EP-3681481-B1 - COMPOSITIONS FOR PREVENTING AND TREATING HETEROTOPIC OSSIFICATION AND PATHOLOGIC CALCIFICATION

Inventors

• VERT-WONG, EKATERINA

Dates

Publication Date

20260506

Application Date

20180309

Claims (9)

1. A combination for use in a method of preventing or treating heterotopic ossification, vascular calcification, or pathologic calcification in a patient, wherein the combination comprises: a) a combination of a Hedgehog (Hh) pathway antagonist together with: i) cholecalciferol; or c) a combination of: i) a Hh pathway antagonist; ii) cholecalciferol; and iii) a statin; wherein said Hh pathway antagonist is arsenic trioxide (ATO), wherein said statin is selected from the group consisting of Pravastatin; and Lovastatin; and wherein the method comprises administering the compounds of paragraphs a) or c) to cells in a co-timely manner, wherein a therapeutically effective amount of a first compound should be present in the patient when the second compound is given and, if a third compound is given, then both a therapeutically effective amount of the first compound and a therapeutically effective amount of the second compound should be present when the third compound is administered.
2. The combination for use of claim 1, wherein the compounds of paragraphs a) or c) are administered within one hour of one another.
3. The combination for use of claim 1 or 2, wherein said combination is used to prevent or treat heterotopic ossification subsequent to spinal cord damage, traumatic injury, head or brain injuries, burns, bone fractures, muscle injuries, or joint replacement surgery.
4. The combination for use of claim 1 or 2, wherein said combination is used to prevent or treat heterotopic ossification resulting from progressive osseous heteroplasia, fibrodysplasia ossificans progressiva or Albright's hereditary osteodystrophy.
5. The combination for use of any one of claims 1-4 , wherein said Hh pathway antagonist is administered to said patient at 1-500 mg/day; cholecalciferol is administered at 300-3000 IU/day; and said statin is administered at 1-500 mg/ day.
6. The combination for use of claim 1, wherein ATO is administered to said patient at a dosage of between 0.05 to 0.20 mg/kg/day.
7. The combination for use of any one of claims 1-6, wherein said compounds are administered to a patient in a single unit dosage form.
8. A pharmaceutical composition in unit dosage form comprising as components: a) a combination of a Hedgehog (Hh) pathway antagonist together with: i) cholecalciferol; or c) a combination of: i) an Hh pathway antagonist; ii) cholecalciferol; and iii) a statin; wherein said Hh pathway antagonist is arsenic trioxide (ATO), wherein said statin is selected from the group consisting of Pravastatin; and Lovastatin; and wherein the respective amounts of these components are effective upon administration of one or more of said unit dosage forms to said patient, to be therapeutically effective.
9. The pharmaceutical composition of claim 8, wherein said unit dosage form is for oral administration and comprises: an Hh antagonist at 1-500 mg; cholecalciferol at 300-3000 IU; and a statin at 1-500 mg.

Description

Field of the Invention The present invention is directed to a combination for use in methods of preventing or treating heterotopic ossification, vascular calcification, or pathologic calcification containing: a) an antagonist of the Hedgehog signaling pathway, wherein said Hh pathway antagonist is arsenic trioxide (ATO); b) cholecalciferol; and/or c) a statin, wherein said statin is selected from the group consisting of Pravastatin; and Lovastatin. It also includes pharmaceutical compositions in unit dosage form a containing the combination. Background of the Invention Heterotopic ossification (HO) is characterized by the formation of ectopic bone in soft tissues, such as the fibrous tissue adjacent to joints. It is most commonly associated with trauma, such as spinal cord injury, brain injuries, head injuries, burns, fractures, muscle contusions, combat-related trauma and surgery (especially joint arthroplasty). In addition, HO may occur in patients that are on neuromuscular blockade to manage adult respiratory distress syndrome and in patients with non-traumatic myelopathies. In rare cases, HO may present as part of a hereditary disease and is sometimes associated with lower motor neuron disorders. The consequences of HO may include, inter alia, joint contracture and ankylosis, pain, spasticity, swelling, fever, neurovascular compression, pressure ulcers, and significant disability. Lesions range from small, clinically insignificant foci to massive deposits throughout the body. NSAIDs, such as indomethacin, can be effective in the prevention of HO if treatment is started early and preoperative radiation may be used to prevent HO after total hip or knee arthroplasty. Combined postoperative radiotherapy and indomethacin has also been suggested to be effective at preventing HO. Unfortunately both radiation therapy and NSAID treatment have significant limitations and may result in serious side effects (see Baird, et al., J. Ortho. Surg. Res. 4:12 (2009)). There are currently no generally effective treatments for ectopic bone formation due to genetic diseases. Areas of well-circumscribed HO can sometimes be surgically removed with successful long-term results but resection of diffuse lesions usually leads to recurrences or complications. Successful functional repositioning of a joint after the development of a contracture from HO may also occasionally be possible. However, treatment options are very limited and these diseases are generally severely disabling. Recent analyses have suggested that the cellular origin for ectopic bone formation may be mesenchymal progenitor cells. The differentiation of these cells into osteogenic lineages is induced by a pathological microenvironment in soft tissues outside the skeletal tissue, which includes inflammation. Recent reports suggest that drugs that act as antagonists of the Hedgehog signaling pathway (which is essential for proper embryonic development and is believed to play a role in the development of some cancers) may be effectively used to prevent or treat HO as well as other pathological conditions characterized by ectopic calcification (see e.g., US 2014/0220154). Further development of treatment methods using Hh pathway antagonists and other agents is clearly warranted. US 2014/220154 A1 relates to methods and compositions for enhancing hair growth and treating hair loss using compositions containing Hedgehog pathway agonists. It includes the use of specific compounds to stimulate hair follicle development and promote hair growth by targeting the Hedgehog signaling pathway. OLESON CHRISTINA V. ET AL: "Association of vitamin D deficiency, secondary hyperparathyroidism, and heterotopic ossification in spinal cord injury", Journal of Rehabilitation Research and Development, Volume 50, Number 9, Pages: 1177-1186 explores the link between vitamin D deficiency, secondary hyperparathyroidism, and the occurrence of heterotopic ossification (HO) in individuals with spinal cord injuries. GALUS R ET AL: "Fluvastatin increases heterotopically induced ossicles in mice", Clinical and Experimental Pharmacology and Physiology, Volume 33, Number 4, Pages: 388-390, investigates the effects of fluvastatin, a commonly used statin, on heterotopic ossification (HO) induced by HeLa cells in mice. Summary of the Invention The present invention is based on the concept that cholecalciferol; and statins can be used to inhibit osteogenesis in mesenchymal stem cells and to prevent or treat heterotopic ossification, vascular calcification, or pathologic calcification in a patient. It is further based on the concept that combinations of these agents, and combinations of these agents together with Hedgehog (Hh) pathway antagonists, can produce a greater effect in functional assays of osteogenesis prevention than agents used alone. Effects may include changes in gene expression and a reduction in alkaline phosphatase (AP) activity, a sign of prevented cell differentiation and HO aversion. As