Combination therapy for preterm infants

Abstract

The present disclosure relates to a method of treating or preventing a preterm infant, the present invention relates to methods for intravenously administering a therapeutic amount of a composition comprising IGF-1 and IBGBP-3 in combination with a therapy selected from the group comprising caffeine, fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine, a low dose of noradrenaline, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (or a composition of the same use), and combinations thereof.

Description

[0001] The present disclosure relates to a combination therapy that includes IGF-1 and IBGBP-3 (eg, as a complex), with compatible drugs / medicines and / or without incompatible drugs / medicines. Background Art

[0002] Premature infants are among the most fragile, vulnerable, and difficult to treat patients.

[0003] The rhIGF-1 / rhIGFBP-3 drug product is a recombinant human (rh) version of the naturally occurring protein complex of insulin-like growth factor-1 (IGF-1) and its most abundant binding protein, insulin-like growth factor binding protein-3 (IGFBP-3). The product is currently being studied for the prevention of complications of preterm birth. It is administered parenterally, particularly by IV infusion. However, in premature infants in the neonatal intensive care unit (NICU), IV access can be a challenge because they often require multiple IV therapies, including different classes of agents and parenteral nutrition (PN).

[0004] Historically, there has been a lack of available compatibility data for medications administered to premature infants. A review of neonatal medication studies found that no documentation of compatibility was available for almost 60% of IV drug-drug infusions and for 34% of IV drug-nutrient co-infusions administered in the neonatal intensive care unit.

[0005] As can be expected, there is a lack of comprehensive drug testing in newborns. US studies report that only 35% of the medicaments administered to newborns are approved for infants by the US Food and Drug Administration, and Italian studies have found that in premature newborn populations, 44% of the medicaments are prescribed off-label. Such findings have potential impacts on the therapeutic efficacy and safety of infants. Most compatibility studies are conducted for the co-administration of small molecules with small molecules. In contrast, the literature is determined for the compatibility testing of only two biologics (insulin and vasopressin), and standard biologic-specific testing methods have not yet been established.

[0006] rhIGF-1 / rhIGFBP-3 is continuously infused and therefore compatibility with other agents is critical.

[0007] The inventors have determined which commonly used drugs can be co-administered with IGF-1 and IGF-BP-3 to premature infants. This may improve the safety and effectiveness of treatment, which is important for the health and survival of these fragile patients. Summary of the invention

[0008] The present invention is provided in the following sections:

[0009] 1. A method of treating or preventing premature infants (also referred to herein as neonates) by intravenously administering a therapeutic amount of a composition comprising IGF-1 and IBGBP-3 (e.g., as a complex) in combination with one or more therapies selected from the group consisting of caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), low-dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (e.g., intravenous fat emulsion with or without electrolytes).

[0010] 1A A composition of IGF-1 and IGFBP-3 (e.g., as a complex) for use in the treatment or prevention of premature infants by intravenous administration in combination with one or more therapies selected from the group consisting of: caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), low-dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (e.g., intravenous fat emulsion with or without electrolytes).

[0011] 1B A composition of IGF-1 and IGFBP-3 (e.g., as a complex) for use in the manufacture of a medicament for treatment or prevention of premature infants by intravenous administration, in combination with one or more therapies selected from the group consisting of: caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), low-dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (e.g., intravenous fat emulsion with or without electrolytes).

[0012] 2. A method of treating or preventing premature infants (also referred to herein as neonates) by intravenously administering a therapeutic amount of a composition comprising IGF-1 and IBGBP-3 (e.g., as a complex) in combination with one or more additional therapies,

[0013] [The one or more additional therapies are, for example, selected from the group comprising: caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), intravenous fat emulsion, parenteral nutrition (e.g., intravenous fat emulsion with or without electrolytes)],

[0014] wherein the additional therapy is not co-administered with a therapy selected from the group consisting of amikacin sulfate, ampicillin sodium, dobutamine (e.g., hydrochloride), dopamine (hydrochloride), furosemide, meropenem, high-dose norepinephrine, penicillin G, vancomycin at a concentration greater than 5 mg / ml, and combinations thereof.

[0015] 2A A composition of IGF-1 and IGFBP-3 (e.g. as a complex) for use in the treatment or prevention of premature infants by intravenous administration, in combination with one or more additional therapies,

[0016] [The one or more additional therapies are, for example, selected from the group comprising: caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), intravenous fat emulsion, parenteral nutrition (e.g., intravenous fat emulsion with or without electrolytes)],

[0017] wherein the additional therapy is not co-administered with a therapy selected from the group consisting of amikacin (sulfate), ampicillin (sodium), dobutamine (e.g., hydrochloride), dopamine (hydrochloride), furosemide, meropenem, high-dose norepinephrine, penicillin G, vancomycin (infused at a concentration of 50 mg / ml or less).

[0018] 2B A composition of IGF-1 and IGFBP-3 (e.g. as a complex) for use in the preparation of a medicament for the treatment or prevention of premature infants by intravenous administration, in combination with one or more additional therapies,

[0019] [The one or more additional therapies are, for example, selected from the group comprising: caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine sulfate, intravenous fat emulsion, parenteral nutrition (e.g., intravenous fat emulsion with or without electrolytes)],

[0020] wherein the additional therapy is not co-administered with a therapy selected from the group consisting of amikacin (sulfate), ampicillin (sodium), dobutamine (e.g., hydrochloride), dopamine (hydrochloride), furosemide, meropenem, high-dose norepinephrine, penicillin G, vancomycin (infused at a concentration of 50 mg / ml or less).

[0021] 3. A method or composition according to any preceding subsection, wherein the combination therapy is co-administered (eg, delivered via the same IV line).

[0022] 4. The method or composition of any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with caffeine (eg, caffeine citrate).

[0023] 5. A method or composition as described in any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with fentanyl.

[0024] 6. A method or composition as described in any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with fluconazole.

[0025] 7. A method or composition as described in any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with gentamicin.

[0026] 8. A method or composition as described in any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with insulin.

[0027] 9. A method or composition as described in any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with midazolam.

[0028] 10. The method or composition of any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with morphine (eg, sulfate).

[0029] 11. A method or composition as described in any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with a low dose of norepinephrine.

[0030] 12. A method or composition according to any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with vancomycin, wherein the latter is infused at a concentration of 5 mg / ml or less, such as less than 5 mg / ml.

[0031] 13. A method or composition according to any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in combination with vancomycin, and the latter is administered as an infusion and does not exceed 50 mg / ml.

[0032] 14. The method or composition of any preceding subsection, wherein IGF-1 and IBGBP-3 are administered in conjunction with parenteral nutrition (eg, intravenous fat emulsion, with or without electrolytes).

[0033] 15. A method or composition according to any one of sections 2 to 14, wherein the additional non-co-administered therapy is administered via a different IV line or by a different route of administration (such as, intramuscular administration).

[0034] 16. A method or composition according to any one of sections 2 to 14, wherein the additional non-co-administered therapy is omitted entirely.

[0035] 17. A method or composition as described in any preceding subsection, wherein the premature infant is within the range of 23 to 34 weeks of gestation when treatment is initiated.

[0036] 18. A method or composition according to any preceding subsection, wherein the premature infant is administered IGF-1 and IGFBP3 by infusion, e.g., continuous infusion, particularly for at least 1 week, e.g., 2 to 6 weeks, such as 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks.

[0037] 19. The method or composition of claim 18, wherein the infusion is initiated within 24 hours after birth, such as within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours and 24 hours after birth, particularly within 1 hour after birth.

[0038] 20. A method or composition according to any one of sections 1 to 19, wherein the composition comprises equimolar amounts of IGF-1 and IGFBP-3.

[0039] 21. A method or composition according to any of the subsections, wherein 200 to 500 μg / Kg / 24 hours of the IGF-1 and IGFBP-3 complex is administered.

[0040] 22. The method or composition of any preceding subsection, wherein 55 to 110 μg / Kg / 24 hours of IGF-1 is administered.

[0041] 23. A method or composition as described in any preceding subsection, wherein serum levels of IGF-1 are maintained within the range of 28 to 109 ng / ml.

[0042] 24. A method or composition according to any one of subsections 1 to 23, wherein the low dose norepinephrine is 0.05 μg / kg / min or less.

[0043] 25. A method or composition according to any one of sections 1 to 23, wherein the pH of the composition comprising IGF-1 and IGFBP3 is 5.5 ± about 0.3, for example wherein the pH is in the range of 5.2 to 5.8.

[0044] Non-combination therapies are incompatible or unstable for formulation or delivery with IGF-1 / IGFBP-3.

[0045] As used herein, "non-co-administered" means: not administered by the same route or not administered in any way, in particular not administered.

[0046] As used herein, IGF-1 / rhIGFBP-3 therapy is recombinant human (rh) insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3), which are typically complexed as a complex, more specifically, in the range of 0.75 to 1.25:1 or 1:0.75-1.25, for example, in a 1:1 complex.

[0047] In one embodiment, the IGF-1 / IGFBP-3 therapy is administered continuously.

[0048] In one embodiment, the combination therapy is administered continuously.

[0049] Therapy as used herein includes parenteral feeding.

[0050] As used herein, "combination" (also called combination therapy) means co-formulation, admixture or co-administration, particularly co-administration by the same route.

[0051] "Generally, a union is a compatible union unless the context indicates otherwise."

[0052] As used herein, "compatible in combination" refers to agents / ingredients / components that are suitable for combined delivery / administration, eg, the components are at least physically and chemically stable when mixed and / or co-formulated.

[0053] Co-administration as used herein refers to simultaneous delivery / administration, particularly by the same route, such as IV, especially via the same IV line. Thus, co-administered agents may be present at the same time, for example, in an IV and / or IV bag.

[0054] In one embodiment, the co-administered agents are in separate formulations.

[0055] Co-formulation as used herein refers to a single pharmaceutical formulation containing two or more agents.

[0056] As used herein, a mixture refers to a preparation / dose that is mixed at or just before administration, i.e., extemporaneously mixed. The latter includes mixing in an IV line or bag, for example by adding a medicament to an already dispensed medicament.

[0057] In one embodiment, combination therapy as used herein refers to therapies that are compatible for delivery with IGF-1 / IGFBP-3, particularly stable when administered in the same formulation, in mixed form, or via the same route, such as the same IV line.

[0058] In one embodiment, the combination therapy employed in the present disclosure is delivered in mixed form (ie, together, simultaneously). Moreover, the stability of the combination agent is sufficient to achieve this.

[0059] In one embodiment, compatible drugs / agents are administered within a short period of time (eg, 1 to 30 min).

[0060] In one embodiment, the compatible drug / agent is administered in the same time period as IGF-1 / IGFBP-3.

[0061] In one embodiment, the stability is physical stability.

[0062] In one embodiment, the stability is chemical stability.

[0063] In one embodiment, the activity of the entity (such as IGF-1 / IGFBP-3 and / or other agent) is stabilized, in particular, the activity is not diminished.

[0064] In one embodiment, the agent is thermally stable, for example at a storage temperature such as 4°C to room temperature.

[0065] In one embodiment, the stability is concentration dependent.

[0066] Changes in physical stability include aggregation, flocculation, and precipitation of particles from solution.

[0067] Changes in chemical stability include degradation, changes in surface charge, changes in pH, or the like.

[0068] Non-combination therapy is generally unstable when mixed with IGF-1 / IGFBP-3. In some embodiments, where available, the additional therapy can be administered separately, for example, from a separate IV line or subcutaneously. Alternatively, the administration of IGF-1 / IGFBP-3 can be stopped to enable the administration of the non-combination therapy. In one embodiment, the administration of IGF-1 / IGFBP-3 is resumed after the administration of the non-combination therapy. If this is not available, the administration of incompatible therapies should be avoided.

[0069] In one aspect, the present invention employs the formulation of IGF-1 and IGFBP-3 described in WO2022 / 086953, which is incorporated herein by reference. The parameters of the disclosed formulations can be used as the basis for amendment of the present claims.

[0070] In some embodiments, the present disclosure employs a pharmaceutical composition comprising a protein complex comprising recombinant insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding protein 3 (rIGFBP-3), and a surfactant at a concentration between about 0.001% v / v and 2.4% v / v (such as, 0.0025% and 0.0075%, in particular about 0.005%), wherein rIGF-1 and rIGFBP-3 are in the range of 0.75 to 1.25:1 or 1:0.75-1.25, for example, complexed in equimolar amounts.

[0071] In some embodiments, the surfactant is a polysorbate surfactant, such as polysorbate 20 (also known as polyoxyethylene sorbitan monolaurate) or polysorbate 80 (also known as polyoxyethylene sorbitan monooleate).

[0072] In some embodiments, the polysorbate surfactant is polysorbate 20.

[0073] In some embodiments, the polysorbate surfactant is polysorbate 80.

[0074] In some embodiments, the concentration of the polysorbate surfactant is between about 0.001% v / v and 2.4% v / v, such as a concentration between about 0.2% and 0.4%.

[0075] In some embodiments, the concentration of the polysorbate surfactant is about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.05%, 0.10%, 0.15%, 0.2%, 0.5%, 0.7%, 1.0%, 1.2%, 1.5%, 1.8%, 2.0%, 2.2%, or 2.4% v / v.

[0076] In some embodiments, the concentration of the polysorbate surfactant is between about 0.0025% v / v and 0.0075% v / v, such as about 0.0025% v / v, about 0.005% v / v or about 0.0075% v / v, in particular about 0.005% v / v.

[0077] In one aspect, the present disclosure relates to a kit comprising a combination therapy according to the present disclosure.

[0078] In one embodiment, the high dose norepinephrine is 2.0 μg / kg / min or more.

[0079] In one embodiment, the high dose norepinephrine is 1.0 μg / kg / min or more.

[0080] In one embodiment, the high dose norepinephrine is more than 0.05 μg / kg / min.

[0081] In one embodiment, the low dose norepinephrine is 1.0 μg / kg / min or less.

[0082] In one embodiment, the pharmaceutical compatibility data is disclosed on the pharmaceutical packaging of IGF-1 / IGFBP-3, leaflets related thereto, a website with its product information, etc.

[0083] In one embodiment, IV administration according to the present disclosure is used in conjunction with surfactant therapy.Surfactants, also known as rescue surfactants, include beracant.

[0084] As used herein, "is" means including.

[0085] In the context of this specification, "comprising" should be interpreted as "including".

[0086] Embodiments of the present invention comprising certain features / elements are also intended to extend to alternative embodiments “consisting of” or “consisting essentially of” the relevant elements / features.

[0087] The embodiments of the present invention may be combined where technically appropriate.

[0088] Technical references such as patents and applications are incorporated herein by reference.

[0089] Any embodiment specifically and explicitly described herein may form the basis for a disclaimer either alone or in combination with one or more further embodiments.

[0090] The background portion can be used as a basis for correction.

[0091] This application claims priority to US63 / 338,221 filed on May 4, 2022, which is incorporated herein by reference, especially the sequence expressly incorporated herein. The priority document may be used to correct errors in this specification.

[0092] The present invention is further described by way of example only, with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] Figure 1 Risk assessment design. RP-HPLC reverse phase high performance liquid chromatography; SEC-HPLC size exclusion high performance liquid chromatography; USP United States Pharmacopeia

[0094] Figure 2-7 Display HPLC graph DETAILED DESCRIPTION

[0095] In this study, the physical compatibility of the rhIGF-1 / rhIGFBP-3 drug product when mixed with commonly administered pharmaceutical agents was investigated. To gain a comprehensive understanding of compatibility, chemical compatibility at the small molecule content level was evaluated as part of a separate study of the protein content / chemical modification.

[0096] This work was undertaken to comprehensively evaluate and establish a comprehensive body of data regarding the compatibility of rhIGF-1 / rhIGFBP-3 with commonly administered intravenous medications to aid clinicians in making decisions regarding co-infusion of rhIGF-1 / rhIGFBP-3.

[0097] Drug compatibility testing studies should be conducted as early as possible in the study period of a neonatal drug to allow sufficient time for the study results to inform clinical trials and ultimately for the drug to be adopted in clinical practice.

[0098] 1.0 Test Reagent

[0099] The test agents were selected based on clinical priority (i.e., agents frequently administered to neonates), as determined by clinical experts and according to the study site of the Phase 2 trial. The 19 agents included in this study were amikacin, ampicillin, caffeine citrate, dobutamine, dopamine, fentanyl citrate, fluconazole, furosemide, gentamicin, insulin, intravenous fat emulsion, meropenem, midazolam, morphine sulfate, norepinephrine bitartrate, penicillin G, custom mixed PN solution (with and without electrolytes), PN solution + intravenous fat emulsion and vancomycin (Table 1 below). Most of the test agents are small molecule drugs, while rhIGF-1 / rhIGFBP-3 (Takeda, Lexington, MA, USA) is a recombinant protein.

[0100] Table 1 Drugs tested in compatibility studies

[0101]

[0102]

[0103] PN Parenteral Nutrition

[0104] a Solutions were studied within 24 h after preparation.

[0105] 2.0 Risk Assessment Design and Overview

[0106] The risk assessment approach was developed by a cross-functional team that included clinicians, neonatal pharmacists, and representatives from the study sponsor’s small molecule, biologics, clinical, and clinical operations product development departments. The risk assessment consisted of three sequential phases: Figure 1 ): (1) in vitro testing to determine the physical and chemical compatibility of rhIGF-1 / rhIGFBP-3 with other agents (small molecules only); (2) a risk assessment for each agent tested, taking into account the known theoretical potential for chemical modification, proximity to the isoelectric point of the protein when not in a mixture (based on pH and the likelihood of chemical modification), and clinical co-infusion history (including co-administration with insulin, which has substantial homology to rhIGF-1); and (3) risk planning, based on an assessment of low, moderate, or high risk of incompatibility.

[0107] 3.0 Hybrid Solution

[0108] A kind of mixed model is developed, wherein rhIGF-1 / rhIGFBP-3 and test agent are mixed with one or more representative clinical doses.For all studies, appropriate standardization (time and neonatal weight) is used for mixed calculation to design a volume-based scheme.For these calculations, a dose of 250 μg / kg / 24 hours (the dose used in Phase 2 trials) and at least two small molecule agents (Table 2) covering doses are used.For each study, multiple controls are designed to represent the concentration and matrix after mixing of rhIGF-1 / rhIGFBP-3 or test agent.Controls are produced by using the formulation buffer (to produce concentration controls) of the rhIGF-1 / rhlGFBP-3 drug product itself or by diluting the drug product with a small molecule matrix to study the impact of changes in the absence of any small molecules.

[0109] Where applicable, the duration of mixing was based on the average infusion rate of rhIGF-1 / rhIGFBP-3 calculated using each test agent at the highest dose (normalized for the same body weight) (e.g., 250 μg / kg / 24 hours normalized for 0.5 kg neonates and target rhIGF-1 / rhIGFBP-3 protein concentration 50 μg / mL) and the volume estimated for the umbilical catheter (Table 2). In all studies, the mixture and control solution were sampled regularly. In addition, a longer duration of mixing was considered as a worst-case scenario (e.g., interruptions may occur in clinical practice, extending the duration of infusion) and the continuation of any observed phenomena occurring at the start of mixing was observed.

[0110] Where applicable, two application scenarios were assumed for the mixed duration calculation. The first scenario was when each of the two medicaments was administered via a pump, in which case the mean value of the two flow rates was selected under the highest small molecule dose. In the second scenario, only rhIGF-1 / rhIGFBP-3 was pumped, and the test medicament was infused in a relatively short time (~15-30 minutes). For these scenarios and any other medicaments that were not pumped or infused, regular observations and sampling (Table 2) were performed at selected time points.

[0111] Table 2 Compatibility study of rhIGF-1 / rhIGFBP-3 drug products and small molecules

[0112]

[0113]

[0114]

[0115] D5W 5% dextrose in water; IGF-1 insulin-like growth factor-1; IGFBP-3 insulin-like growth factor binding protein-3; N / A not applicable (no preparation / reconstitution / dilution required); NS normal saline; OD320 optical density at 320 nm; PN parenteral nutrition; rh recombinant human; RP-HPLC reverse phase high performance liquid chromatography; WFI water for injection

[0116] a Doses were prepared as per package insert; each dose was diluted with the recommended diluent (0.9% saline, 5% dextrose, and sterile water for injection), as applicable.

[0117] b Unless otherwise stated, permeability was tested at 60, 90 and 120 minutes and at 24 hours.

[0118] 4.0 Physical Compatibility

[0119] Physical compatibility determinations of the test samples and corresponding control solutions were compared. Based on the existing literature, we used the following method or its modified version to evaluate the physical compatibility of rhIGF-1 / rhIGFBP-3 with co-infused drugs: Visual observation (United States Pharmacopeia [USP] <790> ), optical density at 320 nm (USP <851> and <857> ), pH measurement (USP <791> ) and room temperature osmotic pressure (USP <785> ).

[0120] The purpose of visual observation is to determine the presence of any precipitation, visible particles and flocculent material, as well as any color change (compared to water) and / or gas formation, which are potential indicators of chemical modification.

[0121] All vials used for physical compatibility testing were examined under the same lighting conditions: with white and black backgrounds, using fluorescent and Tyndall lamps (Spectralight III, Macbeth / X-Rite, Grand Rapids, MI, USA or MIH-DX, Bosch / Eisai Machinery, Waiblingen, Germany). The mixed appearance of the mixture and control samples was analyzed at specific time points (Table 1). Optical density measurements were performed at 320 nm using a UV-visible spectrophotometer (SpectraMax M5, Molecular Devices, San Jose, CA, USA) for turbidity detection, which is an indicator of submicroscopic protein aggregation. At each time point, three measurements were performed on each sample using a quartz cuvette with a 1 cm optical path length, and the average value of the measurements was recorded. The pH values ​​of each solution were recorded three times using a calibrated pH meter (Model 215, Denver Instrument, Denver Instrument, Bohemia, NY, USA; Fischer Scientific Accumet XL150, Pittsburgh, PA, USA), and the average was reported. The osmotic pressure change after mixing at room temperature was recorded using a calibrated osmometer (Model 3250, Advanced Instruments, Norwood, MA, USA). Three readings were determined, and the average was recorded.

[0122] The test agent is considered physically compatible with rhIGF-1 / rhIGFBP-3 if no color change, precipitation, turbidity, or gas evolution is observed, or if there are no clinically relevant changes in osmolarity or pH.

[0123] Any ± about 0.3 variation in the pH of the mixture from the rhIGF-1 / rhIGFBP-3 drug product control (pH 5.5) is considered a variation that may affect the quality of rhIGF-1 / rhIGFBP-3, in which case the small molecule agent will be considered incompatible and further protein-specific data will be required for evaluation. The range considered is based on the control and release specification of rhIGF-1 / rhIGFBP-3 (5.5±0.3) and a priori knowledge of the potential degradation and known stability of the rhIGF-1 / rhIGFBP-3 drug product. Due to existing clinical practice and taking into account the release specification of rhIGF-1 / rhIGFBP-3 (300±30mOsmol / kg), variations in osmotic values ​​are considered using less stringent criteria.

[0124] 5.0 Small molecule chemical compatibility

[0125] The concentration of small molecule test agents (USP monograph or modified version) after mixing was assessed at the last specified time point (Table 2) using reverse phase high performance liquid chromatography (RP-HPLC) with ultraviolet (UV) detection or ion chromatography with electrochemical detection; for example, although RP-HPLC-UV method was used for detection of most molecules, for some molecules, such as amikacin and gentamicin, a modified version of USP ion chromatography determination with electrochemical detection was used. For each agent, validation of the USP method was performed to ensure the specificity, linearity, reproducibility, and accuracy of the method. An example chromatogram for a small molecule (gentamicin) is provided in the Supplementary Information. Chemical incompatibility is considered to be a loss of approximately 10% or more of the small molecule content over a defined testing period. Due to the complex nature of such mixtures, small molecule analysis of PNs or lipids was not possible.

[0126] 6.0 Chemical compatibility of rhIGF-1 / rhIGFBP-3

[0127] Takeda has developed a sensitive mass spectrometry-based protein-specific method to assess the chemical compatibility of the rhIGF-1 / rhIGFBP-3 drug product. The development of the protein-specific method will be reported separately.

[0128] 7.0 Risk Assessment and Risk Planning

[0129] A comprehensive risk assessment was performed for agents indicating in vitro (in)compatibility. (For a description of the risk assessment, see Risk Assessment Design and Overview in Methods.) A risk event was defined as “rhIGF-1 / rhIGFBP-3 incompatibility with the co-infused drug under the duration and conditions of the simulated mixing study.”

[0130] A risk assessment was performed for each co-infused test agent to determine the probability and severity of the risk. Probability is defined as the likelihood of an impact on safety, efficacy, or quality; severity is defined as the severity of the impact if the risk event occurs (Table 3). Based on the level of probability and severity (low, moderate, and high), a risk planning strategy for each agent was developed (Table 4). A cross-functional team of subject matter experts performed the final evaluation and endorsed the clinical recommendations.

[0131] Table 3 Risk assessment definitions

[0132]

[0133] IGF-1 insulin-like growth factor-1; IGFBP-3 insulin-like growth factor binding protein 3; rh recombinant human.

[0134] Table 4 Risk priority grid and related risk planning

[0135]

[0136]

[0137] H high; L low; M medium

[0138] 8.0 Results

[0139] 8.1 In vitro physical compatibility

[0140] Of the 19 agents tested, the physical compatibility of rhIGF-1 / rhIGFBP-3 with caffeine citrate, fentanyl, fluconazole, gentamicin, insulin, intravenous lipid emulsion, midazolam, morphine sulfate, PN solution + intravenous lipid emulsion, PN solution (with and without electrolytes), and vancomycin (when administered from a 5 mg / ml solution) was determined (Table 5). The following agents were considered incompatible with rhIGF-1: amikacin, ampicillin, dobutamine, dopamine, furosemide, meropenem, norepinephrine, penicillin G, and vancomycin (when administered from a 50 mg / ml solution).

[0141] Table 5 Physical and Small Molecule Compatibility of rhIGF-1 / rhIGFBP-3 Drug Product and Small Molecule Test Agents

[0142]

[0143]

[0144]

[0145] IGF-1 insulin-like growth factor-1; IGFBP-3 insulin-like growth factor binding protein-3; N / A not applicable; PN parenteral nutrition; rh recombinant human; RP-HPLC reversed-phase high performance liquid chromatography

[0146] a To date, this agent has been removed from the list of incompatible agents based on these studies and protein-specific analysis, which demonstrated that the observed changes in pH and osmolarity did not result in fragmentation, oxidation, aggregation, adduct formation, or generation of any free rhIGF-1 or rhlGFBP-3 submolecular units.

[0147] b "Development of a protein-specific assay to evaluate the compatibility of recombinant human (rh) IGF-1 / rhIGFBP-3 with intravenous agents co-administered to neonates" has been submitted for publication.

[0148] cCompatible based on physical data; however, final compatibility is informed by other studies

[0149] 8.2 Small molecule chemical compatibility

[0150] For the tested agents, small molecule compatibility was not affected after mixing. No loss of small molecule content was observed for any of the tested agents in the mixtures and corresponding controls (Table 1 above).

[0151] 8.3 Risk assessment and risk planning

[0152] All small molecule test agents have completed risk assessment (except furosemide, where the mixture studied turned turbid within approximately 30 minutes and clearly indicated incompatibility with the rhIGF-1 / rhIGFBP-3 drug product). Where in vitro physical compatibility was confirmed, subsequent risk assessment confirmed that the probability and severity of events under in-use conditions were low. For those drugs that demonstrated in vitro compatibility, the risk of interaction or chemical modification based on pH was also considered low.

[0153] Given the structural similarities between insulin and IGF-1, compatibility of the agent with insulin is an important consideration when evaluating the compatibility of rhIGF-1 / rhIGFBP-3 with a test agent. For example, midazolam and vancomycin have been determined to be compatible with insulin, indicating a low risk of incompatibility with rhIGF-1 / rhIGFBP-3; however, with respect to compatibility with insulin, small molecule concentrations are of particular concern. To date, there are no compatibility data for insulin with fentanyl or fluconazole; however, based on theoretical evaluation and solution pH, no reaction is expected.

[0154] Among the drugs for which incompatibility with rhIGF-1 / rhIGFBP-3 was observed in in vitro studies, the risk was classified as moderate / high and appropriate actions were recommended.

[0155] Table 6 Method: Chromatographic conditions

[0156]

[0157]

[0158] 8.4 Small molecule chemical compatibility

[0159] For each agent, the USP method (or its modified version) was validated to ensure the specificity, linearity, repeatability and accuracy of the method. Gentamycin is provided as an example in this section. Aminosugar-driven antibiotics such as gentamicin and its related substances were analyzed by ion chromatography with electrochemical detection. The USP monograph on the content of gentamicin in gentamicin sulfate was modified to quantify the determination (concentration) of gentamicin sulfate. Several modifications were made to the USP monograph to obtain these results. The samples were quantified using n=5 standard calibrations with a nominal standard concentration of 0.2 mg / ml gentamicin sulfate. The total area (group) of all gentamicin peaks was used to quantify the content (mg / mL) of gentamicin sulfate in the sample. The mixture and control samples were then analyzed according to the modified method to support the study. The mixed sample was diluted in the mobile phase to obtain a suitable working concentration for all samples. Table 6 summarizes the analytical parameters of the provided examples. Figure 2-7 A representative chromatogram of gentamicin is shown.

[0160] 9.0 Conclusion

[0161] In this study, in vitro testing indicated that the rhIGF-1 / rhIGFBP-3 drug product was physically compatible with 11 / 19 pharmaceutical and nutritional therapies under the conditions and doses tested. For the pharmaceutical agents that demonstrated in vitro compatibility, the risk assessment confirmed that the probability and severity of the incompatibility risk were low. Physical compatibility was not determined for 8 / 19 drugs. For the drugs identified as incompatible, redistribution of the infusion fluid was required to optimize the available IV lines.

Claims

1. A method of treating or preventing premature infants by intravenously administering a therapeutic amount of a composition comprising IGF-1 and IBGBP-3 in combination with a therapy selected from the group consisting of caffeine, fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine, low-dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (or a composition for the same use), and combinations thereof (such as combinations of 2, 3, 4 or more thereof).

2. A method of treating or preventing premature infants by intravenously administering a therapeutic amount of a composition comprising IGF-1 and IBGBP-3 in combination with one or more additional therapies, wherein the additional therapies are not co-administered therapies selected from the group consisting of amikacin, ampicillin, dobutamine, dopamine, furosemide, meropenem, high dose norepinephrine, penicillin G, vancomycin at a concentration greater than 5 mg / ml, and combinations thereof, such as combinations of 2, 3, 4 or more thereof (or combinations of the same use).

3. The method of any one of the preceding claims, wherein the combination therapy is co-administered (eg, delivered via the same IV line).

4. A method or composition according to any one of the preceding claims, wherein IGF-1 and IBGBP-3 are administered in combination with caffeine (eg caffeine citrate).

5. The method or composition of any preceding claim, wherein IGF-1 and IBGBP-3 are administered in combination with fentanyl.

6. The method or composition of any preceding claim, wherein IGF-1 and IBGBP-3 are administered in combination with fluconazole.

7. A method or composition according to any one of the preceding claims, wherein IGF-1 and IBGBP-3 are administered in combination with gentamicin.

8. The method or composition of any preceding claim, wherein IGF-1 and IBGBP-3 are administered in combination with insulin.

9. The method or composition of any preceding claim, wherein IGF-1 and IBGBP-3 are administered in combination with midazolam.

10. The method or composition of any preceding claim, wherein IGF-1 and IBGBP-3 are administered in combination with morphine (eg, sulfate).

11. The method or composition of any preceding claim, wherein IGF-1 and IBGBP-3 are administered in combination with a low dose of norepinephrine.

12. The method or composition of any preceding claim, wherein IGF-1 and IBGBP-3 are administered in combination with vancomycin, wherein the latter is infused at a concentration of less than 50 mg / ml.

13. The method or composition of any of the preceding claims, wherein IGF-1 and IBGBP-3 are administered in conjunction with parenteral nutrition (eg, intravenous lipid emulsion, with or without electrolytes).

14. The method or composition of any one of claims 2 to 13, wherein the additional non-co-administered therapy is administered through a different IV line or by a different route of administration (such as intramuscular administration).

15. The method or composition of any one of claims 2 to 14, wherein the additional non-co-administered therapy is omitted entirely.

16. The method or composition of any preceding claim, wherein the premature infant is between 23 and 34 weeks of gestation when treatment is initiated.

17. A method or composition according to any one of the preceding claims, wherein the premature infant is administered IGF-1 and IGFBP3 by infusion, e.g. continuous infusion, in particular for at least 1 week, e.g. 2 to 6 weeks, such as 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks.

18. The method or composition of claim 17, wherein the infusion begins within 24 hours of birth, such as within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours and 24 hours after birth, in particular within 1 hour after birth.

19. The method or composition of any one of claims 1 to 19, wherein the composition comprises equimolar amounts of IGF-1 and IGFBP-3.

20. A method or composition according to any preceding claim, wherein 200 to 500 μg / Kg / 24 hours of the complex of IGF-1 and IGFBP-3 is administered.

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