Compositions and methods for preventing and treating heterotopic ossification and pathologic calcification
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NostopharmaNostopharma is a preclinical stage pharmaceutical innovator developing treatments to address unmet needs in musculo-skeletal health. According to the World Health Organization (WHO), approximately 1.71 billion people worldwide have musculoskeletal conditions. Nostopharma is developing a proprietary sustained delivery nanoformulation platform that was validated with the first therapeutic product that addresses the critical issue of trauma-induced abnormal bone growth. Other complications from trauma often include post-surgical infections, severe bleeding, acute localized inflammation, chronic pain management, and other challenges. Nostopharma envisions developing a precision medicine, "on-demand" platform to facilitate flexible combination treatments in surgical settings, aiming to achieve "complication-free" recovery for millions of trauma patients.
While trauma patients are treated by orthopedic surgeons for bone repair as standard care, their accompanying soft tissue trauma goes unattended. In part, this is due to the lack of medical treatments available to trauma teams and orthopedic surgeons for use in pre-hospital settings and during surgery. Nostopharma’s treatments will be administered as rapid-response measure, pre- and post-operatively, and significantly improve the outcomes for trauma patients by facilitating the complication-free recovery. For the first time, orthopedic surgery and trauma patients will be able to take potent and proven medications without exposure to their toxicities as systemic drugs.
Nostopharma has assembled a world-class team and advisory board, complemented by the best-in-class contract toxicology and manufacturing organizations to de-risk product development execution. Additionally, Nostopharma’s technology offers a versatile and advanced platform for the delivery of other therapeutics, addressing unmet needs of military and civilian trauma (e.g., infections and poor pain management). Nostopharma is following a very capital-efficient pathway (505(b)2 regulatory framework) to enter in the clinic as early as 2026 direct to Phase 2 trial. Discussions with several strategic partners like Johnson&Johnson (DePuy), UBS Pharma, Pfizer, and Stryker have confirmed the potential to partner and license NP102-nano and future pipeline products for commercialization after the successful Phase 2 clinical trial.
Nostopharma is a preclinical stage pharmaceutical innovator developing treatments to address unmet needs in musculo-skeletal health. According to the World Health Organization (WHO), approximately 1.71 billion people worldwide have musculoskeletal conditions. Nostopharma is developing a proprietary sustained delivery nanoformulation platform that was validated with the first therapeutic product that addresses the critical issue of trauma-induced abnormal bone growth. Other complications from trauma often include post-surgical infections, severe bleeding, acute localized inflammation, chronic pain management, and other challenges. Nostopharma envisions developing a precision medicine, "on-demand" platform to facilitate flexible combination treatments in surgical settings, aiming to achieve "complication-free" recovery for millions of trauma patients. While trauma patients are treated by orthopedic surgeons for bone repair as standard care, their accompanying soft tissue trauma goes unattended. In part, this is due to the lack of medical treatments available to trauma teams and orthopedic surgeons for use in pre-hospital settings and during surgery. Nostopharma’s treatments will be administered as rapid-response measure, pre- and post-operatively, and significantly improve the outcomes for trauma patients by facilitating the complication-free recovery. For the first time, orthopedic surgery and trauma patients will be able to take potent and proven medications without exposure to their toxicities as systemic drugs. Nostopharma has assembled a world-class team and advisory board, complemented by the best-in-class contract toxicology and manufacturing organizations to de-risk product development execution. Additionally, Nostopharma’s technology offers a versatile and advanced platform for the delivery of other therapeutics, addressing unmet needs of military and civilian trauma (e.g., infections and poor pain management). Nostopharma is following a very capital-efficient pathway (505(b)2 regulatory framework) to enter in the clinic as early as 2026 direct to Phase 2 trial. Discussions with several strategic partners like Johnson&Johnson (DePuy), UBS Pharma, Pfizer, and Stryker have confirmed the potential to partner and license NP102-nano and future pipeline products for commercialization after the successful Phase 2 clinical trial.
Publication Number
US-10456409-B2
Publication Date
2019-10-29
Expiration Date
2037-09-13
Abstract
The present invention is directed to compositions and methods for the prevention or treatment of treatment of heterotopic ossification, vascular calcification, or pathologic calcification.
Core Innovation
The invention is directed to methods and compositions for the prevention or treatment of heterotopic ossification, vascular calcification, or other forms of pathologic calcification by administering drug combinations that include an antagonist of the Hedgehog (Hh) signaling pathway, vitamin D or its analogs (including cholecalciferol), and statins. The approach is based on the concept that these agents can inhibit osteogenesis in mesenchymal stem cells and prevent pathological calcification either alone or more effectively in combinations.
The problem being addressed is the lack of generally effective treatments for ectopic bone formation and related pathological calcifications, which can arise due to trauma, surgery, genetic diseases, and other conditions. Existing preventive treatments such as NSAIDs and radiation therapy have serious limitations and side effects. There is a need for improved treatment methods that can reduce or prevent heterotopic ossification and pathological calcification more effectively and safely.
The invention provides various methods for inhibiting osteogenesis by using combinations of Hh pathway antagonists with vitamin D or statins, combinations of vitamin D with statins, or all three agents together. These combinations, administered in a co-timely manner, produce greater inhibition of osteogenesis than individual agents alone, showing dose-dependent and synergistic effects. The treatments can be applied to patients with ectopic bone formation or calcification from various causes, and pharmaceutical compositions are also disclosed with defined dosages and formulations.
Claims Coverage
The patent contains multiple independent claims covering methods of preventing or treating heterotopic ossification, vascular calcification, or other pathological calcifications using combinations of therapeutic agents.
Combination of Hedgehog pathway antagonist and vitamin D or analogs
A method comprising administering a combination of a Hedgehog (Hh) pathway antagonist with vitamin D, cholecalciferol, or a vitamin D analog in an effective amount to prevent or treat heterotopic ossification, vascular calcification, or other pathological calcifications.
Combination of Hedgehog pathway antagonist and statin
A method comprising administering a combination of a Hedgehog (Hh) pathway antagonist with a statin in an effective amount to prevent or treat heterotopic ossification, vascular calcification, or other pathological calcifications.
Co-timely administration with specified dosages
Administration of the therapeutic agents in a co-timely manner, preferably concomitantly or essentially simultaneously, at specified dosages: Hh antagonists at 1-500 mg/day, vitamin D forms at 300-3000 IU/day, and statins at 1-500 mg/day, or adjusted dosages based on route of administration.
Specific selections of Hedgehog pathway antagonists and statins
Use of specific Hh pathway antagonists selected from a large group including arsenic trioxide, cyclopamine, GANT-58, GANT-61, among others, and statins selected from Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin, Pitavastatin, Cerivastatin, Lovastatin, and Mevastatin in the therapeutic combinations to treat or prevent pathological calcifications.
Single unit dosage form containing combination of agents
Pharmaceutical compositions in unit dosage form comprising the combination of a Hedgehog pathway antagonist, vitamin D or analog, and/or statin, wherein the components are present in amounts effective for treatment or prevention, and are suitable for oral or transdermal administration.
The independent claims cover methods for preventing or treating heterotopic ossification, vascular calcification, or pathological calcification by co-timely administering therapeutic combinations of Hedgehog pathway antagonists with vitamin D forms and/or statins, employing specific agent selections, dosages, and pharmaceutical formulations including single unit dosage forms to achieve synergistic therapeutic effects.
Stated Advantages
The combination therapies produce a greater degree of inhibition of osteogenesis and pathological calcification than any single agent alone, exhibiting synergistic effects.
The dose-dependent synergy allows minimizing the quantity of each agent, thereby reducing the toxicity and side effects associated with higher doses of individual compounds.
Treatment methods may reduce the frequency or severity of side effects such as weakness, fatigue, nausea, liver and kidney damage, cardiac arrhythmias, and others compared to treatment with individual agents.
Documented Applications
Prevention and treatment of heterotopic ossification and pathologic calcification following traumatic injuries, spinal cord damage, brain and head injuries, burns, fractures, muscle injuries, and surgery, especially arthroplasty.
Treatment of patients with diseases or conditions predisposing to ectopic bone formation or vascular calcification such as atherosclerosis or myocardial infarction.
Treatment of rare genetic diseases associated with ectopic bone formation or calcification including osseous heteroplasia, fibrodysplasia ossificans progressiva, and Albright's hereditary osteodystrophy.
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