Immunotherapy for treatment of allergy

Abstract

This invention relates to methods of immunotherapy comprising administering allergen, such as peanut protein, to an individual in need thereof at regular time intervals. The dose of allergen increases incrementally by 1 to 10% at each administration from an initial dose to a maintenance dose. The maintenance dose of the allergen is then administered at regular time intervals. Also provided are compositions and dosing devices for use in such methods.

Description

[0001] Immunotherapy for Treatment of Allergy

[0002] Field

[0003] The present invention relates to methods and means of immunotherapy for the treatment of allergy, such as food allergy, and formulations and dosing devices for use in such methods.

[0004] Background

[0005] Allergy is a prevalent and potentially life-threatening condition that negatively affects guality of life. Allergy affects nearly every body system, causing wide-ranging symptoms that are often persistent and severe. Allergy is caused by an over production of specific serum IgE by the immune system, directed against otherwise harmless proteins or complex molecules, leading to sensitisation of mast cells and eventual clinical allergic reactions on re-encountering the allergen. Immunotherapy, an established approach for treating allergies, modifies the immune system with repeated exposure to the allergen, inducing it to tolerate specific harmful allergens.

[0006] Immunotherapy uses pre-measured doses of the specific allergens that individual patients are reactive to, administered to patients by multiple alternative routes (e.g., oral, sublingual, injection, inhalation, or transcutaneously). Immunotherapy doses are administered freguently (e.g. daily). Immunotherapy regimens begin with a very small initial dose, before escalation to much larger maintenance doses (for example 100- fold or larger than the initial dose) over an ‘up-dosing phase’, which lasts several months, and is followed by continuation at the same ‘maintenance dose’. Extended periods of maintenance dosing cause desensitization to much larger amounts of the allergen.

[0007] Traditionally, dose escalation during the ‘up-dosing phase’ has been comprised of series of stepwise dose increments, with regimens designed with a small number of dose increments spread over several months. This regimen design is based on i) practicalities of manufacture and supply of the treatment and ii) to ensure that patients are able to span the dose range from initiation dose to maintenance dose within a reasonable time frame. Together, these considerations have resulted in the oral immunotherapy dose regimes requiring the use of large, often 25-100% dose increases given in a single day, with each followed by a series of days of dosing at home at the same dose. Because the discrete up-dosing steps represent such large increases in dose, they are associated with more severe adverse events than the days at the same dose and are thus required to be taken in a clinic under physician supervision. This necessitates immunotherapy requiring multiple lengthy clinic visits, causing inconvenience to physicians, patients and their families.

[0008] There is one existing licensed immunotherapy for food allergy, Palforzia. Palforzia, is licensed for treatment of peanut allergy and is only licenced for children aged 4- 17 years of age. There are no licensed treatments for adults with peanut allergy. Over the past three years, Palforzia has seen limited adoption in both the UK and US. Nestle, which owned Palforzia, pinpointed the primary reason for its subdued reception in a November 2022 announcement: the treatment’s demanding updosing regimen had proved too taxing for both patients and physicians. This regimen mandates 12 clinic visits, over six months, with each visit requiring a long cool off period, which creates large staff and space requirements. Immunotherapy is provided in single dose units. For food allergens, due to the solid nature of most of the food stuffs, this typically contains powdered or granulated formulations to be administered by the oral or sublingual route. The use of single dose units has prevented, to date, the development of oral immunotherapy regimes that do not rely on large dose increases. It is not practicable to manufacture and supply the large number of formulations required to span the wide range from the dose range from initiation dose to maintenance dose as single dose units. A number of clinical trials are investigating using additional drugs (e.g., antibodies designed to reduce the serum and cell bound levels of IgE) as prophylactic treatments in combination with immunotherapy, in order to reduce the frequency and severity of the side effects of allergic nature caused by the immunotherapy. The use of such prophylactic therapy, whilst may be beneficial in reducing side effects caused by immunotherapy, will cause additional side effects per se and be associated with additional cost of therapy and burden to both patients and physician.

[0009] There is a need for a novel, practical approach for enabling patients to safely span the wide range of doses between initiation and maintenance doses without the use of large dose increments or prophylactic therapies, to enable home-based immunotherapy up-dosing. This would greatly reduce the burden of immunotherapy for both patients and physicians, whilst ensuring efficacy and safety, and thus improve accessibility of immunotherapy for patients living with allergy.

[0010] Summary

[0011] The present inventors have developed methods of immunotherapy that employ up-dosing schedules in which allergen is administered at regular time intervals and the dose of allergen is incrementally increased at each administration. This continuous up-dosing reduces adverse side-effects in patients compared to periodic up-dosing. The present inventors have also developed dosing devices and allergen formulations that are advantageously suited for use in these methods.

[0012] A first aspect of the invention provides a method of immunotherapy comprising;

[0013] (a) administering allergen to an individual in need thereof at regular time intervals, wherein the dose of allergen increases incrementally by 1 to 10% at each administration from an initial dose to a maintenance dose, and

[0014] (b) administering the maintenance dose of the allergen at regular time intervals.

[0015] Preferably, the regular time interval of dose administration in steps (a) and (b) is daily.

[0016] Preferably, allergen is administered orally in methods of the first aspect.

[0017] A method of the first aspect may further comprise administering the initial dose of allergen to the individual at regular time intervals before step (a).

[0018] In some preferred embodiments, a method of the first aspect may comprise;

[0019] (i) orally administering an initial dose of an allergen to an individual in need thereof daily, (ii) orally administering a dose of allergen to the individual daily, wherein the dose of allergen increases incrementally by 1 to 10% per day from the initial dose to a maintenance dose, and

[0020] (iii) orally administering the maintenance dose of the allergen daily.

[0021] Preferably, the allergen in methods of the first aspect is peanut protein.

[0022] A second aspect of the invention provides a set of compositions comprising a first allergen composition comprising 1 to 10% (w / w) allergen and a second allergen composition having 20 to 30% (w / w) allergen.

[0023] Preferably, the first allergen composition comprises 5% (w / w) allergen. Preferably, the second allergen composition comprises 20% (w / w) allergen.

[0024] The allergen compositions in the set may be bulk formulations that are not separated into individual doses.

[0025] Preferably, the formulations of the first and second allergen compositions allow for the use of allergen extracts that vary in allergen content. For example, a first allergen composition of the second aspect may have the formula;

[0026] I.5 / x % (w / w) allergen extract

[0027] II.3 / 25 X5 / x % (W / W) hypromellose

[0028] III.72 / 25 X5 / x % (W / W) mannitol powder 2 % (w / w) sodium stearyl fumarate

[0029] V. 100 - (l+ll+lll+IV) % (w / w) mannitol granules wherein x is the % (w / w) allergen in the allergen extract.

[0030] A second allergen composition of the second aspect may have the formula;

[0031] I.20 / x % (w / w) allergen extract

[0032] I I .3ho x20 / x % (w / w) hypromellose

[0033] III.27 / 70 X20 / X % (W / W) mannitol powder

[0034] IV. 2 % (w / w) sodium stearyl fumarate

[0035] V. 100 -(l+ll+lll+IV) % (w / w) mannitol granules wherein x is the % (w / w) allergen in the allergen extract.

[0036] Preferably, the allergen extract is peanut flour.

[0037] The set of allergen compositions of the second aspect may be used in the methods of the first aspect.

[0038] A third aspect of the invention provides a dosing device for use in a method of immunotherapy comprising; a cartridge, wherein the cartridge contains a bulk formulation of allergen for administration, an actuator for dispensing a defined dose of allergen from the bulk formulation in the cartridge, and a control unit comprising a processor, wherein the processor is programmed to operate the actuator to dispense the define dose of allergen in accordance with a predetermined dose regimen.

[0039] The cartridge of the dosing device may contain a first and / or a second allergen composition of the set of compositions of the second aspect.

[0040] A dosing device of the third aspect may be useful in a method of the first aspect.

[0041] Other aspects and embodiments of the invention are described in more detail below.

[0042] Brief Description of the Figures

[0043] Figure 1 shows an embodiment of a dose metering and dispensing device, comprising a reusable control unit, disposable drug-containing cartridge, and detachable cup.

[0044] Figure 2 shows an example of protein profiles of drug substance batches.

[0045] Figure 3 shows the process of manufacture of the allergen compositions.

[0046] Figure 4 shows a granule manufacture flow chart.

[0047] Figure 5 shows a cartridge manufacture flow chart.

[0048] Figure 6 shows an example continuous up-dosing regimen, approximately tracking the discrete up-dosing regimen.

[0049] Detailed Description

[0050] This invention relates to methods of immunotherapy that comprise administering an allergen to an individual in need thereof in a series of administrations, in which the dose of allergen increases incrementally by 1% to 10% on each administration from an initial starting dose to a final maintenance dose. The administrations may be at regular time intervals, preferably daily. These methods of immunotherapy may be performed using a dosing device for metering and dispensing doses of allergen and / or formulations that allow the consistent dispensation of accurate doses of allergen in accordance with the method.

[0051] Immunotherapy induces down-regulation of mast cell and basophil effector cells in the individual leading to a state of desensitization to the allergen. Immunotherapy using the methods described herein reduces or avoids adverse side-effects associated with up-dosing, such as anaphylaxis, thereby reducing or avoiding the need for frequent clinic visits and / or concomitant prophylactic therapies and enhancing the convenience and efficiency of immunotherapy. Furthermore, the methods described herein allow the rate of increase of doses to be personalised to the patient. For example, if a patient experiences adverse effects from treatment, then a slower rate of increase may be employed. Allergen may be administered orally or sub-lingually in the methods described herein. Preferably, the allergen is administered orally (i.e. oral immunotherapy).

[0052] An allergen is an antigen capable of inducing an allergic response in a mammalian subject, preferably a human subject. Allergens may include food allergens and inhalant allergens. The allergen may be a single allergen or a mixture of two or more allergens in powdered, granulated, or other suitable forms.

[0053] Allergens may include proteins, for example plant proteins, such as peanut protein, tree nut protein, soy protein, wheat protein, fruit protein, mustard protein, celery protein, sesame seed protein, nut proteins, such as cashew, pistachio, hazelnut, walnut, pecan, almond or Brazil nut protein, and animal proteins, such as fish protein, shellfish protein, egg protein, beef protein, pork protein, and milk protein. Allergens may also include polysaccharides, such as galactose-alpha-1 , 3-galactose (alpha-gal), pollen, such as grass, weed or tree pollen; animal dander; spores and mold.

[0054] Conveniently, the allergen may be comprised in an allergen extract, for example a dried powder, such as flour, freeze-dried milk, egg powder or animal protein powder. A suitable powder may be generated from a natural source that contains the allergen. In some embodiments, a defatting or drying or desiccating step may be employed. For example, flour may be obtained by grinding raw nuts, grains or roots that contain the allergen, such as peanuts or tree nuts. Dried powders, such as flours, may be produced by conventional techniques or obtained from commercial suppliers. A dried powder, such as a flour, may for example comprise 25% to 60%, 30% to 55% or 35% to 45% allergen. The amount of allergen extract in the allergen composition or formulation depends on the range of doses of allergen that are to be administered to a subject in the dosing regimen. Typically an allergen composition may comprise 1% (w / w) to 95% (w / w) allergen extract.

[0055] Preferably the allergen is peanut protein. Peanut protein is the total protein content of a peanut and may contain multiple allergenic peanut proteins, for example one or more of Ara hi to h9. In some preferred embodiments, peanut protein may comprise Ara h 1 , 2, 3 and 6.

[0056] Peanut protein may be extracted, isolated and / or purified from a peanut. In some embodiments, peanut protein may be provided as a peanut extract, such as peanut flour or peanut powder. A peanut flour may for example comprise 35% to 55% peanut protein, for example 38% to 44% peanut protein. Peanut flour is produced by crushing, grinding and / or milling whole peanuts. The flour may be partially or completely defatted to reduce the fat content. Defatting does not affect the allergenic peanut protein content of the flour. The peanut protein content of peanut flour may be readily determined using standard techniques and is typically 50% (w / w) peanut protein. Peanut flour is widely available from commercial sources (e.g. Golden Peanut Company GA USA). Other peanut extracts which contain peanut protein may also be used in the methods described herein.

[0057] The immunotherapy methods described herein may further comprise an optional initial phase before the updosing phase. The initial phase may comprise one or more administrations of the allergen at an initial dose. The initial dose of allergen may be administered at regular time intervals, for example daily, every two, every three, every four, every five or every six days or weekly. Preferably, the initial dose is administered daily. In some preferred embodiments, the initial dose is administered daily for 1 or more days before the up-dosing phase. For example, the initial dose is administered daily for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13,14, 15, 16, 17, 18, 19, 20 or 21 days or longer. Preferably, the initial dose is administered daily for 14 days.

[0058] The initial dose is selected to cause little or no objective reaction in the patient. For example, a suitable initial dose may elicit an objective reaction in only 5% or less of the relevant allergic population. Preferably, the initial dose of allergen is 2 mg. For example, an initial dose of allergen may be 2mg of peanut protein.

[0059] Following the optional initial phase, the immunotherapy methods described herein comprise an up-dosing phase (step (a)) in which allergen is administered to the patient in a series of administrations in which the dose of allergen is increased incrementally with each administration from the initial dose to the maintenance dose. The administrations of allergen may occur at regular time intervals of 1 day to 1 week. For example, the allergen may be administered daily, every two, every three, every four, every five or every six days or weekly. Preferably, the allergen is administered daily.

[0060] Preferably, the maintenance dose of allergen is 200 mg. For example, a maintenance dose of allergen may be 200mg of peanut protein.

[0061] Preferably, the dose of allergen administered to the patient is increased incrementally with each administration of allergen until it reaches the maintenance dose. For example, the dose of the allergen may be increased over the dose of the previous administration by an increment of between 1 to 10%, preferably 2 to 6%, starting with the initial dose and ending with the maintenance dose. For example, the dose may be increased by an increment of 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10% with each administration of allergen. The increment of the increase in dose may be constant or fixed i.e. the % increase of each dose over the previous dose may be the same. In some preferred embodiments, the dose of the allergen may be increased by an increment of 5% to 6% per administration from the initial dose to the maintenance dose. Most preferably, the dose of allergen is increased by 5.7% per administration. For example, the dose of allergen may be increased by 5.7% per administration.

[0062] The up-dosing phase may last from 70 days to 1 year or longer, until the maintenance dose is reached. For example, the up-dosing phase may last from 3 to 6 months. In some preferred embodiments, the up-dosing phase may last from 77 to 91 days, for example 84 days.

[0063] The patient may be periodically or continuously monitored for adverse reactions during the up-dosing phase. For example, the patient may be assessed and parameters such as pulse, blood pressure, peak expiratory flow rate in 1 second and oxygen saturation measured. The patient may be monitored for the development of adverse allergic reactions or allergic symptoms, other side effects and / or changes in any of the measured parameters. Allergic symptoms may be treated with conventional medication as required. If an individual suffers a severe adverse reaction during the up-dosing phase, for example wheezing or other allergic symptoms assessed as serious by a clinician, then the individual may be subjected to a modified dose regimen or treatment of the individual may be paused or terminated, until the reason for the severe reaction has been identified and corrected. In a modified dose regimen, the incremental increase in dose on each administration may be reduced or the allergen may be administered without an incremental increase, such that the same dose is administered consecutively for two or more administrations, or the allergen may be administered at a reduced dose. After recommencing administration of allergen, smaller increments of increase in dose may be employed for a period of time.

[0064] In some examples of modified dose regimens, the incremental increase in dose may be reduced by 50%. For example, the dose of the allergen may be increased by an increment of 2-3% per day, preferably by 2.85% per day. For example, the dose of the allergen may be increased by an increment of 2-3% per day, preferably by 2.85% per day. The incrementally increasing daily dose may then be administered in the updosing phase for 154 days to 1 year or longer. For example, the up-dosing phase may last from 6 to 12 months. In some preferred embodiments, the up-dosing phase may last from 161 to 175 days, for example, 168 days.

[0065] In other examples of modified dose regimens, the allergen dose may be maintained over multiple consecutive administrations without any increase (i.e. the same dose may be administered two or more times); or the dose may be reduced, and the reduced dose maintained over multiple consecutive administrations without increase.

[0066] The dose of allergen that is administered to the patient is incrementally increased with each administration from an initial dose to a maintenance dose in the up-dosing phase. Following the up-dosing phase, the methods described herein comprise a maintenance phase, in which allergen is administered to the patient at the maintenance dose. The administrations of allergen at the maintenance dose may occur at regular time intervals of 1 day to 1 week. For example, the allergen may be administered at the maintenance dose daily, every two, every three, every four, every five or every six days or weekly. Preferably, the allergen is administered daily at the maintenance dose.

[0067] The maintenance dose may be administered to the individual at regular time intervals in the maintenance phase for at least 3 months, at least 6 months, at least 1 year, at least 1 .5 years or at least 2 years.

[0068] Preferably the allergen is administered daily at the maintenance dose in the maintenance phase. After the patient has demonstrated tolerance to the daily dose in the maintenance phase (e.g. no allergic reactions to doses in the past 3 months), administration of the maintenance dose of allergen may be switched to a weekly regime. For example, the methods described herein may further comprise (c) administering the maintenance dose of the allergen weekly. The maintenance dose may be administered to the individual weekly for at least 6 months, at least 1 year, at least 2 years, at least 2.5 years, at least 3 years or indefinitely. In the optional initial phase and the maintenance phase of the methods described herein, the dose of allergen remains constant at the initial dose and the maintenance dose, respectively, over multiple administrations of the allergen. These doses may be conveniently administered or dispensed in unit dose form i.e. the allergen is distributed into units, each of which contains a defined dose of the allergen. Suitable units are well-known in the art and include capsules.

[0069] In the up-dosing phase (step (a)) of the methods described herein, the dose of each administration of the allergen is increased by a fixed increment over the dose of the previous administration. The dose of allergen may be metered and / or measured for each administration. Conveniently, this may be performed by a dosing device which measures and dispenses the dose of allergen that is required for each administration in accordance with the dose regimen. Suitable devices are described below. A dose of allergen may be increased from the previous dose by dispensing an increased amount or volume of the same allergen formulation as the previous dose or by dispensing the dose from a different allergen formulation with an increased concentration of allergen.

[0070] Also provided are an allergen for use in a method of immunotherapy as described herein and the use of an allergen described herein in the manufacture of a medicament for use in a method of immunotherapy as described herein.

[0071] Allergen for use in methods described herein may be in a pharmaceutical composition or formulation, preferably a solid pharmaceutical composition or formulation. Suitable pharmaceutical compositions or formulations may be stable and allow consistent and accurate dispensing of individual doses from a bulk composition or formulation. For example, a formulation or composition may comprise non-sterile free-flowing oral granules.

[0072] A pharmaceutical composition or formulation may comprise allergen or allergen extract as described above and one or more pharmaceutically acceptable excipients, such as carriers, fillers, binders, and lubricants. In some preferred embodiments, a pharmaceutical composition or formulation may lack a glidant. The term “pharmaceutically acceptable” relates to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound veterinary or medical judgement, suitable for use in contact with the tissues of a subject (e.g., human, or other mammal) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Preferred excipients for use in the compositions described herein are not associated with hypersensitivity. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0073] Suitable carriers, excipients, etc. may be found in standard pharmaceutical texts, for example, Remington’s Pharmaceutical Sciences and The Handbook of Pharmaceutical Excipients, 4th edit., eds. R. C. Rowe et al, APhA Publications, 2003.

[0074] Allergen extracts, such as peanut flour display poor flow characteristics, even when mixed with common excipients. This makes them incompatible with mechanical or automated dosing devices. The allergen compositions described herein display good flow characteristics and are compatible with mechanical or automated dosing devices. These compositions are especially suitable for use in the methods described herein. The amount of allergen in the allergen composition depends on the dosing regimen range that is to be employed. Typically, an allergen composition may comprise 0.3% to 50% (w / w) allergen.

[0075] Preferred allergen compositions are adapted for use in a dosing device. For example, a composition may be adapted to have good flow properties to enable accurate and precise dosing and avoid blockage within a device. In some embodiments, a composition may comprise granules of diluent and allergen. The size of the granules may be selected to provide a uniform composition at low doses (e.g. the initial dose), reduce or prevent the entrapment of granules within a device and / or reduce or prevent the segregation of the diluent and allergen granules with the composition. Granulation may also reduce the surface area of a composition compared with a powder, such as peanut flour. This may reduce the flavour of the allergen in the composition and thus promote patient compliance with the dosing regimen.

[0076] For example, the particle size of the granules in an allergen composition described herein may be less than 750 pm, less than 500 pm or less than 355 pm. In some embodiments, the granules in an allergen composition described herein may be more than 250 pm. For example, the granules in an allergen composition described herein may be 250 to 500 pm. Granule size may be determined by sieving in accordance with standard techniques (for example, ISO Standard 9276, ASTM C136). Compositions comprising granules of a target size may be produced by sieving to exclude larger or smaller granules.

[0077] In some preferred embodiments, a composition or formulation for use as described herein may comprise (i) granules comprising allergen extract, powdered mannitol and hypromellose, (ii) granules of mannitol and (iii) sodium stearyl fumarate.

[0078] In some embodiments, a single allergen composition may be used to provide all of the doses of an allergen required for a method described herein.

[0079] In more preferred embodiments, two or more different allergen compositions may be used to provide the doses of an allergen required for a method described herein. This allows smaller amounts of allergen composition to be used to provide higher doses (e.g. the maintenance dose) and allows lower doses (e.g. the initial dose) to be measured and dispensed accurately. Provided herein are a set of allergen compositions for use in the methods described herein. The allergen compositions in the set may comprise different concentrations of allergen. All of the different doses of allergen required to up-dose a patient from the initial to the maintenance dose may be dispensed using different amounts of the allergen compositions in the set. Preferably, the set of allergen compositions consists of eight or fewer different compositions.

[0080] In some preferred embodiments, the set of allergen compositions consists of two different compositions. For example, the set may include a first composition comprising 1 to 10% (w / w) allergen, preferably 5% w / w allergen and a second composition comprising 15 to 30% (w / w) allergen, preferably 20% w / w allergen. The different doses required for a method described herein may be generated by dispensing different amounts or quantities of the first and second compositions. The allergen compositions in the set may comprise granules of allergen and granules of excipient. For example, the allergen compositions in the set may comprise granules comprising allergen extract, hypromellose and mannitol powder. Suitable granules may for example comprise 25% (w / w) allergen extract, 3% hypromellose and 72% mannitol powder or 70% (w / w) allergen extract, 3% hypromellose and 27% mannitol powder. The allergen granules may be formulated with sodium stearyl formulate and mannitol granules to produce the allergen compositions described herein.

[0081] The allergen compositions in the set may be produced using allergen extracts that vary in allergen content. For example, for an allergen extract containing x% (w / w) allergen, a first allergen composition with 5% allergen may comprise;

[0082] (i) allergen extract5 / x % (w / w)

[0083] (ii) hypromellose3 / 25 x5 / x %(w / w)

[0084] (iii) mannitol powder72 / 25 x5 / x % (w / w)

[0085] (iv) sodium stearyl fumarate 2 % (w / w)

[0086] (v) granular mannitol 100 -(i+ii+iii+iv) % (w / w)

[0087] For example, a first allergen composition may comprise 8 to 17% (w / w) allergen extract, 1 to 3% (w / w) hypromellose, 23 to 46% (w / w) mannitol powder, 33 to 66% (w / w) granular mannitol and 2% (w / w) sodium stearyl fumarate.

[0088] A second allergen composition with 20% allergen may comprise;

[0089] (i) allergen extract20 / x %(w / w)

[0090] (ii) hypromellose3ho x20 / x %(w / w)

[0091] (iii) mannitol powder27ho x20 / x %(w / w)

[0092] (iv) sodium stearyl fumarate 2 %(w / w)

[0093] (v) granular mannitol 100 -(i+ii+iii+iv) % (w / w)

[0094] For example, a second allergen composition with 20% (w / w) allergen may comprise 33 to 67 (w / w) allergen extract, 1 to 4% (w / w) hypromellose, 12 to 26% (w / w) mannitol powder, 2 to 51% (w / w) granular mannitol and 2% (w / w) sodium stearyl fumarate.

[0095] Preferably the allergen is peanut protein, and the allergen extract is peanut flour.

[0096] In some embodiments, the allergen compositions in the set may be in unit dose form for the initial doses of the optional initial phase and the maintenance dose of step (b) and may be in bulk form for the incrementally increasing doses of the up-dosing phase of step (a).

[0097] In some embodiments, allergens or allergen compositions described herein may be administered directly to a subject (i.e. without admixing with a foodstuff). In other embodiments, allergens or allergen compositions may be admixed with a foodstuff before administration. For example, an allergen composition may be admixed with a foodstuff and the foodstuff then ingested by the subject. Suitable foodstuffs include dairy or dairy substitute products, such as yoghurt, milkshake or chocolate, or another food product with similar properties, cooked or baked food products, such as biscuits or cake; confectionery (e.g. chocolate, sweets and jellies) and beverages. Dairy substitute products may include soy-based products. In some embodiments, the foodstuff may be semi-solid.

[0098] Also provided are a set of allergen compositions described above for use in a method of oral immunotherapy as described herein and the use of a set of compositions described above described herein in the manufacture of a medicament for use in a method of oral immunotherapy as described herein.

[0099] Also provided is a method of making an allergen formulation for use in a method of oral immunotherapy as described herein. The method may comprise admixing allergen extract, mannitol powder, hypromellose and water, drying the admixture to produce granules and blending the granules with mannitol granules and sodium stearyl fumarate. Suitable proportions of these ingredients are provided above. Suitable formulation processes that are well-known in the art. For example, as an initial step, the peanut protein content of a peanut flour or other peanut extract containing peanut protein may be determined. Suitable methods for characterising peanut protein content are well-known in the art and include RP-HLPC and LC-MS / MS. The flour or other powder containing the peanut protein may be admixed with the mannitol powder in a granulator. The mixture may then be admixed with an aqueous granulation solution comprising hypromellose and agitated, for example using an impeller, screws, or air, in a wet granulation process. Agitation of the mixture in the granulation solution in the presence of the hypromellose causes particles of the mixture to coalesce to produce wet granules. The wet granules may then be dried, for example by heating to 50 to 70 °C, preferably about 65°C, to remove the aqueous granulation solution, leaving dry granules of peanut flour and mannitol bound together with hypromellose. Suitable wet granulation techniques are well-known in the art. After drying, the granules may be blended with mannitol granules and sodium stearyl fumarate using standard blending techniques and sieved to generate the allergen composition. In some embodiments, the blend may be sieved using a 355 pm sieve to produce a composition comprising granules with a particle size of less than 355 pm. In other embodiments, the blend may be sieved using a 500 pm sieve and a 250 pm sieve, to produce a composition comprising granules with a particle size of 250-500 pm.

[0100] The allergen composition may be distributed into unit dose formulations for use in the initial and maintenance phases, for example by encapsulating into capsules or compressing into tablets, using standard techniques. Dose formulations may be tested using analytical techniques to confirm the purity and allergen content and subsequently packaged, for example in a blister pack.

[0101] The allergen composition may be in a bulk form for use in the up-dosing phase. For example, an allergen composition in bulk form may be packaged into a canister or cartridge for use in a dosing device. The bulk form of the allergen composition may contain multiple doses of allergen and may form a reservoir from which aliquots of allergen of defined dose are dispensed. For example, the dosing device may dispense an amount of the allergen composition that contains a measured dose of allergen for administration in accordance with a method or dosage regimen described herein. Doses of allergen in accordance with a dose regimen or method described herein may be metered and dispensed by a dosing device. For example, during the updosing phase of the methods described herein, the device may provide an amount of allergen for administration having a dose that increases by a fixed increment over the dose of allergen of the previous administration.

[0102] A dosing device for use in a method of oral immunotherapy may comprise; a cartridge that contains an allergen composition for administration, an actuator for dispensing an amount of allergen composition from the cartridge that contains a defined dose of allergen, and a control unit comprising a processor, wherein the processor is programmed to operate the actuator to dispense amounts of allergen composition from the cartridge according to a pre-determined dose regimen.

[0103] The processor may be programmed to operate the actuator in accordance with an OIT method described herein.

[0104] The dosing device may further comprise a receptacle to contain the dispensed amount of allergen composition. The receptacle may be detachable. For example, a detachable cup.

[0105] A dosing device described herein may comprise a cartridge containing an allergen composition for administration. Each cartridge may be designed for insertion into the control unit, with the capacity to hold allergen compositions containing single or mixed allergens as per treatment requirements. The allergen composition in the cartridge may be in bulk form and may form a reservoir of allergen from which portions may be dispensed by the actuator to provide defined doses of allergen.

[0106] The allergen composition in the cartridge may be non-sterile.

[0107] The allergen composition in the cartridge is preferably in a free-flowing solid form, such as powdered or granulated form. Preferably, the allergen composition is a composition as described above.

[0108] The allergen composition may be contained in a canister within the cartridge. The cartridge may contain multiple canisters containing different allergen compositions. For example, cartridge may contain canisters containing a set of allergen compositions as described above. The cartridge may comprise a first canister comprising a first allergen composition and a second canister comprising a second allergen composition.

[0109] Suitable cartridges may be replaceable and / or disposable after use.

[0110] A cartridge may further comprise a microchip containing information about allergen composition in the cartridge. The information may include one or more of the permitted dose range for the cartridge, the concentration of allergen in the allergen composition, the current dose status (quantity of allergen composition remaining), and the expiry date of the allergen composition. The actuator of the dosing device may dispense measured doses of allergen from the cartridge in accordance with a method described herein. For example, the allergen composition in the cartridge may have a defined allergen content (e.g. 5% (w / w) or 20% (w / w)). The actuator of the dosing device may dispense a measured volume of the allergen composition that contains the dose defined by the predetermined dosing regimen. As the dose increases, the volume of allergen composition dispensed by the actuator may increase or the dosing device may dispense a different allergen composition with an increased allergen content.

[0111] Actuators suitable for dispensing allergen composition as known the art and include screw pumps, such as Archimedean screws and auger screws.

[0112] The actuator is operated by the control unit. The control unit may be automated, semi-automated, or manually operated.

[0113] The control unit may comprise a processor. The processor may be programmed or programmable with one or more dosing regimens. These may be stored in firmware on the device. For example, the processor may be programmed to dispense or provide doses of allergen in accordance with a method described herein or in accordance with step (ii) of a method described herein. The processor may be programmed to dispense or provide doses of allergen from a set of allergen compositions describe herein. For example, the processor may be programmed to dispense or provide doses of allergen from a first allergen composition and a second allergen composition as described herein. The processor may be programmed with a primary regimen. This may for example involve a daily dose increment of 5.7% from the previous day’s dose. Alternate regimens may include half-speed up-dosing regimens, maintenance of the current dose, or reductions in the dose by half for a specified duration, all under physician guidance. For example, the processor may be programmed to adjust dosing increments based on feedback or physiological responses from the patient. Dosing adjustments may include real-time or delayed adjustments. In some embodiments, the processor may be programmed with dosing regimens directed to different allergens.

[0114] The device may comprise a display and the processor may be programmed to provide a graphical user interface on the display. This may allow the selection of different regimen options by the user.

[0115] The control unit may have data connectivity, such as wired and wireless data connections. Suitable connectivity may include Bluetooth and USB. This may for example allow the downloading of information to the processor or the uploading of information from the processor. This may allow remote monitoring and consultation with a physician and / or adjustment of the dosing regimen by a physician.

[0116] In some embodiments, the processor may be programmed to notify users regarding drug administration timing for example using alarms, reminders, or other notification mechanisms. In some embodiments, the processor may be programmed to warn the user regarding unusual usage, such as administering doses more frequently, or at a different dose level, than normally expected. In some embodiments, the processor may be programmed to predict future side-effects of the treatment depending on the selected dosing regimen. The processor may be programmed to propose modifications to the dosing regimen based on these predictions of future side-effects. The prediction of future side-effects, or the proposal for a modification of the dosing regimen may be informed for example by automated statistical analysis, machine learning or artificial intelligence.

[0117] The control unit may also comprise sensor to detect levels of allergen composition in the cartridge. The processor may be programmed to automatically track and notify users about the status of the allergens within the device, which may for example include alerts for expiry dates, depletion levels, or other relevant statuses.

[0118] Dosing devices for dispensing drugs or medicaments in solid form are known in the art (see for example EP3724099, EP4149406, EP3873398, EP4125774, and EP3986356) and may be suitable for use in dispensing defined doses of allergen from a bulk formulation as described herein,

[0119] Immunotherapy methods described herein may be useful in the treatment of allergy. For example, the patient may be allergic to the allergen. The sensitivity of the patient to the allergen may be reduced or abolished following the treatment. For example, the maximum oral dose of allergen which may be tolerated by a patient without the onset of allergic symptoms, or the median maximum oral dose of allergen which may be tolerated by a population of patients, may be increased by at least 50-fold, at least 500-fold, at least 750-fold or at least 1000-fold after the treatment relative to before the treatment.

[0120] Patients who are hypersensitive to any allergen or combination of allergens may be treated using the methods described herein.

[0121] The methods described herein may be used for any patient with allergy and are independent of the patient’s sensitivity or challenge threshold to allergen, the weight or height of the patient and other factors.

[0122] In some preferred embodiments, immunotherapy methods described herein may be useful in the treatment of peanut allergy. For example, the sensitivity of the patient to peanut protein may be reduced or abolished following treatment with peanut protein or allergen compositions comprising peanut protein as described herein.

[0123] An individual with peanut allergy may be allergic to any one or more of Ara hi to h9. Individuals with peanut allergy from Western European populations are typically hypersensitive to one or more of Ara hi , h2 and h3 and most individuals display an allergic response to Ara h2. However, other patterns of peanut allergen hypersensitivity may be more typical in individuals from other populations.

[0124] A patient with a peanut allergy may display peanut-specific serum IgE, i.e. IgE which specifically binds to peanut protein. Patients may be diagnosed with peanut allergy according to standard clinical criteria. Standard clinical criteria may include for example, a history of a type-1 hypersensitivity reaction which is temporally related to peanut ingestion (e.g. hives, swelling, wheezing, abdominal pain, vomiting, breathlessness), and the presence of peanut-specific IgE by positive skin prick test (wheal diameter > / =3mm) or ImmunoCap serum IgE >0.35kU / l.

[0125] Following treatment as described herein, an individual may tolerate or show no allergic reaction to the allergen at a dose corresponding to the maintenance dose. For example, an individual may show no allergic reaction to 200mg peanut protein following treatment as described herein. In some embodiments, an individual may show no allergic reaction to the allergen at a dose higher than the maintenance dose. For example, an individual may tolerate or show no allergic reaction to 600mg allergen, 10OOmg allergen or more than 1000mg allergen, following treatment as described herein.

[0126] Other aspects and embodiments of the invention provide the aspects and embodiments described above with the term “comprising” replaced by the term “consisting of” and the aspects and embodiments described above with the term “comprising” replaced by the term “consisting essentially of”.

[0127] It is to be understood that the application discloses all combinations of any of the above aspects and embodiments described above with each other, unless the context demands otherwise. Similarly, the application discloses all combinations of the preferred and / or optional features either singly or together with any of the other aspects, unless the context demands otherwise.

[0128] Modifications of the above embodiments, further embodiments and modifications thereof will be apparent to the skilled person on reading this disclosure, and as such, these are within the scope of the present invention.

[0129] All documents and sequence database entries mentioned in this specification are incorporated herein by reference in their entirety for all purposes.

[0130] “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.

[0131] Experimental

[0132] Summary

[0133] Described herein is a Characterized Peanut Powder formulated in either multi-dose cartridges for a dose metering and dispensing device or in pull-apart capsules. The cartridges require an electronic dosing device (see Figure 1) for dispensing medicinal substance prior to oral administration. Together, the cartridges and capsules have been developed for use as a peanut oral immunotherapy (OIT) for the treatment of patients aged 1 to 55 years with a confirmed diagnosis of peanut allergy. The dose metering and dispensing device (Figure 1) was used during the up-dosing treatment phase, and the capsules were used for the maintenance doses. The dose metering and dispensing device (OnDosis AB, Sweden), is a hand-held device designed to store, meter and dispense granules or pellets for oral use. It consists of 2 main components: a reusable electromechanical control unit, and a disposable drug-containing multi-dose cartridge with a detachable cup. The control unit is drug-specific and is exclusively for use with the corresponding bespoke drug-filled cartridge.

[0134] The treatment program was peanut oral immunotherapy (OIT) for the mitigation or treatment of allergic reactions. It comprised an up-dosing phase and a maintenance phase. During the up-dosing phase, treatment was initiated using small, daily doses, which are gradually increased until a regular, daily maintenance dose can be tolerated. This was followed by maintenance treatment, which may last several years. Maintenance treatment began with daily dosing but may eventually be reduced from daily to weekly dosing.

[0135] The medicinal substance was formulated as non-sterile free-flowing oral granules filled either into canisters within cartridges for product used in the up-dosing phase, or into pull-apart capsules for the maintenance phase.

[0136] The cartridge formulations were two active blend strengths (5% w / w and 20% w / w) with two corresponding placebo formulations using colour-matched placebo granules. The cartridge was docked to the electromechanical hand-held control unit. The cartridge and control unit together functioned as the novel dose metering and dispensing device which was designed to store, meter, and dispense precise and flexible doses.

[0137] Drug Substance

[0138] The drug substance was lightly-roasted, partly-defatted powder of peanut. The material was characterized before its use as a drug substance. Peanut powder is well-established in the food industry. It contains Ara 1 , 2, 3 and 6, which are the main causative allergens for primary peanut allergy. The electropherogram of Figure 2 shows example protein profiles of the drug substance, highlighting the individual allergens: As shown in Table 1 below, the drug substance was typically found to contain about 6.6% Ara h 1 , 3.7% Ara h 2, 11 .0% Ara h 3 and 1 .5% Ara h 6 relative to protein content.

[0139] Table 1 : Individual allergens in drug substance batches Ara % of protein Description and Composition of the Drug Product

[0140] In the dosing device, the drug product was presented in cartridges containing a blend of one of two strengths: 5% w / w and 20% w / w peanut protein. Both comprised the unmodified drug substance (characterized peanut powder) formulated into free-flowing light brown to brown granules in white powder, pre-filled into multi-dose PC-ABS / PBT / PP cartridges to be docked into the control unit (device) for dispensing a specific dosage regimen as part of the up-dosing phase of treatment.

[0141] The composition of the drug product (cartridges) is listed in Table 2; Table 2: Composition of drug product (Cartridge)

[0142] An example of the composition of the 5% w / w and 20% w / w formulations based on two different protein contents (39.4% and 35.8%) using the formulae in Table 2 is shown in Table 3.

[0143] Table 3: Example drug product compositions Batch Formula

[0144] Typical batch formulae for intermediate drug product granules are show in Table 4 and typical batch formulae for final product blends are shown in Table 5.

[0145] Table 4: Typical batch formulae for G25 and G70

[0146] Table 5 Batch formulae for G25 and G70-based drug product blends

[0147] Description of Manufacturing Process and Process Controls

[0148] The steps involved in drug product manufacture are shown in Figure 3. The drug product (cartridges) was manufactured in three stages: Granulation, Microchip flashing and Blending followed by cartridge filling and pouch packing.

[0149] Granulation

[0150] The steps involved in granule manufacture, including the in-process controls are shown in Figure 4.

[0151] Preparation of granulation fluid

[0152] Purified water was added to a beaker. The hypromellose binder, together with a defined amount of powder mannitol, was slowly added and stirred into the beaker using an overhead stirrer until a visually homogeneous solution was formed.

[0153] Granulation in the fluid bed processor

[0154] Peanut powder and granular mannitol were loaded into the granulation bowl of the fluid bed processor. The granulation fluid was then sprayed into the fluidised bed. The granules were then dried by a product temperature of 35°C for 45 minutes and 40°C for 10 minutes, and this cycle repeated as required, until the required moisture content was achieved.

[0155] The intermediate drug product granules produced during the granulation stage are stable and can be stored prior to the blending and cartridge filling and encapsulation stages.

[0156] Cartridges

[0157] The steps involved in cartridge manufacture, including the in-process controls are shown in Figure 5.

[0158] Blending and cartridge filling

[0159] Granules were blended with the diluent granular mannitol and the lubricant sodium stearyl fumarate, in quantities according to the batch formula, until a homogenous powder was achieved. The blend was visually checked for homogeneity and filled into cartridges, depending on the dose concentration, using a manually operated cartridge filler.

[0160] The drug product was presented in two cartridge blend strengths: 5% w / w and 20% w / w. Both comprise the unmodified drug substance (characterised peanut powder) formulated into free-flowing light brown to brown granules in white powder, pre-filled into multi-dose PC-ABS / PBT / PP cartridges to be docked into the control unit (device) for dispensing a specific dosage regimen as part of the up-dosing phase of treatment that was then mixed with, room temperature, semi-solid, food.

[0161] CA003 maintenance dose capsules

[0162] CA003 capsule formulation was comprised of a formulation of characterised peanut powder with hypromellose, trehalose, mannitol and stearic acid. The capsules were pulled apart and the contents mixed with, room temperature, semi-solid, food.

[0163] Device Control Unit

[0164] The hand-held Control Unit is an electromechanical device with a built-in rechargeable battery, embedded software (firmware) and a motor-driven mechanism to dispense precise doses of solid oral medication from within a pre-filled cartridge into a detachable Cup attached to the Cartridge (Figure 1). The Control Unit is configured to only function together with a correct and specific medication-containing Cartridge that is docked into the Control Unit by the user. The Control Unit may be co-packaged with one or more Cartridges.

[0165] Dose adjustments and dispensing is controlled through buttons and a screen on the Control Unit. A graphical user interface with symbols and numeric characters displays information about the dose strength, doses remaining, expiry date, battery level, and selected up-dosing regimen. The Control Unit records and stores information about the Cartridge and the medicine it contains (including batch ID, expiry date, dose concentration, total and remaining doses) and an event log (including cartridge docking and undocking, regimen selection, timing and strength of dose taken) and information about the Control Unit (including expiry date and battery level). The Control Unit is reusable and designed to be used for up to 24 months. The Control Unit has a built-in Bluetooth Low Energy (BLE) antenna to enable connection to an optional, external software platform. The control unit includes the firmware (embedded software) that controls the system. The firmware includes the graphical user interface to provide status information and regimen or dose selection by the patient, caregiver or physician, and a means of activating the dispensing function, if a compatible cartridge with the correct allergen composition is attached.

[0166] Oral immunotherapy regimen

[0167] Oral immunotherapy regimens have been historically designed on the basis of regular fold-wise dose increases with periods of static dosing in between. Doses increase from a very low level to reach the maintenance dose level over a few months. For oral immunotherapy, these discrete updosing steps are relatively large, usually two-fold, with each followed by a series of days of dosing at home at the same dose level. In the case of CA003’s predecessor, CA002, each discrete dose level was taken for at least 14 days before the next updosing visit (discrete dose levels are 2, 5, 12.5, 25, 50, 100 and 200 mg peanut protein). These doses were selected based on the updosing protocol in STOP2, based on their good efficacy and safety profile. Because the discrete updosing steps represent several-fold increases in dose, they are associated with more adverse events than the days at the same dose and are thus required to be taken in a clinic under physician supervision.

[0168] Although the adverse events resulting from large, discrete dose increases are manageable, their increased frequency and severity requires that patients take them in a supervised, clinical setting. This requires many updosing appointments, burdening both patients and physicians.

[0169] STOP3E employs a continuous updosing regimen using a dosing device, starting at 2 mg peanut protein and increasing daily, in tiny steps (5.7%) to 200 mg peanut protein. This is instead of in the large, fold-wise dosing steps every 14 days, to reduce the frequency and severity of allergic reactions to a level where dosing can be safely carried out at home. The dosing device is used only for the updosing part of treatment; patients would switch to capsules after reaching the maintenance phase (200 mg peanut protein).

[0170] A continuous updosing regimen that tracks the discrete regimen of CA002 is shown in Figure 6. As for CA002, updosing starts with the first, 2 dose taken daily for 14 days. Thereafter, compared with CA002, the CA003 regimen is smoother and more conservative, instead of increasing suddenly to 5 mg peanut protein on day 15, the dose is increased by just 5.7% daily. Typically, with CA003, the 200 mg peanut protein maintenance dose is reached after a total of 98 days (14 weeks) of updosing (including the first 14 days at 2 mg peanut protein); an additional 14 days compared to CA002.

Claims

Claims1 . A method of immunotherapy comprising;(a) administering a dose of allergen to an individual in need thereof at regular time intervals, wherein the dose of allergen increases incrementally by 1 to 10% per dose from an initial dose to a maintenance dose, and(b) administering the maintenance dose of the allergen at regular time intervals.

2. A method according to claim 1 wherein the method of immunotherapy is for the treatment of allergy.

3. A method according to claim 1 or claim 2 wherein the regular time interval is daily.

4. A method according to any of claims 1 to 3 wherein the method further comprises administering the initial dose of an allergen to the individual at regular time intervals before step (a).

5. A method according to claim 4 wherein the initial dose is administered daily for 14 days.

6. A method according to any one of the preceding claims wherein the doses of allergen are administered orally.

7. A method according to any one of the preceding claims wherein the allergen is peanut protein.

8. A method according to any one of the preceding claims wherein the initial dose is 2mg.

9. A method according to any one of the preceding claims wherein the dose of allergen increases by between 5% and 6% per administration in step (b).

10. A method according to claim 9 wherein the dose of allergen increases by 5.7% per administration.11 . A method according to any one of the preceding claims wherein the maintenance dose is 200mg.

12. A method according to any one of the preceding claims wherein the allergen is administered in step (b) for 77 or longer until the maintenance dose is reached.

13. A method according to any one of the preceding claims wherein the maintenance dose is administered for at least 6 months in step (b).

14. A method according to claim 13 wherein the maintenance dose is administered daily for at least 6 months in step (b).

15. A method according to claim 14 further comprising (c) administering the maintenance dose weekly for at least 6 months.

16. A method according to any one of the preceding claims wherein the allergen for administration of the initial and maintenance dose is provided in unit-dose form.

17. A method according to claim 16 wherein the unit-dose form is a capsule.

18. A method according to any one of the preceding claims wherein the dose of allergen for each administration in step (a) is measured and dispensed by a dosing device.

19. A method according to claim 18 wherein the allergen in step (a) is provided in bulk-form in the dosing device.

20. An allergen for use in a method according to any one of claims 1 to 1921 . Use of an allergen in the manufacture of a medicament for use in a method according to any one of claims 1 to 19.

22. A set of compositions comprising a first allergen composition comprising 1 to 10% (w / w) allergen and a second allergen composition having 20 to 30% (w / w) allergen, wherein the first and second allergen compositions comprise (i) granules comprising allergen, powdered mannitol and hypromellose, (ii) granules of mannitol and (iii) sodium stearyl fumarate.

23. A set of compositions according to claim 22 wherein the allergen is peanut protein.

24. A set of compositions according to claim 22 or claim 23 wherein the allergen is comprised in an allergen extract.

25. A set of compositions according to claim 24 wherein the allergen extract is peanut flour.

26. A set of compositions according to any one of claims 20 to 25 comprising a first allergen composition comprising 5% (w / w) allergen and a second allergen composition having 20% (w / w) allergen27. A set of compositions according to claim 26rein the first allergen composition has the formula; a5 / x allergen extract b3 / 25 x5 / x hypromelloseC72 / 25 X5 / x mannitol powder d 2 sodium stearyl fumarate e 100 -(a+) mannitol granules wherein x is the % (w / w) allergen in the allergen extract.

28. A set of compositions according to claim 26 or claim 27 wherein the first allergen composition comprises 8 to 17% (w / w) allergen extract, 1 to 3% (w / w) hypromellose, 23 to 46% (w / w) mannitol powder, 33 to 66% (w / w) granular mannitol and 2% (w / w) sodium stearyl fumarate.

29. A set of compositions according to any one of claims 26 to 28 wherein the second allergen composition has the formula; a20 / x % (w / w) allergen extract b3 / ?0 x20 / x % (w / w) hypromellose c27ho x20 / x % (w / w) mannitol powder d 2 % (w / w) sodium stearyl fumarate e 100 -(a+b+c+d) % (w / w) mannitol granules wherein x is the % (w / w) allergen in the allergen extract.

30. A set of compositions according to claim 29 wherein the second allergen composition comprises 33 to 67% (w / w) allergen extract, 1 to 4% (w / w) hypromellose, 12 to 26% (w / w) mannitol powder, 2 to 51% (w / w) granular mannitol and 2% (w / w) sodium stearyl fumarate.31 . A set of compositions according to one of claims 22 to 30 wherein the first and second allergen compositions are in bulk form.

32. A set of compositions according to one of claims 22 to 31 wherein the first and second allergen compositions are produced by a method comprising admixing allergen extract, mannitol powder, hypromellose and water, drying the admixture to produce granules, blending the granules with mannitol granules and sodium stearyl fumarate and sieving the blended granules.

33. A set of compositions according to one of claims 22 to 32 for use in a method of oral immunotherapy.

34. A set of compositions for use according to claim 33 wherein the method is a method according to any one of claims 1 to 19.

35. A dosing device for use in a method of oral immunotherapy comprising; a cartridge, wherein the cartridge contains a bulk formulation of allergen for administration, an actuator for dispensing a defined dose of allergen from the bulk formulation in the cartridge, and a control unit comprising a processor, wherein the processor is programmed to operate the actuator to dispense the defined dose of allergen in accordance with a predetermined dose regimen.

36. A dosing device according to claim 35 wherein the allergen is peanut protein.

37. A dosing device according to claim 35 or 36 further comprising a detachable receptacle for receiving the defined dose of allergen dispensed by the actuator.

38. A dosing device according to any one of claims 35 to 37 wherein cartridge of the dosing device may contain a first and / or a second allergen composition of the set of compositions of any one of claims22 to 32.

39. A dosing device according to any one of claims 35 to 38 wherein the processor is programmed to operate the actuator to dispense a dose of allergen in accordance with a method of any one of claims 1 to 19.

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