EA046025B1 - SUPPRESSION OF TYPE I INTERFERON IN SYSTEMIC LUPUS ERYTHEMATOSUS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to methods and compositions for the treatment of systemic lupus erythematosus (SLE). In particular, the present invention relates to methods comprising administering to a subject in need thereof a type I IFN receptor inhibitor, optionally anifrolumab.

State of the art

Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and morbidity ¹ . Despite intensive clinical trial activity in SLE over the past 60 years, only one drug, belimumab, has received regulatory approval. Many factors have contributed to failures in drug development for SLE, including problems with trial design, heterogeneous patient populations, and lack of reliable endpoints.

Clinical manifestations of SLE include, but are not limited to, constitutional symptoms, alopecia, rashes, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, hemolytic anemia, cognitive dysfunction, and other nervous system lesions. These disease manifestations account for a significant burden of disease and can result in decreased physical functioning, job loss, decreased health-related quality of life (QoL), and a 10-year reduction in life expectancy. Increased hospitalizations and adverse drug events, including long-term use of oral corticosteroids (OCS or glucocorticoids and other immunosuppressive treatments), add to the disease burden in SLE.

Treatment of SLE is challenging due to limited efficacy and poor tolerability of standard therapy ² . All therapies currently used to treat SLE have well-known adverse effect profiles, and there is a medical need to identify new targeted therapies, particularly agents that can reduce the need for corticosteroids and cytotoxic agents.

The problem of finding a cure for SLE.

Clinical development of a new drug is a long and expensive process with a low chance of success. For molecules that enter the clinical development phase, less than 10% will ultimately be approved by health regulators ³ . In addition, clinical development of biotherapeutics, especially monoclonal antibodies, is neither faster nor cheaper than the development of small molecule drugs. The early stages of clinical development of biotherapeutics are much longer than the early stages of small molecule development.

Phase II trials are conducted on a small number of volunteers who have the disease of interest. They are carried out to test safety, pharmacokinetics and pharmacodynamics. A phase II trial can provide preliminary evidence of a drug's effectiveness. However, the small number of participants and major safety concerns within a phase II trial generally limit its ability to establish efficacy. A phase III trial is required to demonstrate the efficacy and safety of the clinical candidate. Critically, many clinical candidates that show promising results in phase II fail to achieve success in phase III. More than 90% of new therapeutics entering phase I trials fail during clinical development, primarily due to lack of efficacy or safety. The success rate in phase III after successful phase II is less than 50% ⁴ .

The drug development process is particularly complex in the case of SLE. This is because SLE is a particularly complex and poorly understood disease compared to diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis. Not only is our understanding of the genetics of SLE insufficient, but our understanding of the pathogenesis of most clinical manifestations is still relatively limited compared to other disease.

The complexity of SLE presents those wishing to develop new therapeutics with the challenge of a patient population with extensive heterogeneity ⁵ . This further complicates the design of clinical trial protocols with SLE, for example regarding the selection of inclusion criteria and primary and secondary endpoints. In addition, it is difficult to predict the course of the disease in each patient. This inevitably increases background noise, which reduces the statistical power of the test. High placebo response rates limit the range over which a new drug being tested can demonstrate a signal of efficacy, further complicating the conduct of clinical trials and the interpretation of their results.

The difficulty of developing effective therapeutics for the treatment of SLE results in an even higher failure rate when developing therapeutics in this area in clinical trials compared to therapeutics for other indications. There is currently only 1 new treatment (belimumab) for SLE approved by the US Food and Drug Administration (FDA) and the European Union.

- 1 046025 by the Medicines Agency (EMA) in the approximately 50 years since hydroxychloroquine was approved for use in discoid lupus and SLE. However, belimumab is not universally approved and its use has been low. Many of the agents currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate/mycophenolic acid mofetil, have not been approved for the treatment of this disease.

In addition, all of these drugs have well-documented safety concerns and are not effective in all patients for all manifestations of lupus. Antimalarials (eg, hydroxychloroquine) and corticosteroids may be used to control arthralgia, arthritis, and types of rashes. Other treatments include nonsteroidal anti-inflammatory drugs (NSAIDs); analgesics for fever, arthralgia and arthritis, and topical sunscreens to minimize photosensitivity. Subjects with moderate to severe disease often find it difficult to taper off completely from OCS, which causes long-term morbidity and may contribute to early cardiovascular mortality. Even small daily doses of prednisone, ranging from 5 to 10 mg, carry an increased risk of side effects such as cataracts, osteoporosis, and coronary heart disease when used over a long period of time.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the symptomatic control of arthralgia, mild arthritis, myalgia, serositis, and fever in patients with SLE. They are not characterized by immunosuppressive properties. NSAIDs can only be used for short periods of time and are not suitable for patients with kidney damage, hypertension and established heart disease. NSAIDs can cause fluid retention, kidney failure, and interstitial nephritis.

Mycophenolate mofetil (MMF) is a specific inosine monophosphate dehydrogenase inhibitor. MMF disrupts de novo purine synthesis. Inosine monophosphate dehydrogenase is involved in an important signaling pathway in activated lymphocytes. Thus, MMF suppresses the proliferation of both T and B lymphocytes and reduces the synthesis of antibodies. A randomized, blinded, multicenter, international trial of 370 SLE patients with active nephritis who were randomly assigned to receive MMF (2–3 g daily) or standard IV cyclophosphamide-based therapy for 6 months demonstrated that MMF is effective was similar in effectiveness to cyclophosphamide, which was the standard of care before the study. However, the responses of African Americans, Americanoids, and Hispanic individuals varied significantly ⁶ .

Thus, the development of new therapeutic agents for the treatment of SLE has proven to be extremely challenging. There are many examples of clinical candidates that showed promising results in phase II but failed to demonstrate efficacy and/or safety in subsequent phase or phase III trials.

Tabalumab.

Tabalumab (LY2127399) is a human IgG4 monoclonal antibody that binds both soluble and membrane-bound B cell activating factor (BAFF). The efficacy and safety of tabalumab were assessed in two 52-week, multicenter, randomized, double-blind, placebo-controlled, phase III trials in patients with moderate to severe SLE (ILLUMINATE-1 and ILLUMINATE-2). The primary endpoint was the proportion of patients achieving a response according to the SLE Subject Response Index 5 (SRI-5) at week 52.

In ILLUMINATE-1 (NCT01196091), the primary endpoint was not met. Key secondary efficacy endpoints (OCS abstinence, time to severe exacerbation, worst fatigue in the last 24 hours) also did not reach statistical significance, despite pharmacodynamic evidence of tabalumab biological activity (significant reductions in anti-dsDNA antibodies, total B-cell levels and immunoglobulins) ⁷ .

The primary endpoint was met in ILLUMINATE-2 (NCT01205438) in the higher dose group (120 mg tabalumab once every 2 weeks). However, no secondary endpoints were achieved, including abstinence from OCS ⁸ . Following ILLUMINATE-1 and ILLUMINATE-2, development of tabalumab was suspended due to small effect sizes and failure to meet other important clinical endpoints.

Blisibimod.

Blisibimod is a fusion protein consisting of four BAFF-binding domains fused to the N-terminal Fc fragment of human Ig IgG1. Blisibimod for the treatment of SLE showed promising results in phase II but failed in phase III.

In a double-blind, randomized, placebo-controlled, phase 2 clinical trial (PEARL-SC), patients with serologically active SLE and a SELENA-SLEDAI score of 6 or greater were randomized to receive 3 different doses of blisibimod or placebo (NCT01162681). At week 24, the highest dose group (200 mg once weekly) had a significantly higher SRI-5 response rate than the placebo group ⁹ .

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However, in a subsequent placebo-controlled, randomized, double-blind phase III trial (CHABLIS-SC1) conducted in seropositive SLE patients with persistently high disease activity (SELENA-SLEDAI score of 10 or greater), the primary endpoint (SRI- 6) was not achieved (NCT01395745). Secondary endpoints (SRI-4 and SRI-8) were also not met ¹⁰ .

Atacycept.

Atacicept (TACI-Ig) is a fully human recombinant fusion protein that neutralizes both BAFF and APRIL. The efficacy of atacicept for the treatment of SLE was assessed in two phase II/III placebo randomized controlled trials (APRIL-LN and APRIL-SLE). The APRIL-LN trial compared the renal response to atacicept versus placebo plus standard of care (new, recently developed MMF and glucocorticoids) in patients with SLE nephritis. The trial was stopped after serious adverse events were reported.

In the APRIL-SLE trial, the primary endpoint of a significant reduction in the proportion of patients who experienced a new exacerbation as measured by BILAG A or BILAG B was not met in the lower dose group (75 mg) (NCT00624338). Patients in the higher dose group (150 mg) were discontinued due to serious AEs ¹¹ .

Abetimus.

Abetimus (LJP 394) contains four synthetic oligodeoxynucleotides attached to a triethylene glycol backbone, with over 97% of these oligonucleotides being derived from dsDNA. This drug was developed to neutralize antibodies to dsDNA. In a double-blind, placebo-controlled study in patients with SLE, treatment with LJP 394 in patients with high-affinity antibodies to its DNA epitope prolonged the time to renal exacerbation and reduced the number of renal exacerbations ¹² . However, in a subsequent phase III trial (NCT00089804) using higher doses of abetimus with the primary endpoint of time to renal exacerbation, the study and further development of this drug were stopped when an interim analysis did not demonstrate rituximab was effective.

Rituximab is a chimeric monoclonal antibody against CD20. Rituximab is an effective treatment for a number of autoimmune diseases, including rheumatoid arthritis and ANCA-associated vasculitis. A small number of uncontrolled trials in lupus nephritis suggested that rituximab may also be potentially effective in patients with lupus nephritis. The efficacy and safety of rituximab were assessed in a randomized, double-blind, placebo-controlled, phase III trial in patients with lupus nephritis treated with concomitant mycophenolate mofetil (MMF) and corticosteroids (LUNAR) (NCT00282347). Rituximab therapy did not improve clinical outcomes after 1 year of treatment ¹⁴ .

The efficacy and safety of rituximab in patients with moderate to severe SLE was assessed in the multicenter phase II/III placebo randomized controlled trial (EXPLORER). In this study, patients with active SLE at baseline (defined as 1 BILAG A score or more or 2 BILAG B scores or more) were randomized to receive rituximab or placebo. The primary endpoint was the proportion of patients treated with rituximab, compared with patients treated with placebo, achieving a complete clinical response (CCR), partial clinical response (PCR), or not achieving a response at week 52. The primary endpoint was not met. after 52 weeks with similar rates of complete and partial responses in the rituximab and placebo groups. Differences in time to first moderate or severe exacerbation and change in HRQOL were also not significant with Abatacept.

Abatacept is a CTLA-4 fusion protein that binds to CD80/86 on the surface of antigen presenting cells and blocks the CD-28 signaling required for T cell activation. In preclinical studies, abatacept was demonstrated to have immunomodulatory activity in the NZB/NZW murine model of lupus ¹⁶ Abatacept for the treatment of nonrenal SLE was evaluated in a randomized, double-blind, placebo-controlled, phase IIb trial ¹⁷ (NCT00119678). The primary endpoint was the proportion of patients with a new exacerbation (recognized) according to the British Lupus Assessment Group (BILAG) A/B score after initiation of steroid tapering. Primary and secondary endpoints were not achieved.

Epratuzumab.

Epratuzumab is a monoclonal antibody that modulates B cell activity by binding to CD22 on the surface of mature B cells. Initial efficiency

- 3 046025 epratuzumab in the treatment of SLE was demonstrated in a phase II trial, but this was not confirmed in either a subsequent second phase IIb trial or a subsequent phase III trial.

Two phase IIb trials assessed the efficacy of epratuzumab with a BILAG-based primary endpoint in patients with moderate to severe SLE (ALLEVIATE 1 and 2). A trend towards clinical efficacy was observed and the primary endpoint was met in more patients treated with epratuzumab than in patients treated with placebo. Treatment with epratuzumab also resulted in improvements in health‐related quality of life (HRQOL) and a reduction in mean glucocorticoid dose ¹⁸ .

Another phase IIb trial (EMBLEM) randomized patients with moderate to severe SLE to one of five doses of epratuzumab or placebo. The BICLA response at 12 weeks in the primary endpoint was higher for all doses of epratuzumab than for placebo, but the effect was not statistically significant.

In the subsequent multicenter phase III trials of EMBODY 1 and EMBODY 2 in patients with moderate to severe SLE, the primary efficacy endpoint of BICLA response at 48 weeks was not met. No significant differences were observed in secondary endpoints such as SLEDAI‐2K total score, PGA or mean glucocorticoid dose ¹⁹ .

PF-04236921.

PF-04236921 is a monoclonal antibody that binds soluble IL-6, a cytokine that is elevated in patients with SLE. The efficacy of PF-0436921 was evaluated in a phase II RCT in patients with active SLE (BUTTERFLY) (NCT01405196). Patients were randomized to receive either 10, 50, or 200 mg of PF-04236921 subcutaneously or placebo once every 8 weeks; The 200 mg dose group terminated the trial early due to 3 deaths. The primary efficacy endpoint was SRI-4 response at 24 weeks with BICLA as a secondary endpoint. The primary endpoint was not met ²⁰ .

Type I IFN suppression and anifrolumab.

Type I interferons (IFNs) are cytokines that form an important link between innate and adaptive immunity and have been implicated in SLE based on genetic predisposition and positive regulation of interferon‐stimulated gene expression in the majority of patients with SLE ²¹ .

Attempts to target the type I IFN signaling pathway to treat SLE have previously been unsuccessful. Rontalizumab is a humanized IgG1 monoclonal antibody against interferon α (anti-IFN-α antibody). A phase II study was conducted to evaluate the efficacy and safety of rontalizumab in patients with moderate to severe SLE (ROSE) (NCT00962832). Patients with active SLE were randomized (2:1) to intravenous rontalizumab 750 mg once every 4 weeks or placebo (Part 1) and subcutaneous rontalizumab 300 mg once every 2 weeks or placebo (Part 2). The primary and secondary endpoints of this trial were not met in all patients ²² . Therefore, development of rontalizumab was stopped.

Sifalimumab is a monoclonal antibody against interferon-a. The efficacy and safety of sifalimumab were assessed in a randomized, double-blind, placebo-controlled, phase IIb trial in adults with moderate to severe active systemic lupus erythematosus (SLE) (NCT01283139), which met primary and some secondary endpoints, but treatment effects were small. In addition, sifalimumab had no significant effect on complement levels and anti-dsDNA antibody levels.

Anifrolumab (MEDI-546) is a monoclonal antibody that binds to IFNAR. In a phase II clinical trial, anifrolumab reduced disease activity compared with placebo in patients with moderate to severe SLE ²³ . The safety and efficacy of anifrolumab for the treatment of SLE were subsequently assessed in two phase III clinical trials, TULIP I and TULIP II. However, TULIP I failed to achieve its primary endpoint ^{24 , 25} .

Conclusion.

There is a large unmet need for a therapy for SLE with a better efficacy and safety profile than currently available therapies ^{26 , 27} .

As described above, a large number and wide range of different biological agents have been proposed and tested in clinical trials, but these trials did not meet clinically relevant endpoints in the pivotal studies. The initial promise in phase II of many proposed therapeutics has not been translated into significant and meaningful clinical benefit in subsequent pivotal phase III clinical trials.

Thus, there remains a need for a safe and effective treatment for SLE that has demonstrated clinical benefit, such as in a double‐blind, randomized, placebo‐controlled phase III trial ²⁸ .

The present invention solves one or more of the above objectives by providing a safe and effective treatment for SLE, for which

- 4 046025 safety and effectiveness of treatment.

The essence of the invention

The present invention provides a method of treating systemic lupus erythematosus (SLE) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a type I interferon receptor (IFN) inhibitor (IFNR), wherein the IFNR inhibitor reduces SLE disease activity in the subject. The ability of an IFNR inhibitor to reduce SLE disease activity in a subject could be demonstrated in a phase III clinical trial, specifically a double-blind, randomized, placebo-controlled trial.

The present invention is based on the results of the double-blind, randomized, placebo-controlled, phase III TULIP II trial of anifrolumab. In TULIP-2, its primary and secondary points were reached. Compared with placebo, treatment with anifrolumab resulted in significantly higher rates of improvement across a broad range of composite and organ-specific measures of disease activity, as well as the achievement and maintenance of low disease activity, tapering of corticosteroids, and a trend toward decreased rates of exacerbations. TULIP II represents the first successful phase III trial in SLE since the belimumab trial more than 10 years ago. Not only did TULIP II actually meet its primary endpoint, but it also demonstrated early and sustained benefit in a patient with SLE, particularly when compared to the only approved biologic treatment for SLE, belimumab. In addition, the administration of anifrolumab allowed gradual reduction of OCS dose in patients with SLE without worsening SLE disease activity. Treatment with belimumab does not support taper of OCS ²⁹ .

The successful TULIP II trial follows the previously reported failure of the previous TULIP I trial (NCT02446912). TULIP-1 did not meet its primary endpoint ((SRI)4). However, analysis of data from TULIP I demonstrated the effectiveness of anifrolumab in prespecified secondary endpoints, including response according to BICLA. After careful analysis of data from TULIP-1 and prior to disclosure of data from the TULIP-2 trial, we changed the primary efficacy endpoint for TULIP-2 from SRI4 to BICLA in a modified version of the protocol. BICLA, unlike SRI4, reflects the presence of disease activity associated with the manifestation of lupus rather than the severity of the manifestation. The use of BICLA allowed the assessment of gradual response rather than requiring more complete resolution of disease manifestations.

Reducing SLE disease activity in a subject in a method of the present invention may involve one or more of the following:

response according to the BILAG-based Comprehensive Lupus Assessment (BICLA) in the subject;

a decrease in the subject's cutaneous lupus erythematosus prevalence and severity index (CLASI) score compared to the subject's CLASI score before treatment;

reducing the number of tender and swollen joints in the subject compared to the number of tender and swollen joints in the subject before treatment;

a subject characterized by a maximum of 1 B score according to BILAG-2004 after treatment;

a subject with a BILAG-2004 score of C or better after treatment;

a subject characterized by an improvement in at least one patient-reported outcome (PRO) compared to the pre-treatment condition;

reducing the frequency of exacerbations of SLE in the subject compared to the frequency of exacerbations in the subject before treatment.

The method may include measuring a BILAG score in a subject before and after administration of an IFNAR inhibitor. The BICLA response may be maintained in the subject for at least 52 weeks. The method may include measuring PRO in a subject before and after administration of an IFNAR inhibitor. PROs may include assessment using the subject's Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire, Short Form 36 Health Questionnaire version 2 (SF-36-v2), the Mental Health Index (MCS), and/or a measure representing the physical health index (PCS), according to the SF-36.

The response under BICLA may include a reduction in category A and B scores under BILAG-2004 to B/C/D and C/D respectively.

A decrease in a subject's CLASI score compared to the subject's pre-treatment CLASI score may involve a decrease in the subject's CLASI-A score compared to the subject's pre-treatment CLASI-A score. Reducing SLE disease activity in a subject may involve decreasing levels of anti-dsDNA antibodies in the subject. A decrease in SLE disease activity in a subject may indicate response according to the BILAG-based Comprehensive Lupus Assessment (BICLA). The method may include reducing the dose of OCS administered to the subject compared to the dose of OCS administered to the subject prior to treatment.

OCS may include prednisone, prednisolone, and/or methylprednisolone.

A decrease in SLE disease activity in a subject may involve a response according to

- 5 046025 BILAG-based comprehensive lupus assessment (BICLA) by at least week 4 of treatment.

Reduction in SLE disease activity may predict response according to the BILAG-based Comprehensive Lupus Assessment (BICLA) by at least week 8 of treatment.

A reduction in SLE disease activity in a subject may include an improvement of at least 50% in the subject's number of tender joints and swollen joints relative to the subject's pre-treatment number of tender joints and swollen joints.

A reduction in a subject's SLE disease activity may not translate into an improvement in the SLE patient response index (SRI)4.

A reduction in a subject's SLR disease activity may not predict an improvement in the Systemic Lupus Erythematosus Patient Response Index (SRI)4 score after 52 weeks of treatment.

A reduction in a subject's CLASI score may be achieved by at least week 8 of treatment.

A reduction in a subject's CLASI score may be achieved after 12 weeks of treatment.

A reduction in SLE disease activity in a subject may include a reduction in the subject's CLASI score by at least 50% compared to the subject's CLASI score before treatment.

A decrease in SLE disease activity in a subject may include a decrease in the subject's CLASI-A score after 12 weeks of treatment.

A subject may have a CLASI-A score of 10 or greater before treatment.

A reduction in SLE disease activity in a subject may include a subject's BILAG-2004 score of C or better after 24 weeks of treatment.

A reduction in SLE disease activity in a subject may involve the subject achieving a maximum of 1 BILAG-2004 score after 24 weeks of treatment.

A reduction in SLE disease activity in a subject may involve a reduction in the subject's BILAG-based annual exacerbation rate compared to the subject's BILAG-based annual exacerbation rate before treatment.

Reducing SLE disease activity in a subject may involve preventing exacerbations in the subject.

An exacerbation may be defined as 1 new (worsening) BILAG-2004 Category A score or more, or 2 new (worsening) BILAG-2004 Category B scores or more, compared with the subject's scores one month earlier.

Reducing SLE disease activity in a subject may include reducing the frequency of exacerbations in the subject compared to the frequency of exacerbations before treatment, where the method includes reducing the dose of OCS administered to the subject compared to the dose of OCS administered to the subject before treatment.

The method may include selecting a subject for treatment, where the subject is selected based on the presence of active SLE. The method may include selecting a subject for treatment, where the subject is selected for the presence of moderate to severe SLE. A subject may be selected for the presence of SLE that does not respond to OCS treatment.

The subject may be an adult. The subject may be an adult. The subject may be an adult with moderate to severe SLE. The subject may be an adult with active SLE.

The present invention also provides a method of reducing the dose of OCS in a subject suffering from an autoimmune disease, comprising administering to the subject a therapeutically effective amount of a type I IFN receptor inhibitor and reducing the dose of OCS administered to the subject compared to the dose of OCS administered to the subject before treatment, wherein the IFNR inhibitor reduces disease activity in the subject.

The present invention also provides a method for preventing OCS-associated organ damage in a subject suffering from an autoimmune disease, wherein the subject is pretreated with OCS, the method comprising administering to the subject a therapeutically effective amount of a type I IFN receptor inhibitor and reducing the dose of OCS administered to the subject, compared to the dose of OCS administered to the subject prior to treatment, wherein the IFNR inhibitor reduces disease activity in the subject.

A subject may receive an OCS dose of approximately 10 mg/day or greater at the start of treatment. The OCS dose may be reduced to approximately 7.5 mg/day or less. The OCS dose may be reduced to 7.5 mg/day or less. The OCS dose may be reduced to approximately 0 mg/day. The OCS dose may be reduced to 0 mg/day. The method may include maintaining a reduced dose of OCS for at least 12 weeks.

The subject may have OCS-associated organ damage. OCS may include prednisone, prednisolone, and/or methylprednisolone. The autoimmune disease may be SLE or moderate to severe SLE. A subject may be selected for the presence of SLE that does not respond to OCS treatment.

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The type I IFN receptor inhibitor can be administered intravenously.

The type I IFN receptor inhibitor may be an anti-type I interferon receptor antibody or an antigen-binding fragment thereof that specifically binds IFNAR1. The antibody may be a monoclonal antibody. The antibody may be anifrolumab.

The method may include administering 300 mg of anifrolumab, where optionally the anifrolumab is administered by intravenous (IV) infusion over a 30-minute period of time. Anifrolumab can be administered by IV infusion over a 30-minute period once every 4 weeks. Anifrolumab can be administered from a single-dose vial. Anifrolumab can be presented in solution at a concentration of 150 mg/ml. Anifrolumab can be administered once every four weeks. Anifrolumab can be administered for at least 52 weeks.

The present invention also relates to a pharmaceutical composition for use in the treatment method of the present invention, wherein the pharmaceutical composition contains a type I IFN receptor inhibitor.

The present invention also relates to the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of SLE, wherein the pharmaceutical composition contains a type I IFN receptor inhibitor.

The pharmaceutical composition may contain anifrolumab at a concentration of 150 mg/ml.

The pharmaceutical composition may contain

150 mg/ml anifrolumab;

mM lysine-HCl;

130 mM trehalose dihydrate;

0.05% polysorbate 80;

mM histidine/histidine-HCl;

wherein the pH value of the pharmaceutical composition is 5.9.

The present invention also provides a unit dose for use in the method of the present invention, where the unit dose contains 300 mg of anifrolumab.

The present invention also provides a kit for use in the method of the present invention, wherein the kit contains:

a unit dose of the present invention; and a glass vial containing a unit dose.

The kit may contain instructions for administering a single dose. Directions may indicate single dose administration once every 4 weeks. The instructions may indicate that the subject has moderate to severe SLE.

The present invention also provides an improved method for assessing the effect of an SLE treatment based on patient-reported outcomes (PROs) of treatment in a subject, comprising measuring a BICLA response in the subject, wherein the BICLA response corresponds to an improvement in patient-reported outcomes (PROs) of treatment in the subject. PROs may include assessment using the subject's Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire, Short Form 36 Health Questionnaire version 2 (SF-36-v2), the Mental Health Index (MCS), and/or a measure representing the physical health index (PCS), according to the SF-36.

Brief description of graphic materials

Fig. 1. Primary and selected secondary efficacy outcomes over time in TULIP-1.

In fig. 1A-1F illustrate the primary and selected secondary efficacy outcomes over time in TULIP-1. In fig. 1A and FIG. Figure 1B shows the primary endpoint: percentage of patients responding according to the SRI(4). In fig. 1C and FIG. Figure 1D shows the percentage of patients with a 50% or greater reduction in CLASI activity score from baseline in patients with a CLASI score of 10 or greater at baseline. In fig. 1E and FIG. Figure 1F shows the percentage of patients with a BICLA response.

Fig. 2. Response according to BICLA and IFNGS type I over time in TULIP I.

In fig. 2A-2B illustrate BICLA response and type I IFNGS suppression over time in TULIP-1. In fig. Figure 2A shows a Kaplan-Meier plot of time to onset of BICLA response that was sustained through week 52. Patients without a BICLA response that was sustained through week 52 are censored at the date of study treatment discontinuation or at week 52, depending on what happened before. In fig. Figure 2B shows the median percentage change in the pharmacodynamic expression profile of genes under the control of type I IFN (21 genes) at baseline at each visit among patients with high type I IFNGS (fold change greater than 2) at baseline.

Fig. 3. Reduce OCS dosage.

In fig. 3A and 3B show a sustained reduction in oral corticosteroid dosage to a target level of 7.5 mg/day or less from week 40 to week 52 in patients with a corticosteroid dosage of 10 mg/day or more at baseline. In fig. Figure 3A shows results using pre-established drug administration rules.

- 7 046025 venous drugs for limited use to determine non-response and in FIG. Figure 3B shows the results of the analysis with the modified restricted drug guidelines.

Fig. 4. Antibodies to dsDNA and C3 concentration in TULIP I.

In fig. 4A-4B illustrate the change from baseline over time (FIG. 4A) in anti-dsDNA antibody levels in patients with elevated anti-dsDNA antibody levels at baseline and (FIG. 4B) change in C3 concentration in patients with low C3 levels at baseline level in TULIP-1.

Fig. 5. Primary and key secondary efficacy outcomes over time for TULIP-2.

In fig. Figures 5A-5C illustrate the primary and key secondary efficacy outcomes over time for TULIP-2. In fig. Figure 5A shows the primary endpoint: percentage (95% CI) of patients with a BICLA response. In fig. 5B shows the percentage (95% CI) of patients with an OCS dosage reduction of 7.5 mg/day or less maintained from week 40 to week 52, among patients with a prednisone dosage of 10 mg/day or more at baseline, or equivalent . In fig. Figure 5C shows the percentage (95% CI) of patients with a 50% or greater reduction in CLASI activity score from baseline among patients with a CLASI score of 10 or greater at baseline.

Fig. 6. Period of sustained response according to BICLA and time to exacerbation in TULIP-2.

In fig. 6A-6B illustrate the period of sustained response in BICLA and time to relapse in TULIP-2. In fig. 6A shows the time to onset of BICLA response, which was sustained until week 52. FIG. 6B shows the time to first exacerbation, with exacerbation defined as either 1 new A BILAG point or more or 2 new BILAG points or more compared to the previous visit. Both outcomes were assessed using the Cox proportional hazards model.

Fig. 7. IFNGS and anti-dsDNA antibodies.

Change from baseline over time in (Figure 7A) IFNGS and (Figure 7B) anti-dsDNA antibody levels in patients with elevated baseline anti-dsDNA antibody levels in TULIP-2. In fig. Figure 7C shows C3 concentrations in patients with low C3 levels at baseline.

Fig. 8. Answer according to BICLA at early time points.

In fig. 8A-8C illustrate the percentage of patients with a BICLA response at early time points in TULIP-1 (FIG. 8A), TULIP-2 (FIG. 8B), and the combined data from TULIP-1 and TULIP-2 (FIG. 8C).

Fig. 9. Percentage of patients with BICLA response sustained from baseline to week 52 in TULIP1, TULIP-2, and combined data from TULIP-1 and TULIP-2.

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; IFNGS: interferon-controlled gene expression profile; OCS: oral corticosteroid; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000. In TULIP-1, TULIP-2, and the pooled data from TULIP, restricted drug use guidelines followed the TULIP-2 protocol. Hazard ratios and 95% CIs are estimated using a Cox regression model with treatment group and stratification factors (SLEDAI-2K at screening, OCS dosage at day 1, and test result for IFNGS type I at screening) as covariates.

Fig. 10. Answer according to BICLA at all time points.

BICLA: British Lupus Group Comprehensive Assessment for Lupus; IFNGS: interferon-controlled gene expression profile; OCS: oral corticosteroid; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000. At early time points, P-values in TULIP-1 and TULIP-2 were 0.207 and 0.238 (week 4), 0.020 and 0.004 (week 8), and 0.054 and 0.029 (week 12 ) respectively. In TULIP-1, TULIP-2, and the combined data from TULIP, the rules for restricted drug use followed the TULIP-2 protocol. Treatment response rates are calculated using a stratified Cochran-Mantel-Haenszel approach with stratification factors being day 1 OCS dosage, SLEDAI-2K, and IFNGS I test results, both at screening. In the pooled analysis, an additional stratification factor is added to the study. Vertical error bars indicate 95% confidence intervals.

Fig. 11. Percentage of patients with response according to BICLA.

In fig. 11A-11C illustrate the percentage of patients with BICLA responses sustained from baseline to week 52 in TULIP-1 (FIG. 11A), TULIP-2 (FIG. 11B), and combined data from TULIP-1 and TULIP-2 (FIG. 11C).

Fig. 12. Time to sustained response according to BICLA.

In fig. 12A-12C illustrate the average time to BICLA response sustained from onset to week 52 in TULIP-1 (FIG. 12A), TULIP-2 (FIG. 12B), and combined data from TULIP-1 and TULIP-2 (FIG. 12C).

Fig. 13. MCP and PCR.

- 8 046025

In fig. 13A-13C illustrate the percentage of patients achieving a good clinical response or partial clinical response at week 24 that was sustained through week 52 in TULIP1 (FIG. 13A), TULIP-2 (FIG. 13B), and combined data from TULIP-1 and TULIP-2 (Fig. 12C). IFNGS: interferon-controlled gene expression profile; MCR: good clinical response; OCS: oral corticosteroid; PCR: partial clinical response; SLEDAI2K: Systemic Lupus Erythematosus Disease Activity Index 2000. In TULIP-1, TULIP-2, and the pooled data from TULIP, restricted drug use guidelines followed the TULIP-2 protocol. Treatment response rates are calculated using a stratified Cochran-Mantel-Haenszel approach with stratification factors being day 1 OCS dosage, SLEDAI-2K, and IFNGS I test results, both at screening.

Fig. 14. BICLA response by demographic subgroup for pooled data from TULIP.

BMI: body mass index; BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; CMH: Cochran-Mantel-Haenszel approach. Data from TULIP-1 were analyzed using pre-established restricted drug use guidelines. Differences in treatment estimates and associated 95% CIs were weighted averages and calculated using the stratified CMH approach.

Fig. 15. Response according to BICLA by race.

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; CMH: Cochran-Mantel-Haenszel approach.

Eight patients in both the placebo and anifrolumab 300 mg groups had missing data from TULIP-1.

Data from TULIP-1 were analyzed using pre-established restricted drug use guidelines. Differences in treatment estimates and associated 95% CIs were weighted averages and calculated using the stratified CMH approach. The combined data from TULIP is subject to final confirmation.

Fig. 16. Answer according to BICLA depending on geographical region.

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; CMH: Cochran-Mantel-Haenszel approach.

^a Countries within each geographic region are identified on slide 7; ^b Treatment difference (95% CI) for rest of world: TULIP-1, -6.7 (-65.3, 51.9); TULIP-2, 66.7 (6.6, 100.0); pooled data, 26.9 (-15.1, 69.0). Data from TULIP-1 were analyzed using pre-established restricted drug use guidelines. Differences in treatment estimates and associated 95% CIs were weighted averages and calculated using the stratified CMH approach.

Fig. 17. BICLA response according to SLEDAI-2K at screening.

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; CMH: Cochran-Mantel-Haenszel approach; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000. Data from TULIP-1 were analyzed using pre-established restricted drug use guidelines. Differences in treatment estimates and associated 95% CIs were weighted averages and calculated using the stratified CMH approach.

Fig. 18. BICLA response as a function of oral corticosteroid dosage at baseline.

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; CMH: Cochran-Mantel-Haenszel approach; OCS: Oral corticosteroid. Data from TULIP-1 were analyzed using pre-established restricted drug use guidelines. Differences in treatment estimates and associated 95% CIs were weighted averages and calculated using the stratified CMH approach.

Fig. 19. Response according to BICLA depending on the status of the expression profile of genes under the control of type I IFN (screening).

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; CMH: Cochran-Mantel-Haenszel approach; IFNGS: expression profile of genes under the control of type I interferon; qPCR: quantitative polymerase chain reaction. ^a Type I IFNGS was classified as high or low by screening at a central laboratory using a 4-gene PNR-based test using DNA isolated from whole blood. Data from TULIP-1 were analyzed using pre-established restricted drug use guidelines. Differences in treatment estimates and associated 95% CIs were weighted averages and calculated using the stratified CMH approach.

Fig. 20. Exacerbations assessed using BILIAG-2004 in treated patients

- 9 046025 with anifrolumab compared with placebo in TULIP-2 and TULIP-1.

BILAG: British Lupus Assessment Group. Note: Exacerbation defined as 1 new (worsening) BILAG-2004 Category A score or less, or 2 new (worsening) BILAG-2004 Category B scores or less, compared to the previous month's visit.

Fig. 21. Time until the last exacerbation in TULIP-2 and TULIP-1.

BILAG: British Lupus Assessment Group. Note: Exacerbation defined as 1 new (worsening) BILAG-2004 Category A score or less, or 2 new (worsening) BILAG-2004 Category B scores or less, compared to the previous month's visit. Time to first exacerbation is obtained by subtracting the date of first administration of the study product from the date of first exacerbation. If the patient did not have an exacerbation, the time to exacerbation is censored at the end of the exposure time.

Fig. 22. Annual exacerbation rates up to week 52 in the TULIP trial.

Fig. 23. Percentage of patients with 1, 2, or three or more exacerbations of SLE before week 52 in the TULIP trials.

BILAG: British Lupus Assessment Group; SLE: systemic lupus erythematosus. Exacerbations were defined as 1 new BILAG-2004 Category A score for organ damage or less or 2 new BILAG-2004 Category B scores for organ damage or less compared to the previous visit.

Fig. 24. Percentage of patients achieving a CLASI-A response over time in patients with SLE receiving anifrolumab and placebo: pooled data from TULIP-1 and TULIP-2.

CLASI: cutaneous lupus erythematosus prevalence and severity index; CLASI-A: CLASI activity score; n: number of patients in the analysis; N: number of patients in the treatment group; NA: no data; OCS: Oral corticosteroids. Response is defined as a decrease in CLASI activity score of 50% or less from baseline for patients with a CLASI-A score of 10 or less at baseline. Treatment response rates are calculated using a stratified Cochrane-Mantel-Haenszel approach with stratification factors representing the SLEDAI-2K score at screening. OCS dosage on day 1, type I IFN-controlled gene expression profile test result in screening and study (TULIP-1 and TULIP-2). Nominal P-values are presented: *P less than 0.05; **P less than 0.01; ***P is less than 0.001.

Fig. 25. Time to CLASI-A response sustained to week 52 in patients with SLE receiving anifrolumab and placebo: TULIP-1 and TULIP-2.

CLASI: cutaneous lupus erythematosus prevalence and severity index; CLASI-A: CLASI activity score; n: number of patients in the analysis; N: number of patients in the treatment group; NA: no data; OCS: Oral corticosteroids. Response is defined as a decrease in CLASI activity score of 50% or less from baseline for patients with a CLASI-A score of 10 or less at baseline. Hazard ratios and 95% CIs were estimated using a Cox regression model with treatment groups stratified (SLEDAI-2K score at screening. OCS dosage on day 1, study, and type I IFN-controlled gene expression test result at screening) as covariates.

Fig. 26. CLASI-A response at week 12 according to baseline CLASI-A response thresholds of 50% and 75%: TULIP-1 and TULIP-2.

Fig. 27. Skin response according to CLASI-A: example of one patient after treatment with anifrolumab (300 mg).

CLASI-A: an activity score that provides an index of the prevalence and severity of cutaneous lupus erythematosus. Response is defined as a decrease in CLASI-A score of 50% or greater from baseline for patients with a CLASI-A score of 10 or greater at baseline. A total of 13 anifrolumab-treated patients from 5 centers participated in skin photography; 2 patients had a CLASI-A response at week 12.

Fig. 28. Exacerbations and oral glucocorticoid use in BICLA responders versus non-responders.

Fig. 28A. Patients with 1 or more exacerbations according to BILAG-2004 before week 52. Error bars represent 95% CI.

Fig. 28B. Mean change in daily oral glucocorticoid dosage, calculated using the LS method, from baseline to week 52 for all patients, regardless of oral glucocorticoid dosage at baseline. Error bars represent 95% CI.

Fig. 28C. Patients achieving a sustained reduction in oral glucocorticoid dosage to 7.5 mg/day or less among patients receiving oral glucocorticoid dosages of 10 mg/day or more at baseline. Sustained reduction in oral glucocorticoid dosage, defined as an oral glucocorticoid dose of 7.5 mg/day or less, maintained from a week

- 10 046025 for week 52. Error bars represent 95% CI.

Fig. 28D. AUC of oral glucocorticoid up to week 52 in all patients, regardless of oral glucocorticoid dosage at baseline. Error bars represent SD. A-D, rate difference, CI, and nominal P-values were calculated using the stratified Cochran-Mantel-Haenszel approach. AUC: area under the curve; BICLA: British Lupus Group Comprehensive Assessment for Lupus; BILAG: British Lupus Assessment Group; CI: confidence interval; LS: least squares method; SD: standard deviation.

Fig. 29. PRO response at week 52 in BICLA responders versus non-responders.

Patients with a response according to (FIG. 29A) FACIT-F, defined as an improvement from baseline to week 52 greater than 3.4; (FIG. 29B) according to the SF-36 PCS, defined as an increase from baseline to week 52 of greater than 3.4 in the PCS category, and (FIG. 29C) according to the SF-36 MCS, defined as an increase from baseline to weeks 52, amounting to more than 4.2, in the MCS category. Fig. 28A-C. Error bars represent 95% CI. Response rates, CIs, and nominal P-values were calculated using the stratified Cochran-Mantel-Haenszel approach. Fig. 28D. Mean LS change in PtGA score from baseline to week 52. Error bars represent 95% CI. Mean differences calculated using the LS method, CI values, and nominal P values calculated using a mixed model for repeated measures. BICLA: British Lupus Group Comprehensive Assessment for Lupus; FACIT-F: questionnaire functional assessment of chronic disease therapy fatigue; MCS: mental health index; PCS: physical health index; PRO: patient-reported outcome; PtGA: patient global assessment; SF-36: Short Form 36 Health Questionnaire.

Fig. 30. Change from baseline in SLEDAI-2K, PGA and BICLA responders compared with non-responders.

Change from baseline to week 52 in (FIG. 30A) SLEDAI-2K and (FIG. 30B) PGA. Error bars represent 95% CI values. Mean differences calculated using the LS method, CI values, and nominal P values calculated using a mixed model for repeated measures. BICLA: British Lupus Group Comprehensive Assessment for Lupus; BILAG: British Lupus Assessment Group; CI: confidence interval; LS: least squares method; PGA: Physician Global Assessment; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000. FIG. 31. Patients with a CLASI-A response at week 52 (defined as a decrease of 50% or greater from baseline to week 52) among patients with a CLASI-A score of 10 or greater at baseline.

Response rates, CIs, and nominal P-values were calculated using the stratified Cochran-Mantel-Haenszel approach. fig. 31B. Change in mean number of joints calculated using the LS method from baseline to week 52 for active (defined as a joint with swelling and tenderness), tender, and swollen joints. Error bars represent 95% CI values. Mean differences calculated using the LS method, CI values, and nominal P values calculated using a repeated measures mixed model. BICLA: BILAG-based comprehensive lupus assessment; BILAG-2004: British Lupus Assessment Group 2004; CI: confidence interval; CLASI-A: activity according to the cutaneous lupus erythematosus prevalence and severity index; LS: least squares method. Response according to CLASI-A and joint count values between BICLA responders and BICLA non-responders. A.

Detailed description

The present invention relates to methods and compositions for the treatment of systemic lupus erythematosus (SLE). In particular, the present invention relates to methods comprising administering anifrolumab to a subject in need thereof.

When used according to the present invention, unless otherwise indicated, all technical and scientific terms should be understood to have the same meaning as commonly understood by one skilled in the art. Unless the context otherwise requires, terms in the singular will include the plural form, and terms in the plural will include the singular form.

Without limiting the present invention, a number of embodiments of the present invention are described herein for purposes of illustration.

Subject.

The term subject is intended to include humans and non-human animals, particularly mammals. The subject may be an adult human patient. The subject may be a patient with moderate to severe SLE.

Treatment.

- 11 046025

As used herein, the terms treatment or treat refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include subjects suffering from SLE, as well as subjects predisposed to SLE or subjects in whom SLE needs to be prevented. In some embodiments, the methods disclosed herein can be used to treat SLE.

Introduction.

As used herein, the terms administration or administration refer to providing, contacting and/or delivering a compound or compounds by any suitable route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic , through inhalation and implants.

Pharmaceutical composition.

As used herein, the term pharmaceutical composition refers to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a subject. In some embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of the present invention.

As used herein, the terms pharmaceutically acceptable carrier or physiologically acceptable carrier refer to one or more materials of the composition suitable for effecting or enhancing the delivery of one or more antibodies of the present invention.

Antigen binding fragment.

The term antigen-binding fragment refers to one or more antibody fragments that retain the ability to specifically bind an antigen. Examples of antigen binding fragments include the following: Fab fragment, F(ab')2 fragment, Fd fragment, Fv fragment, dAb fragment, and scFv. Systemic lupus erythematosus (SLE).

Systemic lupus erythematosus (SLE) is a chronic multisystem disabling autoimmune rheumatic disease of unknown etiology. Systemic lupus erythematosus predominantly affects women of childbearing age, with a recent review reporting that the female to male ratio of childbearing age is approximately 12:1. Accurate data on the current incidence and prevalence of SLE are largely lacking, but there are numerous indications that SLE is more common in non-Caucasian populations; for example, in the United States of America (USA), SLE is more common in African Americans, Americans, and Asians than in Caucasians. As a result, the prevalence of SLE varies among countries. In addition, variation in the prevalence of SLE across countries appears to be influenced by race, genetic differences, complex socioeconomic factors, and age; The incidence among women is usually highest between the ages of 15 and 44 years.

Clinical manifestations of SLE may include constitutional symptoms, alopecia and rashes, serositis, inflammatory arthritis, renal disease, systemic vasculitis, lymphadenopathy, splenomegaly, hemolytic anemia, cognitive dysfunction, and other central nervous system (CNS) lesions. These disease manifestations account for a significant burden of disease and can cause decreased physical functioning, job loss, decreased health-related quality of life (HRQoL), and a reduction in life expectancy of approximately 10 years. Increased hospitalizations and adverse drug events, including long-term use of oral corticosteroids (OCS) and other immunosuppressive treatments, add to the disease burden in SLE. Currently, belimumab is the only new treatment for SLE that has been approved by the US Food and Drug Administration (FDA) in the approximately 50 years since hydroxychloroquine was approved for use in discoid lupus and SLE . The current standard of care for SLE (SOC SLE) otherwise consists of medications used off-label for lupus erythematosus.

Various forms of disease activity in SLE have been identified. A cohort study by Petri et al identified three forms of SLE activity: chronic active, relapsing-remitting, and long-term quiescent. The chronic active form was the most common form, accounting for approximately half of the total person-years observed in this SLE cohort study. Mean disease activity was moderately severe in patients with chronic active disease, suggesting significant morbidity in this subgroup. In addition, most patients with chronic active disease experienced overlapping moderate to severe deterioration during follow-up. The second, relapsing-remitting form of the disease was observed in just over a quarter of patients, and the average disease activity was characterized by a tendency to soften during treatment.

- 12,046,025 periods of disease remission. The least common form was long-term dormant, which occurred in just under a quarter of patients.

Although off-label therapy has improved in recent years, the long-term prognosis remains poor. Compared with the general population, overall mortality in SLE is increased with a standardized mortality ratio (SMR; defined as the ratio of observed to expected deaths) of 2.4 in a large international cohort of 9457 patients followed for more than 70,000 patient-years . In this study, mortality varied by geographic region and was higher in women, patients aged <40 years (SMR 10.7, 9.5–11.9, 95% confidence interval [CI]), and patients with duration disease for less than 1 year (SMR equal to 5.4, 4.7-6.3, 95% CI). The main causes of death were diseases of the circulatory system (SMR equal to 1.7, 1.5-1.9, 95% CI), infections (SMR equal to 5.0, 3.7-6.7, 95% CI) and causes kidney related (SMR 7.9, 5.5-11.0, 95% CI). Other prospective studies have reported increased mortality rates among SLE patients with severe and/or active disease.

There is a significant unmet medical need for a treatment for SLE, especially in patients with moderate to severe disease. Belimumab is the only new treatment for SLE that has been approved by the FDA in the approximately 50 years since hydroxychloroquine was approved for use in discoid lupus and SLE. Many of the agents currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate/mycophenolic acid mofetil, have not been approved for the treatment of this disease. Other available treatments include nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics for fever, arthralgia and arthritis, and topical sunscreens to minimize photosensitivity. Antimalarials (eg, hydroxychloroquine) and corticosteroids may be added to control arthralgia, arthritis, and types of rashes. Patients with moderate to severe disease often find it difficult to taper off corticosteroids completely, which cause long-term morbidity and may contribute to early mortality from cardiovascular disease. Even low dose prednisone when used as a long-term treatment carries an increased risk of side effects.

Clinical trials.

Phase 2/Phase II/Basic studies.

Phase II studies collect preliminary efficacy data. In phase 2 studies, researchers administer a drug to a group of patients with the disease or condition for which the drug is being developed. Study data, typically involving several hundred patients, are not large enough to demonstrate whether a drug will provide a beneficial effect. Instead, phase 2 studies provide researchers with additional safety data. Researchers use these data to refine research questions, develop study methods, and develop new phase 3 study protocols.

Phase 3/Phase III/basic studies or trials.

Researchers are designing phase 3 studies to demonstrate whether a product provides a beneficial effect in treating a specific population. These studies, sometimes called baseline studies, include between 300 and 3,000 participants. Phase 3 studies provide most of the safety data. In previous studies, it is possible that less common side effects may have gone undetected. Because these studies are larger and longer, the results are more likely to show long-term or rare side effects. Regulatory authorities such as the EMA and FDA typically require a Phase III clinical trial demonstrating that the product is safe and at least as effective (if not better) than available drugs before approving a new drug. Phase III clinical trials usually fail even if they follow a successful phase II clinical trial.

CLASI (cutaneous lupus erythematosus prevalence and severity index).

CLASI is a tool used to measure disease severity and response to treatment. A reduction of 4 points or 20% in the CLASI activity score is generally considered the threshold for classifying subjects as treatment responders. In specific embodiments, treatment with anifrolumab results in at least a 50% reduction in the subject's CLASI score compared to the subject's score at baseline.

CLASI is a validated index used to assess skin lesions in SLE and consists of 2 separate scores: the first summarizes the inflammatory activity of the disease; the second is a measure of the damage caused by the disease. The activity score takes into account erythema, desquamation/hypertrophy, mucosal lesions, recent hair loss and non-scarring alopecia. The damage indicator represents dyspigmentation, scarring

- 13 046025 nia/atrophy/panniculitis and scarring of the scalp. Subjects are asked if their dyspigmentation lasted 12 months or longer, in which case the dyspigmentation score is doubled. Each of the above parameters is measured in 13 different anatomical sites, included specifically because they are most commonly affected in cutaneous lupus erythematosus (CLE). The most severe lesion is measured in each area.

In specific embodiments, treatment with anifrolumab reduces the subject's CLASI score by at least week 8, 12, 24, 36, 48, or week 52 of treatment. In certain embodiments, treatment with anifrolumab reduces a subject's CLASI score by at least week 8. In certain embodiments, treatment with anifrolumab reduces a subject's CLASI score by at least week 12.

In specific embodiments, provided herein is a method of treating systemic lupus erythematosus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of anifrolumab, wherein the treatment results in a reduction in a cutaneous lupus erythematosus prevalence and severity index (CLASI) score compared to with a patient receiving placebo.

Corticosteroids for oral use.

Oral corticosteroids include prednisone, cortisone, hydrocortisone, methylprednisolone, prednisolone, and triamcinolone.

In specific embodiments, provided herein is a method of treating systemic lupus erythematosus in a subject in need thereof, wherein the subject is treated with an oral corticosteroid, comprising administering to the subject a therapeutically effective amount of anifrolumab, wherein the treatment results in a reduction in the subject's oral corticosteroid dosage to at least 5.5 mg/day or less, 6.5 mg/day or less, 7.5 mg/day or less, or 8.5 mg/day or less. In specific embodiments, the subject's oral corticosteroid dosage is reduced to at least 7.5 mg/day or less. In specific embodiments, the treatment results in a reduction in the subject's oral corticosteroid dosage from 10 mg/day or more to 7.5 mg/day or less.

In specific embodiments, provided herein is a method of treating systemic lupus erythematosus in a subject in need thereof, wherein the subject is treated with an oral corticosteroid, comprising administering to the subject a therapeutically effective amount of anifrolumab, wherein the treatment results in a reduction in the subject's oral corticosteroid dosage to at least 5.5 mg/day or less, a dose of prednisone or prednisone equivalent of 6.5 mg/day or less, a dose of prednisone or prednisone equivalent of 7.5 mg/day or less, or a dose of prednisone or prednisone equivalent, 8.5 mg/day or less. In specific embodiments, the subject's oral corticosteroid dosage is reduced to at least 7.5 mg/day or less. In specific embodiments, the treatment results in a reduction in the subject's oral corticosteroid dosage from a prednisone or prednisone equivalent dose of 10 mg/day or more to 7.5 mg/day or less.

Examples of equivalent doses of oral prednisone are shown in Table. 2.

table 2

Examples of equivalent doses of oral prednisone

Oral prednisone and equivalents Equivalent dose Oral prednisone 7.5 mg 10 mg 20 mg 30 mg 40 mg Cortisone 37.5 mg 50 mg 100 mg 150 mg 200 mg Hydrocortisone 30 mg 40 mg 80 mg 120 mg 160 mg Methylprednisolone 6 mg 8 mg 16 mg 24 mg 32 mg Prednisolone 7.5 mg 10 mg 20 mg 30 mg 40 mg Triamcinolone 6 mg 8 mg 16 mg 24 mg 32 mg

Painful and swollen joints.

The number of swollen and tender joints is based on a count of left and right shoulder, elbow, wrist, metacarpophalangeal (MCP) 1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP) 1, PIP2, PIP3, PIP4, PIP5 joints of the upper extremities , as well as the left and right knees of the lower extremities. An active joint for joint count assessment is defined as a joint with tenderness and swelling. In specific embodiments, provided herein is a method of treating systemic lupus erythematosus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of anifrolumab, wherein the treatment results in

- 14 046025 improvement from baseline in the number of painful joints and the number of swollen joints by at least 50% compared to a patient taking placebo.

Dosage schedules.

The dose of anifrolumab to be administered to a subject will vary, in part, depending on the size (body weight, body surface area, or organ size) and condition (age and general health) of the subject.

In specific embodiments, the subject is administered one or more fixed doses of anifrolumab, where the dose is 150, 200, 250, 300, or 350 mg. In some embodiments, the subject is administered one or more fixed doses of anifrolumab, where the dose is 300 mg.

In specific embodiments, anifrolumab is administered over a two-week treatment period, over a four-week treatment period, over a six-week treatment period, over an eight-week treatment period, over a twelve-week treatment period, over a twenty-four week treatment period, or over a one-year or longer treatment period. . In specific embodiments, anifrolumab is administered over a three-week treatment period, over a six-week treatment period, over a nine-week treatment period, over a twelve-week treatment period, over a twenty-four week treatment period, or over a one-year or longer treatment period. In specific embodiments, anifrolumab is administered for at least 52 weeks.

In specific embodiments, anifrolumab is administered once per week, once every two weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks.

Methods of administration.

When used for in vivo administration, the compositions of the present invention must be sterile. The compositions of the present invention can be sterilized by various sterilization methods, including, for example, sterilizing filtration or irradiation. In one embodiment, the composition is sterilized by filtration using a pre-sterilized filter with a pore diameter of 0.22 microns. Sterile injectable compositions can be formulated according to standard pharmaceutical practice, as described in Remington: The Science & Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, (2005).

In some embodiments, the type I IFN inhibitor may be formulated for specific routes of administration, such as oral, nasal, pulmonary, topical (including buccal and sublingual), rectal, vaginal, and/or parenteral administration. As used herein, the terms parenteral administration and parenterally administered refer to routes of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

In some embodiments, anifrolumab may be formulated for specific routes of administration, such as oral, nasal, pulmonary, topical (including buccal and sublingual), rectal, vaginal, and/or parenteral administration. As used herein, the terms parenteral administration and parenterally administered refer to routes of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

Compositions.

The compositions may be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. The actual dosage levels of the active ingredients in the composition of the present invention can be varied to provide an amount of the active ingredient that is effective to achieve the desired therapeutic response in a particular subject, composition, and route of administration without causing toxicity to the subject (e.g., a therapeutically effective amount). Dosages may also be administered by continuous infusion (eg, using a pump). The dose administered may also depend on the route of administration.

The pharmaceutical composition may contain approximately 150 mg/ml anifrolumab.

The pharmaceutical composition may contain 50 mM lysine-HCl.

The pharmaceutical composition may contain 130 mM trehalose dihydrate.

The pharmaceutical composition may contain 0.05% polysorbate 80.

The pharmaceutical composition may contain 25 mM histidine/histidine-HCl.

The pharmaceutical composition may have a pH value of 5.9.

- 15 046025

Interferon level test.

Type I IFN is considered important in the pathogenesis of SLE disease, and anifrolumab targets inhibition of this signaling pathway. To understand the relationship between type I IFN expression and response to anti-IFN antibody therapy, it is necessary to know whether a subject's disease is caused by activation of type I IFN. However, direct measurement of target protein levels remains problematic. For this reason, a transcript-based marker was developed to assess the effect of target protein overexpression on a specific set of mRNA markers. Expression of these markers is readily detected in whole blood and shows correlation with expression in diseased tissue such as skin in SLE. The bimodal distribution of transcript-derived measures in subjects with SLE supports the identification of high and low IFN subpopulations by the IFN test. The type I IFN test is described in WO 2011028933 A1, which is incorporated herein by reference in its entirety.

Anifrolumab.

Anifrolumab is a monoclonal antibody that targets IFNAR1 (interferon α, β and ω receptor). Disclosure relating to anifrolumab can be found in US Pat. No. 7,662,381 and US Pat. No. 9,988,459, which are incorporated herein by reference.

Anifrolumab is a monoclonal antibody that binds to IFNAR with high affinity and specificity. This antibody is an IFNAR-blocking (antagonistic) antibody and blocks the activity of receptor ligands, namely type I interferons such as interferon-a and interferon-β. Thus, anifrolumab mediates negative regulation of IFNAR signaling and thus suppression of IFN-induced genes.

Table 3 Anifrolumab sequences

VH of anifrolumab (SEQ IDNO: 1) EVQLVOSGAEVKKPGESLKISCKGSGYIFTNYWIAWVROMP GKGLESMG11YPGDSDIRYSPSFQGOVTISADKSITTAYLOWS SLKASDTAMYYCARHDIEGFDYWGRGTLVTVS S VL of anifrolumab (SEQ Ш NO: 2) EIVLTOSPGTLSLSPGERATLSCRASOSVSSSFFAWYOQKPG QAPRLLIYGASSRATGIPDRLSGSGSGTDFTLTITRLEPEDFA VYYCOQYDSSAITFGOGTRLEIK HCDR1 (SEQ Ш NO: 3) NYWIA HCDR2 (SEQ Ш NO: 4) 11YPGDSDIRYSPSFQG HCDR3 (SEQ Ш NO: 5) HDIEGFDY LCDR1 (SEQ Ш NO: 6) RASQSVSSSFFA LCDR2 (SEQ Ш NO: 7) GASSRAT LCDR3 (SEQ Ш NO: 8) QQYDSSAIT

Thus, anifrolumab is an antibody comprising HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, respectively (or a functional variant thereof), and LCDR1, LCDR2 and LCDR3 of SEQ ID NO : 6, SEQ ID NO: 7 and SEQ ID NO: 8 respectively (or a functional variant thereof). In more detail, anifrolumab referred to herein is an antibody comprising VH of SEQ ID NO: 1 and VL of SEQ ID NO: 2 (or a functional variant thereof).

The present invention covers antibodies as defined herein containing the listed CDR sequences or variable heavy chain and variable light chain sequences (reference (anifrolumab) antibodies), as well as functional variants thereof. The functional variant binds to the same target antigen as the reference (anifrolumab) antibody. Functional variants may have a different affinity for the target antigen compared to the reference antibody, but substantially the same affinity is preferred.

In one embodiment, functional variants of the reference (anifrolumab) antibody exhibit a sequence change in one or more CDRs compared to the corresponding reference CDR sequences. Thus, a functional variant of an antibody may contain a functional variant of a CDR. When the term functional variant is used in the context of a CDR sequence, it means that the CDR is characterized by no more than 2, preferably no more than 1 amino acid difference compared to the corresponding reference CDR sequence and, in combination with the remaining 5 CDRs (or variants thereof), provides the ability of the antibody variant to bind to the same target antigen as the reference (anifrolumab) antibody and preferably exhibits the same affinity for the target antigen as that

- 16 046025 pubic (anifrolumab) antibody.

Without being limited by any theory, because anifrolumab targets (eg, blocks or antagonizes) IFNAR, anifrolumab is believed to treat a disease (such as SLE) by blocking signal transduction initiated by type I interferons (IFNs). Type I interferons are known to be important factors in inflammation (eg, through coordinating the type I interferon response) and thus play a key role in the immune system. However, dysregulation of type I IFN signaling can lead to aberrant (eg, aberrantly high) levels of inflammation and autoimmune response. Such dysregulation of type I IFNs has been reported in numerous autoimmune diseases.

For example, a variant of the reference (anifrolumab) antibody may contain:

Heavy chain CDR1 having no more than 2 amino acid differences compared to SEQ ID NO: 3;

Heavy chain CDR2 having no more than 2 amino acid differences compared to SEQ ID NO: 4;

Heavy chain CDR3 having no more than 2 amino acid differences compared to SEQ ID NO: 5;

Light chain CDR1 having no more than 2 amino acid differences compared to SEQ ID NO: 6;

Light chain CDR2 having no more than 2 amino acid differences compared to SEQ ID NO: 7; And

Light chain CDR3 having no more than 2 amino acid differences from SEQ ID NO: 8;

wherein the antibody variant binds to the target of anifrolumab (eg, IFNAR) and preferably with the same affinity.

Preferably, the reference (anifrolumab) antibody variant may comprise:

Heavy chain CDR1 having no more than 1 amino acid difference from SEQ ID NO: 3;

Heavy chain CDR2 having no more than 1 amino acid difference from SEQ ID NO: 4;

Heavy chain CDR3 having no more than 1 amino acid difference from SEQ ID NO: 5;

Light chain CDR1 having no more than 1 amino acid difference from SEQ ID NO: 6;

Light chain CDR2 having no more than 1 amino acid difference from SEQ ID NO: 7; And

Light chain CDR3 having no more than 1 amino acid difference from SEQ ID NO: 8;

wherein the antibody variant binds to the target of anifrolumab (eg, IFNAR) and preferably with the same affinity.

In one embodiment, the antibody variant may have a total of no more than 5, 4, or 3 amino acid differences in its CDR compared to the corresponding reference (anifrolumab) antibody, provided that there are no more than 2 (preferably no more than 1) amino acid differences per CDR. Preferably, the antibody variant has a total of no more than 2 (more preferably no more than 1) amino acid differences in its CDR compared to the corresponding reference (anifrolumab) antibody, provided that there are no more than 2 amino acid differences per CDR. More preferably, the antibody variant has a total of no more than 2 (more preferably no more than 1) amino acid differences in its CDR compared to the corresponding reference (anifrolumab) antibody, provided that there is no more than 1 amino acid difference per CDR.

The amino acid difference may be an amino acid substitution, insertion or deletion. In one embodiment, the amino acid difference is a conservative amino acid substitution described herein.

In one embodiment, the antibody variant may have a total of no more than 5, 4, or 3 amino acid differences in its framework regions compared to the corresponding reference (anifrolumab) antibody, provided that there are no more than 2 (preferably no more than 1) amino acid differences to the frame area. Preferably, the antibody variant has a total of no more than 2 (more preferably no more than 1) amino acid differences in its framework regions compared to the corresponding reference (anifrolumab) antibody, provided that there are no more than 2 amino acid differences per framework region. More preferably, the antibody variant has a total of no more than 2 (more preferably no more than 1) amino acid differences in its framework regions compared to the corresponding reference (anifrolumab) antibody, provided that there is no more than 1 amino acid difference

- 17 046025 differences per frame area.

Thus, a variant antibody may comprise a heavy chain variable region and a light chain variable region as described herein, wherein:

the heavy chain is characterized by no more than 14 amino acid differences (no more than 2 amino acid differences in each CDR and no more than 2 amino acid differences in each framework region) compared to the heavy chain sequence herein; and the light chain is characterized by no more than 14 amino acid differences (no more than 2 amino acid differences in each CDR and no more than 2 amino acid differences in each framework region) compared to the light chain sequence herein;

wherein the antibody variant binds to the same target antigen as the reference (anifrolumab) antibody (eg, IFNAR), and preferably with the same affinity.

Heavy or light chain variants may be referred to as functional equivalents of the reference heavy or light chains.

In one embodiment, the antibody variant may comprise a heavy chain variable region and a light chain variable region as described herein, wherein:

the heavy chain is characterized by no more than 7 amino acid differences (no more than 1 amino acid difference in each CDR and no more than 1 amino acid difference in each framework region) compared to the heavy chain sequence herein; and the light chain is characterized by no more than 7 amino acid differences (no more than 1 amino acid difference in each CDR and no more than 1 amino acid difference in each framework region) compared to the light chain sequence herein;

wherein the antibody variant binds to the same target antigen as the reference (anifrolumab) antibody (eg, IFNAR), and preferably with the same affinity.

Thus, in one embodiment, the type I interferon receptor inhibitor is anifrolumab or a functional variant thereof.

SRI (systemic lupus erythematosus patient response index to treatment of 4 or greater).

A subject achieves SRI(4) if all of the following criteria are met:

a decrease in SLEDAI-2K of 4 points or more from baseline;

no new organ system is affected, as determined by 1 or more BILAG-2004 A's or 2 or more BILAG-2004 B's compared to baseline using BILAG-2004;

no worsening from baseline in subjects' disease activity, such as lupus, as defined by an increase of 0.30 points or more on the 3-point PGA VAS.

SRI(X) (X equals 5, 6, 7 or 8) is determined by the proportion of subjects meeting the following criteria:

a decrease in SLEDAI-2K of X points or more compared to baseline;

no new organ systems are affected, as determined by 1 or more BILAG-2004 A's or 2 or more BILAG-2004 B's compared to baseline using BILAG-2004;

no worsening from baseline in subjects' disease activity, such as lupus, as defined by an increase of 0.30 points or more on the 3-point PGA VAS.

BILAG-2004: British Lupus Assessment Group 2004.

BILAG-2004 is a translational index assessing 9 organ systems (general, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmological, renal and hematological), which allows recording changes in the severity of clinical manifestations. It has ranking scales in its structure and is not characterized by a general indicator; rather, it provides a visual representation of disease activity in various organ systems by comparing the last 4 weeks with the 4 weeks immediately preceding them. It is based on the principle of physician intention to treat and allows for the categorization of disease activity into 5 different levels from A to E:

Grade A represents very active disease requiring immunosuppressive medications and/or a dose of prednisone or equivalent of 20 mg/day or more;

grade B represents moderate disease activity requiring a lower dose of corticosteroids, topical steroids, immunosuppressants, antimalarials, or NSAIDs;

grade C indicates mild stable disease;

grade D means no disease activity, but the system has been previously affected;

grade E indicates no current or previous disease activity.

- 18 046025

Although the BILAG-2004 was designed based on the intention-to-treat principle, treatment does not influence the score index. The assessment is affected only by the presence of active manifestations.

BICLA: BILAG-based comprehensive lupus assessment (BICLA).

BICLA is a composite index that was originally derived from expert consensus on disease activity indices. BICLA response is defined as (1) at least one grade of improvement in BILAG scores at baseline in all body systems with moderate to severe disease activity at baseline (eg, all A (severe disease) scores fall to B (moderate disease) ), C (mild illness) or D (inactivity), and all B scores drop to C or D); (2) no new A BILAG score or more than one new B BILAG score; (3) no worsening of SLEDAI total score from baseline; (4) no significant worsening (10% or less) as assessed by physicians' global assessment; and (5) no treatment failure (initiation of off-protocol treatment).

Specifically, a subject is a BICLA responder if the following criteria are met:

reduction of all BILAG-2004 A scores at baseline to B/C/D and BILAG-2004 B scores at baseline to C/D and no BILAG-2004 deterioration in other organ systems as determined by 1 new A as per BILAG-2004 or more than 1 new clause B as per BILAG-2004;

no worsening in SLEDAI-2K from baseline, as defined by an increase in SLEDAI-2K from baseline of more than 0 points;

no worsening from baseline in subjects' disease activity, such as lupus, as defined by an increase of 0.30 points or more on the 3-point PGA VAS;

no discontinuation of the investigational product or use of restricted medications beyond the protocol-allowed threshold prior to evaluation.

In specific embodiments, treatment with anifrolumab improves a subject's BICLA response rate by at least week 8, 12, 24, 36, 48, or week 52 of treatment. In specific embodiments, treatment with anifrolumab improves the subject's BICLA response rate by at least week 8.

In specific embodiments, although the subject demonstrates an improvement in BICLA response, the subject does not demonstrate an improvement in the SRI4 index of the systemic lupus erythematosus patient's response to treatment.

In specific embodiments, provided herein is a method of treating systemic lupus erythematosus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of anifrolumab, wherein the treatment results in an improvement in treatment response rate as measured by the BILAG-based Comprehensive Lupus Assessment (BICLA) versus with a patient receiving placebo. The improvement in BILAG response rate may be statistically significant. The improvement in BILAG response rate may be statistically significant after accounting for multiple comparisons. An improvement in BILAG response rate may be statistically significant, where statistical significance is defined as p less than 0.05 or p less than 0.005.

Patient-reported outcomes (PROs).

In specific embodiments, treatment with anifrolumab results in MCR. In specific embodiments, treatment with anifrolumab results in PCR.

The SF-36-v2 (Acute) is a 36-item multi-item questionnaire that measures health status in 8 categories: physical functioning, physical health-related role functioning limitations, physical pain, general health perception, vitality, social functioning , limitations in role functioning associated with emotional problems, and mental health. It provides scale scores for each of these 8 health categories, as well as overall measures of physical and mental health: the Physical Health Index and the Mental Health Index.

The FACIT-F is a 13-item subject-administered questionnaire assessing the impact of fatigue over the previous 7 days. Responses range from 0 (not at all) to 4 (very much). The final scores are the sum of responses and range from 0 to 52; higher scores indicate better QoL (Yellen et al, 1997). Changes in indicators of more than 3 points are considered clinically significant.

The PtGA is a single-item question that considers all the ways in which diseases and health conditions can affect a patient at a given point in time. The patient should consider the previous week when answering this question. Responses range from very good to very poor on the 100mm VAS scale. The clinician and subject must complete the PGA and PtGA, respectively, independently of each other.

- 19 046025

A good clinical response (MCR) is a BICLA score of C or better at week 24, maintained with no new A or B scores from week 24 to week 52. A partial clinical response (PCR) is a maximum of 1 BICLA score at week 24. persisting with no new Category A score or more than 1 new Category B score until week 52.

Physician Global Assessment of Disease Activity (PGA) refers to an assessment where the physician assesses the subject's psoriatic arthritis (PsA) status using a visual analog scale (VAS). The subject is assessed according to his current degree of arthritis. VAS is tied to verbal descriptions ranging from very good to very poor.

The method may include measuring PRO in a subject before and after administration of anifrolumab. PROs may include assessment using the subject's Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire, Short Form 36 Health Questionnaire version 2 (SF-36-v2), the Mental Health Index (MCS), and/or a measure representing the physical health index (PCS), according to the SF-36.

Examples

The following examples are illustrative of specific embodiments of the present invention and various ways of applying them. They are presented for explanatory purposes only and should not be construed as limiting the scope of the present invention in any way.

Example 1. Suppression of type I interferon in active systemic lupus erythematosus.

In TULIP-1 (NCT02446912), a phase 3, double-blind, randomized, controlled trial in adults with moderate to severe SLE, regardless of standard of care (SOC) treatment, patients received (2:1:2) placebo or anifrolumab ( 150 mg or 300 mg) intravenously once every 4 weeks for 48 weeks. Stable SOC was continued except for mandatory attempts to taper oral corticosteroids (OCS) for patients receiving prednisone/equivalent at 10 mg/day or more at baseline. The primary endpoint was the difference between SLE Response Index (SRI[4]) response rates between anifrolumab 300 mg and placebo at week 52. Safety was also assessed.

Patients were aged 18-70 years and met the American College of Rheumatology classification criteria for SLE (Hochberg MC. Arthritis Rheum 1997; 40(9): 1725; Tan EM, et al. Arthritis Rheum 1982; 25(11): 1271- 7). Requirements included a SLE Disease Activity Index 2000 (SLEDAI-2K) (Gladman DD, et al. J Rheumatol 2002;29(2):288-91) score of 6 or greater (excluding scores for fever, lupus headache, or organic brain syndrome), a SLEDAI-2K clinical index score of 4 or greater (excluding laboratory test scores); 1 British Lupus Assessment Group (BILAG) 2004 organ damage category A score (Isenberg DA, et al. Rheumatology (Oxford) 2005; 44(7): 902-6) or more and/or 2 category B or greater (Yee CS, Cresswell L, et al. Rheumatology (Oxford) 2010; 49(9): 1665-9), physician global assessment (PGA) disease activity score (Petri M, et al. N Engl J Med 2005;353(24):2550-8) of 1 or greater (on a scale of 0-3). Patients were seropositive for antinuclear antibodies, or anti-double-stranded DNA antibodies (anti-dsDNA antibodies), or anti-Smith antigen antibodies and were receiving stable treatment with at least one of the following: prednisone or equivalent, antimalarial, azathioprine, mizoribine, mycophenolate mofetil/mycophenolic acid or methotrexate.

To ensure that the investigational product had sufficient time to achieve clinical benefit, we were allowed to administer 1 loading dose of corticosteroids with a gradual dose reduction from week 0 (day 1) to week 12 for increased SLE disease activity/non-SLE disease activity. Patients who received more than 1 loading dose of steroid and tapered from week 0 (day 1) to week 12 or who met any of the above criteria could continue in the study but were considered non-responders during follow-up assessments disease activity, regardless of whether a loading dose of OCS was administered due to increased SLE activity or for reasons unrelated to SLE. From week 12 to week 40, no corticosteroid dose increases were permitted for increased SLE activity. A patient receiving a dose of steroid greater than his or her dose at week 0 (day 1) could continue to participate in the study but was considered a nonresponder at subsequent assessments of disease activity. After week 40, no OCS dose increases were allowed (except for monitoring of adverse events (AEs) or as prophylaxis for adrenal insufficiency). Patients who received an escalated dose of OCS after week 40 were considered non-responders for subsequent disease activity assessments.

Beginning at week 8 and continuing through week 40, attempts to gradually taper the steroid dose to an OCS dose of 7.5 mg/day or less were necessary in all patients with an OCS dose formulation

- 20 046025 10.0 mg/day or more at baseline, if at least 1 of the following criteria was met:

SLEDAI-2K activity that worsened from baseline in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, fever, thrombocytopenia, or hemolytic anemia, or gastrointestinal activity).

Recently affected organ system(s), based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), excluding serological abnormalities (double-stranded DNA antibodies [dsDNA], hypocomplementemia).

Moderate to severe skin disease, as reflected by an activity score, an index of the prevalence and severity of cutaneous lupus erythematosus, of 10 or greater.

Moderate to severe arthritis, as reflected by an active joint count of 8 or more painful and/or swollen joints.

IFNGS type I screening classification was determined by a central laboratory through a quantitative polymerase chain reaction test with DNA isolated from whole blood with 4 analytically validated genes (IFI27, IFI44, IFI44L, RSAD2) (Furie R, Arthritis Rheum 2017; 69( 2): 376-86; Yao Y, et al. Arthritis Res Ther 2010; 12 Suppl 1: S6). Based on the results of phase 2 pharmacokinetic/pharmacodynamic modeling and the benefit-risk profile, 300 mg anifrolumab was selected as the therapeutic dosage; the 150 mg dose was included to elucidate the dose-response relationship. Infusions were administered once every 4 weeks until week 48, with final assessments at week 52.

The primary efficacy measure was the difference in the percentage of patients receiving 300 mg anifrolumab or placebo who achieved SLE Response Index (SRI)(4) responses at week 52. ³⁰ SRI(4) response is an indicative estimate. defined as a decrease in SLEDAI-2K of 4 points or more, less than 1 new BILAG-2004 Organ Damage Category A score or less than 2 new BILAG-2004 Organ Damage Category B scores, an increase in PGA of less than 0 3 points from baseline, no use of restricted medications above protocol-allowed thresholds, and no discontinuation of study product treatment.

Key secondary endpoints were adjusted for multiple comparisons and included the percentage of patients with SRI(4) responses at week 52 in the subgroup with high IFNGS test results; sustained reduction in OCS dosage to 7.5 mg/day or less from week 40 to week 52 among patients with a dosage of 10 mg/day or more at baseline; a 50% or greater reduction in cutaneous lupus erythematosus erythematosus prevalence and severity index (CLASI) ³¹ activity at week 12 in patients with a CLASI score of 10 or greater at baseline and SRI(4) responses at week 24; and annual exacerbation rates up to week 52 (1 new BILAG 2004 organ damage A or greater or 2 new BILAG 2004 organ damage B or greater compared to the previous visit ³² .

Prespecified secondary endpoints, not adjusted for multiple comparisons, were: response according to BILAG-based Comprehensive Lupus Assessment (BICLA) at week 52, higher SRI thresholds at week 52 (5-9), change in physician global assessment ( PGA) from baseline to week 52, change in SLEDAI-2K from baseline to week 52, change in BILAG total score, 50% or greater reduction in CLASI activity score from baseline to week 52, and decrease in scores number of active joints (50% or greater reduction or change in number of joints from baseline to week 52). In addition, SRI(4) responses in the anifrolumab 150 mg group were assessed at week 52.

Safety assessments included adverse events, laboratory evaluations, and vital signs. Pharmacodynamic neutralization of type I IFNGS was assessed through a 21-gene assay. Anti-dsDNA, C3, C4, CH50 and anti-drug antibody (ADA) levels were measured.

Efficacy analyzes included patients who were randomized to receive 1 dose or more of study treatment; patients were analyzed according to randomized treatment (modified intent-to-treat group). Planned efficacy analyzes compared anifrolumab 300 mg to placebo. The primary endpoint compared SRI(4) responses to 300 mg anifrolumab and placebo at week 52 using a stratified Cochran-Mantel-Haenszel (CMH) test with the same stratification factors used for randomization. To adjust for stratification factors, the CMH method uses a stratum-weighted average of stratum-specific differences in proportions, where strata are defined based on 8 possible combinations of 3 factors. Key secondary endpoints

- 21 046025 was analyzed in a similar manner, with the exception of exacerbation rates, which were analyzed using a negative binomial regression model. The weighted Holm procedure with predefined weights was used to control the Type I error rate at the 0.05 level, adjusting for the effect of multiple comparisons for the primary and primary secondary endpoints. This procedure allowed the alpha of 0.05 to be divided according to the predefined weight values and, after deviations from the original null hypothesis, to reuse the corresponding alpha in proportion to the given weight values.

SRI(4) response rates were compared for anifrolumab 150 mg versus placebo using the previously described CMH analysis strategy. Outcomes that were continuous variables were modeled using repeated measures and adjustment for baseline, treatment group, visit, treatment by visit interaction effects, and stratification factors.

Rules defining restricted drugs were determined prospectively and included in the efficacy endpoints. The original rules used to classify patients responding to treatment based on nonsteroidal anti-inflammatory drugs (NSAIDs) were not consistent with the intent of the protocol and did not adequately classify patients who were taking a new NSAID or receiving an increased dosage of an NSAID as not responders to all binary response endpoints, even if NSAID use was temporary or occurred at the start of the 1-year trial. These rules had no impact on the conduct of the study (i.e., they did not affect medical decisions, patient treatment, or data collection; they only affected data analysis). Following disclosure, the SLE panel and the sponsor assessed the clinical appropriateness of all restricted drug policies and revised them. The main analyzes were repeated (post hoc analyses) using the modified restricted drug guidelines and compared with the results of the original analyses. Additional post hoc analyzes were performed to examine time to first BICLA response maintained to week 52 using a Cox proportional hazards model.

The original restricted drug guidelines specified that starting a new or increasing dose of antimalarials and/or immunosuppressants after 1 day resulted in all participants being classified as non-responders (NR) in all subsequent efficacy assessments. . For corticosteroids, the following criteria were applied:

dosages exceeding the protocol-defined maximum at any time point always resulted in participants being classified as NR upon receipt in all subsequent efficacy assessments.

Patients receiving more than one loading dose of a steroid during the first 12 weeks of treatment or who failed any of the loading dose and taper criteria were classified as NR at subsequent efficacy assessments, regardless of the reason for the loading dose (SLE-related activity or not). SLE-related activity).

From week 12 to week 40, only one loading dose of steroid was allowed for non-SLE symptoms. Patients violating this criterion were classified as NR at subsequent efficacy assessments.

Dose increases after week 40 resulted in classification as NR on subsequent efficacy assessments.

Patients were classified as NR at all subsequent efficacy assessments while receiving NSAIDS.

The overall purpose of the revised drug guidelines used in the post hoc analysis was to align drug guidelines with clinically appropriate use at baseline, with more stringent interpretation closer to the primary endpoint. This revision prevented clinically appropriate drug use at the start of the trial from classifying the participant as a non-responder (NR) at week 52, while ensuring that if patients were taking medications that could confound the efficacy assessment at week 52 , they would have been classified as NR at week 52. For antimalarials and/or immunosuppressants, increasing the dose (or starting a new dose) at any time point resulted in an estimated NR status for the duration of the trial. For oral corticosteroids, the following criteria were applied:

dosages exceeding the protocol-defined maximum dosage at any time point always resulted in the participant being classified as NR upon receipt.

Until week 12, one loading dose of steroid and a gradual tapering were permitted; failure to comply with this condition resulted in the participant being classified as NR for subsequent

- 22 046025 weeks.

In general, dosages above baseline dosages were not permitted from week 12 to week 40; overdosing at baseline resulted in the participant being classified as NR for the remainder of the trial.

After week 40, dosages exceeding the week 40 dosage or use of moderate to strong topical corticosteroids resulted in the participant being classified as NR.

For NSAIDs, initiation of a new NSAID within 14 days of week 52 and documented use on the day before the week 52 assessment resulted in the participant being classified as NR at the week 52 visit. NSAID use before week 50 did not result in the participant being classified as NR.

457 patients were randomized (300 mg anifrolumab, n = 180; 150 mg, n = 93; placebo, n = 184). Achievement of SRI(4) response at week 52 was similar for 300 mg anifrolumab (36.2%, 65/180) and placebo (40.4%, 74/184; P = 0.41) (Figure 1A; Table 1A . 1). Similarly, SRI(4) at week 24 and SRI(4) in patients with high IFNGS did not differ between the anifrolumab and placebo groups. In patients with a baseline OCS dosage of 10 mg/day or greater, sustained dose reduction to 7.5 mg/day or less was achieved in 41.0% (42/103) for anifrolumab 300 mg and in 32. 1% (33/102) with placebo (difference 8.9 [95% CI: -4.1, 21.9]). In patients with a CLASI activity score of 10 or greater at baseline, a 50% or greater reduction in CLASI at week 12 was achieved in 41.9% (24/58) of patients receiving 300 mg anifrolumab and in 24.9% (14/54) patients receiving placebo (difference 17.0 [95% CI: (-0.3, 34.3]). Annual exacerbation rates were 0.60 for anifrolumab and 0.72 for placebo ( rate ratio 0.83 [95% CI: (0.60, 1.14]) Response according to the British Lupus Assessment Group comprehensive lupus assessment was achieved in 37.1% (67/180) of patients receiving 300 mg anifrolumab , compared with 27.0% (49/184) for placebo (difference 10.1 [95% confidence interval (CI): 0.6, 19.7]).

Table 1

Primary, core secondary, and additional secondary efficacy outcomes, including outcomes analyzed using modified restricted use drug guidelines to define non-response

End point Predefined Analysis Analysis with modified rules for use of drugs for restricted use Placebo (n = 184) 300 mg anifrolumab (and equals 180) Difference (95% CI)* Nominal value P-value Placebo (n = 184) 300 mg anifrolumab (n = 180) Difference (95% CI)* Nominal value P-value Primary and basic secondary outcomes -4.2 (- 3.9 (- SRI(4) per week 52, 74/184 14.2, 5.8) 79/184 6.3, n/N (%) ¹ ^ (40.4) 65/180 (36.2) P=0.41 ^J 0.41 (43.0) 84/180 (46.9) 14.1) 0.455 SRI(4) per week 52 y patients with high test results 6.4 (- in a relationship 59/151 -3.4 (- 63/151 4.8, IFNGS, n/N (%) ^§ (39.3) 53/148 (35.9) 14.4, 7.6) 0.55 (41.8) 71/148 (48.2) 17.7) 0.261

- 23 046025

SRI(4) per week 24, 75/184 0.6 (-9.4, 79/184 z,z (- 6.7, n/N (%) ^§ Sustained reduction in OCS dose to target by (40.9) 33/102 74/180 (41.5) 10.6) 0.905 8.9(-4.1, (43.1) 33/102 83/180 (46.4) 13.4) 0.515 16.7 (3.5, weeks 52, n/N (%) ^§JI Reduction in CLASI activity score by 50% or more from BL to wk. 12, n/N (32.1) 14/54 42/103 (41.0) 21.9) 0.180 17.0 (- (32.1) 14/54 50/103 (48.8) 29.8) 0.013 18.7 (1.4, (o/ _o )§L Annual frequency of exacerbations up to (24.9) 24/58 (41.9) 0.3, 34.3) 0.054 0.83 (0.60, (24.9) 25/58 (43.6) 36.0) 0.034 0.83 (0.60, weeks 52§4t>il Additional disease outcomes Answer according to BICLA for the week. 52, 0.72 49/184 0.60 1.14) 0.258 Yu,1 (0.6, 0.72 54/184 0.60 1.14) 0.258 16.4 (6.7, n/N (%) (27.0) 67/180 (37.1) 19.7) N/A (29.6) 83/180 (46.1) 26.2) N/A SRI(5) per week 52, n/N (%) SRI(6) per week 52, 55/184 (30.2) 55/184 54/179 (30.2) 0 (-9.5, N/A 9.6) -1.6 (- 58/184 (31.7) 58/184 72/179 (40.4) 8 6 (- N/A 1,2, 18.5) 7.0 (2.8, n/N (%) SRI(7) per week 52, (30.2) 29/176 51/179 (28.6) 11.1,7.8) N/A 5.1 (-3.7, (31.7) 31/176 69/179 (38.7) 16.8) N/A I.5 (2.4, n/N (%) SRI(8) per week 52, (16.5) 26/174 37/173 (21.6) 13.8) N/A 6.1 (-2.5, (17.6) 29/174 50/173 (29.0) 20.6) N/A I.9 (2.9, n/N (%) PGA change from BL to wk. 52, average value determined by LS method (14.9) n=149 -0.89 36/173 (21.0) 14.7) N/A -0.22 (- n=143 0.36, - (16.5) 49/173 (28.5) 21.0) N/A (SE) ^§§ Change SLEDAI-2K from BL to wk. 52, average value, defined (0.052) n=149 -5.3 -1.11 (0.053) 0.08) N/A n=143 -0.7 (- N/A N/A N/A N/A LS method (0.33) -6.0 (0.34) 1.6,0.2) N/A N/A N/A N/A N/A

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(SE) ^§§ Change in overall indicator according to BILAG from BL to wk. 52, mean (SD) ^§§ -10.7 N/A N/A N/A N/A N/A (7.72) -13.0 (8.01) N/A Decline indicator activity CLASI by 50% 14.2 - or more with BL (- 3.7, 21.4 up to a week 52, n/N 23/54 3.7, 32.2 24/54 (3.7, (%)1 (43.1) 33/58 (57.3) 32.2) N/A (44.6) 38/58 (66.0) 39.1) N/A Decline quantities active (swollen and painful) joints by 50% 20.7 or more by 22/68 14.7 (- 22/68 (4.7, weeks 52, n/N (%)** (32.3) 33/70 (47.0) 1.4, 30.8) N/A (32.3) 37/70 (53.0) 36.7) N/A Change quantities active joints (swollen and painful) with BL up to a week 52, average value, certain n=150 LS method -4.8 n=142 -0.4 (- (SE) ^§§ (0.24) -5.2 (0.24) 1.0, 0.2) N/A N/A N/A N/A N/A

For response rates, differences in response rates and associated 95% CIs were weighted averages and calculated using the Cochran-Mantel-Haenszel stratified approach.

^ Primary endpoint. SRI(4) response was defined as a decrease in SLEDAI2K score of 4 points or more, less than 1 new BILAG-2004 Organ Damage Category A score, or less than 2 new BILAG-2004 Organ Damage Category B scores, an increase PGA score of less than 0.3 points (10%) compared to baseline, as well as no discontinuation of treatment with the study product and no use of drugs for restricted use above the threshold allowed by the protocol.

* Because the primary endpoint was not statistically significant, all other comparisons were nonsignificant according to the prespecified analysis plan.

§ Primary secondary endpoint.

¹ In patients with an OCS dose of 10 mg/day or greater at baseline (prednisone or equivalent).

¹¹ In patients with a CLASI activity score of 10 or greater at baseline.

In patients with 8 or more swollen and 8 or more tender joints at baseline.

Exacerbation was defined as 1 new BILAG-2004 A or more or 2 new BILAG-2004 B or more compared to the previous visit (i.e., worsening from E, D, or C to B in at least two organ systems or worsening from score E, D, C or B to score A in any one organ system compared to the previous visit).

The calculation of the exacerbation frequency did not include drugs for limited use; therefore, the values for the prespecified and post hoc analyzes are the same.

§§ Modeled using repeated measures and adjustment for baseline, treatment group, visit, treatment by visit interaction effects, and stratification factors.

Abbreviations: BICLA stands for BILAG-based Comprehensive Lupus Assessment; BILAG stands for British Lupus Assessment Group; BL means baseline; CI means confidence interval; CLASI stands for cutaneous lupus erythematosus prevalence and severity index; IFNGS stands for interferon-controlled gene expression profile; LS stands for least squares; N/A means no data; OCS stands for oral corticosteroids; PGA stands for Physician Overall Assessment; SD means standard deviation; SE means standard error; SLEDAI-2K stands for Systemic Lupus Erythematosus Disease Activity Index 2000; SRI stands for systemic lupus erythematosus patient response index to treatment; weeks means a week.

In the subpopulation with high IFNGS test results (375/457, 82.1% of the study population), SRI(4) responses at week 52 were similar in patients receiving 300 mg anifrolumab (35.9%, 53/148) and placebo (39.3%, 59/151; difference -3.4 [95% CI: -14.4, 7.6]).

Among patients receiving prednisone or equivalent at 10 mg/day or more at randomization, a numerically greater percentage of patients were in the anifrolumab 300 mg group (41.0%, 42/103) compared with placebo (32.1%, 33/103). 102), OCS dosage reduction to target (7.5 mg/day or less) was achieved and maintained from week 40 to week 52 (difference 8.9 [95% CI: -4.1, 21.9]) (Figs. 3A and 3B). Among patients with CLASI activity scores of 10 or greater at baseline, a reduction of 50% or greater at week 12 was achieved in 41.9% (24/58) in the anifrolumab 300 mg group compared with 24.9% (14 /54) in the placebo group (difference 17.0 [95% CI: 0.3, 34.3]) (Fig. 1C, Table 1). SRI(4) results at week 24 were similar to those at week 52. Annual exacerbation rates as determined by BILAG were numerically lower with anifrolumab than with placebo (0.60 versus 0.72, respectively; rate ratio 0.83 [95% CI: 0.60, 1.14]).

Additional secondary measures of disease improvement are shown at the bottom of the table. 1. Response according to BICLA, a stringent measure of comprehensive disease assessment, was achieved in more patients at week 52 in the anifrolumab 300 mg group (37.1%, 67/180) than in the placebo group (27.0%, 49 /184; difference 10.1 [95% CI: 0.6, 19.7]; Fig. 1E, Table 1). Although SRI(4) responses appeared similar among treatment groups, higher SRI cutoffs were slightly more likely to favor anifrolumab (Table 1). Both SLEDAI-2K and BILAG overall scores showed greater numerical change from baseline to week 52 in the anifrolumab group than in the placebo group (Table 1). Similarly, a numerically greater improvement in PGA scores occurred in the anifrolumab group compared with the placebo group (LS mean change from baseline of -1.11 [SE = 0.053] and -0.89 [SE = 0.052] respectively, difference -0.22 [95% CI: -0.36, -0.08]). Numerical differences in favor of anifrolumab were also observed for the additional CLASI scores and 2 other joint count measures (Table 1).

In the anifrolumab 150 mg group, SRI(4) responses at week 52 were similar to those in the placebo group (37.6% [35/93] and 40.4% [74/184], respectively; difference -2.6 [95] % CI: -14.7, 9.6]). Additional efficacy outcomes for the anifrolumab 150 mg group are presented in Table. 2.

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table 2

Anifrolumab 150 mg arm: efficacy outcomes, including outcomes determined using prespecified and modified rules for defining non-response due to use of ______________restricted drugs______________

Analysis with modified rules of application medicines Preset for limited analysis applications 150 mg 150 mg anifrolumab anifrolumab End point* (n equals 93) (n equals 93) SRI(4) per week 52, n/N (%У 35/93 (37.6) 45/93 (48.4) SRI(4) per week 52 in patients with high test results in regarding IFNGS, n/N (%) 30/76 (39.5) 40/76 (52.6) SRI(4) per week 24, n/N (%) 34/93 (36.6) 40/93 (43.1) Sustained reduction of the OCS dose to the target value per week. 52, η/Ν (%) ^:ϊ 17/48 (35.2) 24/48 (49.6) Reduce CLASI activity score by 50% or more with BL up to a week 12, n/N (%) ^§ 15/30 (50) 16/30 (53.3) Annual frequency of exacerbations up to weeks. 52 (95% C1)“ ^l 0.62 (0.44, 0.87) 0.62 (0.44, 0.87) Answer according to BICLA on week. 52, n/N (%) 27/93 (29.0) 35/93 (37.7) SRI(5) per week 52, n/N (%) 29/93 (31.2) 39/93 (42.0) SRI(6) per week 52, n/N (%) 28/93 (30.1) 36/93 (38.7) SRI(7) per week 52, n/N (%) 23/85 (27.0) 29/85 (34.0) SRI(8) per week 52, n/N (%) 21/85 (24.6) 27/85 (31.6) PGA change from BL to wk. 52, average value, defined n=77 LS (SE)1 method -1.07 (0.072) N/A Change SLEDAI-2K from BL to wk. 52, average, n=78 N/A determined by the LS (SE) method ^§§ -5.5 (0.46) Change in overall indicator according to BILAG from BL to wk. 52, n=78 N/A mean (SD) ^§§ -11.0(8.43) Reduce CLASI activity score by 50% or more with BL BEFORE weeks 52 in patients with a CLASI score of 10 or more on BL, n/N (%) ^§ 12/30 (40.0) N/A Reduced number of active (swollen and painful) joints by 50% or more per week. 52, n/N (%)** 17/36 (47.6) 21/36 (59.1) Change in the number of active joints from BL to wk. 52, average n=78 value determined by LS method (SE)1 -5.3 (0.32) N/A

*For response rates, differences in response rates and associated 95% CIs were weighted averages and calculated using the Cochran-Mantel-Haenszel stratified approach.

^ SRI(4) response was defined as a decrease of 4 points or more in the SLEDAI-2K score, less than 1 new BILAG-2004 Organ Damage Category A score, or less than 2 new BILAG-2004 Organ Damage Category B scores organs, an increase in PGA score of less than 0.3 points (10%) compared to baseline, and no discontinuation of treatment with the investigational product and no use of drugs for restricted use above the threshold allowed by the protocol.

¹ In patients with an OCS dose of 10 mg/day or greater at baseline (prednisone or equivalent).

§In patients with a CLASI activity score of 10 or greater at baseline.

¹ Exacerbation was defined as 1 new BILAG-2004 A or more or 2 new BILAG-2004 B or more compared to the previous visit (i.e. worsening from E, D, or C to B at least in two organ systems or deterioration from score E, D, C, or B to score A in any one organ system compared to the previous visit).

¹¹ The calculation of exacerbation rates did not include drugs for limited use; therefore, the values for the prespecified and post hoc analyzes are

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**xt_ ___g" yG _ _ _ g" ____ ___

In patients with 8 or more swollen and 8 or more tender joints at baseline.

Abbreviations: BICLA stands for BILAG-based Comprehensive Lupus Assessment; BILAG stands for British Lupus Assessment Group; BL means baseline; CI means confidence interval; CLASI stands for cutaneous lupus erythematosus prevalence and severity index; IFNGS stands for interferon-controlled gene expression profile; OCS stands for oral corticosteroids; PGA stands for Physician Overall Assessment; SLEDAI-2K stands for Systemic Lupus Erythematosus Disease Activity Index 2000; SRI stands for systemic lupus erythematosus patient response index to treatment; weeks means a week.

In the prespecified SRI(4) analysis, the original restricted drug use rules allowed approximately 8% of the study population to be classified as nonresponders due to the introduction of a new or increased dose of NSAID. Application of post hoc modified restricted drug use rules reduced the number of patients classified as nonresponders on this basis (Table 1, right panel). Achievement of the primary endpoint, SRI(4), was numerically higher under these rules, but the difference in response rates between anifrolumab and placebo remained similar (300 mg anifrolumab: 46.9%; placebo: 43.0%; difference 3.9 [95% CI: -6.3, 14.1]; Figure 1B, Table 1). Similar patterns were observed for SRI(4) response at week 24 and SRI(4) response at week 52 in the high IFNGS subgroup.

In patients receiving prednisone or equivalent at 10 mg/day or more at randomization, sustained OCS dose reduction to 7.5 mg/day or less was achieved in more anifrolumab-treated patients (48.8%, 50/103) , compared with placebo (32.1%, 33/102; difference 16.7 [95% CI: 3.5, 29.8]; Table 1; Fig. 3). CLASI responses in a prespecified subgroup of patients were more common in patients treated with anifrolumab (43.6%, 25/58) than in patients treated with placebo (24.9%, 14/54; difference 18.7 [95] %CI: 1.4, 36.0]; Fig. 1D, Table 1).

Although SRI(4) responses were similar between treatment groups, larger differences were observed between anifrolumab and placebo when using modified SRIs that included higher SLEDAI-2K response thresholds (Table 1). For example, SRI(7) response was achieved in 29.0% of patients treated with anifrolumab compared with 17.6% of patients treated with placebo (difference 11.5 [95% CI: 2.4, 20.6] ). BICLA responses were achieved in more patients treated with anifrolumab (46.1%) compared with placebo (29.6%; difference 16.4 [95% CI: 6.7, 26.2]; Fig 1F, Table 1). Differences in time to sustained responses according to BICLA suggested that patients receiving anifrolumab were 93% more likely to achieve a response that was sustained to week 52 than patients receiving placebo (hazard ratio 1.93, 95 %CI: 1.38, 2.73; Fig. 2A). Additional endpoints for skin and joint response also showed numerically greater improvements in the anifrolumab group (Table 1). For example, improvements in joint count of 50% or greater in a prespecified subgroup of patients were more common with anifrolumab (53.0%, 37/70) than with placebo (32.3%, 22/68; difference 20.00). 7 [95% CI: 4.7, 36.7]).

In patients with high pharmacodynamic type I IFN profiles at baseline (fold change greater than 2) who received 300 mg anifrolumab, neutralization of IFNGS was observed early in treatment (median percentage profile at baseline at week 12, 12.6% [median absolute deviation equal to 6.5], i.e., IFNGS suppression by 87.4%) and was maintained until week 52 (Fig. 2B). No neutralization of IFNGS was observed with placebo and minimal suppression was observed with 150 mg anifrolumab. Anti-dsDNA antibody levels and C3 levels tended to normalize during treatment with 300 mg anifrolumab (Table 3; Figure 4A4B). The percentages of patients who were ADA negative at baseline and ADA positive at any time point after baseline were small and similar among treatment groups (300 mg anifrolumab, 5/164 patients [3.0%]; placebo, 7/171 patients [4.1%]). The numbers of patients who were persistently ADA positive (defined as ADA negative at baseline and ADA positive at 2 assessments or more with 16 weeks or more between the first and last positive test) were 3/164 (1.8%) in the group 300 mg anifrolumab and 4/171 (2.3%) in the placebo group.

A greater percentage of patients experienced at least one adverse event in the anifrolumab 300 mg and 150 mg groups (161/180, 89.4% and 79/93, 84.9%, respectively) compared with placebo (144/184, 84.9%). 78.3%). The incidence of serious adverse events was similar in all treatment groups, with no event being predominant.

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Table 3

Suppression of interferon-controlled gene expression profiles, immune biomarkers and immunogenicity results

Biomarker* Placebo (n = 184) 150 mg anifrolumab (n = 93) 150 mg anifrolumab (and equals 180) Percentage of pharmacodynamic profile of 21 genes under IFN control at baseline in patients with elevated PD profile of 21 genes at baseline n=114 n=56 n=97 Mean (SD) 115-343 (136-4202) 122-841 (349-6918) 30-322 (55-6731) Median value (minimum, maximum) 89 178 (3-80, 1304-72) 63-216(4-82, 2656-28) 11-771 (0.99, 324-75) Change in anti-dsDNA antibody levels compared to BL in patients with elevated antibody levels n=62 n=35 n=62 to dsDNA at baseline, units/ml 64-0 (407-98) -101-4(525-87) -63-8 (158-28) Mean (SD) -6-6 (-1090 17, -21 0(-2026-52, -19-6(-1101.07, Median value (minimum, maximum) 2299 00) 1702-60) 7210) Change in complement concentration compared to BL in patients with abnormal complement levels at baseline n=49 n=29 n=48 SZ, g/l 0 0381 (0 16987) 0 1099 (0-21515) 0 1505 (0 16111) Mean (SD) 0 0410(-0-311, 0-392) 0 0760 (-0 195.0-604) 0 1305 (-0 176, 0-796) Median value (minimum, maximum) n=30 n=15 n=28 C4, g/l 0 0255 (0 04803) 0 0173 (0 03976) 0 0236 (0 02889) Mean (SD) 0 0125 (-0 013, 0-229) 0-0030 (-0-027.0 120) 0 0190 (-0 015, 0 118) Median value (minimum, maximum) n=8 n=12 n=12 CH50, CH50 units 104-9 (84-50) 114-6 (102-81) 130-3 (114-48) Mean (SD) Median value (minimum, maximum) 89 0 (20, 235) 93-5 (-43, 348) 112-5 (-23, 380) ADA-positive at any visit, n/N (%) 15/184 (8.2) 7/93 (7.5) 17/179 (9.5) ADA-positive only after initial 7/171 (4.1) 2/85 (2.4) 5/164 (3.0) level, n/N (%) Constantly ADA-positive,^ n/N (%) 4/171 (2.3) 0/85 3/164(1.8)

* τι O

Measured per week. 52 unless otherwise stated.

^ Treatment-induced ADA detected at two or more assessments (with 16 weeks or more between the first and last positive result), or detected at the last assessment (in patients who are ADA negative at baseline).

Abbreviations: ADA means anti-drug antibody; BL means baseline; C3 stands for third component of the complement system; C4 stands for the fourth component of the complement system; CH50 refers to total levels of complement hemolytic activity; dsDNA means double-stranded DNA; IFNGS stands for interferon-controlled gene expression profile; SD means standard deviation, weeks. means a week.

SRI(4) was selected as the primary endpoint in TULIP-1 due to its widespread use and positive outcome in the phase 2 MUSE trial of anifrolumab. In TULIP-1, SRI(4) response rates did not differ between placebo and anifrolumab groups; however, results in other endpoints, including the other composite endpoint, BICLA, suggest clinical benefit of anifrolumab. Although SRI(4) and BICLA involve the same components, each of these complex endpoints may be optimal in different situations ³³ . SRI(4) is based on SLEDAI-2K, which requires full development resolution before the item score changes. Therefore, SRI(4) does not allow partial resolution within an organ category to be captured, even if such improvement is clinically significant. ³⁴ In contrast, BICLA is based on improvements under BILAG-2004, whereby incremental changes within an organ category are recorded, and, therefore, it is more sensitive to detect improvement. For example, a rash in the SLEDAI-2K Skin and Mucocutaneous Assessment category is assigned a weight of 2, making it impossible to achieve an SRI(4) response based on that presentation alone, even if the patient demonstrates complete resolution of the rash; BICLA, in contrast, allows partial or complete resolution of the rash to be recorded as a response, as with CLASI. Another difference between BICLA and SRI is that BICLA reflects only clinical improvements, whereas response according to SRI(4) can be achieved only with serological improvements. Effects on serologic outcomes are more likely to be observed with therapies that more directly target antibody-producing cells.

The potential for OCS dose reduction during anifrolumab treatment is a particularly important outcome in TULIP-1. OCSs are commonly used to treat SLE, despite a number of serious adverse effects associated with their use, which increase with longer duration and higher dosages ³⁵ . In the current study, 48.8% of anifrolumab-treated patients who were taking high-dose OCS (prednisone or equivalent at 10 mg/day or more) at baseline were able to achieve a sustained dose reduction to the target of 7.5 mg/day or less compared with 32.1% of patients receiving placebo (using modified restricted drug guidelines). Skin and joint disorders are among the most common presentations of SLE, as reflected in the TULIP-1 population at baseline, and data suggest that treatment with anifrolumab may provide improvement in both of these presentations. Among patients with higher skin disease activity at baseline (CLASI 10 or greater), more patients treated with anifrolumab achieved a reduction in CLASI activity scores of 50% or greater than patients treated with placebo (44 % versus 25%, respectively, using modified rules for the use of drugs). Similarly, among patients with higher joint disease activity at baseline (8 or more swollen and 8 or more tender joints), more patients treated with anifrolumab achieved a 50% or greater reduction in the number of swollen and tender joints than in patients treated with placebo (53% vs. 33%, respectively, with modified drug guidelines).

Although the trial did not meet its primary endpoint, SRI(4), anifrolumab 300 mg resulted in numerical improvements compared with placebo in several other global and organ-specific endpoints, including BICLA, Cutaneous Lupus Erythematosus Prevalence and Severity Index (CLASI), number of joints and tapering corticosteroid dose.

Example 2. Efficacy and safety of anifrolumab in active systemic lupus erythematosus.

TULIP-2, a phase 3, randomized, double-blind, placebo-controlled trial, evaluated the efficacy and safety of intravenous anifrolumab 300 mg versus placebo (1:1) once every 4 weeks for 48 weeks in patients with moderate SLE. to severe, regardless of treatment, provided the standard of care (SOC) is met. The primary endpoint was BICLA response at week 52. SOC was stable except for mandatory oral corticosteroid (OCS) taper attempts to 7.5 mg/day prednisone equivalent or less for patients receiving 10 mg/day at baseline research.

The patients were aged 18–70 years and met the American College of Rheumatology classification criteria for SLE ³⁶ . Patients had moderate to severe SLE as measured by the SLEDAI 2000 (SLEDAI-2K score ³⁷ of 6 or greater (excluding scores associated with fever, lupus headache, or organic brain syndrome) and a SLEDAI-2K clinical score of 4 or more (excluding laboratory test scores) They also had severe disease activity in 1 or more organs or moderate disease activity in 2 or more organs (as measured according to BILAG 2004 ³⁸ ), 1 point A as measured by the assessment indicators organs or more or 2 B points according to the indicators for assessing organs or more than ³⁹ and a total disease activity of 1 or more, as determined by the physician's global assessment (PGA) using an analogue scale from 0 (no disease) to 3 (severe disease). screened, patients were seropositive for antinuclear antibodies, anti-double-stranded DNA antibodies (anti-dsDNA antibodies), or anti-Smith antigen antibodies and were receiving stable standard of care (SOC) treatment for SLE with at least 1 of the following: prednisone or equivalent , antimalarial, azathioprine, mizoribine, mycophenolate mofetil/mycophenolic acid, or methotrexate. The classification of gene expression profiles under the control of type I interferon (IFNGS) in screening was determined by the central laboratory using a quantitative polymerase chain reaction test with DNA isolated from whole blood with analytically validated 4 genes (IFI27, IFI44, IFI44L, RSAD2 ) ⁴⁰ Patients with severe active lupus nephritis or neuropsychiatric SLE were excluded.

To ensure that the investigational product had sufficient time to achieve clinical benefit, we were permitted to administer 1 loading dose of corticosteroids with a gradual tapering from week 0 (day 1) to week 12 if disease activity was elevated.

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SLE/non-SLE activity. Patients who received more than 1 loading dose of steroid and tapered from week 0 (day 1) to week 12 or who met any of the above criteria could continue in the study but were considered non-responders during follow-up assessments disease activity, regardless of whether a loading dose of OCS was administered due to increased SLE activity or for reasons unrelated to SLE. From week 12 to week 40, no corticosteroid dose increases were permitted for increased SLE activity. A patient receiving a dose of steroid greater than his or her dose at week 0 (day 1) could continue to participate in the study but was considered a nonresponder at subsequent assessments of disease activity. After week 40, no OCS dose increases were allowed (except for AE control or as prophylaxis for adrenal insufficiency). Patients who received an escalated dose of OCS after week 40 were considered non-responders for subsequent disease activity assessments.

Starting at week 8 and continuing through week 40, attempts to taper the steroid dose to an OCS dose of 7.5 mg/day or less were necessary in all patients with an OCS dose of 10.0 mg/day or more at baseline. if at least 1 of the following criteria was met: SLEDAI-2K activity that worsened from baseline in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, fever, thrombocytopenia, or hemolytic anemia, or gastrointestinal - intestinal activity).

Recently affected organ system(s), based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), excluding serological abnormalities (double-stranded DNA antibodies [dsDNA], hypocomplementemia).

Moderate to severe skin disease, as reflected by an activity score, an index of the prevalence and severity of cutaneous lupus erythematosus, of 10 or greater.

Moderate to severe arthritis, as reflected by an active joint count of 8 or more painful and/or swollen joints.

The primary efficacy measure was the difference between the percentage of patients achieving a BICLA response at week 52 in the anifrolumab 300 mg and placebo groups. Response according to BICLA is defined as all of (i) a decrease in all moderate to severe disease activity at baseline (A or B according to BILAG-2004) to lower levels (B/C/D or C/D, respectively) and no worsening in other organ systems (defined as >1 new BILAG2004 A or >2 new BILAG2004 B); (ii) confirmation of no worsening of disease activity as measured by SLEDAI-2K (no increase from baseline); (iii) an increase in PGA of 0.3 points or more compared to baseline; (iv) no use of restricted drugs in excess of protocol-allowed thresholds; and (v) no discontinuation of the study product. BICLA response was selected as the primary endpoint in a protocol change prior to data disclosure rather than SRI(4) response due to its metric properties and appropriate discriminative power among treatment groups in previous anifrolumab trials.

Key secondary endpoints were adjusted for multiple comparisons and included the percentage of patients achieving a) BICLA response at week 52 among patients who had high IFNGS test scores at baseline; b) reducing the OCS dosage to 7.5 mg/day or less, maintained from week 40 to week 52, among patients with a dosage of 10 mg/day or more at baseline; c) reducing the cutaneous lupus erythematosus erythematosus prevalence and severity index (CLASI) ³¹ by 50% or more at week 12 among patients with moderate to severe skin activity (CLASI score of 10 or more) at baseline and d) reducing the amounts of both swollen and tender joints by 50% or more at week 52 among patients with 6 or more swollen and 6 or more tender joints at baseline. The primary secondary endpoint was also the annualized exacerbation rate at 52 weeks (1 new BILAG 2004 A score or more or 2 new BILAG 2004 B scores or more compared to the previous visit) ³² .

Study endpoints that were not adjusted for multiple comparisons included SRI(4)-SRI(8) response, time to first exacerbation, and time to sustained BICLA response.

Efficacy analyzes included all patients who were randomized to receive 1 dose or more of study treatment. The primary endpoint compared BICLA response rates at week 52 between the anifrolumab and placebo groups using a stratified Cochran-Mantel-Haenszel (CMH) test with the same stratification factors as randomization (SLEDAI-2K, OCS dosage at baseline level and IFNGS type I). Raw numbers of patients responding to treatment were recorded along with response rates and

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CIs that were corrected using the CMH approach. Key secondary endpoints and other response endpoints were analyzed in a similar manner, with the exception of exacerbation rates, which were analyzed using a negative binomial regression model. The weighted Holm procedure with predefined weights was used to control the Type I error rate at the 0.05 level, adjusting for the effect of multiple comparisons for the primary and primary secondary endpoints. Weighting factors were selected based on estimated statistical power and relative clinical importance: BICLA in patients with high IFNGS at baseline (0.8), OCS dose reduction (0.06), CLASI response (0.06), reduction in joint counts (0.06) and exacerbation frequency (0.02). The remaining prespecified study outcomes were not controlled for multiple comparisons. Time to onset of BICLA response maintained through week 52 and time to relapse were assessed using a Cox proportional hazards model.

More patients achieved BICLA response at week 52 with anifrolumab 300 mg (47.8%, 86/180) than with placebo (31.5%, 57/182; difference 16.3 [95% CI [CI]: 6.3, 26.3; P equals 0.001]) (Table 4). When examining BICLA response over time, a numerically greater proportion of patients treated with anifrolumab achieved BICLA response at all time points assessed (Figure 5A), and patients treated with anifrolumab achieved sustained response sooner according to BICLA. BICLA (Fig. 5A).

Table 4

Primary, key secondary and other secondary efficacy outcomes

End point Placebo (n = 182) n/N (%)* 150 mg anifrolumab (n equals I 180) n/N (%)* 'differenceAdjusted/unadjusted Significant difference after correction for multiple comparisons (95%CI)* P-value P-value^· Primary final point: answer according to BICLA for the week. 52^ 57/182 (31.5) 86/180 (47.8) 16.3 (6.3, 26.3) 0.001/ 0.001 N.A. Primary secondary endpoints: response according to BICLA for the week. 52 in patients with high test results for IFNGS type I 46/151 (30.7) 72/150(48.0) 17.3 (6.5, 28.2) 0.002/ 0.002 Yes Reducing the OCS dosage to the target level, continuing over the week. 40 to weeks 52 ¹¹ 25/83 (30.2) 45/87 (51.5) 21.2 (6.8, 35.7) 0.014/ 0.004 Yes

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Decreased activity according to CLASI by 50% 24.0 or more from BL to (4.3, 0.039/ weeks 12 ¹ 10/40 (25.0) 24/49 (49.0) 43.6) 0.017 Yes Decrease in quantity as swollen and painful joints by 4.7 50% or more from BL to (-10.6, 0.547/ weeks 52** 34/90 (37.5) 30/71 (42.2) 20.0) 0.547 No 0.67 Annual frequency (0.48, 0.081/ exacerbations up to a week. 52 « 0.64 0.43 0.94) 0.020 No Other secondary endpoints: 18.2 (8.1, SRI(4) per week 52 « 68/182(37.3) 100/180 (55.5) 28.3) ΝΑ NA 15.9 (6.1, SRI(5) per week 52 « 51/181 (28.1) 79/180 (44.0) 25.8) ΝΑ NA 17.6 (7.8, SRI(6) per week 52 « 48/181 (26.4) 79/180 (44.0) 27.3) ΝΑ NA 13.6 (4.0, SRI(7) per week 52 « 34/169(20.0) 56/167(33.6) 23.2) ΝΑ NA 10.7 (1,2, SRI(8) per week 52 « 33/167(19.6) 50/166(30.2) 20.2) ΝΑ NA *Percentage response, difference in response scores, and corresponding 95% CIs are weighted averages. measured and were calculated using the stratified Cochran-Mantel-Haenszel approach with stratification factors (indicator according to SLEDAI-2K during screening [less than 10 points compared

score of 10 or more], OCS dose at week 0 [less than 10 mg/day versus 10 mg/day or more prednisone or equivalent], and test result for type I IFN gene profile at screening [ high versus low]).

^ BICLA response is defined as a decrease in all BILAG-2004 A scores at baseline to B/C/D, a BILAG-2004 B score at baseline to C/D, and no BILAG-2004 deterioration in other organ systems (> 1 new A as per BILAG-2004 or more than 2 new B as per BILAG-2004); no worsening (greater than 0 point increase) on SLEDAI-2K at baseline, no PGA increase of less than 0.3 points from baseline, no use of restricted medications above protocol-allowed thresholds, and no study discontinuation product.

^:!: Adjusted P-value for comparison of treatment groups using the stratified Cochran-Mantel-Haenszel approach/nominal P-value for comparison of treatment.

¹ In patients with an OCS dose of 10 mg/day or greater at baseline (prednisone or equivalent).

¹¹ In patients with a CLASI activity score of 10 or greater at baseline.

In patients with 6 or more swollen and 6 or more tender joints at baseline.

Values represent annual exacerbation rates and not percentages of patients responding to treatment. Exacerbation was defined as 1 new BILAG-2004 A or more or 2 new BILAG-2004 B or more compared to the previous visit (i.e., worsening from E, D, or C to B in at least 2 organ systems or deterioration from score E, D, C or B to score A in any 1 organ system compared to the previous visit).

$$ SRI(4) response was defined as a decrease of 4 points or more in the SLEDAI-2K score, less than 1 new BILAG-2004 Category A score for organ damage, or less than 2 new BILAG-2004 Category B scores for organ damage. organ damage, an increase in PGA score of less than 0.3 points (10%) compared to baseline, and

- 33 046025 no discontinuation of treatment with the study product and no use of drugs for limited use in excess of the threshold allowed by the protocol. SRI(5), SRI(6), SRI(7), and SRI(8) responses are determined in the same way as SRI(4), except that the SLEDAI-2K score reduction is >5, >6, > 7 or >8 for SRI(5), (6), (7) and (8), respectively.

¹¹ Calculated as rate ratio (anifrolumab/placebo).

In the subpopulation with high IFNGS test results (301/362, a total of 83.1% of patients), the BICLA response rate at week 52 was higher in the anifrolumab group than in the placebo group (difference 17.3 [95% CI: 6.5, 28.2], adjusted P = 0.002]) (Table 4). Among patients receiving prednisone or equivalent at 10 mg/day or more at randomization (47.0%, 170/362), a difference was observed in the proportion of patients achieving sustained reduction to 7.5 mg/day or less (anifrolumab: 51. 5%, 45/87; placebo: 30.2%, 25/83, difference: 21.2 [95% CI: 6.8, 35.7], adjusted P = 0.014) (Table 4; Fig. 5B ). Among patients with at least moderate active skin disease (CLASI score of 10 or greater) at baseline, a 50% or greater reduction in CLASI at week 12 was achieved in more patients treated with anifrolumab (49.0%, 24/49 ), compared with placebo-treated patients (25.0%, 10/40, difference 24.0 [95% CI: 4.3, 43.6], adjusted P = 0.039) (Figure 5C) . The percentages of patients with 6 or more swollen and 6 or more tender joints at baseline who achieved a 50% or greater reduction in both swollen and tender joint counts at 52 weeks were similar between the anifrolumab groups (42.2%, 30/ 71) and placebo (37.5%, 34/90) (difference 4.7 [95% CI: -10.6, 20.0], adjusted P 0.55). The annual exacerbation rate as determined by BILAG was numerically lower with anifrolumab than with placebo (0.43 versus 0.64, respectively; rate ratio 0.67 [95% CI: 0.48, 0.94]) (adjusted P = 0.081), and analysis of time to first exacerbation in the study favored anifrolumab (hazard ratio 0.65; 95% CI: 0.46, 0.91) (Figure 6B).

SRI(4) response at week 52 was numerically higher in the anifrolumab group (55.5%, 100/180) than in the placebo group (37.3%, 68/182; difference 18.2 [95% CI: 8 ,1, 28.3]) (Table 4). At each of the higher SRI cutoffs (5–8), numerical differences in favor of anifrolumab were observed.

In patients with high test results for type I IFNGS at baseline who received anifrolumab (150/180, 83.3%), IFNGS neutralization was achieved early in treatment (median percent neutralization at week 12 was 88.0%) and persisted until week 52 (Table 5; Fig. 7). No neutralization of IFNGS was observed during placebo treatment. Among patients with abnormal levels of anti-dsDNA antibodies at baseline, levels tended to normalize when treated with anifrolumab. Among patients with abnormal (low) complement levels at baseline, a numerically greater increase was observed with anifrolumab. Among anifrolumab-treated patients who were ADA-negative at baseline, some were ADA-positive at any time point after baseline (1/170 patients [0.6%]).

Adverse events were reported in 159/180 (88.3%) of patients treated with anifrolumab and in 153/182 (84.1%) of patients treated with placebo.

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Table 5

Suppression of interferon-controlled gene expression profiles, immune biomarkers and immunogenicity results

Biomarker* Placebo (n = 182) 300 mg anifrolumab (n = 180) Percentage of pharmacodynamic profile of 21 genes, under the control of IFN, at the initial level in patients with an elevated PD profile 21 gene at baseline n=111 n=121 Mean(SD) 153.64 25.66 Median value 99.93 9.94 Change in the level of antibodies to dsDNA compared to BL in patients with elevated levels of antibodies to n=49 n=71 dsDNA at baseline, units/ml Mean(SD) -17.60 8.89 Median value -4.65 -12.56 Change in complement concentration by compared with BL in patients with abnormal complement levels at baseline SZ, g/l n=58 n=64 Mean(SD) 0.0448 (0.16194) 0.1132 (0.19471) Median value 0.0475 0.0890 C4, g/l n=33 n=43 Mean(SD) 0.0071 (0.01854) 0.0225 (0.03761) Median value 0.0060 0.0100 CH50, CH50 units n=13 n=14 Mean (SD) 87.6(67.1) 95.1 (79.7) Median value 75.0 106.0 ADA-positive at any visit, n/N (%) 20/182(11.0) 8/180(4.4) ADA-positive only after initial 9/167 (5.4) 1/170 (0.6) level, n/N (%) Constantly ADA-positive, n/N (%) 3/167(1.8) 1/170 (0.6)

Measured per week. 52 unless otherwise stated.

^ Treatment-induced ADA detected at 2 or more assessments (with 16 weeks or more between the first and last positive result), or detected at the last assessment (in patients who are ADA negative at baseline).

Abbreviations: ADA means anti-drug antibody; BL means baseline; C3 stands for third component of the complement system; C4 stands for the fourth component of the complement system; CH50 refers to total levels of complement hemolytic activity; dsDNA means double-stranded DNA; IFNGS stands for interferon-controlled gene expression profile; SD means standard deviation, weeks. means a week.

Example 2. Early sustained response.

Early and sustained responses with anifrolumab in patients with active systemic lupus erythematosus (SLE) in 2 phase 3 trials.

Theoretical background.

In the phase 3 TULIP-2 and TULIP-1 trials in SLE, treatment with the type I interferon receptor antibody anifrolumab resulted in higher percentages of patients with BICLA responses compared with placebo at week 52, with a difference value of 16 .3% (primary endpoint; P = 0.001, 95% CI 6.3-26.3) and 16.4% (secondary endpoint; 95% CI 6.7-26.2), respectively.

Target.

To better understand the time course of BICLA responses to anifrolumab, the authors

- 35 046025 of the present invention examined responses over time compared to placebo in TULIP-2 and TULIP-1, including responses that remained sustained from onset to week 52. Good clinical response (MCR) was also assessed as an alternative outcome measure. and partial clinical response (PCR). Specifically, time to response was used to compare BICLA responses to anifrolumab versus placebo over time in TULIP-1, TULIP-2, and pooled data from TULIP at early time points, which was sustained through week 52, as well as good and partial clinical response. A good clinical response is defined as all BILAG-2004 C scores or better at week 24, maintained through week 52, with no new A or B scores between weeks 24–52. A partial clinical response is defined as a maximum of 1 BILAG 2004 B score at week 24, persisting to week 52, with no new A scores or more than 1 new B score to week 52.

Ways.

The randomized, double-blind, placebo-controlled trials TULIP-2 and TULIP-1 assessed the efficacy and safety of anifrolumab (300 mg Q4W) for 52 weeks in patients with moderate to severe active SLE treated at standard of care. Time to onset of response according to BICLA, which was sustained from reaching week 52, was assessed using a Cox proportional hazards model. MCR was defined as all BILAG-2004 C scores or better at week 24, maintained with no new A or B scores between weeks 24–52. PCR was defined as 1 BILAG-2004 B value or less at week 24 that persisted with no new A or more than 1 new B value until week 52. For TULIP-1, BICLA response rate and time to onset BICLA responses were analyzed using modified restricted drug use regulations; MCR and PCR were analyzed using a prespecified assay plan.

Results.

At early time points, there were more BICLA responders with anifrolumab compared with placebo (Figures 9, 11, 12). Time to sustained response according to BICLA favored anifrolumab (Figs. 11, 12). There were numerical differences in favor of anifrolumab in the percentage of patients with sustained responses according to BICLA and in the percentage of patients with PCR and MCR (Fig. 13). Overall, 180 patients each received anifrolumab in the TULIP-2 and TULIP-1 trials, compared with 182 and 184 patients in the placebo groups, respectively. At the first 3 assessments in TULIP-2 (weeks 4, 8 and 12), numerically greater percentages of patients treated with anifrolumab (26.8, 35.3 and 42.9%, respectively) were classified as achieving BICLA response compared with placebo (21.3, 21.6 and 31.8%). A similar trend was observed in the TULIP-1 trial with anifrolumab (23.3, 34.2 and 36.5%) compared with placebo (18.3, 23.2 and 27.5%). Time to BICLA response sustained from baseline to week 52 favored anifrolumab in both TULIP-2 (HR 1.55, 95% CI 1.11-2.18) and TULIP-1 (HR 1.93, 95% CI 1.38-2.73). In TULIP-2, 86 (47.8%) patients treated with anifrolumab achieved BICLA responses that were sustained from start time to week 52, compared with 57 (31.3%) patients in the placebo group. In TULIP-1, 85 (47.2%) patients in the anifrolumab treatment group achieved BICLA responses that were sustained from start time to week 52, compared with 55 (29.9%) patients in the placebo group. In TULIP-2 and TULIP-1, MCR was observed in 20.8% and 22.1% of anifrolumab-treated patients, respectively, compared with 10.9% and 15.8% of placebo-treated patients. PCR was observed in 46.8% and 45.4% of patients treated with anifrolumab, compared with 38.4% and 40.2% in the placebo groups, respectively.

Conclusion.

The rapid and durable responses according to BICLA support the clinical benefit of anifrolumab for patients with moderate to severe active SLE. In 2 phase 3 studies, a higher proportion of patients achieved BICLA responses sustained from baseline to week 52 with anifrolumab compared with placebo. Anifrolumab resulted in numerically favorable differences in time to BICLA responses that persisted to week 52 in the TULIP studies. MCR and PCR also supported anifrolumab. These data support the sustainability of the clinical benefit obtained from treatment with anifrolumab in patients with active SLE.

Example 3: Efficacy in patient subgroups.

Target.

To compare BICLA responses to anifrolumab versus placebo to week 52 in protocol-defined patient subgroups in TULIP-1 and TULIP-2, and in pooled data from TULIP-1 and TULIP-2. Characteristics at baseline are shown in Table 1. 6 and 7.

Results.

In TULIP-1, TULIP-2, and the pooled data from TULIP at week 52, robust BICLA response rates were observed for anifrolumab in prespecified subgroups. Not

- 36 046025 there was a significant effect of demographics (Fig. 14-16), disease activity at baseline (Fig. 17), OCS dosage at baseline (Fig. 18), test status for IFNGS type I (Fig. 19) on the magnitude of the effect. Response rates to anifrolumab were similar in patients with high and low IFNGS test results (Figure 19).

Table 6

Patient Demographics at Baseline

Patient Demographics at Baseline Combined data from TULIP ^a Placebo (n equals 366) 300 mg anifrolumab (n equals 360) Age, mean (SD), years 41.0 (11.9) 42.6 (12.0) Women, η (%) 341 (93.2) 333 (92.5) BMI, η (%) 28 kg/ ^m2 or less 223 (60.9) 205 (56.9) more than 28 kg/m ² 143 (39.1) 155 (43.1) Race, ^b η (%) Caucasoid 244 (66.7) 235 (65.3) Black/African American 48 (13.1) 46 (12.8) Mongoloid 35 (9.6) 41 (11.4) Other 31(8.5) 30(8.3) Geographical region,' η (%) Asian-Pacific area 32 (8.7) 38(10.6) Europe 122 (33.3) 115 (31.9) Latin America 57(15.6) 59 (16.4) USA/Canada 140 (38.3) 139 (38.6) Rest of the world 15(4.1) 9(2.5)

BMI: body mass index; IFNGS: expression profile of genes under the control of type I interferon; OCS: oral corticosteroid; SD: standard deviation; SLEDAI2K: systemic lupus erythematosus disease activity index 2000; qPCR: quantitative polymerase chain reaction.

Table 7

Disease characteristics at baseline

Disease characteristics at baseline Combined data from TULIP ^a Placebo (n equals 366) 300 mg anifrolumab (n = 360) SLEDAI-2K (screening) Mean (SD) 11.3 (3.6) 11.4 (3.9) 10 or more, η (%) 260 (71.0) 251 (69.7) OCS dosage, η (%) less than 10 mg/day 181 (49.5) 170 (47.2) 10 mg/day or more 185 (50.5) 190 (52.8) IFNGS type I status,* ¹ η (%) High 302 (82.5) 298 (82.8) Short 64 (17.5) 62 (17.2)

Example 4: Exacerbation Scores.

Theoretical background.

Treatment with anifrolumab resulted in improved British Lupus Assessment Group (BILAG) Comprehensive Lupus Assessment Group (BILAG) response rates in patients with systemic lupus erythematosus (SLE) in the phase 3 TULIP-2 and TULIP-1 trials. In addition, annual exacerbation rates were lower in the anifrolumab-treated groups compared with placebo.

Target.

Data from TULIP-2 and TULIP-1 were analyzed to evaluate the effects of anifrolumab on the number of SLE exacerbations and time to first exacerbation over 52 weeks of treatment.

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Ways.

The randomized, double-blind, placebo-controlled trials TULIP-2 and TULIP-1 assessed the efficacy and safety of 300 mg intravenous anifrolumab compared with placebo once every 4 weeks for 48 weeks, with the primary endpoint assessed at week 52 in patients with Moderate to severe SLE despite standard of care treatment. Exacerbations were defined as 1 new (worsening) BILAG-2004 category A score or more or 2 new (worsening) BILAG-2004 category B scores or more compared to the previous month's visit. Time to first exacerbation was assessed using the Cox proportional hazards model. Annual exacerbation rates were analyzed using a negative binomial regression model.

Results.

In TULIP-2 (anifrolumab: n = 180; placebo: n = 182) and TULIP-1 (anifrolumab: n = 180; placebo: n = 184), fewer patients experienced 1 or more BILAG-2004 exacerbations in the anifrolumab groups (TULIP-2: 31.1%, n = 56; TULIP-1: 36.1%, n = 65) compared with placebo groups (TULIP-2: 42.3%, n = 77; TULIP-1: 43.5%, n equals 80; Fig. 20). Results supporting anifrolumab were observed for time to first exacerbation (TULIP-2: hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.46-0.91, and TULIP-1: HR 0 .76, 95% CI 0.55-1.06; Figure 21) and BILAG-based annual exacerbation rates (TULIP-2: adjusted rate ratio 0.67, 95% CI 0.48-0.94, and TULIP-1: rate ratio 0.83, 95% CI 0.60–1.14) in both trials. BILAG annual exacerbation rates (compared to previous visit) were significantly lower in the anifrolumab group compared with the placebo group in TULIP-2 (Figure 22). Fewer patients experienced 1 or more exacerbations according to BILAG compared with the previous visit in the anifrolumab group in TULIP-1, TULIP-2 and pooled data from TULIP (36.1%, 31.1% and 33.6%, respectively) according to compared with the placebo group (43.5, 42.3 and 42.9%, respectively; Fig. 23).

Conclusions.

In 2 phase 3 trials, we observed a reduction in the total number of exacerbations and annual exacerbation rates, as well as an increase in time to first exacerbation with anifrolumab treatment compared with placebo. These results support the potential of anifrolumab to reduce disease activity and exacerbations, thereby benefiting patients with SLE. Results from the TULIP trial support the ability of anifrolumab to not only reduce disease activity, but also reduce exacerbations in the presence of tapered OCS, which is vital for long-term control of patients with SLE.

Example 5: Interpretation of BICLA.

Theoretical background.

The BILAG-based Comprehensive Lupus Assessment (BICLA) is a validated comprehensive global measure of SLE disease activity that captures both partial and complete improvement in organ systems. BICLA was used as an endpoint in the phase 3 TULIP-1 and TULIP-2 trials studying anifrolumab. This study examined the relationship between BICLA response and clinical/laboratory SLE scores in TULIP-1 and TULIP-2, regardless of treatment.

Ways.

This was a post hoc analysis of the randomized, double-blind TULIP-1 and TULIP2 trials. Patients with moderate to severe active SLE despite standard of care treatment were randomized to receive anifrolumab (150 mg or 300 mg IV Q4W) or placebo for 48 weeks, with the primary endpoint assessed at week 52. BICLA responses were defined by all of the following: reduction in BILAG-2004 categories A and B to B/C/D and C/D, respectively, and no worsening in any organ system; no deterioration in the SLE 2000 Disease Activity Index (SLEDAI-2K); no worsening of 0.3 points or more in Physician Global Assessment (PGA; range 0–3). Continued reduction in oral corticosteroid (OCS) dosage was defined as an OCS dosage of 7.5 mg/day or less achieved by week 40 and maintained through week 52. Response according to the Activity Score, an index of the extent and severity of cutaneous lupus erythematosus. (CLASI-A) was defined as a decrease in CLASI-A score of 50% or greater from baseline for patients with a CLASI-A score of 10 or greater at baseline.

Results.

Characteristics at baseline were generally comparable between BICLA responders (N = 318) and BICLA nonresponders (N = 501). Overall, improved outcomes were observed in BICLA responders compared with BICLA non-responders, including numerically greater improvements in SLEDAI-2K (-7.4 [SD: 3.64] vs. with -4.2 [4.28]) compared to the original

- 38 046025 level up to week 52. A greater reduction in mean daily OCS dose was observed in BICLA responders compared with BICLA non-responders (-5.4 [SD: 6.84] vs - 1.7 [8.08]), compared with baseline to week 52, and continued OCS dosage reduction was achieved in more BICLA responders compared with BICLA non-responders (79 .2% versus 19.1%) at week 52. CLASI-A score reduction was achieved in more BICLA responders compared to BICLA non-responders (92.0% compared with 23.2%) at week 52. A greater decrease in mean anti-dsDNA antibody levels was observed in BICLA responders compared with BICLA non-responders (-46.1 [SD: 335, 69] versus 15.8 [450.92]), versus baseline to week 52; numerical improvements were also observed in the case of complement proteins C3 and C4.

Conclusions.

BICLA response is associated with improvements in many clinical and laboratory measures of SLE, increasing its value as a clinically relevant primary endpoint in SLE trials. Treatment of subjects with SLE with anifrolumab, a type I IFN inhibitor, in two phase III clinical trials resulted in patients achieving BICLA responses associated with other improvements in multiple clinical and laboratory measures of SLE.

Example 5: Early and sustained reduction in skin disease severity as measured by CLASI.

Theoretical background.

The skin is the second most commonly affected organ in SLE, with skin disease affecting up to 85% of patients. The Cutaneous Lupus Erythematosus Prevalence and Severity Index (CLASI) is a validated index for measuring the severity of skin disease, with activity scores (CLASI-A) ranging from 0 (mild) to 70 (severe). CLASI-A includes measurements for erythema, desquamation/hypertrophy, mucosal lesions, recent hair loss, and nonscarring alopecia. In the phase 3 TULIP-1 and 2 trials in patients with SLE, a greater proportion of patients with a baseline CLASI-A score of 10 or greater achieved a 50% or greater reduction in CLASI-A at week 12 with anifrolumab compared with placebo. We further assessed the effect of anifrolumab on skin SLE disease activity using combined data from TULIP1 and -2.

Ways.

TULIP-1 and -2 were 52-week randomized, double-blind, placebo-controlled trials that assessed the efficacy and safety of anifrolumab (300 mg IV once every 4 weeks for 48 weeks) in patients with moderate to severe active SLE despite for treatment in compliance with the standard of care. Results from TULIP-1 and -2 were analyzed separately using the restricted drug use rules of the TULIP-2 protocol, and data from both trials were pooled. We compared skin responses over time in patients receiving anifrolumab versus placebo. CLASI-A response was defined as a decrease in CLASI-A score of 50% or greater from baseline in patients with a CLASI-A score of 10 or greater. Time to response according to CLASI-A was assessed using a Cox proportional hazards model.

Results.

A total of 360 patients received anifrolumab and 366 received placebo. At baseline, the mean (SD) CLASI-A score was 8.1 (7.41); 95.9% (696/726) of patients had a CLASI-A greater than 0 at baseline, and 27.7% (201/726) had a CLASI-A score of 10 or greater at baseline. In the subgroup of patients with a CLASI-A score of 10 or greater at baseline, CLASI-A response (50% or greater reduction) was achieved by week 8 in 36.0% (38/107) of patients receiving anifrolumab, according to compared with 21.7% (21/94) of patients receiving placebo (difference 14.3; 95% CI 1.8%, 26.9%) (Figure 24). Results in favor of anifrolumab were observed for time to CLASI-A response maintained to week 52 in TULIP-1 (hazard ratio [HR] 1.91; 95% CI 1.14, 3.27) and TULIP-2 ( HR 1.55; 95% CI 0.87, 2.85) (Fig. 25). In the subgroup of patients with CLASI-A greater than 0 at baseline, more patients achieved a CLASI-A response (50% or greater reduction) by week 12 in the anifrolumab groups compared with the placebo groups in both TULIP-1 and TULIP -2 (nominal P less than 0.05) (Fig. 26); a similar effect was observed in the subgroup of patients with a CLASI-A score of 10 or greater at baseline in both TULIP-1 and TULIP-2 (nominal P less than 0.05) (Fig. 26). An example of one patient after treatment with anifrolumab (300 mg) is shown in FIG. 27.

Conclusions.

Treatment with anifrolumab was associated with rapid and long-lasting improvements in

- 39 046025 study of skin-specific SLE disease activity as assessed by CLASI in a subgroup of patients with mild to severe skin activity at baseline. These results demonstrate the ability of anifrolumab to reduce skin disease activity in patients with moderate to severe active SLE.

Example 6: Clinical significance of BILCA.

Theoretical background.

The British Interdisciplinary Lupus Assessment (BICLA) Comprehensive Lupus Assessment is a validated overall measurement of treatment response in clinical trials for systemic lupus erythematosus (SLE). To understand the relevance of the BICLA to clinical practice, the relationship between BICLA response and standard SLE scores and patient-reported outcomes (PROs) was examined.

The BICLA was developed following a panel review of disease activity indices used in clinical trials for SLE. Response according to BICLA requires improvement in all categories affected at baseline as assessed by BILAG-2004, no worsening in other categories according to BILAG-2004, no worsening from baseline on both SLEDAI-2K and PGA, no initiation of non-protocol treatment or use of threshold values exceeding those allowed under the protocol and failure to discontinue the study product. Thus, unlike SRI, the performance determinant in BICLA is BILAG-2004, while impairment is assessed using SLEDAI-2K and PGA in addition to BILAG. BILAG-2004-based BICLA allows for uniform assessment of organ systems and distinctions between inactive disease, partial and complete improvement, and worsening disease activity, whereas SLEDAI-2K-based SRI allows for different assessment of organ systems and requires complete resolution of disease activity in the affected system organs to determine improvement.

Comprehensive assessments of SLE are not routinely used in clinical practice. The significance of treatment response assessed in this way may therefore be discounted by clinicians. We therefore examined the relationship between BICLA response and other measures of SLE disease that are relevant in real world clinical practice, including exacerbations, daily oral glucocorticoid dosage and sustained oral glucocorticoid taper, PRO, health care resource utilization and clinical and laboratory measures of general and organ-specific disease and disease. These associations were assessed between BICLA responders and BICLA non-responders using pooled data from the phase 3 TULIP-1 and TULIP-2 trials of anifrolumab, regardless of treatment arm allocation.

Ways.

Patients and study design.

This was a post hoc analysis of pooled data from the randomized, placebo-controlled, double-blind, 52-week phase 3 trials of TULIP-1 and TULIP-2. Briefly, eligible patients were aged between 18 and 70 years, met the revised American College of Rheumatology classification criteria for SLE ( 13 ), and had moderate to severe seropositive SLE despite standard of care treatment. Patients with severe active lupus nephritis or neuropsychiatric SLE were excluded. Patients were randomized to receive intravenous infusions of placebo or anifrolumab once every 4 weeks for 48 weeks in addition to standard of care treatment (TULIP-1: placebo, 150 mg anifrolumab, or 300 mg anifrolumab [2:1:2]; TULIP-2: placebo or 300 mg anifrolumab [1:1]). Primary endpoints were assessed at week 52. Other treatments remained stable throughout the trial except those associated with a protocol-defined intention to taper oral glucocorticoids. For patients receiving an oral glucocorticoid dose of 10 mg/day or more at baseline, an attempt to taper the oral glucocorticoid dose to 7.5 mg/day or less from week 8 to week 40 was necessary; Tapering was also permitted for patients receiving oral glucocorticoids less than 10 mg/day at baseline. From week 40 to week 52, a stable dosage of oral glucocorticoid was required.

Study and evaluation endpoints.

BICLA response was defined as all of the following: reduction in BILAG-2004 categories A and B at baseline to B/C/D and C/D, respectively, and absence of deterioration in other organ systems according to BILAG-2004, which was defined as 1 a new indicator for category A according to BILAG-2004 or more or 2 indicators for category B according to BILAG-2004 or more; no increase in SLEDAI-2K score (compared to baseline); absence

- 40 046025 increase in PGA score (0.3 points or more compared to baseline); absence of discontinuation of the study product and absence of use of drugs for restricted use in excess of the thresholds allowed by the protocol. Pooled data were analyzed according to the restricted drug review rules from TULIP-2 to classify responders/non-responders.

Clinical outcome measures were compared between BICLA responders and BICLA non-responders at week 52, regardless of treatment group allocation, and results are presented in a hierarchical order of clinical significance that was agreed upon by the authors. Outcome measures included the percentage of patients with exacerbations (defined as 1 new BILAG-2004 category A or more or 2 new BILAG-2004 category B or more compared to the previous visit) to week 52, annual exacerbation rate values , the percentage of patients achieving a sustained oral glucocorticoid taper (defined as a reduction in oral glucocorticoid dosage to 7.5 mg/day prednisone or equivalent or less, achieved by week 40 and maintained through week 52, in patients receiving 10 mg/day or more at baseline), and change in daily oral glucocorticoid dosage from baseline to week 52. Changes in PRO were assessed from baseline to week 52, including responses to the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire [ FACIT-F] (defined as an improvement of more than 3 points), physical health score [PCS] and mental health score [MCS] responses to the Short Form 36 Health Questionnaire version 2 [S-36v2] [acute] (defined as an improvement of greater than 3.4 according to PCS and greater than 4.6 according to MCS) and a change in patient global assessment [PtGA] from baseline). Healthcare resource utilization (health monitoring visits, emergency department [ED] utilization, and hospital visits) was also assessed. Other indices compared between BICLA responders and BICLA non-responders included changes from baseline to week 52 in SLEDAI-2K, PGA, joint counts (active, swollen, tender), and responses according to the cutaneous lupus erythematosus prevalence and severity index (CLASI-A) activity measure (defined as a 50% or greater reduction in CLASI-A score among patients with a CLASI-A score of 10 or greater at baseline). Serological parameters (anti-double-stranded DNA antibodies [anti-dsDNA antibodies] and complement C3 and C4 levels) were assessed; dsDNA antibody levels were classified as positive (greater than 15 U/ml) or negative (15 U/ml or less), and complement levels were classified as abnormal (C3 level less than 0.9 g/L; C4 level less than 0 .1 g/L) or normal (C3 level 0.9 g/L or more; C4 level 0.1 g/L or more). Adverse events (AEs) were also assessed.

Statistical analyses.

The similar design of the TULIP-1 and TULIP-2 studies allowed for pooling of results. Sample sizes were adjusted for TULIP-1 and TULIP-2 to obtain appropriately sized safety databases and assess key secondary endpoints. In TULIP-1 and TULIP-2, 180 subjects/group provided statistical power of greater than 99% and 88%, respectively, to reject the hypothesis (no difference in the primary endpoint) using a 2-sided alpha of 0.05. Response rates were calculated using a stratified Cochran-Mantel-Haenszel approach that included stratification factors for SLEDAI-2K score at screening (less than 10 or 10 or greater), oral glucocorticoid dosage at baseline (less than 10 mg/day or 10 mg/day or more) and test status for type I IFNGS at screening (low or high test results). The study was also included in the model. For all analyzes of responders, patients were considered nonresponders if they used restricted medications above protocol-allowed thresholds or discontinued the study product before evaluation. Comparisons of assessed change from baseline to week 52 between BICLA responders and BICLA non-responders were assessed using a repeated measures mixed model with fixed effects for value at baseline, group, visit, study, and stratification factors used in screening; an interaction term was used with the treatment factor effect by visit, and visit was a repeated variable in this model. Missing data were imputed using the last follow-up carried forward to the first visit with missing data; subsequent visits with missing data were not included through imputation. In analyzes of treatment responders, if any component of a variable could not be obtained due to missing data, the patient for that visit was classified as a nonresponder.

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Results.

Populations participating in the trial.

Data were pooled for 457 patients in TULIP-1 and 362 patients in TULIP-2 (N = 819). In both trials, 360 patients received 300 mg anifrolumab, 93 patients received 150 mg anifrolumab, and 366 patients received placebo. Regardless of treatment allocation, at week 52 there were 318 BICLA responders and 501 BICLA non-responders. Patient demographics and clinical characteristics at baseline were generally balanced among BICLA responders and BICLA nonresponders (Table 8 and Table 9). The majority of patients were female (92.5%, responders; 93.0%, non-responders), and the mean (standard deviation [SD]) age was 41.5 (11.67) years for responders and 41.7 (12.13) years for non-responders. Similar proportions of BICLA responders and BICLA non-responders were Caucasian (67.0% versus 65.9%) and Black/African American (14.2% versus 12.6). %) or Asians (9.1% compared to 11.0%).

Overall, better outcomes were observed in patients responding to BICLA treatment compared with patients not responding to BICLA treatment.

Table 8

Demographics and clinical characteristics of patients at baseline

Patients responding Patients not

for treatment according to responsive to treatment Characteristics at baseline BICLA according to BICLA at week 52 (p at week 52 (p equals 318) equals 501)

Age, mean (SD), years 41.5 (11.67)

Women, η (%) 294 (92.5)

Time from SLE diagnosis to randomization, median 85.5 (0-555) (range), months

41.7(12.13)

466 (93.0)

84.0 (4-503)

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High test results regarding IFNGS at screening, η (%) 261 (82.1) 415 (82.8) BILAG-2004 indicator, mean value (SD) 18.9(5.20) 19.2 (5.59) 1 point A or more, η (%) 171 (53.8) 222 (44.3) Absence of points A and 2 points B or more, η (%) 126 (39.6) 254 (50.7) No points A and 2 points B or less, η (%) 21 (6.6) 25 (5.0) SLEDAI-2K score, mean (SD) 10.8(3.19) I.7 (4.01) 10 or less, η (%) 104 (32.7) 127 (25.3) 10 or more, η (%) 214 (67.3) 374 (74.7) PGA Score, Mean (SD) 1.76 (0.425) 1.81 (0.396) Oral glucocorticoid use, ³ η (%) 263 (82.7) 410(81.8) less than 10 mg/day 98 (30.8) 152 (30.3) 10 mg/day or more 165 (51.9) 258 (51.5) Antimalarials 225 (70.8) 361 (72.1) Immunosuppressants 158 (49.7) 230 (45.9) CLASI Activity Score, Mean (SD) 8.5 (7.56) 7.8(7.18) 10 or less, η (%) 215 (67.6) 373 (74.5) 10 or more, η (%) 103 (32.4) 128 (25.5) 0, η (%) 13(4.1) 20 (4.0) Greater than 0, η (%) 305 (95.9) 481 (96.0) Total SDI, mean (SD) 0.6 (1.08) 0.5 (0.89) Number of swollen joints, mean (SD) 6.5 (5.27) 7.4 (6.08)

- 43 046025

Number of painful joints, mean (SD) 9.8 (6.94) I,1 (7.85) Number of active joints ¹³ , mean (SD) 6.1 (5.22) 6.9 (5.97) Positive for antibodies to dsDNA ^c , η (%) 142 (44.7) 224 (44.7) Median value (min., max.) ^a , units/ml 48.2(15, 3790) 57.0 (15.4404) Mean value (SD) ^C , units/ml 142.5 (401.84) 220.4 (526.38) SZ level deviating from the norm ⁶ , η (%) 123 (38.7) 178 (35.5) Median value (min., max.) ^s , g/l 0.729 (0.36, 0.90) 0.715 (0.18, 0.90) Mean value (SD) ^C , g/l 0.711 (0.1279) 0.685 (0.1603) Level C4, deviating from the norm ¹ , η (%) 72 (22.6) 118(23.6) Median value (min., max.) ^s , g/l 0.080 (0.05, 0.10) 0.072 (0.05, 0.10) Mean value (SD) ^C , g/l 0.075 (0.0168) 0.071 (0.0145)

BICLA: BILAG-based comprehensive lupus assessment; BILAG-2004: British Lupus Assessment Group 2004; CLASI: cutaneous lupus erythematosus prevalence and severity index; dsDNA: double-stranded DNA; IFNGS: interferon-controlled gene expression profile; max: maximum; min: minimum; PGA: Physician Global Assessment; SD: standard deviation; SDI: Systemic Lupus Clinic Collaboration International/American College of Rheumatology damage index; SLE: systemic lupus erythematosus; SLEDAI-2K: SLE Disease Activity Index 2000.

^a Oral glucocorticoids include prednisone or equivalent; ^b an active joint is defined as a joint with swelling and tenderness; ^c positive for anti-dsDNA antibodies is defined as a result greater than 15 units/ml. ^d B Summary statistics for relevant variables include only patients with anti-dsDNA antibodies and abnormal complement levels at baseline. ^e Abnormal complement C3 levels are defined as a result of less than 0.9 g/L. f Abnormal complement C4 levels are defined as a result of less than 0.1 g/L.

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Table 9

Patient Demographics and SLE Medications at Baseline in BICLA Responders and BICLA Nonresponders

Patients, Patients, not Demographics and responding to responsive to treatment medicine for treatment according to according to BICLA treatment for SLE at baseline BICLA, in week 52 (p at week 52 (p equals 318) equals 501)

Race, ³ η (%)

Caucasian 213 (67.0) 330 (65.9) Black/African American 45 (14.2) 63 (12.6) Mongoloid 29 (9.1) 55 (11.0) Other 23 (7.2) 45 (9.0) Americanoid or Hispanic ethnic group, η (%) Geographic region, η (%) 80 (25.2) 115 (23.0) United States/Canada 92 (28.9) 226 (45.1) Europe 126 (39.6) 144 (28.7) Latin America 66 (20.8) 63 (12.6) Asian-Pacific area 28 (8.8) 49 (9.8) Rest of the world 6(1.9) 19 (3.8) SLE treatment at baseline, η (%) Oral glucocorticoid ¹³ 263 (82.7) 410(81.8) Antimalarial 225 (70.8) 361 (72.1) Immunosuppressant ⁰ 158 (49.7) 230 (45.9)

BICLA: British Lupus Group Comprehensive Assessment for Lupus; SD: standard deviation; SLE: systemic lupus erythematosus.

^a Pace data were missing for 16 patients (8 from each of the responder and nonresponder groups); ^b oral glucocorticoid included prednisone or equivalent; ^c immunosuppressive agents included azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, and mizoribine.

Exacerbations.

There were fewer exacerbations among BICLA responders than among BICLA non-responders over the 52-week time period (76.1% versus 52.2%), meaning that Fewer BICLA responders than BICLA nonresponders experienced 1 or more exacerbations during the 52-week time period (23.9% vs. 47.8%; difference -23.9% ;95% confidence interval [CI] ranges from -30.4 to -17.5; nominal P-value is less than 0.001) (Figure 28A). Fewer patients experienced 1, 2, or 3 exacerbations or more, and the annual exacerbation rate was lower in BICLA responders compared with BICLA nonresponders (rate ratio [RR] 0.36, 95 % CI 0.29-0.47; nominal P-value less than 0.001) (Table 10).

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Table 10 SLE exacerbations in BICLA responders and BICLA non-responders

BICLA responders at week 52 (n = 318) BICLA non-responders at week 52 (n = 501) Number of exacerbations per patient up to week 52 Patients with 0 exacerbations, η (%) ^a Patients with 1 or more exacerbations, η 242 (76.1) 263 (52.2) (%) Comparison between groups, 76 (23.9) 238 (47.8) difference (95% CI), nominal P value ^a -23.9 (-30.4 to- -17.5), <0.001 1 52 (16.4) 132 (26.3) 2 18(5.7) 69(13.8) 3 or more Frequency of exacerbations up to week ⁵² 6 (1.9) 37 (7.4) Total number of exacerbations Total follow-up time, 107 401 years 318.8 440.6 Annual frequency (95% CI) Comparison between groups, 0.30 (0.24 to 0.38) 0.83 (0.70 to 0.98) frequency ratio (95% CI), nominal P-value 0.36 (0.29 to 0 .47), < 0.0001

BICLA: BILAG-based comprehensive lupus assessment; BILAG-2004: British Lupus Assessment Group 2004; CI: confidence interval; CMH: Cochran-Mantel-Haenszel approach; PGA: Physician Global Assessment; SD: standard deviation; SLE: systemic lupus erythematosus; SLEDAI-2K: SLE Disease Activity Index 2000.

Exacerbations according to BILAG-2004 were defined as 1 new BILAG-2004 category A or more or 2 new BILAG-2004 category B or more compared to the previous visit.

^a Percentages, differences, CIs, and nominal P-values are weighted averages and were calculated using the stratified CMH approach.

^b Exacerbation rates were calculated using a negative binomial regression model that included group and stratification covariates. The logarithm of follow-up time (base e) is used as a compensating variable in the model to adjust for different exposure times.

Use of an oral glucocorticoid and avoidance of steroid use.

At baseline, similar percentages of BICLA responders and BICLA nonresponders were taking oral glucocorticoid at any dose and at 10 mg/day or more. BICLA responders, compared with BICLA non-responders, had a greater reduction in daily oral glucocorticoid dosage from baseline to week 52 (least squares [LS] mean difference of 4. 29 mg/day, 95% CI -5.37 to -3.20, nominal P-value less than 0.001) (Fig. 28B). The secondary endpoint of a sustained reduction in oral glucocorticoid dosage to 7.5 mg/day or less among patients who received oral glucocorticoid at 10 mg/day or more at baseline was achieved by a greater number of patients responding to treatment according to BICLA compared with patients not responding to treatment according to BICLA (79.2% vs 19.1%; difference 60.1%, 95% CI 52.1% to 68.1%, nominal P -value less than 0.001) (Fig. 28C). Mean (SD) cumulative dose of glucocorti

- 46 046025 oral coid up to week 52 was 31.3% lower in BICLA responders compared to BICLA non-responders (2159.20 [1661.39] mg vs. 3140.81 [3081.19] mg) (Fig. 28D).

PRO.

At baseline, FACIT-F, SF-36 MCS, and SF-36 PCS scores were similar between BICLA responders and BICLA nonresponders (Table 11). Improvement according to FACIT-F was reported in more BICLA responders than BICLA non-responders (55.6% vs 15.7%; difference 40.0%, 95% CI vs 33.6% to 46.3%, nominal P-value less than 0.001) (Fig. 29A). Similarly, more BICLA responders than BICLA nonresponders improved above the prespecified SF-36 PCS threshold (57.9% vs. 12.8%; difference 45 .1%, 95% CI 38.9% to 51.3%, nominal P-value less than .001) and SF-36 MCS (42.6% vs. 12.3%; difference 30.3%, 95 % CI 24.1% to 36.5%, nominal P-value less than 0.001) (Fig. 29A-C).

Table 11

PRO Scores at Baseline in BICLA Responders and BICLA Nonresponders

PRO Patients responding to treatment according to BICLA (η equals 318) Patients not responding to treatment according to BICLA (η equals 501) FACIT-F η 311 467 Mean(SD) 26.3 (12.63) 25.3 (11.99) SF-36 PCS η 312 469 Mean(SD) 38.3 (9.20) 37.0 (9.25) SF-36 MCS n 312 469 Mean(SD) 43.8 (11.35) 44.0 (11.24) PtGA n 311 467 Mean(SD) 54.7 (23.36) 55.8 (21.44)

BICLA: British Lupus Group Comprehensive Assessment for Lupus; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire; MCS: mental health index; PCS: physical health index; PRO: patient-reported outcome; PtGA: patient global assessment; SD: standard deviation; SF-36-v2: Health Questionnaire Short Form 36 Version 2 (Acute Relapse).

PtGA.

At baseline, PtGA scores were similar between BICLA responders and BICLA nonresponders. Greater improvements in PtGA scores from baseline to week 52 were observed in BICLA responders than in BICLA non-responders (LS mean difference -11.1, 95% CI of - 14.9 to -7.3, nominal P-value less than 0.001) (Fig. 29D).

Use of medical resources.

During the 52-week trial, fewer BICLA responders than BICLA non-responders had follow-up visits (62.5% vs. 70.7%; difference -8.3 %, 95% CI -14.9% to -1.6%, nominal P-value 0.015) (Table 12). Fewer BICLA responders had emergency department (ED) visits compared with nonresponders (11.9% vs. 21.8%; difference -9.9%, 95% CI -15.2% to 4.5%, nominal P-value 0.001), and fewer ED visits were associated with increased SLE activity (2.6% versus 24.0%; difference -21, 4%, 95% CI -35.3% to -7.5%, nominal P-value 0.003). Similarly, fewer BICLA responders than BICLA nonresponders had hospital visits (4.5% vs. 14.4%; difference -10.0%, 95% CI -14.3% to -5.7%, nominal P-value less than 0.001), and none of the hospital visits were associated with increased activity

- 47 046025

SLE among BICLA responders versus 38.5% among BICLA nonresponders (difference -38.5%, 95% CI -58.8% to -18.2%, nominal P-value is less than 0.001).

Table 12

Use of medical resources by BICLA-responsive and BICLA-nonresponsive patients

Patients responding to Patients not responding to Use of medical resources treatment according to BICLA, at week 52 (n equals 318) treatment according to BICLA, at week 52 (n equals 501)

Health monitoring visits (specialist and primary care)

Patients with 1 follow-up visit

198 (62.5) 348 (70.7) health or more ³ , η (%)

Comparison between groups, difference (95%

-8.3 (-14.9 to -1.6), 0.015 CI), nominal P-value

Emergency Department Visits

Patients with 1 or more ED visit ^3.η (%) 38(11.9) 107(21.8) Comparison between groups, difference (95% CI), nominal P-value -9.9(-15.2 to- 4.5), < 0.001 Visit associated with increased SLE activity ^a , η (%) 1 (2.6) 25 (24.0) Comparison between groups, difference (95% CI), nominal P-value -21.4(-35.3 to -7.5), 0.003 Number of ED visits per patient ¹³ , mean (SD) 1.4 (0.86) 1.7(1.48) G hospitalization Patients with 1 or more hospital visits ^3.η (%) 14 (4.5) 71 (14.4) Comparison between groups, difference (95% CI), nominal P-value -10.0 (-14.3 to -5.7), < 0.001 Visit associated with increased SLE ³ activity, η (%) 0 25 (38.5) Comparison between groups, difference (95% CI), nominal P-value -38.5 (-58.8 to- -18.2), <0.001 Number of hospital visits per patient ¹³ , mean (SD) 1.6(2.13) 1.4 (0.72) Length of hospital stay ¹³ , mean (SD), days 5.7 (2.64) 7.4 (8.02) Total days in ICU ^b , η 0 5 Number of days in ICU, mean (SD) - 1.8 (0.45)

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; ED: emergency department; ICU: intensive care unit; SD: standard deviation; SLE: systemic lupus erythematosus.

^a Percentages, difference values, CI values, and nominal P-values were calculated using the stratified CMH approach. ^b Data on hospital visits and emergency department visits were missing for 8 patients in the BICLA non-responder group.

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SLEDAI-2K and PGA.

Mean (SD) SLEDAI-2K and PGA scores were similar between responders and nonresponders at baseline (Table 1). From baseline to week 52, greater improvements were seen in BICLA responders than in BICLA non-responders as measured by the SLEDAI-2K total score (LS mean difference -3 .5, 95% CI -4.1 to -3.0, nominal P-value less than 0.001) (Figure 30A) and PGA score (LS mean difference -0.59, 95% CI -0.67 to -0.51, nominal P-value less than 0.001) (Fig. 30B).

Activity according to CLASI.

A total of 32.4% of BICLA responders and 25.5% of BICLA nonresponders had a CLASI-A score of 10 or greater at baseline (Table 1). Among these patients, more BICLA responders compared with BICLA non-responders achieved a 50% or greater reduction in CLASI-A at week 52 (92.0% vs 23.2%; difference 68.8%, 95% CI 59.2% to 78.3%, nominal P-value less than 0.001) (Fig. 31A).

Number of joints.

The mean (SD) counts of active joints (defined as joints with swelling and tenderness) at baseline were 6.1 (5.22) and 6.9 (5.97) in BICLA responders and non-responders. responding to treatment according to BICLA, respectively. The mean (SD) numbers of swollen joints were 6.5 (5.27) and 7.4 (6.08), respectively, and numbers of tender joints were 9.8 (6.94) and 11.1 (7.85), respectively. . From baseline to week 52, improvement in joint counts was greater in BICLA responders than in BICLA non-responders for active counts (LS mean difference: - 1.9, 95% CI -2.4 to -1.4, nominal P-value less than 0.001), painful (LS mean difference -3.6, 95% CI -4.4 to -2.8, nominal P-value less than 0.001) and swollen (LS mean difference -2.1, 95% CI -2.7 to -1.6, nominal P-value less than 0.001 ) joints (Fig. 31B).

Serological indicators.

Equal percentages of patients were positive for anti-dsDNA antibodies at baseline between BICLA responders and BICLA non-responders. Improvement in anti-dsDNA antibody status from positive to negative was observed in similar percentages of BICLA responders and BICLA non-responders (5.0% versus 4.4%) (Table 13 ).

Table 13

Changes in serology from baseline to week 52 in BICLA responders and BICLA non-responders

Change from baseline to week 52 BICLA responders at week 52 (n = 318) BICLA non-responders at week 52 (n = 501) Antibodies to dsDNA ^a η 132 147 Shift from positive to 16 (5.0) 22 (4.4) negative, η (%) Shift from negative to 8 (2.5) 16 (3.2) positive, η (%) Remained negative, η (%) 114(35.8) 142 (28.3) Remained positive, η (%) 116(36.5) 125 (25.0) SZ complement system ¹⁵ η 121 127 Shift from abnormal 33 (10.4) 35 (7.0) to normal, η (%) Shift from normal to normal 14 (4.4) 30 (6.0) to deviating from the norm, η (%)

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Remained normal, η (%) 167 (52.5) 193 (38.5)

Remained abnormal, η (27.7) 92 (18.4) (%)

Mean change determined by LS method, % (95% CI) 15.7 (9,489 to 21,926) 12.9 (6,852 to 18,929) Average difference determined by LS method, % (95% CI), nominal P-value Complement system C4 2.8 (-4.19 to 9.82), 0.429 η Shift from abnormal to normal, η (%) Shift from normal to normal to abnormal, η (%) 70 79 24 (7.5) 24 (4.8) 9 (2.8) 20 (4.0) Remained normal, η (%) Remained abnormal, η (%) Average change determined by LS method, % (95% CI), g/l Average difference determined by 222 (69.8) 251 (50.1) 46(14.5) 55 (11.0) 19.5 (5,664 to 33,336) 29.1 (16,066 to 42,198) LS method, % (95% CI), nominal P-value -9.6 (-25.17 to 5.91), 0.223

BICLA: British Lupus Group Comprehensive Assessment for Lupus; CI: confidence interval; dsDNA: double-stranded DNA; max: maximum; min: minimum; SD: standard deviation.

^a Positive or negative for dsDNA antibodies was defined as a result greater than 15 U/mL or 15 U/mL or less, respectively.

^b Abnormal or normal complement C3 levels were defined as a result less than 0.9 g/L or a C3 level less than 0.9 g/L, respectively.

^c Abnormal or normal complement C4 levels were defined as a result of less than 0.1 g/L or a C3 level of less than 0.1 g/L, respectively.

Only patients with anti-dsDNA antibody positivity or abnormal complement C3 or C4 levels at baseline were included in the analysis. Percentage change, difference, CI, and nominal P-values calculated using a repeated measures model with fixed effects for value at baseline, arm, visit, study, and stratification factors. An interaction term with a treatment by visit factor effect was used to account for the different interactions between groups, and visit was a repeated variable in the model. Percentages did not add up to 100% due to missing data.

Similar proportions of BICLA responders and BICLA nonresponders had abnormal C3 and C4 levels at baseline. The percentage changes in complement molecule levels from baseline to week 52 did not differ between BICLA responders and BICLA non-responders in C3 (LS mean difference 2.82, 95% CI -4.185 to 9.819, nominal P-value 0.429) or C4 (LS mean difference -9.63, 95% CI -25.174 to 5.910, nominal P-value 0.223) ( Table 13). More BICLA responders than BICLA nonresponders had improvements in abnormal C3 (10.4% vs. 7.0%) and C4 (7.5% vs. 4.8%) to normal.

Safety.

The incidence of AEs was similar between BICLA responders and BICLA non-responders (83.6% and 85.2%) (Table 14). Mild to moderate AEs were reported at similar rates in BICLA responders and BICLA non-responders, whereas fewer BICLA responders than BICLA non-responders experienced Severe AE (3.8% vs. 9.4%). There were no AEs leading to termination.

- 50 046025 treatment (DAE) in BICLA responders, compared to 8.2% DAE in non-responders. Fewer BICLA responders than BICLA nonresponders experienced serious AEs (5.0% vs. 19.0%). Fewer BICLA responders than BICLA nonresponders had serious nonopportunistic infections (2.2% versus 6.8%). The percentage of patients with herpes zoster was similar among BICLA responders and BICLA non-responders (4.7% versus 3.6%), as was the percentage of patients with influenza (1.9% compared with 2.0%) or malignancy (0.6% compared with 1.0%).

Table 14

AE during treatment in BICLA responders and BICLA non-responders

Patients, BICLA non-responders at week 52 (n = 501) AE, η (%) BICLA responders at week 52 (n = 318) Patients with any AE Any AE with an outcome that is 266 (83.6) 427 (85.2) death Any SAE (including events with an outcome 0 2(0.4) representing death) 16 (5.0) 95 (19.0) Lupus-related SAEs 1 (0.3) 15 (0.3) Lupus nephritis 0 1 (0.2) SLE 1 (0.3) 14 (2.8) Any DAE 0 41 (8.2) Any AE associated with the test product Any AE at maximum recorded intensity 101 (31.8) 160 (31.9) Mild degree 126 (39.6) 183 (36.5) Moderate degree 128 (40.3) 197 (39.3) Severe degree 12(3.8) 47 (9.4) Any AESI 27 (8.5) 67(13.4) Serious non-opportunistic infection 7 (2.2) 34 (6.8) Opportunistic infections 0 1 (0.2) Anaphylaxis 0 1 (0.2) Malignant neoplasm 2 (0.6) 5 (1.0) Herpes zoster 15 (4.7) 18 (3.6) Tuberculosis (including latent TV) 2 (0.6) 1 (0.2) Flu 6 (1.9) 10 (2.0) Vasculitis not associated with SLE Severe cardiovascular adverse event 0 0 phenomenon 1 (0.3) 1 (0.2)

AE: adverse event; AESI: Adverse Event of Special Interest; DAE: adverse event leading to treatment discontinuation; SAE: serious adverse event; SLE: systemic lupus erythematosus; TB: tuberculosis.

Conclusions.

BICLA is a dichotomous treatment outcome measure for SLE that allows a patient to be classified as a treatment responder or non-responder based on changes in activity according to the organ assessment category. Because BICLA is primarily used in clinical trial settings, the purpose of this study was to evaluate the significance of BICLA response in terms of outcomes that are relevant to patients and

- 51 046025 doctors. In this post hoc analysis of pooled data from 819 patients enrolled in the TULIP-1 and TULIP-2 trials, BICLA response was significantly associated with improved clinical outcomes across a range of SLE, core PRO, and health care resource utilization measures.

Exacerbations with or without increasing the dose of glucocorticoid pose significant risks for patients with SLE. In the long term, both disease exacerbations and oral glucocorticoid use have been associated with organ damage, which itself increases the risk of mortality. Exacerbations are also associated with decreased health-related quality of life, and exacerbation severity and oral glucocorticoid use correlate with health care costs. Therefore, the primary goal of treatment for SLE is to prevent exacerbations while minimizing exposure to oral glucocorticoids, which in turn is expected to reduce the use of medical resources. The present inventors observed that patients responding to treatment according to BICLA had fewer exacerbations of the disease along with a lower daily dose of oral glucocorticoid. A greater percentage of BICLA responders achieved a sustained reduction in oral glucocorticoid dose to the target dose. They also had fewer hospitalizations and ED visits than nonresponders, including those associated with increased SLE activity. Greater improvements in global and tissue-specific disease activity were also observed in responders compared with nonresponders, as measured by PGA, SLEDAI-2K, CLASI-A, and joint counts. Because improved patient outcomes with respect to disease activity and exposure to oral glucocorticoids have been shown to be associated with reduced healthcare costs, patients responding to treatment under the BICLA may incur lower healthcare costs than patients not responding to treatment under the BICLA. BICLA.

The present inventors also evaluated adverse events in BICLA responders and BICLA non-responders. Comparable to lower exacerbation rates, decreased healthcare resource utilization, and fewer SLE-related ED visits and BICLA response-related hospitalizations in BICLA responders compared with BICLA non-responders , there was less SAE. Although discontinuation of study product treatment for any reason resulted in the patient being classified as a BICLA nonresponder by definition, it should be noted that BICLA nonresponders were more likely to discontinue treatment due to an AE. than patients responding to treatment according to BICLA.

PROs have been included in almost all clinical trials for SLE. However, analyzes often resulted in discrepancies between clinical outcomes and PROs because patient perceptions of disease activity and disease are highly dependent on fatigue and quality of life and are not reflected by formal measures of disease activity. In the TULIP trials, patients responding to BICLA treatment had improvements in validated PROs, including physical and mental health indices of the SF-36 Health Questionnaire and FACIT fatigue scores. Fatigue, a common symptom in patients with SLE, interferes with daily life, and more than half of BICLA responders in the TULIP trials experienced improvement in fatigue. PtGA and PGA scores showed consistency in improvement and greater improvement among BICLA responders compared with BICLA nonresponders. The results obtained by the present inventors demonstrate that the BICLA response conveys overall improvements in the physical and mental status of patients with SLE.

A study of correlations of SRI(4) response with clinical outcomes in pooled data from 2 phase 2b trials (sifalimumab and anifrolumab) and 2 phase 3 trials of belimumab also demonstrated improved clinical outcomes in patients responding to SRI(4) treatment. , compared with patients who do not respond to treatment according to the SRI(4). While changes in serological outcomes were not significantly different between BICLA responders and BICLA non-responders in the TULIP trials, SRI(4) response was associated with significant improvements in anti-BICLA antibody levels. dsDNA and complement C3 levels (but not C4 levels) in phase 3 trials of belimumab. This discrepancy may be a reflection of different mechanisms of action of the 2 drugs evaluated and/or a reflection that BILAG-2004, which measures improvement under BICLA, does not include serological testing in its scoring system.

The data support the value of BICLA as a clinical trial endpoint and that response according to BICLA correlates with improvements in a range of other outcomes that are consistent with the priorities of both clinicians and patients in daily practice.

- 52 046025

Table 8

PRO Scores at Baseline in BICLA Responders and BICLA Nonresponders

PRO Patients responding to treatment according to BICLA (η equals 318) Patients not responding to treatment according to BICLA (η equals 501) FACIT-F n 311 467 Mean(SD) 26.3 (12.63) 25.3 (11.99) SF-36PCS n 312 469 Mean(SD) 38.3 (9.20) 37.0 (9.25) SF-36 MCS n 312 469 Mean(SD) 43.8 (11.35) 44.0 (11.24) PtGA n 311 467 Mean(SD) 54.7 (23.36) 55.8 (21.44)

BICLA: British Lupus Group Comprehensive Assessment for Lupus; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire; MCS: mental health index; PCS: physical health index; PRO: patient-reported outcome; PtGA: patient global assessment; SD: standard deviation; SF-36-v2: Health Questionnaire Short Form 36 Version 2 (Acute Relapse).

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Sequence listing <110> AstraZeneca AB <120> SUPPRESSION OF TYPE I INTERFERON IN SYSTEMIC LUPUS ERYTHEMATOSUS <130> IFNAR-720-WO-PCT <160> 8 <170> BiSSAP 1.3.6 <210> 1 <211> 117 <212> PROTEIN <213> Artificial sequence

- 56 046025 <220>

<223> VH <400> 1

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly

5 1015

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ile Phe ThrAsn

2530

Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Cys Leu Glu Ser 35 4045

Gly Leu Leu Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser 50 5560

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Thr Thr Ala 65 7075

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr 85 9095

Ala Arg His Asp Ile Glu Gly Phe Asp Tyr Trp Gly Arg Gly Thr 100 105110

Val Thr Val Ser Ser 115 <210> 2 <211> 108 <212> PROTEIN <213> Artificial sequence <220>

<223> VL <400> 2

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro

5 1015

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val SerSer

2530

Phe Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 35 4045

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Leu 50 5560

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu 65 7075

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Ser Ser 85 9095

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100105 <210> 3 <211> 5 <212> PROTEIN <213> Artificial sequence

Glu

Tyr

Met

Phe

Tyr 80

Cys

Leu

Gly

Ser

Leu

Ser

Glu 80 Ala <220>

<223> HCDR1 <400> 3

Asn Tyr Trp Ile Ala 1 5 <210> 4 <211> 17 <212> PROTEIN

- 57 046025 <213>

Artificial sequence <220>

<223>HCDR2 <400>4

Leu Leu Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln

5 10 15

Gly <210> 5 <211> 8 <212> PROTEIN <213> Artificial sequence <220>

<223>HCDR3 <400>5

His Asp Ile Glu Gly Phe Asp Tyr 1 5 <210> 6 <211> 12 <212> PROTEIN <213> Artificial sequence <220>

<223> LCDR1 <400> 6

Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Phe Ala

5 10 <210> 7 <211> 7 <212> PROTEIN <213> Artificial sequence <220>

<223> LCDR2 <400> 7

Gly Ala Ser Ser Arg Ala Thr

5 <210> 8 <211> 9 <212> PROTEIN <213> Artificial sequence <220>

<223> LCDR3 <400> 8

Gln Gln Tyr Asp Ser Ser Ala Ile Thr

5

Claims (10)

CLAIM 1. A method of treating systemic lupus erythematosus (SLE) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a type I interferon receptor (IFN) inhibitor (IFNR), wherein at baseline the subject has a low expression profile of genes under type I interferon control (IFNGS), compared to a healthy subject, wherein the IFNR inhibitor reduces SLE disease activity in the subject and where the IFNR inhibitor is an antibody comprising: a) the complementarity determining region of the heavy chain variable region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 3; b) the complementarity determining region of the heavy chain variable region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 4; c) the complementarity determining region of the heavy chain variable region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 5; d) a light chain variable region 1 complementarity determining region (LCDR1) containing the amino acid sequence of SEQ ID NO: 6; e) a light chain variable region 2 complementarity determining region (LCDR2) containing the amino acid sequence of SEQ ID NO: 7; and a light chain variable region 3 complementarity determining region (LCDR3) containing the amino acid sequence of SEQ ID NO: 8; and wherein the subject's IFNGS at baseline is measurable by a quantitative DNA polymerase chain reaction test, wherein the test measures the expression of IFI27, IFI44, IFI44L and RSAD2 in whole blood of the subject. 2. The method of claim 1, wherein the reduction in SLE disease activity in the subject comprises a response according to the BILAG-based Comprehensive Lupus Assessment (BICLA) in the subject. 3. The method of claim 1 or 2, wherein the subject has moderate to severe SLE. 4. Method according to any one of claims 1-3, where the antibody contains: a) a human heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1; And b) a human light chain variable region containing the amino acid sequence of SEQ ID NO: 2. 5. The method according to any one of claims 1 to 4, where the antibody is anifrolumab or a functional variant thereof. 6. The method of claim 5, wherein the method comprises administering to the subject a 300 mg dose of an IFNR inhibitor. 7. The method of claim 5 or 6, comprising administering a dose of an IFNR inhibitor to the subject once every four weeks. 8. The method according to any one of claims 1 to 7, wherein the IFNR inhibitor is administered to the subject intravenously. 9. The method according to any one of claims 1 to 5, wherein the IFNR inhibitor is administered to the subject subcutaneously. 10. The method of any one of claims 1 to 9, wherein the subject is positive for anti-double-stranded DNA antibodies (anti-dsDNA antibodies), antinuclear antibodies, or anti-Smith antigen antibodies at baseline.