Tryp Therapeuatics (TRYPF) Coverage Report

Exhibit 21: Proposed peripheral contributions to PLP Source: J Clin Invest. 2018; 128: 2168 Complex regional pain syndrome (CRPS). Chronic regional pain syndrome is a condition that is described by continuous pain of a specific region of the body. This type of pain is inconsistent with the time and severity of the cause of the pain (BMJ. 2015; 351: h2730). It typically affects the extremities and causes measurable changes in the sensory, motor, autonomic, and trophic systems at the distressed site.  CRPS is classified into two categories: CRPS Type I is based on the absence of nerve injury, while CRPS Type II based on the presence of nerve injury. Exhibit 22 is a proposed model of the interacting mechanisms that can lead to the development of CRPS.  In the affected area, patients may experience severe hyperalgesia, allodynia, physiological changes to the skin, tremors, and dystonia. Patients may also experience altered limb function. Together all these symptoms can take a toll on the ability to live a quality life. The diagnosis is based on criteria established by the International Association for the Study of Pain and clinical assessment.  The pathophysiology of CRPS involves several possible mechanisms (BMJ. 2015; 351: h2730), including: o Nerve Injury o Ischemic reperfusion injury or oxidative stress o Central and peripheral sensitization o Altered sympathetic nervous system function o Inflammatory and immune related factors o Brain changes o Genetic factors o Psychological factors  The current standard of care in CRPS is a combination of pharmacological and non-pharmacological treatments. Treatment is hindered due to a poor understanding of the pathophysiology. However, evidence suggests that treatment earlier on during the onset of the disease and those that target peripheral mechanisms are more successful (Expert Opin Pharmacother. 2019; 20(11): 1377). Michael Higgins 212.409.2074 Tryp Therapeutics, Inc. (TRYPF) Page 29