In WuXi AppTec’s latest series on novel drug development for pancreatic cancer, most of the companies featured have concentrated on ways to directly stimulate the patient’s own immune system to fight this stubborn disease. Halozyme, a clinical stage oncology company based in San Diego, has adopted a different, unique strategy based on the tumor’s microenvironment.
The company is testing its lead drug candidate, investigational drug pegvorhyaluronidase (PEGPH20), in a Phase 3 trial in patients with HA-high metastatic pancreatic cancer. PEGPH20 targets the area around the tumor rather than the tumor itself, increasing the delivery of oxygen and chemotherapy to the immune cells of the tumor.
The tumor microenvironment (TME) includes the malignant cancer cells as well as the many non-malignant cells within a tumor (for example fibroblasts and immune cells), blood vessels, and extracellular matrix components, such as collagen and the polymeric carbohydrate hyaluronan (HA).
The cancer cells within the tumor can recruit other cell types into the TME and then stimulate them to generate growth factors, signaling molecules and other matrix components that can further optimize the TME for malignant cell growth and result in an immunosuppressive microenvironment.
Decades of investigation have led to the current mechanism-based hypothesis for the role of HA in the TME. Accumulation of HA and associated water within some solid tumors can lead to increased pressure within the tumor microenvironment. The increased pressure can lead to blood vessel compression, restricting blood flow, leading to increased areas of hypoxia, and impeding access of therapeutic intervention into the tumor.
WuXi AppTec communications asked Halozyme’s Senior VP of Research and Development, Dr. Alison Armour, to explain why the company decided to take this unique approach and how PEGPH20 works. Dr. Armour has over 15 years of practice as a clinical oncologist and a strong record of overseeing successful regulatory submissions. Dr. Armour joined Halozyme in May 2019 and she is responsible for Halozyme’s research, clinical development, regulatory, safety and pharmacovigilance efforts.
Prior to Halozyme, Dr. Armour served as the Chief Medical Officer at Endocyte, where she was responsible for the company’s clinical division, including all medical operations, clinical operations, regulatory, data management and pharmacovigilance activities. Prior to this role, she served as Vice President of Development and team lead for TYKERB® at GSK and then at Novartis. Earlier in her career Dr. Armour also served as global medical science director at AstraZeneca.
Dr. Armour received her B.Sc. in Biochemistry, her M.B., Ch.B. MSc, and Doctorate of Medicine from the University of Glasgow; her FRCR at the Royal College of Radiologists London, UK and her FRCP at the Royal College of Physicians in London, UK, for contributions to the field of oncology.
WuXi: Dr. Armour, what is your opinion about the challenges in pancreatic cancer early screening and diagnosis? Are there any specific biomarkers?
Alison Armour: It is incredibly challenging to screen for pancreatic cancer at its early stages. A robust biomarker for example hasn’t been developed yet. The pancreas is deep within the abdomen. It’s not easy to detect on routine clinical examination and the symptoms can be non-specific. For example nausea, vomiting, weight loss or pain, which can often be misdiagnosed as other conditions.
The current blood biomarker tests are not specific, but CA19 or CEA may sometimes be elevated. Standard tests include CT, MRI and tissue via ERCP, which is an invasive procedure. Panels of potential diagnostic biomarkers are currently being explored.
WuXi: What are the hot targets in the field of drug development for pancreatic cancer?
Alison Armour: Pancreatic cancer is an extremely resistant cancer in the world of drug development, but so was melanoma until we found the right target. There are multiple targets being explored for pancreatic cancer, including KRAS and CTHRC1. At Halozyme, we believe there’s great promise in targeting hyaluronan (HA)—let me explain why.
Pancreatic cancer is known to be surrounded by very dense fibrous tissue. In fact, only around 10 percent of the cells are tumor. We also know that pancreatic tumor cells surround themselves with HA. That’s what we are targeting at Halozyme.
HA is a large, complex carbohydrate molecule. It accumulates on the surface of tumor cells and the space around them. It provides a barrier to immune cells from infiltrating the tumor and compresses the blood vessels, which impedes the delivery of chemotherapy to the tumor.
PEGPH20 breaks down the large molecule and has been shown in preclinical models to increase the perfusion of oxygen and chemotherapy to the tumor. The breakdown products may also have a role in recruiting immune cells into the tumor. That’s an area that we are actively researching now.
WuXi: In recent years, what breakthroughs have been made in drug development for pancreatic cancer?
Alison Armour: Sadly, not many. The first real breakthrough came with chemotherapy in the 1970s, then along came gemcitabine in the ‘90s. Since then, people have just combined drugs. There really haven’t been any significant breakthroughs in pancreatic cancer, and that’s why we must keep trying and explore the tumor microenvironment in its entirety. We are starting to target the molecular defects in all cancers though and PARP inhibitors showed some interesting data in the small numbers of patients whose tumors had a DNA repair defect.
WuXi: How is your drug (PEGPH20) different from existing pancreatic cancer treatments? Is it a new approach? What are the results of your research so far?
Alison Armour: Our lead therapeutic candidate, PEGPH20, utilizes a unique mechanism of action compared to standard anti-cancer therapies. Our preclinical research shows that it doesn’t target the cancer cells, but instead it targets a component of the microenvironment. It breaks down HA in the tumor itself and makes it easier for the blood vessels to deliver oxygen and chemotherapy as well as immune cells in the tumor area.
In our Phase 2 study, PEGPH20 plus standard chemotherapy of ABRAXANE and gemcitabine suggested meaningful clinical trends in OS and PFS in patients whose tumors expressed high levels of HA. We are waiting for the results of a confirmatory Phase 3 study later this year.
WuXi: What is the specific mechanism of action?
Alison Armour: PEGPH20 targets the accumulation of HA in the tumor microenvironment. When HA accumulates, it creates a significant barrier to drug delivery. Enzymatically degrading this accumulated HA has been shown in animal models to reduce tumor pressure, improve vascular perfusion and decrease hypoxia, enabling increased access of anti-cancer therapeutics and immune cells.
WuXi: How did you choose to focus on pancreatic cancer? It has been a very difficult disease to treat.
Alison Armour: Pancreatic tumors have very high levels of HA, the prime target for PEGPH20. This makes pancreatic cancer an ideal indication for Halozyme to pursue.
WuXi: Are you planning to develop the drug through regulatory approval and market it?
Alison Armour: Absolutely. We fully intend to commercialize PEGPH20 for the treatment of pancreatic cancer pending the results of our Phase 3 data readout.
WuXi: Have patients been involved in the development of your drug, other than participating in clinical trials of course?
Alison Armour: Our work with patients predominantly surrounds advocacy and support groups including the Pancreatic Cancer Action Network (PanCAN).
WuXi: What major challenges have you faced in trying to bring a new drug for pancreatic cancer to patients?
Alison Armour: The biggest challenge in drug development for pancreatic cancer is that we haven’t been able to target the pathways that really drive the development and growth of pancreatic cancer, but as drug developers we will keep trying. Patients are often very ill by the time they present and they succumb quickly to their disease, so we need to find agents that are effective and work rapidly.
WuXi: What other drug candidates do you have in the pipeline?
Alison Armour: Right now, we are concentrating on developing PEGPH20. Beyond pancreatic cancer, we are conducting studies across multiple solid tumor types to examine if PEGPH20’s demonstrated ability to degrade accumulated HA may help increase the effectiveness of anti-cancer and immuno-oncology therapeutics.
WuXi: What are the top impediments in our delivery of “better” medicines “faster” and “cheaper” to patients?
Alison Armour: We work tirelessly to create the best treatment options we can, as quickly as possible, because patients are waiting. People often rush through the early stages of development to see if the molecule works, but when a drug gets into trouble, the signs are usually there in the data and the science. We must not underestimate the value of really understanding the target and the drug.
WuXi: For the disease area you are working on, what would be the one thing that would have the most potential to lead a paradigm shift “from treatment to cure?”
Alison Armour: It’s the biology of the disease. There are many mutations in pancreatic cancer, but if we could define one or two pathways that really drive the growth of the disease, we could unlock it.