Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
  • C07K16/244—Interleukins [IL]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/515—Complete light chain, i.e. VL + CL
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

• This invention generally relates to formulations comprising anti-IL-23pl9 antibodies, such as risankizumab, which bind the pl9 subunit of human IL-23. More specifically, pharmaceutical formulations comprising a high concentration of the anti-IL-23pl9 antibody risankizumab, as well as related products and uses for the treatment of various diseases and disorders, are disclosed. Disclosed herein are stable liquid pharmaceutical formulations, comprising 150 mg/ml of the antibody risankizumab.
• Human IL-23 is composed of a common subunit (p40) with IL-12 and a unique pl9 subunit. Despite this shared p40 subunit, the roles for IL-23 and IL-12 are quite different. IL-12 is important for Thl responses via promotion of Thl cell differentiation, proliferation and activation. In contrast, IL-23 supports the development and maintenance of a set of CD4 + T helper cells termed Thl7 cells due to their ability to produce IL-17 and related cytokines. IL- 23 is involved in chronic autoimmune inflammation and the modulation of IL-23 activity provides effective therapies against autoimmune diseases.
• psoriasis a chronic, immune-mediated inflammatory disease characterized by the hyper proliferation of keratinocytes and skin-infiltrating T-lymphocytes that overexpress pro-inflammatory mediators.
• the disease is a chronic, painful immune-mediated inflammatory skin disease and has a lifelong remitting and relapsing course with varying factors that trigger exacerbations in susceptible individuals, thus making treatment challenging.
• the uncontrolled inflammation of psoriasis may contribute to commonly associated comorbidities, including cardiovascular (CV) disease (including hypertension and increased risk for myocardial infarction, stroke, and CV death), obesity, type 2 diabetes, arthritis, and chronic renal disease.
• CV cardiovascular
• Psoriasis is also associated with serious psychiatric comorbidities, including depression, anxiety, and suicidality, as well as substance abuse.
• Risankizumab is a humanized immunoglobulin G1 (IgGl) monoclonal antibody that is directed against the pl9 subunit of IL-23. Binding of risankizumab to IL-23 pl9 inhibits the action of IL-23 to induce and sustain T helper (Th) 17 type cells, innate lymphoid cells, gdT cells, and natural killer (NK) cells responsible for tissue inflammation, destruction and aberrant tissue repair.
• Th T helper
• NK natural killer
• the recommended dose approved for treatment of psoriasis is 150mg which is administered subcutaneously as two 75 mg injections, on week 0, 4 and thereafter every 12 weeks.
• subcutaneous route is preferred for therapeutic indications where home (self) medication is desirable, for example, for chronic diseases such as psoriasis.
• the subcutaneous administration route is, however, limited by the injection volume as attributable to tissue backpressure and injection pain. This also depends on the injected formulation.
• Most drugs that are administered by subcutaneous injection, such as risankizumab, are commonly used in unit dosages with volumes not exceeding 1 ml. Therefore, for higher volumes, such as greater than 2 ml, multiple injections are typically used, but this approach may increase the attrition rate or reduce patient adherence.
• HMWS high molecular weight species
• the present disclosure provides a liquid antibody formulation that comprises 150mg/ml of the antibody as defined herein.
• the antibody is risankizumab or an antibody comprising the same heavy and light chain sequences as risankizumab.
• No formulations of said antibody having such a high antibody concentration were described or available in the art and by providing such high concentration antibody formulation, the present disclosure makes an important contribution to the art.
• the formulations according to the present disclosure are stable and are suitable for therapeutic use.
• the formulations according to the present disclosure comprising 150 mg/ml of the antibody risankizumab provide advantageous stability characteristics and are well suitable for subcutaneous administration. They can provide long-term stability.
• a 150mg dose of the antibody can be administered with a single 1ml injection.
• a liquid pharmaceutical formulation comprising 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2.
• the liquid pharmaceutical formulation comprises a) 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2; b) a polyol; and c) a surfactant.
• This formulation may additionally comprise d) a buffer.
• a buffer may additionally comprise d) a buffer.
• the present disclosure provides buffer-free formulations comprising 150 mg/ml of the antibody.
• the liquid pharmaceutical formulations according to the first sub-aspect are stable.
• a stable liquid pharmaceutical formulation comprising a) 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2; b) a tonicity modifier; and c) a surfactant, wherein the formulation has a pH of 5.5-5.9 and the formulation is isotonic.
• This formulation may additionally comprise d) a buffer.
• formulations according to the first and second sub-aspect of the 150 mg/ml antibody formulation according to the first aspect may also be provided in lyophilized form.
• a sealed container which contains a formulation according to the present disclosure.
• the present disclosure pertains to the formulations according to the present disclosure or the container containing a formulation according to the present disclosure for therapeutic treatment of a human subject.
• the disease to be treated may be selected from psoriasis and inflammatory bowel disease.
• the disease to be treated may be selected from psoriatic arthritis and Crohn’s disease.
• Figure 1 shows the amino acid sequence of the light chain of the antibody (SEQ ID NO: 1).
• Figure 2 shows the amino acid sequence of the heavy chain of the antibody (SEQ ID NO: 2).
• a liquid pharmaceutical formulation comprising 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2.
• a liquid pharmaceutical formulation comprising a) 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2; b) a polyol; and c) a surfactant.
• the formulation according to this first sub-aspect may additionally comprise d) a buffer. Furthermore, the present disclosure provides buffer-free formulations comprising 150 mg/ml of the antibody. As is disclosed herein, the liquid pharmaceutical formulations according to the first sub-aspect are stable.
• a stable liquid pharmaceutical formulation comprising a) 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2; b) a tonicity modifier; and c) a surfactant, wherein the formulation has a pH of 5.5-5.9 and the formulation is isotonic.
• the stable formulation according to this second sub-aspect may additionally comprise d) a buffer.
• the formulation according to the present disclosure comprises a high antibody concentration of 150mg/ml. Despite this high antibody concentration, the liquid pharmaceutical formulations of the present disclosure are stable and advantageously can provide long-term stability.
• the formulations according to the present disclosure moreover address core administration challenges for a high concentration antibody formulation that is suitable for injection, by providing inter alia a suitable viscosity and good syringeability, whereby the formulation according to the present disclosure is particularly suitable for injection, such as subcutaneous injection.
• the advantageous properties of these formulations are demonstrated in the examples.
• the formulation according to the first aspect solves the challenges facing formulations for injection by providing a stable and robust formulation comprising 150mg/ml of the antibody, thereby enabling the subcutaneous administration of a 150mg dose of the antibody using a target volume of only 1 ml.
• the formulations according to the first aspect can be provided as buffer- free or buffer-containing formulations.
• the liquid pharmaceutical formulation according to the first aspect comprises d) a buffer. In another embodiment, the liquid pharmaceutical formulation does not contain a buffer as additive.
• components of the 150 mg/ml antibody formulation according to the first aspect are described in further detail.
• suitable embodiments and characteristics of components a), b), c) and optionally d) that are comprised in the formulations according to the first sub-aspect and the second sub-aspect are disclosed.
• the antibody comprised in the formulation comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2.
• SEQ ID NO: 1 and 2 are shown in Figure 1 and Figure 2.
• the light and heavy chains of the antibody risankizumab correspond to the light and heavy chain sequences as shown in SEQ ID NO: 1 and 2.
• the antibody has the same light and heavy chains as the antibody risankizumab (see INN risankizumab, WHO Drug Information, Vol. 29, No. 2, 2015) and such antibody is referred to herein as risankizumab.
• the present disclosure provides stable, high concentration liquid pharmaceutical formulations for the antibody risankizumab, which is approved for the treatment of psoriasis.
• the whole disclosure provided herein is specifically directed and applies to the antibody risankizumab that is comprised in the disclosed formulations.
• Risankizumab may be recombinantly produced in various host cells and suitable cells for recombinant antibody production are known in the art.
• the antibody is recombinantly produced in a mammalian cell. Suitable mammalian cells are known in the art and comprise rodent as well as human cell lines. In one embodiment, the antibody has been recombinantly produced in a hamster cell. In one embodiment, the antibody has been recombinantly produced in a CHO cell.
• the formulation according to the first sub-aspect of the 150 mg/ml formulation according to the first aspect comprises a polyol as component b).
• Suitable polyols that can be used as excipient in a pharmaceutical formulation are known in the art and are described herein.
• the formulation according to the second sub-aspect of the 150 mg/ml formulation according to the first aspect comprises a tonicity modifier as component b).
• a tonicity modifier is an agent that is suitable to adjust the tonicity of the formulation.
• Tonicity modifiers useful for adjusting the tonicity of a pharmaceutical formulation are known in the art, and include compounds such as salts and furthermore polyols, such as sugars and sugar alcohols. Therefore, the tonicity modifier used as component b) in the stable 150 mg/ml formulation according to the second sub-aspect may be a polyol as it is used as component b) in the 150 mg/ml formulation according to the first sub-aspect.
• the tonicity modifier that is comprised in the stable liquid formulation according to the second sub-aspect is thus a polyol, optionally a sugar and/or a sugar alcohol.
• polyol refers to a substance with multiple hydroxyl groups, and includes sugars (reducing and nonreducing sugars) and sugar alcohols.
• the polyol may comprise at least three, at least four or at least five hydroxyl groups.
• polyols have a molecular weight that is ⁇ 600 Da (e.g., in the range from 120 to 400 Da).
• a "reducing sugar” is one that contains a free aldehyde or ketone group and can reduce metal ions or react covalently with lysine and other amino groups in proteins.
• a "nonreducing sugar” is one that lacks a free aldehyde or ketone group and is not oxidised by mild oxidising agents such as Fehling's or Benedict's solutions.
• Examples for reducing and nonreducing sugars suitable for use in pharmaceutical formulations are known to the skilled person.
• Nonreducing sugars include e.g. sucrose and trehalose. The use of trehalose is particularly useful as is disclosed herein.
• sugar alcohols suitable for use in pharmaceutical formulations are known to the skilled person and include e.g. mannitol and sorbitol.
• the polyol may be used as tonicity agent in the formulation.
• a polyol can act and may be used as tonicity modifier in order to adjust the tonicity.
• Certain polyols e.g. sugars, may also act as stabilizer, thereby supporting the stability of the provided formulation.
• the polyol may be selected from a sugar and a sugar alcohol. Furthermore, combinations of two or more different polyols may be used as component b), as is also demonstrated in the examples. As is shown in the examples, sugars and sugar alcohols, as well as combinations thereof, can be advantageously used in the 150mg/ml formulation according to the present disclosure. According to one embodiment, the polyol is selected from trehalose, sucrose, sorbitol, mannitol and combinations thereof. According to one embodiment, the formulation only comprises a polyol that is selected from sugars and/or sugar alcohols as component b). According to one embodiment, the formulation only comprises a single polyol as component b).
• the polyol is a sugar.
• the polyol may be selected from trehalose and sucrose.
• the formulation may comprise trehalose as polyol and the use of trehalose is advantageous.
• Trehalose can be used either alone or in combination with a further polyol, e.g. a further sugar or a sugar alcohol.
• the formulation only comprises a single sugar, such as trehalose, as single polyol. Using a single polyol as excipient, e.g. to adjust the tonicity, can be advantageous.
• the polyol is a sugar alcohol.
• the sugar alcohol may be selected from sorbitol and mannitol.
• the formulation comprises mannitol as polyol.
• the formulation comprises sorbitol.
• mannitol and sorbitol may either be used as single polyol, or may be used in combination either with each other or in combination with a different polyol, such as a sugar or other sugar alcohol.
• Sorbitol can be used to provide a stable formulation according to the present disclosure.
• a sorbitol-free formulation is provided. Sorbitol-free formulations are advantageous for patients with hereditary fructose intolerance.
• the liquid pharmaceutical formulation therefore does not comprise sorbitol.
• the formulation does not comprise a sugar alcohol.
• mannitol and/or trehalose can be used as polyol in the formulation of the present disclosure, in order to adjust the desired osmolality.
• the amount of mannitol within the 150 mg/ml formulation is limited by the mannitol solubility and the amount of stock solution, which can be added during the formulation step. Therefore, in embodiments, mannitol is used in combination with a sugar, such as the highly soluble trehalose. It was found that for the antibody formulation disclosed herein, trehalose is advantageous because it is soluble enough to achieve an isotonic formulation with one excipient. Therefore, in certain embodiments, trehalose is used as polyol and trehalose may be the only polyol in the formulation that is used to adjust the isotonicity.
• the polyol can be used to adjust the osmolality.
• the formulation has an osmolality in a range of 200 mOsm/kg to 400 mOsm/kg, such as in a range of 225 mOsm/kg to 375 mOsm/kg.
• the osmolality is within a range of 250 mOsm/kg to 350 mOsm/kg, such as 275 mOsm/kg to 330 mOsm/kg or 290 mOsm/kg to 320 mOsm/kg.
• the formulation may be isotonic, wherein "isotonic" means that the formulation of interest has essentially the same osmotic pressure as human blood. Osmolality can be measured, for example, using a vapor pressure or ice-freezing type osmometer.
• the concentration of the polyol in the formulation may be at least 80 mM or at least 95 mM. In embodiments, the concentration of the polyol in the formulation is at least 115 mM, at least 125 mM, at least 135 mM, at least 140 mM, at least 150 mM or at least 160 mM. In embodiments, the concentration of the polyol in the formulation is ⁇ 500 mM, ⁇ 450 mM or ⁇ 400 mM. As disclosed herein, also two or more polyols may be used as excipient b). As disclosed herein, in one core embodiment the polyol is a sugar that is used in such concentration. In one embodiment, the sugar is trehalose. The same applies with respect to the tonicity modifier that is used as component b) in the formulation according to the second sub aspect. As disclosed herein, the tonicity modifier may be a polyol.
• the concentration of the polyol in the formulation according to the first aspect, in particular the first and second sub-aspect thereof, may be in the range of 95 mM to 400 mM, such as 95 mM to 300 mM or 95 mM to 250 mM.
• Exemplary concentration ranges for a polyol in the formulation include, but are not limited to, 125 mM to 250 mM and 125 mM to 225 mM.
• the concentration of the polyol in the formulation is in one embodiment in the range of 125 mM to 225 mM. In one embodiment, the concentration of the polyol is in the range of 145 mM to 225 mM.
• the polyol is a sugar that is used in such a concentration as described herein. In one embodiment, the sugar is trehalose.
• the polyol is a sugar and wherein the concentration of the sugar is in the range of 125 mM to 250 mM, 150 mM to 250 mM, 150 mM to 200 mM or in the range of 160 mM to 200 mM. In a further embodiment, the concentration of the sugar is in the range of 170 mM to 200 mM. The concentration may be 185 mM. In one embodiment, said sugar is trehalose. Hence, also disclosed herein is a liquid pharmaceutical formulation comprising 150 mg/ml antibody and 185 mM trehalose as polyol. Trehalose may be added e.g. in the form of trehalose dihydrate. c) Surfactant
• the liquid formulation according to the first aspect further comprises a surfactant.
• a surfactant in the 150 mg/ml formulation is advantageous.
• a surfactant is comprised as component c) in the formulation according to the first and second sub-aspect of the 150 mg/ml formulation according to the first aspect.
• the surfactant is a non-ionic surfactant.
• Non-ionic surfactants suitable for pharmaceutical formulations are known in the art and are also described herein.
• the at least one surfactant may be a polysorbate (e.g. polysorbate 20) or a poloxamer (e.g. poloxamer 188). Combinations of surfactants may also be used.
• the surfactant is a polysorbate.
• the non-ionic surfactant may be selected from polysorbate 20 and/or polysorbate 80. Combinations may also be used.
• the surfactant is polysorbate 20.
• the formulation according to the present disclosure comprises a single surfactant, such as a single non-ionic surfactant, e.g. a single polysorbate.
• the concentration of the surfactant in the formulation is at least 0.05 mg/ml.
• the concentration may be at least 0.075 mg/ml.
• the surfactant concentration in the formulation is at least 0.1 mg/ml, at least 0.125 mg/ml, at least 0.15 mg/ml, at least 0.175 mg/ml or at least 0.185 mg/ml.
• the concentration of the surfactant in the formulation is ⁇ 1 mg/ml, optionally ⁇ 0.75 mg/ml or ⁇ 0.5 mg/ml.
• the surfactant concentration in the formulation is ⁇ 0.4 mg/ml, ⁇ 0.3 mg/ml or ⁇ 0.25 mg/ml.
• the surfactant may be a non-ionic surfactant.
• the surfactant is a polysorbate, optionally selected from polysorbate 20 and/or polysorbate 80.
• the surfactant is polysorbate 20.
• Polysorbate 20 can be advantageously used in such concentrations as disclosed herein as is demonstrated by the examples.
• the concentration of the surfactant in the formulation may be in a range of 0.05 mg/ml to 0.75 mg/ml.
• Exemplary concentration ranges for a surfactant in the formulation include, but are not limited to, 0.05 mg/ml to 0.5 mg/ml, 0.075 mg/ml to 0.4 mg/ml or 0.075 mg/ml to 0.3 mg/ml.
• the concentration of the surfactant in the formulation is in the range of 0.05 mg/ml to 0.5 mg/ml, 0.075 mg/ml to 0.3 mg/ml or 0.1 mg/ml to 0.3 mg/ml.
• the concentration of the surfactant in the formulation may be 0.2 mg/ml.
• the surfactant may be a non-ionic surfactant.
• the surfactant is a polysorbate, optionally selected from polysorbate 20 and/or polysorbate 80.
• the surfactant is polysorbate 20 which can be advantageously used in such concentration ranges as is demonstrated by the examples.
• the formulation of the present disclosure comprises 0.2 mg/ml polysorbate 20 as surfactant.
• This formulation may comprise a sugar as component b), wherein the concentration of the sugar is in the range of 95 mM to 250 mM, 125 mM to 250 mM or 145mM to 225mM.
• the comprised sugar may be trehalose. pH
• the pH of the liquid pharmaceutical formulation which in core embodiments is an aqueous formulation, may be in the range of pH 5.0 to 7.5, such as pH 5.0 to 7.0.
• the pH of the liquid pharmaceutical formulation may be ⁇ 6.8, such as ⁇ 6.7, ⁇ 6.6, ⁇ 6.5, ⁇ 6.4, ⁇ 6.3 or ⁇ 6.2.
• the pH of the liquid pharmaceutical formulation is ⁇ 6.1, such as ⁇ 6.0 or ⁇ 5.9.
• the pH of the liquid pharmaceutical formulation is > 5.2, such as > 5.3, > 5.4 or > 5.5.
• Exemplary ranges for the pH of the liquid pharmaceutical formulation which has a pH > 5.2 include but are not limited to 5.2 to 6.8, such as 5.2 to 6.7, 5.2 to 6.6, 5.2 to 6.5, 5.2 to 6.4, 5.2 to 6.3 and 5.2 to 6.2.
• Exemplary ranges for the pH of the liquid pharmaceutical formulation which has a pH > 5.3 include but are not limited to 5.3 to 6.8, such as 5.3 to 6.7, 5.3 to 6.6, 5.3 to 6.5, 5.3 to 6.4, 5.3 to 6.3 and 5.3 to 6.2.
• Exemplary ranges for the pH of a liquid pharmaceutical formulation which has a pH > 5.4 include but are not limited to 5.4 to 6.8, such as 5.4 to 6.7, 5.4 to 6.6, 5.4 to 6.5, 5.4 to 6.4, 5.4 to 6.3 and 5.4 to 6.2.
• Exemplary ranges for the pH of the liquid pharmaceutical formulation which has a pH > 5.5 include but are not limited to 5.5 to 6.8, such as 5.5 to 6.7, 5.5 to 6.6, 5.5 to 6.5, 5.5 to 6.4, 5.5 to 6.3 and 5.5 to 6.2.
• Exemplary ranges for the pH of the liquid pharmaceutical formulation which has a pH > 5.6 include but are not limited to 5.6 to 6.8, such as 5.6 to 6.7, 5.6 to 6.6, 5.6 to 6.5, 5.6 to 6.4, 5.6 to 6.3 and 5.6 to 6.2.
• the pH of the formulation is in a range of 5.6 to 6.0 or 5.6 to 5.9.
• the pH of the liquid pharmaceutical formulation is in the range of 5.2 to 6.5. According to one embodiment, the pH of the liquid pharmaceutical formulation is in the range of 5.2 to 6.2. Lower pH values showed less aggregation during stability and physical stress studies as can be seen from the examples.
• the pH of the liquid pharmaceutical formulation is in the range of 5.5 to 6.5. In one embodiment, the pH of the liquid pharmaceutical formulation is in a range of 5.5 to 6.2.
• the pH is 5.5 to 5.9. In one embodiment, the pH is 5.6 to 5.8. 150 mg/ml risankizumab formulations having such pH were tested in the examples and showed favorable characteristics.
• the pH of the liquid pharmaceutical formulation is 5.7.
• the pH of the liquid pharmaceutical formulation is 6.2.
• the pH of the stable liquid pharmaceutical formulation according to the second sub-aspect is 5.5 to 5.9. It may be in the range of 5.5 to 5.8. In embodiments, the pH of the stable 150 mg/ml formulation according to the second sub-aspect is 5.7. d) Buffer
• the 150 mg/ml antibody formulation according to the first aspect can be provided as buffer- free or as buffer-containing formulation.
• the pharmaceutical formulation comprises d) a buffer.
• Formulations comprising a buffer showed in experiments less increase in glide forces (max and average) compared to buffer- free formulations.
• a buffer may be used as component d) in the formulation according to the first and second sub-aspect of the 150 mg/ml risankizumab formulation according to the first aspect.
• a buffer can be used to maintain the solution pH of the liquid pharmaceutical formulation. Suitable buffers for pharmaceutical formulations are known in the art and are described herein.
• the buffer may be an organic buffer.
• the buffer has a pKa within 1.5 or 1 pH unit of the final pH of the liquid pharmaceutical formulation at 25°C.
• the buffer has a pKa in the range of pH 4.2 to 7.2 or 4.5 to 7 at 25°C.
• the buffer may comprise a combination of buffers.
• a single buffer is used in the formulation as component d).
• the formulation may comprise a carboxylic acid buffer as buffer d).
• the buffer is selected from an acetate buffer and a succinate buffer. As is demonstrated by the examples, formulations comprising such buffers provide advantageous stability features for the high concentration formulation of the antibody that is herewith provided.
• the buffer is a histidine buffer.
• the buffer is an acetate buffer.
• An acetate buffer may comprise sodium acetate and acetic acid. Other acetate salts may also be used in the acetate buffer.
• buffers that may be used include but are not limited to citrate, glutamate, glycine, lactate, maleate, phosphate or tartrate buffer.
• a buffer salt may support the stability of the comprised antibody which is according to the present disclosure risankizumab.
• the buffer d) comprised in the formulation is not a succinate buffer.
• the formulation is free of a succinate buffer.
• a single buffer is used which is an acetate buffer, e.g. provided by an acetate salt (e.g. sodium acetate) and acetic acid.
• the buffer When used, the buffer will be included in a sufficient amount to maintain the selected pH of the formulation at storage conditions for the product shelf life.
• the liquid pharmaceutical formulation disclosed herein may comprise at least 1 mM, at least 2 mM buffer, at least 3 mM buffer.
• the buffer concentration may be at least 4 mM, at least 4.5 mM or at least 5 mM.
• the buffer concentration is 100 mM or less, such as 75 mM or less or 50 mM or less.
• the buffer concentration in the formulation is 80 mM or less, such as 75 mM or less, 70 mM or less, 60 mM or less or 50 mM or less.
• the buffer concentration is 45 mM or less, such as 40 mM or less, 35 mM or less, 30 mM or less or 25 mM or less.
• the buffer concentration is 20 mM or less or 15mM or less.
• Exemplary concentration ranges for the comprised buffer include but are not limited to 3 mM to 100 mM, such as 4 mM to 75 mM, 4 mM to 60 mM and 4 mM to 50 mM.
• Further exemplary buffer concentration ranges include but are not limited to 4 mM to 45 mM, such as 5 mM to 40 mM, 5 mM to 35 mM and 5 mM to 30 mM.
• Still further exemplary buffer concentration ranges include but are not limited to 5 mM to 25 mM, such as 5 mM to 20 mM and 5 mM to 15 mM.
• the buffer concentration is in the range of 7 mM to 12 mM. Suitable buffers are disclosed herein.
• the formulation comprises an acetate buffer in such concentration as described.
• the buffer concentration is 20 mM or less or 15 mM or less. In further embodiments the buffer concentration is in the range of 4 mM to 50 mM.
• the buffer concentration of the formulation may be in the range of 5 mM to 25 mM or 5 mM to 20 mM.
• the buffer concentration may also be in the range of 5 mM to 15 mM or 7 mM to 12 mM. In embodiments, the buffer concentration is 10 mM.
• the formulation comprises a single buffer.
• the single buffer is an acetate buffer.
• buffer-containing formulations comprising 150mg/ml antibody
• the liquid pharmaceutical formulation comprises a) 150 mg/ml of the antibody; b) a sugar; c) a non-ionic surfactant; and d) a buffer; optionally wherein the pH of the formulation is in a range of pH 5.2 to pH 6.5, e.g. in the range of 5.2 to 6.2 or 5.5 to 6.2.
• the concentration of the sugar is in the range of 145 mM to 225 mM and/or the concentration of the non-ionic surfactant is in the range of 0.05 mg/ml to 0.5 mg/ml or 0.075 mg/ml to 0.3 mg/ml.
• the sugar may be trehalose and the non-ionic surfactant may be a polysorbate, such as polysorbate 20.
• the pH may be 5.7. In a further embodiment the pH is 62
• the liquid pharmaceutical formulation comprises a) 150 mg/ml of the antibody; b) trehalose; c) a polysorbate; and d) a buffer; optionally wherein the pH of the formulation is in a range of pH 5.2 to pH 6.5, e.g. in the range of 5.2 to 6.2 or 5.5 to 6.2.
• the concentration of trehalose is in the range of 145 mM to 225 mM and/or the concentration of the polysorbate is in the range of 0.05 mg/ml to 0.5 mg/ml or 0.075 mg/ml to 0.3 mg/ml.
• the pH may be 5.7. In a further embodiment the pH is 6.2.
• the buffer comprised in these liquid pharmaceutical formulations may be acetate or succinate, optionally wherein the buffer concentration is in the range of 5 mM to 25 mM.
• the polysorbate may be polysorbate 20.
• the liquid pharmaceutical formulation comprises a) 150 mg/ml of the antibody; b) 170 mM to 200 mM trehalose; c) 0.1 mg/ml to 0.3 mg/ml polysorbate, optionally polysorbate 20; and d) a buffer, optionally wherein the buffer is an acetate buffer.
• the pH of this formulation may be in a range of pH 5.2 to pH 6.5, e.g. in the range of 5.2 to 6.2 or 5.5 to 6.2.
• the liquid pharmaceutical formulation comprises a) 150 mg/ml of the antibody; b) 185mM trehalose; c) 0.2mg/ml polysorbate 20; and d) lOmM acetate buffer; wherein the pH is 5.7.
• This liquid formulation may be an aqueous formulation and in one embodiment, does not comprise any further additives.
• buffer-free formulations comprising 150 mg/ml antibody
• the liquid pharmaceutical formulation comprises a) 150 mg/ml of the antibody; b) a polyol, optionally wherein the polyol is a sugar or sugar alcohol; and c) a non-ionic surfactant, optionally a polysorbate; d) no buffer.
• the present disclosure also provides buffer-free formulations and no buffer is added as excipient.
• the antibody having the light and heavy chain sequences as shown in SEQ ID NO: 1 and 2 has a high buffering capacity.
• Storage-stable buffer-free formulations can be provided based on the disclosure provided herein as is also shown in the examples.
• the pH of the buffer-free formulation is in a range of pH 5.2 to pH 6.5.
• the pH may be in the range of 5.2 to 6.2 or 5.5 to 6.2. In one embodiment, the pH is 5.7. In a further embodiment, the pH is 6.2.
• the buffer-free formulation comprises 80 mM to 250 mM polyol. Suitable polyols such as sugars and sugar alcohols were disclosed in detail above and it is referred to this disclosure.
• the sugar is trehalose.
• the concentration of the non-ionic surfactant in the buffer-free formulation is in the range of 0.05 mg/ml to 0.5 mg/ml, 0.075 mg/ml to 0.4 mg/ml or 0.1 mg/ml to 0.3 mg/ml.
• the non-ionic surfactant is a polysorbate. It may be selected from polysorbate 20 and polysorbate 80 and is one embodiment polysorbate 20.
• the liquid pharmaceutical formulation according to the present disclosure comprises an amino acid as further additive.
• Suitable embodiments for amino acids that can be added as excipient to a pharmaceutical formulation are known in the art and are also disclosed in the examples.
• the formulation comprises an amino acid which has a charged side chain, optionally a positive-charged side chain.
• amino acid is L-arginine.
• the formulation comprises an amino acid, wherein the amino acid is present in the formulation as a salt, optionally a hydrochloride (HC1) salt.
• a salt optionally a hydrochloride (HC1) salt.
• HC1 hydrochloride
• the formulation comprises methionine. According to one embodiment, the formulation comprises amino acid L-proline.
• the 150 mg/ml formulation according to the present disclosure does not comprise arginine. It was found that arginine containing formulations showed slightly elevated particle count during freeze/thaw stress studies as well as higher turbidity vales, even though there was no increase in turbidity over time. The viscosity was found to be higher. The amount of aggregates was slightly lower compared to other formulations comprising 150mg/ml antibody but no arginine.
• the formulation according to the present disclosure does not comprise an amino acid with a positive-charged side chain as excipient. According to one embodiment, the formulation according to the present disclosure does not comprise an amino acid with a charged side chain as excipient. According to one embodiment, the formulation according to the present disclosure does not comprise methionine as excipient. According to one embodiment, the formulation according to the present disclosure does not comprise an amino acid as additive.
• a storage stable formulation of the antibody risankizumab can be provided with a formulation that consists essentially of or consists of a) the antibody (150mg/ml); component b); c) a surfactant and optionally d) a buffer.
• the formulation may comprise only a single polyol, a single surfactant and if present, a single buffer. Thereby a non-complex but nevertheless storage stable formulation is provided for the 150mg/ml formulation of the antibody risankizumab.
• liquid pharmaceutical formulations comprising 150 mg/ml of the antibody are provided that are stable. Providing such stable, high-concentration formulation of the antibody risankizumab is particularly advantageous for therapeutic uses.
• a stable antibody formulation is a formulation wherein the antibody essentially retains its physical stability and/or biological activity upon storage.
• Various analytical techniques for measuring protein stability are available in the art and are disclosed herein. Stability can be measured at a selected temperature for a selected time period.
• the stable liquid pharmaceutical formulation of the present disclosure shows no significant changes at a refrigerated temperature (2-8°C) for at least 3 months, such as 6 months, or 1 year, or even up to 2 years or longer.
• a stable liquid formulation includes one that exhibits desired features at temperatures including 25°C and 40°C for periods including 1 month, 3 months, 6 months, 12 months, and/or 24 months.
• the antibody in particular retains its physical stability in the pharmaceutical formulation, if it shows no significant increase of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering, size exclusion chromatography (SEC) and/or dynamic light scattering.
• SEC size exclusion chromatography
• the changes of protein conformation can be evaluated by fluorescence spectroscopy, which determines the protein tertiary structure, and by FTIR spectroscopy, which determines the protein secondary structure.
• the antibody in particular retains its biological activity in the pharmaceutical formulation, if the biological activity of the antibody at a given time is within a predetermined range of the biological activity exhibited at the time the pharmaceutical formulation was prepared.
• the biological activity of the antibody can be determined, for example, by an antigen binding assay.
• Aggregates can differ in origin, size, and type. Aggregates that can affect a biologic product's efficacy or safety are of particular concern, e.g. aggregates that can enhance immune responses and cause adverse clinical effects. High molecular weight aggregates, also called High Molecular Weight Species (HMWS) can be of particular concern. Aggregation can also potentially affect the subcutaneous bioavailability and pharmacokinetics of a therapeutic protein. It is advantageous that the present disclosure provides formulations, wherein the amount of high molecular weight species is low, also over extended storage times. The present disclosure in particular provides stabilized (or stable) aqueous pharmaceutical formulations as demonstrated by the reduced amounts of aggregates and/or reduced aggregate formation rates following storage.
• HMWS High Molecular Weight Species
• HMWS high molecular weight species
• HMWS refers to higher order aggregates of the antibody of the formulations, as well as lower order aggregates of the antibody of the formulations.
• Lower order aggregates include, for example, dimer species.
• the aggregate amounts and rates of formation may be measured or monitored by various techniques, including those disclosed in the examples.
• LMWS low molecular weight species
• fragments of the antibody that are smaller than the monomer, including but not limited to free light chains, free heavy chains, molecules comprising one light chain and one heavy chain, antibody molecules missing one or both light chains, and antibody fragments obtained by cleavage of polypeptide chain(s) such as proteolytic fragments or other enzymatically or chemically degraded antibody molecules.
• the antibody in the formulation disclosed herein is essentially maintained in monomeric form during storage.
• the formulation may fulfill one or more of the following stability characteristics:
• At least 94% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 3% or more than 2.5%.
• at least 95% or at least 96% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 2% or more than 1.5%.
• At least 94% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 3% or more than 2.5%.
• at least 95% or at least 96% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 2% or more than 1.5% or more than 1%.
• At least 96% or at least 96.5% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 1.5% or more than 1%.
• at least 96% or at least 97% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 1% or more than 0.7% or more than 0.5%.
• At least 90% or at least 92% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 7% or more than 6% or more than 5%.
• at least 95% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 3% or more than 2%.
• At least 96% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 2% or more than 1%.
• at least 87% or at least 88% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 10% or more than 9% or more than 8%.
• the antibody following storage at 40°C for 1 month, at least 93% or at least 94 % of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 5% or more than 4%.
• at least 95% or at least 96% of the antibody is present as a monomer as measured by UP-SEC, and/or the relative monomer content of the antibody does not decrease by more than 2% or more than 1%.
• the decrease of the relative monomer content is calculated for the indicated storage time and temperature and in particular determined by comparing the relative monomer content at the beginning and at the end of the indicated storage. In particular embodiments, the measurements are performed as is described in the examples.
• the antibody in the formulation disclosed herein does not form significant amounts of HMWS during storage.
• the formulation fulfills one or more of the following stability characteristics:
• HMWS following storage at 5°C for 36 months, less than 4% or less than 3% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5%. In certain embodiments, following storage at 5°C for 24 months, less than 4% or less than 3% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5% or more than 1%.
• HMWS following storage at 5°C for 9 months, less than 4% or less than 3% or less than 2.5% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 1% or more than 0.8% or more than 0.6%.
• HMWS following storage at 5°C for 3 months, less than 4% or less than 3% or less than 2.5% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 1% or more than 0.8% or more than 0.6%.
• HMWS following storage at 25°C for 12 months, less than 5% or less than 4% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 3% or more than 2.5% or more than 2%.
• HMWS following storage at 25°C for 3 months, less than 4% or less than 3.5% or less than 3.2% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5%.
• HMWS following storage at 25°C for 1 month, less than 4% or less than 3.5% or less than 3% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 1.5% or more than 1%. In certain embodiments, following storage at 40°C for 3 months, less than 6.5% or less than 6% or less than 5.5% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 5% or more than 4%.
• HMWS following storage at 40°C for 1 month, less than 5% or less than 4.5% or less than 4% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 2.5% or more than 2%.
• HMWS following shaking at 25°C for 21 days, less than 3% or less than 2% of the antibody is present as HMWS as measured by UP-SEC, and/or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5% or more than 1%.
• the increase of the relative HMWS content is calculated for the indicated storage time and temperature and in particular determined by comparing the relative HMWS content at the beginning and at the end of the indicated storage. In particular embodiments, the measurements are performed as is described in the examples.
• the antibody in the formulation disclosed herein does not form significant amounts of LMWS during storage.
• the formulation may fulfill one or more of the following stability characteristics:
• LMWS as measured by UP-SEC
• the relative LMWS content of the antibody does not increase by more than 1.5% or more than 1.5% or more than 0.5%.
• less than 2% or less than 1.5% of the antibody is present as LMWS as measured by UP-SEC, and/or the relative LMWS content of the antibody does not increase by more than 1.5% or more than 1.5% or more than 0.5%.
• LMWS as measured by UP-SEC
• the relative LMWS content of the antibody does not increase by more than 1.5% or more than 1.5% or more than 0.5%.
• less than 2% or less than 1.5% or less than 1% of the antibody is present as LMWS as measured by UP-SEC, and/or the relative LMWS content of the antibody does not increase by more than 1% or more than 0.5% or more than 0.25%.
• LMWS as measured by UP-SEC
• the relative LMWS content of the antibody does not increase by more than 5% or more than 4% or more than 3%.
• less than 3% or less than 2% or less than 1.8% of the antibody is present as LMWS as measured by UP-SEC, and/or the relative LMWS content of the antibody does not increase by more than 2% or more than 1.5% or more than 1%.
• LMWS as measured by UP-SEC
• the relative LMWS content of the antibody does not increase by more than 1% or more than 0.6% or more than 0.4%.
• less than 8% or less than 7% or less than 6% of the antibody is present as LMWS as measured by UP-SEC, and/or the relative LMWS content of the antibody does not increase by more than 8% or more than 7% or more than 6%.
• LMWS as measured by UP-SEC
• the relative LMWS content of the antibody does not increase by more than 3% or more than 2.5% or more than 2.2%.
• the increase of the relative LMWS content is calculated for the indicated storage time and temperature and in particular determined by comparing the relative LMWS content at the beginning and at the end of the indicated storage. In particular embodiments, the measurements are performed as is described in the examples.
• the relative amount of the antibody being in monomeric form, HMWS and/or LMWS is determined using UP-SEC, in particular as described in the examples.
• UPLC ultra-performance liquid chromatography
• SEC size exclusion chromatography
• Proteins eluting from the SEC column may be detected by UV absorption at 280 nm and determining of the relative amounts may be done by calculating the area under the curve (AUC) for each elution peak. Peaks may be assigned to the different species by their elution time corresponding to the molecular size of the species.
• relative HMWS content and/or relative LMWS content of the antibody in the formulation in particular the monomeric antibody, HMWS and LMWS are separated from each other, if present in the formulation.
• the relative content or amount is indicated as a percentage value and the sum of monomeric antibody, HMWS and LMWS is 100%.
• the turbidity or opalescence of the formulation disclosed herein does not significantly increase during storage.
• the formulation may fulfill one or more of the following stability characteristics:
• the formulation following storage at 5°C for at least 36 months, has an opalescence of 12 FNU (Formazin Nephelometry Units) or less or 10 FNU or less, and/or the opalescence does not increase by more than 5 FNU or more than 3 FNU. In certain embodiments, following storage at 5°C for at least 3, 6, 9, 12, 18 or 24 months, the formulation has an opalescence of 12 FNU (Formazin Nephelometry Units) or less or 10 FNU or less, and/or the opalescence does not increase by more than 5 FNU or more than 3 FNU.
• the formulation following storage at 25°C for at least 1, 3, 6, 9 or 12 months, the formulation has an opalescence of 12 FNU or less or 10 FNU or less, and/or the opalescence does not increase by more than 7 FNU or more than 5 FNU. In certain embodiments, following storage at 40°C for at least 1 or 3 months, the formulation has an opalescence of 12 FNU or less or 10 FNU or less, and/or the opalescence does not increase by more than 5 FNU or more than 3 FNU.
• the formulation following shaking at 25°C for 21 days, has an opalescence of 12 FNU or less or 10 FNU or less, and/or the opalescence of the formulation does not increase by more than 3 FNU or more than 2 FNU.
• the increase of the opalescence is calculated for the indicated storage time and temperature and in particular determined by comparing the opalescence at the beginning and at the end of the indicated storage. In particular embodiments, the measurements are performed as is described in the examples.
• the opalescence or turbidity is measured according to pharmacopeia or according to industrial standard ISO 7027.
• the opalescence or turbidity of the formulation is determined using a nephelometer such as a HACH Lange opalescence meter of Hach-Lange GmbH (Germany), in particular as described in the examples.
• Opalescence may be measured at different wavelengths, including at 400-600 nm.
• the FNA values indicated above are measured at 400-600 nm. Higher FNU values indicate a higher opalescence and turbidity.
• the antibody in the formulation disclosed herein does not form significant additional amounts of acidic or basic variants during storage.
• the formulation may fulfill one or more of the following stability characteristics:
• At least 55%, at least 60% or at least 65% of the antibody is present as main peak variants, and/or the relative content of main peak variants of the antibody does not decrease by more than 8% or more than 7% or more than 5%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• At least 60% or at least 65% of the antibody is present as main peak variants, and/or the relative content of main peak variants of the antibody does not decrease by more than 5% or more than 4%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• following storage at 5°C for 3 months at least 60% or at least 65% of the antibody is present as main peak variants, and/or the relative content of main peak variants of the antibody does not decrease by more than 4% or more than 3% or more than 2%, as determined by ion exchange chromatography (IEC).
• At least 35% or at least 40% or at least 45% of the antibody is present as main peak variants, and/or the relative content of main peak variants of the antibody does not decrease by more than 35% or more than 30% or more than 25%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• following storage at 25°C for 3 months at least 55% or at least 60% of the antibody is present as main peak variants, and/or the relative content of main peak variants of the antibody does not decrease by more than 15% or more than 10%, as determined by ion exchange chromatography (IEC).
• At least 60% or at least 65% of the is present as main peak variants, and/or the relative content of main peak variants of the antibody does not decrease by more than 10% or more than 5%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• following storage at 5°C for 36 months less than 30% or less than 28% of the antibody is present as acidic peak group variants, and/or the relative content of acidic peak group variants of the antibody does not increase by more than 4% or more than 3% or more than 2%, as determined by ion exchange chromatography (IEC).
• the antibody following storage at 5°C for 24 months, less than 30% or less than 28% of the antibody is present as acidic peak group variants, and/or the relative content of acidic peak group variants of the antibody does not increase by more than 4% or more than 3% or more than 2%, as determined by ion exchange chromatography (IEC). In certain embodiments, following storage at 5°C for 6 months, less than 30% or less than 28% of the antibody is present as acidic peak group variants, and/or the relative content of acidic peak group variants of the antibody does not increase by more than 4% or more than 3% or more than 2%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• the antibody following storage at 5°C for 3 months, less than 30% or less than 28% of the antibody is present as acidic peak group variants, and/or the relative content of acidic peak group variants of the antibody does not increase by more than 3% or more than 2% or more than 1%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• following storage at 25°C for 12 months, less than 50%, less than 45% or less than 40% of the antibody is present as acidic peak group variants, and/or the relative content of acidic peak group variants of the antibody does not increase by more than 30% or more than 25% or more than 20%, as determined by ion exchange chromatography (IEC).
• the antibody following storage at 25°C for 3 months, less than 40% or less than 35% or less than 30% of the antibody is present as acidic peak group variants, and/or the relative content of acidic peak group variants of the antibody does not increase by more than 10% or more than 8% or more than 6%, as determined by ion exchange chromatography (IEC). In certain embodiments, following storage at 25°C for 1 month, less than 35% or less than 30% or less than 28% of the antibody is present as acidic peak group variants, and/or the relative content of acidic peak group variants of the antibody does not increase by more than 4% or more than 3%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• the antibody following storage at 5°C for 36 months, less than 20%, less than 17%, less than 15% or less than 13% of the antibody is present as basic peak group variants, and/or the relative content of basic peak group variants of the antibody does not increase by more than 10% or more than 8% or more than 6%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• the antibody following storage at 5°C for 6 months, less than 15% or less than 10% of the antibody is present as basic peak group variants, and/or the relative content of basic peak group variants of the antibody does not increase by more than 4% or more than 3% or more than 2%, as determined by ion exchange chromatography (IEC). In certain embodiments, following storage at 5°C for 3 months, less than 15% or less than 10% of the antibody is present as basic peak group variants, and/or the relative content of basic peak group variants of the antibody does not increase by more than 3% or more than 2%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• the antibody following storage at 25°C for 12 months, less than 30% or less than 25% or less than 22% of the antibody is present as basic peak group variants, and/or the relative content of basic peak group variants of the antibody does not increase by more than 25% or more than 20% or more than 15%, as determined by ion exchange chromatography (IEC). In certain embodiments, following storage at 25°C for 3 months, less than 20% or less than 15% or less than 12% of the antibody is present as basic peak group variants, and/or the relative content of basic peak group variants of the antibody does not increase by more than 9% or more than 7% or more than 5%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• the relative content of basic peak group variants of the antibody does not increase by more than 3% or more than 2%, as determined by ion exchange chromatography (IEC).
• IEC ion exchange chromatography
• the relative amount of the antibody being main peak variants, acidic peak variants and/or basic peak variants is determined using ion exchange chromatography (IEC), in particular as described in the examples.
• IEC ion exchange chromatography
• WCX weak cation exchange chromatography
• HPLC high-performance liquid chromatography
• HPLC high-performance liquid chromatography
• Proteins eluting from the WCX column may be detected by UV absorption at 280 nm and determining of the relative amounts may be done by calculating the area under the curve (AUC) for each elution peak or each group of elution peaks.
• Peaks may be assigned to the different species by their elution conditions corresponding to the surface charge of the antibody species.
• the main peak is the largest peak in an IEC chromatogram of the non-degraded antibody.
• the acidic peak group includes all peaks prior to the main peak. These peaks include antibody variants which are more acidic than the native antibody variants of the main peak, and/or which have more negative charges on their surface under the chromatography conditions.
• the basic peak group includes all peaks after the main peak.
• peaks include antibody variants which are more acidic than the native antibody variants of the main peak, and/or which have more positive charges on their surface under the chromatography conditions.
• acidic peak group variants and/or basic peak group variants of the antibody in the formulation in particular the main peak is separated from the acidic peak group and the basic peak group, if present in the formulation.
• the relative content or amount is indicated as a percentage value and the sum of main peak variants, acidic peak group variants and basic peak group variants is 100%.
• the antibody in the formulation disclosed herein essentially maintains its specific binding activity to human IL-23 during storage.
• the formulation fulfills one or more of the following stability characteristics:
• At least 90% or at least 95% of the specific binding activity to IL-23 is measured compared to a reference antibody, wherein the reference antibody has not been stored.
• the measurements are performed as is described in the examples.
• the specific binding activity to human IL-23 of the antibody in the formulation is determined using surface plasmon resonance measurements, for example using a Biacore instrument such as Biacore T200 of GE Healthcare Life Science (United Kingdom), in particular as described in the examples.
• the liquid pharmaceutical formulation of the present disclosure is an aqueous formulation. All liquid formulations disclosed herein are in one embodiment an aqueous formulation. The following description applies to the 150 mg/ml formulation according to the first aspect and therefore, also applies to the formulations according to the first and second sub-aspect as disclosed herein, unless the specific context indicates otherwise.
• the dynamic viscosity of the liquid pharmaceutical formulation according to the first aspect measured at 20°C is ⁇ 30 mPas (mPa s), such as ⁇ 25 mPas or ⁇ 20 mPas.
• the dynamic viscosity of the formulation measured at 20°C is ⁇ 18 mPas, such as ⁇ 16 mPas, ⁇ 15 mPas, ⁇ 14 mPas, ⁇ 13 mPas or ⁇ 12 mPas.
• the dynamic viscosity is such that the formulation is suitable for subcutaneous administration, as is also shown in the examples. The dynamic viscosity may be determined as described in the examples.
• the formulation of the present disclosure has a conductivity in a range of 0.8 to 5 mS/cm.
• the conductivity range is 1 to 2 mS/cm or 1.2 to 1.8 mS/cm.
• the formulation is characterized in that the change of conductivity over a storage time of at least 12 months at 25°C is ⁇ 1 mS/cm, such as ⁇ 0.75 mS/cm, ⁇ 0.5 mS/cm or ⁇ 0.3 mS/cm.
• the liquid formulation according to the present disclosure is a pharmaceutical formulation.
• a pharmaceutical formulation in particular refers to compositions which are in such form as to permit the active ingredient (here the antibody comprising a light chain as shown in SEQ ID NO: 1 and a heavy chain as shown in SEQ ID NO: 2) to be effective, and which contains no additional components which are toxic to the subjects to which the formulation would be administered.
• the active ingredient here the antibody comprising a light chain as shown in SEQ ID NO: 1 and a heavy chain as shown in SEQ ID NO: 2
• the formulations according to the first aspect disclosed herein are advantageously suitable for parenteral delivery.
• Parenteral administration includes e.g. subcutaneous, intramuscular, intradermal, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal and intravitreal.
• Drugs can be administered in a variety of conventional ways, such as intraperitoneal, parenteral, intraarterial or intravenous injection.
• the disclosed formulation is an injectable formulation.
• the formulation disclosed herein is in embodiments suitable for subcutaneous, intravenous, or intramuscular administration.
• the disclosed formulation is suitable for subcutaneous injection.
• the 150mg/ml formulation disclosed herein is particularly advantageous, because overall characteristics are achieved which makes the formulation particularly suitable for subcutaneous administration.
• the high concentration allows to administer a small volume of the formulation while still achieving a high antibody dose (here e.g. 1ml for 150mg dose).
• the formulations according to the present disclosure show a good syringeability. They moreover have advantageous viscosity and osmolality characteristics and achieve good glide forces (max and average), also upon storage as is disclosed in the examples.
• the liquid pharmaceutical formulation according to the present disclosure is isotonic with the intended site of administration. For example, if the formulation is intended for administration parenterally, it can be isotonic with blood (which is about 300 mOsm/kg osmolality). Suitable osmolality ranges are described elsewhere.
• the liquid antibody formulation can be made by taking the drug substance which is in liquid form (e.g., in an aqueous pharmaceutical formulation) and buffer exchanging and preparing it into the desired buffer as the last step of the purification process.
• the drug substance in the final buffer may be concentrated to a desired concentration or a more concentrated form of the antibody is diluted to achieve the 150mg/ml concentration. Concentration of the formulation can be carried out by any suitable method. In one aspect, the concentration process can include ultrafiltration.
• the liquid pharmaceutical formulation according to the first aspect is in one core embodiment not a formulation that has been prepared by reconstituting a lyophilized formulation.
• this core embodiment there is no lyophilization step during the preparation of the liquid pharmaceutical formulation.
• Excipients such as component b) and surfactant c) may be added to the drug substance which may be diluted using the appropriate buffer to final protein concentration of 150mg/ml.
• a pharmaceutical formulation to be used for in vivo administration typically is sterile. In certain embodiments, this may be accomplished by filtration through sterile filtration membranes.
• the final formulated drug substance may thus be filtered (e.g. using 0.22 pm filters) and may be filled into a final container (e.g. glass vials or syringe).
• the prepared liquid formulation is in this embodiment for direct administration to the patient so that there is no lyophilization or reconstitution step.
• Such liquid pharmaceutical formulations are disclosed herein and were also made and analysed in the examples.
• the liquid pharmaceutical formulation according to the first aspect is prepared from a lyophilized pharmaceutical formulation by reconstitution.
• the liquid pharmaceutical composition described herein is thus a reconstituted formulation. This applies to the liquid formulations according to the first and second sub aspect of the 150 mg/ml antibody formulation according to the first aspect.
• lyophilization in particular refer to a process by which the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment. Such technologies are well-known in the art and therefore, are not described in detail herein.
• An excipient may be included in pre-lyophilized formulations to enhance stability of the lyophilized product upon storage.
• the lyophilized formulation may comprise a cryoprotectant, which generally includes agents which provide stability to the protein against freezing-induced stresses. They may also offer protection during primary and secondary drying, and long-term product storage. Examples include sugars such as sucrose and trehalose and surfactants such as polysorbates.
• the lyophilized formulation may also include a lyoprotectant, which includes agents that provide stability to the protein during the drying or dehydration process (primary and secondary drying cycles). This helps to maintain the protein conformation, minimize protein degradation during the lyophilization cycle and improve the long-term product stability.
• a lyoprotectant includes agents that provide stability to the protein during the drying or dehydration process (primary and secondary drying cycles). This helps to maintain the protein conformation, minimize protein degradation during the lyophilization cycle and improve the long-term product stability.
• examples include polyols, such as sugars, e.g. sucrose and trehalose.
• the liquid pharmaceutical formulations disclosed according to the first aspect comprise excipients that qualify as cryo- and/or lyoprotectant. accordingly, lyophilized formulations may be prepared from such formulations.
• the antibody risankizumab is formulated as a lyophilized powder for reconstituting and utilizing for intravenous administration.
• a "reconstituted" formulation is one that has been prepared by dissolving a lyophilized pharmaceutical antibody formulation in a diluent such that the antibody is dispersed in the reconstituted formulation.
• the reconstituted formulation is suitable for administration, and may optionally be suitable for subcutaneous administration.
• the lyophilized pharmaceutical formulation is prepared in anticipation of reconstitution at the desired concentration, here 150mg/ml of the antibody.
• a lyophilized formulation of an anti-IL-23pl9 antibody wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2.
• the lyophilized formulation of the antibody risankizumab is defined in terms of the solution used to make the lyophilized formulation, e.g. the pre- lyophilization solution.
• This lyophilized formulation is made by lyophilizing the liquid 150 mg/ml antibody formulation according to the first aspect, such as the liquid pharmaceutical formulation according to the first aspect as defined in any one of the below embodiments 1 to 86.
• the liquid formulation is in one embodiment an aqueous formulation. Such aqueous formulation may be used to prepare the lyophilized pharmaceutical formulation.
• the lyophilized formulation of the antibody risankizumab is defined in terms of the reconstituted solution generated from the lyophilized formulation.
• a lyophilized formulation of an anti-IL-23pl9 antibody is thus provided, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, said lyophilized formulation providing upon reconstitution the liquid 150 mg/ml antibody formulation according to the first aspect, in particular the first and second sub-aspect thereof.
• the lyophilized formulation provides upon reconstitution the liquid pharmaceutical formulation as defined in any one of the below embodiments 1 to 86 or 104 to 119.
• This risankizumab formulation may be an aqueous formulation.
• a lyophilized formulation comprising a) an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, in an amount that upon reconstitution provides an antibody concentration of 150mg/ml; b) a polyol; c) a surfactant; and d) optionally a buffer.
• the lyophilized pharmaceutical formulation comprises 150mg of the antibody.
• the antibody is risankizumab.
• a lyophilized formulation comprising a) an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, in an amount that upon reconstitution provides an antibody concentration of 150mg/ml; b) a tonicity modifier; c) a surfactant; and d) optionally a buffer.
• the lyophilized pharmaceutical formulation comprises 150mg of the antibody.
• the antibody is risankizumab.
• Suitable polyols include sugars and sugar alcohols, which may also be used in combination.
• the polyol may have one or more of the characteristics as defined in any one of the below embodiments 6 to 13 of the liquid pharmaceutical formulation according to the first aspect.
• the polyol is a sugar, optionally selected from trehalose and sucrose.
• the sugar is trehalose.
• Suitable surfactants were already disclosed above in conjunction with the liquid pharmaceutical formulation and it is referred to the above disclosure which also applies here.
• the surfactant may have one or more of the characteristics as defined in any one of the below embodiments 22 to 25 of the liquid pharmaceutical formulation according to the first aspect.
• the surfactant is a polysorbate, optionally selected from polysorbate 20 and 80.
• the polysorbate is polysorbate 20.
• the lyophilized formulation comprises in one embodiment a buffer.
• Buffers suitable to prepare lyophilized formulations are known in the art and suitable buffers were also disclosed above in conjunction with the liquid pharmaceutical formulation according to the first aspect and it is referred to the above disclosure.
• the lyophilized formulation is characterized in that the formulation has upon reconstitution a pH as disclosed herein for the liquid pharmaceutical formulation according to the first aspect. Suitable pH values were disclosed above and it is referred to the respective disclosure which also applies here.
• the pH may be as defined in any one of the below embodiments 31 to 36 of the liquid 150 mg/ml pharmaceutical formulation.
• the pH upon reconstitution, may be as defined for the formulation according to second sub-aspect. The pH upon reconstitution may be 5.5 to 5.9, e.g. 5.6 to 5.8.
• lyophilized risankizumab formulations of the present disclosure are reconstituted prior to administration. In some instances, it may be desirable to lyophilize the risankizumab formulation in the container in which reconstitution of the antibody is to be carried out in order to avoid a transfer step.
• a sealed container which contains the liquid pharmaceutical formulation or the lyophilized pharmaceutical formulation according to the first aspect of the present disclosure.
• the container may be a vial or pre-filled syringe.
• the container contains 2ml or less of the liquid pharmaceutical formulation, optionally 1.5ml or less or 1 ml or less.
• Such container may comprise the advantageous stable liquid pharmaceutical formulation according to the first or second sub aspect of the 150 mg/ml antibody formulation according to the first aspect.
• the container such as the syringe comprises a single dose of 150mg antibody.
• the antibody is risankizumab.
• the liquid pharmaceutical formulation according to the first aspect of the present disclosure is comprised in a syringe which is equipped with a needle.
• the needle is suitable for subcutaneous administration.
• the needle may be a 27 Gauge spinal thin-wall needle or other needle suitable for subcutaneous use.
• the pre- filled syringe equipped with a needle has an average gliding force that is 20 N or less. In embodiments, the average gliding force is in the range of 5 to 20 N or 5 to 15 N. In embodiments, the pre- filled syringe has a break loose force of 3 to 12 N, preferably 3 to 9 N.
• the syringe equipped with a needle and comprising the liquid pharmaceutical formulation according to the first aspect essentially maintains the maximum and/or average gliding force needed to eject it from a syringe during storage.
• the maximum gliding force of the syringe pre-filled with the liquid formulation is 14 N or lower, 12 N or lower or 10 N or lower, and/or the maximum gliding force does not increase by more than 5 N or more than 4 N or more than 3 N.
• the maximum gliding force of the syringe pre-filled with the liquid formulation is 14 N or lower, 12 N or lower, 10 N or lower or 8 N or lower, and/or the maximum gliding force does not increase by more than 3 N or more than 2 N or more than 1.5 N. In certain embodiments, following storage at 5°C for 9 months, the maximum gliding force is 9 N or lower or 8 N or lower, and/or the maximum gliding force does not increase by more than 2 N or more than 1.5 N or more than 1 N.
• the maximum gliding force is 8 N or lower or 7.5 N or lower, and/or the maximum gliding force does not increase by more than 1.5 N or more than 1 N. In certain embodiments, following storage at 25°C for 3 months, the maximum gliding force is 10 N or lower or 8 N or lower, and/or the maximum gliding force does not increase by more than 3 N or more than 2 N or more than 1.5 N.
• the maximum gliding force of the pre-filled syringe equipped with a needle is 8 N or lower or 7.5 N or lower, and/or the maximum gliding force does not increase by more than 1.5 N or more than 1 N. In certain embodiments, following storage at 40°C for 1 month, the maximum gliding force is 16 N or lower or 13 N or lower, and/or the maximum gliding force does not increase by more than 10 N or more than 8 N or more than 6 N.
• the average gliding force of the syringe prefilled with the liquid formulation according to the first aspect and equipped with a needle is 14 N or lower, 12 N or lower, 10 N or lower or 9 N or lower, and/or the average gliding force does not increase by more than 5 N or more than 4 N or more than 3 N.
• the average gliding force of the syringe prefilled with the liquid formulation according to the first aspect and equipped with a needle is 14 N or lower, 12 N or lower, 10 N or lower or 8 N or lower, and/or the average gliding force does not increase by more than 3 N or more than 2 N or more than 1.5 N.
• the average gliding force of the pre-filled syringe equipped with the needle is 9 N or lower or 7.5 N or lower, and/or the average gliding force does not increase by more than 2 N or more than 1.5 N or more than 1 N. In certain embodiments, following storage at 5°C for 3 months, the average gliding force is 8 N or lower or 7 N or lower, and/or the average gliding force does not increase by more than 1.5 N or more than 1 N or no more than 0.5 N.
• the average gliding force is 15 N or lower or 13 N or lower, and/or the average gliding force does not increase by more than 9 N or more than 8 N or more than 7 N. In certain embodiments, following storage at 25°C for 3 months, the average gliding force is 9 N or lower or 8 N or lower, and/or the average gliding force does not increase by more than 3 N or more than 2 N or more than 1.5 N. In certain embodiments, following storage at 25°C for 1 month, the average gliding force is 8 N or lower or 7 N or lower, and/or the average gliding force does not increase by more than 1.5 N or more than 1 N or no more than 0.5 N.
• the average gliding force is 18 N or lower or 15 N or lower, and/or the average gliding force does not increase by more than 12 N or more than 10 N or more than 9 N. In certain embodiments, following storage at 40°C for 1 month, the average gliding force is 13 N or lower or 10 N or lower, and/or the average gliding force does not increase by more than 7 N or more than 5 N or more than 3 N.
• the increase of the maximum or relative gliding force is calculated for the indicated storage time and temperature and in particular determined by comparing the maximum or relative gliding force at the beginning and at the end of the indicated storage.
• the measurements are performed as is described in the examples.
• the maximum gliding force of the formulation refers to the maximum mechanical force needed to eject the formulation from a syringe.
• the average gliding force of the formulation refers to the average mechanical force needed to eject the formulation from a syringe.
• the gliding force is determined according to industrial norms such as ISO 7886, ISO 11040 and ISO 11499.
• the maximum and average gliding force of the formulation is determined using a tensile and compression testing machine such as a Zwick 2.5TS/N of Zwick (Germany), in particular as described in the examples.
• the measurement may be performed using a 1 ml syringe with a 27 gauge x 1 ⁇ 2 inch needle, such as a Neopak 1 ml syringe of Becton Dickinson (USA), in particular a syringe equipped with a needle as used in the examples.
• the measurement may be performed using a speed of about 300 to 500 mm/min such as about 380 mm/min, in particular 379.2 mm/min, for example for 5 seconds.
• a further aspect according to the present disclosure pertains to the liquid pharmaceutical formulations or the lyophilized pharmaceutical formulations according to the first aspect or the container according to the further aspect disclosed herein for therapeutic treatment of a human subject.
• the disease to be treated is a disease that can be treated with an anti-IL-23pl9 antibody and such diseases are known in the art.
• the disease may be selected from the group consisting of inflammatory diseases, autoimmune diseases, respiratory diseases, metabolic disorders and cancer.
• the disease is a chronic disease.
• the disease to be treated may be selected from psoriasis and inflammatory bowel disease.
• the disease to be treated may be selected from psoriatic arthritis and Crohn’s disease.
• Administering the high concentration 150mg/ml liquid pharmaceutical formulation according to the present disclosure to the patient for therapy is advantageous for the reasons discussed herein.
• a liquid pharmaceutical formulation comprising a) 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2; b) a polyol; and c) a surfactant.
• the concentration of the polyol in the formulation is at least 95mM
• the concentration of the polyol in the formulation is at least 125 mM
• the concentration of the polyol in the formulation is at least 150 mM
• the concentration of the polyol in the formulation is ⁇ 500 mM, ⁇ 450 mM or ⁇ 400 mM;
• the concentration of the polyol in the formulation is ⁇ 350 mM, ⁇ 300 mM or ⁇ 275 mM;
• the concentration of the polyol in the formulation lies in the range of 95 mM to 450 mM or 125 mM to 400 mM; optionally wherein the polyol is a sugar and/or a sugar alcohol.
• the buffer is an acetate buffer, optionally wherein the acetate buffer comprises sodium acetate and acetic acid.
• the buffer is a histidine buffer or wherein the formulation fulfills at least one of the following characteristics: (i) it comprises a carboxylic acid buffer; (ii) it does not comprise a succinate buffer.
• the formulation according to one or more of embodiments 2 to 40 comprising at least 1 mM, at least 2 mM or at least 3 mM buffer, optionally comprising at least 4 mM, at least 4.5 mM or at least 5 mM buffer.
• 51. The formulation according to any one of embodiments 2 to 48 or 50, comprising a) 150 mg/ml of the antibody; b) a sugar, optionally wherein the concentration of the sugar is in the range of 95 mM to 250 mM or 145 mM to 225 mM; c) a non-ionic surfactant, optionally wherein the concentration of the non-ionic surfactant is in the range of 0.05 mg/ml to 0.5 mg/ml or 0.075 mg/ml to 0.3 mg/ml; and d) a buffer.
• the formulation according any one of embodiments 2 to 48 or 50 to 51 comprising a) 150 mg/ml of the antibody; b) trehalose, optionally wherein the concentration of trehalose is in the range of 95 mM to 250 mM or 145 mM to 225 mM; c) a polysorbate, optionally wherein the concentration of the polysorbate is in the range of 0.05 mg/ml to 0.5 mg/ml or 0.075 mg/ml to 0.3 mg/ml; and d) a buffer.
• the formulation according any one of embodiments 2 to 48 or 50 to 55 comprising a) 150 mg/ml of the antibody; b) 170 mM to about 200 mM trehalose; c) 0.1 mg/ml to 0.3 mg/ml polysorbate, optionally polysorbate 20; and d) a buffer, optionally wherein the buffer is an acetate buffer.
• liquid pharmaceutical formulation comprising a) 150 mg/ml of the antibody; b) a polyol, optionally wherein the polyol is a sugar or sugar alcohol; and c) a non-ionic surfactant, optionally a polysorbate; d) no buffer.
• liquid pharmaceutical formulation according to any one of embodiments 2 to 68, comprising a) 150 mg/ml of the antibody; b) 185 mM trehalose; c) 0.2 mg/ml polysorbate 20; and d) 10 mM acetate buffer; wherein the pH is in the range of 5.2 to 6.2 and optionally is 5.7.
• the formulation has an opalescence of 12 FNU (Formazin Nephelometry Units) or less or 10 FNU or less, and/or the opalescence does not increase by more than 5 FNU or more than 3 FNU;
• the formulation has an opalescence of 12 FNU (Formazin Nephelometry Units) or less or 10 FNU or less, and/or the opalescence does not increase by more than 5 FNU or more than 3 FNU;
• the formulation has an opalescence of 12 FNU or less or 10 FNU or less, and/or the opalescence does not increase by more than 7 FNU or more than 5 FNU; (iv) following storage at 40°C for at least 1 or 3 months, the formulation has an opalescence of 12 FNU or less or 10 FNU or less, and/or the opalescence does not increase by more than 5 FNU or more than 3 FNU; and/or
• the formulation has an opalescence of 12 FNU or less or 10 FNU or less, and/or the opalescence of the formulation does not increase by more than 3 FNU or more than 2 FNU.
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• HMW high molecular weight
• LMW low molecular weight
• LMW low molecular weight
• LMW low molecular weight
• LMW low molecular weight
• LMW low molecular weight
• LMW low molecular weight
• LMW low molecular weight
• a lyophilized formulation of an anti-IL-23pl9 antibody wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, made by lyophilizing the liquid formulation as defined in any one of embodiments 1 to 69, optionally wherein the liquid formulation is an aqueous solution.
• a lyophilized formulation of an anti-IL-23pl9 antibody wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, providing upon reconstitution the liquid formulation as defined in any one of embodiments 1 to 69 or 82 to 86.
• a lyophilized formulation comprising a) an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, in an amount that upon reconstitution provides an antibody concentration of 150mg/ml; b) a polyol; c) a surfactant; and d) optionally a buffer.
• the lyophilized formulation according to any one of embodiments 91 to 94 comprising d) a buffer, wherein the buffer has one or more of the characteristics as defined in any one of embodiments 37 to 40.
• a sealed container optionally, a vial or pre-filled syringe, containing the liquid pharmaceutical formulation according to any one of embodiments 1 to 87.
• a container optionally, a sealed vial, containing the lyophilized formulation according to any one of embodiments 88 to 96.
• a stable liquid pharmaceutical formulation comprising a) 150 mg/ml of an anti-IL-23pl9 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2; b) a tonicity modifier; and c) a surfactant, wherein the formulation has a pH of 5.5-5.9 and the formulation is isotonic.
• the stable formulation according to any one of embodiments 104 to 111 comprising d) a buffer, optionally wherein the buffer has one or more of the characteristics as defined in any one of embodiments 37 to 40 and 48.
• the surfactant is a non-ionic surfactant
• the surfactant is a polysorbate, optionally selected from polysorbate 20 and polysorbate 80;
• concentration of the surfactant in the formulation is in a range of 0.05 mg/ml to 0.5 mg/ml, optionally within a range of 0.075 mg/ml to 0.4 mg/ml or 0.1 mg/ml to 0.3 mg/ml; and/or
• a lyophilized formulation of an anti-IL-23pl9 antibody wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, made by lyophilizing the liquid formulation as defined in any one of embodiments 104 to 118, optionally wherein the stable liquid formulation is an aqueous solution.
• a lyophilized formulation of an anti-IL-23pl9 antibody wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, providing upon reconstitution the stable liquid formulation as defined in any one of embodiments 104 to 118.
• compositions are described as comprising components or materials, it is contemplated that the compositions can in embodiments also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise.
• the technology illustratively disclosed herein suitably may be practiced in the absence of any element which is not specifically disclosed herein.
• the starting material of risankizumab, produced in CHO cells and purified, was adjusted to pH 5.9, where necessary, prior to UF/DF process. At the end, the solution was concentrated and the concentrated starting material was used for preparing formulations according to the subsequent examples.
• Neopak syringes with rubber stopper of Becton Dickinson (USA).
• the break loose force, as well as the maximum and average gliding force were measured using such syringes.
• 1 ml Neopak syringes with a 27 gauge 1 ⁇ 2 inch needle and a rubber stopper of Becton Dickinson (USA) were used.
• RALS right-angle light scattering
• Table 1 Results of the RALS measurements for different pH values.
• the buffer capacity of the antibody starting material was determined inter alia in order to facilitate the pH adjustment of the formulation solutions of the subsequent stability studies and to avoid protein damage.
• the titration to determine the buffer capacity of the antibody was performed at the following concentrations: 150 mg/mL; 100 mg/mL; 50 mg/mL (twice) and 20 mg/mL.
• Table 2 Dilution scheme for determination of the buffering capacity of the starting material.
• Table 4 Composition of the analyzed formulations.
• 0.02 % PS20 corresponds to 0.2 mg/mL PS20.
• Neopak syringes were filled into Neopak syringes. The filling within a laminar flow was set to a volume of 1.1 mL. The syringes were closed with a stopper and analyzed visually for particles before storage. Afterwards, the syringes were stored hanging in syringe-trays at the respective temperature. In parallel, the buffer solutions were stored as controls. After preparing the formulations, each solution was sterile filtered and the prepared formulations were stored in syringes (Neopak syringes of Becton Dickinson (USA).
• HP-SEC high pressure size exclusion chromatography
• UP-SEC ultra-performance size exclusion chromatography
• the syringeability of the formulations stored in syringes (Neopak) was analyzed by measuring the mechanical forces that are required to release/inject the formulation.
• a pressure test was performed with a speed of 379.2 mm/min (5sec).
• the viscosity of the formulations was measured at 20°C using the HAAKE RheoStress 600 with a C35/1 rotor. Double measurements were performed.
• Table 5 Results HP-SEC monomer in % analysis over 18 months storage at different temperatures in syringes.
• Table 5a Results UP-SEC monomer in % analysis over 18 months storage at different temperatures in syringes.
• the monomer content (UP-SEC) was between 88- 91%. The strongest decrease was measured for FI with -6.4%; the lowest decrease was measured with -5.1% and -5.4% for formulation 4 and 5. Over a storage time of 18 months at 5°C the monomer content (UP-SEC) was between 93-95%. The strongest decrease was measured for FI with -2.2%; the lowest decrease was measured with -1% for formulation 4 and 5.
• Table 7 Results of the turbidity at 860 nm in FNU over 18 months at different storage temperatures in syringes.
• the turbidity was measured at a wavelength of 860 nm, showing an increase in Formazine Nephelometric Units (FNU) of 1 to 3 during the storage time of 18 months at 25°C.
• FNU Formazine Nephelometric Units
• Formulation 1 had the strongest increase in 3 FNU and formulation 2 the smallest increase in 1 FNU.
• Formulation 4 containing L-arginine had the highest turbidity from the beginning on.
• the turbidity was measured at a wavelength of 860 nm, showing an increase of 0-1 FNU during the storage time of 18 months at 5°C.
• Table 8 Results of the conductivity measurements in mS/cm at a storage temperature at 25°C for up to 18 months.
• the conductivity remained constant for all 5 formulations over a storage time of 18 months and at a temperature of 5°C and 25°C. While the conductivity of FI, F2, F3 and F5 has a value between 1 to 2 mS/cm, the L-arginine containing formulation F4 had a relatively high conductivity of just below 4 mS/cm.
• the pH value remained essentially constant over the storage time of 18 months and at the different storage temperatures tested. Measured pH values were thus in a range from 5.7-6.3. • The osmolality remained essentially constant over the storage time of 18 months and at the different storage temperatures tested. The tested values ranged from 296-333 mOsm/kg.
• the dynamic viscosity at 20 °C remained essentially constant over the storage time of 18 months and at the different storage temperatures tested.
• the dynamic viscosity was in a range of 10-14 mPas.
• the HP-SEC fragments contents remained essentially constant over the storage time of 18 months and at the different storage temperatures tested.
• the fragments content was in a range of 0.2-1.4%.
• the UP-SEC LMW contents remained essentially constant over the storage time of 18 months and at the different storage temperatures tested. In particular, a low increase of 3% was measured for 25°C and 0.1-0.3% for 5°C over 18 months.
• the LMW content was in a range of 1.0-4.5%.
• the hydrophobic interaction chromatography (HIC) main peak content remained essentially constant over the storage time of 12 months at 25°C or 8 months at 5°C.
• the post peak increased by about 2-3% over at the storage temperature and time.
• the pre-peak was slightly increased by 5-7% over 12 months at 25°C and did not increase at 5°C over 8 months. No differences between the formulations were observed regarding the main peak, post peak and pre-peak.
• the specific binding activity remained essentially constant over the storage time of 18 months and at the different storage temperatures tested with only minimal reduction of 3% and 1-2% for 25°C and 5°C, respectively, for 18 months.
• the specific binding activity was in a range of 96-101%.
• Formulation 4 All 5 formulations were stable over 18 months storage time at 25°C and 5°C.
• Formulation 4 comprises an additional auxiliary agent.
• Formulation 3 was stable and did not have an additional auxiliary agent in contrast to the arginine-containing formulation F4. At a pH of about 5.7 less aggregate formation was observed.
• the freezing was performed by a controlled freezing process. Afterwards, the bags were transferred into a -40°C freezer and kept frozen for the indicated storage times.
• Each freeze/thaw cycle comprised freezing at -40°C in a lyophilizer and subsequent transfer into a -40°C freezer and thawing in a lyophilizer at a maximal thawing rate of 20°C/min until room temperature after 3 weeks.
• the tested formulations are shown in Table 9.
• Table 9 Composition of the formulations.
• the starting material was stored at 2-8°C in a fridge until use.
• the bags (“Mini Flexboy Bags”) having a sample volume of 10 mL were frozen using a lyophilizer with a controlled freezing rate of 0.5°C/min until reaching a temperature of- 40°C.
• the samples were directly before analysis thawed in a controlled manner using a lyophilizer.
• HP-SEC analysis was performed and the binding activity was measured.
• the turbidity was measured at 860 nm and at 400-600 nm. Further details on the utilized analysis methods are described below.
• Table 10 Results HP-SEC monomer content in % after 3 weeks storage (frozen at -40°C and at 2-8°C) and initial values.
• Table 10a Results UP-SEC monomer content in % after 3 weeks storage (frozen at - 40°C and at 2-8°C) and initial values.
• the remaining antibody content missing to 100% was present as HMW species.
• the binding activity against rhIL-23 was measured utilizing surface plasmon resonance (Biacore) measurements.
• the binding activity is overall the same in all formulations, demonstrating applicability of the formulations.
• the binding activity was measured to be in a range between 95 to 110% and the specific binding activity was about 100%.
• the 3 weeks of storage in a frozen state or at 2-8°C did not change the binding activity.
• viscosity Another important parameter of protein formulations is the viscosity, which preferably is not too high in order to allow the formulation to be injected (e.g. pass a needle without excessive use of force). Therefore, the dynamic viscosity was measured.
• the dynamic viscosity is very similar for FI, F2 and F3 being in a range of 8.7 to 10 mPas.
• the sub-visible particle content (> 25 pm, > 10 pm, > 5 pm) remained essentially constant over 3 weeks at 5°C or at -40°C including a freeze/thaw cycle. The sum of counted particles was essentially the same for all three formulations.
• the osmolality remained essentially constant over 3 weeks at 5°C or at -40°C including a freeze/thaw cycle.
• the tested values ranged from 299-321 mOsm/kg for 150 mg/mL formulations.
• the turbidity at 860 nm and 400-600 nm remained essentially constant over 3 weeks at 5°C or at -40°C including a freeze/thaw cycle.
• the tested values ranged from 2-7 FNU at 860 nm and 4-13 FNU at 400-600 nm.
• the protein concentration remained essentially constant over 3 weeks at 5°C or at - 40°C including a freeze/thaw cycle. Small deviations of protein concentration are due to analytical variations, leading to ranges of 149-157 mg/mL for initial protein contents of 150 mg/mL.
• the hydrophobic interaction chromatography (HIC) main peak content remained essentially constant over 3 weeks at 5°C or at -40°C including a freeze/thaw cycle.
• the HIC main peak values ranged from 97.1-97.7%.
• the post peak and pre peak remained essentially constant over 3 weeks at 5°C or at -40°C including a freeze/thaw cycle.
• the weak cation exchange (WCX) chromatography main peak content remained essentially constant over 3 weeks at 5°C or at -40°C including a freeze/thaw cycle.
• the WCX main peak values range from 72.5-73.8%.
• the acidic peak group (APG) and basic peak group (BPG) remained essentially constant over 3 weeks at 5°C or at - 40°C including a freeze/thaw cycle. No differences between the formulations were observed regarding main peak, APG and BGP.
• the capillary gel electrophoresis (CGE) analysis showed essentially constant values over 3 weeks at 5°C or at -40°C including a freeze/thaw cycle.
• the non-reduced main peak contents ranged from 96.7-97.6%.
• the results of the present example demonstrate stability of risankizumab provided in different 150 mg/mL formulations over freeze/thaw cycle.
• a particularly suitable pH is in the range of 5.2 to 6.2 such as 5.5 to 6.2 or about 5.7.
• a higher pH can lead to increased protein aggregation, measured by SEC.
• a lower pH can lead to chemical degradation.
• sorbitol was used to adjust the tonicity.
• trehalose and mannitol were used instead of sorbitol to adjust the tonicity.
• Seven sorbitol-free formulations were chosen and tested at following three conditions (i) 5 °C for 18 months, r.h. not monitored; (ii) 25 °C/60 % r.h. for 18 months and (iii) 40 °C/75 % r.h. for 6 months.
• the compositions of formulation 1 - 7 are depicted below in Table 11.
• Table 11 Composition of the analyzed formulations.
• the formulations and formulation buffers were sterile-filtered (filter type 0.22 pm) and filled under laminar flow with a fill volume of 1.04 mL in syringes (Neopak).
• the formulations were prepared by mixing the starting material with a concentration solution comprising the auxiliary agents (excipients, buffer, etc.).
• the filled syringes were stored horizontally in rondotrays protected from light using cardboard boxes at 2 - 8 °C. Following packing materials were used:
• Neopak syringe (1 ml syringe with 27 gauge 1 ⁇ 2 inch needle)
• HP-SEC and UP-SEC were performed and the turbidity (also referred to as opalescence) was measured. Following devices were used for analysis:
• UPLC, UPSEC UPLC 29/31 Waters ACQUITY, Waters, MA HPLC, WCX / SEC: HPLC 82/83/107 Waters ALLIACE, Waters, MA - Particle count / size by MFI: Micro Flow Imagine, 5200 BOT A/B (Roboter), Protein
• Osmometer Osmomat 3000 Gonotec GmbH
• GER pH-meter SevenGo, Mettler Toledo, GER
• Turbidity photometer 2100 AN Turbidimeter, Hach-Lange GmbH, GER - Protein concentration by Solo VPE: Solo VPE, C. Technologies, Inc., NJ
• Biacore Biacore T200, GE Healthcare Life Science, UK
• UP-SEC and HP-SEC were used to determine the loss of monomer content.
• Monomer content is a key quality attribute of protein stability and quality during stress-induced storage.
• Table 12 Monomer content measured by UP-SEC [%] of seven formulations stored at 5°C, 25°C and 40°C.
• HP-SEC confirms the results of UP-SEC. Compared to UP-SEC, no additional information were generated by HP-SEC.
• UP-SEC and HP-SEC were used to determine levels of HMW formation.
• the following table shows the results of the UP-SEC measurement.
• the HMW content correlates with the monomer content. Loss of monomer leads to increase of HMW.
• Table 13 HMW measured by UP-SEC [%] of seven formulations stored at 5°C, 25°C and 40°C.
• HP-SEC confirms the results of UP-SEC. Compared to UP-SEC, no additional information were generated by HP-SEC.
• UP-SEC was used to determine levels of LMW formation.
• the following table shows the results of the UP- SEC measurement.
• Table 14 LMW content measured by UP-SEC [%] of seven formulations stored at 5°C, 25°C and 40°C. Results and discussion
• Table 15 LMW content measured by HP-SEC [%] of seven formulations stored at 5°C, 25°C and 40°C. Results and discussion
• the LMW content increases only slightly over time but all tested formulations generally resulted in low levels of fragmentation.
• L-arginine HCL containing formulations showed increased opalescence.
• the dynamic viscosity measured at 20 °C remained essentially constant over the storage time of 18 months and at the different storage temperatures tested.
• the dynamic viscosity was in a range of 8.3-10.7 mPas.
• the present example describes the storage stability of seven different 150 mg/mL risankizumab formulations. Trehalose and mannitol instead of sorbitol were used to adjust the tonicity. F2 was additionally analyzed after 18 months.
• UP-SEC showed that a pH of 6.0 compared to pH 5.7 leads in the tested formulations to a slightly larger degradation of risankizumab in form of lower monomer content and higher HMW.
• L-arginine HC1 containing formulations showed slightly lower degradation measured by UP-SEC but increased opalescence and slightly increased LMW contents.
• IEC showed no relevant differences between the formulations and were therefore not a decisive factor. The same applies to pH, protein concentration, osmolality, viscosity, break loose and gliding force, subvisible particles and visible particles. No differences between the formulations were seen by this data.
• the present example analyzes the storage stability of seven different 150 mg/mL risankizumab formulations in Neopak syringes to analyze the storage stability of the formulations and identify advantageous formulations.
• the tonicity was slightly modified. Three conditions were again tested (as identified above). The formulations analyzed are summarized in Table 17.
• Table 17 Composition of the analyzed formulations.
• the formulations were prepared by mixing the starting material with a concentrated spike solution (comprising the auxiliary agents, i.e. the excipients and buffers).
• a concentrated spike solution comprising the auxiliary agents, i.e. the excipients and buffers.
• Table 18 Measured HMW content in % of the UP-SEC analysis for long-term storage at 5°C, 25°C and 40°C. Results and discussion
• the HMW content remained overall low in all tested formulations indicating that the used formulations can stabilize risankizumab at high concentrations.
• the UP-SEC results further show that a pH of 6.0 compared to pH 5.7 leads to a larger degradation of risankizumab in form of lower monomer contents and higher HMW levels. Therefore, a pH of 5.7 is particularly advantageous for formulations according to the present disclosure. Nevertheless, also the formulations having a higher pH value of 6.0 such as F4, F5 and F6 showed overall good performance in view of the UP-SEC analysis results.
• Table 19 Measured LMW content in % of the UP-SEC analysis for long-term storage at 5°C, 25°C and 40°C.
• the tested formulations were stable over the measurement time for all tested temperatures. Therefore, high protein concentrations of 150 mg/mL risankizumab were effectively stabilized using the tested formulations. At higher storage temperature, a slight increase of LMW content was observed for L-arginine HC1 containing formulations. This is a surprising finding, as L-arginine containing formulations typically are known to further stabilize formulations. Hence, a formulation of 150 mg/mL risankizumab is different from other protein formulations in this respect. A formulation according to the present disclosure without arginine is therefore preferred.
• Table 20 Measured opalescence in FNU for long-term storage at 5°C, 25°C and 40°C.
• F2 was additionally analyzed after 18 months. Noteworthy, also formulations FI and F7 were stable. Buffer-free formulations and formulations comprising more than one type of tonicity agent were also stable and are thus suitable to provide a formulation comprising 150mg/mL risankizumab.
• formulation F2 was found to be particularly stable in respect to the measured LMW and HMW content, as well as opalescence, indicating a superior stability.
• This result was very surprising, as typically risankizumab is known to be used at higher pH values. Hence, the particularly high concentration of risankizumab shifts the optimal pH value to about 5.7, which was unexpected.
• L-arginine HC1 did not result in further stabilization but in fact reduced the stability of the formulations, supported by the higher opalescence and measured LMW content. Consequently, the particular properties of risankizumab at a high concentration, e.g. 150 mg/mL, necessitate different optimal conditions than formerly known formulations of risankizumab.
• the goal of the present example was to evaluate the influence of shaking stress on the product quality of different formulations at 150 mg/mL risankizumab. Different formulations were tested regarding their ability to stabilize risankizumab against shaking stress. Therefore, the formulation was exposed to different shaking stresses at the antibody concentration of 150 mg/mL.
• 11 risankizumab test formulations were prepared (see table 21) and subjected to: a) shaking of vials for 1, 5, 7, 14, 21 days in a horizontal shaker with 300 U/min (protected from light); b) shaking of syringes for 1, 5, 7, 14, 21 days in a rocking shaker, movement adjusted to respective viscosity to ensure air bubble movement (protected from light); and c) room temperature (25°C) for 1, 5, 7, 14, 21 days (protected from light).
• Table 21 Formulations chosen for shaking study.
• the formulations were added to vials (Schott) or Neopak syringes.
• the sterile filtered protein solutions were filled under laminar flow into the sterilized primary packaging materials.
• the filling volume for the vials was defined to be 3.6 mL.
• the syringes were filled with 1.04 mL each. All vials and syringes were inspected for visual particles and results were recorded.
• UV-Vis spectrophotometer Solo VPE Cone at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc., NJ, USA - Opalescence meter: HACH Lange opalescence meter; filter: 400-600 nm; Hach Lange
• Ultra performance size exclusion chromatography UPLC26, H-Class UV- detection at 280 nm Waters, Milford, MA
• IL-23 binding activity Biacore T200 Chip: CM5 GE Healthcare, Chalfont St Giles, UK pH-meter: SevenGo - Mettler Toledo, Columbus, OH
• Particel sizer Micro Flow ImagingTM Flow Microscope; By micro flow imaging (MFI); Brightwell Technologies Inc, Ottawa, ON, Canada
• Osmometer Osmomat 030 By freezing point depression, Gonotec GmbH, Berlin, Germany
• Monomer content is a key quality attribute of protein stability and quality during stress- induced storage.
• HP-SEC and UP-SEC were used to measure the monomer content of the formulations.
• Table 22 UP-SEC-Monomer in % of syringe and vial: Initial values and values after 1 / 5 / 7 / 14 / 21 days of shaking and after 21 days without movement at 25 °C. * corresponds to no movement, whereas the other samples were shaken for the indicated amount of time.
• HP-SEC and UP-SEC were used to measure the monomer content of the formulations.
• HP- SEC was used to determine levels of aggregate (HMW) formation during shaking of the syringes and vials.
• UP-SEC analysis
• Formulations containing L-arginine like F3 and F7 showed the lowest level of aggregation after 21 days of shaking.
• the differences in monomer content for the eleven formulations tested in this study observed in UP-SEC and HP-SEC are not significant.
• the loss of monomer content was in an acceptable range for all formulations being tested.
• the shaking does not significantly increase the HMW content in comparison to the results after 21 days without movement.
• the data obtained using the UP- SEC is summarized in Table 23.
• Table 23 UP-SEC HMW content in % of syringe and vial: Initial values and values after 1 / 5 / 7 / 14 / 21 days of shaking and after 21 days without movement at 25 °C. * corresponds to no movement, whereas the other samples were shaken for the indicated amount of time.
• HP-SEC analysis The trend of the data of the HP-SEC analysis are analogous to those of the UP-SEC and thus confirm these results.
• Opalescence, osmolality, pH-values and protein concentrations of all tested formulations remained essentially unchanged following 21 days of shaking for syringes on a horizontal shaker as well as for vials on a rocking shaker (see subsequent data).
• the lowest level of opalescence was observed in the buffer-free formulation Fll without any additional buffer like acetate or succinate. No observations could be made with regard to visual inspection. No significant difference can be observed by comparing the generated data of vials and syringes.
• Table 24 Shaking of formulations in syringe and vial: Initial values, values after 1 / 5 / 7 / 14 / 21 days of shaking and values after 21 days without (w/o) movement of opalescence, osmolality, pH-values and protein cone (shaking at room temperature). * corresponds to no movement, whereas the other samples were shaken for the indicated amount of time.
• the opalescence depends on the formulation composition and ranges from 5 FNU in an excipient-free or buffer-free respectively to 14 FNU, but did not significantly increase over time.
• the HP-SEC fragments contents remained essentially constant over the shaking time in vials and syringes.
• the fragments content was in a range of 0.3-0.5%.
• the UP-SEC LMW contents remained essentially constant over the shaking time in vials and syringes.
• the fragments content was in a range of 1.3-1.4%.
• formulations F3 and F7 showed highest monomer content (HP-SEC & UP-SEC) but they also showed the highest level of opalescence. It can be summarized that the formulations being tested in this study would be a viable formulation.
• Table 25 Overview of the experimental schedule ight gray shading: freeze; darker gray shading: thaw
• the freezing step was performed using a freeze-thaw setup provided by a classical freeze- dryer.
• the mini -bags with a sample volume of 12 mL were frozen controlled with a freezing ramp of 0.5°C/min to -40°C. At this point the temperature remained constant over sixteen hours to ensure complete freezing of the sample volume.
• the thawing step was performed according to the freezing step with a heating rate of 0.5°C/min.
• the hold time at room temperature was set to four hours.
• a complete freeze/thaw cycle (lx F/T) is defined as follows:
• a further formulation F12 was prepared which is excipient-free containing 0.02 % PS20, pH 5.7. 12 mL sterile filtered protein solutions were filled under laminar flow into the sterilized primary packaging materials, which are Mini Flexboy bags having a volume of 15 mL. All bags were inspected for visual particles and results were recorded.
• each freeze-thaw run twelve bags were put on each plate within the freeze-dryer. In total 36 bags were freeze/thawed each run including three bags per formulation. The bags were distributed in a defined scheme to eliminate influences of the bag position within the freeze- dryer.
• UV-Vis spectrophotometer Solo VPE Cone at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc., NJ, USA
• Ultra performance size exclusion chromatography UPLC26, H-Class UV- detection at 280 nm Waters, Milford, MA Charge heterogeneity by weak cation exchange chromatography (WCX): HPLC75; Fluorescence detection Extinction: 278 nm, Emission: 350 nm; Waters, Milford, MA IL-23 binding activity: Biacore T200 Chip: CM5 GE Healthcare, Chalfont St Giles, UK - pH-meter: SevenGo - Mettler Toledo, Columbus, OH
• Particel sizer Micro Flow ImagingTM Flow Microscope; By micro flow imaging (MFI); Brightwell Technologies Inc, Ottawa, ON, Canada
• Osmometer Osmomat 030 By freezing point depression, Gonotec GmbH, Berlin, Germany
• Monomer content is a key quality attribute of protein stability and quality during stress- induced storage.
• HP-SEC and UP-SEC was used to determine levels of aggregate formation during freeze/thaw of the mini-bags.
• the subsequent table summarizes the results of the HP- SEC & UP-SEC analytic.
• Table 26 HP-SEC / UP-SEC: Initial values and values after 1 / 3 / 6 F/T cycles and three weeks at 5°C in %.
• Opalescence, osmolality, pH-values and protein concentrations of all tested formulations remained unchanged following 6 F/T cycles and after storage at 5°C for three weeks. The lowest level of opalescence was observed in buffer-free formulations (FI 1 & F12).
• Table 27 Initial values and values after 1 / 3 / 6 F/T cycles of opalescence in FNU, osmolality in mOsm/kg, pH-values and protein cone in g/L.
• the results of the SPR (Biacore) measurements of the IL23 binding activity show that the freeze/thaw cycles do not influence the binding activity of the molecule.
• the binding activity ranges between 96- 117%.
• the subsequent table summarizes the number of particles for each STP. No clear trends could be observed for all formulations being tested.
• the formulations F3, F7 and F9 show a slightly increased amount of SVP in comparison to other formulations being tested. This observation was mainly seen for the SVP >2 pm and >10 pm.
• Table 28 Subvisible Particles - MFI: Initial values and values after one, three and six F/T cycles and three weeks at 5°C. Results and discussion
• Opalescence The opalescence depends on the formulation and ranges from 4 FNU in an excipient-free or buffer-free formulation to 13 FNU.
• Table 29 Composition of formulations.
• Measurements of the samples were performed at 1, 3, 6, 9, 12, 18, 24 and 36 months storage, as well as initially before storage.
• Various methods for analysis were used, including HIC, UP-SEC, IEC, as well as viscosity, break loose and gliding force and binding specificity measurements. Further details on the utilized analysis methods are described below.
• Table 31 UP-SEC-HMW measurements in % of the formulations having different pH- values.
• the LMW content was measured by UP-SEC analysis, which revealed following results: Table 32: UP-SEC-LMW-measurements in % of the formulations having different pH- values.
• Table 34 IEC measurements of APG in % of the formulations having different pH-values.
• Table 35 IEC measurements of BPG in % of the formulations having different pH-values. Uo°C 13 120 1 15 10 19 18 17
• HIC hydrophobic interaction chromatography
• Table 36 HIC measurements of the main peak in % of the formulations having different pH- values.
• Table 37 HIC measurements of pre-peaks in % of the formulations having different pH- values.
• Table 40 Specific binding activity in % of the formulations having different pH-values.
• the binding activity measurement show overall high values of the tested formulations.
• the tested formulations stabilize risankizumab such that a high binding activity at a pH range from 5.0 to 6.2 was achieved.
• the viscosity and the syringe forces were measured, which include the average and maximal gliding force, as well as the break loose force. Following results were obtained: Table 41: Measurement of the viscosity in mPas of the tested formulations having different pH-values over time. Table 42: Measurement of the maximal gliding force in N of the tested formulations having different pH-values over time.
• Table 43 Measurement of the average gliding force in N of the tested formulations having different pH-values over time.
• Formulations containing different concentrations of acetate were stored over different time points at three different temperatures (5°C, 25°C and 40°C).
• Table 45 Composition of formulations.
• Measurements of the samples were performed at 1, 3, 6, 9, 12, 18, 24 and 36 months storage, as well as initially before storage.
• the storage temperatures were adjusted to 5°C, 25°C or 40°C.
• Analytics were performed by measurement using an UP-SEC for monomer, HMW and LMW content and Biacore for the binding activity.
• the required forces for gliding and break loose force were measured, as well as the osmolality, opalescence and the pH value. Further details on the utilized analysis methods are described below.
• the monomer measurements show that the formulation is stable over a range of acetate contents, indicating stability for buffer containing and buffer-free formulations with 150 mg/mL risankizumab and formulations according to the present example.
• Table 47 UP-SEC-HMW measurements in % of formulations comprising varying amounts of acetate.
• the HMW content measurements show that the formulation is stable over a range of acetate contents, indicating stability for buffer containing and buffer-free formulations with 150 mg/mL risankizumab and formulations according to the present example.
• Table 48 UP-SEC -LMW-measurements in % of formulations comprising varying amounts of acetate.
• the LMW measurements show that the formulation is stable over a range of acetate contents, indicating stability for buffer containing and buffer-free formulations.
• Table 49 Osmolality in mOsm/kg of the formulations at different temperatures and storage times of formulations comprising varying amounts of acetate.
• the measurements show that the osmolality varies from about 290 to 338 mOsm/kg depending on the amount of added acetate. The more acetate was added, the higher the measured osmolality. An osmolality of approximately 310 mOsm/kg is typically desired and an acetate concentration of 10 mM resulted in the tested formulations in a desired osmolality of around 310 mOsm/kg (measured range from 305 to 314 mOsm/kg).
• the opalescence of the formulations of the present example was also measured to evaluate the stability.
• the measured opalescence is overall the same for the different formulations ranging between 4-9 FNU. Higher concentrations of acetate led to a slightly higher opalescence of 7- 9 FNU for 20 mM acetate than lower concentrations (4-6 FNU for 0 mM acetate). All formulations according to the present example were stable in view of the measured opalescence. 8.3.7. Measurement of pH
• the measurements of the pH value demonstrate that the pH is overall kept constant for the tested formulations according to the present example. Therefore, for all acetate contents, including a formulation comprising no acetate, the formulations were stable regarding the pH value.
• Table 51 Maximum gliding force in N, initially and after the indicated storage time at 5°C, 25°C or 40°C of formulations comprising varying amounts of acetate.
• Table 52 Average gliding force in N, initially and after the indicated storage time at 5°C, 25°C or 40°C of formulations comprising varying amounts of acetate.
• Table 53 Break loose force in N, initially and after the indicated storage time at 5°C, 25°C or 40°C of formulations comprising varying amounts of acetate.
• the HIC main peak content remained constant over 24 months at 5°C in a range of 96.8-97.2%, as well as 1.4-1.7% pre peak and 1.5-1.9% post peak. Over 36 months at 5°C HIC main peak contents in a range of 96.3-97.2% were obtained, as well as 1.4- 1.7% pre peak and 1.5-2.2% post peak. At 25°C for up to 12 months storage time main peak contents between 94.3-97.1% were obtained, as well as 1.4-3.0% pre peak and 1.5-2.7% post peak. At 40°C for up to 3 months storage time main peak contents between 92.0-97.1% were obtained, as well as 1.4-4.6% pre peak and 1.5-3.4% post peak. No differences between the formulations were observed regarding the main peak, pre peak and post peak.
• the dynamic viscosity remained essentially constant up to a storage time of 24 and 36 months at the different storage temperatures tested.
• the dynamic viscosity was in a range of 8.9-10.0 mPas.
• Formulations were prepared (see Table 54) wherein the PS20 (polysorbate 20) content was varied from 0, 0.05, 0.075, 0.1, 0.2, 0.3 to 0.5 mg/mL and analyzed during shaking times of 0, 1, 5, 7, 14 and 21 days.
• Table 54 Composition of formulations.
• the formulations were prepared as described above.
• the formulations were packaged in 2R vials (1.0 mL) or pre-filled syringes (PFS, Neopak, 1.0 mL) for each formulation, as well as for the control and non-shaken formulations.
• Table 55 Opalescence in FNU of the formulations having varying amounts of PS20 in syringes.
• Table 56 Opalescence in FNU of the formulations having varying amounts of PS20 in vials.
• the prepared formulations (see Table 54) were analyzed over different time points stored at three different temperatures (5°C, 25°C and 40°C).
• Measurements of the samples were performed at 1, 3, 6, 9, 12, 18, 24 and 36 months storage, as well as initially before storage.
• UP-SEC analysis was performed in order to determine the monomer, HMW and LMW contents.
• sub-visible particle content, gliding force and break loose force were measured. Further details on the utilized analysis methods are described below.
• the monomer measurements show that the formulation is stable over a range of PS20 contents. Particular high monomer values were obtained for PS20 contents around 0.2 mg/mL.
• Table 59 UP-SEC -LMW-measurements in % of formulations comprising varying amounts of PS20.
• the LMW content correlates with the monomer measurements. Overall, the tested formulations were stable over a range of PS20 contents. Particular low increases of the LMW contents were obtained for PS 20 contents of 0.2 mg/mL. The lowest tested PS20 content (see FI) appears to have led to slightly higher LMW values.
• Table 61 Measurement of the sub-visible particle content of particles with a size of >2, >10 and >25 pm stored for up to 24 and 36 months at 5°C of formulations comprising varying amounts of PS20.
• Table 62 Maximal gliding force in N.
• the formulations comprised varying amounts of PS20.
• Table 63 Average gliding force in N.
• the formulations comprised varying amounts of PS20.
• Table 64 Break loose force in N.
• the formulations comprised varying amounts of PS20.
• the specific binding activity remained essentially constant up to a storage time of 24 and 36 months at the different storage temperatures tested.
• the specific binding activity was in a range of 97-101%.
• the protein concentration remained essentially constant up to a storage time of 24 and 36 months at the different storage temperatures tested. Small deviations of protein concentration are due to analytical variations, leading to ranges of 147-155 mg/mL (24 months) and 147-159 mg/mL (36 months).
• the dynamic viscosity remained essentially constant up to a storage time of 24 and 36 months at the different storage temperatures tested.
• the dynamic viscosity was in a range of 9.2-11.0 mPas.
• the tested formulations were stable over long term storage up to 24 and 36 months at temperatures ranging from 5°C up to 40°C.
• formulations comprising a surfactant such as PS20 were found to be stable, whereas formulation lacking PS20 showed some formation of sub-visible particles and an increase in opalescence.
• the LMW content was slightly increased for formulations lacking PS20.
• a particularly suitable content of a surfactant such as the non-ionic surfactant PS20 appeared to be 0.2 g/L under the tested conditions.
• the trehalose concentration was varied from 145, 165, 185, 205 to 225 mM and analyzed over different time points stored at three different temperatures (5°C, 25°C and 40°C).
• the prepared formulations are shown in Table 65.
• Table 65 Composition of formulations. 3.1. Analytics
• Table 66 UP-SEC-Monomer-measurements in % of formulations comprising different amounts of trehalose.
• the monomer measurements show that the formulation is stable over a range of trehalose contents, indicating stability over a range of trehalose contents.
• the HMW content measurements show that the formulation is stable over a range of trehalose contents.
• Table 68 UP-SEC-LMW-measurements in % of formulations comprising different amounts of trehalose.
• the LMW measurements show that the formulation is stable over a range of trehalose contents.
• the binding activity of the risankizumab comprised in the formulations according to the present disclosure was measured.
• the measurements of antigen binding show high binding activity to IL-23 for all tested formulations ranging from 92-122% binding activity and 96- 100% specific binding activity.
• Table 69 Measured osmolality in mOsm/kg of the formulations comprising varying amounts of trehalose.
• the osmolality values range from around 245 to 380 mOsm/kg for trehalose concentrations from 145 to 225 mM. As an optimal osmolality is around 310 mOsm/kg, it can be advantageous to provide formulations having such osmolality. This can for instance be achieved using a trehalose concentration of 185 mM in combination with the formulation according to the present example.
• the HIC main peak content remained constant over 24 months at 5°C in a range of 96.4-97.4%, as well as 1.4-1.8% pre peak and 1.2-2.0% post peak. Over 36 months at 5°C HIC main peak contents in a range of 96.0-97.4% were obtained, as well as 1.4- 1.8% pre peak and 1.2-2.3% post peak. At 25°C for up to 12 months storage time main peak contents between 94.2-97.4% were obtained, as well as 1.4-3.0% pre peak and 1.2-2.8% post peak. At 40°C for up to 3 months storage time main peak contents between 90.3-97.4% were obtained, as well as 1.4-5.9% pre peak and 1.2-3.7% post peak. No differences between the formulations were observed regarding the main peak, pre peak and post peak.
• the protein concentration remained essentially constant up to a storage time of 24 and 36 months at the different storage temperatures tested. Small deviations of protein concentration are due to analytical variations, leading to ranges of 145-153 mg/mL (24 months) and 148-158 mg/mL (36 months).
• the opalescence remained essentially constant up to a storage time of 24 and 36 months at the different storage temperatures tested.
• the opalescence was in a range of 5-9 FNU.
• a particularly suitable formulation comprises the following compounds: - 150 mg/mL risankizumab,
• this formulation was clear to slightly opalescent and essentially free of foreign particles.
• the osmolality was about 310 mOsm/kg.
• the formulation is particularly suitable for injection, especially for subcutaneous injection. Moreover, a viscosity of about 9.6 mPas was measured, making it suitable for injection using a syringe.
• the conductivity at 20°C was about 1.53 mS/cm, the density at 20°C was about 1.067 g/cm 3 and the density at 4°C was about 1.071 g/cm 3 .
• This 150 mg/ml risankizumab formulation may be provided as follows:

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