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): June 4, 2018
Dynavax Technologies Corporation
(Exact name of registrant as specified in its charter)
Commission File Number: 001-34207
| Delaware | 33-0728374 | |
| (State or other jurisdiction of incorporation) |
(IRS Employer Identification No.) |
2929 Seventh Street, Suite 100
Berkeley, CA 94710-2753
(Address of principal executive offices, including zip code)
(510) 848-5100
(Registrant’s telephone number, including area code)
(Former name or former address, if changed since last report)
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:
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
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 ☐
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. ☐
| Item 8.01 | Other Events |
On June 4, 2018, Dynavax Technologies Corporation, a Delaware corporation (“Dynavax”), issued a press release and presented a corresponding poster and investor presentation announcing data from its ongoing Phase 1b/2 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA® (pembrolizumab), an anti-PD-1 therapy developed by Merck & Co., Inc. (known as MSD outside the United States and Canada) in patients with advanced melanoma at the 2018 American Society of Clinical Oncology Annual Meeting, in Chicago, IL. A copy of the press release, the poster and the investor presentation are filed as Exhibits 99.1, 99.2 and 99.3 to this Current Report on Form 8-K and are incorporated herein by reference.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
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.
| Dynavax Technologies Corporation |
| Date: June 4, 2018 | By: | /s/ STEVEN N. GERSTEN | ||
| Steven N. Gersten | ||||
| Vice President, General Counsel and Chief Ethics and Compliance Officer | ||||
Exhibit 99.1
Dynavax Reports Data for Phase 1b/2 Trial of SD-101 in Combination with KEYTRUDA®
(pembrolizumab) in Advanced Melanoma at the 2018 American Society of Clinical Oncology
(ASCO) Annual Meeting
Overall Response Rate (ORR) of 70% and 6-month Progression Free Survival (PFS) rate of 76% in
Patients Naïve to Anti-PD-1 Treatment who Received the £ 2mg Dose of SD-101
Combination showed Similar Rates of Immune-related Adverse Events as Seen with KEYTRUDA
Monotherapy
2mg SD-101 Dose Selected for Phase 3
BERKELEY, Calif., June 4, 2018 – Dynavax Technologies Corporation (NASDAQ:DVAX) today announced data from its ongoing Phase 1b/2 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA® (pembrolizumab), an anti-PD-1 therapy developed by Merck (known as MSD outside the United States and Canada) in patients with advanced melanoma.
The company reported results on a total of 69 patients comparing two doses of SD-101, £ 2mg (n=30) versus 8mg (n=39) administered by intratumoral injection. These data are being presented in poster and discussion session today at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, in Chicago, IL. The primary endpoints of this dose-expansion/dose-finding study are safety and preliminary efficacy. The results of this study showed a 70% overall response rate (ORR) in advanced melanoma patients who received the £ 2 mg dose of SD-101 in up to four lesions versus a 38% ORR in the group receiving the 8 mg dose of SD-101 in one lesion. The combination of SD-101 and KEYTRUDA was well tolerated with adverse events related to SD-101 being transient, mild to moderate flu-like symptoms.
“These data provide further evidence of the potential for SD-101 to improve responses in first-line advanced melanoma patients in combination with an anti-PD-1 therapy,” commented Eddie Gray, Chief Executive Officer. “Our studies continue to demonstrate the potential value of SD-101 across multiple tumor types. We plan to build upon this momentum and update our progress with additional data planned for a medical conference later in the year.”
Highlights from Poster Presentation (Abstract #9513)
| • | Overall response rate (ORR) of 70% (21 of 30), with a complete response (CR) rate of 17%, for advanced melanoma patients who received the £ 2 mg dose of SD-101 in up to four lesions |
| • | ORR of 38% (15 of 39) in patients who received the 8 mg dose of SD-101 in one lesion |
| • | Durable response in patients who received £ 2 mg dose of SD-101 with 74% 6-month progression free survival (PFS) rate |
| • | Observed responses in injected lesion(s) and distant lesions, including visceral metastases in the liver |
| • | Responders included 8 of 10 PD-L1 negative patients in the £ 2 mg dose cohort |
| • | AEs related to SD-101 treatment were transient, mild to moderate flu-like symptoms at both the £ 2mg and the 8 mg dosing levels |
| • | No increase in the frequency of immune-related adverse events over individual monotherapies reported in other studies1,2 nor evidence of any new safety signals |
Additional details on response rates based on patient characteristics including stage of disease, ECOG score, and PD-L1 status are also included in the poster presentation which can be accessed here.
“We are moving forward with the 2mg dose of SD-101 for our Phase 3 trial which we believe is the optimal dose based on these efficacy, safety and biomarker data showing increased immune activation consistent with the biology of TLR9 activation. We continue to collect and analyze data from this trial to finalize details of the Phase 3 study design,” stated Rob Janssen, Chief Medical Officer.
The details of the poster presentation and discussion session are as follows:
Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy
Session Title: Melanoma/Skin Cancers
Abstract: 9513
Poster Board: 340
Poster Session Date/Time: Monday, June 4, 2018, 1:15 PM - 4:45 PM CDT
Poster Session Location: McCormick Place South, Hall A, Advanced Disease Poster Section
Discussion Session Date/Time: Monday, June 4, 2018, 4:45 PM - 6:00 PM CDT
Discussion Session Location: McCormick Place Lakeside Center, Level 4 - E451
Analyst/Investor Presentation
Today at 6:30pm CDT, Dynavax will host a presentation for analysts and investors. The presentation will be available via live webcast only and can be accessed in the “Investors and Media” section of the company’s website at www.dynavax.com.
About SYNERGY-001 (KEYNOTE-184)
SYNERGY-001, previously referred to as MEL-01, is the dose-escalation and expansion study of SD-101 in combination with KEYTRUDA which includes patients with histologically or cytologically confirmed unresectable Stage IIIC/IV melanoma. The primary endpoints of the trial are safety and preliminary efficacy of intratumoral SD-101 in combination with KEYTRUDA.
About SD-101
SD-101, the Company’s lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating this intratumoral TLR9 agonist in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA® (pembrolizumab), an anti-PD-1 therapy, in patients with advanced melanoma and in patients with head and neck squamous cell cancer, in a clinical collaboration with Merck. Dynavax maintains all commercial rights to SD-101.
About Dynavax
Dynavax is a fully-integrated biopharmaceutical company focused on leveraging the power of the body’s innate and adaptive immune responses through toll-like receptor (TLR) stimulation. Dynavax discovers
and develops novel vaccines and immuno-oncology therapeutics. The Company’s first commercial product, HEPLISAV-B® [Hepatitis B Vaccine (Recombinant), Adjuvanted], was approved by the United States Food and Drug Administration in November 2017 for prevention of infection caused by all known subtypes of hepatitis B virus in adults age 18 years and older. Dynavax’s lead immunotherapy product, SD-101, is an investigational cancer immunotherapeutic currently being evaluated in Phase 1/2 studies and its second cancer immunotherapeutic, DV281, is in Phase 1 development. For more information, visit www.dynavax.com.
Forward Looking Statement
This press release contains “forward-looking” statements, including statements regarding the conduct of clinical trials of SD-101, including results from the Phase 1b/2 trial, planned optimal dosage for the Phase 3 trial, and potential value of SD-101 across multiple tumor types. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether we can timely provide adequate clinical supplies; initiation, enrollment and completion of clinical trials of SD-101; the results of clinical trials and the impact of those results on the initiation or continuation of subsequent trials and issues arising in the regulatory process; the ability to successfully develop and commercialize SD-101; and whether or not Dynavax and parties with whom we are collaborating may reach any future agreement on further studies or a more extensive collaboration beyond the clinical trials contemplated under the existing agreements, as well as other risks detailed in the “Risk Factors” section of our Annual Report on Form 10-K for the fiscal year ended December 31, 2017 and in Quarterly Report on Form 10-Q for the quarter ended March 31, 2018, as well as discussions of potential risks, uncertainties and other important factors in our other filings with the U.S. Securities and Exchange Commission. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available. Information on Dynavax’s website at www.dynavax.com is not incorporated by reference in our current periodic reports with the SEC.
KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
1. Ribas A, et al. JAMA. 2016;315(15):1600-1609.
2. Specenier P. Expert Opin Biol Ther. 2017;17(6):765-780.
# # #
| Contact: David Burke Director, IR & Corporate Communications 510.665.7269 dburke@dynavax.com |
Media Contact: Rachel St. Martin W2O wcg 646.894.5757 rstmartin@w2ogroup.com |
US-18-01-00103
Exhibit 99.2
|
Poster 9513 Phase 1b/2, Open-Label, Multicenter Study of the Combination of SD-101 and Pembrolizumab in Patients With Advanced Melanoma Who Are Naïve to Anti-PD-1 Therapy (SYNERGY-001)Antoni Ribas,1 Mohammed Milhem,2 Christopher Hoimes,3 Asim Amin,4 Inderjit Mehmi,5 Christopher Lao,6 Robert Conry,7 Montaser Shaheen,8 Sekwon Jang,9 April Salama,10 Sanjeev Deva,11 Theresa Medina,12 Shivaani Kummar,13 Joseph J Drabick,14 Minal Barve;15 Gregory A Daniels,16 Deborah L Wong,1 Emmett V. Schmidt,17 Abraham C.F. Leung,18 Albert Candia,18 Biao Xing,18 Robert Janssen,18 Georgina Long191David Geffen School f Medicine at the University of California Los Angeles, Los Angeles, CA, USA; 2University of Iowa Health Care, Iowa City, IA, USA; 3University Hospitals Seidman Cancer Center, Cleveland, OH, USA; 4Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA; 5West Virginia University—Mary Babb Randolph Cancer Center, Morgantown, WV, USA; 6The University of Michigan Health System, Ann Arbor, MI, USA; 7University of Alabama, Birmingham, AL, USA; 8University of Arizona Cancer Center, Tucson, AZ; 9Inova Health System, Fairfax, VA, USA; 10Duke University Medical Center, Durham, NC, USA; 11Auckland City Hospital, Auckland, NZ; 12University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 13Stanford University, Palo Alto, CA, USA; 14Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, PA, USA; 15Mary Crowley Cancer Research Center, Dallas, TX, USA; 16University of California, San Diego, San Diego, CA, USA; 17Merck & Co., Kenilworth, NJ, USA; 18Dynavax Technologies Corporation, Berkeley, CA, USA; 19Melanoma Institute Australia, Wollstonecraft, NSW, AustraliaPoster 9513 BACKGROUND SD-101 is a synthetic Class-C CpG-oligodeoxynucleotide that stimulates plasmacytoid dendritic cells (pDCs) through engagement of Toll-like receptor 9 (TLR9). This stimulation causes pDCs to release interferon-alpha and mature into efficient antigen-presenting cellsstrengthening both innate and acquired immune responses (Figure 1).1 Pembrolizumab is a PD-1 inhibitor that has been approved for treatment of unresectable or metastatic melanoma.2 SD-101 in combination with pembrolizumab induced a 33% ORR in 18 patients with head and neck squamous cell carcinoma.3 Previously, we presented the best overall response in evaluable patients naïve to anti-PD-1 therapy (ASCO 2017)4 and durability data from the Phase 1b portion of this study (AACR 2018)5: –ORR in evaluable patients=78% (ITT, 2 CR, 5 PR, 2 not evaluable) –Landmark 12-month PFS rate=88% (ITT), with 86% of responses ongoing (median follow up of 18 months). Results from dose-finding in the Phase 1b and Phase 2 portions of the study are presented hereFigure 1. Both Innate and Adaptive Immune Responses Are Increased by Intratumoral Injection of SD-101. SD-101 engages TLR9 on plasmacytoid dendritic cells (pDCs) to secrete high levels of interferon-alpha, a potent immunomodulatory cytokine that is able to boost natural killer cell cytotoxic activity and induce recruitment of T cells to the TME. In addition, SD-101 induces DC maturation and the ability to cross-present tumor associated antigens, inducing CD8+ T cell responses (CTL). Turnor-specific T cells activated by DC and IFN in lymph node Dendritic cells take up antigens from dying tumor cells and migrate to the lymph nodes tumor antigens T cell IFN DC Lymph node Duing tumor DC SD-101 induces IFN and DC maturation SD-101 Blood vessel dying tumor CTL Uninjected tumors are destroyed by CTL generated in the SD-101 injected sites Chemokines (CXCL9, 10) T cell Tmor PD1, PD-L1 Anti-PD 1 IFNs stimulate tumor killing by NK cells Uninjected tumors are destroyed by CTL generated in the SD-101 injected sites CTL = CD8+ T cell; DC = dendritic cell; IFN = interferon; NK = natural killer; TLR = Toll-like receptor.OBJECTIVES RESULTSTable 1. Demographic and Baseline Characteristics of Patients by Dose Group (ITT Population) Characteristics£ 2 mg*(N=37)8 mg(N=39)Age (years)Median (Min, Max)67 (37, 81)66 (33, 89)Sex, n (%)Male25 (68)26 (67)Female12 (32)13 (33)ECOG PS, n (%)024 (65)30 (77)113 (35)9 (23)Baseline LDH (U/L), mean (SD)292 (362)216 (79)£ ULN, n (%)29 (78)31 (79)> ULN8 (22)8 (21)Time Since Diagnosis (years)Median (Min, Max)1.3 (0, 17)1.0 (0, 16)Stage at Screening, n (%)IIIC15 (41)9 (23)IVM1a8 (22)6 (15)IVM1b2 (5)6 (15)IVM1c9 (24)16 (41)Missing3 (8)2 (5) Organ Involvement, n (%)Lung9 (24)19 (49)Liver4 (11)2 (5)Lymph nodes18 (49)23 (59)Skin/ Subcutaneous 21 (57)14 (36)Bone3 (8)2 (5)Other12 (32)15 (38)PD-L1 Expression, n (%)Positive (³ 1%)8 (22)11 (28)Negative (< 1%)10 (27)13 (33)Pending19 (51)15 (38)Prior Systemic Therapy, n (%)10 (27)10 (26)Prior anti-CTLA4 therapy6 (16)4 (10)Prior lines of therapy, n (%)027 (73)29 (74)18 (22)9 (23)22 (5)03 or more01 (3)ECOG PS = Eastern Cooperative Oncology Group performance status; NA = not applicable; SD = standard deviation; ULN = upper limit of normal. *3 patients received 1 mg/lesion of SD-101.Table 2. Overview of Safety (Safety Population) Event, n (%)£ 2 mg(N=37)n (%)8 mg(N=39)n (%)Total(N=76)n (%)Any Treatment-related AE28 (76)36 (92)64 (84)Grade 3–4 8 (22)14 (36)22 (29)Chills3 (8)1 (3)4 (5)Myalgias6 (16)1 (3)7 (9)Injection-site pain2 (5)0 2 (3)Fatigue2 (5)4 (10)6 (8)Headache3 (8)2 (5)5 (7)Malaise2 (5)3 (8)5 (7)Any irAEs 6 (16)4 (10)10 (13)Grade 3–43 (8)2 (5)5 (7)irAEs (preferred term) All gradesHypothyroidism4 (11)2 (5)6 (8)Pneumonitis1 (3)1 (3)2 (3)Myositis01 (3)1 (1)Autoimmune retinopathy01 (3)1 (1)Autoimmune hepatitis01 (3)1 (1)Myasthenia gravis01 (3)1 (1)Colitis1 (3)01 (1)Autoimmune colitis1 (3)01 (1)Hypophysitis1 (3)01 (1)Autoimmune myocarditis01 (3)1 (1)Optic neuritis01 (3)1 (1)AEs leading to d/c of either or both drugs4 (11)10 (26)14 (18)SAEs9 (24)12 (31)21 (28)Death01 (3)1 (1)d/c = discontinuation; irAE = immune-related adverse event; SAE = serious adverse event; TEAE = treatment-emergent adverse event.Figure 3. Best Percent Change From Baseline in All Target Lesions Percent Change From Baseline, % Subjects £ 2 mg 8 mg 0 20 40 60 80 100 120 -20 -40 -60 -80 -100 -120 Table 3. Best Overall Response by Investigator Using RECIST v1.1 Response Rate£ 2 mg8 mgmITT*N=30N=39Overall Response Rate, n (%) (95% CI)21 (70) (52, 83)15 (38) (25, 54)CR5 (17)1 (3)PR16 (53)14 (36)SD3 (10)10 (26)PD4 (13)7 (18)Not evaluable†2 (7)7 (18)All enrolled patientsN=37N=39Not evaluable**7 (19)0 (0)*mITT = ITT excluding patients on study who have not yet had time to reach a first scan.†Patients discontinued prior to first scan: 1 or 2 mg—clinical progression (n=1), irAE (n=1); 8 mgclinical progression (n=2), AE/death (n=1); irAE (n=3), withdrew consent (n=1). **Patients on study who have not yet had a scan.Table 4. Durability of Responses £ 2 mg8 mgPFS6-month rate76% (16/21)41% (14/34)Median (months) Not reached4.2Median DOR (months)4.7+ (not reached)2.1+ (not reached)Median follow up (months)6.04.9 In subgroup analyses by baseline characteristics, the ORR in the 2 mg group was higher than in the 8 mg group (see Figure 4).Figure 4. Subgroup Analyses Favor £ 2 mg Dose Over 8 mg Dose £ 2 mg8 mgNORRNORRRR (95% CI)Age, yearOverall< 651275%1753%1.4 (0.8, 2.5)3070%3939%1.8 (1.1, 2.9)³ 651867%2227%2.4 (1.1, 5.2)SexMale2171%2642%1.7 (0.99, 2.9)Female967%1331%2.2 (0.8, 5.5)ECOG 01872%3043%1.7 (1.0, 2.7)11267%922%3.0 (0.8, 10.9)LDH£ ULN2568%3139%1.8 (1.0, 2.9)> ULN580%838%2.1 (0.8, 5.8)Stage at screeningIIIC1354%933%1.6 (0.6, 4.6)M1a-c1782%3040%2.1 (1.3, 3.4)M1a888%729%3.1 (0.9, 10.2)M1b1100%6 67%1.5 (0.9, 2.6)M1c875%1735%2.1 (0.99. 4.5)Number of prior lines of therapy02181%2935%2.3 (1.4, 4.0)1+944%1050%0.9 (0.3, 2.3) 4Risk Ratio Favors 8 mgFavors £ 2 mg CI = confidence interval; ECOG = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; ORR = overall response rate; RR = risk ratio; ULN = upper limit of normalFigure 5. Percent Change From Baseline Over Time in All Target Lesions for Patients Who Received £ 2 mg Versus 8 mg SD-101 Per Lesion –501070130190250310370430490550610670730610580550520490460430400370340310280250220190160130100704010–20–507507106706305905505104704303403903503102702301901501107030–10–50Days–501070130190250310370430490550610670730Days–501070130190250310370430490550610670730DaysAll Targets£ 2 mg/LesionInjected£ 2 mg/LesionNon-Injected£ 2 mg/LesionDaysDaysDaysAll Targets8 mg/LesionInjected8 mg/LesionNon-Injected8 mg/Lesion–100–80–60–40–20020406080100–100–80–60–40–20020406080100120140Percent Change From Baseline, %–100–80–60–40–20020406080100120140Percent Change From Baseline, %–100–80–60–40–20020406080100120140–100–80–60–40–20020406080100120140–100–80–60–40–20020406080100120140Percent Change From Baseline, %Percent Change From Baseline, %Percent Change From Baseline, %Percent Change From Baseline, %7507106706305905505104704303403903503102702301901501107030–10–50 Figure 6. Percent Change From Baseline in Target Lesions by Organ System Among Patients Who Received £ 2 mg SD-101 Per Lesion –50–20107040130100190160250220310280370340430400490550520610580460670700640730DaysLiver–100–80–60–40–20020406080100120140Percent Change From Baseline, % –50–20107040130100190160250220310280370340430400490550520610580460670700640730DaysLung–100–80–60–40–20020406080100120140Percent Change From Baseline, % –50–20107040130100190160250220310280370340430400490550520610580460670700640730DaysSubcutaneous Tissue–100–80–60–40–20020406080100120140Percent Change From Baseline, % Only 1 patient with a response discontinued due to progressive disease.8 mg/Lesion £ 2 mg/Lesion 050100150200250300350400450500550600650700750800850900DaysOngoingStable DiseaseProgressive DiseaseComplete ResponsePartial Response050100150200250300350400450500550600650700750800850900DaysSubjectsOngoingStable DiseaseProgressive DiseaseComplete ResponsePartial ResponseSubjectsFigure 7. Duration of Follow Up and Subject Status by DosageFigure 8. SD-101 in Combination With Pembrolizumab Leads to Antitumor Activity in Patients With Positive or Negative PD-L1 Expression at Baseline. A. Patients receiving a £ 2 mg dose. B. Patients receiving an 8 mg dose. Data sorted by PD-L1 expression. PD-L1 expression was assessed by immunohistochemistry using a validated assay with the DAKO 22C3 antibody. –50–20107040130100190160250220310280370340430400490550520610580460670700640730DaysOther–100–80–60–40–20020406080100120140Percent Change From Baseline, % –50–20107040130100190160250220310280370340430400490550520610580460670700640730DaysLymph Nodes–100–80–60–40–20020406080100120140Percent Change From Baseline, % –50–20107040130100190160250220310280370340430400490550520610580460670700640730DaysSkin–100–80–60–40–20020406080100120140Percent Change From Baseline, % A.B.Patients received £ 2 mg Patients received 8 mgPatient IDPD-L1 Expression (%TPS)BORPatient IDPD-L1 Expression (%TPS)BOR1010050CR1105080PR3055510CR1015530PR1104010PR1055040SD1155380PR1125070SD1015180PR1235280SD3055650PR1105110PD1020040PR1335470PD1085690SD1405500PD1010030Clinical PD1105220WC110501<1PR1305600Death AE1045301PR126542<1PR 1135233PR135519<1PD1265253SD123524<1PD3055453PD1235551PD11040430PR123552 2PR10100230PR1335105CR10153950PR13451510SD11557280PR11051225PR13356630PR13453230SD10951330PD10452080SD11050390CR12353390PRData presented here represent currently available samples. Analysis with other samples is ongoing.TPS = Tumor Proportion Score; BOR = Best Overall Response; WC = withdrew consent Figure 9. Administration of SD-101 and Pembrolizumab Results in an Increase in Infiltrating CD4 and CD Lymphocytes Supporting info:Subject 110404Naïve to prior anti-PD-1/L1BOR PR30% tumor PD-L1 expressionStill on study—Day 473ScreenDay 29Supporting info:Subject 110401Naïve to prior anti-PD-1/L1BOR PR0% tumor PD-L1 expressionTime to progression–Day 463 Red = CD4 T cells; Cyan = CD8 T cells; Yellow = Ki67; Green = S100; Dark blue = DAPI.Subject 110404 was devoid of CD4 T cells but not CD8 T cells at screening. Subject 110401 appeared to be devoid of CD4 and CD8 T cells at screening.Figure 10. The Combination of SD-101 and Pembrolizumab Induces Broad Immune Activity and Checkpoint Gene Expression in the Tumor Microenvironment. A. Postdose biopsies show a significant increase P<0.02) in a variety of immune cells. Values above the graphs represent the means and 95% confidence intervals. B Higher levels of checkpoint gene activity in post-dose biopsies are consistently observed at 8 mg. 050100150200CD8 T CellsPrePostActivity of GenesDefining Cell TypeActivity of GenesDefining Cell Type050100150200250Cytotoxic CellsPrePostPre: 24.5 ± 12.8Post: 77.2 ± 21.85020406080100NK CellsABPrePostPre: 16.2 ± 7.4Post: 47.6 ± 13.6Pre: 35.6 ± 26.9Post: 120.9 ± 34.6050100150200250Th1 CellsPre: 39.8 ± 19.5Post: 108.3 ± 36.3PrePost8 mg05001000150020002500IDO18 mg0100020003000LAG-3Normalized Gene ExpressionGeomean ± 95% CI£ 2 mg£ 2 mg£ 2 mg£ 2 mg8 mg0100200300400500600700800PD-L1Normalized Gene ExpressionGeomean ± 95% CI8 mg0500100015002000TIM-3 £ 2 mg dose8 mg dose CONCLUSIONSIn this non-randomized single-arm study, all patients had injectable lesions and were enrolled contemporaneously by the same investigators. The comparison of two different dose groups was prespecified to support the selection of a dose for phase 3. While not a randomized stu, the 8 mg group can potentially serve as an appropriate active-control group.SAFETY: The combination of SD-101 and pembrolizumab was well tolerated, consistent with previous reports. No evidence of an increased incidence or severity of AEs over monotherapy. No increase in immune-related AEs over pembrolizumab monotherapy.7,8 AEs associated with SD-101 were transient, mild to moderate injection-site reactions and flu-like symptoms that were manageable withover-the-counter medications. The combination of SD-101 and pembrolizumab appears to be much less toxic than the combination of nivolumab and ipilimumab.EFFICACY: The addition of SD-101 to pembrolizumab appears to improve pembrolizumab responses; £ 2 mg of SD-101 per lesion induced a much higher (ORR 70%) and more durable response rate than pembrolizumab with 8 mg of SD-101 (ORR 38%). In the £ 2 mg group, the median PFS has not been reached, the 6-month PFS rate is 76%, and the median DOR is 4.7+ months. In the 8 mg group, the median PFS is 4 months, the 6-month PFS rate is 41%, and the median DOR is 2.1+ months. Overall responses were higher in the £ 2 mg group than in the 8 mg group in every disease stage. Tumor shrinkage has been observed in both injected lesions and non-injected visceral lesions, including in the liver and lung. Preliminary data suggest that SD-101 may improve the immune response to PD-L1-negative tumors over pembrolizumab monotherapy. Multiple patients with negative PD-L1 expression at baseline had tumor responses. BIOMARKERS: Clinical responses were supported by immunologic data consistent with the mechanism of SD-101.1 Increases in CD4+ cells, CD8+ cells, NK cells, cytotoxic cells and Th1 cells in the tumor microenvironment were observed. Immune checkpoints are elevated by treatment in a higher proportion of patients who received 8 mg than in patients who received £ 2 mg.The combination of SD-101 and pembrolizumab was well tolerated and induced durable tumor responses. The SD-101 dose going forward in this patient population will be 2 mg.ACKNOWLEDGMENTSThis study was funded by Dynavax Technologies Corporation who provided SD-101. Merck & Co., Inc., Kenilworth, NJ USA provided pembrolizumab. We thank the patients and their families and caregivers for participating in the study; the participating study teams; and Brit Harvey and Tripta Dahiya for contributions to the analysis of the data (Dynavax Technologies Corporation). REFERENCES1. Guiducci et al. J Exp Med. 2006;203(8):1999-2008. 2. Merck & Company, Inc. KEYTRUDA (pembrolizumab). Prescribing information. 2016. Whitehouse Station, NJ.3. Cohen et al. AACR 2018. Abstract CT098.4. Leung ACF et al. ASCO 2017. Abstract 193149. 5. Ribas et al. AACR 2018. Abstract CT139.6. Eisenhauer EA et al. N Eur J Cancer. 2009;45:228–47.7. Ribas A, et al. JAMA. 2016;315(15):1600-1609.8. Specenier P. Expert Opin Biol Ther. 2017;17(6):765-780.
Analyst & Investor Presentation June 2018 Exhibit 99.3
Forward Looking Statement This presentation contains "forward-looking" statements, including statements regarding the conduct of clinical trials of SD-101, including results from the Phase 1b/2 trial, planned optimal dosage for the Phase 3 trial, and potential value of SD-101 across multiple tumor types. Actual results may differ materially from those set forth in this presentation due to the risks and uncertainties inherent in our business, including whether we can timely provide adequate clinical supplies; initiation, enrollment and completion of clinical trials of SD-101; the results of clinical trials and the impact of those results on the initiation or continuation of subsequent trials and issues arising in the regulatory process; the ability to successfully develop and commercialize SD-101; and whether or not Dynavax and parties with whom we are collaborating may reach any future agreement on further studies or a more extensive collaboration beyond the clinical trials contemplated under the existing agreements, as well as other risks detailed in the "Risk Factors" section of our Annual Report on Form 10-K for the fiscal year ended December 31, 2017 and in Quarterly Report on Form 10-Q for the quarter ended March 31, 2018, as well as discussions of potential risks, uncertainties and other important factors in our other filings with the U.S. Securities and Exchange Commission. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available. Information on Dynavax's website at www.dynavax.com is not incorporated by reference in our current periodic reports with the SEC.
Presenters COMPANY Eddie Gray – Chief Executive Officer Robert L. Coffman, PhD – Chief Scientific Officer Rob Janssen, MD – Chief Medical Officer Jean Chang – VP, Cancer Strategy and Business Development Michael Ostrach – Chief Financial Officer (available for Q&A) Erick Gamelin – VP, Clinical Development – Oncology (available for Q&A) GUEST PRESENTER Antoni Ribas, MD, PhD Professor of Medicine, Surgery, Molecular and Medical Pharmacology, Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC); Director, Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA Chair, Melanoma Committee at SWOG
Agenda TLR9 Agonists for Cancer Immunotherapy – Mechanisms Robert L. Coffman Resistance to PD-1 Blockade Due to Lack of Pre-existing Antitumor immunity Toni Ribas Clinical Development – Ph1b/2 Melanoma Data and Additional Programs Rob Janssen Maximizing Value of Dynavax’s TLR9 Agonist Portfolio in the Evolving Treatment Landscape Jean Chang Conclusion Eddie Gray 2 3 4 5 1
Deep and Growing Clinical Pipeline RESEARCH PRECLINICAL PHASE 1 PHASE 2 PHASE 3 COMMERCIAL VACCINE IMMUNO-ONCOLOGY SD-101 + Pembrolizumab* for Melanoma SD-101 + Pembrolizumab* for Head and Neck SCC Inhaled DV281 for NSCLC Additional Programs (including TLR 7/8 agonists) IMMUNE-MEDIATED AZD1419 (Asthma Disease Modification) Commercialized: U.S. Launch in January 2018 * Clinical collaboration with Merck; Dynavax maintains all commercial rights to SD-101 Study conducted by Dynavax
Robert L. Coffman, PhD
SD-101: Optimized TLR9 Agonist for Cancer Immunotherapy SD-101 Synthetic DNA oligonucleotide with TLR9-reactive CpG motifs Optimized for two key dendritic cell activation pathways TLR9 activation of dendritic cells complements other major classes of immuno-oncology agents. NF-kB IRF-7 Nucleus IFNa IL-12 Dendritic Cell Late Endosome Early Endosome MyD88 MyD88 TLR9 TLR9 CD40 CD86 MHC CD8+ T Cell Antigens
SD-101: Optimized TLR9 Agonist for Cancer Immunotherapy Triggering dual pathways provides more potent response Activates dendritic cells to become efficient antigen-presenting cells Induces type 1 IFN, leading to development of cytotoxic T cells (CTL) SD-101 CTL NF-kB IRF-7 Nucleus IFNa IL-12 Dendritic Cell Late Endosome Early Endosome MyD88 MyD88 TLR9 TLR9 CD40 CD86 MHC CD8+ T Cell
SD-101: Optimized TLR9 Agonist for Cancer Immunotherapy Inside tumor, CTL recognize and kill tumor cells, releasing more tumor antigens Establishes self-amplifying process leading to control or elimination of malignant cells SD-101 CTL NF-kB IRF-7 Nucleus IFNa IL-12 Dendritic Cell Late Endosome Early Endosome MyD88 MyD88 TLR9 TLR9 CD40 CD86 MHC CD8+ T Cell Tumor Cell Tumor antigen
Actions of Intratumoral SD-101 in Cancer Immunotherapy Tumor IFN DC T cell Dendritic cells take up antigens from dying tumor cells and migrate to the lymph nodes SD-101 Tumor antigens Lymph node DC Dying tumor Tumor-specific T cells activated by DC and IFN in lymph node Blood vessel CTL CTL CTL SD-101 induces IFN production & DC maturation Tumor-specific CTL kill tumor cells, releasing more tumor antigens Tumor Tumor-specific CTL enter circulation and return to the tumor Tumor antigens
Actions of Intratumoral SD-101 in Cancer Immunotherapy Tumor IFN DC T cell Dendritic cells take up antigens from dying tumor cells and migrate to the lymph nodes SD-101 Lymph node DC Dying tumor Tumor-specific T cells activated by DC and IFN in lymph node Blood vessel CTL CTL CTL SD-101 induces IFN production & DC maturation Tumor-specific CTL kill tumor cells, releasing more tumor antigens Tumor Tumor-specific CTL enter circulation and return to the tumor Radiation Inducers of cell death can increase availability of antigens & neoantigens Tumor antigens Tumor antigens
Actions of Intratumoral SD-101 in Cancer Immunotherapy Tumor IFN DC T cell Dendritic cells take up antigens from dying tumor cells and migrate to the lymph nodes SD-101 Lymph node DC Dying tumor Tumor-specific T cells activated by DC and IFN in lymph node Blood vessel CTL CTL CTL SD-101 induces IFN production & DC maturation IFNs stimulate NK cells and T cell-attracting chemokines Tumor Tumor-specific CTL enter circulation and return to the tumor Radiation IFN IFN Chemokines (CXCL9, 10) NK cell Tumor antigens Tumor antigens
Actions of Intratumoral SD-101 in Cancer Immunotherapy Tumor IFN DC T cell Dendritic cells take up antigens from dying tumor cells and migrate to the lymph nodes SD-101 Lymph node DC Dying tumor Tumor-specific T cells activated by DC and IFN in lymph node Blood vessel CTL CTL CTL SD-101 induces IFN production & DC maturation To be effective, this approach must generate CTL that will home to non-injected tumor lesions Tumor Radiation IFN IFN Chemokines (CXCL9, 10) NK cell CTL Tumor antigens Tumor antigens
SD-101 + Local Radiation in Lymphoma Leads to Abscopal Response in Many Patients 1 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 2 3 4 5 6 7 8 9 10 11 12 13 14 Subject 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1 mg 2 mg 4 mg 8 mg Cohort Percent Change From Baseline (%) Best objective responses in untreated lesions in study LYM-01 Radiation SD-101 Clinical response assessment Previously untreated NHL patients were given low dose radiation (2Gy on days -1 and 0) followed by 5 weekly injections of SD-101 into the irradiated lesion
Actions of Intratumoral SD-101 in Cancer Immunotherapy Tumor IFN DC T cell SD-101 Lymph node DC Dying tumor Blood vessel CTL CTL CTL Tumor IFN IFN Chemokines (CXCL9, 10) NK cell CTL T cell PD-L1 PD1 Anti-PD1 Tumor PD-1/PD-L1 blockade will enhance killing by CTL
Combination with Anti-PD-1 Increases Anti-tumor Response Tumor IFN DC T cell SD-101 Lymph node DC Dying tumor Blood vessel CTL CTL CTL Tumor IFN IFN Chemokines (CXCL9, 10) NK cell CTL T cell PD-L1 PD1 Anti-PD1 Tumor PD-1/PD-L1 blockade will enhance killing by CTL Anti-PD-1 will also increase both the number and cytotoxic activity of CTL in both injected and non-injected tumor lesions CTL CTL CTL CTL CTL CTL CTL CTL
Preclinical Studies in Mice Provide Support for Combining SD-101 With Checkpoint Inhibitors In preclinical studies, addition of intratumoral SD-101 reverses tumor escape from anti-PD-1 therapy and leads to durable immune-mediated rejection of CT26 tumors Untreated Anti-PD-1+SD-101 Anti-PD-1 Untreated Days Tumor volume (mm3) 1000 800 600 400 200 0 0 10 20 30 40 50 60 100 80 60 40 20 0 100 80 60 40 20 0 Percent survival Days after treatment SD-101 Anti-PD-1+SD-101 Untreated Anti-PD-1 Anti-PD-1 A-PD-1/SD-101 A-PD-1 Wang et al, PNAS (2016) 113:7240-7249
SD-101 and Anti-PD-1 Synergize to Increase Functional CD8+ T Cells in the Injected Tumor Stimulated CD3+CD8+ T cells IFN-γ TNF-α The combination of SD-101 and anti-PD-1 leads to substantial increases in both the numbers and functionality of the tumor-infiltrating CD8+ T cells Control Anti-PD1 non-responder Anti-PD1 responder Anti-PD-1+SD-101 SD-101 Control Anti-PD-1 NR SD-101 Anti-PD-1 R Wang et al, PNAS (2016) 113:e7240-7249 Anti-PD-1+SD-101
Biomarkers Show Increased Immune Activity with Combination Cytotoxic T and NK Cells Increase in Melanoma Patients Treated with Intratumoral SD-101 + Pembrolizumab
Toni Ribas, MD, PhD
Resistance to PD-1 blockade due to lack of pre-existing antitumor immunity Antoni Ribas, M.D., Ph.D. Professor of Medicine, Surgery, Molecular and Medical Pharmacology Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC) Director, Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA University of California Los Angeles (UCLA) Chair, Melanoma Committee at SWOG
Management of Cancer in the Anti-PD-1/L1 Era Features likely for response Features unlikely for response Upfront combination therapy Durable response Mixed response or delayed progression . . . . . . . . Delayed combined therapy
Tumor foreignness Mutational load General immune status Lymphocyte count Immune cell infiltration Intratumoral T cells Absence of Checkpoints PD-L1 Absence of soluble inhibitors IL6->CRP/ESR Tumor sensitivity to immune effectors MHC expression IFN-g sensitivity Absence of inhibitory tumor metabolism LDH, glucose utilization Blank, Haanen, Ribas, Schumacher. Science 2016 The Cancer Immunogram anti-PD-1/L1
Anti-PD-1/L1 Approved Indications and Suspected Mechanism of Action Group Indication ORR Agents approved* Main driver of response High response rate Hodgkin’s disease 87% Nivolumab, pembrolizumab PDJ amplicon Desmoplastic melanoma 70% Nivolumab, pembrolizumab Mutations from chronic sun exposure Merkel cell carcinoma 56% Avelumab, pembrolizumab Merkel cell virus and sun exposure MSI-h cancers 53% Nivolumab, pembrolizumab Mutations from mismatch repair deficiency Intermediate response rate Skin melanoma 35-40% Nivolumab, pembrolizumab Mutations from intermittent sun exposure Lung cancer 20% Atezolizumab, nivolumab, pembrolizumab Mutations from cigarette smoking Head and neck cancers 15% Nivolumab, pembrolizumab Mutations from cigarette smoking Gastro-esophageal cancer 15% Pembrolizumab Mutations from cigarette smoking Bladder/urinary tract cancers 15% Atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab Mutations from cigarette smoking Renal cell carcinoma 25% Nivolumab, pembrolizumab Insertion/deletions (indels) Hepatocellular carcinoma 20% Nivolumab Hepatitis virus Ribas and Wolchok, Science 2018
Anti-PD-1/L1 Approved Indications and Suspected Mechanism of Action Group Indication ORR Agents approved* Main driver of response High response rate Hodgkin’s disease 87% Nivolumab, pembrolizumab PDJ amplicon Desmoplastic melanoma 70% Nivolumab, pembrolizumab Mutations from chronic sun exposure Merkel cell carcinoma 56% Avelumab, pembrolizumab Merkel cell virus and sun exposure MSI-h cancers 53% Nivolumab, pembrolizumab Mutations from mismatch repair deficiency Intermediate response rate Skin melanoma 35-40% Nivolumab, pembrolizumab Mutations from intermittent sun exposure Lung cancer 20% Atezolizumab, nivolumab, pembrolizumab Mutations from cigarette smoking Head and neck cancers 15% Nivolumab, pembrolizumab Mutations from cigarette smoking Gastro-esophageal cancer 15% Pembrolizumab Mutations from cigarette smoking Bladder/urinary tract cancers 15% Atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab Mutations from cigarette smoking Renal cell carcinoma 25% Nivolumab, pembrolizumab Insertion/deletions (indels) Hepatocellular carcinoma 20% Nivolumab Hepatitis virus Ribas and Wolchok, Science 2018
Inhibiting PD-1-mediated Adaptive Immune Resistance TCR MHC Melanoma cell or tumor macrophage PD-1 PD-L1 IFN-g Anti-PD-1 Anti-PD-L1 Pardoll, NRC 2012 Taube et al. STM 2012 Tumeh et al. Nature 2014
Inhibiting PD-1-mediated Adaptive Immune Resistance Tumeh et al. Nature 2014 TCR MHC Melanoma cell or tumor macrophage PD-1 PD-L1 IFN-g Anti-PD-1 Anti-PD-L1
Baseline Day +27 Day +92 Day +130 Delayed Response to PD-1 Blockade after Transient Progression Tumeh et al. Nature 2014
Pembrolizumab Keynote 001 trial. Central radiology review by RECIST v1.1 What Differentiates Anti-PD-1-responsive from Non-responding Melanomas? Ribas et al. JAMA 2016 Ayers et al, JCI 2017
Melanoma cell or tumor macrophage PD-L1 Hypothesis formulated based on quantitative IHC analyses of 46 cases from UCLA Response Progression CD8 PD-1 PD-L1 Patient #1 Patient #2 PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance Adapted from Tumeh et al. Nature 2014 TCR MHC Melanoma cell or tumor macrophage PD-1 PD-L1 IFN-g
Reversing T Cell Exclusion with Intra-tumoral Therapies Anti-PD-1/anti-PD-L1 IT injection oncolytic virus TLR agonist, MDA5 agonist STING agonist May bring rare antitumor T cells into tumors and improve responds to anti-PD-1/L1 therapy + Anti-PD-1/anti-PD-L1
Intra-tumoral T-VEC (oncolytic virus) Plus Systemic Pembrolizumab Induces High Response Rates by Increases in Tumor CD8 Infiltration T-VEC T-VEC+ pembro –100 –75 –50 –25 0 25 50 75 100 Stage IV M1c (N = 8) Stage IV M1b (N = 4) Stage IV M1a (N = 2) Stage IIIC (N = 6) Stage IIIB (N = 1) N = 21 Percentage Change from Baseline Pembrolizumab 6 T-VEC Intralesional 1 30 Wk: 62% objective response rate 33% complete response rate Ribas et al. Cell 2017 Sep 7; 170 (6): 1109-1119.e10.
Intra-tumoral TLR9 Agonists Plus Systemic Checkpoint Blockade Anti-PD-1/L1 Naïve SD101 + pembrolizumab Progressing on prior anti-PD-1/L1 CMP-001 + pembrolizumab IMO-2125 + ipilimumab [ 240 ]
Conclusions Inhibiting adaptive immune resistance is the mechanistic basis of the antitumor activity of PD-1 blockade therapies Patients without a pre-existing tumor antigen-specific T cell infiltrate inducing reactive PD-L1 expression are unlikely to respond to PD-1 blockade therapy Inducing intratumoral infiltration by antigen-specific T cells is likely to potentiate the antitumor activity of PD-1 blockade therapy
Rob Janssen, MD
SYNERGY-001 (MEL-01) Phase 1b/2 study of the combination of SD-101 and pembrolizumab in advanced melanoma and head and neck squamous cell cancer OBJECTIVES: Evaluate the safety of the combination Evaluate the preliminary efficacy of the combination Establish the dose of SD-101 for the Phase 3 trial (2 mg vs. 8 mg)
Understanding Dose Selection SD-101 Mechanism of Action is to stimulate the immune system to respond to specific antigens Efficacy may be most informative – Looking for “sweet-spot”/the Goldilocks dose. Not too hot, not too cold! Blood PK not informative – Primary mechanism is local in the tumor and draining lymph nodes Safety may not be informative – Benign profile may not distinguish between doses—no MTD No biomarkers of CpG-mediated anti-tumor effects established – Immune stimuli generally stimulate dose-dependent feedback mechanisms complicating interpretation of markers of stimulation Seeking balance to achieve most potent immune response
Study Design Data cutoff – May 9, 2018 Patients Stage IIIc, Stage IV metastatic melanoma* ECOG performance status of 0 or 1 At least one injectable site Response by RECIST v1.1 Prior anti-PD-1 or anti-PD-1 naive Phase 1b Dose Escalation** Phase 2 Expansion SD-101 2 mg i.t. + Pembrolizumab 200 mg i.v. SD-101 4 mg i.t. + Pembrolizumab 200 mg i.v. SD-101 8 mg i.t. + Pembrolizumab 200 mg i.v. SD-101 1 mg i.t. + Pembrolizumab 200 mg i.v. SD-101 2 mg i.t. in up to 4 lesions + Pembrolizumab 200 mg i.v. OR SD-101 8 mg i.t. in one lesion + Pembrolizumab 200 mg i.v. *Histologically confirmed **DLT period 29 days, i.t. = intratumoral; i.v. = intravenous. 3 patients received 1 mg/lesion
Response Rate Higher in the 2 mg Dose Group * mITT excludes patients on study with no Day 64 scan yet. † Patients discontinued prior to first scan: ≤ 2 mg—clinical progression (n=1), irAE (n=1); 8 mg—clinical progression (n=2), AE/death (n=1); irAE (n=3), withdrew consent (n=1). ** Patients on study who have not yet had a first scan. Best ORR ≤2 mg/lesion 8 mg/lesion mITT* (N=30) (N = 39) ORR, n (%) (95% CI) 21 (70) (52, 83) 15 (38) (25, 54) CR 5 (17) 1 (3) PR 16 (53) 14 (36) SD 3 (10) 10 (26) PD 4 (13) 7 (18) Non-evaluable† 2 (7) 7 (18) All Enrolled Patients (N=37) (N=39) Non-evaluable** 7** 0
Subgroup Analyses Support 2 mg Dose CI = confidence interval; ECOG = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; ORR = overall response rate; RR = risk ratio; ULN = upper limit of normal.
2mg 8mg Responses in Patients with PD-L1 Negative or Positive Tumors Reponses seen in patients with negative and positive PD-L1 expression at baseline 80% (8 out of 10) of PD-LI negative patients responded with 2mg of SD-101
Best Percent Change in Target Lesions
Tumor Shrinkage Seen in Injected and Non-injected Lesions
6 month PFS rate = 76% Median PFS (months) = not reached Median DOR (months) = 4.7+ (not reached) Median Follow up (months) = 6.0 6 month PFS rate = 41% Median PFS (months) = 4.2 Median DOR (months) = 2.1+ (not reached) Median Follow up (months) = 4.9 Durability and Time on Study by Dose Group 2 mg More Durable than 8 mg
Increase in Infiltrating CD4 and CD8 Lymphocytes in the Tumor Red = CD4 T cells; Cyan = CD8 T cells; Yellow = Ki67; Green = S100; Dark blue = DAPI. Subject 110404 was devoid of CD4 T cells but not CD8 T cells at screening. Subject 110401 appeared to be devoid of CD4 and CD8 T cells at screening. Screen Day 29
Combination of SD-101 and Pembrolizumab is Well Tolerated Event ≤2 mg/lesion (N=37) 8 mg/lesion (N = 39) Total (N=76) n (%) n (%) n (%) Any Treatment-related AE 28 (76) 36 (92) 64 (84) Grade 3-4 8 (22) 14 (36) 22 (29) Chills 3 (8) 1 (3) 4 (5) Myalgia 6 (16) 1 (3) 7 (9) Injection-site pain 2 (5) 0 2 (3) Fatigue 2 (5) 4 (10) 6 (8) Headache 3 (8) 2 (5) 5 (7) Malaise 2 (5) 3 (8) 5 (6) Any irAEs 6 (16) 4 (10) 10 (13) Grade 3-4 3 (8) 2 (5) 5 (7) AEs leading to d/c of either or both drugs 4 (11) 10 (26) 14 (18) SAEs 9 (24) 12 (31) 21 (28) Death 0 1 (3) 1 (1) d/c = discontinuation; irAE = Immune-related adverse event; SAE = Serious adverse event;
Encouraging Early Data in Anti-PD-1/L1 Naïve HNSCC Patients (AACR 2018) *Includes all patients who had a tumor assessment and patients who discontinued the study prior to a scan. Cut-off date, 27 March 2018. Among patients who had a scan, ORR = 38%. †Two patients had clinical disease progression, including one death, prior to a scan on study. **Four patients on study have not yet had a tumor assessment. Response Rate n (%) Modified ITT* N=18 Objective response rate, n (%) 6 (33) 95% confidence interval (16, 56) Best overall response, n (%) Complete response 0 Partial response 6 (33) Stable disease 4 (22) Progressive disease† 8 (44) All enrolled patients N=22 Not evaluable** 4 (18) Time to response (days) Median 64 Min, max (62, 128) Promising ORR for hard to treat tumor type supports potential breadth of SD-101 in multiple tumor types
SYNERGY-001 Conclusions Efficacy - addition of SD-101 to pembrolizumab appears to improve pembrolizumab responses ≤ 2 mg of SD-101 per lesion induced a higher and more durable response rate than pembrolizumab with 8 mg of SD-101 ≤ 2 mg dose better than 8 mg dose in all disease stages Tumor shrinkage in injected and non-injected lesions including lung and liver Responses in patients with negative or positive baseline PD-L1 expression Safety Transient, mild-moderate flu like symptoms No increase in frequency or severity of irAEs No treatment-related, unexpected safety event
Proceeding to Phase 3 Continue to enroll patients in Phase 2 to receive 2 mg SD-101: Melanoma: anti-PD-1/L1 experienced HNSCC: anti-PD-1/L1 naïve and experienced Proposed Phase 3 study design: Randomized, double-blind, placebo controlled 2 mg of SD-101 in 1 to 4 lesions Unresectable or metastatic melanoma in patients who have not received anti-PD-1/L1 therapy Endpoints Primary — PFS Secondary — OS, ORR, safety Approximately 600 patients
Jean Chang
Evolution of Cancer Therapy Landscape Combinations Checkpoint IO Targeted Chemotherapy Kills all rapidly dividing cells Toxicities Response rates limited Specific genes or proteins in cancer cells Rapid responses Better tolerated Responses not durable Activate immune system against the tumor by inhibiting tumor’s suppressive mechanisms Long lasting responses in multiple tumor types Minority of patients respond Hit multiple pathways Improve response rates Durable, longer lasting responses Expand treatment options for refractory and resistant patients
A Range of Combinations Will Emerge Over Time Immune system is intricate Multiple and redundant feedback mechanisms Mechanisms maintain immune system balance Patients are heterogeneous Prior therapies Tumor microenvironment Tumor mutational burden
Four Classes of Agents Appear Particularly Well Suited to Complement PD-1 Blockade Increasing appreciation in IO field that stimulation of innate immune system is required to optimally exploit T cell activation Other agents that inhibit or block a checkpoint Activate or expand T cells Agents that alter the TME Innate immune activators TLR9 agonists SD-101, DV281
TLR9 Agonists + Anti-PD1: A Promising Combination Characteristics of a successful combination treatment Robust response Durable disease control Not reliant on predictive biomarkers Minimal additive toxicity burden for patients Implications Earlier use may maximize outcomes, e.g. neoadjuvant setting Basis of triplet combinations going forward Opportunity for other modes of local delivery DV281 inhaled for lung
SD-101+ Anti-PD1: Development in Melanoma Establish SD-101 + pembrolizumab as core combination Advance SD-101+ pembrolizumab combination into earlier treatment settings Unresectable or metastatic melanoma naïve population Phase 3 SD-101 + pembrolizumab Unresectable or metastatic melanoma refractory/resistant to anti-PD-1 Phase 2 SD-101+pembrolizumab Neoadjuvant in melanoma
SD-101 + Anti-PD1: Leveraging Shift in Melanoma Treatment towards Neoadjuvant Setting Checkpoint blockade, anti-PD1 in particular, is moving into the neoadjuvant setting (earlier is better) Pembrolizumab is showing early efficacy SD-101 fits well within this shift TLR9 agonists can improve responses to PD-1 blockade; opportunity to expand upon this Intratumoral injection leverages primary tumor as an antigen source for expansion and activation of T cells; SD-101 orchestrates and primes T cell response Potential benefits Greater fitness of host immunity Significantly higher proportion of patients amenable to intratumoral injection
TLR9 Agonists + Anti-PD1: Application to Additional Indications in Neoadjuvant Setting Criteria for cancer selection Stage at diagnosis Amenable to series of injections or inhalation Evidence of anti-PD1 activity Potential to raise the bar for outcomes Clinical response Pathologic complete/major response Breast cancer SD-101 Lung cancer DV281
Building on the Strength of Dynavax’s SD-101 + Pembrolizumab Data: Strong Basis for Additional Combinations T cells Checkpoint inhibitors or Activators anti-PD1 anti-ICOS* anti-OX-40* … … Epigenetic modulators* LD Chemo* … … … TLR9 SD-101 or DV281 Innate Immunity Antigen Presentation/Prime T-cells TME Alter the TME by boosting tumor immunogenicity or decreasing suppressor cell types SD-101 + pembrolizumab + X SD-101/DV281 + X * Tested pre-clinically for synergistic effect
Dynavax TLR9 Agonists Fill Gap in Pharma Combination Therapy Pipelines Pharmaceutical companies continue to build combination optionality across multiple mechanisms Considerable opportunity exists within our class of agents Dynavax clinical programs can fill Pharma’s pipeline gap, creating opportunities for pre-clinical/clinical collaborations and partnerships
Use Partnering to Make TLR9 Agonists Broadly Available and Integral to Combination Therapy Goals for collaborations and partnerships Maximize breadth across tumor types Maximize combination use Doublets or triplets with anti-PD1 treatments Doublets with other T cell agonists, particularly in tumors not responsive to anti-PD1 Triplets with T cell agonists and TME targeting agents
Dynavax: Developing TLR-mediated Immune Stimulation in Multiple Cancer Applications Pre-clinical assessment of novel combinations Cancer Vaccine DV230 Ficoll for liver indications NSCLC Neoadjuvant NSCLC Lung mets Phase 3 MEL naive Phase 2 MEL anti-PD1 refractory/resistant HNSCC tx-naïve HNSCC anti-PD1 refractory/resistant Breast cancer neoadjuvant MEL neoadjuvant Multiple agonists and delivery strategies in preclinical development TLR9 agonists in combination with anti-PD1 or other TLR7/8 agonists SD-101 i.t. DV281 inhaled Discovery Phase 1 Phase 2/3
Eddie Gray
Concluding Remarks TLR9 agonist technology has demonstrated encouraging potential in immuno-oncology as a combination agent Growing immuno-oncology database validates our ongoing studies and expansion of our program Positioning ourselves to take advantage of anti-PD-1 therapy shift into neoadjuvant setting Upcoming catalysts in 2H18 consist of new data in melanoma and HNSCC, safety data in DV281 (lung), and initiation of Phase 3 in advanced melanoma Business development efforts focused on partnerships/collaborations to maximize use of SD-101 in tumor types and in combinations