Heterotopic ossification (HO) is defined by bone formation in soft tissue and is a frequent debilitating complication of surgical procedures required by musculoskeletal and neurological injuries. Unfortunately, it is not possible to accurately predict which patients will develop symptomatic HO, which is characterized by pain and impaired function. The current prophylactic standard of care, systemic NSAID treatment, is effective in reducing HO mineralization, but has also has been associated with gastrointestinal bleeding, increased cardiovascular events, and impaired fracture healing. Due to this challenging risk/reward ratio, HO often remains untreated until symptomatic. Once symptomatic, the only treatment option is surgical excision, which is costly and has a high rate of reoccurrence. Given the direct and indirect costs associated with HO, it is not surprising that the associated health care burden exceeds $1B per year in the US alone. In this context, In Situ Therapeutic Solutions, Inc. (ISTheraSol) has developed novel IP demonstrating that distributed, intramuscular (IM) targeting of the neuromuscular inhibitor botulinum toxin A (BTxA) mitigates HO formation. Our IP also suggests that inhibition of HO can be achieved using BTxA dosing that is approximately 90% less than is currently used as an adjunct in orthopaedic procedures and that a prototype template enables superior tissue coverage compared to freehand injection. Thus, the goal of ISTheraSol is to develop and commercialize disposable intraoperative devices that will focally inhibit HO for a variety of indications. In this proof of concept Phase I STTR, we will design, fabricate, and validate a prototype delivery device that will demonstrate superior tissue coverage of BTxA within a targeted soft tissue volume vs freehand injection (SA#1). We will then demonstrate that a single intraoperative application of BTxA using our prototype device will significantly reduce trauma-induced HO in a pre-clinical rabbit model that mimics human HO following acetabular fracture (SA#2). We will also demonstrate that our proprietary technology will achieve significantly greater efficacy vs indomethacin, an NSAID representing the current standard of care. We will then submit a Phase II STTR proposal to optimize dosing parameters (minimizing dose while retaining efficacy), demonstrate that the dose required for HO inhibition is gender independent, and confirm an enhanced safety/efficacy profile vs indomethacin. In collaboration with our clinical Co-Investigator, ISTheraSol leadership has selected acetabular fracture as our first treatment indication as its low frequency (? 12,000/yr) and high incidence of HO (> 50%) will support an FDA Orphan Drug Application. Importantly, this filing strategy will lower development costs, reduce regulatory burden, and accelerate time to market. As we anticipate that the optimal dose distribution will be independent of indication, we believe that our IP can be rapidly leveraged to commercialize products to treat additional HO indications regardless of causal pathology.
Heterotopic ossification (HO) is the formation of bone in soft tissue where bone normally does not exist and is a frequent, debilitating, and costly complication of musculoskeletal and/or neurologic trauma. ISTheraSol has developed IP demonstrating that very small doses of BTxA, when distributed within a tissue volume, will inhibit formation of HO. This Phase I STTR will establish proof of concept for our IP by developing a prototype device that will demonstrate superior efficacy to inhibit trauma-induced HO compared to the current standard of care (systemic NSAIDs).
