Targeting HPV’s Hidden Mechanism: Q&A with Sandra Coufal, MD

In a conversation with Pharmaceutical Executive, Sandra Coufal, MD, founder and CEO of Toragen, discusses the company’s novel approach to targeting human papillomavirus (HPV)-driven cancers and explains why the overlooked E5 protein could represent a new therapeutic pathway in a space where previous drug development efforts have struggled.

Drawing on Toragen’s early clinical findings and the broader challenges in HPV oncology, Coufal outlines how the company’s small molecule viral ion channel inhibitor is designed to expose infected cells to the immune system, potentially creating a synergistic effect alongside checkpoint inhibitors such as Merck’s Keytruda. She also discusses the investment landscape surrounding women’s health and HPV-related cancers, the strategic implications of Toragen’s partnership with the Gates Foundation, and how the company is positioning itself across both first-world commercial markets and global access initiatives.

A transcript of the conversation with Pharmaceutical Executive can be found below.

Pharmaceutical Executive: HPV causes nearly 5% of all cancers globally —yet the E5 protein has been largely overlooked as a drug target. Why?"
Sandra Coufal: So historically, the approach has really been to target e6 and e7. HPV has a simple genome. It only has eight genes, and five of them are not chemically druggable, but three of them are, and they're e5 e6 and e7 and from the research, it has shown that e6, and e7 are really responsible for the proliferation of the virus, so that's where the focus has been.

Research wise to inhibit that proliferation, we're finding more and more in the few labs that had studied e5 protein that it really is an essential part of the viruses mechanism to hide within cells from the immune cells, that if the virus is discovered to be infected in those cells, it will kill the cells that are infected. So this is how HPV has evolved to become what we call an indolent infection, meaning it's a chronic infection that our own immune cells can't recognize, and so so Toragen really went after that, because we know that there really, you know, there's been no small molecule in human trials against any of the abnormal proteins that HPV genes produce. 

There's been 20 attempts against e6, one attempt against e7, and they've all failed in pre clinical testing. So why is e5 different? Because we know that when e5 protein is produced, six of them coalesce to form a viral ion channel. Basically they link up to form a circle that we call a Viroporins, and it's the center of that Viroporin that our drug inhibits, and that's really why we are a viral ion channel inhibitor.

PE: Women’s health has seen increased investment attention — but where is the real gap, and how is Toragen navigating it?
Coufal: Well, you know, we're fortunate, because we have multiple indications for HPV cancers, some of which are exclusively male related, and others are exclusively female related, and a couple that are both so we kind of meet all seekers for a relevant in fact, investment.

Human nature is when you're talking about disease, you think about yourself. You know, even medical students do this when they're in training, myself being one of them going to medical school, since I'm an MD and not a PhD, we often joke that you end up having all the disease you're studying in the second year of medical school. So, I think that subconsciously happens with investors.

They say they want to do investments that improve women's health, making those investments, but that's that's not really what they do, because when it comes down to it, they look at the market size, and all of the clinical trials have been skewed to testing men, by the way, with disease, so those total addressable market numbers for women are far below, you know, they're an underestimate of what really exists. So, I think that has to do with it as well.

At Toragen, HPV positive head and neck cancer, the majority happens in men, but some women do get that. Of course, the largest indication is cervical cancer, which only happens in women, but there are a number of genital urinary cancers. For men, it's penile cancer, and all of these GU cancers increase in incidence as we age, but nobody wants to talk about them, because, you know, it's about a private part of the body, even though it's another organ to physicians, especially obviously on exam and on treatment.

Then for women, it's vulvar cancer and vaginal cancer, again, they increase as we age, but also anal cancer, which occurs in both sexes. We have had neck cancer and anal cancer that apply to both men and women, and then the individual cancers that are, you know, genitourinary related, that are per sex.

PE: Toragen recently announced a partnership with the Bill & Melinda Gates Foundation. How did that come about, and what does it mean for your commercial rights?
Coufal: So I have a long history of interaction with the Gates Foundation. I was at the Genomics Institute for the Novartis Research Foundation for 21 of the 25 years I've been in biotech, and the Gates Foundation has funded a number of things that I have been on the teams of to develop there.

So my mentor, Dr Peter Schultz, who's the current president of the Scripps Research Institute, was the first director of the Genomics Institute of the Novartis Research Foundation. He's had a prolific career in biotech, very successful in the startup world and the academic world and is a world renowned chemist. So, he has a special relationship with the Gates Foundation and when Toragen was really in need of funds and wewere in the midst of completing our Phase I trial, I approached Dr Schultz and said, you know, this is where we're at. We need money and support. And he said, okay, I'm going to talk to the Gates Foundation, which he did.

I got a meeting presented and they loved it because it met their mission of treating, really, one of the most dire cancers. Cervical cancer is the number one cause of death in women on the continent of Africa, and over 99% of it is HPV induced, and we are a small molecule pill form that you just ingest. So everything else on the market for HPV cancers is a biologic that is injected and that presents a whole host of problems for the Gates Foundation, even with their extensive distribution networks in the third world to try totreat patients that can't afford to be treated and that rarely seek health care unless there's, you know, a real, obvious problem.

So they were very attracted to the fact that we were a small molecule, but they really wanted our Phase I results, which we finished that trial and got results in March of 2025, and we met safety, we reached maximum tolerated dose, and had drug activity in 53% of patients.We couldn't say efficacy, because there weren't enough patients enrolled in the trial.

As a Phase I trial, there typically are not to prove efficacy, it's just meant to prove that, you know, safety and reach maximum tolerant dose. They really liked that and then said, ok, we really want to help fund what I call our foundational science, meaning, investigating, in particular, cancer cell types, doing those cell killing assays and proving out extensively our mechanism of action, and so they gave us a grant.

We began our work November one, and now we meet monthly with them to report our data. So, they said, we are exclusively interested in third world rights, and I said, we're interested in first world rights, because that's where the paying public is, and we're for profit.

So, they said, our interests are completely aligned. Let's move forward.

PE: Merck’s Keytruda is the dominant force in this space — a $25 billion drug. How does Toragen think about its path to market alongside that?
Coufal: So Keytruda has a patent expiration in 2028 that's the first thing to know. The second thing to know is we're a small molecule, so we don't inherently interact chemically with any biologic including Keytruda. So we're positioning ourselves as synergistic to Keytruda, and that's really why in our Phase I trial, we had two parts.

One was monotherapy, our drug by itself, and the second was our drug combined with Keytruda. Our premise for that is really baked into the mechanism of action, our drug inhibits the e5 protein, and that e5 protein does two main things in the cell. One, it doesn't allow proper acidification in a particular organelle called a lysosome, and that acid normally is used to chop up proteins into small enough pieces to lodge on a carrier molecule that transports it to the cell membrane surface to show the immune cells what's inside the cell. That piece of protein acts like a flag to the immune cells. That carrier protein is called MHC in mice and HLA in human cells.

Well, our drug binds to the heavy chain, or e5 protein binds to the heavy chain of that carrier molecule. But our drug inhibits that e5 protein action there, and it also inhibits the blocking of the acidification, so that you get proper acidification, proper lodging of a small enough protein, HPV protein piece to the carrier molecule, and that gets transported to cell membrane surface because we're able to inhibit that e5 protein, preventing both of those actions. So, we know that we basically uncloak infected cells to the immune cells so that they can recognize the ones that are infected with HPV and kill them.

So, we basically uncover the indolent infection to our own immune system. Keytruda and all other drugs, either on the market or in development for HPV cancer, simply stimulate immune cells. 

They're biologic immuno-stimulants. So, you can imagine that you give Keytruda to stimulate the immune cells, and then they can recognize with our drug, the infected cells, and you get a synergism.

We have positioned ourselves in development. Another main reason we did two parts in our Phase I trial to be synergistic with Keytruda, which puts us right in first line treatment, is because Keytruda is the only drug in immunotherapy approved first line to treat HPV positive head and neck cancer, and you know, there's HPV positive cervical cancer, and in either one of those cancers, Keytruda only has a 15% overall response rate, so that's a pretty low bar to get over for us.