WO2023122355A2

WO2023122355A2 - Methods of treating or preventing infusion-related reactions

Info

Publication number: WO2023122355A2
Application number: PCT/US2022/054033
Authority: WO
Inventors: Barry Jay KAPPEL; Gene Merutka; Jimmy Andrew ROTOLO; Alice Susannah BEXON; Robert E. MICHAEL
Original assignee: Sapience Therapeutics, Inc.
Priority date: 2021-12-24
Filing date: 2022-12-26
Publication date: 2023-06-29
Also published as: WO2023122355A3

Abstract

Provided are methods of treating or preventing an infusion-related reaction (IRR) in a subject receiving an intravenous infusion of a pharmaceutical composition, the method comprising administering a leukotriene inhibitor to the subject before and/or during infusion.

Description

METHODS OF TREATING OR PREVENTING INFUSION-RELATED REACTIONS

BACKGROUND

[0001] Infusion-related reactions (IRRs) are adverse events associated with intravenous administration of pharmaceutical products. IRRs have been observed with administration of various therapeutic agents, including small molecules, such as taxanes or platinum products; proteins, such as monoclonal antibodies; and nanotechnology-based products, such as those comprising liposomes, micelles, microparticles, or nanoparticles (Foley 2010; Szebeni 2018; Caceres 2019).

[0002] Peptides have unique therapeutic properties because they combine the advantages of small-molecule drugs, such as cell permeability, with the advantages of therapeutic proteins, such as selectivity and target potency, with fewer adverse side effects and drug-drug interactions, and lower antigenicity, immunogenicity, and toxicity (Apostolopoulos 2021). Despite the advantages of peptide therapeutics, IRRs can be observed upon their administration.

[0003] IRRs can be antibody -mediated or non-antibody -mediated (Asselin 2016). Unlike antibody-mediated IRRs, non-antibody-mediated IRRs-sometimes referred to as anaphylactoid or pseudo-allergic reactions-can occur with the first administration of a drug and are caused by mast cell degranulation (Asselin 2016; Caceres 2019).

[0004] There appears to be a correlation between the overall charge of the administered peptide and the occurrence and severity of IRRs, with positively charged peptides inducing mast cell degranulation and more severe IRRs (Watt 2002; Grimes 2019). For example, pseudoallergic reactions have been described following intravenous administration of peptides containing cationic, arginine-rich sequences, such as penetratin and TAT (Basheer 2011; Li 2017). Peptide pseudoallergy varies in degree depending upon the species and drug concentration, with reactions ranging from flushing, urticaria, pruritus, piloerection and hypoactivity accompanied by a significant decrease in body temperature to death.

[0005] Without wishing to be bound by theory, it has been hypothesized that positively charged peptides could activate a Mas-related G protein-coupled receptor (MrgX2) expressed on mast cells, thereby contributing to the more severe anaphylactoid reactions observed with their administration (Grimes 2019). While net charge may play a role in interactions between peptides and mast cells, biophysical factors such as helicity and hydrophobicity of the peptide also influence the degree of mast cell degranulation (Watt 2002).

[0006] Symptoms of IRR can range from mild, such as flushing or itching, to severe, including cardiac effects or respiratory distress. Patients experiencing IRRs have reported feeling stressed or fearful, even where symptoms were mild (Foley 2010). In addition, the occurrence of IRRs can require slowing or interrupting infusion, which lengthens the duration of administration. And in some cases, IRRs can result in discontinuation of the therapy (Foley 2010; Caceres 2019). IRRs can also increase the economic burden of treatment, as patients require more attention from clinical staff, and may even require hospitalization.

[0007] IRRs are typically treated with some combination of anti-inflammatory compounds, including antihistamines, corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs), and/or pain relievers, including acetaminophen/paracetamol (Lenz 2007; Caceres 2019). Administration of mast cell degranulation inhibitors, such as cromolyn or lodoxamide, or of Mrg receptor antagonists has also been suggested (Tymianski 2016; Lerner 2019; Xinzhong 2020). Other approaches include interruption of infusion, and desensitization protocols that modify infusion dose and/or duration (Castells 2006; Patton 2018; Caceres 2019).

[0008] Many studies and guidelines focus on mitigation of IRRs once they have occurred (Vaughan 2013). However, even when pre-treatment with acetaminophen, diphenhydramine, and/or corticosteroids is administered, patients have still experienced serious IRRs (Lenz 2007; Asselin 2016). Despite the availability of protocols for managing IRRs, there remains a need for reliable, effective methods for preventing and treating IRRs (Vaughan 2013; Szebeni 2018; Caceres 2019), particularly with administration of peptide therapeutics.

SUMMARY OF THE INVENTION

[0009] Some of the main aspects of the present invention are summarized below.

Additional aspects are described in the Detailed Description of the Invention, Examples, Drawings, and Claims sections of this disclosure. The description in each section of this disclosure is intended to be read in conjunction with the other sections. Furthermore, the various embodiments described in each section of this disclosure can be combined in various different ways, and all such combinations are intended to fall within the scope of the present invention.

[0010] The disclosure provides methods of treating or preventing an infusion-related reaction (IRR) in a subject receiving an intravenous infusion of a pharmaceutical composition, the method comprising administering a leukotriene inhibitor to the subject. The disclosure further provides the use of a leukotriene inhibitor in a method of treating or preventing an infusion-related reaction (IRR) in a subject receiving an intravenous infusion of a pharmaceutical composition. In a particular embodiment, the leukotriene inhibitor is selected from the group consisting of montelukast, zafirlukast, and zileuton.

[0011] In one embodiment, the leukotriene inhibitor is administered within two days before infusion and/or during infusion. In some embodiments, the leukotriene inhibitor is administered to the subject two days before infusion and on the day of infusion. In a particular embodiment, the leukotriene inhibitor is administered to the subject two days before infusion, one day before infusion, and on the day of infusion. In one embodiment, the leukotriene inhibitor is administered to the subject about 48 hours before infusion, about 24 hours before infusion, and/or about 0-3 hours before infusion.

[0012] In some embodiments the pharmaceutical composition comprises a peptide, for example, a peptide of 5-70 amino acids in length. In one embodiment, the peptide has a net charge of at least +2. In one embodiment, the peptide comprises a cell-penetrating region. In one embodiment, the peptide comprises one or more D-amino acids. In a particular embodiment, the peptide is ST101 (SEQ ID NO: 1).

[0013] In some embodiments, one or more secondary agents can be administered to the subject. In one embodiment, the secondary agent is an antihistamine. One method or use of the invention involves administering at least one antihistamine to the subject within 24 hours before infusion and/or during infusion. In one example, the antihistamine is administered to the subject within 3 hours before infusion. In particular embodiments, the antihistamine can be an Hl receptor antagonist and/or an H2 receptor antagonist. In certain embodiments, the Hl receptor antagonist is selected from the group consisting of chlorphenamine and diphenhydramine. In certain embodiments, the H2 receptor antagonist is famotidine.

[0014] Some methods or uses of the invention comprise administering acetaminophen (paracetamol) to the subject within 6 hours before infusion and/or during infusion. In one embodiment, aspirin is not administered to the subject for at least 48 hours prior to administration of the pharmaceutical composition. In one embodiment, aspirin is not administered to the subject during administration of the pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A and IB show reduced pseudoallergic reaction in mice administered a leukotriene inhibitor prior to intravenous (IV) bolus injection of 25 mg/kg (FIG. 1 A) or 50 mg/kg (FIG. IB) of STlOl.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The practice of the present invention can employ, unless otherwise indicated, conventional techniques of pharmaceutics, formulation science, protein chemistry, cell biology, cell culture, molecular biology, microbiology, recombinant DNA, immunology, clinical pharmacology, and clinical practice, which are within the skill of the art.

[0017] In order that the present invention can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention is related.

[0018] Any headings provided herein are not limitations of the various aspects or embodiments of the invention, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0019] All references cited in this disclosure are hereby incorporated by reference in their entireties. In addition, any manufacturers’ instructions or catalogues for any products cited or mentioned herein are incorporated by reference. Documents incorporated by reference into this text, or any teachings therein, can be used in the practice of the present invention. Documents incorporated by reference into this text are not admitted to be prior art.

F _ Definitions

[0020] The phraseology or terminology in this disclosure is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance. [0021] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents, unless the context clearly dictates otherwise. The terms “a” (or “an”) as well as the terms “one or more” and “at least one” can be used interchangeably.

[0022] Furthermore, “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” is intended to include A and B, A or B, A (alone), and B (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to include A, B, and C; A, B, or C; A or B; A or C; B or C; A and B; A and C; B and C; A (alone); B (alone); and C (alone).

[0023] Wherever embodiments are described with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of’ and/or “consisting essentially of’ are included.

[0024] Units, prefixes, and symbols are denoted in their Systeme International d’Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range, and any individual value provided herein can serve as an endpoint for a range that includes other individual values provided herein. For example, a set of values such as 1, 2, 3, 8, 9, and 10 is also a disclosure of a range of numbers from 1-10, from 1-8, from 3-9, and so forth. Likewise, a disclosed range is a disclosure of each individual value (i.e., intermediate) encompassed by the range, including integers and fractions. For example, a stated range of 5-10 is also a disclosure of 5, 6, 7, 8, 9, and 10 individually, and of 5.2, 7.5, 8.7, and so forth.

[0025] Unless otherwise indicated, the terms “at least” or “about” preceding a series of elements is to be understood to refer to every element in the series. The term “about” preceding a numerical value includes ± 10% of the recited value. For example, a concentration of about 1 mg/mL includes 0.9 mg/mL to 1.1 mg/mL. Likewise, a concentration range of about 1% to 10% (w/v) includes 0.9% (w/v) to 11% (w/v).

[0026] The term “peptide” refers to a polymer of at least two amino acid residues, and their salts. The polymer can be linear or branched, can comprise modified amino acids, and can be interrupted by non-amino acids. Except where indicated otherwise, e.g., for the abbreviations for the uncommon or unnatural amino acids set forth herein, the three-letter and one-letter abbreviations, as used in the art, are used herein to represent amino acid residues. Except when preceded with a “D” or in lower case, the amino acid is an L-amino acid. Groups or strings of amino acid abbreviations are used to represent peptides. Except where specifically indicated, peptides are indicated with the N-terminus of the left and the sequence is written from the N-terminus to the C-terminus.

[0027] An “isolated” molecule is one that is in a form not found in nature, including those which have been purified.

[0028] An “active agent” is an ingredient that is intended to furnish biological activity. The active agent can be in association with one or more other ingredients. An active agent that is a peptide can also be referred to as an “active peptide.”

[0029] An “effective amount” of an active agent is an amount sufficient to carry out a specifically stated purpose. For example, if the stated purpose is treatment of a disease or condition in a subject, the “effective amount” is the amount sufficient to achieve treatment of the disease or condition in the patient. In such embodiments, the “effective amount” is a “therapeutic amount” or “therapeutic dose.”

[0030] The term “pharmaceutical composition” refers to a preparation of an active agent that is in such form as to permit the biological activity of the active agent to be effective and which contains no additional components that are unacceptably toxic to a subject to which the composition would be administered. Such composition can be sterile and can comprise a pharmaceutically acceptable carrier, such as physiological saline. Suitable pharmaceutical compositions can comprise one or more of a buffer (e.g., acetate, phosphate, or citrate buffer), a surfactant (e.g., polysorbate), a stabilizing agent (e.g., polyol or amino acid), a preservative (e.g., sodium benzoate), and/or other conventional solubilizing or dispersing agents.

[0031] A “subject” or “individual” or “animal” or “patient” or “mammal,” is any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, sports animals, and laboratory animals including, e.g., humans, non-human primates, canines, felines, porcines, bovines, equines, rodents, including rats and mice, rabbits, etc.

[0032] Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a condition. In certain embodiments, a subject is successfully “treated” for a condition if the patient shows total, partial, or transient alleviation or elimination of at least one symptom or measurable physical parameter associated with the condition. Subjects to be treated have experienced or are experiencing the condition. For example, subjects that will receive or are receiving intravenous infusion of a pharmaceutical composition and have experienced or are experiencing an IRR can be treated by the methods of the invention.

[0033] “Prevent” or “prevention” refers to prophylactic or preventative measures that prevent and/or slow the development of a condition. Thus, those in need of prevention include those at risk of or susceptible to developing the condition. For example, subjects that will receive or are receiving intravenous infusion of a pharmaceutical composition are at risk of or susceptible to developing IRRs. In certain embodiments, a condition is successfully prevented according to the methods provided herein if the patient develops, transiently or permanently, e.g., fewer or less severe symptoms than a patient who has not been subject to the methods of the invention.

[0034] A patient treated by a method of the invention can experience fewer and/or less severe IRR symptoms from IV administration of a pharmaceutical composition, compared with the IRR symptoms experienced by the patient when administered the pharmaceutical composition in the absence the given treatment. IRRs are prevented by a method of the invention when a patient experiences fewer and/or less severe IRR symptoms from IV administration of a pharmaceutical composition, compared with the IRR symptoms experienced by a control patient or the average or expected IRR symptoms of a population of control patients.

[0035] A “control patient” is a subject that has not received a given treatment. A “control population” or a “population of control patients” is a group of subjects that have not received a given treatment.

[0036] An “antagonist” is a substance that prevents, blocks, inhibits, neutralizes, or reduces a biological activity or effect of another molecule, such as a receptor or ligand.

[0037] The terms “inhibit,” “block,” and “suppress” are used interchangeably and refer to any statistically significant decrease in occurrence or activity, including full blocking of the occurrence or activity. For example, “inhibition” can refer to a decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in activity or occurrence. An “inhibitor” is a molecule, factor, or substance that produces a statistically significant decrease in the occurrence or activity of a process, pathway, or molecule.

II. Compositions and Administration

[0038] The invention provides methods of treating or preventing an infusion-related reaction (IRR) in a patient receiving a pharmaceutical composition via intravenous (IV) administration. In embodiments of the invention, a subject is administered by IV infusion a pharmaceutical composition comprising an active agent. The active agent can be, for example, a protein, including a monoclonal antibody; a peptide; a nucleic acid, including oligonucleotides and inhibitory RNAs (e.g., siRNA, shRNA, etc.); or a small molecule drug. The active agent can be administered in a particle, for example, a micelle, a liposome, microparticle, or nanoparticle.

[0039] In one embodiment, the active agent is a peptide. Peptides for use in the methods of the invention can be, for example, 2-100, 4-75, 5-70, 5-60, 5-50, 10-70, 10-60, 10-50, 14- 38, or 16-67 amino acids in length. The peptide can comprise L-amino acids, D-amino acids, or both L- and D-amino acids.

[0040] In certain embodiments, the peptide comprises one or at least one, two or at least two, three or at least three, four or at least four, five or at least five, six or at least six, seven or at least seven, or eight or at least eight positively charged amino acid residues. In some embodiments, the net charge of the peptide is +1, at least +1, +2, at least +2, +3, at least +3, +4, at least +4, +5, at least +5, +6, at least +6, +7, at least +7, +8, at least +8, +9, at least +9, +10, or at least +10. Net charge is determined by totaling the charges of all ionizable groups at a given pH. For purposes of the present invention, amino acids with positively charged side chains at neutral pH are lysine, arginine, histidine, and ornithine. For purposes of the present invention, amino acids with negatively charged side chains at neutral pH are aspartic acid and glutamic acid. Pharmaceutical compositions for IV administration in methods of the invention are preferably at about pH 4.0 to pH 8.0. Calculation of net charge of a peptide at a given pH is well within the skill of those in the art.

[0041] In some embodiments, the peptide comprises one or at least one, two or at least two, three or at least three, four or at least four, five or at least five, six or at least six, seven or at least seven, or eight or at least eight hydrophobic amino acid residues. Amino acids have varying degrees of hydrophobicity in different environments (Zhu 2016). For purposes of the present invention, hydrophobic amino acids are alanine, isoleucine, leucine, methionine, phenylalanine, proline, tyrosine, tryptophan, and valine. Percent hydrophobicity refers to: of hydrophobic amino acid residues in the peptide

of total amino acid residues present in the peptide

[0042] In some embodiments, the peptide is at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% hydrophobic.

[0043] The peptide can be a cell-penetrating peptide. In one embodiment, the peptide comprises a cell-penetrating domain. Numerous cell-penetrating domain sequences are described and characterized in the literature (see US 10,815,276; WO 2015/179691; WO 2019/136125; WO 2019/217,682; Bachem 2021). Some cell-penetrating sequences are positively charged and can result in moderate to severe IRRs (Basheer 2011; Li 2017). In other instances, the cell-penetrating sequence does not contribute to the overall charge of the peptide. In one embodiment, the peptide for administration in methods of the invention comprises a cell-penetrating region, which may be a positively charged cell-penetrating region. Non-limiting examples of cell-penetrating peptides are listed in Table 1.

Table 1. Cell-Penetrating Peptides

[0044] In one embodiment, the peptide is a cyclic peptide. Cyclized peptides, for example, using hydrocarbon staples (Bernal 2007; Bird 2016) or other cyclization methods known in the art, can enter cells via passive diffusion, endocytosis/endosomal escape, or other mechanisms (Dougherty 2019). Peptides can also be delivered to cells via mechanisms that exploit cellular receptors, for example, integrin-targeting, RGD-like sequences. Examples include the L-amino acid sequences GRGDS (SEQ ID NO: 21) and GRGDNP (SEQ ID NO: 22), and the D-amino acid sequences SDGRG (SEQ ID NO: 23) and PNDGRG (SEQ ID NO: 24). Alternatively, peptides can be encapsulated and delivered to cells in vesicles, such as exosomes or liposomes, or in micelles.

[0045] Accordingly, some embodiments involve a method of treating or preventing an IRR in a subject receiving an intravenous infusion of a pharmaceutical composition comprising a peptide, wherein the peptide comprises an amino acid sequence of any one of SEQ ID NO: 2-24, or a combination thereof. For example, the peptide can comprise more than one cell-penetrating region, more than one integrin-targeting sequence, at least one cellpenetrating region and at least one integrin-targeting sequence, etc.

[0046] Methods of the invention comprise administration of a leukotriene inhibitor to a patient, in conjunction with IV infusion of a pharmaceutical composition. The inventors have surprisingly discovered that the administration of a leukotriene inhibitor to a patient receiving a pharmaceutical composition via IV infusion treats or prevents IRRs.

[0047] Leukotrienes are inflammatory mediators produced by metabolism of arachidonic acid in macrophages. Vasoconstriction is one effect of leukotrienes. Leukotriene inhibitors are typically used in the treatment of asthma. Non-limiting examples of leukotriene inhibitors for use in the methods of the invention include montelukast, zafirlukast, and zileuton. Exemplary doses of montelukast include 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 20 mg, and 25 mg. Exemplary doses of zafirlukast include 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg. Exemplary doses of zileuton include 300 mg, 600 mg, 900 mg, 1200 mg, 1500 mg, and 1800 mg.

[0048] The leukotriene inhibitor can be administered by the same route as the pharmaceutical composition, or can be administered by a different route (e.g., orally). The leukotriene inhibitor can be administered one, two, three, four, five, six, or seven days, or 24, 48 or 72 hours, prior to IV administration of a pharmaceutical composition. Alternatively, or in addition, the leukotriene inhibitor can be administered 0-30, 30-60, 60-90, or 90-120 minutes prior to IV administration of a pharmaceutical composition. The leukotriene inhibitor can be administered multiple times at any of the foregoing timepoints prior to IV administration of a pharmaceutical composition.

[0049] In certain methods of the invention, the leukotriene inhibitor is administered about 30 minutes before IV administration of a pharmaceutical composition. In one embodiment, the leukotriene inhibitor is administered two days, one day, and about 30 minutes before IV administration of a pharmaceutical composition.

[0050] In some embodiments, the leukotriene inhibitor is administered during infusion.

[0051] The leukotriene inhibitor can be administered by a different route as the pharmaceutical composition, for example, orally or via inhalation.

[0052] In certain methods of the invention, one or more secondary agents can be administered in addition to the leukotriene inhibitor, for instance, to block histamine release, to reduce fever or inflammation, and/or to relieve itching and/or urticaria. Examples of secondary agents for administration in methods of the invention include, but are not limited to, antihistamines, including Hl antagonists, H2 antagonists, and mast cell degranulation inhibitors (e.g., acrivastine, astemizole, azatadine, azelastine, bepotastine, bromopheniramine, burfroline, cetirizine, chlorzoxazone, chlorphenamine, cimetidine, cromolyn, cyproheptadine, desloratadine, dexbromphenir amine, dimenhydrinate, diphenhydramine, doxantrozole, doxylamine, ebastine, epinastine, etodroxizine, famotidine, fexofenadine, forskolin, hydroxyzine, isoproterenol, ketotifen, lafutidine, levocabastine, levocetirizine, loratadine, lodoxamide, mequitazine, methdilazine, mizolastine, nedocromil, nizatidine, olopatadine, oxatomide, pemirolast, pimecrolimus, pirbuterol, pizotifen, promethazine, proxicromil, quifenadine, ranitidine, roxatidine, terfenadine, terbutaline); nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, aspirin); acetaminophen/paracetamol; corticosteroids (e.g., hydrocortisone, dexamethasone, prednisone, prednisolone); antinausea medications (e.g., prochlorperazine, ondansetron); and saline and/or electrolytes. In some embodiments, the secondary agent is selected from the group consisting of acetaminophen/paracetamol, an Hl antagonist, and H2 antagonist, an antiemetic, and combinations thereof.

[0053] In one embodiment, the secondary agent is not aspirin. The methods of the invention can exclude administration of aspirin prior to and/or during IV infusion of a pharmaceutical composition comprising an active agent. In particular embodiments, aspirin is not administered to the subject for at least 48 hours, 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes prior to administration of the pharmaceutical composition comprising an active agent. In certain embodiments, aspirin is not administered to the subject during administration of the pharmaceutical composition comprising an active agent.

[0054] In particular embodiments, the secondary agent comprises an antihistamine. In certain embodiments, the secondary agent comprises an Hl receptor antagonist, such as acrivastine, cetirizine, chlorphenamine, desloratadine, diphenhydramine, fexofenadine, levocetirizine, or loratadine. In certain embodiments, the secondary agent comprises an H2 receptor antagonist, such as cimetidine, famotidine, lafutidine, nizatidine, ranitidine, and roxatidine. In a particular embodiment, the secondary agent comprises an Hl receptor antagonist and an H2 receptor antagonist. In one preferred embodiment, the secondary agent is an antihistamine, such as chlorpheniramine or diphenhydramine, or a combination of antihistamines, such as famotidine and chlorphenamine or famotidine and diphenhydramine.

[0055] The secondary agent(s) can be administered prior to and/or during and/or after IV infusion of a pharmaceutical composition. In certain embodiments, the secondary agent is administered to the subject prior to administration of the pharmaceutical composition, such as within about 7 days prior, or within about 6 days prior, or within about 5 days prior, or within about 4 days prior, or within about 72 hour prior, or about 48 hours prior, or about 24 hours prior, or about 8-12 hours prior, or about 6-8 hours prior, or about 4-6 hours prior, or about 2-4 hours prior, or about 1-2 hours prior, or within about 1 hour prior, within about 30 minutes prior, or immediately prior to IV infusion of a pharmaceutical composition. In some embodiments, the secondary agent is administered within 24 hours after administration of the pharmaceutical composition. For example, the secondary agent can be administered immediately after, about 0.5-1 hour after, about 1-2 hours after, about 2-4 hours after, about 4-6 hours after, about 6-8 hours after, about 8-12 hours after, or about 24 hours after the completion of administration of the pharmaceutical composition.

[0056] The secondary agent(s) can be administered by the same route as the pharmaceutical composition, or can be administered by a different route. The secondary agent(s) can be administered in a separate composition from the pharmaceutical composition and/or the leukotriene inhibitor, or can be combined with the pharmaceutical composition and/or the leukotriene inhibitor.

[0057] The secondary agent(s) can be administered multiple times before, during, and/or after administration of the pharmaceutical composition. Combinations of secondary agents can be administered concurrently or at different times. For example, an antihistamine could be administered before administration of the pharmaceutical composition, and a corticosteroid could be administered after administration of the pharmaceutical composition.

[0058] Administration of a secondary agent to a subject includes self-administration by the subject.

[0059] In certain embodiments, the methods of the invention exclude desensitization protocols. A “desensitization protocol” comprises administration of a small dose of an active agent that can elicit or has elicited an IRR in a patient, followed by gradually increasing doses, until the full therapeutic dose is reached. Accordingly, in one embodiment, the methods of the invention comprise administration of a pharmaceutical composition comprising a therapeutic amount of an active agent.

EXAMPLES

[0060] Embodiments of the present disclosure can be further defined by reference to the following non-limiting examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.

Example 1. Mitigation of IRRs to BCAP1 in a Rat Model

[0061] BCAP1 is a P-catenin antagonist peptide that binds P-catenin and disrupts its interaction with the oncogenic co-activator B cell lymphoma 9 (BCL9). BCAP1 is comprised of all D-enantiomer amino acids, and is 25 amino acids in length, which includes a cell-penetrating region. BCAP1 comprises 16 hydrophobic amino acid residues and has a net charge of +4 at neutral pH. High-dose, bolus intravenous (IV) administration of BCAP1 can induce a pseudoallergic reaction in Sprague Dawley rats. Here, we investigated the impact of a leukotriene inhibitor, Montelukast, plus an anti-histamine, diphenhydramine, on BCAP1 pseudoallergic reaction in Sprague Dawley rats.

[0062] Briefly, 270mM trehalose solution (TH) was prepared in MilliQ water. A fresh solution of 10 mg/ml BCAP1 was prepared in the TH. Female Sprague Dawley rats at 6-8 weeks of age were dosed with BCAP1 by intravenous injection (200 pL) via the lateral tailvein using a 19-gauge tuberculin syringe (weight of rats in grams x 10 = volume of solution to be injected in pL). Animals were observed for a minimum of 30 minutes and acute toxicity scores were recorded at times 0, 1, 5, 10, 20 and 30 min post BCAP1 exposure using the following scoring system:

0- Animals do not display any evidence of acute adverse reactions.

1- Animals display piloerection and swelling/redness of the nose and muzzle.

2- Animals display piloerection and swelling/redness of the nose and muzzle, along with irregular gait and/or slightly reduced activity.

3- Animals develop a reaction within 5 minutes of exposure to cell penetrating peptide that is characterized by hypoactivity, reduced responsiveness to touch, lack of inquisitiveness and panting. The reaction may be accompanied by piloerection and swelling/redness of the nose and muzzle. The entirety of the acute reaction resolves 20-30 minutes post peptide exposure.

4- Animals develop a severe reaction within 5 minutes of exposure to cell penetrating peptide that is characterized by lack of activity or responsiveness to touch and panting. The reaction may be accompanied by piloerection and swelling/redness of the nose and muzzle. 5- Animals succumb to the acute reaction. The response may be an immediate reaction, including spasm and erratic movements, culminating in death within 1-2 minutes following peptide exposure.

[0063] Bolus intravenous administration of 10 mg/kg BCAP1 resulted in hypoactivity and panting, with reddening and swelling of paws and snout (maximum pseudoallergic score of 4). Full recovery was observed 30 minutes post peptide exposure (n=2).

[0064] In rats pre-administered Montelukast (20 mg/kg PO) on days -2, -1 and 0 prior to BCAP1 exposure and diphenhydramine (DPH) (10 mg/kg SC) on day 0, at 30 min prior to BCAP1 exposure, BCAP1 -induced pseudoallergic reaction was mitigated. Rats administered 20 mg/kg BCAP1 via bolus IV, following pre-treatment with Montelukast plus diphenhydramine, showed minimal piloerection over 30 minutes (maximum pseudoallergic score of 1-2). Rats administered 30 mg/kg BCAP1 via bolus IV, following pre-treatment with Montelukast plus diphenhydramine, displayed slow movement, moderate piloerection and slight hunched posture (maximum pseudoallergic score of 2). Rats administered 40 mg/kg BCAP1 via bolus IV, following pre-treatment with Montelukast plus diphenhydramine, displayed labored breathing, lack of mobility, hunched posture and piloerection (maximum pseudoallergic score of 4). Results are summarized in Table 2.

Table 2

[0065] These data demonstrate that Montelukast plus diphenhydramine mitigates the pseudoallergic reaction in Sprague-Dawley rats up to 30 mg/kg BCAP1 IV administration. Example 2. Mitigation of IRRs to ST101 in a Mouse Model

[0066] ST101 is a C/EBPp antagonist peptide that interacts with the basic leucine zipper domain (bZIP) domain of C/EBPP, preventing C/EBPP from interactions with co-factors that promote oncogenic gene transactivation. ST101 is comprised of all D-enantiomer amino acids, and is 38 amino acids in length, which includes a cell-penetrating region. ST101 comprises 15 hydrophobic amino acid residues, and has a net charge of +5 at pH 5.3. The D- amino acid sequence of ST101 is VAEAREELERLEARLGQARGELVV VA//?/? J/’ /.V/.O/? (SEQ ID NO: 1), with the cell-penetrating region italicized.

[0067] In C57BL/6 mice, clinical signs of pseudoallergic reactions are observed following bolus IV injection of ST101. Reactions are dose-dependent, and range in severity from mild, characterized by flushing and piloerection, to severe, characterized by hypoactivity accompanied by a significant decrease in body temperature, and in extreme cases, death. Here, we investigated the impact of a leukotriene inhibitor, Montelukast, on the ST101 pseudoallergic reaction in C57BL/6 mice.

[0068] Mice were dosed with 25 or 50 mg/kg ST101 by intravenous injection via the lateral tail-vein. Mice received no pre-treatment; one pre-treatment with 50 mg/kg Montelukast (PO in water) at 30 minutes prior to IV administration of ST101; or three pretreatments with 50 mg/kg Montelukast (PO in water) at two days, one day, and 30 minutes prior to IV administration of ST101. Body temperature was recorded at intervals of 1, 5, 10, 20, and 30 minutes following ST101 exposure.

[0069] Results are shown in FIG. 1A and IB. Body temperature measurements following IV bolus injection of ST101 indicated a decrease in body temperature following ST101 exposure in mice receiving no pre-treatment with Montelukast, while the observed decrease in body temperature was attenuated in mice receiving pre-treatment. These data demonstrate that Montelukast mitigates the pseudoallergic reaction in mice.

Example 3. Mitigation of IRRs to ST101 in Human Patients

[0070] In an ongoing open-label phase 1-2 dose-finding study, ST101 was administered intravenously to patients with advanced unresectable and metastatic solid tumors. Target total infusion time for each administration was 90 minutes. Patients were dosed once weekly (QW) as shown in Table 3. Table 3

[0071] Most of the adverse events experienced by the patients were IRRs that occurred in the first six hours. Of the 21 patients receiving ST101, 16 (67%) displayed IRR symptoms, most commonly pruritus and urticaria.

[0072] To manage IRR, patients in Cohort 5 were administered (i) 10 mg Montelukast PO two days before and on the day of ST101 dosing, (ii) 20 mg famotidine PO or IV on the day of dosing, and (iii) 10 mg chlorphenamine PO or 50 mg diphenhydramine IV on the day of dosing. Patients with other conditions, such as allergies, can be administered a leukotriene inhibitor daily. Premedication resulted in a decrease in the number of IRRs as well as a shortening of the infusion duration despite increasing the dose from cohort 4 to cohort 5.

Example 4. Mitigation of IRRs to Various Peptides in a Mouse Model

[0073] IV administration of various peptides causes a pseudoallergic reaction in C57BL/6 mice. A summary of peptides administered and reactions observed is shown in Table 3. Mice were administered the indicated peptide via bolus tail vein injection and monitored for 30 minutes for clinical signs of pseudoallergic reaction, include decreased activity piloerection, swelling of muzzle and paw, and decreased body temperature. Reaction (Rxn) Grade was assigned using the 0-5 scale described in Example 1. Sapience.019. W01

PATENT

Table 3

Sapience.019. W01

PATENT

Sapience.019. W01

PATENT

Sapience.019. W01

PATENT

Sapience.019. W01

PATENT

* Peptide has a lactam bridge between the bold, underlined residues

[0074] Peptides comprising acetyl-RQIKIWFQNRRMKWKKI-cyclo-[KQLED]- RNYALRKEIEDLQ-cyclo-[KQLED]-L-NH₂ (SEQ ID NO: 58), or cyclo-[F-2Nal-RRRR- yE]-AEAAAKAA-OH (SEQ ID NO: 59), wherein 2Nal is 3-(2-naphthyl)-L-alanine, are additional examples of peptides that may be encompassed by methods of the invention. Accordingly, some embodiments of the invention involve a method of treating or preventing an IRR in a subject receiving an intravenous infusion of a pharmaceutical composition comprising a peptide, wherein the peptide comprises an amino acid sequence of any one of SEQ ID NO: 25-59.

[0075] To demonstrate mitigation of pseudoallergic reaction, mice receive one pretreatment with 25 mg/kg or 50 mg/kg Montelukast (PO in water) at 30 minutes prior to IV administration of a test peptide; or three total pre-treatments with 25 mg/kg or 50 mg/kg Montelukast (PO in water) at two days, one day, and 30 minutes prior to IV administration of a test peptide. Mice are optionally administered an anti-histamine. Body temperature is recorded at intervals of 1, 5, 10, 20, and 30 minutes following peptide administration and Reaction Grade is assigned using the 0-5 scale described in Example 1. Pre-treated mice experience reduced instance or severity of infusion-related reactions, compared with mice receiving no pre-treatment.

REFERENCES

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***

The present invention is further described by the following claims.

Claims

1. A method of treating or preventing an infusion-related reaction (IRR) in a subject receiving an intravenous infusion of a pharmaceutical composition comprising a peptide, wherein the peptide is 5-70 amino acids in length, the method comprising administering a leukotriene inhibitor to the subject within two days before infusion and/or during infusion.

2. The method of claim 1, wherein the leukotriene inhibitor is selected from the group consisting of montelukast, zafirlukast, and zileuton.

3. The method of claim 1 or claim 2, comprising administering at least one antihistamine to the subject within 24 hours before infusion and/or during infusion.

4. The method of claim 3, wherein the antihistamine is an Hl receptor antagonist.

5. The method of claim 3, wherein the antihistamine is an H2 receptor antagonist.

6. The method of claim 3, comprising administering to the subject an Hl receptor antagonist and an H2 receptor antagonist.

7. The method of any one of claims 3 to 6, wherein the antihistamine is an Hl receptor antagonist selected from the group consisting of chlorphenamine and diphenhydramine, and/or wherein the H2 receptor antagonist is famotidine.

8. The method of any one of claims 3 to 7, wherein the antihistamine is administered to the subject within 3 hours before infusion.

9. The method of claim 1, wherein the leukotriene inhibitor is administered to the subject two days before infusion and on the day of infusion.

10. The method of any one of claims 1 to 8, further comprising administering acetaminophen to the subject within 6 hours before infusion and/or during infusion.

11. The method of any one of claims 1 to 10, wherein aspirin is not administered to the subject for at least 48 hours prior to administration of the pharmaceutical composition.

12. The method of any one of claims 1 to 11, wherein aspirin is not administered to the subject during administration of the pharmaceutical composition.

13. The method of claim 1, wherein the peptide has a net charge of at least +2.

- 25 -

14. The method of claim 1, wherein the peptide comprises a cell-penetrating region.

15. The method of claim 1, wherein the peptide comprises one or more D-amino acids.

16. The method of any one of claims 1 to 15, wherein the peptide is ST101.

17. Use of a leukotriene inhibitor in a method of treating or preventing an infusion- related reaction (IRR) in a subject receiving an intravenous infusion of a pharmaceutical composition comprising a peptide, wherein the peptide is 5-70 amino acids in length, the method comprising administering a leukotriene inhibitor to the subject within two days before infusion and/or during infusion.