US-12622945-B2 - Hard tissue therapeutics

Abstract

Compounds, pharmaceutical compositions, and a method of treating hard tissue diseases and disorders are disclosed. The compounds may be a peptide and is structured to bind integrin α v β 3 expressed by osteocytes and by selective binding to the cell surface integrin on hard tissue forming cells regulate three-dimensional bone shape, cartilage formation and repair.

Inventors

• Yoshinari Kumagai
• Dawn McGuire
• Meghan Miller
• David Rosen

Assignees

• ORTHOTROPHIX, INC.

Dates

Publication Date

20260512

Application Date

20230905

Claims (12)

1. 1 . A method of determining efficacy of a peptide comprising: (a) testing and confirming that the peptide binds integrin α v β 3 expressed on osteocytes, wherein the binding affinity of the peptide to integrin α v β 3 expressed on osteocytes is found to be at least 300 times higher than its binding affinity to the integrins α v β 1 , α v β 6 , α v β 8 , α 1 β 1 , α 2 β 1 , α 3 β 1 , α 4 β 1 , α 5 β 1 , α 6 β 1 , α 8 β 1 , α 9 β 1 , and α 10 β 1 and wherein the peptide is found to bind integrin α v β 5 with a lower affinity than the peptide's affinity to integrin α v β 3 , (b) testing and confirming that the peptide is agonistic on binding to integrin α v β 3 expressed on osteocytes, and is not antagonistic, inhibitory, or blocking; and (c) injecting a subject with the peptide confirmed in step (a) to potentially be efficacious and thereby determining if binding to integrin α v β 3 is at a level so as to result in improving joint function upon injection into a subject; (d) testing and confirming that the peptide binding to integrin α v β 3 expressed on osteocytes is at a level so as to result in improving joint function upon injection into a subject.
2. 2 . The method of claim 1 , further comprising: (e) measuring 3D bone shape change by obtaining a bone image of the subject injected in (c) and analyzing the image with an algorithm which calculates the 3D bone shape, and wherein the 3D bone shape is determined by a B-score, wherein the algorithm is based on active appearance modeling (AAM).
3. 3 . The method of claim 2 , further comprising: (f) determining if the injecting results in impacting a change of three-dimensional (3D) bone shape in the subject.
4. 4 . The method of claim 3 , further comprising: (g) continuing the injecting of the subject at different points in time and determining if the peptide delays, arrests, or reverses 3D bone shape change in the subject.
5. 5 . The method of claim 4 , further comprising: (h) determining if the 3D bone shape change occurs in a joint of the subject.
6. 6 . The method of claim 5 , wherein the 3D bone shape change occurs in a knee joint.
7. 7 . The method of claim 5 , wherein the 3D bone shape change in the joint is determined to be associated with natural aging.
8. 8 . The method of claim 5 , wherein the 3D bone shape change in the joint is determined to be pathological.
9. 9 . The method of claim 5 , wherein the 3D bone shape change in the joint is associated with one or more of osteoarthritis, rheumatoid arthritis, trauma, osteoporosis, disc herniation, spinal injury, or temporomandibular disorder; and wherein the 3D bone shape change occurs in one or more of the joints of knee, hip, ankle, toe, finger, hand, wrist, elbow, shoulder, spine, or jaw.
10. 10 . The method of claim 2 , wherein the bone image is obtained using imaging technology selected from the group consisting of magnetic resonance (MR), radiography (X-ray), computer tomography (CT) and ultrasound.
11. 11 . The method of claim 8 , wherein the peptide reduces a pathological event selected from the group consisting of excessive mineralization of the bone, and excessive bone sclerosis.
12. 12 . The method of claim 1 , wherein the peptide binds to integrin α v β 3 at a binding affinity at least three (3) times higher than its binding affinity to the integrin α v β 5 .

Description

FIELD OF THE INVENTION The invention relates to compounds that treat hard tissue diseases and disorders, pharmaceutical compositions containing the compounds, and method of use thereof to treat hard tissue diseases and disorders. More specifically the invention related to such compounds that are peptides which bind integrin αvβ3 expressed by osteocytes and are formulated for injection and administered repeatedly over time until the composition delays, arrests, or reverses 3D bone shape change in the patient. Incorporation by Reference of Sequence Listing Provided as a Sequence Listing XML File A Sequence Listing is provided herewith as a Sequence Listing XML, “BEAR-021CON Seq List” created on Aug. 27, 2024, and having a size of 15,508 bytes. The contents of the Sequence Listing XML are incorporated by reference herein in their entirety. BACKGROUND Hard Tissue Formation Bone, cartilage, and dentin make up the hard tissues of vertebrates. Hard tissue forming cells differentiate from mesenchymal stem cells (MSCs). Depending on the microenvironments in which they reside, MSCs become committed to specific hard tissue cell lineages and differentiate into those respective lineages. When they commit to the bone lineage, MSCs differentiate into osteoblasts, then further differentiate into mature osteocytes. When they commit to the cartilage lineage, they differentiate into chondroprogenitor cells or chondroblasts, then further differentiate into mature chondrocytes. In a joint, synoviocytes (or synovial cells) can migrate from the synovial membrane to articular cartilage and differentiate into chondrocyte lineage cells in that microenvironment. When osteoblastic cells are differentiating to become mature osteocytes, they produce biomaterials and enzymes specific to and necessary for bone formation such as type I collagen, osteopontin, osteocalcin, and alkaline phosphatase. Chondroprogenitor cells, in the course of differentiation into chondroblasts and mature chondrocytes, produce cartilage-specific biomaterials including type II collagen and aggrecan. Production of these materials by the respective cell types are upregulated while they are actively differentiating. Hard Tissue Damages, Diseases, and Disorders Hard tissue diseases and disorders often seriously limit the physical mobility of patients, which leads to a poor quality of life and a sedentary lifestyle. This can increase the risk for comorbid conditions such as obesity, diabetes, cardiovascular disease, and dementia. Hard tissue diseases and disorders often progress and may never heal. A new therapy that accelerates healing of hard tissues or arrests or delays progression of pathological conditions damaging hard tissues is highly desirable. Osteoarthritis Osteoarthritis (OA) is the most common disease of the joints and one of the most widespread of all chronic diseases. In the US, this debilitating condition is second only to heart disease as a cause of work disability in men over 50 years of age. Globally, osteoarthritis is the 6th leading cause of years living with disability (Woolf 2003). Pain is a common symptom in patients with knee OA. Pain typically is treated with non-steroidal anti-inflammatory drugs (NSAIDs). However, further to the initial Boxed Warning and Warnings and Precautions sections of the prescription labels of NSAIDs in 2005, the United States Food and Drug Administration (FDA) in 2015 strengthened the existing label warning that non-aspirin NSAIDs, including over-the-counter products, increase the chance of a heart attack or stroke (FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes: Jul. 9, 2015). Intra-articular treatments using corticosteroids or hyaluronic acid products are also used to reduce pain in knee OA. Corticosteroid injections have been implicated in further cartilage degeneration in the knees (McAlindon 2017), making many clinicians reluctant to use this treatment modality. Corticosteroid injections are not recommended by The American Academy of Orthopaedic Surgeons or The American Association of Orthopaedic Surgeons for treatment of knee OA (Recommendation 8 in AAOS Treatment of Osteoarthritis of the Knee—2nd Edition, Evidence-Based Clinical Practice Guideline: Adopted by American Academy of Orthopaedic Surgeons Board of Directors, May 18, 2013). While hyaluronic acid or “viscosupplementation” products may reduce joint pain for weeks to months in some patients (Cohen 1998), multiple clinical trials have failed to demonstrate a clinically meaningful treatment effect. The American Academy of Orthopaedic Surgeons and American Association of Orthopaedic Surgeons state “We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee.” (Recommendation 9 in AAOS Treatment of Osteoarthritis of the Knee—2nd Edition, Evidence-Based Clinical Practice Guideline: Adopted by American Academy of Ort