Australia-based Kazia Therapeutics licensed-in a drug called EVT801, originally discovered by France-based Sanofi. Now owned by Evotec, they work with many licensees and were looking for a partner to take to clinical trials. The drug hasn’t been in clinical trials, yet but the preclinical results are first class. The deal involved a deal, including $1.2 million upfront for Evotec, $308 million Euros in milestone payments as well as a tiered single-digit royalties structure. Kazia works in a partnership model and will collaborate with Evotec to develop EVT801. Kazi will lead the development and commercialization effort but Evotec will remain very involved. EVT801 targets lymphangiogenesis. The first trials will start in 2021 in a Phase 1 safety trial but sophisticated measures will be in place to identify how the drug will work. According to Kazia’s CEO, recently the first focus areas will include liver cancer and kidney cancer. They are good ways to test a drug like this at an early stage, in combination with immuno-oncology drugs. Hence a rich plan to take the drug forward is in place.
What is EVT801?
EVT801 is a small molecule inhibitor of vascular endothelial growth factor receptor 3 (VEGFR3). It is orally available, and so can be administered to patients by mouth.
Angiogenesis a Target for Two Decades but Challenges
For more than two decades, one of the most successful approaches in the treatment of cancer has been to target angiogenesis, the formation of new blood vessels. Drugs which inhibit angiogenesis, such as Avastin® (bevacizumab), starve the growing tumor of nutrients. However, inhibiting angiogenesis also results in hypoxia (low levels of oxygen) around the tumor, and this is thought to generate resistance to treatment. Almost all cancers treated with current anti-angiogenic drugs will eventually develop resistance.
Alternative Approach: Target Lymphangiogenesis
An alternative approach, which may avoid this problem, is to target lymphangiogenesis, which is the formation of new lymphatic vessels. Doing so achieves many of the same objectives as targeting angiogenesis but may avoid the problem of resistance induced by hypoxia. Moreover, the lymphatic system is a common route by which tumors spread (metastasize) throughout the body, and so inhibiting lymphangiogenesis may help to limit the ability of the tumor to spread.
In recent years, several new drug candidates have attempted to inhibit lymphangiogenesis. For example, Nexavar® (sorafenib) inhibits several forms of VEGFR, as well as other targets, and is approved for the treatment of renal cell carcinoma and hepatocellular carcinoma. Several drugs described as angiokinase inhibitors are in development, and some of these inhibit VEGFR3.
Distinguishing Feature of EVT801
However, each of these drugs have multiple targets, leading in many cases to significant side effects. The distinguishing feature of EVT801 is a high degree of specificity for VEGFR3, which should allow it to minimize toxicity.
In addition, EVT801 has shown powerful evidence in the laboratory of an ability to change the balance of immune cells within the tumor. Many tumors are resistant to the newest generation of immuno-oncology therapies because they do not contain the right immune cells for the drugs to act upon. It is hoped that administration of EVT801 may help to sensitize these tumors to immuno-oncology therapies such as Keytruda® (pembrolizumab) and Opdivo® (nivolumab) and thereby extend their use.
Kazia expects to explore all these potential uses of EVT801 during the clinical program.
The initial focus will be on a phase I study, which is expected to be conducted at one or more leading hospitals in France and to commence in CY2021. The focus will be on renal cell carcinoma (kidney cancer), hepatocellular carcinoma (liver cancer) and soft tissue sarcoma.
In this deal, Evotec grants Kazia an exclusive worldwide license to develop, manufacture and commercialize EVT801 in all territories and indications. Under the terms of the deal, Kazia will pay Evotec an immediate upfront amount of €1 million (AU$ 1.6 million), contingent milestones of up to €308 million (AU$ 480 million) related to achievement of clinical, regulatory, and commercial outcomes over the lifetime of the drug, and a tiered single-digit royalty on net sales.
The deal also includes a “Master Services Agreement” under which the two companies will collaborate closely on the further development of the early-stage investigational product.
About Kazia Therapeutics
Publicly traded on both NASDAQ (KZIA) and ASX (KZA) this oncology-focused venture called Kazia Therapeutics is based in Sydney, Australia. The company’s lead program is paxalisib, a brain-penetrant inhibitor of the PI3K / Akt / mTOR pathway, which is being developed to treat glioblastoma, the most common and most aggressive form of primary brain cancer in adults. Licensed from Genentech in late 2016, paxalisib commenced recruitment to GBM AGILE, a pivotal study in glioblastoma, in January 2021. Seven additional studies are active in other forms of brain cancer.
Paxalisib was granted Orphan Drug Designation for glioblastoma by the US FDA in February 2018, and Fast Track Designation for glioblastoma by the US FDA in August 2020. In addition, paxalisib was granted Rare Pediatric Disease Designation and Orphan Designation by the US FDA for DIPG in August 2020.
Kazia is also developing EVT801, a small-molecule inhibitor of VEGFR3, which was licensed from Evotec SE in April 2021. Preclinical data has shown EVT801 to be active against a broad range of tumor types and has provided compelling evidence of synergy with immuno-oncology agents. A phase I study is expected to begin in CY2021.