subcutaneously once weekly for 8 weeks in a multiple ascending dose study design.

[0185] Adult patients were included with chronic AD present for years before screening, and the following atopic dermatitis (AD) parameters at screening and baseline: eczema area and severity index (EASI) 16, Investigator's Global Assessment (IGA) score (scale of 0 to 4), and 10% body surface area (BSA) of AD involvement. Rescue medication (moisturizer with active ingredient, topical corticosteroids, topical calcineurin inhibitors) was not allowed; LOCF was used for participants who used rescue med.

[0186] Efficacy assessments included percent change from baseline (%CFBL) in EASI, proportions of patients with 50% or 75% improvement in EASI score (EASI 50 or EASI 75) or IGA 0/1, and % CFBL in percent BSA involvement. Further data are presented from a prespecified subgroup of patients from an excluded site with atypical AD.

[0187] Inferential statistical analysis was performed for 600 mg vs. placebo groups at week 8 only; results for 200 and 400 mg groups were descriptively described due to small sample size.

[0188] Efficacy analysis in the Phase 1b study used a modified Intent to Treat (mITT) population in which 9 study patients from one site were excluded (excluded site group) from the ITT analysis prior to unblinding as the participants did not have disease characteristics consistent with moderate to severe AD (FIG. 16).

Results

[0189] The Excluded site set was markedly different from the mITT set at baseline with substantially lower serum TARC/CCL17 (7,350 pg/mL and 461 pg/mL, respectively), serum IgE (12,225 kU/I vs 527 kU/I), and EASI scores (mean 31.2 vs 19.3) showing lower extent and severity of disease. Other notable differences included older age, and lower IGA and BSA. Participants in this site had no atopic disease history but reported other comorbidities including diabetes and hypertension (FIG. 17).

[0190] In the mITT analysis set, improvements in EASI score were seen early and progressed over the trial duration with eblasakimab treatment compared with placebo, with the 400 and 600 mg doses producing a great magnitude of response than the 200 mg dose (FIG. 19).

[0191] Significant improvements in %CFBL in EASI score at week 8 were noted for eblasakimab 600 mg vs. placebo in the mITT set (−65% vs. −27%, P=0.014), but not the Excluded site population (FIG. 20). The difference in adjusted means was apparent early for the mITT set by week 6 but not for the Excluded site set (FIG. 21).

[0192] Though the study was not powered to achieve statistical significance in any of the binary outcomes, improvements were nonetheless observed in the mITT set in the proportions of patients taking eblasakimab who achieved EASI-50, EASI-75 and EASI-90 over time vs. placebo at week 8 (EASI-50: 81% vs. 31%; EASI-75: 69% vs. 15%; EASI-90: 38% vs. 15%) (FIG. 4). No such improvement was apparent in the Excluded site*population.

[0193] A higher percentage of patients achieved an IGA 0/1 at week 8 for eblasakimab 600 mg vs placebo in the mITT set (44% vs. 15%, P=0.107) but not the Excluded site population (FIG. 23).

[0194] Mean % CFBL in BSA at week 8 was −51% for eblasakimab 600 mg vs. −13% for placebo in the mITT set and −39% vs. −44% in the Excluded site population (FIG. 24).

[0195] Rescue medication use was low, but higher in the placebo group (data not shown). Rates of moderate-to-severe Adverse events (AEs) were comparable between 600 mg and placebo. AEs related to treatment were similar between groups (FIG. 18).

[0196] Interestingly, AEs leading to treatment discontinuation were higher in the placebo group. 1 serious adverse event (SAE) reported in the study (mild abdominal pain, 400 mg); considered unrelated to treatment. No deaths were reported.

CONCLUSION

[0197] This study indicates that eblasakimab was well tolerated with significant improvements vs. placebo in several efficacy outcomes in a Phase 1b study in adults with moderate to severe AD. Robustness of the data from the small study was supported by sensitivity analyses on the primary analysis set Including the Excluded site data did not change the primary endpoint or conclusions.

[0198] That these significant improvements were seen within the 8-week study period offers the potential for a greater magnitude of effect with prolonged treatment, supporting further investigation in an ongoing Phase 2b clinical trial.