TREGZI

5 WARNINGS AND PRECAUTIONS Graft Failure: Monitor patients closely for laboratory evidence of hematopoietic recovery. ( 5.1 ) Graft-Versus-Host Disease (GVHD): Treat patients with a single agent calcineurin inhibitor as prophylaxis to decrease the risk of GVHD. Monitor for signs and symptoms of GVHD. ( 5.2 ) Infusion Reactions: Monitor patients for signs and symptoms of infusion reactions during and after TREGZI administration. When a reaction occurs, pause the infusion and institute supportive care as needed. ( 5.3 ) Secondary Malignancies and Malignancies of Donor Origin: Monitor for secondary malignancies and malignancies of donor origin. ( 5.4 ) Transmission of Infectious Agents: Monitor patients closely for serious infections. ( 5.5 ) 5.1 Graft Failure Graft failure has occurred after TREGZI administration [see Adverse Reactions (6.1) ]. Screen TREGZI recipients for antidonor antibodies that may prevent engraftment. Monitor patients closely for laboratory evidence of hematopoietic recovery. 5.2 Graft-Versus-Host Disease Acute and chronic Graft-Versus-Host disease (GVHD), including life-threatening and fatal cases, occurred following treatment with TREGZI [see Adverse Reactions (6.1) ] . Acute GVHD manifests as maculopapular rash, gastrointestinal symptoms, and elevated bilirubin. Chronic GVHD may include skin rash, mouth sores, dry eyes, liver inflammation, and development of scar tissue in the skin and joints and damage to the lungs. Treat patients with a single agent calcineurin inhibitor as prophylaxis to decrease the risk of GVHD. Monitor for signs and symptoms of GVHD, and treat if GVHD develops. 5.3 Infusion Reactions Infusion reactions (IRs) may occur during or following treatment with TREGZI. Serious hypersensitivity reactions including anaphylaxis may occur due to DMSO, human serum albumin (HSA), Dextran or murine protein present in TREGZI. IRs may begin within minutes of the start of TREGZI infusion, although symptoms may continue to intensify and not peak for several hours after the completion of the infusion. Monitor patients for signs and symptoms of IRs during and after TREGZI administration. When a reaction occurs, pause the infusion and institute supportive care as needed. Premedicate patients with antipyretics and histamine antagonists prior to infusion to reduce the incidence and intensity of infusion reactions. 5.4 Secondary Malignancies and Malignancies of Donor Origin Secondary malignancies and malignancies of donor origin may occur following treatment with TREGZI [see Adverse Reactions (6.1) ] . Development of secondary malignancies, including posttransplantation lymphoproliferative disorder (PTLD) may occur many years after transplantation. PTLD manifests as a lymphoma-like disease favoring non-nodal sites. PTLD is usually fatal if not treated. Serial monitoring of blood for EBV DNA may be warranted in patients with persistent cytopenias. No patient treated with TREGZI has developed PTLD. Monitor for malignancies of donor origin and secondary malignancies. Contact Orca Bio at 1-877-290-6722 if any patient is diagnosed with a secondary malignancy or a malignancy of donor origin. 5.5 Transmission of Infectious Agents Transmission of serious infectious or communicable disease or agents may occur with TREGZI treatment as it is derived from human donor blood and manufactured using animal-derived reagents. Risks of transmission of infectious agents may occur despite screening or testing of donors. Risks of transmission of serious infections include, but are not limited to, human immunodeficiency virus, human T cell lymphotropic virus (HTLV)-1 and -2, hepatitis B virus (HBV), hepatitis C virus (HCV), Treponema pallidum, Trypanosoma cruzi, West Nile virus (WNV), cytomegalovirus, transmissible spongiform encephalopathy agents and vaccinia. Monitor patients for signs and symptoms of infections, perform tests for infectious agents and treat as clinically indicated.

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥20%) were mucositis, diarrhea, rash, viral infections, infections - pathogen unspecified, abdominal pain, vomiting, nausea, bacterial infections, hemorrhage, aGVHD, edema, and fungal infections. ( 6.1 ) The most common Grade 3-4 laboratory abnormalities (≥ 20%) are lymphocyte count decreased, platelet count decreased, leukocyte count decreased, neutrophil count decreased, and hemoglobin decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Orca Bio at 1-877-290-6722 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflects exposure to TREGZI in one clinical study (Precision-T Study) which enrolled patients with advanced hematologic malignancies eligible for HLA-matched allogeneic stem cell transplantation following myeloablative preparative regimen. The study treated 88 patients with TREGZI and 94 patients with standard of care (SoC) unmanipulated graft. The patients were followed for a duration of 24 months [see Clinical Studies (14) ]. Serious adverse reactions within the first 100 days occurred in 25 patients (28%) treated with TREGZI including bacterial infections (n=12; 14%), pyrexia (n=4; 5%), venooclusive liver disease (n=3; 3%), and viral infections (n=3; 3%). Fatal adverse reactions occurred in 3 patients (3%). Non-relapse deaths at 12 months occurred in 3/88 (3.4%) patients in the TREGZI group and in 11/94 (11.7%) patients in the SoC control group [see Clinical Studies (14) ]. In the TREGZI treated safety population, the most common (greater than or equal to 10%) Grade 3 or 4 nonlaboratory adverse reactions were mucositis (28%), bacterial infection (18%), infection – pathogen unspecified (18%), and viral infection (14%). Table 3 summarizes the most common nonlaboratory adverse reactions occurring in ≥10% patients treated with TREGZI or unmanipulated allograft control group in Precision-T Study. Table 3 Adverse Reactions occurring in ≥10% of patients treated with TREGZI or unmanipulated allograft control arm in Precision-T Study Adverse Reactions TREGZI (N = 88) SoC Control (N=94 ) All Grades % Grade 3 or Higher % All Grades % Grade 3 or Higher % Infections and infestations Infections and infestations were calculated for the first 2 years after transplantation. Abbreviations: GVHD, Graft-Versus-Host disease. Viral infections 51 14 47 19 Infections - pathogen unspecified 45 18 56 30 Bacterial infections 40 18 38 16 Fungal infections 20 3 18 0 Gastrointestinal disorders Diarrhea includes multiple related terms 69 1 79 6 Abdominal pain 45 0 54 1 Vomiting 44 1 35 0 Nausea 41 1 44 2 Immune system disorders Acute graft-versus-host disease Acute GVHD graded by MAGIC standardization criteria (Harris 2016) as determined by an independent review committee; calculated for the first year after transplantation. 38 6 46 15 General disorders and administration site conditions Mucositis 85 28 88 37 Edema 30 0 38 3 Respiratory, thoracic and mediastinal disorders Pneumonia 5 5 17 15 Skin and Subcutaneous Tissue Disorders Rash 65 0 55 0 Vascular Disorders Hemorrhage 39 6 33 1 Other clinically important adverse reactions that occurred in less than 10% of patients treated with TREGZI include the following: Hepatobiliary disorders: veno-occlusive liver disease 3% in TREGZI group and 2% in control group. Immune system disorders: moderate to severe chronic Graft-versus-host disease (GVHD) 13% in TREGZI group and 41% in control group as per International NIH Chronic GVHD Diagnosis and Staging. Injury, poisoning, and procedural complications: Secondary graft failure 1% in TREGZI group and 0% in control group. Table 4 summarizes the most common Grade 3 or 4 laboratory abnormalities occurring in ≥10% of patients in Precision-T Study. Laboratory Abnormalities Table 4 Grade 3 or 4 Laboratory Abnormalities Occurring in ≥10% of Patients in Precision-T Study Laboratory Abnormality Includes lab abnormalities for the first 100 days , Baseline lab values were assessed prior to conditioning regimen. Denominators ranged from 79 to 87 for TREGZI arm and 90 to 93 for Control arm for lab tests, based on the number of patients with a baseline value and at least one post treatment value for each lab test. TREGZI Grade 3 or 4 % SoC Control Grade 3 or 4 % Lymphocyte count decreased 98 94 Platelet count decreased 93 96 Leukocyte count decreased 89 89 Neutrophil count decreased 77 83 Hemoglobin decreased 71 81 Alanine aminotransferase increased 12 7

<table width="85%"><caption>Table 3 Adverse Reactions occurring in &#x2265;10% of patients treated with TREGZI or unmanipulated allograft control arm in Precision-T Study</caption><col width="39%" align="left" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="16%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" align="center">Adverse Reactions</th><th styleCode="Rrule" colspan="2">TREGZI (N = 88)</th><th styleCode="Rrule" colspan="2">SoC Control (N=94 )</th></tr><tr styleCode="Botrule"><th styleCode="Rrule" align="center">All Grades %</th><th styleCode="Rrule">Grade 3 or Higher %</th><th styleCode="Rrule">All Grades %</th><th styleCode="Rrule">Grade 3 or Higher %</th></tr><tr><th colspan="5" styleCode="Lrule Rrule">Infections and infestations<footnote>Infections and infestations were calculated for the first 2 years after transplantation.</footnote></th></tr></thead><tfoot><tr><td colspan="5">Abbreviations: GVHD, Graft-Versus-Host disease. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Viral infections</td><td styleCode="Rrule">51</td><td styleCode="Rrule">14</td><td styleCode="Rrule">47</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Infections - pathogen unspecified</td><td styleCode="Rrule">45</td><td styleCode="Rrule">18</td><td styleCode="Rrule">56</td><td styleCode="Rrule">30</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Bacterial infections</td><td styleCode="Rrule">40</td><td styleCode="Rrule">18</td><td styleCode="Rrule">38</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fungal infections</td><td styleCode="Rrule">20</td><td styleCode="Rrule">3</td><td styleCode="Rrule">18</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea<footnote ID="fn1">includes multiple related terms</footnote></td><td styleCode="Rrule">69</td><td styleCode="Rrule">1</td><td styleCode="Rrule">79</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnoteRef IDREF="fn1"/></td><td styleCode="Rrule">45</td><td styleCode="Rrule">0</td><td styleCode="Rrule">54</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">44</td><td styleCode="Rrule">1</td><td styleCode="Rrule">35</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea<footnoteRef IDREF="fn1"/></td><td styleCode="Rrule">41</td><td styleCode="Rrule">1</td><td styleCode="Rrule">44</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Immune system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Acute graft-versus-host disease<footnote>Acute GVHD graded by MAGIC standardization criteria (Harris 2016) as determined by an independent review committee; calculated for the first year after transplantation. </footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">6</td><td styleCode="Rrule">46</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Mucositis<footnoteRef IDREF="fn1"/></td><td styleCode="Rrule">85</td><td styleCode="Rrule">28</td><td styleCode="Rrule">88</td><td styleCode="Rrule">37</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema<footnoteRef IDREF="fn1"/></td><td styleCode="Rrule">30</td><td styleCode="Rrule">0</td><td styleCode="Rrule">38</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pneumonia</td><td styleCode="Rrule">5</td><td styleCode="Rrule">5</td><td styleCode="Rrule">17</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash<footnoteRef IDREF="fn1"/></td><td styleCode="Rrule">65</td><td styleCode="Rrule">0</td><td styleCode="Rrule">55</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"> <content styleCode="bold">Vascular Disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Hemorrhage<footnoteRef IDREF="fn1"/></td><td styleCode="Rrule">39</td><td styleCode="Rrule">6</td><td styleCode="Rrule">33</td><td styleCode="Rrule">1</td></tr></tbody></table>

<table width="80%"><caption>Table 4 Grade 3 or 4 Laboratory Abnormalities Occurring in &#x2265;10% of Patients in Precision-T Study </caption><col width="48%" align="left" valign="middle"/><col width="24%" align="center" valign="middle"/><col width="28%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="center">Laboratory Abnormality<footnote>Includes lab abnormalities for the first 100 days </footnote>^,<footnote>Baseline lab values were assessed prior to conditioning regimen. Denominators ranged from 79 to 87 for TREGZI arm and 90 to 93 for Control arm for lab tests, based on the number of patients with a baseline value and at least one post treatment value for each lab test.</footnote></th><th styleCode="Rrule">TREGZI Grade 3 or 4 %</th><th styleCode="Rrule">SoC Control Grade 3 or 4 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphocyte count decreased</td><td styleCode="Rrule">98</td><td styleCode="Rrule">94</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Platelet count decreased</td><td styleCode="Rrule">93</td><td styleCode="Rrule">96</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Leukocyte count decreased</td><td styleCode="Rrule">89</td><td styleCode="Rrule">89</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophil count decreased</td><td styleCode="Rrule">77</td><td styleCode="Rrule">83</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemoglobin decreased</td><td styleCode="Rrule">71</td><td styleCode="Rrule">81</td></tr><tr><td styleCode="Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Rrule">12</td><td styleCode="Rrule">7</td></tr></tbody></table>