ViewPoints Interview: Aravive’ s Dr. Gail McIntyre Shares Insight on AVB-500 and its Potential Against ccRCC

 ViewPoints Interview: Aravive’ s Dr. Gail McIntyre Shares Insight on AVB-500 and its Potential Against ccRCC

ViewPoints Interview: Aravive’ s Dr. Gail McIntyre Shares Insight on AVB-500 and its Potential Against ccRCC

In an interview with PharmaShots, Dr. Gail McIntyre, CEO of Aravive shared her views on the AVB-500, its potential against ccRCC, and the design of the clinical trial evaluating the therapy. He also shed light on epidemiology of Clear Cell Renal Cell Carcinoma.

Shots:

  • AVB-500 is being evaluated in ccRCC, has been tested in preclinical models of ccRCC, and demonstrated an effect in reducing metastasis and reversing resistance to tyrosine kinase inhibitors
  • The company will initiate some “basket” single-arm trials by the end of 2021 that would investigate AVB-500 in numerous cancers and in multiple combinations simultaneously to quickly explore and expand the pipeline
  • Aravive anticipates filing a BLA by the end of 2023 for approval of AVB-500 in platinum-resistant ovarian cancer, assuming the trial is positive

Tuba:  Can you discuss the epidemiology of Clear Cell Renal Cell Carcinoma?

Gail:  Kidney cancer is a leading cause of cancer-related deaths in the United States and is among the 10 most common cancers in both men and women. Metastasis to distant organs including the lung, bone, liver, and brain is the primary cause of death in kidney cancer patients as only 12% of metastatic kidney cancer will survive past 5 years. According to the American Cancer Society, it is estimated that there will be approximately 76,080 new cases of kidney cancer and 13,780 people will die from this disease in the United States during 2021.

Clear cell renal cell carcinoma (ccRCC) is a cancer of the kidney. Genetic predisposition conditions, e.g., von Hippel Lindau syndrome which involves a genetic mutation in VHL, a tumor suppressor gene controlling tumor initiation in ∼90% of ccRCC tumors, may contribute to the development of this type of cancer.

Tuba:  Why Aravive has committed to investigate AVB-500 in ccRCC patients?

Gail:  Aravive’s scientific founder, Dr. Amato Giaccia, identified the GAS6/AXL pathway is critical for cancer cell survival from a VHL lethal screen. As noted above, 90% of ccRCC tumors have a genetic mutation in the VHL tumor suppressor gene and AXL and GAS6 expression are upregulated as a result. As such, ccRCC expresses the target of AVB-500, Aravive’s lead compound.

Importantly, AVB-500, the lead compound being tested in ccRCC, has been tested in preclinical models of ccRCC and demonstrated an effect in reducing metastasis and reversing resistance to tyrosine kinase inhibitors (e.g., sorafenib).

Tuba:  Discuss the clinical trial design of Phase 1b/2 clinical trial of AVB-500 in patients with Clear Cell Renal Cell Carcinoma?

Gail:  The trial has a dose-escalation (P1b) portion to test doses of 15, 20 and 25mg/kg AVB-500 administered IV every 2 weeks in combination with daily cabozantinib. The 20 and 25mg/kg doses are higher than what we are testing in our P3 platinum-resistant ovarian cancer registrational trial because cabozantinib is known to increase serum GAS6 levels (target of AVB-500) and higher doses of AVB-500 may be required to fully suppress serum GAS6 levels. We know from our preclinical studies that full suppression of serum GAS6 is required for anti-tumor activity. Importantly, the safety profile of AVB-500 has been favorable and neither preclinical toxicology studies nor clinical studies impose a limit to the AVB-500 dose that we can test.

We expect to select the P2 dose based on the pharmacokinetics, pharmacodynamics (specifically, serum GAS6 suppression), and safety by the end of 3Q2021. Clinical activity will also be collected for the patients in the P1b portion. The P2 portion of this trial is an open-label, randomized, controlled trial comparing AVB-500 + cabozantinib vs cabozantinib with the objective of assessing clinical activity assessed by investigator-assessed RECIST V1.1 criteria for progression-free survival. This trial will continue throughout 2022.

Tuba:  Discuss the working on AVB-500 and its potential against ccRCC?

Gail:  The biological rationale for testing AVB-500 as a treatment for ccRCC is strong. The literature demonstrates AXL plays a significant role in ccRCC invasion & metastasis, is highly expressed in aggressive ccRCC tumors, and associated with poor outcome, and high levels of GAS6 and/or AXL are associated with poor prognosis and shorter survival in ccRCC. As such, GAS6/AXL signaling pathway is an established therapeutic target to prevent/treat metastatic ccRCC. As noted above, 90% of ccRCC tumors have a genetic mutation in the VHL tumor suppressor gene and AXL and GAS6 expression are upregulated as a result. As such, ccRCC is associated with activation of the GAS6/AXL pathway, the target of AVB-500.

Importantly, AVB-500, the lead compound being tested in ccRCC, has been tested in preclinical models of ccRCC and demonstrated an effect in reducing metastasis and reversing resistance to tyrosine kinase inhibitors (e.g., sorafenib).

Tuba:  Do you think disruption of GAS6/AXL signaling can be the potential approach in treating cancer?

Source: Aravive

Gail:  There is a wealth of publications over the past 2 decades showing the association of high levels of GAS6 and AXL with poor prognosis and survival in cancer patients. The pathway is implicated in the epithelial to mesenchymal transition which results in a tumor cell migrating, invading, and growing over healthy tissue (i.e., metastasizing). The pathway is also upregulated in tumor cells that have become resistant to a number of anticancer drugs, including chemotherapies, biologics, and checkpoint inhibitors. However, targeting the pathway has proven challenging for a few reasons. First, the binding affinity between endogenous AXL and GAS6 is very high, making it challenging to disrupt the interaction. Second, AXL is a kinase but small drug kinase inhibitors target the region of kinases that are highly conserved across other kinases, typically resulting in a promiscuous inhibitor. Aravive’s lead candidate, AVB-500, is an AXL decoy protein that has been engineered to bind to GAS6, the sole activator of AXL, with a much higher affinity than the endogenous AXL protein. As such, AVB-500 captures and removes GAS6 so that it is not available to bind and activate AXL. This is a unique approach with the potential for AVB-500 to be a “best-in-class” therapeutic as there are no other drugs or development candidates that target GAS6.

We know from our preclinical program that the higher the affinity of the AXL decoy protein, the better the antitumor activity. AVB-500 has a 200-fold higher affinity than the endogenous AXL protein and it has demonstrated antitumor activity in a number of preclinical cancer studies. We also know that suppression of serum GAS6 (using our proprietary biomarker assay) is required for the antitumor effect. Importantly, we have demonstrated clinical activity in combination with paclitaxel in a platinum-resistant ovarian cancer population at a dose that suppresses serum GAS6 levels. All of our data thus far show a clear association between suppression of this pathway and the antitumor effect.

Tuba:  What are the indications in which you are evaluating or plans to evaluate your lead candidate? Can we know reason behind discontinuation of IgAN program?

Gail:  Aravive made the decision last year to focus on oncology and that is the reason we decided to discontinue the IgAN program.

We are currently doing in our P1b/P2 ccRCC trial, have initiated the P3 platinum-resistant ovarian cancer trial, and have two investigator-sponsored trials (ISTs) ongoing. The ISTs are in platinum-resistant ovarian cancer and bladder cancer in combination with anti-PD-L1 proteins. Given the wealth of preclinical data for AVB-500, we could potentially go into any number of cancers and all lines of therapy. We’d like to initiate some “basket” single-arm trials by the end of 2021 that would investigate AVB-500 in numerous cancers and in multiple combinations simultaneously to quickly explore and expand the pipeline.

Tuba:  What we can expect from the company in terms of initiating clinical studies, announcing results in 2021?

Gail:  Aravive is focused on the P3 platinum-resistant ovarian cancer program and we expect to dose a patient soon. We received advice from FDA on our program last year and this one P3 trial, if successful, could support the registration of AVB-500 in platinum-resistant ovarian cancer. The preclinical and clinical pharmacology programs are complete so this is the last trial needed. We do have an interim analysis planned for Q12022 during which we will assess the potential to see a treatment effect in patients who had previously been on bevacizumab prior to trial entry. This is important as our P1b data suggest the effect is lower in such patients and this will provide the opportunity to only include patients who have never received bevacizumab as our P1b data showed those patients did very well. (Of note, this phenomenon has been noted with other cancer therapies and may be related to bevacizumab’s effect on decreasing the tumor vasculature, resulting in decreased delivery of the subsequent anticancer therapy to the tumor.) The adaptive design affords us the opportunity to continue with the trial without any disruption and complete the trial with the highest chance of success.

The ccRCC trial will be ongoing for the next 2 years and will be open-label and will provide safety, pharmacokinetic, pharmacodynamic, and potentially clinical activity data over this time.

Tuba:  Discuss your collaborations with other companies. Are you looking for more collaboration in advancing your lead product in other indications?

Gail:  We will always be opportunistic and consider opportunities that come our way. We are very excited about the safety profile and clinical activity of AVB-500 and want to see this drug tested in as many indications and lines of therapy as possible.

Tuba:  Can we have more details on Aravive’s product pipeline?

Gail:  Below is a picture of our current pipeline. At this time, it does not include expansion into basket trials mentioned above. In addition to the trials in PROC and ccRCC and the two ISTs, we have a discovery program in collaboration with WuXi Biologics. The focus of that program is to develop bispecific antibodies to CTGF (also known as CCN2) that is a clinically validated target for idiopathic pulmonary fibrosis (or IPF) and pancreatic cancer. Our approach is unique and could provide a best-in-class therapeutic. The investigational new drug application (IND) for this program, allowing us to initiate clinical trials, is expected in 2023.

Source: Aravive

Tuba:  When are you expecting or planning to file an application for seeking approval for your first product?

Gail:  We anticipate filing a BLA by the end of 2023 for approval of AVB-500 in platinum-resistant ovarian cancer, assuming the trial is positive. We have completed all of the necessary preclinical studies and other clinical studies. The P3 trial we have initiated is the last trial needed to submit the BLA.

Main Source Image: Dialysis Patient Citizens Education Center

About Author:

Dr. Gail McIntyre is the CEO of Aravive since April 2020. Previously she was Chief Scientific Officer since February 2019 and has been with the company since August 2016 as head of R&D.

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Tuba Khan

Tuba Khan is Senior Editor at PharmaShots. She is curious, creative, and passionate about recent updates and innovation in the Life sciences industry. She covers Biopharma, MedTech, and Digital health segments. Tuba also has an experience of digital and social media marketing and runs the campaigns independently. She can be contacted on tuba@pharmashots.com

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