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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• Onapristone is an anti-progestin drug and progesterone receptor antagonist which was originally developed for potential contraceptive use and the use in benign
• gynecological disorders such as the treatment of uterine leiomyomas.
• ONA binds to the progesterone receptor (PR), preventing the PR from binding to DNA and thereby inhibiting or eliminating PR-induced DNA transcription.
• PR progesterone receptor
• Klijn et al Progesterone antagonists and progesterone receptor modulation in the treatment of breast cancer, Steroids, v. 65, pp. 825-830 (2000); Jonat et al., The clinical efficacy of progesterone antagonists in breast cancer, Endocrine Therapy of Breast Cancer, pp. 117-124.
• Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- induced DNA transcription.
• PR progesterone receptor
• Onapristone anti-cancer activity is documented in multiple pre-clinical models and clinical studies in patients with hormone therapy-naive or tamoxifen-resistant breast cancer. Despite promising activity in breast cancer models, the development of onapristone as an oncology drug was terminated due to liver function test abnormalities. See, e.g., Robertson et al, Eur J Cancer. 35(2):214-8 (Feb.
• PRA and PRB nuclear receptor proteins
• both PR isoforms are expressed and are required to mediate the physiological effects of progestin ligands [Mote 2002, Arnett-Mansfield 2004].
• the two PR isoforms have both been detected in malignant tissues, such as breast, endometrial, ovarian and prostate cancers [Cottu 2015].
• ONA is a type I antiprogestin which prevents PR monomers from dimerizing, inhibits ligand-induced phosphorylation, prevents association of the PR with its co-activators, and thus prevents PR-mediated DNA transcription. ONA does not allow the PR complex to bind to DNA, does not or minimally modulates PR-mediated genes, and inhibits ligand-induced PR
• APR Transcriptionally activated PR
• IHC immunohistochemistry
• onapristone was provided to patients with cancer (e.g., breast, endometrial, others) in an immediate release formulation of 100 mg and provided QD (once per day).
• Onapristone has also been given to patients in endocrinology studies, at immediate release doses of 1 and 10 mg doses resulting in a dose-dependent effect of onapristone on suppression of gonadotrophin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) secretion. Cameron 2003.
• these studies used immediate release formulations of onapristone of unknown purity.
• these studies addressed the dose and formulation of onapristone suitable for potential contraceptive use rather than the dose and formulation suitable for treating a disease such as cancer.
• extended-release pharmaceutical compositions comprising onapristone as the active ingredient in an amount from about 2 mg to about 100 mg.
• the extended-release pharmaceutical compositions (also referred to herein as ER formulations) further comprise excipients suitable for the desired dosage form (e.g., tablet, capsule, etc.) and for delaying the release of the active ingredient.
• onapristone ER formulations utilizing highly purified onapristone (e.g., at least about 98%).
• the ratio of onapristone to inactive excipients in the ER formulations is about 0.05 to about 5%.
• the AUC (area under the curve) of onapristone is at least about 1578 ng*h/ml over about an 8-12 hour period after administration of a 10 mg dose BID (i.e., twice per day) to a patient.
• the Cmax (maximum plasma concentration) of onapristone is at least about 240 ng/ml over about an 8-12 hour period after administration of a 10 mg dose BID to a patient.
• a steady state plasma concentration of onapristone is achieved at about 8 days following the initial dose of the extended release onapristone pharmaceutical composition.
• the extended-release onapristone pharmaceutical composition comprises at least about 10 mg to about 50 mg of onapristone.
• Figure 1 shows the exemplary Cmax (maximum active ingredient concentration) levels per ONA dose level (10 mg, 20 mg, 30 mg, 40 mg, 50 mg extended-release BID (twice per day) and 100 mg QD (once per day));
• Figure 2 shows the exemplary AUC (area under the curve) per ONA dose level (10 mg, 20 mg, 30 mg, 40 mg, 50 mg extended-release formulations BID (twice per day) and 100 mg QD (once per day));
• Figure 3 shows the exemplary accumulation of ONA over time per ONA dose level (10 mg, 20 mg, 30 mg, 40 mg, 50 mg extended-release formulations BID (twice per day) and 100 mg QD (once per day)); and
• Figures 4A and 4B show exemplary ONA plasma levels over time per dose levels for the extended-release formulations BID ( Figure 4 A) and the 100 mg formulation QD.
• onapristone ER formulations comprise onapristone (ONA)
• ER formulations of onapristone are provided.
• extended release refers to a pharmaceutical compositions or drug formulation that is administered to a patient and has a mechanism to delay the release an active ingredient (i.e., drug).
• ER pharmaceutical compositions include the active ingredient (e.g., onapristone) and excipients that delay release of the active ingredient (e.g., hydroxypropyl methylcellulose, ethyl cellulose, Eudragit® (Evonik Industries) sustained release formulations (polymethacrylates),
• IR immediate release
• Exemplary extended release formulations are provided, for example, in Table 4 herein.
• the terms “treat,” “prevent,” or similar terms, as used herein, do not necessarily mean 100% or complete treatment or prevention. Rather, these terms refer to various degrees of treatment or prevention of a particular disease (e.g., 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1%) as recognized in the art as being beneficial.
• treatment or
• prevention also refer to delaying onset of a disease for a period of time or delaying onset indefinitely.
• treatment or “treating” refers to administering a drug or treatment to a patient or prescribing a drug to a patient where the patient or a third party (e.g., caretaker, family member, or health care professional) administers the drug or treatment
• One aspect provides an extended-release pharmaceutical composition comprising onapristone wherein onapristone is present in an amount from about 2 mg to about 50 mg.
• Onapristone can be provided, for example, in quantities of 2 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 37.5 mg, and 50 mg in any suitable extended release formulation (e.g., formulations of Table 4) multiple times per day (e.g., twice per day) or once per day.
• ER formulations can include excipients that delay the dissolution of the tablet and the subsequent release of onapristone into the gastrointestinal track which then is absorbed into the bloodstream of a patient over time thereby reducing the C max concentration compared to an IR formulation.
• a similar release profile can be achieved through the use of an osmotic tablet or a tablet film coated with a polymer that results in an extended release profile of the tablet.
• onapristone ER formulations can be provided in any suitable dosage form (e.g., tablet, capsule, etc.) with a total weight of active ingredients plus excipients ranging from about 50 mg to 400 mg.
• the tablet can be a matrix tablet, film coated tablet or osmotic pump.
• onapristone ER formulations can be administered to a patient in need of treatment with onapristone once per day, twice per day (BID), or more to achieve the desired dose of onapristone.
• the ratio of onapristone to inactive excipients in the onapristone ER formulation is about 0.05 (e.g., Table 4) to about 5%.
• ER formulations wherein the AUC of onapristone following the administration of 10 mg of the onapristone ER formulation to a patient BID is at least about 1578 ng*h/ml over about 8-12 hours.
• the time period can vary by about plus or minus two hours.
• Another aspect provides onapristone ER formulations where the Cmax of onapristone following the administration of 10 mg of the onapristone ER formulation to a patient BID is at least about 240 ng/ml over about 8-12 hours. In one aspect, the time period can vary by about plus or minus two hours.
• Another aspect provides onapristone ER formulations where a steady state plasma concentration of onapristone is achieved at about 8 days following the administration of the onapristone ER formulations to a patient twice a day (BID).
• Further aspects provide methods of administering onapristone to a patient comprising administering an onapristone ER formulation twice per day (BID) to a cancer patient, where the onapristone ER formulation comprises of at least about 10 mg to about 50 mg of onapristone.
• the ER formulation is administered once per day.
• the onapristone in the onapristone ER formulation is at least about 98% pure.
• the onapristone administered to a patient it at least about 98% pure.
• onapristone in the onapristone ER formulations can be provided, for example, in quantities of 2 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 37.5 mg, and 50 mg.
• the onapristone ER formulations can be administered twice per day (BID) to a human subject in need of treatment, where the onapristone ER formulation comprises of at least about 10 mg to about 50 mg of onapristone.
• the ER formulation is administered once per day.
• the disorder is selected from the group consisting of breast cancer, endometrial cancer, prostate cancer, ovarian, uterine endometrioid cancers, and other types of cancer which express the PR.
• the onapristone ER formulation is administered to a human subject having a disorder capable of treatment with onapristone wherein the the AUC of onapristone following the administration of 10 mg of the onapristone ER formulation to a patient BID is at least about 1578 ng*h/ml over about 8-12 hours.
• the time period can vary by about plus or minus two hours.
• the onapristone ER formulation is administered to a human subject having a disorder capable of treatment with onapristone by administering an onapristone ER formulation to the subject twice per day (BID) where the Cmax of onapristone in the human subject is at least about 240 ng/ml over about 8-12 hours.
• BID twice per day
• the onapristone ER formulation is administered once per day.
• the time period can vary by about plus or minus two hours.
• an onapristone ER formulation is administered to a human subject having a disorder capable of treatment with onapristone twice per day (BID) where a steady state plasma concentration is achieved at about 8 days.
• BID onapristone twice per day
• PK results for onapristone are available for 52 patients from the a first study (ARN- AR18-CT-101) (Table 1). Variability for onapristone PK is moderate and greater for the IR versus the ER formulation.
• Onapristone Cmax and AUC values for the ER form are proportional to administered dose ( Figures 1 and 2). Based on observed mean AUC values, oral
• bioavailability for the ER versus the IR formulation is approximately 50% (Figure 24).
• a later Tmax value for the ER form results in somewhat lower dose-corrected Cmax values for the ER form compared to the IR form.
• Steady state is attained before day 8 with a mean t1 ⁇ 2 of 7.5 hrs.
• Table 1 compares descriptive statistics for the primary onapristone pharmacokinetic exposure parameters following single oral doses from 10 to 50 mg of extended -release onapristone compared to that from 100 mg immediate -release onapristone (Study ARN-AR18- CT-101). Exposure following ER onapristone appears later than that for IR onapristone, consistent with extended release formulations. However, the extended-release aspects are not reflected in the overall duration of exposure. Although study size is small, onapristone exposure generally increases in proportion to ER onapristone dose. Exposure at 50 mg ER onapristone is approximately 20-50% that of 100 mg IR onapristone depending on the formulation. Variability in these parameters is similar for both formulations and across ER onapristone dose levels.
• PK results are available in 19 patients from a second study (ARN-AR18-CT- 102) and show linear dose relationships for C max and AUC (Table 2) following single oral doses from 10 to 50 mg of extended -release onapristone.
• the ER formulation appears to be performing according to the dose release specifications with a t 1 ⁇ 2 of approximately 8 hours and a T max of approximately 3-4 hours. Steady state is also achieved within 8 days in this study. Day 29 and 57 data indicate no evidence of accumulation over time, once steady state is reached.
• Onapristone exposure generally increases less than proportionally with the ER onapristone dose formulation. Variability in these parameters is similar across ER onapristone dose levels.
• Figures 1 and 2 show the results of an exemplary comparison of the relative systemic onapristone exposure following single oral doses from 10 to 50 mg of extended release onapristone compared to that from 100 mg immediate -release onapristone (Study ARN-AR18- CT-101).
• Onapristone exposure assessed by Cmax ( Figure 1) and AUC ( Figure 2), increases linearly across the ER onapristone dose range and is lower than that for IR onapristone at all ER dose levels.
• the ER onapristone formulations provided clinical benefit to patients despite lower onapristone exposure.
• Figure 3 shows the results of an exemplary comparison of the degree of onapristone accumulation following twice-daily oral doses from 10 to 50 mg of extended -release
• Figures 4A and 4B show exemplary plasma onapristone concentration-time profiles for individual subjects following single oral doses of 50 mg extended -release onapristone compared to that from 100 mg immediate -release onapristone (Study ARN-AR18-CT-101).
• the profiles for ER onapristone generally reach maximum concentrations more slowly than those for
• IR onapristone supporting the extended release of drug from the ER formulation. Concentrations at all dose levels of ER onapristone are generally lower than those for 100 mg IR onapristone. Surprisingly, as disclosed herein, the ER onapristone formulations provided clinical benefit to patients despite lower onapristone exposure.
• Clinical benefit responses defined as RECIST 1.1 partial response or stable disease for at least 24 weeks, were seen only in patients receiving ER. Of interest, 7/9 of the patients with clinical benefit (78%) received doses below the established lOOmg IR dose and the patient with a partial response was treated at the lowest ER dose level, lOmg BID.
• Table 4 provide exemplary onapristone extended release formulations.
• the tablets can be provided to a patient alone or in any desired combination to achieve the desired dose.
• Onapristone extended-release formulations can be prepared by the following exemplary method:
• Step 1 De-lump onapristone drug substance by milling or by passing through a wire screen followed by further passing the resulting de-lumped onapristone through a wire screen of appropriate mesh size (e.g., 425 or 710 microns).
• appropriate mesh size e.g., 425 or 710 microns.
• Step 2 Screen the colloidal silicon dioxide and approximately half of the
• pregelatinized starch separately through a screen of appropriate mesh size (e.g., 425 or 710 microns) into a stainless steel blending container.
• appropriate mesh size e.g. 425 or 710 microns
• the previously-screened onapristone drug substance from Step 1 is added to this blend.
• Step 3 The mixture is blended and screened through a screen of appropriate mesh size (e.g., 425 or 710 microns).
• Step 4 The remaining pregelatinized starch is screened through a screen of appropriate mesh size (e.g., 425 or 710 microns) into the stainless steel blending container (from Step 2). The previously screened mixture from Step 3 is added to the container.
• appropriate mesh size e.g. 425 or 710 microns
• Step 5 The mixture is blended to achieve a homogenous mix.
• Step 6 Approximately half of the microcrystalline cellulose, half of the lactose monohydrate and half of the hydroxypropyl methylcellulose are separately screened into a larger stainless steel blending container through a screen of appropriate mesh size (e.g., 425 or 710 microns). The blend from Step 5 is added to this container, and the remaining microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose are screened into the container through a screen of appropriate mesh size (e.g., 425 or 710 microns).
• a screen of appropriate mesh size e.g., 425 or 710 microns
• Step 7 The mixture is blended further to achieve a homogeneous mix.
• Step 8 The mixture from Step 7 is co-screened with magnesium stearate through a screen of appropriate mesh size (e.g., 425 or 710 microns) into the container from Step 4.
• appropriate mesh size e.g., 425 or 710 microns
• Key exclusion criteria included significantly impaired liver or kidney function, creatinine clearance lower than 60 mL/min, total bilirubin > upper limit of normal (ULN), alkaline phosphatase > ULN (or > 2.5 x ULN with liver or > 5 x ULN with bone metastases), ALT/AST > ULN (or > 2.5 x ULN with liver metastases), QTcF > 480 msec, chronic inflammatory liver condition, severe concomitant disease, uncontrolled brain metastases, inadequate washout from previous therapy, inability to swallow or absorb tablets, use of inhibitors, inducers or substrates of CYP3A4, or use of progestin-based hormone replacement therapy.
• ONA tablets can be by standard pharmaceutical chemistry purification methods by those skilled in the art. ER formulation with release kinetics from 10-12 hours depending on tablet dose. The original study design included a 20-patient expansion component. An 8-week dose-limiting toxicity (DLT) observation period was utilized to characterize thoroughly the safety profile, as previous ONA studies demonstrated a spike in the LFTs at approximately 6 weeks of treatment.
• DLT dose-limiting toxicity
• UPLC-MS/MS ultra-performance liquid chromatography with tandem mass spectrometry detection
• Taplin ME Manola J, Oh W et al. A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. J Compil BJU Int 2008; 101 : 1084-1089.
• Thigpen JT Brady M, Alvarez R et al. Oral Medroxyprogesterone Acetate in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Dose-Response Study by the Gynecologic Oncology Group. J Clin Oncol 1999; 17: 1736-1744.
• Yin P Lin Z, Reierstad S, et al. Transcription Factor KLF11 Integrates Progesterone Receptor Signaling and Proliferation in Uterine Leiomyoma Cells. Cancer Res 2010; 70(4); 1722-30.

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