BIONEEX STORY WITH THE FOUNDER AND CEO OF A28 THERAPEUTICS, STANLEY LEWIS
The spark for A28 Therapeutics, which aims to revolutionize the targeted treatment of cancer by developing drugs that destroy tumors and are safer and easier to take, started in Texas.
Founder and CEO Dr. Stanley Lewis began his medical career there treating HIV patients at a time when the medicines were very difficult to take due to their toxicities. No one at that time was developing more tolerable alternatives. So, he decided to try to change that paradigm, transitioning to drug development, and ultimately helped develop TROGARZOTM, the first monoclonal antibody treatment for HIV that was approved in 2018.
He then moved to California to join another biotechnology company that only had a single asset in the pipeline. There, he was tasked to help find a molecule for potential development. After evaluating several candidates, he came across a lytic peptide compound that was reminiscent of an antibiotic but had been retooled to kill cancer cells. His company passed on licensing it, but Lewis thought the opportunity was too good to pass up; so, he founded A28 Therapeutics, and acquired the clinical stage molecule and the underlying platform.
“This compound, AT-101, aligns with the key principles of my drug development philosophy,” Lewis says. “First, do no harm. This molecule appears to be remarkably well tolerated. I left medical practice because I felt patients needed better options, which proved to be possible in HIV. I believe it is also possible for cancer patients because they're faced with some of the same quality of life vs quantity of life choices as HIV patients struggled with several years ago.”
Second, Lewis says that nature gives us clues as to how we should treat disease and how your body naturally wants to overcome disease. Lytic peptides are natural parts of the human immune system that help fight infections and malignant cells.
“We give lytic peptides to treat bacteria in the form of antibiotics like vancomycin, but we don't give lytic peptides to treat cancer,” says Lewis. “Why not? They are safe and effective as antibiotics. Why don't we use them for cancer?”
Finally, Lewis is from Texas and follows the KISS principle: keep it simple, stupid: “Sometimes the solution is really something very straightforward like our lead compound, AT-101. We call it the blue-collar cancer killer because it's really, really simple.”
The company’s name A28 derives from its lead molecule, which is a conjugate of the 10 amino acid LHRH hormone and an 18 amino acid lytic peptide—10 plus 18, or A28. Lewis founded the company in late 2021, raised seed financing, and acquired the asset in early 2022 from Esperance Pharmaceuticals, which had already progressed the compound through phase 2a testing with mixed results.
Now the company is seeking $25 million in a series A financing round to get the drug back into the clinic. It turns out that the receptors to the LHRH hormone (luteinizing hormone releasing hormone), which indirectly controls gonadal tissue, are found on many kinds of cancer cells. These receptors are also found on some healthy cells in the hypothalamus and the pituitary. AT-101 uses these LHRH receptors as a binding site on the tumor cells.
AT-101 targets only LHRH-expressing cancer cells. It works by the principle of “opposites attract”—AT-101 is positively charged while cancer cells are negatively charged. AT-101 doesn’t cross the blood-brain barrier and doesn’t interact with healthy cells because they are neutrally charged.
The ionic interaction between the positive and the negative causes the lytic peptide to be in close proximity to the cancer cell membrane, which will then disrupt that membrane, lysing the cancer cell and leading to immunogenic cell death and releasing the tumor neoantigens.
“It's almost like giving a vaccine,” says Lewis, “because the tumor cell essentially explodes releasing all the tumor-specific antigens. Now, your immune system can engage those antigens and fight the cancer all throughout the body. These two mechanisms, direct killing and immune system activation, are the basis of the anti-cancer activity.”
There are some issues, however, with its past development path. The molecule was originally tested in a Phase 1 clinical trial that demonstrated that it was very well tolerated with only one noteworthy side effect—it causes a transient rash.
“Even if you don't treat the rash, it's usually gone by the time a patient leaves the infusion center with no scarring, no blistering, etc. Patients don't lose hair, you don't puke have nausea and vomiting, or uncontrollable diarrhea. Patients don’t experience neuropathy or neutropenia, or any of the terrible side effects normally associated with chemotherapies,” Lewis notes.
Esperance then tested AT-101 in a small Phase 2 trial in ovarian cancer, which did not meet the primary endpoint of efficacy. There were several reasons for this outcome. The compound has a very short half-life systemically but accumulates and persists in the liver for three days. So, while the broader population of advanced ovarian cancer patients showed no difference between AT-101 treated patients and standard of care, in the subset of patients who had ovarian cancer and liver metastases, 69% had tumor shrinkage versus 17% who were on the standard of care alone. This translated into a 61% improvement in overall survival.
“There was definitely anti-cancer activity when there was good exposure to the drug,” Lewis says. “So, picking the right tumor, one that has liver involvement, is key.”
A28 plans to test AT-101 in hepatocellular carcinoma (primary liver cancer) and is going to go with a higher dose since no maximum tolerated dose has yet been determined.
A28 believes it also has an ace in the hole. The company has developed a biomarker assay that is very specific for the LHRH receptors that are found on cancer cells, and they can use the assay to test a cancer biopsy ahead of treatment to see if it has the specific LHRH receptor, thus increasing the likelihood of response to the therapy.
“Looking at patients from the previous Phase 2 trial, we noted a one hundred percent response rate in patients who tested positive on our new assay, says Lewis. “So going into the next trial, we'll use our new biomarker assay to select all the patients that we bring into the trial, and we feel very confident that they will respond to the drug.”
A28 is currently raising a $25 million Series A financing to conduct a Phase 2 clinical trial using the new assay, a higher dose, and targeting hepatocellular carcinoma with the expectation of achieving proof of concept and eventually moving to a registrational trial to garner FDA accelerated approval.
The company is exploring all financing options, including family offices, and high net worth individuals, which Lewis feels is their sweet spot.
“I think that really matters because our message is not just about efficacy, which gets venture capitalists really excited,” he says. “Our message is also about safety. It's also about tolerability. It's about a medication that you can give to patients and have them shrink their tumors, live longer, and tolerate the medicine at the same time. Our vision for our company is a world where we don't fear cancer or its treatments. And often this message will resonate strongly with family offices because they tend to be more balanced between their desire for return and their desire for impact.”
The company is also positioning AT-101 to be an adjunct therapy to immunotherapies even though it has potential as a stand-alone therapy. Lewis says it could be a winning combination. “In our future clinical trials, we will test AT-101 with checkpoint inhibitors,” he says. “It has no overlapping toxicities with other medications that are being given for the treatment of cancer now, including chemotherapies, oncolytic viruses, the ADCs, etc. Our drug appears to play very well in the sandbox with other medications.”
Partnering is another avenue for financing, especially globally, since the company’s lead indication, hepatocellular carcinoma, is an orphan indication in the U.S. but the second leading cause of cancer death in Asia.
A28 recently joined the Bioneex matchmaking platform, primarily because it has partnered with the AI company GATC Health, which analyzes molecules and predicts how they will do in future trials. AT-101 had already scored high on GATC’s platform, and Bioneex suggested that since it already had the AI assessment done, why not list on Bioneex where A28 would be designated as having undergone the AI analysis, which could enhance its visibility to investors. Lewis says the listing is already bearing results.
“At some point we feel very strongly that this is a treatment that should be explored and given the opportunity to demonstrate its potential,” says Lewis. “When you've got the right tumor, the right dose, and you've got an assay that can select the right patients, we are confident in the outcome. And in the process, we can change the paradigms of cancer care.”