Patent Application
20120004307
The present application relates to therapeutic methods and, in particular, to oral therapeutic methods for treating ischemic diseases and conditions associated with such diseases, such as digital ischemic lesions.
In one embodiment, the present invention relates to a method of treating a digital ischemic lesion and/or ameliorating or reducing at least one symptom and/or a functional deficit associated with a digital ischemic lesion: comprising orally administering to a subject in need thereof a formulation comprising an effective amount of treprostinil or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to a method of treating a disease or condition selected from Raynaud's disease, scleroderma, including systemic sclerosis, and a combination thereof, comprising orally administering to a subject in need thereof a formulation comprising an effective amount of treprostinil or a pharmaceutically acceptable salt thereof.
The application file contains at least one drawing executed in color. Copies of this patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
ACA stands for anti-centromere autoantibody.
ATA stands for anti-topoisomerase autoantibody.
AUC stands for area under the curve.
BID means twice (two times) a day.
CHFS stands for CHFS stands for Cochin Hand Function Scale.
CLI stands for critical limb ischemia.
DU stands for digital ulcer(s).
ERA stands for endothelin receptor antagonist.
MTD stands for maximum tolerated dose.
PAD stands for periphepheral arterial disease.
PAH stands for pulmonary arterial hypertension.
PDEI or PDI stands for a phosphodiesterase inhibitor.
SF-36 stands short form-36 (Quality of Life Instrument).
SF-MPQ stands for Short Form McGill Pain Questionnaire.
SHAQ stands for Scleroderma Health Assessment Questionnaire.
SHAQ VAS stands for Scleroderma Health Assessment Questionnaire visual analog scale.
SSc stands for scleroderma (systemic sclerosis).
VAS stands for visual analogue scale or score.
Unless otherwise specified, “a” or “an” means “one or more”.
An oral formulation comprising treprostinil or a pharmaceutically acceptable salt thereof preferably includes a diethanolamine salt of treprostinil (treprostinil diethanolamine). The formulation may be effective for treating an ischemic disease or condition, such as scleroderma, including systemic sclerosis, or Raynaud's Phenomenon. The oral formulation comprising treprostinil diethanolamine may be also effective for treating one or more digital ischemic lesions, such as a digital ulcer or a necrotic lesion, ameliorating or reducing at least one symptom and/or functional deficit associated with a digital ischemic lesion. The term “digital ischemic lesion” refers to a lesion on a digit, i.e. a toe or a finger, of a subject, such as a human being. In many embodiments, the digital ischemic lesion may be caused by or associated with an ischemic disease or condition, such as scleroderma, including systemic sclerosis, or Raynaud's Phenomenon. The symptom that may be ameliorated and/or reduced may be, for example, a pain associated with a digital ischemic ulcer and/or scleroderma. In some embodiments, administering the oral formulation comprising treprostinil diethanolamine may provide amelioration or reduction of one or more functional deficits associated with a digital ischemic lesion. For example, in some embodiments, the formulation may provide amelioration or reduction in a hand function deficit, i.e. provide an improvement in the hand function of the treated subject.
In some embodiments, the treated subject may have a particular profile or status with respect to one or more antibodies associated with scleroderma and/or systemic sclerosis. For example, the treated subject may be a subject with a negative status with respect to one or more antibodies associated with scleroderma and systemic sclerosis or a subject with a positive status with respect to one or more antibodies associated with scleroderma and/or systemic sclerosis. Examples of antibodies associated with scleroderma and/or systemic sclerosis include, but not limited to, anti-endothelial cell antibodies, antifibroblast antibodies, anti-matrix metalloproteinase antibodies, and antifibrillin-1 antibodies; antinuclear antibodies, such as antitopoisomerase-I antibodies, anticentromere antibodies and antihistone antibodies; antinucleolar antibodies, such as anti-polymyositis/scleroderma antibodies, anti-Th/To antibodies, anti-U3-small nucleolar ribonucleoprotein particle antibodies, anti-U1-small nuclear ribonucleoprotein particle antibodies, anti-RNA polymerase antibodies, and anti-B23 antibodies; antiphospholipid antibodies, antineutrophil cytoplasmic antibodies, and antimitochondrial antibodies, see e.g. Chung and Utz, Current Rheumatology Reports 2004, 6:156-163, which is incorporated herein by reference in its entirety.
In some embodiments, the treated subject may be a subject with a negative anti-centromere autoantibody (ACA) status. In such a case, administering the oral formulation comprising treprostinil diethanolamine may reduce a net burden in the subject associated with the digital ulcer.
In some embodiments, oral administration of a formulation comprising treprostinil diethanolamine may provide at least one of the following favorable effects: a) increase digital perfusion in the subject, to whom the formulation is administered; b) increase digital skin temperature in the subject. For example, in some embodiments, the oral administration of the treprostinil diethanolamine formulation may increase digital perfusion in a human being to at least 200 units or at least 250 units from a starting value of below 180 units or below 160 units before the administering. The oral administration of the treprostinil diethanolamine formulation may increase a digital skin temperature in a human being to at least 29° C. or at least 29.5° C. or at least 30° C. or at least 30.5° C. from a value of below 28° C. or below 27.5° C. or below 27° C. or below 26.5° C. prior to the administering.
In some embodiments, oral administration of the treprostinil diethanolamine formulation may allow sustaining in the subject for at least 4 hours or for at least 6 hours or for at least 8 hours or at least 10 hours or at least 12 hours at least one of the following favorable effects: a) increase level of digital perfusion to whom the formulation is administered; b) increased digital skin temperature. For example, in some embodiments, the oral administration of the treprostinil diethanolamine formulation may allow sustaining a digital perfusion in a human being at least 200 units or at least 250 units for at least 4 hours or for at least 6 hours or for at least 8 hours or at least 10 hours or at least 12 hours. In some embodiments, the oral administration of the treprostinil diethanolamine formulation may allow sustaining a digital skin temperature in a human being to at least 29° C. or at least 29.5° C. or at least 30° C. or at least 30.5° C. for at least 4 hours or for at least 6 hours or for at least 8 hours or at least 10 hours or at least 12 hours.
Treprostinil is a chemically stable analog of prostacyclin, and as such is a potent vasodilator and inhibitor of platelet aggregation. The sodium salt of treprostinil, (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid monosodium salt, is sold as a solution for injection as Remodulin® which has been approved by the Food and Drug Administration (FDA) for treatment of pulmonary hypertension.
Treprostinil was first described in U.S. Pat. No. 4,306,075. U.S. Pat. Nos. 6,765,117 and 6,809,223 disclose stereoselective process for treprostinil synthesis. US patent application publication no. 2009/0163738 discloses an alternative process for preparation treprostinil. U.S. Pat. Nos. 7,384,978, 7,417,070 and 7,544,713 disclose oral forms of treprostinil. U.S. patent application publication no. 2010-0282622 discloses solid formulations of treprostinil. US application no. 13/151,465 filed Jun. 2, 2011 discloses an alternative process for preparation treprostinil.
The oral formulation comprises the diethanolamine salt of treprostinil (treprostinil diethanolamine). The diethanolamine salt of treprostinil can be in an amorphous or a crystalline state. In the crystalline state, the diethanolamine salt of treprostinil can have two polymorphs, with two forms, A and B, which are disclosed in U.S. Pat. Nos. 7,384,978, 7,417,070 and 7,544,713. In some embodiments, form B of treprostinil diethanolamine as disclosed in U.S. Pat. Nos. 7,384,978, 7,417,070 and 7,544,713 may be preferred. In many embodiments, the oral formulation may be in a dosage form, such as a tablet or a capsule. In some embodiments, the oral formulation may be in a form of a liquid or a suspension.
In some embodiments, the oral formulation may be a sustained release oral formulation, such as a sustained release osmotic formulation. The sustained release formulation may release treprostinil diethanolamine for at least 4 fours or at least 6 hours or at least 8 hours or at least 10 hours or at least 12 hours. In some embodiments, the sustained release formulation may allow sustaining a therapeutically effective concentration of treprostinil in a blood of the subject at least 4 fours or at least 6 hours or at least 8 hours or at least 10 hours or at least 12 hours. Treprostinil diethanolamine sustained release formulations, such as sustained release tablets and sustained release capsules, and methods of their making are disclosed, for example, in U.S. Pat. Nos. 7,384,978, 7,417,070 and 7,544,713.
The oral formulation preferably contains an effective amount treprostinil diethanolamine, i.e. an amount that allows to achieve a desired therapeutic effect. Besides treprostinil diethanolamine, the oral formulation may contain an appropriate oral excipient or an oral pharmaceutically acceptable carrier. Examples of appropriate oral excipients include, but not limited to, maltodextrin, sodium lauryl sulfate, magnesium stearate and/or xylitol.
In some embodiments, the oral formulation may contain at least 0.1 mg, or at least 0.2 or at least 0.5 mg or at least 1.0 mg of treprostinil diethanolamine.
In some embodiments, the oral formulation may contain at least 2 mg of treprostinil diethanolamine. In many embodiments, the oral formulation may contain more than 2 mg of treprostinil diethanolamine, such as up 4 mg of treprostinil diethanolamine. The use of such higher dose formulations may allow limiting the number of administering events to 3 or less or 2 or less per day, while still achieving the desired therapeutic effect.
In some embodiments, a daily dose of treprostinil diethanolamine may be from 0.1 mg to 20 mg or from 0.25 to 16 mg per day or any dose in between. In some embodiments, treprostinil diethanolamine may be administered 4 times per day or 3 times per day or twice per day or once per day.
The present invention can be illustrated in more detail by the following example, however, it should be understood that the present invention is not limited thereto.
Raynaud's phenomenon (RP) and a small vessel obliterative vasculopathy in systemic sclerosis (SSc) frequently lead to ischemic digital ulcers (DU).
Prior studies have demonstrated a therapeutic effect of IV prostacyclin analogs for ischemic DU, but oral prostacyclin analogs have had limited success; the lack of sustained plasma concentrations, particularly with immediate release oral prostacyclin analogues, may have limited the ability of prostanoids to produce sustained benefits in these earlier studies. Treprostinil diethanolamine (UT-15C) is an innovative salt form of the prostacyclin analog treprostinil for oral delivery as a sustained-release (SR) osmotic tablet.
During a phase I PK trial of oral treprostinil in SSc patients, the goal was to quantify changes in perfusion as assessed by laser Doppler imaging (LDI) and to determine whether improvements in perfusion correlated with drug concentration.
10 SSc patients with recent or active DU participated in the study.
Dosing: Oral treprostinil titrated up to 4 mg twice daily (BID) as tolerated over 6-8 weeks. Pharmokinetics (PK) and laser Doppler imaging (LDI) assessments: performed when subjects achieved the 2 mg and 4 mg (or maximally tolerated dose) doses. Subjects who did not reach a dose of 2 mg BID during the study had assessments performed only at the end of study visit. 8 serial measures of digital perfusion and drug concentration were obtained over 12 hours at each of the 2 study visits.
Repeated measures analyses were performed using random effects model. Dependent variables were perfusion and skin temperature. The predictor of interest was log-transformed drug concentration. Covariates with p-values less than 0.15 were kept in the model. All data was used, across time points, visits, and hands.
Table 1 presents baseline characteristics of study participants.
Nine subjects tolerated the 2 mg BID dose by the first PK visit, and 6 subjects tolerated the 4 mg BID dose by the 2nd PK visit. Two subjects completed the study at 0.5 mg BID and 1 mg BID, respectively.
Adverse effects were transient and typical of prostacyclin therapy: headache, jaw pain, photosensitivity, fatigue, insomnia, myalgias, nausea, emesis, diarrhea, abdominal bloating, edema, flushing.
The oral sustained release formulation of treprostinil diethanolamine was absorbed to reach therapeutic levels and may provide new therapy for Raynaud's Phenomenon (RP) and the peripheral vascular disease of scleroderma.
Controlling for baseline perfusion, hour, and hand, concentration was a significant predictor of perfusion and temperature at the 4 mg visit. An increase in digital perfusion was observed with increased treprostinil blood concentrations, suggesting a dose-response relationship.
The following references may be useful for understanding the present invention:
Primary: To assess the effect of oral treprostinil in reducing net ulcer burden compared to placebo in patients with systemic sclerosis (SSc) as measured by the change in net ulcer burden from Baseline to Follow-up between treatment groups at 20 weeks.
Secondary: To assess the effect of treprostinil diethanolamine as compared to placebo on one or more of the following:
Ulcers qualifying for the study were defined as follows:
Baseline and Weeks 5, 10, 15, and 20:
Background rate in overall mean change of DUs in RAPIDS-2 trial was approximately −1.5 (sd=3) at 5 months. Allocation ratio of 1:1 between treprostinil diethanolamine and placebo, a fixed sample size of 128 patients would provide 80% power to detect a between-treatment difference at a significance level of 0.05 (two-sided hypothesis) assuming the active group leads to a change of −3 DUs. Target enrollment of 50 patients to complete 128 subjects. Estimated drop out rate 15%.
Primary analysis: effect of treprostinil versus placebo on change in net ulcer burden at Week 20 evaluated using non-parametric analysis of covariance within the framework of the extended Cochran-Mantel-Haenszel test.
Values for missing assessments imputed, see Table 2.
Planned Subgroup Analysis:
Table 3 presents demographics and baseline characteristics:
Table 4 presents data for subject accountability.
Table 5 presents study drug dosing—median (mg BID).
Table 6 summarizes ulcer healing status.
Table 7 presents results regarding formation new ulcers.
Tables 8 and 9 provide results for net ulcer burden sorted by patients' subgroups.
Tables 10 and 11 present results for secondary endpoints.
In the primary analysis change, in net ulcer burden at Week 20 did not achieve statistical significance. However, statistically significant changes were observed in the ACA negative subset of patients.
The following secondary endpoints did achieve statistical significance: Physician Global VAS, SHAQ Grip, Hand Function and Breathing VAS components, Patient Impression of Change Overall and on Raynaud's. These data demonstrate that orally administered treprostinil diethanolamine provided symptomatic relief of pain (e.g. improvement in Raynaud's symptoms) and functional deficits associated with ischemic vascular disease in patients with scleroderma and digital ulcers. It can be expected that a compound that provides this level of functional and symptomatic improvement due to improvement in digital vascular pathology can also improve digital ulcer healing, further supporting the strong trend toward improvement in digital ulcer healing observed in the trial.
Improvement not reaching statistical significance was seen in Patient Global and Digital Ulcer pain VAS at Week 20.
In order to be included in the study, each subject had to satisfy each of the following criteria:
Subjects satisfying at least one of the following criteria were excluded from the study:
Permitted background therapy included the following:
Prohibited background therapy: ERA, statins (unless for hypercholestermia), oral or topical products containing nitric oxide, other prostanoids, Regranex.
Although the foregoing refers to particular preferred embodiments, it will be understood that the present invention is not so limited. It will occur to those of ordinary skill in the art that various modifications may be made to the disclosed embodiments and that such modifications are intended to be within the scope of the present invention. All the publications, patent applications and patents cited in this specification are incorporated herein by reference in their entirety.
The present application claims priority to U.S. provisional application No. 61/354,949 filed Jun. 15, 2010, which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61354949 | Jun 2010 | US |
