PERTH, Australia – Sydney-based Kazia Therapeutics Ltd.’s shares soared nearly 82% this week on positive interim results for lead molecule GDC-0084 in a phase II glioblastoma trial.

Data from the first nine patients in the study show that GDC-0084 treatment resulted in a median progression-free survival (PFS) rate of 8.4 months compared to the standard of care, temozolomide, which has a PFS of around 5.3 months.

Kazia CEO James Garner told BioWorld Asia that caution was needed in drawing exact comparisons because this is an early, first look at the data. “But the fact that it is a larger figure gives us huge confidence that our drug is working better and that we have a strong signal,” he said.

Median overall survival (OS) could not yet be calculated due to insufficient death events in the study. Roughly 75% of evaluable patients remained alive at the analysis cut-off date

“Although it has not yet been possible to calculate overall survival, the majority of patients in the first stage of the study remain alive more than a year after diagnosis, which suggests that a meaningful OS benefit may emerge as the study matures. That would be a remarkable finding,” Garner said.

James Garner, CEO, Kazia Therapeutics Ltd.

The primary endpoint for the first stage of the phase II dose-escalation study was safety and tolerability. PFS and OS were included as exploratory efficacy endpoints.

Glioblastoma is the most common and most aggressive form of brain cancer, but there has been little progress in treating the disease in almost 20 years. The standard of care is surgery followed by radiotherapy and treatment with temozolomide, which the FDA approved in 1999. It is the only FDA-approved drug to treat newly diagnosed glioblastoma.

Temozolomide, however, is ineffective in two-thirds of patients, and Kazia is targeting those nonresponders, Garner said.

GDC-0084 was designed specifically for brain cancer because it crosses the blood-brain barrier. It inhibits the phosphoinositide 3-kinase (PI3K) signaling pathway, which is implicated in roughly 85% of glioblastoma tumors, the CEO said.

Licensed from Roche Holding AG unit Genentech in late 2016, GDC-0084 is a small molecule inhibitor of the PI3K/AKT/mTOR pathway. It entered phase II trials in 2018.

The group of patients being treated in the phase II study are newly diagnosed with glioblastoma and were treated with surgery and radiotherapy. All patients had unmethylated MGMT promoter status, a genetic switch that makes them resistant to temozolomide.

“For this group of patients, there is really nothing else working,” Garner said, noting that clinical guidelines recommend involving patients in clinical trials.

The current phase II study is expected to complete recruitment for the second part of the study in the early part of next year, Garner said. “We don’t see full and final completion of this study as rate-limiting for the pivotal registrational study. We’ve learned a lot about GDC-0084’s use, we’ve seen a great signal, we’ve got a dose… There are some questions that still need to be answered about whether the drug should be administered on a full stomach.”

He said he anticipates initiating the pivotal trial in in early 2020, and that trial will be run in parallel with the phase II study, which will enroll about 29 patients for the second half of the study.

Competitive space

There are now four approved PI3K inhibitors on the market. Gilead Sciences Inc’s Zydelig (idelalisib) is approved for chronic lymphocytic leukemia (CLL) and follicular lymphoma. Bayer AG’s Aliqopa (copanlisib) is an intravenous treatment for relapsed follicular lymphoma, and Verastem Oncology’s Copiktra (duvelisib) is approved for CLL and some lymphomas. In May, the FDA approved Novartis AG’s Piqray (alpelisib) as an oral combination therapy with fulvestrant for metastatic breast cancer in patients with the PI3KCA mutation.

“The PI3K class has been well-researched. It’s one we know and understand quite well – there’s been evidence of proof of concept in a range of tumor types. A lot of the PI3K inhibitors only target certain types of PI3K isotopes, whereas our drug is differentiated because it is a pan-PI3K inhibitor and hits all four main isoforms,” Garner said.

“Although there are other PI3K inhibitors on the market, and it is becoming a very interesting class of drugs, none of those drugs cross the blood-brain barrier and are not being studied in brain cancer.

“The GDC-0084 program has ended up being a much bigger thing than we had anticipated,” Garner added. “We thought it is was a niche opportunity when we in-licensed it from Genentech, but we’ve ended up building the company around it.”

In addition to the ongoing phase II study in glioblastoma, GDC-0084 is also the subject of four other ongoing clinical trials in diffuse intrinsic pontine glioma and brain metastases, several of which are expected to report interim data in early 2020.

Proprietary ovarian cancer drug Cantrixil (TRX-E-002-1) is a third-generation benzopyran molecule that has shown activity against cancer stem cells. The drug is in a phase I platinum-resistant ovarian cancer study in 60 patients in Australia and the U.S. Interim data were presented at the ESMO Congress in September 2019, and the study remains ongoing. Cantrixil was granted orphan designation for ovarian cancer by the FDA in April 2015.

“The program is deep and broad and one that any pharma company would be proud of,” Garner said.

“It feels like it’s been a long journey, but we’ve only been working on this drug for two to three years, and potentially we are within a few years of registration. For our company, that will take us from being a preclinical company to a phase III company, so by the standards of drug development, it has moved incredibly fast.

“In one sense, that’s exactly how it should be for a drug with as terrible a prognosis as glioblastoma,” he added. “But it also reflects what we’ve tried to do in Kazia. Our goal has been to put forward this agile model for drug development, and the GDC-0084 story is a good illustration of exactly what we’ve been trying to do as a company.”

With a market cap of roughly AU$52 million (US$35 million), Kazia’s shares on Australia’s Securities Exchange (ASX:KZA) shot up nearly 82% from AU44 cents to AU70 cents on the news, nearly doubling the company’s valuation. Shares closed Tuesday at 74 cents.

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