Immune-modulating, clinical-stage product candidates targeting underserved conditions and offering the potential for differentiation.
PROGRAM & TARGET
CAPS: US & Japan
DIRA: US & Japan
PROGRAM & TARGET
In the Phase 2 portion of a Phase 2/3 trial of mavrilimumab in severe COVID-19-related ARDS, 116 non-mechanically ventilated patients were randomized in a 1:1:1 ratio to receive a single intravenous (IV) dose of mavrilimumab 10 mg/kg, 6 mg/kg, or placebo. Data showed that patients treated with mavrilimumab demonstrated a reduction in mechanical ventilation and death at Day 29 pooled across dose levels. Clinical improvement was observed on top of steroids and/or antivirals.
Kiniksa continues to enroll patients in the Phase 3 portion of the Phase 2/3 clinical trial of mavrilimumab in severe COVID-19-related ARDS.
Giant cell arteritis (GCA)
Monoclonal antibody targets granulocyte macrophage colony-stimulating factor receptor alpha (GM-CSFRα) and inhibits the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF).
GM-CSF is a key growth factor and cytokine that can govern the development and function of dendritic cells, monocytes, macrophages, and granulocytes (e.g., neutrophils, basophils, and eosinophils).
We estimate that there are approximately 75,000 to 150,000 patients with GCA in the United States.
Orphan Drug designation granted by the US Food and Drug Administration (FDA) for mavrilimumab for the treatment of giant cell arteritis.
We believe that by blocking GM-CSF signaling, mavrilimumab may be able to reverse the course of GCA by upstream targeting of the cell types driving the inflammatory process, a mechanism that is different from currently available therapies.
- The GM-CSF signaling pathway has been shown to be upregulated in GCA biopsies versus control at both the messenger ribonucleic acid (mRNA) and protein levels.
- Mavrilimumab reduced inflammatory molecules characteristic of GCA pathophysiology in an ex vivo GCA artery culture model.
- Mavrilimumab reduced arterial inflammation compared to control in an in vivo model of vasculitis.
- In previous Phase 2b trials in rheumatoid arthritis, mavrilimumab demonstrated reductions in interleukin-6 (IL-6) production.
We reported data from a randomized, double-blind, placebo-controlled Phase 2 clinical trial of mavrilimumab in GCA.
The Phase 2 trial randomized 70 patients in a 3:2 ratio to mavrilimumab 150 mg (N=42) or placebo (N=28) biweekly injected subcutaneously, co-administered with a protocol-defined 26-week oral corticosteroid taper. Patients were stratified by new onset (n=35) or relapsing/refractory (n=35) disease.
The primary efficacy endpoint of time-to-first adjudicated GCA flare by Week 26 in all treated patients was statistically significant (Hazard Ratio = 0.38, p=0.0263). There was a 62% lower risk of flare in mavrilimumab recipients compared to placebo recipients.
The secondary efficacy endpoint of sustained remission at Week 26 in all treated patients was also statistically significant. The sustained remission rate was 33.3 percentage points higher in mavrilimumab recipients (83.2%) compared to placebo recipients (49.9%) (p=0.0038).
There were no drug-related serious adverse events, and the rates of drug-related treatment-emergent adverse events between mavrilimumab recipients and placebo recipients were similar.
A 12-week washout safety follow-up period is ongoing, and additional analyses of this Phase 2 trial are planned.
Corticosteroids are the mainstay for the treatment of GCA, but approximately 50% to 70% of patients are corticosteroid refractory or corticosteroid dependent. Long-term administration of corticosteroids carries significant morbidity, especially in an elderly population such as in those with GCA. The FDA recently approved an inhibitor of IL-6 activity as an adjunct to a corticosteroid taper for the treatment of GCA; however, IL-6 production is downstream of GM-CSF and does not address all of the underlying causes of inflammation.
PROGRAM & TARGET
Vixarelimab Phase 2
Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by severely pruritic skin nodules.
Monoclonal antibody inhibiting signaling through oncostatin M receptor beta (OSMRβ).
Vixarelimab inhibits signaling of interleukin-31 (IL-31) and oncostatin M (OSM), two key cytokines implicated in inflammation, pruritus, and fibrosis.
We estimate that there are approximately 300,000 patients with PN in the United States.
Breakthrough Therapy designation granted by the US Food and Drug Administration (FDA) to vixarelimab for the treatment of pruritus associated with prurigo nodularis.
Studies link many pruritic and inflammatory diseases to both IL-31 and OSM via signaling through OSMRβ. By targeting both pathways simultaneously, vixarelimab may disrupt the pathologic cycle in patients afflicted by a variety of pruritic diseases.
- Internal research shows IL-31, OSM, and OSMRβ mRNA are all upregulated in lesional biopsies of subjects with PN with severe pruritus versus normal healthy controls.
- Our Phase 2a study of vixarelimab in PN met its primary efficacy endpoint: the reduction in weekly average Worst-Itch Numeric Rating Scale (WI-NRS) from baseline at Week 8 was statistically significantly greater in patients who received vixarelimab versus those who received placebo. Additionally, a statistically significant percentage of vixarelimab recipients achieved a PN-investigator’s global assessment (PN-IGA) score of 0/1 at Week 8 compared to placebo recipients, and the majority of vixarelimab recipients showed a clinically meaningful weekly average reduction in WI-NRS of greater than 4 points.
We are conducting a dose-ranging Ph2b trial of vixarelimab in patients with prurigo nodularis.
- The Phase 2b trial is a randomized, double-blind, placebo-controlled study designed to investigate the efficacy, safety, and pharmacokinetics of vixarelimab in reducing pruritus in subjects with prurigo nodularis. The trial is expected to enroll approximately 180 patients with moderate-to-severe prurigo nodularis experiencing severe pruritus (WI-NRS ≥ 7 at the screening visit and a mean weekly WI-NRS of ≥ 7 for each of the two consecutive weeks immediately prior to randomization). Patients are required to stop antihistamines and topical treatments, including corticosteroids, for at least two weeks prior to dosing. Prurigo nodularis treatments, other than study drug, are not allowed except for rescue. Patients will be randomized in a 1:1:1:1 fashion to receive vixarelimab 540 mg, 360 mg, 120 mg, or placebo subcutaneously monthly. The primary efficacy endpoint is the percent change from baseline in the weekly-average Worst-Itch Numeric Rating Scale (WI-NRS) at Week 16. Key secondary endpoints include the proportion of patients achieving greater-than-or-equal-to 4-point weekly-average WI-NRS reduction at Week 16 and the proportion of patients achieving a 0/1 score (clear/almost clear) on the prurigo nodularis-investigator’s global assessment (PN-IGA) at Week 16.
In 2020, we reported data from a randomized, double-blind, placebo-controlled Phase 2a clinical trial of vixarelimab in patients with prurigo nodularis.
- The trial met its primary efficacy endpoint: the reduction in weekly-average WI-NRS from baseline at Week 8 was statistically significantly greater in patients who received vixarelimab versus those who received placebo. Additionally, a statistically significant percentage of vixarelimab recipients achieved a PN-IGA score of 0/1 at Week 8 compared to placebo recipients, and the majority of vixarelimab recipients showed a clinically meaningful greater-than-or-equal-to 4-point weekly-average WI-NRS reduction at Week 8. No dose-limiting adverse experiences were observed. There were no serious adverse events or atopic dermatitis flares.
We are not aware of any current therapies approved by the FDA for the treatment of PN.
- The treatment approach for PN ranges from topical corticosteroids and occlusive corticosteroid-containing bandages for patients who have milder forms of PN to systemic corticosteroids, ultraviolet phototherapy, and systemic therapies such as thalidomide, methotrexate, and cyclosporine for those patients whose conditions don’t improve on initial treatments. Patients have reported using opioid pain medications to attempt to control the disease in its most severe form.
- Based on market research, we believe ~25% to 30% of subjects are refractory to treatment.
PROGRAM & TARGET
KPL-404 Phase 1
Monoclonal antibody inhibitor of CD40 signaling. KPL-404 is designed to inhibit CD40-CD40L interaction, a key T-cell costimulatory pathway critical for B-cell maturation and immunoglobulin class switching.
CD40-CD40L interaction is an attractive target for blocking T-cell–mediated B-cell–driven autoimmunity and prevention of solid organ transplant rejection. External proof-of-concept for inhibition of this pathway has been previously established in patients with a broad range of autoimmune diseases, including rheumatoid arthritis, Sjögren’s syndrome, Graves’ disease, systemic lupus erythematosus and solid organ transplant.
We reported final data for our single-ascending-dose Phase 1 study in healthy volunteers for KPL-404, supporting further development in patients. KPL-404 was well tolerated and showed dose-dependent increases in concentration across cohorts. Subjects dosed with KPL-404 10 mg/kg intravenous (IV) showed full receptor occupancy through Day 71 and complete suppression of T-cell Dependent Antibody Response (TDAR) to keyhole limpet hemocyanin (KLH) challenge and rechallenge through at least Day 57. Subjects dosed with KPL-404 5 mg/kg SC showed full receptor occupancy through Day 43 and suppression of TDAR after KLH challenge through at least Day 29. The 3 mg/kg IV dose level had previously demonstrated complete suppression of memory TDAR response to a second KLH challenge on Day 29. Kiniksa plans to initiate a Phase 2 proof-of-concept trial of KPL-404 in the second half of 2021.
1 Approved in the U.S.
* The FDA granted Breakthrough Therapy designation to rilonacept for recurrent pericarditis in 2019 and Orphan Drug designation to rilonacept for pericarditis in 2020.
** The FDA granted Orphan Drug designation to mavrilimumab for giant cell arteritis in 2020.
*** The FDA granted Breakthrough Therapy designation to vixarelimab for pruritus associated with prurigo nodularis in 2020.
****Kiniksa plans to initiate a Phase 2 proof-of-concept trial in patients in the second half of 2021. The planned trial will provide safety and characterization of chronic administration as well as the potential to evaluate KPL-404 across a range of other autoimmune diseases.