WITH LOW-DOSE MAINTENANCE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No.

62/852,159, filed on May 23, 2019, the contents of which are incorporated herein by reference in its entirety for all purposes.

FIELD OF INVENTION

[0002] Described herein are methods for treating peanut allergy using an oral immunotherapy comprising a maintenance phase.

BACKGROUND OF THE INVENTION

[0003] Peanut allergy is a hypersensitivity reaction of the immune system to peanut protein. Peanut allergy often develops in childhood and is usually a lifelong affliction. Allergic reactions to peanut can be severe and life threatening, and are a major source of severe food- induced anaphylaxis.

[0004] Until recently, the standard of care for treating peanut allergy included dietary elimination and avoidance of peanuts, education on the signs of anaphylaxis, and

administration of injectable epinephrine. However, accidental ingestion of peanuts is common, due to difficulty in interpreting food labels and the presence of undeclared ingredients in unlabeled food. Oral immunotherapy (OIT) is a promising new treatment for peanut allergy. For example, AR101, an oral immunotherapy for treating peanut allergy, has been shown to be both safe and effective in clinical trials. See, for example, Bird et al., Efficacy and Safety ofAR.101 in Oral Immunotherapy for Peanut Allergy: Results of

ARCOOl; a randomized Double-Blind, Placebo-Controlled Phase 2 Clinical Trial , J. Allergy Clin. Immunol. Pract., vol. 6, no. 2, p. 476-485 (2018), the entire contents of which are incorporated herein by reference. Peanut OIT includes exposing patients to peanut protein to gradually induce desensitization, reducing the risk of a serious reaction upon accidental exposure to peanut.

[0005] In some instances, subjects undergoing peanut OIT can experience an adverse reaction during the course of therapy. Subjects who experience adverse reactions may discontinue the oral immunotherapy by necessity (e.g., due to severe anaphylaxis) or due to choice (e.g., due to other untoward clinical occurrences). Oral immunotherapy methods that lower incidence of adverse events can greatly expand the population of patients that can be treated for peanut allergy.

SUMMARY OF THE INVENTION

[0006] Described herein is a method of treating a subject for a peanut allergy by an oral immunotherapy comprising an up-dosing phase and a maintenance phase, the method comprising daily administration to the subject of a maintenance phase dose of about 10 mg to about 100 mg peanut protein during the maintenance phase of the oral immunotherapy.

[0007] In some embodiments, the maintenance phase dose of peanut protein is about 10 mg. In some embodiments, the maintenance phase dose of peanut protein is about 30 mg. In some embodiments, the maintenance phase dose of peanut protein is about 60 mg. In some embodiments, the maintenance phase dose of peanut protein is about 100 mg.

[0008] In some embodiments, the subject is less than 18 years old. In some embodiments, the subject is between about 6 months old and less than 18 years old. In some embodiments, the subject is between about 4 and about 17 years old.

[0009] In some embodiments, the maintenance phase is at least 3 months. In some embodiments, the maintenance phase is at least 6 months. In some embodiments, the maintenance phase is at least 1 year.

[0010] In some embodiments, the up-dosing phase comprises at least one dose of about 3 mg to about 100 mg. In some embodiments, the up-dosing phase comprises at least one dose of about 100 mg to about 300 mg.

[0011] In some embodiments, the up-dosing phase is between 1 day and 6 months. In some embodiments, the up-dosing phase is between 6 months and 2 years.

[0012] In some embodiments, the oral immunotherapy further comprises an initial escalation phase.

DESCRIPTION OF THE INVENTION

[0013] Described herein are methods of treating a subject for a peanut allergy by an oral immunotherapy comprising an up-dosing phase and a maintenance phase. The peanut protein dose administered during the maintenance phase can be, for example, between about 10 mg to about 100 mg peanut protein.

[0014] Oral immunotherapy is a method of inducing desensitization to an allergen in a subject by regular exposure of the subject to increasing doses of the allergen. For peanut allergy, protocols for OIT typically involve an up-dosing phase (also called a build-up phase) and a maintenance phase. Preferably, the OIT further includes an initial escalation phase, although this phase is optional and not required for treatment. The initial escalation phase involves exposure to small doses of peanut protein under clinical supervision to determine the sensitivity of the patient to the peanut protein. This initial escalation phase generally occurs over the course of several (e.g., three or more) hours to two days. These small doses are increased until the subject reaches a goal dose or a highest tolerated dose for the initial escalation phase. The subject then usually begins an up-dosing phase, with regular consultation with a caregiver, usually beginning with the highest tolerated dose administered in the initial escalation phase or a slightly lower dose, and escalating through a series of doses in an up-dosing phase. Additionally, peanut OIT includes a maintenance phase involving the long-term administration of peanut protein. The primary goal of oral immunotherapy is establishing a desensitized state, wherein the subject being treated is less likely to suffer a severe or life-threatening allergic reaction upon accidental exposure to peanut protein.

[0015] While reported peanut oral immunotherapies have used at least 300 mg peanut protein as a maintenance dose, a low-dose maintenance phase less than 300 mg peanut protein per dose, such as between 10 mg and 100 mg peanut protein per dose, may be better tolerated, without reducing the effectiveness of the OIT.

Definitions

[0016] As used herein, the singular forms“a,”“an,” and“the” include the plural references unless the context clearly dictates otherwise.

[0017] Reference to“about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of“X”.

[0018] The term“desensitized” is used herein to refer to an increased reaction threshold to a food allergen by a subject as a result of an oral immunotherapy for the food allergen.

Desensitization to a food allergen can be tested using methods known in the art, including an oral food challenge. Desensitization may be partial, wherein the subject tolerates an increased amount of the food allergen compared to prior to treatment, but still reacts to higher doses of the food allergen; or the desensitization may be complete, wherein the patient tolerates all tested doses of the food allergen.

[0019] The terms“effective,”“efficacy,” or“effectiveness” are used herein to refer to the ability of a therapy to induce immune modulation, such as desensitization, or sustain a desired immune state, such as a desensitized state, unless otherwise indicated. [0020] As used herein,“maintenance phase” refers to a phase of a peanut protein oral immunotherapy that includes administration of peanut protein (i.e., a maintenance dose) to the patient, and occurs after completion of the up-dosing phase.

[0021] As used herein, a“mild allergic adverse event” refers to an observed or experienced OGG-treatment-related allergic adverse event associated with transient discomfort, but does not require immediate medical intervention such as hospitalization or epinephrine, and does not substantially interfere with daily activities.

[0022] As used herein, a“moderate allergic adverse event” refers to an observed or experienced OIT-treatment-related allergic adverse event that is associated with discomfort of a sufficient degree to interfere with daily activities and that may prompt medical intervention and/or additional observation.

[0023] As used herein, the phrase“serious allergic adverse event” refers to an observed or experienced OIT-treatment-related allergic adverse event leading to anaphylaxis that requires hospitalization and/or administration of epinephrine or other life-saving medical intervention.

[0024] The term“subject” or“patient” is used synonymously herein to describe a human of any age.

[0025] A subject“tolerates” a dose when the dose is administered to the subject without any moderate or severe allergic adverse event. A subject is considered to tolerate the dose even if a mild allergic adverse event is observed or experienced.

[0026] The terms“treat,”“treating,” and“treatment” are used synonymously herein to refer to any action providing a benefit to a subject afflicted with a disease state or condition, including improvement in the condition through lessening, inhibition, suppression, or elimination of at least one symptom; delay in progression of the disease; delay in recurrence of the disease; inhibition of the disease; or partially or fully reducing a response or reaction to an allergen.

[0027] An“up-dosing phase” refers to a phase of an oral immunotherapy characterized by a series of increasing food allergen doses, beginning with administration of a dose of food allergen lower than the highest dose administered to the patient during the oral

immunotherapy, and ending when the highest dose administered to the patient during the oral immunotherapy is achieved.

[0028] It is understood that aspects and variations of the invention described herein include “consisting” and/or“consisting essentially of’ aspects and variations.

[0029] When a range of values is provided, it is to be understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that states range, is encompassed within the scope of the present disclosure. Where the stated range includes upper or lower limits, ranges excluding either of those included limits are also included in the present disclosure.

[0030] The section headings used herein are for organization purposes only and are not to be construed as limiting the subject matter described. The description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a patent application and its requirements. Various modifications to the described embodiments will be readily apparent to those persons skilled in the art and the generic principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiment shown but is to be accorded the widest scope consistent with the principles and features described herein.

[0031] The disclosures of all publications, patents, and patent applications referred to herein are each hereby incorporated by reference in their entireties. To the extent that any reference incorporated by reference conflicts with the instant disclosure, the instant disclosure shall control.

Peanut Oral Immunotherapy

[0032] A subject having a peanut allergy can be treated for the peanut allergy by

administering a series of doses of a peanut protein composition, according to a dosing schedule, to the subject during the course of an oral immunotherapy, thereby desensitizing the subject to the peanut allergy. The dosing schedule, for example the duration of the up dosing and/or maintenance phases, may vary between subjects depending on the age, health conditions, the nature and type of peanut allergy, concurrent interventions, complicating indications, etc.

[0033] The full length of the oral immunotherapy, for example the duration of the up-dosing phase, may vary between subjects depending on the age, health conditions, the nature and type of peanut allergy, concurrent interventions, and/or complicating indications, among others. The therapy is generally multi-phasic, and includes at least an up-dosing phase and a maintenance phase. In some embodiments, the oral immunotherapies may further include an initial escalation phase preceding the up-dosing phase. The size of the doses of the peanut protein composition administered in the up-dosing and maintenance phases can be adjusted as necessary based on the judgment of a subject’s medical caregiver and/or the needs of the subject. [0034] Methods of diagnosing peanut allergy are known in the art and include immunological assays (such as peanut- specific IgE), skin prick tests, food challenges, and trial elimination diets. For diagnosis of peanut allergy by food challenge, the subject receives increasing doses of peanut protein. An observed allergic reaction to the peanut protein during the food challenge indicates the subject has a peanut allergy and is a candidate for peanut oral immunotherapy. The judgment of whether a subject reacts to a particular dose during the food challenge depends on the test criteria, which can vary. A reaction in a food challenge can be judged by the severity of symptoms (e.g., mild, moderate, or severe) and/or the observability of the symptom (e.g., whether a symptom is subjectively reported by the patient or objectively observed by the medical caregiver).

[0035] A subject undergoing peanut OIT as described herein for treatment of a peanut allergy has a known or suspected peanut allergy. In some embodiments, the subject has previously attempted or completed a peanut protein OIT. In some embodiments, the previous peanut protein OIT was ineffective (for example, by failing to induce acceptable desensitization, producing unacceptable adverse reactions, or failing to impart adequate protection from accidental exposure to peanut protein), was terminated by the patient due to discomfort or necessity (for example, due to reaction to the peanut protein doses and/or due to adverse events during the course of OIT), or was terminated by the patient’s medical caregiver (for example, due to adverse reaction to peanut protein doses and/or due to adverse events during the course of OIT).

[0036] A subject undergoing peanut OIT as described herein for treatment of a peanut allergy may be treatment naive, having never undergone a peanut OIT for the treatment of a peanut allergy. A subject being diagnosed for peanut allergy by diagnostic exposure to peanut protein, such as in a DBPCFC, but with no other history of clinical exposure to peanut protein, is still considered treatment naive after the diagnostic exposure for the purposes of this application.

[0037] The subject receiving the oral immunotherapy treatment for peanut allergy is a human subject. In some embodiments, the subject is about 12 months or older, such as about 12 months to about 48 months (for example, about 12 months to about 24 months, about 24 months to about 36 months, or about 36 months to about 48 months). In some embodiments, the subject is about 4 years or older. In some embodiments, the subject is between 4 years and less than 18 years old. In some embodiments, the subject is 18 years or older.

[0038] The up-dosing phase precedes the maintenance phase, and includes administration of a series of escalating doses to reach the maximum dose administered to the subject during the course of oral immunotherapy. The length of time of the up-dosing phase can be adapted according to the needs of an individual patient, although it is generally completed in about 22 to about 40 weeks. For some patients, the up-dosing phase may last as long as 2 years or more. The up-dosing phase may be extended, for example, if a patient experiences allergic adverse events after beginning a higher dose in the dosing series.

[0039] The up-dosing phase of a peanut OIT typically involves incrementally increasing the administered peanut protein dose after a period of time (e.g., approximately every 1-4 weeks). A particular dose in the series is repeatedly (e.g., daily) administered to the patient until advancing to the next dose in the series. In some instances, such as when the subject does not tolerate a particular dose in the series or the subject experiences one or more allergic adverse events, the dose is decreased or the dose in the series is repeated for a period of time prior to advancing to the next dose in the series. The rate of up-dosing (e.g., the length of time an individual dose in the series is administered or the size of the dose increment between doses in the series) may be adjusted based on one or more observed allergic adverse events.

[0040] Optionally, the oral immunotherapy includes an initial escalation phase before the up dosing phase, wherein the subject is administered over the course of one or two days a series of escalating doses. The initial escalation phase is distinguished from the up-dosing phase by a lower dose range, shorter intervals between dose escalations, and, typically, closer monitoring by the subject’s medical caregiver. For example, a two day initial escalation may comprise a series of doses from about 0.5 mg to about 6 mg peanut protein, such as individual doses of about 0.5 mg, about 1 mg, about 1.5 mg, about 3 mg, and about 6 mg peanut protein. The highest tolerated dose of the initial escalation phase, or a dose lower than the highest tolerated dose in the initial escalation phase, may be the first dose of the up dosing phase. If a subject does not tolerate at least a certain dose in the initial escalation phase, the subject may be excluded from the oral immunotherapy. For example, if a subject suffers a serious allergic adverse event after administration of the 0.5 mg, 1 mg, or 1.5 mg peanut protein dose, the subject may not be allowed to proceed to the up-dosing phase. The purposes of the initial escalation phase include calibrating the doses of the up-dosing phase (e.g., the initial dose of the up-dosing phase), and ensuring the suitability of the subject for safely proceeding through an up-dosing phase.

Low-Dose Maintenance Phase

[0041] The oral immunotherapies described herein include a maintenance phase in which a plurality of doses each comprising less than 300 mg peanut protein, such as between about 10 mg and about 100 mg of a peanut protein, are periodically administered to the subject after completion of an up-dosing phase. The maintenance dose can be administered to the subject according to a regular schedule, for example once a day (i.e., daily).

[0042] Described herein is a method of treating a subject for a peanut allergy by an oral immunotherapy comprising an up-dosing phase and a maintenance phase, comprising periodic, preferably daily, administration to the subject of a low-dose maintenance phase dose of about 10 mg to about 100 mg peanut protein during at least part or all of a maintenance phase of a peanut oral immunotherapy.

[0043] The up-dosing phase precedes the maintenance phase, is typically about 20 to about 36 weeks, and optionally includes additional monitoring compared to the maintenance phase. The up-dosing phase of a peanut OIT is divided into sub-phases and typically involves incrementally increasing the peanut protein dose approximately every 1-4 weeks, although the rate of up-dosing (either faster or slower) may be adjusted based on observed adverse events. In some embodiments, the maintenance phase dose is the same as the dose of the final dose of the up-dosing phase. In some embodiments, the maintenance phase dose is less than the dose of the final dose of the up-dosing phase. By way of non-limiting example, the final dose of the up-dosing phase is about 300 mg peanut protein, and the dose of the maintenance phase is between about 10 mg and about 100 mg peanut protein. In another example, the final dose of the up-dosing phase is about 100 mg peanut protein, and the dose of the maintenance phase is between about 10 mg and about 100 mg peanut protein.

[0044] In some embodiments, the maintenance phase dose is administered for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 60 weeks, or at least 72 weeks. In some embodiments, the maintenance phase dose is administered for 72 weeks or more. In some embodiments, the maintenance phase dose is administered for about 1 month to about 3 months, about 3 months to about 6 months, about 6 months to about 9 months, about 9 months to about 12 months, about 12 months to about 18 months, about 18 months to about 24 months, and about 24 months to about 36 months. In some embodiments, the maintenance phase dose is administered for the life of the patient.

[0045] The dosage of peanut protein administered to the subject during a low-dose maintenance phase is between about 10 mg and about 100 mg peanut protein. For example, in some embodiments, the dose of the maintenance phase is between about 10 mg and about 20 mg peanut protein, about 20 mg to about 30 mg peanut protein, about 30 mg to about 40 mg peanut protein, about 40 mg to about 50 mg peanut protein, about 50 mg to about 60 mg peanut protein, about 60 mg to about 70 mg peanut protein, about 70 mg to about 80 mg peanut protein, about 80 mg to about 90 mg peanut protein, or about 90 mg to about 100 mg peanut protein. In some embodiments, the dose of the maintenance phase is about 10 mg peanut protein, about 15 mg peanut protein, about 20 mg peanut protein, about 25 mg peanut protein, about 30 mg peanut protein, about 35 mg peanut protein, about 40 mg peanut protein, about 45 mg peanut protein, about 50 mg peanut protein, about 55 mg peanut protein, about 60 mg peanut protein, about 65 mg peanut protein, about 70 mg peanut protein, about 75 mg peanut protein, about 80 mg peanut protein, about 85 mg peanut protein, about 90 mg peanut protein, about 95 mg peanut protein, or about 100 mg peanut protein.

Up-Dosing Phase

[0046] The up-dosing phase of an oral immunotherapy comprises administering to the patient a series of escalating doses, beginning with a lower dose than the highest dose of the oral immunotherapy and ending with the highest dose of the oral immunotherapy. Each dose in the series of doses is administered periodically, such as daily. Each dose in the series can comprise daily administration of the peanut protein composition for a period of time, such as about 1 week to about 4 weeks, such as about 2 weeks. After the completion of a particular dose in the series for a period of time, treatment can be advanced to a higher dose in the series. In some embodiments, the up-dosing phase of the treatment comprises a series of between 2 and 10 different dose levels. If a subject tolerates a particular dose level during the up-dosing phase for a period of time, the subject can advance to the next dose level in the series of the up-dosing phase. If a subject does not tolerate a particular dose level during the up-dosing phase for a period of time, the subject may repeat the current dose level in the series. Alternatively, if a subject does not tolerate a particular dose level during the up-dosing phase for a period of time, the subject may return to an earlier dose level in the series. The duration of the up-dosing phase therefore depends on the specific responses of the subject. The subject may repeat doses in the series as many times as necessary to achieve the highest dose in the series. The up-dosing phase ends when the highest dose is tolerated for two weeks.

[0047] The pharmaceutical composition of peanut protein of a dose administered during the up-dosing phase comprises between about 0.5 mg and about 5,000 mg of peanut protein, such as about 0.5 mg to about 10 mg peanut protein, about 10 mg to about 100 mg peanut protein, about 100 mg to about 300 mg peanut protein, about 300 mg to about 500 mg peanut protein, about 500 mg to about 1,000 mg peanut protein, about 1,000 mg to about 2,000 mg peanut protein, or about 2,000 mg to about 5,000 mg peanut protein and values and ranges therebetween. In a non-limiting exemplary embodiment, the doses of the up-dosing phase are daily administrations of the maximum tolerated dose of the initial escalation phase, such as 3 mg or 6 mg peanut protein, followed by a series of doses of about 12 mg peanut protein, about 20 mg peanut protein, about 40 mg peanut protein, about 80 mg peanut protein, about 120 mg peanut protein, about 160 mg peanut protein, about 200 mg peanut protein, about 240 mg peanut protein, and about 300 mg peanut protein, wherein each dosage level is administered for about 1 week to about 4 weeks (such as about 2 weeks) before advancing to the next dose in the series. In another exemplary embodiment, the doses of the up-dosing phase are daily administrations of the maximum tolerated dose of the initial escalation phase, such as 3 mg or 6 mg peanut protein, followed by a series of escalating daily doses prescribed by a subject’s medical caregiver, wherein each daily dose comprises one or more capsules or sachets selected from the group consisting of: 0.5 mg peanut protein capsules, 1 mg peanut protein capsules, 10 mg peanut protein capsules, 20 mg peanut protein capsules, 100 mg peanut protein capsules, or 300 mg peanut protein sachets, wherein each dosage level is administered for about 1 week to about 4 weeks (such as about 2 weeks) before advancing to the next dose in the series.

[0048] The series of doses of the up-dosing phase are distinguished by adjustment of the administered dose. The size of the dose in the series of doses of the up-dosing phase are adjusted periodically, such as between once every week and once every six weeks. In some embodiments, the up-dosing phase comprises weekly dose adjustment, dose adjustment every two weeks, dose adjustment every third week, dose adjust every fourth week, dose adjustment every fifth week, dose adjustment every sixth week, or adjustment as needed based on the judgment of the subject’s medical caregiver. The dose may be increased to the next scheduled dose in the series, lowered to a previous in the series in response to an allergic adverse event, maintained for an additional interval at the current dose in the series, increased to a higher dose in the series based on the judgment of the subject’s medical caregiver, or decreased to a lower dose in the series based on the judgment of the subject’s medical caregiver. In some embodiments, the up-dosing phase is adjusted at any time based on the judgment of the subject’s medical caregiver that the subject did not tolerate the current dose in the series.

[0049] The up-dosing phase proceeds until the subject achieves the final dose in the up dosing series. In some embodiments, the up-dosing phase is about 1 month to about 6 months, such as about 1 month to about 3 months, or about 3 months to about 6 months. In some embodiments, the up-dosing phase is about 6 months to about 2 years, such as about 6 months to about 1 year, about 1 year to about 18 months, or about 18 months to about 2 years. In a non-limiting exemplary embodiment, the up-dosing phase continues for 22 weeks to 2 years, depending on the number of dose reductions and re-escalations and dose level repeats, through doses of 12 mg peanut protein, 20 mg peanut protein, 40 mg peanut protein, 80 mg peanut protein, 120 mg peanut protein, 160 mg peanut protein, 200 mg peanut protein, 240 mg peanut protein, and terminating at 300 mg peanut protein. In any of the described embodiments, the up-dosing phase terminates when the subject tolerates the scheduled dose of the final dose in the series of the up-dosing phase for 2 weeks, thereby beginning the maintenance phase.

[0050] Each dose of the series of the up-dosing phase may be scheduled to last about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or values and ranges therebetween. Based on the observation of an allergic adverse event, a subject’s caregiver may repeat the subject’s current dose in up-dosing series. A particular portion with a particular dose may be repeated as many times as necessary, such as once, two times, three times, or four times, or more, to adequately desensitize a subject to that dose, such as when the subject no longer experiences a moderate or serious allergic adverse event upon accidental (or deliberate) exposure to the food allergen.

Initial Escalation Phase

[0051] Optionally, the oral immunotherapy includes an initial escalation phase preceding the up-dosing phase. The initial escalation phase can ensure the safety and suitability of oral immunotherapy for a particular subject. The initial escalation phase is administered over a short period, such as one or two days, at an appropriate medical facility, such as a doctor’s office or allergy clinic. The subject is usually closely monitored by a medical caregiver, who can provide interventions such as epinephrine, albuterol, and diphenhydramine in the event of an allergic adverse reaction that necessitates intervention. The initial escalation phase of the oral immunotherapy, if present, includes administration of a plurality of small doses of the peanut protein composition to the subject. The small doses can be spaced by a period of time, such as about 10 minutes to about 60 minutes, and can include 1, 2, 3, 4, or 5 or more doses.

[0052] The initial escalation phase may comprise doses between about 0.5 mg and about 6 mg peanut protein, such as about 0.5 mg to about 1.5 mg peanut protein, about 1.5 mg to about 3 mg peanut protein, or about 3 mg to about 6 mg peanut protein. In a non-limiting example, the initial escalation phase comprises an incremental escalation over one day from about 0.5 mg peanut protein to a maximum of about 6 mg peanut protein in a single day, with single doses of about 0.5 mg, about 1 mg, about 1.5 mg, about 3 mg, and about 6 mg of peanut protein, wherein tolerance of the 3 mg or 6 mg peanut protein dose indicates the subject can safely proceed to an up-dosing phase of an oral immunotherapy.

Compositions for Oral Immunotherapy

[0053] Exemplary compositions for treating peanut allergy are described in detail in U.S. Publication No. 2014/0271721, the contents of which are incorporated by reference herein in its entirety. Exemplary methods for preparing peanut protein formulations are described in detail in U.S. Publication No. 2014/0271836, the contents of which are incorporated by reference herein in its entirety.

[0054] A subject having a peanut allergy can be treated for the peanut allergy by

administering a series of doses of a peanut protein composition to the subject during the course of a peanut protein oral immunotherapy. The peanut protein composition is preferably a pharmaceutical composition comprising one or more peanut allergen proteins for treating peanut allergy. In some embodiments, peanut proteins may be isolated from peanut flour and, optionally, further comprise one or more diluents, one or more glidants, and one or more lubricants. In some embodiments, the pharmaceutical composition of peanut protein comprises between about 0.05% to about 100% w/w of peanut protein.

[0055] In some embodiments, the pharmaceutical composition of peanut protein comprises characterized peanut protein. In some embodiments the characterized peanut protein comprises characterized peanut allergen proteins Ara hi, Ara h2, and/or Ara h6. In one embodiment, a final formulation for treating peanut allergy comprises peanut flour, comprising characterized peanut allergen proteins Ara hi, Ara h2, and/or Ara h6, formulated with a diluent, a glidant, and a lubricant in graduated doses comprising capsules containing between about 0.5 and about 1,000 mg of peanut protein for administration in up-dosing, maintenance, and/or initial escalation phases of an oral immunotherapy.

[0056] In any of the methods described herein, the pharmaceutical composition of peanut protein for administration in a maintenance phase of an oral immunotherapy may comprise a maintenance phase dose of between about 10 mg to about 100 mg peanut protein. In some embodiments, the maintenance phase dose comprises between about 100 mg to about 3000 mg peanut protein, such as more than about 100 mg peanut protein, more than about 300 mg peanut protein, more than about 500 mg peanut protein, or more than about 1,000 mg peanut protein. [0057] In some embodiments, the pharmaceutical composition of peanut protein for administration in an up-dosing phase of an oral immunotherapy comprises between about 0.5 mg and about 5,000 mg peanut protein, such as individual doses in a series of about 3 mg, about 6 mg, about 10 mg, about 12 mg, about 20 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, and about 300 mg peanut protein. In a non-limiting exemplary embodiment, the doses of peanut protein for

administration in an up-dosing phase of an oral immunotherapy are daily administration of the maximum tolerated dose of the initial escalation phase, such as about 3 mg peanut protein or about 6 mg peanut protein, followed by a series of escalating daily doses prescribed by a subject’s medical caregiver, wherein each daily dose comprises one or more capsules or sachets selected from the group consisting of: about 0.5 mg peanut protein capsules, about 1 mg peanut protein capsules, about 10 mg peanut protein capsules, about 20 mg peanut protein capsules, about 100 mg peanut protein capsules, or about 300 mg peanut protein sachets, wherein each dosage level is administered for about 1 week to about 4 weeks (such as about 2 weeks) before advancing to the next dose.

[0058] In the methods described herein, an oral immunotherapy may optionally comprise an initial escalation phase. In some embodiments, the pharmaceutical composition of peanut protein for administration in an initial escalation phase of an oral immunotherapy comprises between about 0.5 and about 6 mg of peanut protein, such as individual doses of about 0.5 mg, about 1 mg, about 1.5 mg, about 3 mg, and about 6 mg peanut protein. In some embodiments, the pharmaceutical composition of peanut protein for administration in an initial escalation phase of an oral immunotherapy comprises between about 0.5 and about 6 mg of peanut protein, such as individual doses of about 0.5 mg, about 1 mg, about 1.5 mg, about 3 mg, about 6 mg, and about 12 mg peanut protein.

EXAMPLES

[0059] The application may be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the application. The following examples are presented in order to more fully illustrate embodiments and should in no way be construed, however, as limiting the broad scope of the application. While certain

embodiments of the present application have been shown and described herein, it will be obvious that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the spirit and scope of the invention. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the methods described herein.

Example 1 - Low-dose Maintenance Clinical Trial

[0060] A clinical trial is conducted with peanut- allergic children and adults. Subjects undergo an entry double-blind placebo-controlled oral food challenge (DBPCFC) and a peanut protein skin prick test (SPT). Baseline total IgE, peanut- specific IgG4, and peanut- specific IgE serum levels is assayed. Treated subjects undergo an initial escalation, followed by an up-dosing phase to a target dose of 300 mg per day of peanut protein, followed by a maintenance phase. In one treatment cohort of the clinical trial, subjects will receive a normal maintenance phase dose of 300 mg per day of peanut protein. In another treatment cohort, subjects will receive a low-dose maintenance phase dose of between 10 mg and 100 mg per day of peanut protein. The maintenance phase will proceed for a scheduled period of at least 3 months.

[0061] All subjects in each cohort who complete their schedule will undergo an exit

DBPCFC and skin prick test. Exit measurements of total IgE, peanut- specific IgG4, and peanut- specific IgE will be taken.

[0062] The safety (such as incidence of allergic adverse events) and efficacy (such as highest tolerated dose at exit DBPCFC, wheal size of SPT, measures of serum IgE and IgG4, and reaction to accidental peanut protein ingestion) will be compared between treatment cohorts.

[0063] In an alternative clinical trial, another cohort will complete a double-blind regimen of placebo. Safety and efficacy of the oral immunotherapy with normal-dose maintenance (300 mg per day of peanut protein) and low-dose maintenance (10-100 mg per day of peanut protein) will be compared to placebo.

Example 2 - Subject Receiving Low-dose Maintenance Dose

[0064] A subject diagnosed with peanut allergy is treated by a peanut protein oral immunotherapy. The subject undergoes an up-dosing phase to 300 mg peanut protein followed by a maintenance phase. Early in the maintenance phase the subject receives a daily dose of approximately 100 mg peanut protein. As the maintenance phase progresses, the subject receives lower daily doses such as 60 mg per day, 30 mg per day, and finally 10 mg per day of peanut protein. The safety and efficacy of the oral immunotherapy is assessed throughout the maintenance phase by any of an oral food challenge, a SPT, incidence of allergic adverse events, and/or serum IgE and/or IgG4 levels. The reactivity of the subject to accidental ingestion of peanut is recorded if it occurs.