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 randomized, double-blind, placebo-controlled Phase 2 clinical study. The study results suggest that TPX-100 improves joint health in moderate to severe knee osteoarthritis patients 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 as 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 with excellent safety and tolerability, 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 outline of the study is posted at the government clinical study site: ClinicalTrials.gov. In this one-year study, 115 subjects with moderate to severe knee osteoarthritis received 4 weekly doses of TPX-100 by intra-articular administration in one knee and identical placebo injections in the other. Investigational MRI measurements of cartilage thickness and volume showed less than 15% of all knees underwent MRI-detectable changes during the 12-month study period. As a result, no difference between drug and placebo-treated knees were observed with regard to cartilage thickness or volume. On the other hand, a 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. These clinical benefits were sustained through 12 months after the drug administration. A trend towards pain alleviation in TPX-100-treated knees was observed at 6 months and 12 months. Pain going up or downstairs, most common complaint by knee osteoarthritis patients, was markedly reduced in TPX-100 treated knee at 12 months as compared with placebo-exposed knees. Overall physical health conditions measured by VR-12 Physical Component Score demonstrated highly significant improvements as compared to the baseline, and use of NSAIDs (non-steroidal anti-inflammatory drugs, one of the most commonly used pain medications in knee osteoarthritis) was reduced by over 60% after TPX-100 treatment as compared to prior to the drug administration.

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 knee osteoarthritis, including more than half of those individuals 65 years of age or older.

Two major health problems with knee osteoarthritis are pain and deteriorating functions in their knees. Typically, the patients who started to feel pain and/or knee function problems are consulted by their primary care physicians and advised to try physical therapies and weight loss to alleviate the problems. They are often advised to take over the counter analgesics. They are sometimes treated with prescription pain killers such as non-steroidal anti-inflammatory drugs (NSAIDs) and weak opioids. Once those preliminary treatments become insufficient to control the symptoms, intra-articular therapies are typically added. Two major intra-articular therapies are inert substances for joint lubrication such as hyaluronic acid products and corticosteroids. Knee joint replacement is ultimately the only option at the most advanced stages of the disease.

These widely-used therapies offer only limited solutions for knee osteoarthritis patients. The latest evidence-based knee osteoarthritis treatment guideline by American Academy of Orthopaedic Surgeons (AAOS) recommends that hyaluronic acid should not be used for its lack of efficacy (https://www.aaos.org/research/guidelines/TreatmentofOsteoarthritisoftheKneeGuideline.pdf). Corticosteroids are known for their damaging effects on cartilage and bone. The most recent controlled trial of intra-articular corticosteroid (McAlindon, JAMA, May 2017) showed significantly decreased knee cartilage with no significant analgesic efficacy compared with placebo exposed knees. In addition, physicians are cautious about NSAIDs use because the majority of knee osteoarthritis patients are elderly with other health problems limiting safe NSAID use.

The approximate cost of knee joint replacement therapy, treatment of last resort of knee OA, is roughly $100,000 per knee including post-operational follow-up and rehabilitation. Further, artificial knee joints typically must be replaced in 15 to 20 years. Clearly, knee osteoarthritis presents huge unmet need for safe, effective, and affordable therapy. TPX-100 offers the potential solution for this unmet need.

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, which is associated with side effects such as pain and inflammation. TPX-100 seems to induce 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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