$AVEO – Aveo Pharmaceuticals
Aveo Pharmaceuticals (Aveo Oncology, for some reason they have one name for their company and one for their website) is a biopharmaceutical company dedicated to developing targeted treatments for oncology and other unmet medical needs. The company has a flagship product tivozanib, a compound that not only provides a long half-life, but servers as an inhibitor of vascular endothelial growth factor 1, 2, and 3 receptors as a treatment for renal cell carcinoma and other types of cancers. With several partnerships in the works, the company is leveraging their position to develop and commercialize their pipeline which already has traction in Europe.
The CEO, Michael Bailey, has been with Aveo for eight years originally coming in as the company’s chief commercial officer, then served as chief business officer in 2013. In 2015, Bailey took the position of chief executive officer and president of the company. Prior to being at Aveo, Bailey worked at executive level positions at Synta, ImClone Systems (now Eli Lilly), and SmithKline Beecham, where he helped market and commercialize drugs such as ERBITUX, CYRAMZA, and necitumumab. With more than 20 years of experience in the biotechnology and pharmaceutical industry and experience in commercializing drugs in the oncology space, Bailey brings a solid track record to the table to help advance the company he runs.
Aveo Pharmaceuticals has 6 different candidates in their pipeline with a total of 10 combined indications of use. This robust pipeline is headed by their flagship product, Tivozanib. With three different indications, tivozanib has been approved in Europe as a first line treatment in patients with RCC (renal cell carcinoma) as well as for adult patients who are vascular endothelial growth factor receptor (VEGFR) and mTOR pathway inhibitor-naïve following disease progression after one treatment with cytokine therapy for advanced RCC.
With their six different products boasting a total of 10 different indications combined, Aveo shows great promise. Their lead candidate is tivozanib, which has 3 current indications of which 1 is already approved in the EU since August 2017. With an already proven treatment and potential for more, it is hard not to get excited about the potential with tivozanib. The remainder of the company’s pipeline is still very early stage of the development process ranging from Preclinical to Phase III. They have two different sectors that they break their products down into, Oncology and Non-Oncology.
· TIVO-1 – 1st Line RCC (Approved)
· TIVO-3 – US Phase III Registration Study in 3rd Line RCC (Phase III)
· TiNivo – +Opdivo RCC (Phase II)
· SCCHN (Investigator) (Phase II)
· Pancreatic (Investigator) (Phase I)
· AML (Investigator) (Phase I)
· Esophageal Cancer (Phase 1)
· AMD (Preclinical)
· Cachexia (Preclinical)
· PAH (Preclinical)
While they do have a robust and outstanding pipeline, we want to turn our focus towards tivozanib as they will be presenting Phase II data at the ESMO this coming October. This data is representing the TiNivo trial of tivozanib and nivolumab (Opdivo) in aRCC, as an immune checkpoint, PD-1, inhibitor.
Tivozanib is an oral, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) which is approved for the treatment of adult patients with advanced RCC in the EU. This potent inhibitor features a long half life which is selective of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities. This essentially makes the compound more efficient and potentially less toxic while requiring minimal dose modifications. In the US, tivozanib is being investigated in a Phase II trial in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, Opdivo (nivolumab) in RCC. Tivozanib’s distinct tolerability among VEGF TKI’s creates a unique situation where it is a prime candidate to use alongside PD-1 inhibitors.
The vascular endothelial growth factor (VEGF) pathway plays a significant role in angiogenesis, which is critical in cancer. Angiogenesis, the formation of new blood vessels, is essential for endothelial cell proliferation, migration and survival. There are five known VEGF ligands (A, B, C, D, PLGF) and three VEGF receptors (1, 2 and 3). Each ligand exhibits distinct but overlapping binding profiles for the three VEGF receptors.
To optimally inhibit the VEGF pathway, it may be critical to effectively block all three VEGF receptors as each plays an important role in cancer angiogenesis:
VEGF receptor 1 is critical for the modulation of endothelial cell survival and vessel morphogenesis;
VEGF receptor 2 is thought to be the predominant receptor for endothelial cell proliferation and migration; and,
VEGF receptor 3 promotes endothelial sprouting and vascular network formation.
Preclinical studies have demonstrated tivozanib is a potent, selective, long half-life inhibitor of all three VEGF receptors that is designed to optimize VEGF blockade while minimizing off-target toxicities.
With that overview done on the drug, lets dive a little deeper into this.
TKIs have recently revolutionized the treatment of RCC while inhibitors of VEGF pathways have become the standard treatment option for patients with RCC. Tivozanib is a novel VEGF receptor TKI inhibitor which has demonstrated antitumor efficacy. The unique selectivity of tivozanib has shown minimal off-target toxicities and prevented many adverse effects. Also, VEGFR TKIs have shown modulation of antitumor immunity, providing synergy between VEGFR and programmed cell death protein-1 (PD-1) inhibition, showing tivozanib to enhance PD-1 activity through regulatory T-cell reduction.
When tivozanib was compared to competitors axitinib, pazopanib, sorafenib, and sunitinib, only tivozanib and sunitinib significantly reduced the percentage of regulatory T cells. Where P = % CD4/CD25/FoxP3 (all regulatory T Cells analyzed by flow cytometry), the drugs produced the following results 16 hours after last TKI application.
Tivozanib – P = 0.034
Axitinib – P=0.908
Pazopanib – P=0.354
Sorafenib – P=0.427
Sunitinib – P=0.002
As you can see, only tivozanib and sunitinib showed a significant reduction in regulator T cells. However, due to the specify of tivozanib, its unique adverse effect profile makes it an ideal candidate for combination therapies.
The Phase II study of TiNivo is to determine the safety, tolerability, and maximum tolerable dose of tivozanib in combination with nivolumab in patients with RCC. All patients are over 18 that present RCC, which is a measurable disease, and have no prior exposure to tivozanib or nivolumab with a life expectancy greater than 3 months. Patients of the study received tivozanib QD for 21 days, followed by a rest period of 7 days, and nivolumab intravenously 240 mg Q2W. Dose of tivozanib included 1.0 mg QD and 1.5 mg QD. Phase II was an expansion of cohorts of maximum tolerated dose enrolled patients to further evaluate the safety and tolerability of tivozanib.
In Phase I, no patients experienced dose limiting toxicity in cycle 1 (4 weeks) and MTD was determined to be full-dose tivozanib 1.5mg/d + nivolumab 240 mg. In Phase II, an additional 21 patients were enrolled at MTD on top of the Phase I 6 patients. In Phase II, a total of 6 patients discontinued tivozanib and 7 discontinued nivolumab, and there was 1 dose reduction for tivozanib (cycle 6 or 24 weeks in) and a total of 17 dose interruptions.
For safety, 14 (51.9%) of patients experienced 1 or more grade 3 or 4 adverse effect of any cause. Nearly half of the adverse effects that were experienced could have potentially been immune-related adverse effects rather than an adverse effect of the compound itself. These include rash, pruritus, increased ALT, increased amylase, increased AST, increase lipase, sarcoidosis, and diarrhea. The most common adverse effect was hypertension, but the mean age for patients was 63.
Preliminary Antineoplastic Activity and preliminary efficacy was assessed in 14 patients who started therapy at MTD and had 2 or more treatment scans, being on treatment for 4 months or greater. Of the 14, 11 are undergoing treatment including 3 in cycle 8 with a partial response. The results showed that of the 14 patients, none had seen a complete response, 9 (64.3%) saw a partial response, and 5 (35.7%) showed stable disease with no progression. No patients displayed progressive disease. The charts indicate that patients who have been treated for 24 or more weeks almost all saw some partial response, giving the potential that extended treatment will generate a response.
Although preliminary, the results of the data indicated before a 64% response rate and a 100% disease control rate in patients receiving the MTD suggesting promising antitumor efficacy. This data demonstrates efficacy for tivozanib in combination with PD-1 inhibitors. The updated Phase II data to be presented in October of 2018 will hopefully affirm these numbers and show greater response rates and no disease progression in all patients.
RCC is the most common type of kidney cancer in adults, accounting for 90-95% of malignant neoplasms involving the kidneys. It is estimated that over 63,000 cases of new kidney cancer will occur in the United States and over 14,000 individuals will die because of it. According to Grand View Research, the global kidney cancer drug market was valued at $4.4 billion in 2016, and expected to grow at a CAGR of 5.4%. Incidence of RCC is highest in North America and Western Europe. Globally, there are an estimated 270,000 new cases diagnosed each year and over 116,000 deaths because of RCC.
While previously the treatment for kidney cancer was simply removing the kidney, various forms of treatment methods have been implemented among the currently approved drugs, including immune modulation therapy, cytokine therapy, mTOR inhibitor, and Vascular Endothelial Growth Factor (VEGF) inhibitor.
Rising preference for novel immunotherapies and immune-oncologic agents will push the use of targeted therapies to specific patient subpopulations or later lines of treatment. Programmed death-1 (PD-1) inhibitors are poised to displace TKIs and mTOR inhibitors as the standard of care in first-and second-line RCC settings. Combination regimens, specifically those including PD-1 inhibitors will be introduced in the first-line setting to target major unmet needs, giving Aveo a prime opportunity to grab a large share of the market treatment.
Competition in the space includes major companies such as; Amgen/Allergan, Argos Therapeutics, AstraZeneca, Aveo Pharmaceuticals, Bayer, Exelixis, Incyte, Merck, and Roche.
PD-1 and PD-L1 inhibitors represent a paradigm shift in kidney cancer treatment. Several PD-1 and PD-L1 agents with novel therapies are in early development and are being evaluated both as monotherapy and in combination with already approved immuno-oncology agents. Again, another position that Aveo has an opportunity to shine in.
Recently, Aveo ended Q2 2018 with $18.1 million in cash and cash equivalents and generated a total revenue of $0.4 million, the same revenue amount generated the same quarter last year. Expenses have gone down in R&D and administrative combined. With a net income of $4.0 million for Q2 2018, the company posted an income of $0.03 per basic share and a loss of -$0.06 per diluted share, which compares to a -$0.30 loss per basic share Q2 2017. Approximately $11.1 million of Q2 2018 net income was due to the decrease in value of the 2016 warrants which resulted from the decrease in stock price in the quarter. The company believes that the $18.1 million will fund operations into the first quarter of 2019. With a market cap of just under $400 million, this small company is going to look to raise funds soon to continue funding their trials, resulting in an upcoming dilution.
I like this company a lot. They have a drug in a large, unmet market that is developing and going to grow fairly rapidly. With an already approved indication and several more products in their pipeline, I believe they will see success. The data in Phase I showed promise and building off the safety and efficacy of Phase II I believe the additional cohorts put in will bring about positive data in favor of the drug showing specificity and low toxicity. Having already demonstrated not a single progression in disease, it is unlikely we will see progression moving forward, and we will start to see partial responses from more patients.
I do expect a dilution in the coming two months, however they did just gain value from the warrant situation, creating an opportunity for the company to take advantage and present a dilution to raise funds to continue operations for the next year or two. Their burn rate is pretty high but that should be assumed due to their pipeline and stages of development. The stock has been trading up the past 2 months, almost doubling its low since July. Although, I have no issue buying below $3.50 for a long term hold.