Efficacy results

For people ages 12+

Joenja showed significant improvements for patients 12+ with APDS

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Clinical trial design

Co-primary end points

Secondary & exploratory end points

CLINICAL TRIAL DESIGN

The Joenja clinical trials for people 12+ years of age

Part 1: Dose Finding

Timing

12 weeks

Participants

6 patients

Age

Patients 12+

Conditions

Non-randomized, open-label, dose-finding study in 6 patients with APDS; dose range was 10 mg, 30 mg, and 70 mg BID for 4 weeks at each dose
Oral dose 70 mg BID selected for part 2

Part 2: Efficacy and Safety Evaluation

Timing

12 weeks

Participants

31 participants

Age

Patients 12+

Conditions

Randomized, triple-blinded (patient, caregiver, investigator), placebo-controlled, fixed-dose study of 70 mg BID
Co-primary efficacy end points (improvement in lymphoproliferation and normalization of immunophenotype)
- Change from baseline in the log₁₀-transformed SPD of index lesions
- Change from baseline in percentage of naïve B cells out of total B cells
Secondary and exploratory end points assessments
Safety assessment

Joenja was studied in patients with confirmed PI3Kδ variants

Baseline demographic and disease characteristics in patients with APDS

Demographics

Joenja

(n=21)

Placebo

(n=10)

Age, y (mean SD)

22.2 (10)

26.7 (13.43)

Age categories

<18 y, n (%)
(min, max)
≥18 y, n (%)
(min, max)

8 (38)
(12, 17)
8 (38)
(12, 17)

4 (40)
(15, 17)
4 (40)
(15, 17)

Sex, n (%)

Male
Female

11 (52)
10 (48)

4 (40)
6 (60)

Disease characteristics

Baseline concomitant glucocorticoids, n (%)

(57)

(60)

Baseline concomitant IgG, n (%)

(67)

(70)

Previous sirolimus use, n (%)

(19)

(30.0)

Lymphoproliferation, n (%)

(71.4)

(70.0)

Chronic infections, n (%)

(85.7)

(70.0)

Asthma, n (%)

(33.3)

(40.0)

Bronchiectasis, n (%)

(38.1)

(80.0)

Cytopenias, n (%)

(61.9)

(50.0)

Gastrointestinal disease, n (%)

(47.6)

(70.0)

BID, twice a day; IgG, immunoglobulin G; SD, standard deviation; SPD, sum of product diameters.

Patients had nodal and/or extranodal lymphoproliferation, as measured by index nodal lesion selected by the Cheson methodology on CT or MRI and clinical findings and manifestations compatible with APDS (eg, history of repeated oto-sino-pulmonary infections, organ dysfunction). Immunosuppressive medications or PI3Kδ inhibitors (selective or non-selective) were prohibited within 6 weeks of baseline (day -1 and the visit prior to first study drug administration) and throughout the study. In addition, patients who had previous or concurrent B cell depleters (eg, rituximab) within 6 months of baseline were excluded from the study unless absolute B lymphocytes in the blood were normal. B cell depleters were prohibited throughout the study.

CO-PRIMARY END POINTS

Joenja delivers clinically proven efficacy with long-term benefits

Log₁₀-transformed SPD of index lesions (excluding patients with 0 lesions at baseline) at week 12^1*

Improvement in lymphoproliferation as measured by a change from baseline in lymphadenopathy measured by the log₁₀-transformed SPD of index lymph nodes¹

Joenja
(n/N=18/21)^†

Placebo
(n/N=18/21)^†

Baseline mean (SD)

3.03 (0.42)

3.05 (0.39)

Change from baseline, LS mean (SE)

-0.27 (0.04)

-0.02 (0.05)

Difference vs placebo (95% CI)

-0.25 (-0.38,-0.12)

Joenja significantly reduced lymphadenopathy, helping to restore immune balance

The size of swollen lymph nodes for each person in the trial was studied before and after treatment
The results showed that lymph nodes shrank more in people taking Joenja vs those receiving placebo

At week 12, patients saw a significant reduction in lymphadenopathy^‡ with Joenja vs placebo¹

That is an ~8x greater improvement with Joenja vs placebo

Significant increase in naïve B cells

Significantly improved immunophenotype vs placebo at week 12

In patients with <48% of naïve B cells at baseline,§ the adjusted mean difference between Joenja (n=8) and placebo (n=5) in the percentage of naïve B cells out of total B cells was 37.30 (95% CI: 24.06, 50.54), P=0.0002^||
The adjusted mean change from baseline (SE) for Joenja was 37.39 (5.35) and 0.09 (6.66) for placebo^§

Absolute percentage of naïve B cells over time^||¶

Mean naïve B-cell levels within normal range by week 4 and maintained through week 12 with Joenja

CI, confidence interval; LS, least squares; SE, standard error; SPD, sum of product diameters.

The LS mean change from baseline, difference in LS mean change from baseline between Joenja and placebo and its P value, were obtained from an ANCOVA model with treatment, glucocorticoid use, and immunoglobulin replacement therapy at baseline, and baseline measurement as covariates.

†

The analysis excluded 2 patients from each treatment group due to protocol deviations and 1 Joenja patient having complete resolution of the index lesion identified at baseline.

‡

The LS mean change from baseline, difference in LS mean change from baseline between Joenja and placebo and its P value, were obtained from an ANCOVA model with treatment, glucocorticoid use and IRT at baseline, and baseline measurement as covariates.1

The analysis excluded 2 patients from each treatment group due to protocol deviations and 1 Joenja patient having complete resolution of the index lesion identified at baseline.1

Normal range for percentage of naïve B cells indicated by shaded bar in graph.

Cell surface markers used to distinguish naïve B cells on flow cytometry were CD19+, CD27-, and CD10-. Baseline is defined as the arithmetic mean of the baseline and day 1 values when both were available, and if either was missing, the existing value was used.

The analysis excluded 2 patients from each treatment group due to protocol deviations, 5 Joenja patients and 3 placebo patients with ≥48% naïve B cells at baseline, 5 Joenja patients with no day 85 measurement, and 1 Joenja patient with no baseline measurement.

SECONDARY & EXPLORATORY ENDPOINTS

Joenja significantly reduced splenomegaly

Significant reductions in spleen size by 2D and 3D analysis compared to placebo

The adjusted mean difference in bidimensional spleen size between Joenja (n=19) and placebo (n=9) was -13.5 cm² (95% CI: -24.1, -2.91), P=0.0148
The adjusted mean difference in 3D spleen volume between Joenja (n=19) and placebo (n=9) was -186 cm³ (95% CI: -297, -76.2), P=0.0020

Secondary measure: Spleen volume scan results of actual patient illustrate average improvement documented for patients taking Joenja

Prior to treatment
491 mL

At week 12
314 mL

27%

REDUCTION IN 3D SPLEEN VOLUME^#

Actual images of a 29-year-old female’s response of spleen size reduction, representing the average response in the study. As individual results vary, images may not be representative of all patients.

Other secondary end points included patient-reported benefits with Joenja that were assessed using the SF-36 (Short Form 36) Survey and WPAI-CIQ (Work Productivity Activity Impairment plus Classroom Impairment Questionnaire), visual analogue scales for Physician’s Global Assessment (PGA), and Patient’s Global Assessment (PtGA), and patient narratives by investigator. Clinical relevance from these assessments was not established.

An exploratory end point showed Joenja reduced IgM levels_³

Mean serum IgM reduced

In the Joenja arm, IgM was elevated above normal limits in 6 patients at baseline, and by week 12 was reduced in all, with 50% returning to within normal limits
In contrast, IgM was elevated above normal limits at baseline in 4 patients in the placebo arm, and by day 85, levels remained stable or elevated, with 0% returning to within normal limits

Mean serum IgM reduced to within normal limits

Normal range for IgM indicated by shaded bar in graph

Joenja helps restore normal balance to the immune system in patients with APDS,  leading to tangible improvements within weeks

Treatment with Joenja helped reduce healthcare utilization in patients with APDS, including a 22% reduction in outpatient/emergency department visits, a 36% reduction in clinical manifestation–related visits, and a 29% reduction in infection-related visits
Infection management burden decreased, with a 23% reduction in antibiotics and a 34% reduction in mean monthly IRT doses

IV, intravenous; PD, pharmacodynamics; SD, standard deviation.

Soluble biomarkers, including IgM, were prespecified exploratory end points in the protocol. Although an observational decrease in IgM was noted in some patients, no statistical significance can be made from this analysis, and no conclusions should be drawn.

This analysis excluded 2 patients in each treatment group. In the Joenja group, 1 patient with a complete index lesion response was excluded, and 3 patients were excluded for no non-index lesion at baseline.

In the PD analysis set, the mean (SD) percentage change from baseline to week 12 in 3D spleen volume (mm3) was -26.68% (12.137) with Joenja (n=19) and -1.37% (24.238) with placebo (n=9). The ANCOVA model was used with treatment as a fixed effect and log10-transformed baseline as a covariate for index and non-index lesions. The use of both glucocorticoids and IV immunoglobulin at baseline was included as categorical (yes/no) covariates.

Efficacy results
(For children ages 4-11)

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APDS, activated PI3K delta syndrome.

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Efficacy results