arav-8k_20190927.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): September 27, 2019

 

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, including zip code)

 

(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 (17 CFR §230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (17 CFR §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 September 27, 2019, Aravive, Inc. (the “Company”) issued a press release announcing that the Company presented positive data from the initial 12 patients of the ongoing Phase 1b portion of the Company’s Phase 1b/2 study of AVB-500 in ovarian cancer patients in a late breaking oral presentation at the European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain. The Company additionally reported data on the initial 28 evaluable patients in its ongoing expansion study as well as an expansion cohort dose increase based on drug exposure-response analysis.

The ESMO presentation and the press release are attached as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.

 

Item 9.01.

Financial Statements and Exhibits.

(d) Exhibits.

The following exhibits are filed with this Current Report on Form 8-K:

 

Exhibit

No.

 

Description

 

 

 

99.1

 

ESMO Presentation

 

 

 

99.2

 

Press release issued by Aravive, Inc. dated September 27, 2019

 


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.

 

 

 

 

 

 

 

 

Dated: September 27, 2019

 

 

 

ARAVIVE, INC.

(Registrant)

 

 

 

 

 

 

                    

 

By:

 

/s/ Jay P. Shepard

 

 

 

 

Name:

 

Jay P. Shepard

 

 

 

 

Title:

 

Chief Executive Officer

 

 

arav-ex991_7.pptx.htm

Slide 1

Phase 1B/2 Study of AVB500 (High Affinity Inhibitor of GAS6/AXL Path) in Combination with PAC and PLD in Platinum Resistant Recurrent Ovarian Cancer (NCT03639246) Abstract 6602 Authors: B. Monk1, R. Coleman2, K. Moore3, K. Fuh4, L. Bonifacio5, G. McIntyre5, D. Prohaska5, A. Giaccia5, M.J. Baker5, R. Tabibiazar5, M. Bookman6 1Gynecologic Oncology, US Oncology, Phoenix, AZ, United States of America, 2Gynecologic Oncology and Reproductive Medicine, The M. D. Anderson Cancer Center, Houston, TX, United States of America, 3Gynecologic Oncology, Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, United States of America, 4Obstetrics and Gynecology, Washington University School of Medicine In St. Louis, St. Louis, MO, United States of America, 5Clinical Operations, Aravive Inc, Houston, TX, United States of America, 6Gynecologic Oncology, Kaiser Permanente Northern California, San Francisco, CA, United States of America Exhibit 99.1 Company logo

Slide 2

DISCLOSURE SLIDE All authors are either employees of Aravive, Inc. or paid consultants to Aravive, Inc. Company logo

Slide 3

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 Company logo chart

Slide 4

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

Slide 5

AVB500 Inhibits AXL Signaling by Neutralizing GAS6, Sole Ligand for AXL AXL-Fc protein 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) As biologic, does not compete for metabolism with chemotherapies; facilitates combination with other therapies Small molecules targeting AXL can have off target activities J Clin Invest. 2017;127(1):183–198 Company logo

Slide 6

AVB500 Demonstrated Activity in Multiple Preclinical Platinum-Resistant Ovarian Cancer Models Single agent activity, synergistic with DNA damaging agent in multiple PROC models (OVCAR8 and SKOV3.IP) at 1mg/kg daily, a regimen that suppressed sGAS6 for 24h. Lower doses did not demonstrate same effect. 20-30% cures seen and minimal detectable disease with all mice given combination J Clin Invest. 2017;127(1):183–198 Control AVB500 Dox AVB500 + Dox Control AVB500 Dox AVB500 + Dox Company logo Bar Chart

Slide 7

Serum Biomarker-Guided Dose Escalation in First in Human Study Conducted in Healthy Volunteers *Escalations after independent Data Monitoring Committee review of: 1) Safety, and 2) Target suppression via serum biomarker Single Ascending Dose Repeat Dose 1 mg/kg 2.5 mg/kg 5 mg/kg 10 mg/kg 5 mg/kg weekly x 4 weeks * * * * RESULTS 42 Subjects enrolled No SAEs Well tolerated at all dose levels sGAS6 BLQ at all dose levels with higher doses providing longer suppression PK consistent with Target Mediated Drug Disposition (TMDD) Company logo Chart

Slide 8

PK/PD Model Using Biomarker Data from Healthy Volunteers Guides Dose Selection for Studies in Cancer Patients Healthy Volunteer Data Simulations in HV (top) & OC Pts (bottom) Red dashed line shows 50% target engagement Purple envelope represents 10-90% interval Minimum targets based on modeling: 3720 ng/mL AVB trough BLQ (<2 ng/mL) sGAS6 Simulations assume 3x higher GAS6 in pts HV= healthy volunteers OC= ovarian cancer Company logo bar chart graph

Slide 9

AVB500-OC-002: A P1b Study of AVB-S6-500 in Combination with Single Agent Chemotherapy in Platinum-Resistant Ovarian Cancer AVB500 (AVB; AVB-S6-500): 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 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 AVB + PLD n=6 AVB + Pac n=6 Goals for expansion: Safe & tolerated AVB serum biomarker targets met Expansion Cohort Pac: n = 18 PLD: n = 18 NOS=not otherwise specified ECOG = eastern cooperative oncology group Company logo Bar chart

Slide 10

Distribution of Baseline Characteristics and Prognostic Factors (Efficacy Population) Pac arm (n=6) PLD arm (n=6) Age, years median (min, max) 63.5 (55, 82) 66 (53, 81) Prior lines 1 0 3 (50) 2 5 (83) 2 (33) 3 1 (17) 1 (17) Platinum Free Interval > 3mo 4 (67) 4 (67) < 3mo 2 (33) 2 (33) ECOG 0 5 (83) 4 (67) 1 1 (17) 2 (33) Company logo

Slide 11

First Cycle Safety Data for the First Patients in Each Cohort Number of Subjects With (Safety Population) AVB+Pac (n=6) AVB+PLD (n=7) AE 6 (100) 5 (71.4) SAE 0 0 Dose Limiting Toxicity 0 0 Related AE with G>3 0 0 N=3 had Grade 2 infusion reactions with AVB infusion. A premedication regimen (anti-H2, anti-H1 ± steroid) now used for all pts in C1 per a subsequent protocol amendment. There have been no AVB-related infusion reactions in premedicated patients. Adverse Events (Preferred Term) Experienced During the First Cycle of Treatment by More Than 1 Patient in each Cohort (Safety Population) AVB+Pac (N=6) N (%) AVB+PLD (N=7) N (%) Constipation Nausea Vomiting 2 (33.3) 2 (28.6) 3 (42.9) 2 (28.6) Fatigue 3 (50.0) 2 (28.6) Headache 2 (28.6) Infusion related reaction 2 (28.6) Company logo

Slide 12

First Cycle PK and PD Data for the First 6 Patients in Each Cohort Serum AVB Conc (ng/mL) AVB+PLD AVB+Pac GAS6 concentrations immediately decreased from baseline levels to BLQ in every patient, and remained BLQ throughout the two-week dosing period AVB500 concentrations did not decrease below 3720 ng/mL, the minimally acceptable trough exposure based on PK/PD modeling that incorporated animal and human data from the healthy volunteer clinical study Company logo bar chart

Slide 13

Best Response Determined by Investigator-Assessed RECIST for First 12 Patients Response Rate AVB+PLD 33% AVB+Pac 50% Overall 42% Clinical Benefit 58% * 2 Progressive Disease patients (both in Pac arm) are not shown as CTs were not obtainable at time of progression Green = AVB + Pac Blue = AVB + PLD Company logo Bar chart

Slide 14

Current Average Treatment Duration for Responders is 7 Months = partial response (PR) = progressive disease (PD) Time on Treatment (days) AVB+Pac AVB+PLD 4/5 PRs still ongoing 2 of the 4 continue to receive chemo + AVB 2 of the 4 are currently receiving AVB alone (no more chemotherapy) Company logo bar chart

Slide 15

Conclusions Based on Available Data from the First 12 Patients AVB500 effectively sequesters serum GAS6, the sole ligand for AXL, in platinum-resistant ovarian cancer patients AVB500 administration was not associated with any dose-limiting toxicities nor serious adverse events Infusion reactions mitigated by premedication The efficacy data from these patients show early proof of concept with best overall response rate by Investigator-determined RECIST that is better than historical control Company logo

Slide 16

Next Steps Phase 2 Study Design ClinicalTrials.gov Identifier: NCT03639246 P1b study expanded to Determine ORR data across larger population Continuously update PK/PD model with additional data to identify optimal AVB500 dose Using Model-Informed Drug Development (MIDD) to guide selection of higher AVB doses for evaluation in P1b Seeing preliminary data with lower RR in subsequent patients with higher GAS6 and lower AVB500 troughs Exposure response analysis indicates potential weak correlation with AVB500 trough levels and response Dose that is tolerated and has optimal PK/PD will be investigated in P2 Company logo Chart

arav-ex992_6.htm

Exhibit 99.2

 

Aravive Presents Positive Data from initial 12 Patients in Phase 1b portion of its Phase 1b/2 Ovarian Cancer Study of AVB-500 in Late Breaking Oral Presentation at European Society for Medical Oncology Congress in Barcelona

 

Company additionally reports data on initial 28 evaluable patients in ongoing expansion study as well as expansion cohort dose increase based on drug exposure-response analysis

 

HOUSTON– September 27, 2019 – Aravive, Inc. (Nasdaq: ARAV) today presented positive data from the initial 12 patients of the ongoing Phase 1b portion of the company’s Phase 1b/2 study of AVB-500 in ovarian cancer patients in a late breaking oral presentation at the European Society for Medical Oncology (ESMO) Congress in Barcelona.

 

The open-label, Phase 1b portion of the study of AVB-500 in patients with platinum-resistant recurrent ovarian cancer enrolled patients into two cohorts, one investigating a combination of AVB-500 with pegylated liposomal doxorubicin (PLD) and the other, a combination with paclitaxel (PAC). In both study groups, AVB-500 treatment led to early proof of concept with overall best response rate (ORR) by investigator determined RECIST v1.1 criteria and durable response in responders. AVB-500 was well tolerated with no dose limiting toxicities (DLT). The data from the initial 12 patients are summarized as follows:

 

 

Clinical benefit [Partial Response (PR) + Stable Disease (SD)] in 7 out of 12 patients (58 percent)

 

Partial responses (PR) in 5 out of 12 patients (42 percent)

 

o

The mean response rate in patients treated was 50 percent with AVB-500+PAC, and 33 percent with AVB-500+PLD

 

o

Three responders had at least 60 percent tumor regression

 

o

Two responders had more than 80 percent tumor regression

 

The current average treatment duration for responders is 7 months and 4 of 5 patients who responded remain on study  

 

o

Two patients who responded have completed their chemotherapy regimen and are receiving AVB-500 alone

 

“Due to its aggressive nature, ovarian cancer has been particularly challenging to address therapeutically, so we are encouraged by the early positive efficacy signal,”


said investigator Bradley J. Monk, M.D., professor and director of the division of gynecologic oncology at Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center in Phoenix, Arizona. This clinical study continues to support previous literature that highlights the potential for agents that can inhibit the GAS6/AXL pathway to provide new treatment options for ovarian cancer patients.”

 

The company continues to use Model-Informed Drug Development (MIDD) to guide selection of higher drug doses for evaluation in Phase 1b and identify the optimal drug dose for AVB-500 in the treatment of cancer.

 

Preliminary data from subsequent patients enrolled in the study have demonstrated an exposure-response relationship which has guided the company to study higher doses of the drug in the expansion cohort (15 mg/Kg and 20 mg/kg every two weeks).  

 

The following updated information from the initial 28 evaluable patients in the ongoing expansion study is reported by the company in conjunction with, but separate from, the ESMO presentation:

 

 

AVB-500 continues to be well tolerated.

 

Current response rates correlate with drug exposure:

 

o

Peak and trough levels after first dose of AVB-500 appear to predict anti-tumor activity. The relationship of peak drug level with response rate (PR) and clinical benefit rate (PR + SD) were statistically significant with p-values of 0.0236, 0.0337 respectively.

 

o

72.7 percent of patients with peak drug level > 225 mg/L (high drug level) achieved clinical benefit (PR + SD) compared to 17.6 percent with peak drug level <= 225 mg/L (low drug level). At a confidence level of 0.95, the p-value was 0.0118.

 

o

The clinical benefit rate in the initial 28 patients is currently at 61 percent with 25 percent PR. As the data continues to mature, the best response rates are subject to change.

 

o

A review of the baseline characteristics and demographics of the patients did not reveal any apparent differences, suggesting that the drug exposure is the primary driver of anti-tumor activity.

 

o

The company cautions that the statistical significance associated with these estimates is marginal, given the n=28, and results should be interpreted with caution.

 

“Understanding that there is an exposure-response relationship where higher clinical benefit is seen in patients achieving higher drug levels is very promising for our program at this stage,” said Gail McIntyre, Ph.D., chief scientific officer of Aravive. “It


demonstrates that AVB-500 is contributing to the clinical benefit and it informs the dose that should be tested in pivotal studies.”

 

Aravive plans to report the detailed analysis once the data from the initial 30 patients on the current 10 mg/kg dose mature toward the end of the year. That data analysis will be evaluated to inform the regulatory strategy for AVB-500 as a treatment for platinum-resistant ovarian cancer. If current exposure response relationships are confirmed in the dose escalation portion of the expansion study by mid 2020, Aravive intends to explore the potential for an accelerated regulatory pathway for AVB-500 with the FDA.

 

The company is further exploring feasibility of biomarker-driven individualized dose adjustments. Aravive plans to incorporate the exposure-response information into their planned studies in clear cell renal cancer and renal fibrosis trials.

 

About Ovarian Cancer

Each year in the United States, more than 22,000 women develop ovarian cancer and there are approximately 14,240 attributed deaths annually, making ovarian cancer the deadliest of gynecologic malignancies. Most women with ovarian cancer are diagnosed with advanced disease, after the tumor has already spread, and their disease rapidly becomes resistant to existing chemotherapies.

 

About AVB-500

AVB-500 (previously called AVB-S6-500) is a therapeutic recombinant fusion protein that has been shown to neutralize GAS6 activity by binding to GAS6 with very high affinity. In doing so, AVB-500 selectively inhibits the GAS6-AXL signaling pathway. In preclinical studies, GAS6-AXL inhibition has shown anti-tumor activity, both as a single agent or in combination with a variety of anticancer therapies including radiation therapy, immuno-oncology agents, and chemotherapeutic drugs that affect DNA replication and repair. Increased expression of AXL and GAS6 in tumors is correlated to poor prognosis and survival and has been implicated in therapeutic resistance to conventional chemotherapeutics and targeted therapies.

 

Aravive is currently enrolling the expansion cohort in the phase 1b portion of a phase 1b/2 clinical trial of AVB-500 in platinum-resistant recurrent ovarian cancer. An investigator-studied Phase 1 study of AVB-500 in combination with durvalumab in patients with platinum-resistant, recurrent epithelial ovarian cancer is also ongoing. A Phase 1 clinical trial in healthy volunteers (NCT03401528) investigating the safety, pharmacokinetics, and pharmacodynamics of AVB-500 met the safety and tolerability endpoints and demonstrated clinical proof-of-mechanism for AVB-500 in neutralizing GAS6. Based on AVB-500’s favorable safety profile, coupled with its specifically


targeted mechanism of action, the protein has the potential to be used both in combination with existing therapies, as well as a maintenance drug. U.S. FDA granted Fast Track Designation to Aravive Biologics’ AVB-500 in platinum-resistant recurrent ovarian cancer in 2018.

 

About Aravive
Aravive, Inc. (Nasdaq: ARAV) is a clinical-stage biopharmaceutical company developing treatments designed to halt the progression of life-threatening diseases, including cancer and fibrosis. Aravive’s lead product candidate, AVB-500, is an ultra-high affinity decoy protein that targets the GAS6-AXL signaling pathway. By capturing serum GAS6, AVB-500 starves the AXL pathway of its signal, potentially halting the biological programming that promotes disease progression. AXL receptor signaling plays an important role in multiple types of malignancies by promoting metastasis, cancer cell survival, resistance to treatments, and immune suppression. The GAS6-AXL signaling pathway also plays a significant role in fibrogenesis. Aravive is evaluating AVB-500 in platinum-resistant ovarian cancer, and intends to expand development into additional oncology and fibrotic indications. Aravive is based in Houston, Texas and received a Product Development Award from the Cancer Prevention & Research Institute of Texas (CPRIT) in 2016. Aravive was one of FierceBiotech's Fierce 15 in 2017. For more information, please visit www.aravive.com.

 

Forward Looking Statements
This communication contains forward-looking statements (including within the meaning of Section 21E of the United States Securities Exchange Act of 1934, as amended, and Section 27A of the United States Securities Act of 1933, as amended), express or implied, concerning the Company’s goals, intentions and expectations as to future plans or events, including statements regarding plans to report the detailed analysis toward the end of the year, exploring the potential for an accelerated regulatory pathway for AVB-500 with the FDA, exploring the feasibility of biomarker-driven individualized dose adjustments and plans to incorporate exposure-response information into planned studies in clear cell renal cancer and renal fibrosis trials, the potential of AVB-500 halting the biological programming that promotes disease progression and the expansion of the development of AVB-500 into additional oncology and fibrotic indications. Forward-looking statements are based on current beliefs and assumptions, are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results to differ materially from those contained in any forward-looking statement as a result of various factors, including, but not limited to, risks and uncertainties related to: the Company’s ability to report a detailed analysis from the initial 30 patients on the current 10 mg/kg dose toward the end of the year, the


Company’s ability to explore the potential for an accelerated regulatory pathway for AVB-500 with the FDA, the Company’s ability to explore the feasibility of biomarker-driven individualized dose adjustments, the Company’s ability to incorporate exposure-response information into planned studies in clear cell renal cancer and renal fibrosis trials, the Company’s ability to expand development in 2019 into additional oncology and fibrotic indications, the Company’s dependence upon AVB-500, AVB-500’s ability to have favorable results in clinical trials or receive regulatory approval, potential delays in the Company's clinical trials due to regulatory requirements or difficulty identifying qualified investigators or enrolling patients; the risk that AVB-500 may cause serious side effects or have properties that delay or prevent regulatory approval or limit its commercial potential; the risk that the Company may encounter difficulties in manufacturing AVB-500; if AVB-500 is approved, risks associated with its market acceptance, including pricing and reimbursement; potential difficulties enforcing the Company's intellectual property rights; the Company's reliance on its licensor of intellectual property and financing needs. 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 the Company's Annual Report on Form 10-K and Form 10-K/A for the fiscal year ended December 31, 2018,  recent Current Reports on Form 8-K and subsequent filings with the SEC. Except as required by applicable law, the Company 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.

Contacts for Aravive:


Investors:

Christina Tartaglia
Stern Investor Relations
christina@sternir.com

 

Media:

Heidi Chokeir

Canale Communications

heidi@canalecomm.com

619-203-5391