NEW THERAPEUTIC USE OF ANAKINRA FOR COVID-19

Abstract

A method treats a SARS-CoV-2 infection with anakinra. In particular the method treats or alleviates symptoms of respiratory distress and/or hyperinflammation in a patient. The treatment includes administering to a patient in need thereof a daily dose of at least about 400 mg of anakinra.

Claims

1-34. (canceled)

35. A method of treatment of a SARS-COV-2-infection in a subject in need thereof, said treatment comprising: administering a daily dose of at least about 400 mg of anakinra to the subject in need thereof.

36. The method of treatment of a SARS-COV-2-infection according to claim 35, wherein said daily dose is distributed over four administration occasions of 100 mg each.

37. The method of treatment of a SARS-COV-2-infection according to claim 36, wherein said administration occasions are from about 4 to about 8 hours apart.

38. The method of treatment of a SARS-COV-2-infection according to claim 37, wherein said administration occasions are about 6 hours apart.

39. The method of treatment of a SARS-COV-2-infection according to claim 35, wherein said treatment is continued for at least 7 days.

40. The method of treatment of a SARS-COV-2-infection according to claim 35, wherein anakinra is administered by intravenous (i.v.) infusion.

41. The method of treatment of a SARS-COV-2-infection according to claim 35, wherein said treatment further comprises administration of a further therapeutic agent selected from the group consisting of one or more of: an anti-inflammatory agent, an antibiotic, an anti-fungal agent, and an anti-viral agent.

42. The method of treatment of a SARS-COV-2-infection according to claim 41, wherein said agent is an antiinflammatory agent.

43. The method of treatment of a SARS-COV-2-infection according to claim 42, wherein said anti-inflammatory agent is methylprednisolone.

44. The method of treatment of a SARS-COV-2-infection according to claim 43, wherein methylprednisolone is administered at daily dose of at least 15 mg.

45. The method of treatment of a SARS-COV-2-infection according to claim 44, wherein said daily dose of methylprednisolone is distributed over three administration occasions.

46. The method of treatment of a SARS-COV-2-infection according to claim 44, wherein methylprednisolone is administered at a daily dose of 60 mg for at least 3 days.

47. The method of treatment of a SARS-COV-2-infection according to claim 44, wherein methylprednisolone is administered at a daily dose of 60 mg, distributed over three administration occasions, on day 1 to day 5 of a treatment period.

48. The method of treatment of a SARS-COV-2-infection according to claim 44, wherein methylprednisolone is administered at a daily dose of 30 mg distributed over three administration occasions for at least 3 days.

49. The method of treatment of a SARS-COV-2-infection according to claim 48, comprising administration of methylprednisolone at a daily dose of 30 mg, distributed over three administration occasions, on day 6 to day 10 of a treatment period.

50. The method of treatment of a SARS-COV-2-infection according to claim 44, wherein methylprednisolone is administered at a daily dose of 15 mg distributed over three administration occasions for at least 4 days.

51. The method of treatment of a SARS-COV-2-infection according to claim 50, wherein methylprednisolone is administered at a daily dose of 15 mg, distributed over three administration occasions, on day 11 to day 14 of a treatment period.

52. The method of treatment of a SARS-COV-2-infection according to claim 35, wherein said treatment does not include concomitant administration of one or more of the following agents: tocilizumab, canakinumab, TNF inhibitors, MK inhibitors, and/or hydroxychloroquine.

53. The method of treatment of a SARS-COV-2-infection according to claim 35, wherein the treatment comprises a treatment of symptoms of SARS-CoV-2 infection.

54. The method of treatment of a SARS-COV-2-infection according to claim 53, wherein said treatment of symptoms is for the symptoms of hyperinflammation and/or respiratory distress.

55. The method of treatment of a SARS-COV-2-infection according to claim 54, wherein said subject exhibits signs of respiratory distress.

56. The method of treatment of a SARS-COV-2-infection according to claim 55, wherein said subject exhibits one or more of the following signs of respiratory distress: PaO2/FiO2 ≤300 mmHg and >200 mmHg, RR ≥30 breaths/min, and/or SpO23 93% in air at rest.

57. The method of treatment of a SARS-COV-2-infection according to claim 54, wherein said subject exhibits signs of hyperinflammation.

58. The method of treatment of a SARS-COV-2-infection according to claim 57, wherein said subject exhibits one or more of the following signs of hyperinflammation: Ferritin >500 ng/mL, LDH >300 LA, and/or D-dimers >1000 ng/mL.

Description

DETAILED DESCRIPTION

[0032] SARS-CoV-2 belongs to the broad family of viruses known as coronaviruses. It is a positive-sense single-stranded RNA (+ssRNA) virus. Its RNA sequence is approximately 30,000 bases in length. The SARS-CoV-2 genome sequence information has been made publicly available and can be found e.g. in the NCBI database, genome ID: MN908947.

[0033] Components in a protein drug formulation of anakinra may include buffering agents, tonicity agents, antioxidants, stabilizers, surfactants, bulking agents, chelating agents and preservatives. Kineret®, a formulation of anakinra at pH 6.5 suitable for injection, contains sodium citrate, sodium chloride, disodium EDTA, polysorbate 80 and water.

[0034] The following clinical study protocol synopsis describes a phase 2/3, randomized, open-label, parallel group, 3-arm, multicenter study to investigate the efficacy and safety of intravenous administrations of anakinra, an interleukin-1 (IL-1) receptor antagonist, and emapalumab, an anti-interferon gamma (anti-IFNγ) monoclonal antibody, versus standard of care in reducing hyper-inflammation and respiratory distress in patients with SARS-CoV-2 infection.

[0035] Main Study Objectives

[0036] The main objectives of the study are: [0037] To assess the effect of emapalumab and anakinra on hyper-inflammation and pulmonary function in patients with SARS-CoV-2 infection [0038] To evaluate the safety and tolerability profile of intravenous (i.v.) administrations of emapalumab and anakinra in patients with SARS-CoV-2 infection [0039] To confirm the proposed dosing regimen of emapalumab and anakinra.

[0040] Study Population

[0041] Patients with documented SARS-CoV-2 infection with respiratory distress and hyperinflammation.

[0042] Inclusion Criteria [0043] Patients of both genders [0044] Age >30 years and <80 years [0045] Documented presence of SARS-CoV-2 infection [0046] Presence of respiratory distress defined as: [0047] PaO2/FiO2 <300 mm Hg and >200 mm Hg or [0048] RR ≥30 breaths/min or [0049] SpO2 ≤93% in air at rest [0050] Note: Patients in CPAP are eligible. [0051] Presence of hyper-inflammation defined as: [0052] Ferritin >500 ng/mL [0053] LDH >300 U/L [0054] D-dimers >1000 ng/mL [0055] Signed informed consent provided by the patient, or by the patient's legally authorized representative(s), as applicable.

[0056] Exclusion Criteria [0057] Patients in mechanical ventilation or with MEWS score >4 with evidence of moderate or above ARDS (Berlin definition, namely with PaO2/FiO2 >100, but ≤200 mm Hg) or severe respiratory insufficiency or evidence of rapid worsening (respiratory distress requiring mechanical ventilation or presence of shock or presence of concomitant organ failure requiring ICU admission) [0058] Impairment of cardiac function defined as poorly controlled heart diseases, such as NYHA class II (mild*) and above, cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, supraventricular or respiratory insufficiency or evidence of rapid worsening (respiratory distress requiring mechanical ventilation or presence of shock or presence of concomitant organ failure requiring ICU admission) [0059] Impairment of cardiac function defined as poorly controlled heart diseases, such as NYHA class II (mild*) and above, cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, supraventricular or ventricular arrhythmia need treatment or intervention. [0060] * Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain [0061] Severe renal dysfunction (estimated glomerular filtration rate ≤30 mL/min/1.73 m.sup.2) or receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis [0062] Uncontrolled hypertension (seated systolic blood pressure >180 mmHg, or diastolic blood pressure >110 mmHg) [0063] Administration of plasma from patients recovered from SARS-CoV-2 infection [0064] Clinical suspicion of latent tuberculosis [0065] History of hypersensitivity or allergy to any component of the study drug [0066] Pregnancy

[0067] Study Drug

[0068] Anakinra is the recombinant form of the IL-1 human receptor antagonist (IL-1ra). Emapalumab is a fully human IgG1 monoclonal antibody (mAb) neutralizing human IFNγ.

[0069] Dosing Regimen, Frequency of Administration and Treatment Duration:

[0070] Anakinra will be administered at a total dose of 400 mg per day, divided in 4 i.v. doses of 100 mg every 6 hours. Anakinra treatment will continue for 15 days i.e., days 1 to 15.

[0071] Emapalumab will be administered at the initial dose of 6 mg/kg by i.v. infusion i.e., Day 1. Emapalumab treatment will be continued at the dose of 3 mg/kg, every 3 days for a total of 4 additional infusions i.e., Days 4, 7, 10 and 13.

[0072] Background Therapy and Concomitant Medication

[0073] All patients participating in the study will receive background therapy with methylprednisolone. methylprednisolone will be given at 20 mg×3/day for 5 days, then 10 mg×3/day for 5 days, then 5 mg×3/day for 4 days. Concomitant use of tocilizumab, canakinumab, TNF inhibitors, JAK inhibitors and hydroxychloroquine is not allowed.

[0074] Antimicrobial therapy and prophylaxis are not limited.

[0075] Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, i.v. parenteral nutrition, inotropic support, antibiotics, anti-fungal and anti-viral treatments, ultrafiltration or hemodialysis, as well as general supportive care are permitted.

[0076] Sample Size

[0077] 54 patients in total

[0078] Study Duration and Study End Definition

[0079] The study consists of screening, a 2-week treatment period and an 8-week follow-up period. The 2-week treatment period is open, and the patients will be randomized to treatment with emapalumab, anakinra or standard of care in a 1:1:1 ratio. The primary endpoint will be evaluated at Day 15.

[0080] A follow-up by visit or phone call will be performed 4 and 8 weeks after the end of the treatment period (Weeks 6 and 10).

[0081] The study duration for an individual patient will not exceed 10 weeks.

[0082] The end of the study is defined as last patient last follow-up visit/phone call (LPLV).

[0083] Data Review Committee

[0084] A committee composed of experts in intensive care, inflammation, infectious diseases will be involved in study oversight and interpretation of the study results.

[0085] Study Endpoints

[0086] The assessment of emapalumab and anakinra efficacy in this patient population will be based on: [0087] Primary endpoint: Rate of treatment success, defined as the percentage of patients not requiring any of the followings: [0088] Invasive mechanical ventilation or [0089] Extracorporeal membrane oxygenation (ECMO) or [0090] Continuous positive airway pressure (CPAP) [0091] Secondary efficacy endpoints: [0092] Time to mechanical ventilation [0093] Change from baseline in MEWs score [0094] Evolution of hyperinflammatory parameters during treatment until SD15 with measurements performed every 3 days: Ferritin, LDH, D-dimers. [0095] Evolution of other relevant laboratory parameters during treatment until SD15 with measurements performed every 3 days: WBC with differential counts, RBC, Hb, Platelet count, Fibrinogen, Complement C3/C4, Prothrombin Time, Cardiac troponin, Liver tests (AST, ALT, total bilirubin levels), CRP and ESR, Creatinine, Survival [0096] Safety Endpoints: [0097] Treatment-emergent severe fatal and life-threatening serious adverse events (SAEs). [0098] Adverse events leading to premature discontinuation of study treatment. [0099] Anaphylactic/anaphylactoid reactions [0100] Emapalumab treatment emergent AEs of special interest: infections caused by pathogens potentially favored by IFN-y neutralizations such as mycobacteria, salmonella, shigella, herpes zoster, and histoplasma capsulatum; severe infusion related reactions [0101] Anakinra treatment emergent AEs of special interest: severe neutropenia [0102] Treatment-emergent laboratory abnormalities. [0103] CXCL9, IL-1, IL-6, sIL-2R and selected exploratory parameters every 3 days, whenever possible.

[0104] Visits Schedule and Assessments

[0105] The clinical and laboratory parameters to be collected at given time points are indicated in Table 1 (Schedule of Events). This schedule also includes information on the patient's demographics, medical history and prior medication. High resolution CT scan is required at screening (within 72 hours prior to start of treatment) to document the presence of pulmonitis. All parameters indicated in the Schedule of Events will be assessed at the study site.

[0106] Statistics

[0107] Each of the study drug treatment arms is compared independently to standard of care.

[0108] The trial design consists of two stages, with equal numbers of patients randomised into Stage 1 and into Stage 2 per treatment arm.

[0109] At the end of Stage 1 the success rates are compared between each of the two treatment arms and standard of care. There is the potential to stop for futility or for efficacy of emapalumab or anakinra. Note: these rules are binding.

[0110] If the trial continues beyond Stage 1, the groups will be compared to standard of care at the end of Stage 2 for efficacy. The overall one-sided significance level for efficacy for either emapalumab or anakinra is 0.097 (9.7%) to allow the initial acceptance of a potentially valuable new treatment.

[0111] The design has a total sample size of 54, 27 recruited in Stage 1 and 27 recruited in Stage 2 with equal 1:1:1 randomisation.

[0112] This design has the following characteristics for the comparison of each of emapalumab and anakinra with standard of care: [0113] Stop either emapalumab or anakinra (or both) at the end of Stage 1 for futility if the one-sided p-value in favour of emapalumab/anakinra is >0.690 [0114] Stop either emapalumab or anakinra (or both) at the end of Stage 1 for demonstration of efficacy if the one-sided p-value in favour of emapalumab or anakinra is <0.025 [0115] If the trial continues for either emapalumab or anakinra (or both) to

[0116] Stage 2, declare efficacy at the end of Stage 2 if the one-sided p-value in favour of emapalumab or anakinra is <0.159.

[0117] This design has acceptable properties in terms of the false positive potential, controlling the overall type I error at 7.9% for each of the 2 comparisons. The power of this design for each of those comparisons is 74% under the assumption that the true success rates are 50% in the SoC group increasing to 80% in the emapalumab or anakinra groups. The calculations on the operating characteristics of this design have been undertaken using PASS, Version 14: Group-Sequential Tests for Two Proportions (Simulation).

[0118] The value for the type I error has been chosen in recognition of the urgent unmet medical need to allow the identification of a signal, at least, from a statistical perspective. Having seen a statistical signal, it is then a matter of evaluating whether the observed treatment differences represent clinically relevant effects that can satisfy that unmet need.

[0119] In case indications of efficacy require to be confirmed, additional patients may be added into this study. In case the outcome is statistically convincing, i.e. statistically significant on a 5% level in the stage 2 analysis, efficacy will be considered confirmed and the results will, where warranted, be used to seek regulatory approvals.

TABLE-US-00001 TABLE 1 Schedule of events SCREENING TREATMENT PERIOD Up to 3 Visit 1 FOLLOW-UP PERIOD days prior Day 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7/TC Visit 8/TC ASSESSMENT to Visit 1 (Baseline) Day 4 Day 7 Day 10 Day 13 Day 15 Week 6 Week 10 Informed consent X Eligibility criteria X .sup. X.sup.1 Patient information.sup.2 X Physical examination X Vital signs assessment.sup.3 X X X X X X X ECG assessment X X CT scan .sup. X.sup.4 X Laboratory assessments (local).sup.5 X X X X X X X Randomization X IMP administration X-----------------------------------------------------------X Concomitant medication X X X X X X incl background therapy.sup.6 Assessment of pulmonary X X X X X X function.sup.7 Survival X X X X X X X Hospital discharge X X Adverse events.sup.8 X X X X X X X X Biomarkers (CXCL9, IL-1, X X X X X X IL-6, sIL-2R).sup.9 Abbreviations: CPAP, continuous positive airway pressure; CT, computed tomography; ECG, electrocardiogram; ECMO, extracorporeal membrane oxygenation; FDP, Fibrinogen Degradation Products; IMP, Investigational Medicinal Product During the treatment period (Days 1 to 14), clinical and laboratory assessments and procedures should preferably be performed before IMP administration. .sup.1Before IMP administration. .sup.2Includes demographics, medical history and prior medication. .sup.3Body temperature, blood pressure, heart rate, respiratory rate and oxygen saturation. .sup.4Not to be repeated if performed within 72 hours of the first IMP administration. .sup.5Ferritin, LDH, D-dimers. WBC with differential counts, RBC, Hb, Platelet count, Fibrinogen, Complement C3/C4, Prothrombin Time, Cardiac troponin, AST, ALT, total bilirubin levels, CRP, ESR and Creatinine. .sup.6For details, see section on background and concomitant medication. .sup.7Requirement for invasive mechanical ventilation, ECMO, CPAP or high flow oxygen devices and MEWs score. .sup.8Incidence, severity, causality and outcomes of treatment-emergent severe fatal and life-threatening serious AEs, including anaphylactic and anaphylactoid reactions to study drugs, adverse events leading to premature discontinuation of study treatment and adverse events of special interest. .sup.9If possible

[0120] The person skilled in the art realizes that the present invention by no means is limited to the preferred embodiments described above. On the contrary, many modifications and variations are possible within the scope of the appended claims.

[0121] Additionally, variations to the disclosed embodiments can be understood and effected by the skilled person in practicing the claimed invention, from a study of the disclosure and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage.