Dr. Stanley Lewis is the founder and CEO of A28 Therapeutics, a clinical-stage biopharmaceutical company focused on the development of its targeted lytic peptide platform for the treatment of cancer.
In this interview, Dr. Lewis discusses his inspiration for starting A28 Therapeutics, the company’s focus on targeted oncolytic peptides (TOPs), and the promise of AT-101 in the treatment of metastatic ovarian cancer with liver metastases and hepatocellular carcinoma.
He also shares his advice for aspiring entrepreneurs and researchers looking to make a significant impact in the field of healthcare and biotechnology.
Can you tell us a bit about your background and what inspired you to start A28 Therapeutics?
I am an internal medicine physician by training. I graduated from the University of Texas McGovern Medical School in Houston and obtained a master’s degree in public health. After completing my internship, residency, and fellowship, I joined the faculty of the medical school in the Department of Internal Medicine.
As an academic physician, I saw patients, taught students and residents, and conducted dozens of clinical trials. My area of interest was HIV/AIDS, and in my practice, I cared for mostly indigent patients in the Houston area. I was recruited from academia to join a small biotech company and lead a program for the development of a new treatment for HIV. After quite a few twists and turns, we were fortunate to earn FDA approval for TROGARZO, the first long-acting medication for the treatment of multi-drug resistant HIV disease.
There are several reasons for founding A28 Therapeutics. First, I really take the Hippocratic Oath seriously. In particular, the commitment to “First, do no harm” really guides me. During those early days of treating HIV patients, the medicines were very difficult to tolerate.
I felt terrible that my patients had the unenviable choice of taking some very toxic medications to control the virus or not taking the medicines and dying of AIDS. This was the primary reason I agreed to develop TROGARZO as my clinical trial patients commented that it was perhaps the most tolerable medicine they had ever taken.
In many ways, I see current cancer patients having to face a similar dilemma as they weigh the risks and benefits of enduring toxic chemotherapies in exchange for a few more months of life. At A28 Therapeutics, we want to change that. Our vision is a world where patients no longer fear cancer or its treatments.
My second reason for starting the company is rooted in the type of molecules we develop. Interestingly, cancer and infectious diseases have a lot in common. In particular, bacteria have negatively charged cell walls and have been treated with lytic peptides such as vancomycin for decades. In fact, your body makes lytic peptides as part of the immune system. Well, cancer cells are also negatively charged; so, why not treat them with lytic peptides?
In many ways, our molecules are like antibiotics that have been retooled to treat cancer. I appreciated their unique mechanism of eliminating cancer and their remarkable tolerability. To me, lytic peptides are just what the infectious disease doctor ordered. Hopefully, soon, lytic peptides will be just what the oncologist orders.
My final reason for founding this company is deeply personal. My father died of metastatic gastric cancer. It was his dream that his son become a doctor, but before I could graduate, he died of this terrible disease. Like many solid tumors, gastric cancer can be cured surgically if you can diagnose it early before it spreads. However, when my father was diagnosed, his tumor had spread to his liver, and he was only given three months to live.
The medications we are developing at A28 have an interesting biodistribution pattern such that they accumulate and persist in the liver for three days. This high exposure in liver tissue is believed to make them particularly useful in patients who have cancer that has metastasized to the liver or originates in this organ. So, when I had the opportunity to develop a drug that could help people who, like my father, had metastatic disease to their liver, I knew that I hadn’t found this medication, it found me.
A28 Therapeutics is known for its focus on targeted oncolytic peptides (TOPs) for cancer treatment. Could you explain the concept of TOPs and what differentiates them from traditional cancer therapies?
Targeted Oncolytic Peptides are a combination of a hormone-targeting unit and a lytic peptide payload. Our first molecule, AT-101, is a 10-amino acid hormone (luteinizing hormone releasing hormone – LHRH) targeting unit combined with a highly positively charged 18-amino acid lytic peptide payload. The LHRH hormone targeting unit binds to hormone receptors found on the surface of a myriad of different tumor types. This binding brings the positively charged lytic peptide in proximity to the negatively charged cancer cell membrane resulting in a disruption of the membrane and killing of the tumor cell. An animation of this mechanism can be viewed on the website.
Healthy cells do not have a strong negative charge and therefore are not harmed by this medication. The most noteworthy side effect observed through Phase 2 clinical trials with AT-101 is a transient, treatable rash. Another feature that differentiates our lead compound from traditional chemotherapies is that the killing of tumor cells by lytic peptides causes the tumor cell to release its antigens. This type of cancer cell death alerts the immune system much like a vaccine allowing for amplification of cancer killing throughout the body.
Finally, in laboratory testing, AT-101 synergies with all manner of chemotherapy and newer immunotherapies and may even resensitize resistant tumor cells to chemotherapies that have stopped working. When you think about all the ways you would want cancer therapy to work, AT-101 really has it all.
What motivated you to concentrate on developing AT-101, and how has it shown promise in the treatment of metastatic ovarian cancer with liver metastases and hepatocellular carcinoma?
For a variety of reasons, most solid tumors metastasize to the liver, and patients with liver metastases invariably have shorter life expectancy than patients without liver metastases. In addition to being remarkably well tolerated, in a retrospective analysis of the Phase 2 study, the subset of patients with metastatic ovarian cancer and liver metastases who received AT-101 plus paclitaxel (standard of care chemotherapy) vs paclitaxel alone, the AT-101 treated patients experienced a 61% increase in overall survival.
We want to confirm this observation prospectively in our next trial. Additionally, we plan to test AT-101 in hepatocellular (liver) cancer because the molecule achieves high and prolonged concentrations in the liver allowing for potentially high anticancer activity.
What have been the most significant milestones or achievements for A28 Therapeutics thus far in its mission to transform cancer care?
A28 Therapeutics was recognized as a 2023 Cool Company by Connect San Diego. This award is bestowed on companies considered to be the fastest and most exciting startups in Southern California.
What are the company’s top priorities for the next 12-18 months?
We are seeking to raise a $20M Series A round of financing to prospectively validate the retrospectively observed efficacy signal from the Phase 2 clinical trial. Our next trial is a 2-stage adaptive trial design. The first stage will confirm the efficacy signal, and the second stage will expand to a sufficient number of patients to support an application for accelerated approval.
What advice do you have for aspiring entrepreneurs and researchers looking to make a significant impact in the field of healthcare and biotechnology?
The most important thing I’ve learned is that there is no blueprint for this stuff. You must have integrity because lives depend on your honest and thoughtful assessments of data.
You must be resilient because things will not always go as planned. You must be patient as it will always take longer and cost more than you expect. You should build a strong network because this is not something you can do alone.
And finally, it helps if you are passionate about your work. You will need this to drive and sustain you on this journey.
