Sorrento Therapeutics : Abivertinib November 2021

Abivertinib - A Franchise Oral Therapeutic

for Cancer, COVID-19 and Autoimmune Diseases

EXECUTIVE SUMMARY

Abivertinib - A Broad Pipeline for Cancer, COVID-19 and Autoimmune Diseases ($61B Market)

About Abivertinib:

• Abivertinib is a novel dual target, small molecule tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) and Bruton's tyrosine kinase (BTK).
• Abivertinib is a third-generation epidermal growth factor receptor (EGFR) inhibitor that irreversibly targets mutant forms of EGFR in advanced non-small cell lung cancer ( NSCLC) patients resistant to first-line EGFR kinase inhibitor therapies.
• Abivertinib also irreversibly binds to the BTK receptor, preventing the phosphorylation of the receptor that occurs during activation. Abivertinib has shown potent immunomodulatory activities in vitro with potent inhibition of key pro-inflammatory cytokine production, including IL-1 beta, IL-6 and TNF-alpha. These cytokines are associated with acute respiratory distress syndrome (ARDS) and cytokine release syndrome (CRS) or cytokine storm complicating COVID-19 resulting in disease progression with poor outcomes in patients.

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Abivertinib Drug Targets:

• Abivertinib Targets Epidermal Growth Factor Receptor (EGFR) Mutations in Cancer Cells
  Figure 1. EGFR Signaling Transduction Pathway in Regulation of NSCLC Cell Proliferation

• Abivertinib Targets Bruton's Tyrosine Kinase (BTK)

Figure 2. BTK Signaling Transduction Pathways in Regulation of Malignant B Lymphocyte

Proliferation and Cytokine Expression

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Abivertinib - Mode of Actions

• Abivertinib as EGFR Inhibitor for NSCLC

Acquired T790M mutation in EGFR is the most common cause of resistance for patients with advanced NSCLC who have progressed after first line EGFR TKIs. The development of the third- generation (3G) EGFR TKIs focused on three key aspects: i) the inhibition of T790M isoform-specific kinase activity, ii) maintaining efficacy against exon 19 and 21 mutations, and iii) sparing the inhibition of wild-type EGFR. Abivertinib, discovered by ACEA Therapeutics (a wholly-owned subsidiary of Sorrento Therapeutics), is a pyrrolopyrimidine-based irreversible 3G EGFR TKI, and is structurally distinct from all other 3G pyrimidine-based EGFR inhibitors.

• Abivertinib as BTK Inhibitor for B-Cell Malignancies

Bruton's tyrosine kinase (BTK) is a clinically validated target for the treatment of B-cell malignancies, including relapsed or refractory (R/R) B-cell lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL)/small lymphocytic.

Abivertinib is also a potent BTK inhibitor, selectively, and irreversibly inhibiting the phosphorylation of BTK with IC50 value at 1.6 nM and its downstream target proteins at low nM range. Abivertinib occupied BTK targets in human peripheral blood mononuclear cells (PBMCs) with IC50 value at 0.78 nM.

• Abivertinib as Potent Inhibitor of Cytokines for COVID-19 Associated Cytokine Storm

BTK is a critical molecule in immune regulation and host inflammatory responses. Abivertinib has shown potent anti-inflammatory and immune modulation activities by inhibiting key pro- inflammatory cytokines including IL-1beta,IL-6 and TNF-alpha. These cytokines are associated with the acute respiratory distress syndrome (ARDS) in the COVID-19 patients.

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Abivertinib - Clinical Experience and Preclinical Experiments

• Abivertinib for Cancer Indications

NSCLC (Pivotal Trial)- Among 209 response evaluable NSCLC patients who developed resistance to first line TKIs (Figure 3):

1. 93.3 % (n/N: 195/209) subjects achieved tumor shrinkage at target lesions

1. 57.4% (n/N: 120/209) subjects achieved the best overall responses (confirmed + unconfirmed PR) o 52.2% (n/N: 109/209) subjects achieved confirmed PR
   o 24.9 months OS

In	the	pivotal	study conducted	in	China	using Abivertinib	as	a	second	line	treatment
of	227 heavily	pretreated	NSCLC	patients	with	resistant	EGFR	mutations	were	enrolled.
Among	209 response evaluable	patients, confirmed	ORR was	52.2%. Disease control	rate (DCR)
was	88.0%.	The	median	duration	of	response (DoR) and	progression-free survival (PFS)
was 8.5 months	and	7.5 months, respectively. The median overall survival (OS) was 24.9 months.

The study result of the data as of March 2019 was published online in Clinical CancerResearch at: https://clincancerres.aacrjournals.org/content/early/2021/11/04/1078-0432.CCR-21-2595.

Abivertinib showed similar efficacy compared to Osimertinib, the only FDA-approved third generation EGFR inhibitor, but with a different resistant mechanism it can provide a potential alternative in NSCLC (Xu, X, et al Mol Cancer Ther 15: 2586-2597, 2016; Zhang, YC et al, EBioMedicine 43:180-187, 2019; Zhang, YC et al, Neoplasia 41: 41-51, 2019; Zhang YC et al, Sci. Bull. 64:499-503, 2019).

Figure 3. Waterfall plots for best percentage change in target-lesion size by investigator assessment are

shown for evaluable patients in Phase 2.

The color key indicates the response to 300 mg BID of Abivertinib.

Abbreviation: CR, complete response; NE: not evaluable; PD, progressive disease; PR,partial response; SD, stable disease

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B-CellLymphoma(Phase 1/2 Trial) (as of 08/28/2020)

• 63.6% ORR (n/N: 14/22)
• 95.5% DCR (n/N: 21/22)
• 19.7 Months PFS

Table 1: Efficacy of Abivertinib for treatment of R/R B-Cell Lymphoma

§ A Phase 1 study designed to determine the recommended Phase 2 dose (RP2D) of Abivertinib in patients with pre-treated R/R B-cell lymphoma (part 1) and to evaluate the safety and preliminary efficacy in patients with selected disease (part 2) was completed. Abivertinib has been investigated in an open-label phase 1 study with dose optimization (part 1) and dose expansion (part 2) (NCT03060850) in patients with R/R B-cell lymphoma. Twenty-nine patents were enrolled into 4 dose cohorts (200 mg QD, 150 mg BID, 200 mg BID and 300 mg BID). In all dose cohorts, Abivertinib occupied BTK target up to 100% in patient's PBMCs and achieved ORR of 54.2% and DCR of 95.8%. At 200 mg BID, the ORR was 81.8% (9/11) and the DCR was 100%. Abivertinib was shown to be well tolerated across the dosing cohorts. The most common adverse events (AEs) (all grades) regardless of causality were neutropenia (58.6%), thrombocytopenia (44.8%), diarrhea (34.5%), anemia (34.5%) and ALT elevation (34.5%). The most common (>10%) grade 3 or 4 AEs regardless of causality were neutropenia (24.1%), and thrombocytopenia (17.2%). Treatment- related serious adverse events (SAEs) occurred in 27.6% (8/29) of patients, and no death occurred during the treatment period. The SAEs associated with first generation BTK inhibitors such as Ibrutinib, including serious bleeding, atrial fibrillation, bruising, and tumor lysis syndrome, were not reported with Abivertinib treatment. Based on the safety and efficacy data, 150 mg BID was selected as RP2D for B-cell malignancies.

• The Phase 1 results were published in EHA, 2019. The abstract is available at:https://library.ehaweb.org/eha/2019/24th/266315/ min.yang.a.phase.i.study.of.the.btk.inhibitor.abivertinib.28ac001029.in.patients.html?f=listing% 3D3%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D1
• Abivertinib is effective for the treatment of R/R B-cell lymphoma in multiple disease types including MZL, MCL, CLL and follicular lymphoma (FL). Based on the effective dose cohorts (200mg QD, 150mg BID and 200mg BID) of 22 response evaluable subjects, the ORR was 63.6%, DCR was 95.5, and PFS was 19.7 months (data cut off time: 08/28/2020)

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