TPX-100

The development of TPX-100 as a novel therapeutic for cartilage repair is OrthoTrophix’ most advanced program. TPX-100-treated knees have demonstrated both statistically significant and clinically meaningful improvements in key knee-related outcome measures of Knee injury and Osteoarthritis Outcome Score as compared to placebo-treated knees for at least 12 months in its double-blind, placebo-controlled Phase 2 clinical study. The study results suggest that TPX-100 improves joint health and may be able to prevent or delay the need for knee replacement surgery.

Compound

TPX-100 is a novel 23-amino-acid peptide derived from matrix extracellular phosphoglycoprotein (MEPE), a 525-amino-acid protein that occurs naturally in humans and is known to be involved in the regulation of hard tissue and phosphate metabolism. Because of its small size, TPX-100 is being manufactured by a chemical synthesis process.

Cartilage Repair Activities of TPX-100

TPX-100 has been studied in multiple knee cartilage defect models including large animal models. The Spanish goat model, in which standardized critical-size defects are created in weight-bearing joints, was employed to assess the ability of TPX-100 to stimulate cartilage regeneration. In this stringent model, in which animals remain ambulatory, cartilage repair and regeneration does not naturally occur. This model is considered to be especially rigorous in mimicking human cartilage damage and for assessing cartilage repair. TPX-100 was administered for four weekly injections into the joint space and was associated with regeneration of articular cartilage as assessed histologically. Repair tissue in defects treated with TPX-100 showed positive staining for type II collagen and proteoglycans, indicating the presence of normal hyaline cartilage. Injections were well tolerated, with no observed synovial inflammation or local or systemic toxicity.

The ability of TPX-100 to induce the regeneration of normal hyaline cartilage was also independently confirmed in a well-recognized osteoarthritis model involving surgical joint destabilization. Statistically significant reduction in the total histological damage score in the TPX-100 treated joints was demonstrated compared with controls, suggesting repair benefit of TPX-100 administration.

Clinical Safety

Over 220 human subjects have received systemic or local administrations of TPX-100, of which 118 subjects have received intra-articular administration of TPX-100 to date, and there has been no withdrawal due to an adverse event. TPX-100 has been tested in a Phase 1 and multiple Phase 2 clinical studies in the U.S. The Phase 1 study was a double-blind, placebo-controlled safety trial in healthy volunteers. Subcutaneous (systemic) administration of TPX-100 was well tolerated even at the highest dose tested. The first Phase 2 study in the U.S. was a double-blind, placebo-controlled safety study in human subjects with hard tissue (dentin) defects in teeth that were scheduled for extraction. TPX-100 was administered locally in the mouth and was well tolerated. After scheduled extraction, histological analysis indicated a trend toward regeneration of new dentin tissue in teeth treated with TPX-100 versus placebo-treated teeth. The second Phase 2 study in the U.S. was a randomized, double-blind, placebo-controlled safety and efficacy study in human subjects having osteoarthritis in both knees. TPX-100 was administered locally into the knee joint for four weekly injections. All routes of administration have been well tolerated.

Clinical Efficacy in Knee Osteoarthritis

Clinical efficacy of TPX-100 in knee osteoarthritis subjects was tested in a Phase 2 clinical study in the U.S. The study was entitled, “A Randomized, Double-blind, Placebo-controlled, Multi-dose Phase 2 Study Evaluating the Safety and Efficacy of Intra-articular Injections of TPX-100 in Subjects with Mild to Moderate Patello-Femoral Osteoarthritis Involving Both Knees.” The outline of the study is posted at the government clinical study site: ClinicalTrials.gov. In this one-year study, 115 subjects with mild to moderate bilateral patella-femoral osteoarthritis received 4 weekly doses of TPX-100 by intra-articular administration in one knee and identical placebo injections in the other. While investigational MRI measures of cartilage thickness and volume showed no difference between drug and placebo-treated knees, the majority of standardized, patient-reported measures of knee daily function, quality of life and sports and recreation function as measured by the Knee injury and Osteoarthritis Outcome Score (KOOS) demonstrated both statistically significant and clinically meaningful improvements in the TPX-100-treated knees as compared to the placebo-treated knees at 6 and/or 12 months after the drug administrations. It is anticipated that more advanced MRI measures may reveal structure-modifying effects of TPX-100 in subsequent trials, consistent with its effects on cartilage repair demonstrated in animal models.

Osteoarthritis

Osteoarthritis, the most common disease of the joints, is one of the most widespread of all chronic, disabling diseases. In the US, osteoarthritis is second only to heart disease as a cause of work disability in men over 50 years of age. Osteoarthritis was the sixth leading cause of years living with disability at a global level, accounting for 3% of the total global years of living with disability. In the US, it is estimated that more than 27 million people suffer from osteoarthritis, including more than half of those individuals 65 years of age or older. Approximately 80% of osteoarthritis patients need treatment in the knee.

In osteoarthritis, the cartilage in the joints wears away, either gradually as part of the aging process, or more abruptly following trauma. Normal articular (hyaline) cartilage does not regenerate naturally in mammals.

There are no approved drugs, nor any non-surgical methods that promote regeneration of lost or damaged hyaline cartilage. Treatment for osteoarthritis is limited to analgesics, inert substances for joint lubrication, or invasive surgical procedures. Knee joint replacement is ultimately the only option at the most advanced stages of the disease.

A treatment that is safe, office-based, administered by well-established techniques of intra-articular injection, and that can improve cartilage repair and viability will address a critical unmet need. This may delay or eliminate the need for invasive and expensive surgeries, including total joint replacement. TPX-100 is being developed first to meet this unmet need in people who suffer from osteoarthritis of the knee.

Clinical Merits

TPX-100 is believed to act on the cells committed to become hard tissue cells such as chondroprogenitor cells (cells which are destined to become mature cartilage cells; chondrocytes), and stimulate production of new hard tissue matrix. TPX-100’s binding to those cells appears to trigger attachment or adhesion of those cells to the surrounding extracellular matrix in the hard tissues. It is widely recognized that attachment or adhesion to the extracellular matrix is an important step for chondroblasts to differentiate and produce new matrix. TPX-100 has been shown to induce production of Type II Collagen and Aggrecan in human mesenchymal cells when cultured in an appropriate three-dimensional matrix. Type II Collagen and Aggrecan are two major structural components of cartilage tissue.

This unique property of TPX-100 provides with some important clinical merits when it is used to treat cartilage defects. Due to its selectivity to act on cells in the hard tissue lineage, TPX-100 does not cause undesirable adverse events through actions on other cell types. For example, no pain or inflammation has been reported in any prior clinical or non-clinical studies. TPX-100 promotes cartilage formation only in cartilage defects, and does not form ectopic bone tissue or bone in undesirable locations such as osteophyte formation in cartilage tissue. TPX-100 promotes the differentiation and maturation of chondroprogenitor cells with production of new extracellular matrix molecules such as Type II Collagen and Aggrecan. TPX-100 is not a cell growth factor such as FGF-18, associated with side effects such as pain and inflammation. TPX-100 seems to prime a long term pharmacodynamic effect, since clinical benefits in the knee are sustained after a single series of injections through 12 months.

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