Patent Application
20240041870
The present disclosure is directed to methods of treating systemic lupus erythematosus (SLE) with the selective JAK1 inhibitor, upadacitinib.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by antibodies to nuclear and cytoplasmic antigens, multisystem inflammation, protean clinical manifestations, and a relapsing and remitting course. SLE causes widespread inflammation and tissue damage in the affected organs, which may include joints, skin, brain, lungs, kidneys, and blood vessels. Symptoms of SLE vary depending on the affected organs, but may include fatigue, skin rashes, fevers, and pain or swelling in the joints.
Currently, there is no cure for SLE, and existing therapies focus on improving quality of life by controlling symptoms and minimizing flare-ups, primarily through use of immunosuppressive drugs such as hydroxychloroquine and corticosteroids, and immunomodulators such as belimumab and anifrolumab. Despite these treatments, significant unmet therapeutic needs remain for SLE patients. Provided herein are methods of treating SLE.
The present disclosure provides methods for treating systemic lupus erythematosus (SLE) with the selective JAK1 inhibitor, upadacitinib. The treatment methods generally comprise administering to a patient in need thereof a therapeutically effective amount of upadacitinib.
In one aspect is provided a method of treating a human patient having moderately to severely active systemic lupus erythematosus, the method comprising orally administering once daily to the patient 30 mg of upadacitinib.
In another aspect is provided a method of treating a human patient having moderately to severely active systemic lupus erythematosus, the method comprising orally administering once daily to the patient 15 mg of upadacitinib.
In yet another aspect is provided a method of treating a human patient having moderately to severely active systemic lupus erythematosus, the method comprising orally administering once daily to the patient 45 mg of upadacitinib. In some embodiments, the 45 mg of upadacitinib is an induction dose, followed by orally administering once daily to the patient a maintenance dose. In some embodiments, the maintenance dose is 30 mg. In some embodiments, the maintenance dose is 15 mg.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 52 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 52 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 52 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 52 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 52.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 52.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 48 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 48 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 48 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 48 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 48.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 48.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 24 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 24 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 24 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 24 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 24.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 24.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 20 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 20 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 20 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 20 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 20.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 20.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 16 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 16 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 16 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 16 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 16.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 16.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 12 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 12 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 12 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 12 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 12.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 12.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 8 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 8 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 8 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 8 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 8.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 8.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 4 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 4 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 4 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 4 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 4.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 4.
In some embodiments, the method results in a significant decrease in the levels of anti-dsDNA autoantibodies and complement C3 and C4.
In some embodiments, the method results in a significant increase in the numbers of circulating memory, naïve, and total B cells.
In some embodiments, the patient has had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
In some embodiments, the patient has had an inadequate response or intolerance to methotrexate.
In some embodiments, the patient has had an inadequate response or intolerance to an anti-malarial agent.
In some embodiments, the patient has had an inadequate response or intolerance to an immunomodulator.
In some embodiments, the patient has had an inadequate response or intolerance to a corticosteroid.
In some embodiments, the patient has had an inadequate response or intolerance to prednisone (or prednisone equivalent), an antimalarial agent, azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, or methotrexate.
In some embodiments, the patient has had an inadequate response or intolerance to belimumab.
In some embodiments, the patient has had an inadequate response or intolerance to rituximab.
In some embodiments, the patient has had an inadequate response or intolerance to anifrolumab.
In some embodiments, the patient is concomitantly treated with an anti-malarial agent.
In some embodiments, the patient is concomitantly treated with an immunomodulator.
In some embodiments, the patient is concomitantly treated with a corticosteroid.
In some embodiments, the patient is concomitantly treated with prednisone (or prednisone equivalent), an antimalarial agent, azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, or methotrexate.
This written description uses examples to disclose the invention and also to enable any person skilled in the art to practice the invention, including making and using any of the disclosed compositions, and performing any of the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have elements that do not differ from the literal language of the claims, or if they include equivalent elements.
Section headings as used in this section and the entire disclosure are not intended to be limiting.
Where a numeric range is recited, each intervening number within the range is explicitly contemplated with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated. In the same manner, all recited ratios also include all sub-ratios falling within the broader ratio.
The singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
The term “about” generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term “about” may include numbers that are rounded to the nearest significant figure.
As used herein, the term “Patient” refers to an adult human. The terms “patient” and “subject” are used interchangeably herein.
“Pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, mono-malic acid, mono oxalic acid, tartaric acid such as mono tartaric acid (e.g., (+) or (−)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or (−)-amino acids or mixtures thereof), and the like. These salts can be prepared by methods known to those skilled in the art.
SLE Responder Index (SRI)-4 is defined as follows with all criteria compared to Baseline:
BILAG-Based Combined Lupus Assessment (BICLA) is defined as follows:
Lupus Low Disease Activity State (LLDAS) is defined as follows:
Upadacitinib (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide), or a pharmaceutically acceptable salt or solid state form thereof, is an oral Janus kinase (JAK) inhibitor that displays unique selectivity for the JAK1 receptor. Upadacitinib has the structure shown below:
The dosage strength of upadacitinib recited in the present application is based on the weight of anhydrous freebase upadacitinib present in the active ingredient delivered to the patient. For example, a dose of “15 mg of upadacitinib” or “UPA 15 MG” refers to the 15 mg amount of the neutral upadacitinib freebase present in the active ingredient, not including any coformer (e.g., solvent or water molecule(s)) of a solvate or hydrate (including hemihydrate) or counteranions of a pharmaceutically acceptable salt), that may also be present in the active ingredient. So, for example, the administration of “15 mg of upadacitinib” includes the administration of 15.4 mg of crystalline upadacitinib freebase hemihydrate (which includes ½ of a water conformer molecule per upadacitinib freebase molecule) which delivers 15 mg of anhydrous freebase upadacitinib to a patient.
The dosage strength of upadacitinib recited in the present application is based on the weight of anhydrous freebase upadacitinib present in the active ingredient delivered to the patient. For example, a dose of “30 mg of upadacitinib” or “UPA 30 MG” refers to the 30 mg amount of the neutral upadacitinib freebase present in the active ingredient, not including any coformer (e.g., solvent or water molecule(s)) of a solvate or hydrate (including hemihydrate) or counteranions of a pharmaceutically acceptable salt), that may also be present in the active ingredient. So, for example, the administration of “30 mg of upadacitinib” includes the administration of 30.7 mg of crystalline upadacitinib freebase hemihydrate (which includes ½ of a water conformer molecule per upadacitinib freebase molecule) which delivers 30 mg of anhydrous freebase upadacitinib to a patient.
The dosage strength of upadacitinib recited in the present application is based on the weight of anhydrous freebase upadacitinib present in the active ingredient delivered to the patient. For example, a dose of “45 mg of upadacitinib” or “UPA 45 MG” refers to the 45 mg amount of the neutral upadacitinib freebase present in the active ingredient, not including any coformer (e.g., solvent or water molecule(s)) of a solvate or hydrate (including hemihydrate) or counteranions of a pharmaceutically acceptable salt), that may also be present in the active ingredient. So, for example, the administration of “45 mg of upadacitinib” includes the administration of 46.1 mg of crystalline upadacitinib freebase hemihydrate (which includes ½ of a water conformer molecule per upadacitinib freebase molecule) which delivers 45 mg of anhydrous freebase upadacitinib to a patient.
As described herein above, upadacitinib has anti-inflammatory properties, and accordingly, is predicted according to the present disclosure to be effective in decreasing signs and symptoms associated with active SLE in patients. Particularly, Janus kinase 1 (JAK1) inhibition via upadacitinib is expected to disrupt T cell activation and Type I interferon (IFN) signaling. Without wishing to be bound by theory, it is believed that inhibition of JAK1 will result in amelioration of lupus disease activity, and treatment with upadacitinib has the potential to provide greater clinical efficacy compared to current SLE standard of care while maintaining an acceptable safety profile. To explore the safety, tolerability, and efficacy of the upadacitinib in SLE, several Phase I and II clinical studies have been conducted.
Accordingly, in one aspect is provided a method of treating a human patient having systemic lupus erythematosus. In some embodiments, provided is a method of treating a human patient having systemic lupus erythematosus who is receiving standard therapy. In some embodiments, provided is a method of treating a human patient having moderately to severely active systemic lupus erythematosus. In some embodiments, provided is a method of treating a human patient having moderately to severely active systemic lupus erythematosus who is receiving standard therapy. In some embodiments, provided is a method of treating a human patient with moderate to severe systemic lupus erythematosus. In some embodiments, provided is a method of treating a human patient with moderate to severe systemic lupus erythematosus who is receiving standard therapy. In some embodiments, provided is a method of treating a human patient with active, auto-antibody positive systemic lupus erythematosus. In some embodiments, provided is a method of treating a human patient with active, auto-antibody positive systemic lupus erythematosus who is receiving standard therapy.
In some embodiments, the standard therapy the patient is receiving includes a corticosteroid, an antimalarial agent, or a combination thereof. In some embodiments, the standard therapy includes prednisone (or prednisone equivalent) and an antimalarial agent. In some embodiments, the standard therapy includes an antimalarial agent, such as hydroxychloroquine.
In some embodiments, the standard therapy further includes azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, methotrexate or a combination thereof.
In another aspect is provided a method of treating a human patient having moderately to severely active systemic lupus erythematosus, the method comprising orally administering once daily to the patient 30 mg of upadacitinib.
In another aspect is provided a method of treating a human patient having moderately to severely active systemic lupus erythematosus, the method comprising orally administering once daily to the patient 15 mg of upadacitinib.
In another aspect is provided a method of treating a human patient having moderately to severely active systemic lupus erythematosus, the method comprising orally administering once daily to the patient 45 mg of upadacitinib.
In yet another aspect is provided a method of treating a human patient having moderately to severely active systemic lupus erythematosus, the method comprising orally administering once daily to the patient an induction dose of upadacitinib for a period of time. In some embodiments, the induction dose is 45 mg, administered once daily.
In some embodiments, the induction dose is followed by administration of a maintenance dose. In some embodiments, the maintenance dose is 30 mg. In some embodiments, the maintenance dose is 15 mg.
Accordingly, in some embodiments, the method comprises orally administering once daily to the patient a 45 mg induction dose of upadacitinib for a period of time, followed by orally administering once daily to the patient a maintenance dose of 30 mg or 15 mg.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 52 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 52 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 52 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 52 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 52.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 52.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 48 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 48 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 48 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 48 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 48.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 48.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 24 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 24 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 24 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 24 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 24.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 24.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 20 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 20 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 20 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 20 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 20.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 20.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 16 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 16 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 16 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 16 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 16.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 16.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 12 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 12 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 12 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 12 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 12.
In some embodiments, the p method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 12.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose 10 mg at 8 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 8 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 8 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 8 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 8.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 8.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response and Prednisone Equivalent Steroid Dose ≤10 mg at 4 weeks after the first daily administration.
In some embodiments, the method results in a SLE Responder Index (SRI)-4 response at 4 weeks after the first daily administration.
In some embodiments, the method results in a BILAG-Based Combined Lupus Assessment (BICLA) response at 4 weeks after the first daily administration.
In some embodiments, the method results in a Lupus Low Disease Activity State (LLDAS) response at 4 weeks after the first daily administration.
In some embodiments, the method results in a reduction in steroid burden, assessed as change from Baseline in prednisone equivalent steroid dose at Week 4.
In some embodiments, the method results in a reduction in the number of mild, moderate, or severe flares per patient-year (respectively and overall) by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index (SFI), assessed by number and types of flare (mild/moderate, severe, and any) per subject through Week 4.
In some embodiments, the method results in a significant decrease in the levels of anti-dsDNA autoantibodies and complement C3 and C4. In some embodiments, the method results in a significant increase in the numbers of circulating memory, naïve, and total B cells.
In some embodiments, the patient has had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. In some embodiments, the patient has had an inadequate response or intolerance to methotrexate. In some embodiments, the patient has had an inadequate response or intolerance to an anti-TNF biologic agent. In some embodiments, the patient has had an inadequate response or intolerance to an anti-malarial agent.
In some embodiments, the patient has had an inadequate response or intolerance to an immunomodulator.
In some embodiments, the patient has had an inadequate response or intolerance to a corticosteroid.
In some embodiments, the patient has had an inadequate response or intolerance to prednisone (or prednisone equivalent), an antimalarial agent, azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, or methotrexate.
In some embodiments, the patient is concomitantly treated with an anti-malarial agent.
In some embodiments, the patient is concomitantly treated with an immunomodulator.
In some embodiments, the patient is concomitantly treated with a corticosteroid.
In some embodiments, the patient is concomitantly treated with Methotrexate. In some embodiments, the patient is concomitantly treated with 20 mg/wk Methotrexate with concomitant folic acid ≤5 mg/wk.
In some embodiments, the patient is concomitantly treated with Azathioprine. In some embodiments, the patient is concomitantly treated with ≤150 mg/day Azathioprine.
In some embodiments, the patient is concomitantly treated with Mycophenolate mofetil.
In some embodiments, the patient is concomitantly treated with ≤2,000 mg/day Mycophenolate mofetil.
In some embodiments, the patient is concomitantly treated with Mycophenolate sodium.
In some embodiments, the patient is concomitantly treated with ≤1,440 mg/day Mycophenolate sodium.
In some embodiments, the patient is concomitantly treated with Hydroxychloroquine. In some embodiments, the patient is concomitantly treated with ≤400 mg/day Hydroxychloroquine.
In some embodiments, the patient is concomitantly treated with Chloroquine. In some embodiments, the patient is concomitantly treated with ≤500 mg/day Chloroquine.
In some embodiments, the patient is concomitantly treated with Quinacrine. In some embodiments, the patient is concomitantly treated with ≤100 mg/day Quinacrine.
In some embodiments, the patient is concomitantly treated with Leflunomide. In some embodiments, the patient is concomitantly treated with ≤20 mg/day Leflunomide.
In some embodiments, the patient is concomitantly treated with Cyclosporine. In some embodiments, the patient is concomitantly treated with Cyclosporine dosed by serum levels.
In some embodiments, the patient is concomitantly treated with Tacrolimus. In some embodiments, the patient is concomitantly treated with Tacrolimus dosed by serum levels.
In some embodiments, the patient is concomitantly treated with corticosteroids (prednisone-equivalent). In some embodiments, the patient is concomitantly treated with ≤20 mg/day corticosteroids, decreased no faster than 5 mg QD per week. In some embodiments, corticosteroids are increased by no more than 5 mg QD per week regardless of Baseline dose, to a maximum dose of 25 mg, through Week 8 of treatment.
Upadacitinib can be administered to a human patient by itself or in pharmaceutical composition where it is mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
The pharmaceutical compositions of the present disclosure may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
This was a Phase 2 Study (M19-130) to Investigate the Safety and Efficacy of Upadacitinib Given in Subjects with Moderately to Severely Active Systemic Lupus Erythematosus.
Approximately 130 adult male or female subjects who were 18 to 65 years of age, inclusive, and had a clinical diagnosis of SLE at least 24 weeks prior to Screening, meeting at least 4 of the 11 revised Criteria for Classification of SLE according to the 1997 Update of the 1982 American College of Rheumatology (ACR) OR meeting at least 4 of the 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) classification criteria, including at least 1 clinical criterion and 1 immunologic criterion. Subjects must have had active SLE by SLEDAI-2K ≥6 as reported and independently adjudicated (clinical score ≥4, excluding lupus headache and/or organic brain syndrome) at Screening and Baseline. If 4 points of the required entry points were for arthritis, there must also have been a minimum of 3 tender and 3 swollen joints.
The primary efficacy endpoint was achievement of SLE Responder Index (SRI)-4 and steroid dose ≤10 mg prednisone equivalent once a day (QD) at Week 24. SLE Responder Index (SRI)-4 is defined as ≥4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score without worsening of the overall condition (no worsening in Physician's Global Assessment [PhGA], <0.3 point increase) or the development of significant disease activity in new organ systems (no new British Isles Lupus Assessment Group ([BILAG]) A or >1 new BILAG B).
The following secondary efficacy endpoints were evaluated:
The following additional efficacy endpoints were evaluated at all visits unless otherwise noted:
Routine safety evaluations included adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiograms (ECGs), and clinical laboratory testing (hematology, chemistry, and urinalysis as a measure of safety and tolerability for the entire study duration. SAEs were assessed at any dose that resulted in a death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital anomaly.
The following areas of safety interest were routinely assessed to identify any major safety findings related to immunosuppression or potential risks associated with the individual classes of therapy: serious and/or opportunistic infections, herpes zoster, active TB, malignancies (all types), adjudicated gastrointestinal (GI) perforations, adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE]), anemia, neutropenia, lymphopenia, renal dysfunction, hepatic disorders, and adjudicated embolic and thromboembolic events (non-cardiac, non-central nervous system [CNS]) including venous thrombotic events defined as pulmonary embolism and deep vein thrombosis. Specific toxicity management measures were utilized for serious infections, serious GI events, cardiovascular events (MACE), malignancies, ECG abnormalities, and select laboratory abnormalities. In addition, a 30-day follow-up phone call from the last dose of study drug occurred to determine the status of any ongoing AEs/SAEs, or the occurrence of any new AEs/SAEs. An unblinded internal DMC was established to ensure the overall integrity and conduct of the study. DMC reviews were conducted at regular intervals. Regular systematic reviews of emerging safety data from all clinical studies with upadacitinib was conducted by AbbVie. An independent external Cardiovascular Adjudication Committee (CAC) adjudicated all blinded cardiovascular and cerebrovascular events, embolic/thrombotic events, and deaths, as defined in the CAC charter.
Upadacitinib plasma concentrations were summarized at each sampling time point using descriptive statistics. A mixed-effects modeling approach may have been used to estimate the population central value and the empirical Bayesian estimates of the individual values for upadacitinib oral clearance (CL/F) and volume of distribution (Vss/F). Additional parameters and pharmacokinetic (PK)/pharmacodynamic relationships may have been estimated if useful in the interpretation of the data.
Biospecimens (whole blood, peripheral blood mononuclear cells [PBMCs], plasma, and serum) were collected at specified time points throughout the study to evaluate known and/or novel disease-related or drug-related biomarkers. Types of biomarkers may have included nucleic acids, proteins, lipids, RNA, DNA, and/or metabolites. The objective of this research was to analyze samples for biomarkers that would help to understand SLE, related conditions, and response to treatment with upadacitinib or similar compounds.
Type I IFN is a key driver of disease pathogenesis in lupus, and high IFN signature is associated with active SLE. Approximately 60% of lupus patients express an elevated Type I IFN gene signature in the blood, suggesting higher Type I IFN activity in these individuals. JAK1 inhibition is expected to disrupt Type I IFN signaling; therefore, lupus patients expressing the Type I gene signature may be more likely to benefit from treatment with upadacitinib. A Type I IFN RNA signature consisting of 4 genes (IFI6, IFI27, IFIT1, and MX1) was evaluated using a validated assay with a cut point set at ≥−0.25 for IFN high vs <−0.25 for IFN low (−0.25 is the upper limit of the cut point) using the Type I IFN Gene Expression Assay Score.
In the event an IFN score could not be collected or analyzed at Screening due to COVID-19 lab access, that subject was still be enrolled in the study and assigned a score of Not Applicable for the Screening visit. Samples drawn at the Week 4 and Week 24 visits may have been used for analysis, if collected.
These results robustly dichotomize the IFN high and low population. The assay was performed on Screening samples and at subsequent time points unless precluded by local regulations or restrictions (IFN signature samples were not collected at sites in China). Screening values were used as a criterion for subject enrichment with the goal of enrolling 80% of the study subjects with high composite core. Stratifying the study to include approximately 80% high IFN score population allowed for increased confidence in the subject population.
Research may also have included analysis of genes, epigenetics, gene expression, and proteomic biomarkers that may associate with SLE, related conditions, or the subject's response to treatment. This research was exploratory in nature and the results may not have been included with the clinical study report. Required biomarker samples were collected and analyzed from all subjects, unless precluded by local regulations or restrictions (for such cases, optionality of collection/analysis is given through an appropriate Informed Consent Form).
The study was designed to investigate the safety and efficacy of upadacitinib in subjects with moderately to severely active SLE despite standard of care therapy. The study duration included a 42-day maximum screening period, a 48-week randomized, placebo-controlled, double-blind, parallel-group treatment period, and a 30-day follow-up phone call. The Week 24 Primary Analysis was performed when all subjects completed the Week 24 visit or discontinued the study. Sites and subjects remained blinded throughout the study. The study team remained blinded until the Week 24 Primary Analysis. Study visits were conducted at Screening, Baseline, and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48/Premature Discontinuation (PD). A 30-day follow-up phone call from the last dose of study drug occurred to determine the status of any ongoing adverse events (AEs)/serious adverse events (SAEs) or the occurrence of any new AEs/SAEs.
A long-term extension (LTE) study is being conducted under a separate protocol (LTE Study M20-186) at sites where it was permitted by the local Competent Authority and Ethics Committee. Subject rollover from the initial randomized portion of the study occurred at Week 48. A planned unblinded interim analysis was performed when 50% of the planned subjects completed their Week 24 assessments. The objective of this analysis was to reassess the treatment regimens in Study M19-130 and the benefit/risk for rollover into LTE Study M20-186. The interim analysis was performed by an independent team at AbbVie that is separate and apart from the blinded study team. The Study M19-130 team remained blinded through the Week 24 Primary Analysis.
The following were the key eligibility criteria for the study:
Study drug was taken orally as 1 film-coated tablet containing 30 mg of upadacitinib and/or matching placebo once daily with or without food for 24 weeks.
Overall Study Design and Plan
This was a multi-center, randomized, double-blind, and placebo-controlled Phase 2 study, with a Week 24 primary endpoint, to investigate the safety and efficacy of upadacitinib in subjects with moderately to severely active SLE. The study was continued through Week 48 to further assess maintenance of efficacy and safety of each treatment beyond 24 weeks.
Approximately 130 male and female subjects, 18 to 65 years of age, inclusive, with a diagnosis of moderately to severely active SLE (clinical diagnosis of SLE at least 24 weeks prior to Screening, meeting at least 4 of the 11 revised Criteria for Classification of SLE according to the 1997 Update of the 1982 American College of Rheumatology [ACR] OR meeting at least 4 of the 2012 Systemic Lupus Erythematosus International Collaborating Clinics [SLICC] classification criteria, including at least 1 clinical criterion and 1 immunologic criterion) despite standard of care therapy were be randomized as follows:
Randomization was stratified based on the following factors:
The study duration included a 42-day maximum screening period and a 48-week randomized, placebo-controlled, double-blind, parallel-group treatment period with a 30-day follow-up phone call. Sites and subjects remained blinded throughout the study. The Week 24 Primary Analysis was performed when all subjects completed the Week 24 visit or had discontinued the study. The study team remained blinded until the Week 24 Primary Analysis. A 30-day follow-up phone call from the last dose of study drug occurred to determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.
A schematic illustration of the study is shown in
This was a parallel-group study consisting of treatment groups receiving upadacitinib or matching placebo to assess the safety and efficacy of upadacitinib once daily for 24 weeks in subjects with moderately or severely active SLE. Placebo served as a reference for efficacy assessment.
All efficacy and safety measurements in this study were standard for assessing disease activity in subjects with SLE being treated with immunosuppressant therapies. The first safety evaluation was at Week 2, and at all subsequent visits. All clinical and laboratory procedures in this study were standard and generally accepted.
Eligible for this study were adult male or female subjects, 18 to 65 years of age, inclusive, with a clinical diagnosis of SLE at least 24 weeks prior to Screening, meeting at least 4 of the 11 revised Criteria for Classification of SLE according to the 1997 Update of the 1982 ACR OR meeting at least 4 of the 2012 SLICC classification criteria, including at least 1 clinical criterion and 1 immunologic criterion, and at least one of the following at Screening: positive antinuclear antibody (ANA) (titer ≥1:80), anti-double stranded DNA (dsDNA), or anti-Smith antibodies. The selection criteria identified individuals with active SLE that were the intended target population for treatment with upadacitinib, based on the current knowledge of the drug.
Subjects must have met all of the following criteria in order to be included in the study. Anything other than a positive response to the questions below resulted in exclusion from study participation.
Subjects with a history of gastric banding/segmentation are not excluded.
Medications and therapies with a washout period were prohibited while subjects were on study drug. In addition to the medications listed in the eligibility criteria, the following were prohibited while subjects were on study drug:
Investigators were encouraged to taper steroids in subjects who were stable or improving. The investigator may have decided not to initiate a taper or to delay a taper at any time. Target steroid dose was ≤10 mg QD by Week 16. Steroid dose may have been increased, no more than 5 mg QD per week to a maximum of 25 mg, as needed for rescue purposes up to Week 8. Tapering to the steroid goal of ≤10 mg was permitted up until Week 16. No changes in steroid dose were allowed between Weeks 16 and 24. Starting at Week 24, steroid tapering was again permitted per PI discretion with goal of ≤10 mg QD. Subjects not achieving the steroid goal of ≤10 mg QD at Week 24 were considered non-responders for the primary endpoint. Subjects requiring rescue treatment between Weeks 8 and 48 were considered non-responders from the visit the subject takes rescue treatment. Steroid doses may have been increased or decreased as necessary for safety purposes. Subjects requiring increases of more than 5 mg QD per week were considered non-responders. Subjects requiring an intra-articular injection during the study were considered non-responders. Subjects considered non-responders were allowed to continue on study drug, at the investigator's discretion, if they had not received a prohibited medication.
Subjects must have remained on their background therapy throughout the entirety of the study. The only permitted change of background therapy was steroid tapering. If applicable, subjects continued on their stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and low-potency narcotics. For NSAIDs, acetaminophen/paracetamol, tramadol, codeine, hydrocodone, and propoxyphene that were part of background therapy, changes in dose, including initiation, were not allowed, with the exception of protocol-defined rescue therapy. The following medications taken as needed (PRN) were allowed but were not to be taken within the 24 hours prior to any study visit: NSAIDs, acetaminophen/paracetamol, tramadol, codeine, hydrocodone, and propoxyphene. In the event of tolerability (or other safety) issues, the doses of NSAID and/or acetaminophen may have been decreased or discontinued with substitution of another NSAID.
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or herbal supplements) that the subject was receiving at the time of enrollment or received during the study must have been recorded through the post-treatment visit (30-day follow-up phone call). Subjects must have been able to safely discontinue any prohibited medications 30 days prior to initial study drug administration. Subjects must have been consented for the study prior to discontinuing any prohibited medications for the purpose of meeting study eligibility. See Table 2 for a list of allowed concomitant medications.
Subjects could request to be discontinued from participating in the study at any time for any reason including but not limited to disease progression or lack of response to treatment. The Investigator could discontinue any subject's study treatment at any time for any reason, including but not limited to disease progression, lack of response to treatment, safety concerns, or failure to comply with the protocol.
At Week 24, the Investigator assessed and documented in source if continuing in the study was in the best interest of the subject. Subjects were discontinued from study drug immediately if any of the following occurred:
Upadacitinib or matching placebo manufactured by AbbVie (Table 3) was administered on Day 1 (Baseline) and taken at approximately the same time each day. Subjects were instructed to take study drugs orally, and only 1 tablet of upadacitinib or placebo from the dispensed bottle per day, with or without food. Subjects were instructed to take only 1 capsule or tablet from each dispensed bottle per day. If subjects forgot to take their upadacitinib or matching placebo dose at their regularly scheduled dosing time, they were to take the forgotten dose as soon as they remembered as long as it was at least 10 hours before their next scheduled dose. Otherwise, they were to take the next dose at the next scheduled dosing time. Subject dosing was recorded on a subject dosing diary. The subject was instructed to return all drug containers (even if empty) to the study site personnel at each study visit. Study site personnel documented compliance. Upadacitinib and matching placebo were packaged in bottles with quantities sufficient to accommodate study design. Each kit was labeled per local requirements and this label remained affixed to the kit. Upon receipt, study drug was to be stored as specified on the label and kept in a secure location. Each kit contained a unique kit number. This kit number was assigned to a subject via interactive response technology (IRT) and encoded the appropriate study drug to be dispensed at the subject's corresponding study visit. Site staff completed all blank spaces on the label before dispensing to subjects. Study drug was only to be used for the conduct of the study.
All subjects were assigned a unique identification number by the IRT at the Screening visit. For subjects who rescreened, the screening number assigned by the IRT at the initial Screening visit was used. The IRT assigned a randomization number that encoded the subject's treatment group assignment according to the randomization schedule generated by the statistics department at AbbVie. Randomization was stratified based on the following factors:
Baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, MTX, mycophenolate, or leflunomide) (yes/no)
Once approximately 2000 of total subjects had been randomized who were IFN signature low, further enrollment of such subjects may have been suspended. The investigator, study site personnel, and the subject remained blinded to each subject's treatment throughout the study. To maintain the blind, upadacitinib tablets and matching placebo tablets provided for the study were identical in appearance.
Results from Week 24 Interim Analysis
A table summarizing the demographics for subjects in the placebo and upadacitinib 30 mg QD treatment groups of the clinical study are provided in Table 4.
A table of baseline disease characteristics for subjects in the placebo and upadacitinib 30 mg QD treatment groups of the clinical study are provided in Table 5.
A summary of subject disposition in the placebo and upadacitinib 30 mg QD treatment groups of the clinical study is provided in Table 6.
A graphical depiction of response rate over time with respect to the primary endpoint (achievement of SRI-4 and Steroid Dose ≤10 mg prednisone equivalent QD) for subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks is provided as
A graphical depiction of response rate overtime with respect to achievement of SRI-4 for subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks is provided as
A graphical depiction of response rate over time with respect to achievement of BICLA for subjects treated with placebo and upadacitinib 30 mg QD over 24 weeks is provided as
A tabular summary of the primary and secondary endpoints and associated statistics for the full analysis set are provided in Table 7, which further shows that upadacitinib 30 mg achieved greater efficacy than placebo in LLDAS at Week 24 (p<0.001), as well as a lower flare rate through Week 24 (p=0.075).
The model-estimated median (9000 prediction interval) steady-state (SS) Cavg in subjects with SLE was 28.4 (19.1-46.6) ng/mL for upadacitinib 30 mg QD.
Quartile plots for the relationships between upadacitinib steady-state (SS) Cavg and efficacy responses at Week 24 are shown in
A plateau for efficacy was not reached at the upadacitinib plasma exposures evaluated in the study (associated with 30 mg QD).
The highest upadacitinib steady-state (SS) Cavg quartile (which would be equivalent to 45 mg QD exposures) was consistently associated with the highest observed response across the three endpoints and was the primary driver for upadacitinib exposure-response trends. The exposure-response model-predicted median (90% prediction interval) percentage of subjects achieving SRI-4 and steroid dose ≤10 mg prednisone equivalent QD, BICLA, and SRI-4 at Week 24 is 50% (42% to 58%), 57% (50% to 65%), and 55% (47% to 62%), respectively, for upadacitinib 30 mg UPA QD compared to 38% (31% to 46%), 39% (32% to 46%), and 40% (32% to 47%), respectively, for placebo. A upadacitinib 45 mg QD dose is predicted to provide 6% to 8% greater responses compared to 30 mg QD.
Upadacitinib 30 mg treatment group showed a significant decrease in the levels of C3, C4 complement, and IgM, compared to Baseline, as well as significant decreases in the level of anti-dsDNA autoantibodies and IgG. Increased circulating memory, naïve, and total B cells were also observed.
This was an extension of the Phase 2 Study of Example 1. Specifically, the study of Example 1 was extended a further 24 weeks to a total of 48 weeks to further assess the maintenance of efficacy and safety of upadacitinib 30 mg treatment beyond 24 weeks. A schematic illustration of the study is shown in
The Week 24 and Week 48 results from selected efficacy endpoints for continued groups are presented in Table 8 and
After Week 24, the response rates in BICLA and SRI-4 in both the upadacitinib 30 mg group were generally maintained, while the placebo rate either remained stable (SRI-4) or decreased (BICLA). Upadacitinib 30 mg showed a higher response rate than Placebo (53.200 vs. 25.30; stratum-adjusted treatment difference: 30.8; p 0.001) for achievement of BICLA at Week 48. Upadacitinib 30 mg showed a higher response rate than Placebo (45.2% vs. 32.0%; stratum-adjusted treatment difference: 30.4; p=0.075) for achievement of SRI-4 at Week 48. Upadacitinib 30 mg also showed reductions in flare and delays in time-to-first flare compared to placebo. Overall, the totality of the data suggests that upadacitinib 30 mg QD provides additional benefits over that of background medication alone in subjects with moderate to severe SLE.
1Adj. Diff: stratum-adjusted treatment difference except for the flares, which were summarized as observed.
There was a clear exposure-response relationship (p<0.05) for upadacitinib with SRI-4 and steroid dose ≤10 mg prednisone equivalent, SRI-4, and BICLA at Week 48. Quartile plots for the relationships between upadacitinib Cavg and efficacy responses at Week 48 are shown in
The exposure-response model-predicted median (90% prediction interval) percentage of subjects achieving SRI-4 and steroid dose ≤10 mg prednisone equivalent QD, BICLA, and SRI-4 at Week 48 is 50% (41% to 58%), 56% (47% to 64%), and 54% (45% to 61%), respectively, for upadacitinib 30 mg UPA QD compared to 34% (25% to 44%), 25% (18% to 34%), and 32% (24% to 42%), respectively, for placebo. A upadacitinib 30 mg QD dose is predicted to provide 8% to 16% greater efficacy responses compared to 15 mg QD.
The Week 48 predefined biomarker analyses confirmed the trends observed at Week 24. Namely, treatment with upadacitinib 30 mg QD resulted in meaningful decreases in anti-dsDNA autoantibodies and an early reduction (a known effect of JAK inhibitors) followed by a progressive normalization in complement C3 and C4 levels.
This application claims the benefit of U.S. Provisional Application No. 63/393,158, filed Jul. 28, 2022, and claims the benefit of U.S. Provisional Application No. 63/411,785, filed Sep. 30, 2022, each of which are herein incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63393158 | Jul 2022 | US | |
| 63411785 | Sep 2022 | US |
