arav-8k_20200113.htm

 

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): January 13, 2020

 

Aravive, Inc.

(Exact name of registrant as specified in its charter)

 

 

Delaware

 

001-36361

 

26-4106690

(State or other jurisdiction

of incorporation)

 

(Commission

File Number)

 

(IRS Employer

Identification No.)

 

River Oaks Tower

3730 Kirby Drive, Suite 1200

Houston, Texas 77098

(Address of principal executive offices)

 

(936) 355-1910

(Registrant’s telephone number, including area code)

 

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 (see General Instruction A.2. below):

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))

 

 

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

 

ARAV

 

Nasdaq Global Select Market

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.

Aravive, Inc. (the “Company”) will be making several investor presentations over the next several weeks.  In connection with the presentations, the Company intends to discuss the investor presentation attached as Exhibit 99.1 hereto, which is incorporated herein by reference.

The investor presentation attached as Exhibit 99.1 to this Current Report on Form 8-K includes “safe harbor” language pursuant to the Private Securities Litigation Reform Act of 1995, as amended, indicating that certain statements contained in the investor presentation are “forward-looking” rather than historical.

The Company undertakes no duty or obligation to update or revise information included in this Current Report on Form 8-K or the investor presentation attached as Exhibit 99.1 hereto.

 

Item 9.01.  Financial Statements and Exhibits.

(d) Exhibits.

The following exhibit is filed with this Current Report on Form 8-K:

 

 

 

 

 

 

 

Exhibit
Number

  

Description

 

 

99.1

  

Aravive, Inc. Investor Presentation dated January 2020

 

 

 

 



SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

 

Date: January 13, 2020

ARAVIVE, INC.

(Registrant)

 

 

 

By:

 

/s/ Vinay Shah

 

Name:

 

Vinay Shah

 

Title:

 

Chief Financial Officer

 

 

 

 

arav-ex991_6.pptx.htm

Slide 1

Halting Disease Progression in its Tracks © 2019 Aravive, Inc. Aravive Corporate Presentation January 2020 Exhibit 99.1

Slide 2

Important Information © 2019 Aravive, Inc. Forward-Looking Statements This presentation contains forward-looking statements that may discuss Aravive’s plans, goals, intentions and expectations as to future trends, events, results of operations, financial condition or other matters. Forward- looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and they often include words such as “may,” “will,” “should,” “would,” “expect,” “anticipate,” “plan,” “likely,” “believe,” “estimate,” “project,” “intend,” and other similar expressions. Statements that are not historical facts are forward-looking statements. Forward-looking statements included in this presentation include statements regarding Aravive’s planned clinical activities, including the design, initiation, patient enrollment and availability of data from clinical studies, future indications and cash position and the anticipated safety, activity and manufacturability of Aravive’s product candidates. Forward-looking statements are based on Aravive’s current beliefs and assumptions, 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 unpredictability of clinical development activities; risks related to Aravive’s ability to estimate and control its operating expenses; Aravive’s ability to protect its intellectual property rights; changes in the competitive environment; and legislative, regulatory, political and economic developments. The foregoing review of important factors that could cause actual events to differ from expectations should not be construed as exhaustive and should be read in conjunction with statements that are included herein and elsewhere, including the risk factors included in Aravive’s most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q and Current Reports on Form 8-K filed with the Securities and Exchange Commission. Except as required by law, Aravive undertakes no obligation to revise or update any forward-looking statement or to make any other forward-looking statements, whether as a result of new information, future events or otherwise.

Slide 3

Company Overview The Company Lead Clinical Program (AVB-500) Aravive is a clinical stage company developing treatments designed to halt the progression of life-threatening diseases, including cancer and fibrosis NASDAQ-listed company (ARAV) Offices in Houston, TX (hdqtrs.) and Palo Alto, CA $20 million Product Development Award from the Cancer Prevention & Research Institute of Texas (CPRIT) Led by a team of industry veterans with decades of target biology, drug development, & commercialization expertise Multiple clinical and program milestones during 2020 A first-in-class, ultra-high affinity, Fc-fusion protein designed to selectively block the novel GAS6-AXL signaling pathway Proof-of-mechanism established in clinic using proprietary biomarker for target engagement Early proof-of-concept for anti-tumor activity demonstrated in platinum-resistant ovarian cancer Currently in expanded Phase 1b/2 for platinum-resistant ovarian cancer; Fast-track designation granted by the FDA Ideal profile for combination with chemo, check-point inhibitors and PARP inhibitors in broad range of indications IP coverage through 2033 and beyond Our approach draws on novel insights into targeting signaling pathways that drive the activation, migration and invasion of abnormal cells into healthy tissues © 2019 Aravive, Inc.

Slide 4

Pipeline Focused on GAS6/AXL Signaling in Oncology & Fibrosis Indication Preclinical Phase 1 Phase 1*Phase 1b Phase 2 Phase 3 AVB-S6-TBD Ovarian Cancer platinum resistant Clear Cell Renal Cancer 3rd Oncology (undisclosed indication) Kidney Fibrosis (IgAN) Chronic Fibrosis (undisclosed indication) AVB-500 Status: IND Open Status: P1b expansion to confirm early efficacy Status: Recruiting © 2019 Aravive, Inc. Ovarian Cancer platinum resistant (PD-L1i combo; AZ; IST) Status: Recruiting IST= investigator sponsored trial

Slide 5

AXL Tyrosine Kinase Promotes Invasion, Metastasis, and Resistance AXL is a member of tyrosine kinases that include Tyro3, AXL, and Mer (TAMs) AXL is activated by a single ligand, growth arrest–specific 6 (GAS6); Mer and Tyro3 can be activated by GAS6 and Protein S 1 Upregulated in many cancers 2, AXL overexpression linked to metastasis 3,4, poor survival 5-7, and drug resistance 8,9 Unusually strong binding affinity between GAS6 and AXL of ~ 30 pM makes development of inhibitors to the pathway challenging 1 1 J Clin Invest. 2017;127(1):183–198. 2 Adv Cancer Res. 2008;100:35–83. 3 Oncogene. 2009;28(39):3442–3455 4 Cancer Res. 2010;70(19):7570–7579 5 Proc Natl Acad Sci U S A. 2006;103(15):5799–5804 6 Ann Diagn Pathol. 2013;17(5):425–429 7 Proc Natl Acad Sci U S A. 2010;107(3):1124–1129 8 Nat Genet. 2012;44(8):852–860 9 Cancer Res. 2013;73(1):331–340 Figure from Clinical Science Apr 01, 2012, 122 (8) 361-368

Slide 6

GAS6/AXL Signaling: Decoy Receptor is the Best Approach for Potent and Selective Inhibition WT AXL has pM Affinity; AVB-500 AXL Decoy has fM Affinity Selectivity limited by RTK homology Off-target toxicity Multiple resistance mechanisms Many potential competitors Decoy AXL Receptor AXL or GAS6 Antibody Tyrosine Kinase Inhibitor Requires a mAB affinity that competes with receptor Not achievable for AXL Many potential competitors Binds more tightly to GAS6 than WT AXL Complete target coverage with no anticipated off-target toxicity First-in-Class with strong IP position kinase domain © 2019 Aravive, Inc.

Slide 7

Other Drugs Targeting AXL Signaling in Clinical Development are Not Selective Drug (Stage) Company Target Selective for AXL AVB-500 (Ph Ib/II) Aravive GAS6 YES Gilterinib (Market) Astellas AXL NO Cabozantinib (Market) Exelixis AXL NO Sitravatinib (Ph III) Mirati (BeiGene) AXL NO Merestinib (Ph II) Lilly AXL NO BGB324 (Ph II) BergenBio AXL NO S49076 (Ph i/II) Servier AXL NO TP-0903 (Ph I/II) Tolero (Sumitomo) AXL NO BPI-9016M (Ph I) Betta Pharmaceuticals AXL NO ONO-7475-01 (Ph I) Ono Pharmaceuticals AXL NO RXDX-106 (Ph I) Ignyta AXL NO © 2019 Aravive, Inc. VS.

Slide 8

AVB-500 Inhibits AXL Signaling by Neutralizing GAS6, Sole Ligand for AXL Decoy receptor engineered for very high affinity for GAS6 – ~200 fold greater than native AXL Favorable safety and PK profile GAS6 not needed by normal tissue GLP preclinical studies demonstrate ≥ 30-fold safety margin (relative to max feasible dose in tox; 3-month tox study completed) As biologic, does not compete for metabolism with chemotherapies; facilitates combination with other therapies Small molecules targeting AXL can have off target activities Strong IP position on GAS6 inhibition Proprietary biomarker tests to monitor GAS6 levels; serum GAS6 levels associated with efficacy in preclinical studies Robust CMC Drug candidate manufactured at high yield and purity AVB-500 Demonstrated Favorable Safety Profile and Proof-of-Mechanism in FIH Phase 1 Trial J Clin Invest. 2017;127(1):183–198

Slide 9

GAS6/AXL Signaling is Critical in Resistant Metastatic Ovarian Cancer Expression in 0% (0/10) of normal ovarian tissue Expression in 73% (219/297) ovarian tumor samples including low grade serous, endometroid and advanced stage tumors1 Preclinical in vitro 1,2,3 Inhibition decreases invasion/migration Preclinical in vivo 1,2,3 Inhibition decreases tumor Correlates with chemoresistance to carboplatin and paclitaxel Inhibition improves sensitivity to platinum and taxane therapies Rankin et al, Cancer Res. Oct 1; 70 (19) 2010 Divine et al, Oncotarget 7 (47) 2016; Quinn et al, Mol Cancer Ther November 26 2018; Kariolis et al, J Clin Invest. 2017 Quinn et al. Mol Cancer Therapeutics 2019

Slide 10

AVB-500: A Novel Lead Clinical Program With Attractive Attributes Fast-track designation granted by the FDA for platinum-resistant ovarian cancer; currently in expanded Phase 1b/2 trial with early proof-of-concept data Well-tolerated to date and no anticipated drug-drug interactions facilitate combination studies (unlike small molecules) The ability to combine with common standards of care allows access to a large total accessible market Robust chemistry manufacturing control with high yield and purity © 2019 Aravive, Inc.

Slide 11

AVB500-OC-002: A P1b Study of AVB-500 in Combination with Single Agent Chemotherapy in Platinum-Resistant Ovarian Cancer Key Eligibility Criteria 1-3 prior lines Measurable disease Platinum free interval ≤ 6mo after most recent platinum-containing regimen Adenocarcinoma NOS, high grade endometroid adenocarcinoma, mixed epithelial (≥ 80% high grade serous), high grade serous, or undifferentiated carcinoma ECOG performance status 0-1 Goals for expansion: 1. Safe & tolerated 2. AVB serum biomarker targets met Expansion Cohort PAC: n = 18 PLD: n = 18 AVB + PLD n=6 AVB + PAC n=6 AVB-500 (AVB): Initial dose 10 mg/kg q14 days Pegylated liposomal doxorubicin (PLD): 40 mg/m2 d1; 28 day cycle Paclitaxel (PAC): 80 mg/m2 day 1, day 8, day 15; 28-day cycle NOS= Not Otherwise Specified ECOG= Eastem Cooperative Oncology Group Trial Design (NCT03639246) © 2019 Aravive, Inc.

Slide 12

Safety data for the first 31 patients: AVB-500 (10mg/kg) well-tolerated No serious and unexpected adverse reactions No dose limiting toxicities Infusion reactions managed by premedication regimen 40 patients total have been dosed at 10mg/kg Similar safety profile as that seen with first 31 patients 6 patients have been dosed at 15mg/kg To date, similar safety profile to the 10mg/kg dose © 2019 Aravive, Inc. Safety Summary from Phase 1B PROC Study to Date

Slide 13

Exposure-Response Analysis Demonstrated AVB-500 Levels at 10mg/kg Dose Predict Clinical Benefit © 2019 Aravive, Inc.   Above Minimal Efficacious Exposure Below Minimal Efficacious Exposure Number of Patients (n) 17 14 Complete Response (CR) 1 (6%) 0 Partial Response (PR) 4 (24%) 2 (14%) Overall Response Rate (ORR) 5 (29%) 2 (14%) Stable Disease (SD) 9 (53%) 4 (28%) Clinical Benefit (SD+ORR) 14 (82%) 6 (43%) Median DOR (months) 7.62  3.96 Median PFS (months) 8.1 1.8 Progressive Disease (PD) 3 (18%) 8 (57%) Patients remaining on study as of Oct 31 2019 8 (47%) 0 Sufficient AVB-500 exposures doubled ORR, Clinical Benefit Rate, and duration of response Response rate in below minimal efficacious exposure patients consistent with historical control rates of 10-15% for PAC or PLD PFS will be primary endpoint for registration study Best Response Determined by Investigator-Assessed RECIST 1.1

Slide 14

Response and CBR in Second and Third Line Treatments Better with AVB-500 than Historical Control Cancer Chemotherapy and Pharmacology (2019) 84:33-39 37 European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 94–98 Prior Lines AVB500-OC-002 Data from Literature (Plat-S/Plat-R not parsed) 2 (N=14) ORR 29% 12% (6.9%CR) CBR 64% 16% 3 (N=8) ORR 25% 2.9% (0 CR) CBR 75% 9% 26% of the 62 patients in the less than 3 mo PFI group had primary refractory disease

Slide 15

Observations on Patients On Study as of October 31 2019 (10mg/kg dose) The patient with CR achieved the minimal efficacious concentration of AVB-500 while on PAC. She had a baseline serum GAS6 level that was typical of the platinum-resistant ovarian cancer population and 2-fold higher than that observed in healthy volunteers. She also exhibited poor prognostic factors, including two prior lines of therapy and PFI less than 3 months. (Confirmed Dec 2019.) Among the patients who responded to AVB-500, four of seven remain responders and on study, and two patients remain on AVB-500 as single agent. All 4 achieved minimal efficacious AVB-500 concentration. Among the 13 patients whose best response was SD, four who achieved the minimal efficacious concentration of AVB-500 remain on study. One SD patient whose trough level was below the minimal efficacious concentration did not progress but withdrew consent. Eight (47%) of the patients who achieved the minimal efficacious concentration of AVB-500 remain on study versus none of the patients whose trough values were below that concentration. Because the study is still ongoing, DOR and PFS may continue to evolve.

Slide 16

Best Response Determined by Investigator-Assessed RECISTv1.1 for First 31 Patients (10mg/kg): One CR Percent Change in Sum of Target Tumors from Baseline to Best Response Note: 2 pts who were PD at best response (Pac arm) are excluded from the waterfall Pac PLD High exposure patients

Slide 17

Summary of First 31 Patients’ Response as of October 31 2019 CT Scans PAC PLD Partial response Progressed Complete response Stable disease represented by continuous bar * * * * * * * * * * * * * * * * * * High exposure patients Withdrew consent and off study

Slide 18

Comparable Demographics and Baseline Characteristics Confirming AVB-500 Exposure Drives Anti-Tumor Activity Above Minimal Efficacious Concentration Below Minimal Efficacious Concentration Age, years median (min, max) 71 (52-82) 63.0 (53-80) Prior lines* 1 (%) 6 (35.3%) 2 (14.3%) 2 (%) 8 (47.1%) 6 (42.9%) 3 (%) 3 (17.6%) 5 (35.7%) Platinum Free Interval ≥ 3mo 11 (64.7%) 8 (57.1%) < 3mo 6 (35.3%) 6 (42.9%) ECOG 0 11 (64.7%) 6 (42.9%) 1 6 (35.3%) 8 (57.1%) * PAC PT IN BELOW MINIMAL EFFICACIOUS GROUP MISSING VALUE

Slide 19

Next Steps Data confirm strategy to investigate higher doses in the current Phase 1b study to determine if a greater proportion of patients achieve high drug exposure levels PK modeling predict a dose of 20 mg/kg should allow >90% of patients to achieve desired high exposure levels Anticipate 18-24 more patients across both cohorts and at 15 and 20mg/kg Will evaluate percentage of patients achieving minimal efficacious concentration and correlate to response rates Anticipate preliminary data read-out middle of 2020 for 15 and 20mg/kg

Slide 20

Platinum-Resistant Ovarian Cancer Phase 2/3 P1b Will Determine RP2D Anticipate initiating 2H20 Same population as P1b portion Effect size from P1b (all AVB-500 doses) will drive regulatory strategy, statistical plan, Ns Randomized (2:1), double-blind, placebo- controlled study to compare efficacy and tolerability of AVB-500 in combination with PLD or Pac versus placebo plus PLD or Pac Primary objective to assess anti-tumor activity of AVB-500 in combination with Pac Or PLD as measure by PFS Secondary objectives include assessment of PK/PD and additional efficacy endpoints (ORR, OS, DOR, DCR) Platinum Resistant Ovarian Cancer 1-3 prior lines PLD SOC + placebo SOC= standard of care; PLD or PAC SOC + AVB-500

Slide 21

Rationale for AVB-500 in Kidney Cancer Strong biological rationale for clear cell Renal Cell Cancer1 VHL tumor suppressor gene mutated, causes increase in AXL AXL/GAS6 levels predict prognosis & survival in human1 Strong in vivo activity in preclinical models1,2 single agent combo with TKI 2 Xiao et al, Cancer Research October 4, 2019; © 2019 Aravive, Inc. 1 Rankin et al, PNAS | September 16, 2014 | vol. 111 | no. 37 | 13375

Slide 22

Overview of P1b/P2 Clear Cell Renal Cell Carcinoma Histologically confirmed stage IV ccRCC (according to the American Joint Commission on Cancer, seventh edition, classification) and has progressed on/after or was intolerant to front-line treatment ECOG 0-1 Phase 1b safety run-in with AVB-500 in combination with cabozantinib Up to 18 patients in P1b, ability to increase/decrease dose based on tolerability, pk/pd 90 patients in P2 controlled, randomized, blinded portion Primary endpoint in P2 is PFS; Secondary endpoints: ORR, DOR, DCR, and OS

Slide 23

Rationale for AVB-500 in Kidney Fibrosis GAS6 acts as a mitogen, stimulating mesangial cell proliferation through binding to its cell-surface receptor AXL Mesangial proliferation is a hallmark of IgAN 1 Coppo et al, Kidney Intl (2014) 86:828-36; Reich et al, J Am Soc Nephrol (2007) 3177-83; Nagai K, Miyoshi M, Kake T, Fukushima N, Matsuura M, et al. (2013) Dual Involvement of Growth Arrest-Specific Gene 6 in the Early Phase of Human IgA Nephropathy. PLoS ONE 8(6): e66759. doi:10.1371/journal.pone.0066759 M. Yanagita, et al. (1999) J Am Soc Nephrol 10: 2503–2509. 2 Yanigati et al, (2001) Am J Pathol. Apr; 158(4): 1423–1432; Zhen et al Journal of Autoimmunity 93 (2018) 37–44 © 2019 Aravive, Inc. Strong biological rationale for IgA nephropathy (IgAN)1 GAS6 is more highly expressed in IgAN tissue relative to normal tissue GAS6 stimulates mesangial cell proliferation GAS6 expression correlates with severity of IgA Nephropathy and predict prognosis in humans Strong in vivo activity in preclinical models2

Slide 24

Overview of Phase 2A IgAN Study Small (N of 12-24) Proof of Concept Study in IgA patients Sites in USA and Ukraine Diagnosis of biopsy-proven IgAN Proteinuria ≥ 1g to 3g/24hr Monitor safety, PK/PD Ensure sGAS6 levels suppressed throughout dosing interval Open-label Monitor proteinuria and other renal functions Ability to increase dose based on data

Slide 25

AXL Promotes a Suppressive Myeloid Micro-environment ISTs Investigating Combinations of AVB-500 + PDL1 inhibitor AXL presence Decreases tumor T cells (killer) infiltration Decreases Tumor antigen presentation Increases suppressive myeloid cells and macrophages AXL loss Increases Tumor antigen expression Decreases suppressive myeloid cells and macrophage Increases Tumor T cell infiltration Sensitizes tumor cells to checkpoint immunotherapy when they were previously resistant AXL expressed in patients unresponsive to PD-1/PD-L1 immunotherapy Adapted from NATURE COMMUNICATIONS | 7:13898 | DOI: 10.1038/ncomms13898 | © 2019 Aravive, Inc.

Slide 26

Experienced, Methodical, Efficient Development Execution Strong Clinical Development Team © 2019 Aravive, Inc. Dev Plan Enabled Bifurcated Strategy- Oncology and Fibrosis 4Q 2017- IND filed 1Q 2018- FIH in NHV initiated 2Q 2018- POM in NHV 3Q 2018- Tolerability in NHV 4Q 2018- P1b in Ovarian Cancer initiated 2Q 2019- POM in Ovarian Cancer 2Q 2019- Tolerability in Ovarian Cancer 3Q 2019- Early POC in Ovarian Cancer 3Q 2019- Expanded P1b Ovarian Cancer 4Q2019- Kidney fibrosis trial initiation 1Q2020- IND open for ccRCC study Mid-2020- RP2D established from Ph1b Ovarian (after 15 and 20mg/kg doses) 2H-2020- P2/P3 Platinum-resistant ovarian cancer initiation 2020- Safety and early efficacy in kidney fibrosis 2020- Safety and early efficacy in ccRCC Achieved MilestonesUpcoming Milestones FIH=first in human; IND= investigational new drug application; POM=proof of mechanism; POC=proof of concept; R2PD=recommended P2 dose

Slide 27

Financials and Capitalization NASDAQ: ARAV; Shares Outstanding*: 14.9M basic * As of September 30, 2019 adjusted for net proceeds from recent public offering, closed on December 2, 2019 Cash and cash equivalents*: $70M Cash and cash equivalents expected to enable the company to fund its operating plans through 2021 © 2019 Aravive, Inc.

Slide 28

AVB-500 Offers First- and Best-In-Class Opportunity in Oncology and Fibrosis Uniquely positioned in competitive landscape Robust pipeline addressing significant drivers of mortality in oncology and fibrosis: metastasis and drug resistance © 2019 Aravive, Inc. AVB-500: high affinity decoy protein, a potent and selective drug targets GAS6/AXL signaling Validated pathway drives activation, migration and invasion of abnormal cells Suppresses GAS6 to undetectable levels in early clinical studies; prolonged target engagement Safety and tolerability profile to date support use as combination and/or maintenance therapy Compelling early efficacy signal in platinum-resistant ovarian cancer No adverse events that limit dosing High AVB-500 levels predictive of anti-tumor activity; statistically significantly association with PFS (p=0.006568) In first 31 patients, median PFS for patients with high drug levels was 4-fold greater than those with low drug levels (p=0.0016). Expanded P1b portion to validate efficacy signal, evaluate higher doses and explore the most efficient regulatory path to approval Additional programs advancing into the clinic in high need indications Kidney fibrosis (IgA nephropathy) trial recruiting Renal cell carcinoma IND open ISTs

Slide 29

Halting Disease Progression in its Tracks © 2019 Aravive, Inc. Thank You