Exicure, Inc 8-K, filed Sep 16, 2020
Exicure, Inc. (XCUR)
8-K
2020-09-16
For: 2020-09-16
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Added on
April 10, 2026
About this 8-K
Exicure, Inc filed this 8-K on September 16, 2020.
Items reported
- Item 7.01: Regulation FD disclosure
- Item 8.01: Other events
- Item 9.01: Financial statements and exhibits
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
____________________
FORM 8-K
____________________
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): September 16, 2020
____________________
EXICURE, INC.
(Exact name of Registrant as specified in its charter)
____________________
| Delaware | 001-39011 | 81-5333008 | ||||||
| (State or other jurisdiction of incorporation) | (Commission File Number) | (IRS Employer Identification No.) | ||||||
2430 N. Halsted St.
Chicago, IL 60614
(Address of principal executive offices)
Registrant’s telephone number, including area code: (847) 673-1700
____________________
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading symbol(s) | Name of each exchange on which registered | ||||||||||||
| Common Stock, par value $0.0001 per share | XCUR | The Nasdaq Stock Market LLC | ||||||||||||
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company x
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. x
Item 7.01 Regulation FD Disclosure.
On September 16, 2020, Exicure, Inc. (the “Company”) issued a press release announcing preliminary data from the Company’s ongoing Phase 1b/2 clinical trial of cavrotolimod (AST-008) to be presented at a Key Opinion Leader (“KOL”) event to be held later that same day. A copy of the press release is furnished herewith as Exhibit 99.1 to this Current Report on Form 8-K. A copy of the presentation to be presented at the KOL event is furnished herewith as Exhibit 99.2 to this Current Report on Form 8-K.
The information contained in this Item 7.01, including Exhibits 99.1 and 99.2, are being “furnished” and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or otherwise subject to the liability of that section or Sections 11 and 12(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”). The information in this Item 7.01, including Exhibits 99.1 and 99.2, shall not be incorporated by reference into any registration statement or other document pursuant to the Securities Act or into any filing or other document pursuant to the Exchange Act, except as otherwise expressly stated in any such filing.
Item 8.01 Other Events.
On September 16, 2020, the Company issued a press release announcing preliminary data from the Company’s ongoing Phase 1b/2 clinical trial of cavrotolimod (AST-008).
To date, the trial has enrolled 20 patients consisting of: ten (10) melanoma patients, five (5) MCC patients, two (2) CSCC patients, two (2) head and neck squamous cell carcinoma patients, and one (1) leiomyosarcoma patient. The objectives of the Phase 1b dose-escalation stage of the study clinical trial were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cavrotolimod alone and in combination with pembrolizumab, and to identify a recommended Phase 2 dose.
The preliminary data shows cavrotolimod (AST-008) had been well-tolerated at all doses studied, with 98% of all treatment-emergent adverse events (AEs) assessed as Grade 1 or 2 in severity. No treatment-related serious adverse events were reported to date. The most common adverse events were flu-like symptoms and injection site reactions, which are commonly expected effects from a TLR9 mechanism of action. These results are preliminary in nature and may change as additional patients are enrolled and progress in the trial.
Forward-Looking Statements
Any statements in this Current Report on Form 8-K about future expectations, plans and prospects for the Company and other statements containing the words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties inherent in the initiation of future clinical studies and in the availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial such as the interim data referenced in this Current Report on Form 8-K will be predictive of the final results of the trial; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future trials; whether results from clinical studies will warrant meetings with regulatory authorities or submissions for regulatory approval; whether the Company will be able to satisfy the pathway to regulatory approval that it has identified; whether the Company will obtain regulatory approvals to conduct trials or to market products on a timely basis or at all; whether the Company’s cash resources will be sufficient to fund the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements; other matters that could affect the availability or commercial potential of the Company’s therapeutic candidates; and other factors discussed in the “Risk Factors” section of the Company’s most recent Form 10-K filed with the Securities and Exchange Commission (the “SEC”) and in the Company’s other filings from time to time with the SEC. In addition, the forward-looking statements included in this Current Report on Form 8-K represent the Company’s views as of the date hereof and should not be relied upon as representing the Company’s views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Company’s views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
| Exhibit No. | Description | |||||||
| 99.1 | ||||||||
| 99.2 | ||||||||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934 the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Date: September 16, 2020 | EXICURE, INC. | |||||||
| By: | /s/ David A. Giljohann | |||||||
| David A. Giljohann, Ph.D. | ||||||||
| Chief Executive Officer | ||||||||
| Exhibit 99.1 | |||||
 | |||||
Exicure Presents Promising Interim Results from Ongoing Phase 1b/2 Trial of Cavrotolimod at Virtual KOL Event Today
•Confirmed overall response rate (ORR) of 21% in the dose-escalation stage across all doses, confirmed ORR 33% at the highest and selected Phase 2 dose
•Target tumor shrinkage was observed in 37% of patients
•Preliminary data show activity in patients with melanoma, Merkel cell carcinoma (MCC), and cutaneous squamous cell carcinoma (CSCC)
•Phase 2 arms in both MCC and CSCC are currently recruiting
CHICAGO & CAMBRIDGE, Mass.—September 16, 2020 — Exicure, Inc. (NASDAQ: XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing proprietary spherical nucleic acid (SNA™) technology, announced that it will host a virtual Key Opinion Leader (KOL) event to present preliminary Phase 1b efficacy and safety data for its intratumoral product candidate, cavrotolimod, the company’s SNA-enabled TLR9 agonist being developed for the treatment of solid tumors, in combination with pembrolizumab. The event will take place today from 10:30 am – 12:00 pm ET.
The principal investigators of the Phase 1b portion of the trial, Dr. Steven O’Day and Dr. Shailender Bhatia, will be presenting and joining Exicure’s leadership team in discussing the clinical data and trial progress to date.
"We are excited by the durable responses we have seen in anti-PD-1 refractory patients, and look forward to further exploring the efficacy of cavrotolimod in these highly treatment refractory Merkel cell carcinoma and cutaneous squamous cell carcinoma patients," said Dr. Douglas Feltner, Chief Medical Officer of Exicure.
The event will be webcast live today, September 16th at 10:30 am ET through a link on the Events and Presentations section of Exicure’s website. An archived webcast will also be available on Exicure’s website following the event. To RSVP for the event, please use the link here (https://troutaccess.com/investor.php/c/ExicureKOLDay2020) or email rjohn@troutgroup.com.
Description of the Trial
The objectives of the Phase 1b dose-escalation stage of the clinical trial were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cavrotolimod alone and in combination with pembrolizumab, and to identify a recommended Phase 2 dose. Cavrotolimod was dosed weekly for 8 weeks then every three weeks thereafter. Pembrolizumab was added to the treatment regimen starting in week three of the study. The first two weeks of the trial, the period in which only cavrotolimod was dosed, allowed for the assessment of cavrotolimod safety, tolerability, pharmacokinetics and pharmacodynamics alone. Efficacy was assessed every 12 weeks. Twenty patients have been enrolled and dosed in the dose-escalation stage of the trial consisting of: ten (10) melanoma patients, five (5) MCC patients, two (2) CSCC patients, two (2) head and neck squamous cell carcinoma patients, and one (1) leiomyosarcoma patient. At the
1
time of enrollment, 85% of patients were experiencing progressive disease while on anti-PD-1 antibody therapy.
Highlights from the data
Highlights from the data update include:
–Confirmed ORR 21% (4/19 patients) overall in the Phase 1b dose-escalation stage
–Confirmed ORR 33% (2/6 patients) in the highest dose cohort (32 mg), which was selected as Phase 2 recommended dose
–Overall responses occurred in two patients with advanced MCC and two patients with melanoma
–Three of four responders were progressing on anti-PD-1 therapy at the time of enrollment
–In addition to the four confirmed responses, target tumor shrinkage occurred in one CSCC patient and two melanoma patients. Systemic (abscopal) effects were observed, with regression in noninjected tumors distant from injected lesions.
–The cavrotolimod pharmacodynamic profile corroborated the efficacy data, as increased serum cytokines/chemokines, activated immune cells, and tumor infiltration by immune cells were observed.
The median duration of response has not been reached as all four confirmed responders have not progressed after a median follow-up of 11 months. The longest response to date is 16 months from initial dosing and is ongoing as of the data cut-off date.
Exicure continues to observe that cavrotolimod is well tolerated with 98% of all treatment-emergent adverse events (AEs) assessed as Grade 1 or 2 in severity. No treatment-related serious adverse events were reported to date. The most common adverse events were flu-like symptoms and injection site reactions, which are commonly expected effects from a TLR9 mechanism of action.
Updated guidance
Exicure expects to provide interim ORR results from the MCC and CSCC cohorts of the Phase 2 portion of the clinical trial in the first half of 2021 and final ORR results by year end 2021.
About Exicure, Inc.
Exicure, Inc. is a clinical-stage biotechnology company developing therapeutics for neurology, immuno-oncology, inflammatory diseases and other genetic disorders based on our proprietary spherical nucleic acid, or SNA technology. Exicure believes that its proprietary SNA architecture has distinct chemical and biological properties that may provide advantages over other nucleic acid therapeutics and may have therapeutic potential to target diseases not typically addressed with other nucleic acid therapeutics. Exicure is in preclinical development of XCUR-FXN, an SNA–based therapeutic candidate, for the treatment of Friedreich’s ataxia (FA). Exicure's therapeutic candidate cavrotolimod is in a Phase 1b/2 clinical trial in patients with advanced solid tumors. Exicure is based in Chicago, IL and in Cambridge, MA.
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For more information, visit Exicure’s website at www.exicuretx.com.
Exicure Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements in this press release other than statements of historical fact could be deemed forward looking including, but not limited to, statements regarding the company’s ongoing Phase 1b/2 clinical trial of cavrotolimod (AST-008) including the design, clinical development, therapeutic potential and clinical results and expectations as to the reporting of data;. The forward-looking statements in this press release speak only as of the date of this press release, and the company undertakes no obligation to update these forward-looking statements. Forward-looking statements are based on management’s current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: the risks that the ongoing COVID-19 pandemic may disrupt the company’s business and/or the global healthcare system more severely than it has to date or more severely than anticipated, which may have the effect of impacting or delaying the company’s ongoing Phase 1b/2 clinical trial; unexpected costs, charges or expenses that reduce the company’s capital resources; the company’s preclinical or clinical programs do not advance or result in approved products on a timely or cost effective basis or at all; the results of early clinical trials are not always being predictive of future results; the cost, timing and results of clinical trials; that many drug candidates do not become approved drugs on a timely or cost effective basis or at all; the ability to enroll patients in clinical trials; possible safety and efficacy concerns; regulatory developments; and the ability of the company to protect its intellectual property rights. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the company’s actual results to differ from those contained in the forward-looking statements, see the section titled “Risk Factors” in the company’s Annual Report on Form 10-K for the year ended December 31, 2019, as updated by the company’s subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and the company undertakes no duty to update this information, except as required by law.
# # #
For Media:
Karen Sharma
MacDougall
781-235-3060
ksharma@macbiocom.com
For Investors:
Thomas Hoffmann
Solebury Trout
+1-646-378-2931
thoffmann@troutgroup.com
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Sept Exhibit 99.2 16 2020 Cavrotolimod (AST-008) Intratumoral Immunotherapy KOL Day 16 Sept 2020
Cautionary Note Regarding Forward Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "anticipate," "expect," "plan," "may," "will," and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. All statements other than statements of historical fact in this presentation are forward looking including, but not limited to, statements regarding of Exicure, Inc. (“Exicure” or the “Company”); including the development of product candidates based on its proprietary SNA technology; the initiation, timing, progress, scope and results of the Company’s preclinical studies, clinical trials and research and development programs; its plans for development of cavrotolimod (AST-008), including its ongoing Phase 1b/2 clinical trial; the timing, availability and presentation of preclinical, clinical and regulatory developments; the potential benefits of the Company’s product candidates and notably, cavrotolimod; the development and the commercial potential, growth potential and market opportunity for the Company’s product candidates, if approved, and the drivers, timing, impact and results thereof; potential and future results of current and planned collaborations; and the timing or likelihood of regulatory filings and approvals. Forward-looking statements are based on management’s current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: the risk that the COVID-19 pandemic and the associated containment efforts may have a material adverse impact on the Company’s business, operations and financial results; the Company’s preclinical or clinical programs do not advance or result in approved products on a timely or cost effective basis or at all; unexpected safety or efficacy data observed during preclinical or clinical studies; the failure of the data from the Company’s preclinical trials to be indicative in human trials; clinical site activation rates or clinical trial enrollment rates that are lower than expected; the cost, timing and results of clinical trials; changes in the regulatory environment; unexpected litigation or other disputes; the ability of the Company to protect its intellectual property rights; and the actual funding required to develop and commercialize the Company’s product candidates and operate the Company. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, see the section titled “Risk Factors” in the Company’s most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in its subsequent filings with the Securities and Exchange Commission. The forward-looking statements in this presentation speak only as of the date of this presentation, and the Company undertakes no obligation to update these forward-looking statements, unless required by law. 2
Today’s Speakers David Giljohann, PhD Doug Feltner, MD Matthias Schroff, PhD Steven O’Day, MD Exicure Exicure Exicure Executive Director CEO CMO COO John Wayne Cancer Institute and Cancer Clinic Shailender Bhatia, MD Emil deGoma, MD Weston Daniel, PhD Associate Professor Exicure Exicure University of Washington Vice President, Vice President, and Fred Hutchinson Clinical Development Translational Research Cancer Research Center 3
Program Agenda Cavrotolimod (AST-008): Exicure Vision and Spherical Nucleic Closing Remarks Q&A Session Strategy Acid TLR9 Agonist Immunotherapy for Oncology David Giljohann, PhD All David Giljohann, PhD All 4
Vision and Strategy David Giljohann PhD; CEO
The Exicure Difference PLATFORM THERAPEUTICS VALUE Better Uptake, Greater Stability Growing Development Pipeline XCUR (NASDAQ) RARE DISEASE FORMS MARKET CAP CASH 3-D architecture drives NEURO IMMUNO- better uptake Friedreich’s Ataxia ONCOLOGY $200M $99M (IND-enabling CAVRO 8/1/20 3/31/20 and greater stability studies late 2020) Phase 2 PARTNERSHIPS POTENTIAL MILESTONE PAYMENTS Preclinically demonstrated local delivery in CNS, eye, GI tract, liver, lung, skin AbbVie/Allergan Dermelix up to up to $725M $166M/program (2 programs underway) (up to 6 programs) Mechanism-agnostic: antisense, siRNA, TLR9 modulation, splice-switching Potential for additional partners CASH RUNWAY INTO 2022 6
SNAs Differentiated from Conventional Linear Oligos The Benefits Differentiated Uptake 1 HIGH CELL UPTAKE SNA Others Without encapsulation or SNAs Linear Oligos chemical modifications 2 Binding ENHANCED STABILITY VS Extended therapeutic half-life Cell surface in cells Scavenger receptor 3 EXTRA-HEPATIC DELIVERY SNA enters cells via ubiquitous scavenger receptors Shown in humans and mice 7
Our Broad NEUROLOGY IMMUNO- Near-Term Therapeutic ONCOLOGY SNA Therapeutic Opportunity Focus Technology DERMATOLOGY SNA technology allows nucleic acids to be OPHTHALMOLOGY delivered to local sites throughout the body, GI TRACT expanding the potential application of nucleic LUNG acid therapeutics LIVER 8
Focused Development Pipeline PRECLINICAL DEV PHASE 1 PHASE 2 IMMUNO-ONCOLOGY MERKEL CELL CARCINOMA1 CAVROTOLIMOD (TLR9 AGONIST) CUTANEOUS SQUAMOUS CELL CARCINOMA1 NEUROLOGY XCUR-FXN FRIEDREICH’S ATAXIA XCUR-NEURO-02 UNDISCLOSED DERMATOLOGY XCUR17 (ANTI-IL17RA) INFLAMMATORY DISORDERS currently unpartnered Undisclosed Target HAIR LOSS DISORDERS 2 Undisclosed Target NETHERTON SYNDROME 1 In combination with checkpoint inhibitors 2 On May 8, 2020, Allergan plc was acquired by AbbVie Inc. 9 Cavrotolimod is the proposed international non-proprietary name for AST-008
NEUROLOGY IMMUNO- ONCOLOGY Cavrotolimod SNA Technology DERMATOLOGY Targeting Merkel cell carcinoma and cutaneous OPHTHALMOLOGY squamous cell carcinoma GI TRACT LUNG LIVER 10
Cavrotolimod (AST-008) Douglas Feltner MD; CMO
Summary of Cavrotolimod and Dose Escalation Results • Cavrotolimod (AST-008) is a TLR9 agonist that leverages Exicure’s SNA platform • Cavrotolimod has shown a positive efficacy profile in the Phase 1b dose escalation study evaluating intratumoral (IT) cavrotolimod + IV pembrolizumab in patients with advanced solid tumors • Overall response rate (ORR) of 33% (2/6) at highest dose, 21% (4/19) overall • Durable response: Responses have persisted for at least 6+ months and are ongoing in all 4 responders; longest observed response duration is 16 months • Regional and systemic anti-tumor effects: Evidenced by regression of noninjected lesions, supporting a systemic response 12
Advancing Cavrotolimod in Nonmelanoma Skin Cancers with Significant Unmet Need INDICATIONS PHASE 1 PHASE 2 Merkel Cell Carcinoma Refractory to Anti-PD-(L)-1 Cavrotolimod + Pembrolizumab Cutaneous Squamous Cell Carcinoma Refractory to Anti-PD-1 Cavrotolimod + Cemiplimab 13
Shailender Bhatia, MD Dr. Bhatia is Associate Professor of Medical Oncology at the University of Washington and Fred Hutchinson Cancer Research Center. Focused on immunotherapy clinical trials that aim at improving outcomes in skin cancer Especially interested in intratumoral and other novel therapeutic approaches that stimulate the immune system against cancer Principal Investigator for clinical trials for Merkel cell carcinoma focused on improving the immune response against this cancer 14
Steve O’Day, MD Dr. O’Day is the Executive Director of John Wayne Cancer Institute and Cancer Clinic at Providence Saint John’s Health Center, Regional Director of Research and Professor of Medical Oncology. Recognized as one of the preeminent melanoma specialists in the world Leader in the development of ipilimumab, pembrolizumab and nivolumab Principal investigator on over 100 clinical trials including several large, international Phase III trials Published more than 200 manuscripts, abstracts and reviews in prestigious journals such as The New England Journal of Medicine (NEJM) and Journal of Clinical Oncology (JCO) 15
Disclosures Steve O’Day, MD • Advisory Board – Exicure, Biothera, BMS, BioNTech, Immunsys, Merck • Consultant – Agenus, Immunsys • Grants/Research Support – Agenus, Amgen, Biothera, BMS, Exicure, Genocea, Incyte, Merck, Ultimovacs, Viralytics • Speaker’s Bureau – BMS Shailender Bhatia, MD • Advisory Board: Exicure, Genentech, EMD-Serono, BMS (received honoraria) • Research Support (to the institution): EMD-Serono, BMS, Merck, Oncosec, ImmuneDesign, NantKwest, Novartis • Speaker: None 16
Cancer Immunotherapy and TLR9 Agonism Shailender Bhatia MD
Immune Checkpoint Blockade, a Transformational Therapeutic Advance, Established The Role Of Immunotherapy For Cancer Anti-PD-1 Mechanism FDA Approved Indications › Cervical Cancer › Colorectal Cancer Merkel Cell › Cutaneous Squamous Cell Carcinoma Carcinoma › Endometrial Carcinoma › Esophageal Cancer › Gastric Cancer ORR 33-56% 1 › Head and Neck Squamous Cell Cancer for single agent anti-PD-(L)1 › Hepatocellular Carcinoma › Hodgkin Lymphoma › Melanoma › Merkel Cell Carcinoma Cutaneous Squamous › MSI-high/dMMR Colorectal Cancer › Non-Small Cell Lung Cancer Cell Carcinoma › Primary Mediastinal B-cell Lymphoma › Renal Cell Carcinoma Small Cell Lung Cancer ORR 34-46% › 2 › Tumor Mutational Burden-High for single agent anti-PD-1 Cancer › Urothelial Carcinoma PD-1: programmed cell death protein-1. PD-L1: programmed death ligand-1. CTLA-4: cytotoxic T-lymphocyte-associated protein-4. 1Keytruda USPI. Bavencio USPI. 2Libtayo USPI. Keytruda USPI. 18
Cancer Immunity Cycle as an Immunotherapy Pharmacodynamic Model 4 Step Release of cancer cell antigens 1 3 Step Cancer antigen presentation 2 Step Priming and activation 5 3 Step Trafficking of T cells to tumors 4 Step Infiltration of T cells into tumors 2 5 6 Step 6 Recognition of cancer cells by T cells Step Killing of cancer cells 1 7 7 Immunity, Volume 39, Issue 1, 25Jul2013, Pages 1-10. 19
Anti-PD-1 Antibody Pharmacodynamics Help Propagate Two, not All, Steps of the Cancer Immunity Cycle Step Release of cancer cell antigens 1 3 Step 2 Cancer antigen presentation Step Priming and activation 3 Disinhibited by anti-PD-1 / anti-PD-L1 Step 4 Trafficking of T cells to tumors Step 5 Infiltration of T cells into tumors Step 6 Recognition of cancer cells by T cells Step Killing of cancer cells 7 7 Disinhibited by anti-PD-1 / anti-PD-L1 Immunity, Volume 39, Issue 1, 25Jul2013, Pages 1-10. 20
Hypothesis: A TLR-Targeting SNA will Help Promote the Remaining Steps of the Cancer Immunity Cycle and Produce Anti-tumor Responses in Anti-PD-1 Resistant Tumors 4 Step Release of cancer cell antigens 1 Driven by activated NK and T cells 3 Step Cancer antigen presentation 2 Driven by TLR agonism Step Priming and activation 5 3 Disinhibited by anti-PD-1 / anti-PD-L1 Driven by IL-12 Step Trafficking of T cells to tumors 4 Driven by IP-10 (CXCL10) Step Infiltration of T cells into tumors 2 5 Driven by LFA-1 expression 6 Step 6 Recognition of cancer cells by T cells Driven by T-cell receptor complex expression Step Killing of cancer cells 1 7 7 Disinhibited by anti-PD-1 / anti-PD-L1 Driven by interferon gamma and granzymes Immunity, Volume 39, Issue 1, 25Jul2013, Pages 1-10. 21
TLR9 and SNAs Weston Daniel PhD; VP Translational Research
SNAs are Ideal for TLR9 Activation SNA Scavenger Receptors Toll like receptor 9 (TLR9) agonism can produce the desired pharmacodynamics TLR9 is found in the endosome of cells - SNAs are colocalized in the endosome Endosome after internalization into cells TLR9s The SNAs are coated externally with oligonucleotides allowing for facile interaction with TLR9 SNAs have high cellular uptake, driving potency IL-12 IP-10 Activated NK cell Activated T cell 23
Cavrotolimod (AST-008) is Exicure’s TLR9 Agonist TLR9 agonist oligonucleotides – potent activators Cavrotolimod of immunity • Cytokines/chemokine signaling (IP-10, IL-12) for immune cell trafficking • T cell activation • NK cell activation Benign lipid nanoparticle • Scaffold for SNA structure Oligonucleotides + nanoparticle = SNA • Increased cellular uptake and endosomal uptake → Location of TLR9 target 24
Cavrotolimod and Anti-PD-1 Robustly Activate All Steps of the Cancer Immunity Cycle 4 Step Release of cancer cell antigens 1 ✓ 3 Step Cancer antigen presentation 2 ✓ Step Priming and activation 5 3 ✓ Step Trafficking of T cells to tumors 4 ✓ Step Infiltration of T cells into tumors 2 5 ✓ 6 Step 6 Recognition of cancer cells by T cells ✓ Step Killing of cancer cells 1 7 7 ✓ Immunity, Volume 39, Issue 1, 25Jul2013, Pages 1-10. 25
Nonclinical Studies Matthias Schroff PhD; COO
Cavrotolimod Demonstrates Higher Cell Uptake than Linear Structures 100 Cavrotolimod Linear TLR9 agonist SNAs 50 VS Loaded PBMC (%) Others 0 0.1 1 10 100 Linear Oligos Oligonucleotide (μM) PBMC = peripheral blood mononuclear cells 27
Cavrotolimod Demonstrates Better TLR9 Activation than Linear Structures 4 Cavrotolimod Linear TLR9 agonist GpC control SNA 3 SNAs VS 2 B Activation (fold PBS) (fold B Activation κ After 4 hr IncubationAfter 4 Others - NF 1 0.1 1.0 10 Linear Oligos Oligonucleotide (μM) 28
Murine Cavrotolimod Produces a Superior Anti-tumor Response Versus Linear Oligonucleotides Cavrotolimod Superior to Linear Naïve Mice Naïve Mice Naïve Mice Vehicle EMT6 4T1 ) Anti-PD-1 CT26 3 2000 Anti-PD-1+Linear Oligo Cavro-Treated Mice Cavro-Treated Mice Anti-PD-1+Cavro EMT6 4T1 CT26 1500 1000 500 Mean Tumor Volume (mm Volume Mean Tumor 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Cavro or Linear Days (SC, 0.8 mg/kg) Anti-PD-1 (IP, 10 mg/kg) Linear oligo + anti-PD-1: p = 0.009 vs vehicle on day 27; murine cavro + anti-PD-1: p < 0.0001 vs vehicle on day 27. BALB/c mice; N = 8/group; data presented as mean + SEM. 29 SC = subcutaneous, IP = intraperitoneal
Murine Cavrotolimod Produces a Tumor-specific Memory Response Cavrotolimod Cavrotolimod-Treated Mice Superior Develop Long Term Immunity to to Linear EMT6 Tumors Naïve Mice Naïve Mice Naïve Mice Vehicle EMT6 4T1 ) Anti-PD-1 CT26 3 2000 Anti-PD-1+Linear Oligo Cavro-Treated Mice Cavro-Treated Mice Anti-PD-1+Cavro EMT6 4T1 CT26 1500 1000 500 Mean Tumor Volume (mm Volume Mean Tumor 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Cavro or Linear EMT6 Days (SC, 0.8 mg/kg) Re-challenge Anti-PD-1 (IP, 10 mg/kg) Linear oligo + anti-PD-1: p = 0.009 vs vehicle on day 27; murine cavro + anti-PD-1: p < 0.0001 vs vehicle on day 27. BALB/c mice; N = 8/group; data presented as mean + SEM. 30 SC = subcutaneous, IP = intraperitoneal
Murine Cavrotolimod Produces Both a Superior Anti-tumor Response Versus Linear Oligonucleotides and a Tumor-specific Memory Response Cavrotolimod Cavrotolimod-Treated Mice Immunity is Tumor- Superior Develop Long Term Immunity to Specific to Linear EMT6 Tumors Naïve Mice Naïve Mice Naïve Mice Vehicle EMT6 4T1 ) Anti-PD-1 CT26 3 2000 Anti-PD-1+Linear Oligo Cavro-Treated Mice Cavro-Treated Mice Anti-PD-1+Cavro EMT6 4T1 CT26 1500 1000 500 Mean Tumor Volume (mm Volume Mean Tumor 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Cavro or Linear EMT6 Days 4T1 or CT-26 (SC, 0.8 mg/kg) Re-challenge Challenge Anti-PD-1 (IP, 10 mg/kg) Linear oligo + anti-PD-1: p = 0.009 vs vehicle on day 27; murine cavro + anti-PD-1: p < 0.0001 vs vehicle on day 27. BALB/c mice; N = 8/group; data presented as mean + SEM. 31 SC = subcutaneous, IP = intraperitoneal
Dose Escalation Data Steve O’Day MD
Phase 1b Dose Escalation Summary Clinically meaningful overall Durable response Systemic effects response rate Proof of concept in largely Pharmacodynamic profile Good safety profile and well refractory population corroborating efficacy tolerated 33
Phase 1b Dose Escalation Summary Clinically meaningful overall response rate ORR 21% (all doses) ORR 33% (highest and Phase 2 dose) 34
Phase 1b Dose Escalation Summary Clinically meaningful overall Durable response response rate ORR 21% (all doses) 16 months to date and ongoing in all 4 responders ORR 33% (highest and Phase 2 dose) 6+ months in all 4 responders 35
Phase 1b Dose Escalation Summary Clinically meaningful overall Durable response Systemic effects response rate ORR 21% (all doses) 16 months to date and ongoing in Regression in distant and regional all 4 responders lesions ORR 33% (highest and Phase 2 dose) 6+ months in all 4 responders 36
Phase 1b Dose Escalation Summary Clinically meaningful overall Durable response Systemic effects response rate ORR 21% (all doses) 16 months to date and ongoing in Regression in distant and regional all 4 responders lesions ORR 33% (highest and Phase 2 dose) 6+ months in all 4 responders Proof of concept in largely refractory population Progressive disease on prior anti- PD-1: 85% Two or more lines of systemic therapy: 65% 37
Phase 1b Dose Escalation Summary Clinically meaningful overall Durable response Systemic effects response rate ORR 21% (all doses) 16 months to date and ongoing in Regression in distant and regional all 4 responders lesions ORR 33% (highest and Phase 2 dose) 6+ months in all 4 responders Proof of concept in largely Pharmacodynamic profile refractory population corroborating efficacy Progressive disease on prior anti- Increased serum PD-1: 85% cytokines/chemokines Two or more lines of systemic Increased activation therapy: 65% of immune cells Increased tumor infiltration by immune cells 38
Phase 1b Dose Escalation Summary Clinically meaningful overall Durable response Systemic effects response rate ORR 21% (all doses) 16 months to date and ongoing in Regression in distant and regional all 4 responders lesions ORR 33% (highest and Phase 2 dose) 6+ months in all 4 responders Proof of concept in largely Pharmacodynamic profile Good safety profile and well refractory population corroborating efficacy tolerated Progressive disease on prior anti- Increased serum No treatment-related serious AEs PD-1: 85% cytokines/chemokines or grade 4 AEs Two or more lines of systemic Increased activation Most common AEs are flu-like therapy: 65% of immune cells symptoms, injection site reactions, expected from mechanism of action Increased tumor infiltration by immune cells Support highest dose (32 mg) in Phase 2 39
Seamless Phase 1b/2 Dose Escalation and Dose Expansion Study STUDY ELEMENTS PHASE 1b DOSE ESCALATION Open-label, multicenter Phase 1b/2 combined dose-escalation/dose-expansion study Intratumoral (IT) cavrotolimod plus pembrolizumab across all solid tumors in the Phase 1b dose escalation portion Two or more lesions required; one tumor to remain noninjected with cavrotolimod to observe regional and systemic immune effects Intensive local and systemic pharmacodynamic assessments Single-arm Phase 2 cohorts in anti-PD-(L)1 antibody progressive MCC and CSCC populations 40
Study Dosing Schedule and Assessments DOSING CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4+ W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 Cavrotolimod IT Pembrolizumab IV Assessments CT/MRI scans (RECIST v1.1) Peripheral pharmacodynamic assessments: • Cytokines/chemokines Tumor photography • Immune cell profiling Tumor biopsy analyses: Pharmacokinetics • Immunohistochemistry • Gene expression profiling Safety W: week. 41
Dose Escalation Mostly Enrolled Patients with Cutaneous Tumors that had Previously Progressed on Anti-PD-1 Antibodies Baseline characteristics (N=20) n (%) Melanoma 10 (50%) Merkel cell carcinoma 5 (25%) Cancer type Cutaneous squamous cell carcinoma 2 (10%) Head & neck squamous cell carcinoma 2 (10%) Leiomyosarcoma 1 (5%) Cancer stage Metastatic disease 19 (95%) History of anti-PD-1 use 19 (95%) Best prior response: progressive disease 12 (60%) Prior anti-PD-1 Last prior response: progressive disease 17 (85%) Time since last dose ≤12 weeks (N=19) 15 (79%) 1 7 (35%) Prior lines of systemic therapy 2 5 (25%) 3+ 8 (40%) 42
Clinically Meaningful Confirmed Overall Response Rate Observed in Phase 1b Patients 21% ORR 33% ORR All Dose Levels 32 mg Dose Level 4 PR of 19 evaluable patients 2 PR of 6 patients 43
Durable Confirmed Responses Observed After Treatment All Four Responses Ongoing, All at Least 6 Months in Duration; One Patient With 16 Month Response End of combination treatment 10 Merkel2- Follow-up after end of combination treatment 2 mg0… 10 Merkel1- 4 mg0… 10 Melanoma4- 32 mg0… End of cavrotolimod treatment 10 Melanoma4- Follow-up 32 mg0… 0 12 24 36 48 60 72 84 Time from First Dose of Cavrotolimod in Weeks Overall response: Partial response Overall response: Stable disease Active treatment 44
Confirmed Responses Observed in Anti-PD-1 Refractory Tumors Three of Four Responders Were Progressing on Anti-PD-1 at Enrollment Prior Anti-PD-1 Time Between Last Tumor Last Response Dose of PD-1 and First Cavro Dose End of combination treatment MCC Relapsed off anti-PD-1 69 weeks Follow-up after end of treatment MCC Progressive disease 3 weeks Mel. Progressive disease 6 weeks End of cavrotolimod treatment Mel. Progressive disease 8 weeks Follow-up 0 12 24 36 48 60 72 84 Time from First Dose of Cavrotolimod in Weeks Overall response: Partial response Overall response: Stable disease Active treatment 45
Response in Refractory Melanoma Patient with Progression on Anti-PD-1 at Enrollment PRIOR TO CAVRO, PROGRESSION ON PEMBROLIZUMAB Before pembrolizumab After 3 cycles of pembrolizumab 76-year-old man with melanoma 46
Response in Refractory Melanoma Patient with Progression on Anti-PD-1 at Enrollment RESPONSE TO CAVROTOLIMOD + PRIOR TO CAVRO, PROGRESSION ON PEMBROLIZUMAB PEMBROLIZUMAB AT 12 WEEKS Before pembrolizumab After 3 cycles of pembrolizumab PR ongoing through 36 weeks 76-year-old man with melanoma 47
Response in Refractory Melanoma Patient with Progression on Anti-PD-1 at Enrollment RESPONSE TO CAVROTOLIMOD + LESIONS AT BASELINE PEMBROLIZUMAB AT 12 WEEKS Effects on both lesions Non-injected Injected 76-year-old man with melanoma 48
Robust Pharmacodynamic Response in Refractory Melanoma Patient with Progression on Anti-PD-1 at Enrollment Peripheral Chemokine and Cell Activation IP-10 NK Cells Cytotoxic T Cells (pg/mL) (% Activated) (% Activated) 2399 86 63 26 25 132 Predose Postdose Predose Postdose Predose Postdose 49 Postdose: 24 hours post cavrotolimod 32 mg + pembrolizumab
Complete Response of Injected and Noninjected Tumors in Anti- PD-1 Relapsed Merkel Cell Patient Week 3 86-year-old woman with Merkel cell carcinoma Complete response on pembrolizumab; relapsed after discontinuation On cavrotolimod + pembrolizumab, overall partial response/complete target response observed at 12 weeks (initial assessment) through 16 months (ongoing) 50
Complete Response of Injected and Noninjected Tumors in Anti- PD-1 Relapsed Merkel Cell Patient Week 3 Week 12 86-year-old woman with Cavrotolimod + Merkel cell carcinoma pembrolizumab Complete response on pembrolizumab; relapsed after discontinuation On cavrotolimod + pembrolizumab, overall partial response/complete target response observed at 12 weeks (initial assessment) through 16 months (ongoing) 51
Systemic Immune Activation Observed after Cavrotolimod Dosing in Relapsed Merkel Cell Patient Peripheral Chemokine and Cell Activation IP-10 NK Cells Cytotoxic T Cells (pg/mL) (% Activated) (% Activated) 547 57 51 17 11 46 Predose Postdose Predose Postdose Predose Postdose 52 Postdose: 24 hours post cavrotolimod 2 mg
Decreased Target Tumor Diameter Observed in 37% of Patients Target Tumor Response: Sum of Injected and Noninjected Lesions 100% 0% Mel CSCC MCC Mel Mel Mel MCC MCC HSNCC Mel Mel Mel MCC MCC LMS Mel Mel Change in from Change Baseline Target Lesion Diameters (%) Lesion Diameters Target -100% Figure excludes 3 patients who did not have post-treatment CT scan assessment 53
Regression Observed in Both Cavrotolimod-Injected and Noninjected Tumors Target Tumor Response: Sum of Injected Lesions vs Sum of Noninjected Lesions 100% Mel Mel 0% n/a Mel CSCC MCC Mel MCC MCC HSNCC Mel Mel Mel MCC MCC LMS Mel Mel n/a Change from Baseline from Change in Target Lesion Diameters (%) Lesion Diameters in Target Injected Noninjected -100% In one patient, injected and noninjected lesions fused; in another patient, all target lesions were inadvertently injected 54
Tumor Regression Observed in Distant, Noninjected Lesions Injected Noninjected CSCC -33% R face -33% L neck -20% R lung 55
Tumor Regression Observed in Distant, Noninjected Lesions Injected Noninjected CSCC MCC Melanoma MCC -33% R face -33% -29% L neck R axillary LN -47% L abdomen -20% R lung -100% -50% L leg -30% L axillary LN R axillary LN -29% L abdomen -100% L leg Overall response PD (new lesion) PR PD (new lesion) PR 56 PD: progressive disease; PR: partial response
Cavrotolimod Safe and Generally Well Tolerated Injection Site Reactions and Flu-like Symptoms as Expected from Local and Systemic Immune Activation • Majority (98%) of treatment-related adverse events (AEs) were Grade (G) 1 or 2 • Injection site reactions and flu-like symptoms were the most commonly reported AEs ‒ Dose response; observed in 100% of patients at the highest dose (32 mg) ‒ Tolerable; G1 or G2 except for one G3 ISR • No dose-limiting toxicities, supporting the highest dose (32 mg) in Phase 2 stage • No treatment-related serious AEs • No treatment-related G4 AEs • G3 treatment-related AEs in 2 subjects 57
Pharmacodynamic Data Weston Daniel, PhD; VP Translational Research
Comprehensive Pharmacodynamic Profile Consistent with Antitumor Immune Activation INCREASED CYTOKINES AND CHEMOKINES ACTIVATED CIRCULATING IMMUNE EFFECTOR CELLS >20x IP-10/CXCL10 35% → 91% 21% → 62% >1.5x IL-12p40 Activated NK cells Activated Cytotoxic T cells (% that are activated) (% that are activated) cavrotolimod 16-32 mg monotherapy vs baseline. N = 8 cavrotolimod 16-32 mg monotherapy. N = 8 59
Comprehensive Pharmacodynamic Profile Consistent with Antitumor Immune Activation INCREASED CYTOKINES AND CHEMOKINES ACTIVATED CIRCULATING IMMUNE EFFECTOR CELLS >20x IP-10/CXCL10 35% → 91% 21% → 62% >1.5x IL-12p40 Activated NK cells Activated Cytotoxic T cells (% that are activated) (% that are activated) cavrotolimod 16-32 mg monotherapy vs baseline. N = 8 cavrotolimod 16-32 mg monotherapy. N = 8 INDUCED TUMOR INFILTRATION AND KILLING BY CYTOTOXIC IMMUNE CELLS Cavrotolimod Effects Injected Tumors 2x more cytotoxic cells and CD8 T cells 3x more granzyme B transcript expression 3x less TGF-β2 transcript expression cavrotolimod 2-32 mg monotherapy vs baseline. N = 9 60
Comprehensive Pharmacodynamic Profile Consistent with Antitumor Immune Activation INCREASED CYTOKINES AND CHEMOKINES ACTIVATED CIRCULATING IMMUNE EFFECTOR CELLS >20x IP-10/CXCL10 35% → 91% 21% → 62% >1.5x IL-12p40 Activated NK cells Activated Cytotoxic T cells (% that are activated) (% that are activated) cavrotolimod 16-32 mg monotherapy vs baseline. N = 8 cavrotolimod 16-32 mg monotherapy. N = 8 INDUCED TUMOR INFILTRATION AND KILLING BY CYTOTOXIC IMMUNE CELLS Cavrotolimod Effects Cavrotolimod + Pembrolizumab Effects Injected Tumors Injected Tumors Non-injected Tumors 2x more cytotoxic and CD8 T cells 2x more LFA-1 3-5x more T cell transcript expression receptor complex and 2x more expression of 3x more granzyme B granzyme transcript expression select interferon- transcript expression inducible genes 3x less TGF-β2 transcript 4x more cytotoxic and 2-3x more interferon expression CD8 T cells gamma transcript expression cavrotolimod 2-32 mg monotherapy vs baseline. N = 9 cavrotolimod 2-32 mg + pembro vs baseline. N = 9 cavrotolimod 2-32 mg + pembro vs baseline. N = 8 61
Cavrotolimod Promotes the Remaining Steps of the Cancer Immunity Cycle and Contributes to Anti-tumor Responses in Anti-PD-1 Resistant Tumors 4 Step Release of cancer cell antigens 1 Driven by activated NK and T cells 3 Step Cancer antigen presentation 2 Driven by TLR agonism Step Priming and activation 5 3 Disinhibited by anti-PD-1 / anti-PD-L1 Driven by IL-12 Step Trafficking of T cells to tumors 4 Driven by IP-10 (CXCL10) Step Infiltration of T cells into tumors 2 5 Driven by LFA-1 expression 6 Step 6 Recognition of cancer cells by T cells Driven by T-cell receptor complex expression Step Killing of cancer cells 1 7 7 Disinhibited by anti-PD-1 / anti-PD-L1 Driven by interferon gamma and granzymes Immunity, Volume 39, Issue 1, 25Jul2013, Pages 1-10. 62
Phase 1b Dose Escalation Summary Clinically meaningful overall Durable response Systemic effects response rate ORR 21% (all doses) 16 months to date and ongoing in Regression in distant and regional all 4 responders lesions ORR 33% (highest and Phase 2 dose) 6+ months in all 4 responders Proof of concept in largely Pharmacodynamic profile Good safety profile and well refractory population corroborating efficacy tolerated Progressive disease on Increased serum No treatment-related serious AEs prior anti-PD-1: 85% cytokines/chemokines or grade 4 AEs Two or more lines of Increased activation Most common AEs are flu-like systemic therapy: 65% of immune cells symptoms, injection site reactions, expected from mechanism of action Increased tumor infiltration by immune cells Support highest dose (32 mg) in Phase 2 63
Merkel Cell Carcinoma and Cutaneous Squamous Cell Carcinoma Shailender Bhatia MD
Skin, the Largest Organ, is Also the Most Vulnerable to Cancer Development Non-melanoma Skin Cancers Skin Cancer Incidence (US) Skin Cancer Deaths (US) (NMSCs) Mel: 60,000 BCC: 1,250 • 5.4 million diagnosed in 2012 CSCC: 700,000 • 3.3 million treated MCC: 600 CSCC: 1,250 – 80% BCCs MCC: 3,000 – 20% CSCC – <1% others (including MCC) BCC: Mel: 8,000 2,800,000 NOTE: Numbers don’t represent recent estimates. Rogers HW, et al. JAMA Dermatol. 2015. BCC: Basal cell carcinoma; CSCC: cutaneous squamous cell carcinoma; MCC: Merkel cell carcinoma 65
Alarming Increase in Incidence of Aggressive Skin Cancers 2500 New MCC Cases in 2013; Incidence Rate by Age Estimated ~3300 by the Year 2025 Paulson K, et al. J Am Acad Dermatol. 2017. MCC: Merkel cell carcinoma 66
Merkel Cell Carcinoma (MCC): An Aggressive Cancer With Poor Outcomes Rapid Progression of MCC After ~1 year • Disease-mortality rate ~45% (3-fold higher than melanoma) • Historical 5-year overall survival for stage IV MCC < 20% Lemos BD, et al. J Am Acad Dermatol. 2010. 67
Cutaneous Squamous Cell Carcinoma (CSCC): Like MCC, an Aggressive Cancer With Poor Outcomes Metastatic CSCC Overall Survival for Metastatic CSCC • Historical 5-year overall survival rate of 26% for stage 4 disease • Historical median overall survival was 2.2 years Gutzmer R, et al. Dtsch Arztebl Int. 2019. Chang ALS, et al. J Am Acad Dermatol. 2015. 68
NMSCs Have a Strong Rationale for Immunotherapy BCC also has a very high TMB (median ~45/MB) Yarchoan, et al. NEJM. 2017. Harms, et al. CA Res. 2015. Walter A, et al. CCR. 2010. Paulson, et al. Unpublished. BCC: basal cell carcinoma; CSCC: cutaneous squamous cell carcinoma; MB: megabase; MCC: Merkel cell carcinoma; NMSC: non-melanoma skin cancer 69
High Response Rates with Anti-PD-1 Therapy in NMSCs Like MCC But Distinct Populations with Unmet Need Have Emerged Intrinsic Resistance First Line Pembrolizumab in MCC Non-responders to PD-1 blockade Acquired Resistance Progressors after initial response Nghiem P, Bhatia S et al. 2016 NEJM 70
Nonmelanoma Skin Cancers Are Optimal Tumors for Development of Intratumoral Immunotherapies Like Cavrotolimod Rare but Strategic Confluence of favorable factors 71
Nonmelanoma Skin Cancers Are Optimal Tumors for Development of Intratumoral Immunotherapies Like Cavrotolimod Rare but Strategic Confluence of favorable factors Responsive to Immunotherapy Among cancers with the highest tumor mutational burdens (TMB) Large diversity of neoantigens available as immune targets, including viral antigens 72
Nonmelanoma Skin Cancers Are Optimal Tumors for Development of Intratumoral Immunotherapies Like Cavrotolimod Rare but Strategic Unmet Medical Need High morbidity and mortality of Confluence of favorable factors advanced MCC and CSCC; even greater than melanoma Responses to anti-PD-(L)1 appear less durable than melanoma Responsive to Immunotherapy No second-line therapies approved Among cancers with the highest in MCC or CSCC tumor mutational burdens (TMB) Large diversity of neoantigens Relatively limited number of available as immune targets, therapies in development including viral antigens 73
Nonmelanoma Skin Cancers Are Optimal Tumors for Development of Intratumoral Immunotherapies Like Cavrotolimod Practical, Personalized Rare but Strategic Unmet Medical Need Dosing High morbidity and mortality of Superficial lesions amenable to advanced MCC and CSCC; even Confluence of favorable factors injection in outpatient clinics greater than melanoma Repeated dosing and dosing of Responses to anti-PD-(L)1 appear multiple lesions captures antigenic less durable than melanoma diversity and evolving neoepitopes Responsive to Immunotherapy No second-line therapies approved No antigen identification or Among cancers with the highest in MCC or CSCC isolation needed in advance tumor mutational burdens (TMB) Large diversity of neoantigens Relatively limited number of available as immune targets, Off-the-shelf in situ immunization therapies in development including viral antigens 74
Phase 2 Dose-Expansion Stage Emil deGoma MD; VP Clinical Development
Rationale for Prioritization of Advanced MCC and CSCC Refractory to Anti-PD-(L)1 Therapy in Phase 2 Dose-Expansion Stage UNMET MEDICAL NEED RESPONSIVE TO IMMUNOTHERAPY EFFICIENT DEVELOPMENT • High morbidity and mortality of • Robust mechanistic rationale • Rare refractory skin tumors, advanced MCC and CSCC; even ‒ Among cancers with the highest with significant unmet need, greater than melanoma tumor mutational burdens (TMBs) in combination with positive preliminary efficacy data, • Responses to anti-PD-(L)1 less Large diversity of neoantigens ‒ support efficient development durable than melanoma available as immune targets • No second-line therapies • Cavrotolimod Phase 1b results • Orphan Drug and Fast Track approved in MCC or CSCC ‒ Tumor responses, including • Relatively limited number of regression of MCC, CSCC therapies in development ‒ Pharmacodynamic data support immune activation 76
Phase 2 Dose-Expansion Stage in Anti-PD-(L)1 Refractory Patients Merkel cell carcinoma Documented progression on anti-PD-(L)1 therapy Cavrotolimod 32 mg IT + pembrolizumab IV N=29 Cutaneous squamous cell carcinoma Documented progression on anti-PD-1 therapy Cavrotolimod 32 mg IT + cemiplimab IV N=29 Solid tumors (including melanoma) Anti-PD-(L)1 Refractory Disease Definition: All Cohorts • Documented and confirmed radiographic and/or clinical progression • Minimum duration of approved anti-PD-(L)1 therapy 77
Phase 2 Dosing Schedule and Assessments DOSING CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4+ W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 Cavrotolimod 32 mg IT Pembrolizumab IV (MCC) or Cemiplimab IV (CSCC) Assessments CT/MRI scans (RECIST v1.1) Peripheral pharmacodynamics: Cytokines/chemokines; Tumor photography Immune cell profiling Patient-reported outcomes Tumor pharmacodynamics: Immunohistochemistry; Pharmacokinetics gene expression profiling Safety CSCC: cutaneous squamous cell carcinoma. MCC: Merkel cell carcinoma. W: week. 78
Support from Leading Investigators and Top-Tier Sites Dana-Farber Cancer Institute Northwestern University University of Seattle Cancer Care Alliance University of Iowa Pittsburgh (University of Washington) University of Cincinnati Memorial Sloan Kettering Mount Sinai University of California San Francisco Norton Cancer Center John Wayne Cancer Institute (Providence St. John’s) Duke University University of California Irvine University of Arizona University of Miami University of Washington Colorado University MD Anderson Baylor University 79
Timelines for Phase 2 Stage INDICATIONS 2020 2021 2022 Merkel Cell Carcinoma Refractory to Anti-PD-(L)1 Cavrotolimod IT + pembrolizumab IV Phase 2 ORR readout N=29 Interim ORR readout Cutaneous Squamous Cell Carcinoma Refractory to Anti-PD-1 Cavrotolimod IT + cemiplimab IV Phase 2 ORR readout N=29 Interim ORR readout 80
Vision for Expansion Douglas Feltner MD; CMO
Leveraging Experience to Address Additional Skin Cancers Cutaneous Squamous Merkel Cell Carcinoma Cell Carcinoma Skin Cancers Amenable to intratumoral injection Highly immunogenic Basal Cell Carcinoma Overlapping provider population Melanoma • Addressable population • Further assess as data of 7,500 accrue in Phase 2 cohort • High tumor mutational burden • Supportive anti-PD-1 data 82
Adjacent Skin Cancers as Most Proximal Potential Next Steps Locally Advanced/Metastatic Melanoma • Responses (2/4) observed in PD-1 resistant patients with cavrotolimod in Phase 1b at 32 mg • Further assess ORR in Phase 2 cohort • Encouraging data from other TLR9 agonists Locally Advanced/Metastatic Basal Cell Carcinoma (BCC) • Responsive to immunotherapy – Superficial BCCs treated with TLR agonist imiquimod – 29% ORR observed in advanced/metastatic BCC after treatment with anti-PD-1 antibody cemiplimab1 – Intralesional injection of TLR9 agonist PF-3512676 produced injected lesion response in 5/5 patients dosed2 • Anticipated cemiplimab approval to accelerate combination use in BCC • Unmet need persists despite first line drug 1: Sanofi announcement May 2020; 2: J Immunother 2008;31:520–527 83
Indication Expansion Opportunities Market Opportunity (2026, estimated) Indication Primary or Secondary Incident Cavro Target Resistance to anti-PD-1 Patient Population Melanoma 70-80% ~10,000 Basal Cell Carcinoma 70-80% ~7,500 Head and Neck Squamous Cell Carcinoma 75-85% ~13,000 Non-Small Cell Lung Cancer 70-80% ~40,000 Sarcoma (Mismatch repair deficient) 80-90% ~4,000 GlobalData data; Munhoz 2018; Betof-Warner 2020; Sanofi press release 2020; KEYNOTE-048 trial data; Cancer Research Institute; SARC028 trial data; Wan 2019; KEYNOTE-042 data 84
Cavrotolimod Positioning Douglas Feltner MD; CMO
Cavrotolimod Clinical Profile Highly Competitive vs Other TLR9 Agonists Sponsor Efficacy Combination ORR Durability Safety All solid tumors: Median: not reached Unrelated SAEs: 5% Exicure Pembrolizumab 21% (all doses) ≥6 months: 100% Related SAE: 0 33% (highest dose) (4 of 4) Median: 20 months Checkmate Pembrolizumab Melanoma: 23-28% >6 months: 97% Related SAEs: 17% Pharma1 (36 of 37) Median: 11 months Idera2 Ipilimumab Melanoma: 22% >6 months: 64% Any SAEs: 32% (7 of 11) Median: 7 months TriSalus3 Pembrolizumab Melanoma: 13-19% Related G3/4: 16-23% (8 mg) 1) Checkmate Pharmaceuticals IPO roadshow presentation, August 2020. 2) Idera corporate presentation August 2020. 3) Previously Dynavax. Amin ASCO 2019. Ribas ESMO 2018. https://investors.dynavax.com/news-releases/news-release-details/trisalus-life-sciences-acquires-dynavaxs-sd-101-oncology-program. 86
Cavrotolimod Summary Douglas Feltner MD; CMO
Summary of Cavrotolimod and Dose Escalation Results • Cavrotolimod (AST-008) is a TLR9 agonist that leverages Exicure’s SNA platform • Cavrotolimod has shown a positive efficacy profile in the Phase 1b dose escalation study evaluating intratumoral (IT) cavrotolimod + IV pembrolizumab in patients with advanced solid tumors • Overall response rate (ORR) of 33% (2/6) at highest dose, 21% (4/19) overall • Durable response: Responses have persisted for at least 6+ months and are ongoing in all 4 responders; longest observed response duration is 16 months • Regional and systemic anti-tumor effects: Evidenced by regression of noninjected lesions, supporting a systemic response • Corroborative pharmacodynamic data supports regional and distant anti-tumor effects 88
Summary of Cavrotolimod and Dose Escalation Results Continued • Highest Phase 1B dose (32 mg) chosen for Phase 2, as recommended by Data Review Committee • The cavrotolimod clinical profile is highly competitive compared with other TLR9 agonists in development • First-to-market opportunity in two rare skin cancers with high unmet medical need-- 2nd line advanced/metastatic Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (CSCC), supporting an efficient development and registration strategy and eventual accelerated approval • Strong IP position (composition of matter coverage until 2035) • Robust, scalable, and reproducible CMC process 89
Closing Remarks David Giljohann PhD, CEO
Q&A