Halozyme Therapeutics announced on November 4, 2019, that PEGPH20 had not met its clinical trial goals of increasing overall survival and further development of this drug has been discontinued.
Data presented at the American Society of Clinical Oncology‘s Annual Conference in June showed some positive results from an ongoing trial testing a new investigational drug in the fight against pancreatic cancer.
The name of the drug is PEGPH20.
Early Results Show Significant Effect
The results presented at the conference were from a randomized, double-blinded trial that included 135 participants with metastatic pancreatic cancer. The trial was sponsored by Halozyme Therapeutics and these results are from the first stage of its phase II trial.
In the trial, one group of participants was randomized to receive PEGPH20 in combination with the standard of care, first-line treatment of Abraxane (nab-paclitaxel) and gemcitabine. This is called the PAG arm of the trial. PAG was compared to a control group of patients receiving Abraxane and gemcitabine alone, which is called the AG arm.
- Median progression-free survival in the PAG arm was 9.2 months compared to 6.0 months in the AG arm.
- The overall response rate also favored the PAG arm, 50% versus 33%.
- The median duration of response was 8.1 months for the PAG arm versus 3.7 months for the AG arm.
- Median overall survival was similar: 11.8 months for the PAG arm compared to 10.9 for the AG arm. There are a few potential reasons for this including less aggressive disease among patients in the AG arm of the trial, for example, as well as a large number of patients who received only very few doses of PEGPH20 before the study was placed on clinical hold for several months, according to Halozyme. All patients were included in the analysis.
Mature response rate and progression-free survival data from stage 2 of this study will be released later this year.
What Exactly is PEGPH20?
Very simply, PEGPH20 is a synthetic version (developed by Halozyme) of a naturally occurring enzyme that breaks down hyaluronic acid (HA) in the tumor.
HA is something you may be familiar with if you ever suffered knee pain from osteoarthritis and received HA injections.
HA binds to fluid in the joint space and acts like a shock absorber for joints. But with osteoarthritis, HA breaks down. And it is the breakdown of HA that contributes to joint pain and stiffness. Injections of HA help restore fluid and reduce pain and increase mobility.
But HA could also be the culprit behind pancreatic cancer’s resistance to treatment.
It seems that some malignant tumors, such as pancreatic cancer tumors, actually produce too much HA, which is linked to a poorer prognosis.
How PEGPH20 Works
“Basically, what happens is that HA grabs all the water from surrounding tissues and draws it right into the tumor,” explains Sunil Hingorani, M.D., Ph.D., the principal investigator of the phase II PEGPH20 trial (NCT01839487). (Hingorani has no personal or financial interest in Halozyme Therapeutics, Inc.)
All that water, which then morphs into a kind of gel, creates very high pressure inside the tumor. It’s that pressure that causes structural changes in the tumor that make it so resistant to chemotherapy.
“Basically, the blood that carries the drugs can’t get to the cancer cells to eradicate them because the blood vessels are crushed,” says Hingorani, a medical oncologist and biophysics experts who is Director of the Center for Accelerated Translation in Pancreas Cancer at Fred Hutchinson Cancer Research Center in Seattle,WA.
Several years ago, Hingorani and his team published research showing that lowering tumor pressure by breaking down HA with the HA-destroying enzyme PEGPH20 allows chemotherapy drugs to hit their target.
The work was done on mouse models that faithfully mimic human pancreatic cancer. The hope was that these findings would translate to patients. And, so far, the results of early trials are promising.
“I want to emphasize this is very early, and the trials have been small, but moving forward with this is important,” he says. “The knowledge we’ve gained about how pancreatic tumors have evaded treatment with drugs could potentially make a significant difference for patients.”
Phase III Trial Underway
An international, multi-center phase III trial called Halo-301 began enrolling patients this past spring.
The enrollment target is 420 patients with pancreatic tumors expressing high levels of HA. Researchers will look at progression-free survival and overall survival in the patients receiving PEGPH20 plus Abraxane and gemcitabine compared to those receiving placebo plus Abraxane and gemcitabine.
To learn more about this trial: NCT02715804.
“There are many aspects of pancreatic tumors that defied everything we thought we knew about malignancies,” says Hingorani, who was among the first researchers to show that pancreatic tumors do not grow new blood vessels. In addition, many of the vessels that are present are collapsed from the high pressures. And it was that finding that spurred ongoing interest targeting the biophysics of pancreatic tumors.
As a medical oncologist, Hingorani says he has been frustrated with the inability of drugs to treat pancreatic cancer effectively. And for him, it’s very personal. His father died of pancreatic cancer.
“As a scientist, engaging in intellectual challenges and unraveling important processes in nature is absolutely fascinating,” he says.
“But I also know first-hand how difficult this disease is for patients and for their families and friends.