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Robert Den, MD: Exploring the Potential of Alpha DaRT in Skin Cancer


Den, the chief medical officer of Alpha Tau, discusses the alpha particle-emitting atom treatment and its ability to target cancer cells without harming healthy tissue.

A new cancer therapy by Alpha Tau known as Alpha DaRT harnesses alpha particle-emitting atoms to specifically attack cancer cells while sparing healthy tissue. By directly damaging cancer cell DNA with double-strand breaks, it effectively kills them. The breakthrough approach has earned US Food and Drug Administration Breakthrough Device Designation for treating skin or oral cavity squamous cell carcinoma and recurrent glioblastoma multiforme.

Robert Den, MD, is the chief medical officer (CMO) of Alpha Tau and has been with the company since 2019. Prior to joining Alpha Tau, Den was, and still is, an associate professor of radiation oncology, urology, and cancer biology at Thomas Jefferson University. Den attended Yale University for undergraduate studies and trained in medical school at Harvard College and MIT in a joint program, as well as completed a Howard Hughes Fellowship. Prior to working with Alpha Tau, Den ran a lab and clinical trials. Since his appointment as CMO in 2019, Den been primarily focused on bringing Alpha Tau products to market.

Den recently spoke with Dermatology Times to discuss the mechanisms of Alpha DaRT and its potential role in the future of dermatology and skin cancer treatment.

If dermatologists are interested in Alpha DaRT, including in participating in US and global trials, Den encourages clinicians to reach out to Alpha Tau directly via its website.

Robert Den, MD
Robert Den, MD


Q: Could you provide an overview of the Alpha DaRT treatment and how it differs from traditional cancer treatments?

A: The Alpha DaRT treatment is a unique product. It is a product that really doesn't have any comparators, which is both good and bad for us. The way the Alpha DaRT system works is that we have figured out a way to deliver alpha-based radiation therapy locally. Now, the challenge with this is that alpha particles, in general, have a very short range in tissue of only about 40 to 90 microns. So to use this in the localized setting has been, heretofore, impractical. We've figured out a way to actually overcome this limitation of distance by relying on the movement of radioactive emitting atoms as opposed to the particles themselves. What we've been able to do, and we've patented, is to be able to deliver biocompatible sources that are covered with a thin layer of radium-224. Through the decay of radium, and recoil, we're able to then have the radioactive atoms actually move through the tissue and continue to move and explode, move and explode, and deliver the radiation that way. In a sense, we are akin to a localized radio pharmaceutical, like you've seen in the market currently.

Q: What are some key findings, results, or observations from trials conducted for Alpha DaRT?

A: We have a very robust efficacy signal. In our US pilot trial, we had 100% overall response rate with 100% complete responses. What we've seen from the pilot data, and from looking at some of our longer-term data, is that the patients that have a complete response have a very high local control rate well over 90%, even in a pretreated population. That's very, very encouraging for us.

We've seen the feasibility of delivering the darts in many, many different scenarios. We have successfully delivered the dart in the setting of pancreas cancer, where we delivered the sources through an endoscopic approach. We've seen the ability to do deliver it intracranially using a neuro-navigation system, and this has been done thus far in the preclinical setting in large animal models. What we've seen is that if there is an ability to target a tumor, either with CT guidance, ultrasound guidance, or through some type of endoscopy or bronchoscopy, we can use that current technology to reverse engineer it as a delivery device in order to actually deliver our sources directly into the tumors.

We rely on the use of Alpha-based radiation therapy, so we are not impinged by the presence or absence of oxygen, which is one of the challenges with standard radiation therapy. What this means is that even in the setting of hypoxic or anoxic tumors, where there is very low or no oxygen tension at all, we see the exact same results that we see in the normoxic setting. Additionally, what we see is that there's actually a difference in the diffusion pattern between tumor and normal healthy tissue. Because again, we're getting the movement of the radiation through the movement of the atoms themselves. So they get trapped locally in the setting of tumors, whereas in normal healthy tissue, they leave that local microenvironment much faster. What this means is that our margin, and our amount of destruction that would occur in the normal healthy tissue, is much more minimized than with standard treatment alone. So we think we can have higher efficacy, as well as a better safety profile, with our product than other products in the market.

Now, we are not necessarily looking to replace products; we're looking for this to supplement. But in addition, we know that in certain situations, there are cancers, which cannot redeliver therapy, and what we've found is that we can actually redeliver our therapy in a very safe manner. I think this provides patients with a brand new avenue of treatment that they didn't heretofore have.

Q: How does Alpha DaRT contribute to improving the quality of life for patients with cancer, particularly when looking at side effects and enhanced recovery?

A: In terms of side effects, we have seen in our clinical data, published clinical data, we've not seen any grade 3 or higher acute toxicities, and these are the severe ones that require patients to either be hospitalized or to have a major intervention. We have not seen that occurring. We've seen that the grade 1 and grade 2s tend to be short lived and recover with standard treatment. What this means is that the patients themselves are not experiencing some of the more undue side effects that we see with other types of treatment. This means an overall improvement in quality of life.

In fact, in our first study, what we found was that the patient's quality of life, and we specifically ask quality of life validated questionnaires around the types of cancers that they have, improved after treatment, as opposed to going down, which we sometimes see. Now, quality of life is a little bit challenging in that we as people get used to new things. So what may seem very dramatic in terms of quality of life for one person may be normal as it were for another. But that's why it's important for us to look across different populations. It's important for us to ask the patients directly what's happening to them, as opposed to just judging it from the physician perspective, because sometimes we can underestimate the true severity of what they're experiencing. What I think is that the Alpha DaRT is providing patients with the opportunity to not have to have that same balance between toxicity and efficacy, because we're able to still achieve the efficacy without that same degree of toxicity.

Q: Could you discuss any challenges or limitations that you have encountered during development and testing of Alpha DaRT?

A: I think we have similar challenges to other companies. There's challenges on the production side that we've had that we've been able to overcome. On the regulatory side, the regulatory process is built in a way to ensure and maximize patient safety, which we are 100% in agreement with, but from the development side, it also slows down development, meaning that you can't have multiple trials running simultaneously. Some regulatory agents want to see some initial data before they'll let you go into a bigger trial, and I completely understand that; as a physician, we always put patient safety first. What I would say is that's been some of our bigger hurdles; however, the approach that we've taken globally is to really look and see what the current standard of care is and what the current workflow is for the physicians, and then tailor our delivery systems in and around that, meaning that we see that gastroenterologists, pancreatic surgeons, will use endoscopy for both biopsies as well as for stent placement. We understood early on that this would be something that they would be used to doing in this context of pancreatic cancer. And thus, we built a solution for delivery using this approach, such that we don't have to teach the physicians new techniques in order for them to be able to maximize the benefit to the patient. So that's maybe an opposite end of your question, of how we've been actually able to reduce some of the barriers of entry by really focusing on current workflows, current practices, and trying to match that as much as possible in the delivery of the dart.

Q: How do you envision the future of cancer treatment with widespread adoption of this technology?

A: I think that what we will find is that over time, we will have, like any new adaption, the early adopters, and then the rest of the field will catch up. You'll always have some people that will be further behind. I think what we will find is more and more physicians that use the product, want to use the product, and think of new ways to use the product. I anticipate that we will have to build out a very robust, investigator-initiated trial system, because I'm sure that will be a lot of investigators, if they use it in one indication, will say, "Well, I have a very select patient group that I'd like to use it in others."

What we would like, ultimately, is to get a global approval for the product, as we don't see it, unlike a drug, as being specific for any one given disease site, we see it working across multiple tumor types. Really on our side, it's figuring out the challenges of the delivery system, but once we're able to deliver it into the tumor, the mechanism of action is all the same. There's no specific mutation or gene expression that you need in order to see the efficacy for this product. What we would like to do is to be able to continually build the clinical evidence that supports our contention that this is something that can be used very, very broadly, like other types of radiation.

That being said, I see this as being something that we could potentially utilize both in the localized setting, but also, we're looking as a company in the metastatic setting, especially in light of combinations with different immune checkpoint inhibitors, and other immune modulatory agents, which potentially have the ability to allow us to further unlock the immune system. I think that's something that we would aspire to. But if we achieved it, I think we could see a major paradigm shift, because what we hypothesize is that even in tumors that previously had been shown to not respond to these types of agents, where we can generate the ability for an immune response, that this could then tip it further. I'll say in addition, as more and more drugs come out, we don't see that as a barrier or competitor in the oncology landscape, but we actually see our product being able to work across the board with all new agents that come out. From our perspective, newer agents are just potentially more and more indications that we can prove additional benefit for.

Q: What else do you feel would be pertinent for dermatology clinicians to be aware of or to consider?

A: I think that especially for the dermatology community, this is something that can really have a major impact in their patients, in their recurrent patients, in their patients that have larger lesions, where surgery is going to be more complicated, where there could be need for more plastics intervention, flaps, etcetera, that this is a really nice alternative.

In addition, I think it's a good alternative for the dermatology community to be thinking about, especially with organ preservation. If you have lesions on the nose, lesions on the lips, lesions around the ear, in the head and neck space, where patients can get very good oncologic control but may have some challenges in cosmesis, this is actually a very nice alternative for that, and we look forward at for dermatologists, if they're interested, please contact us through our website, as we're looking to open more and more trials, both in the US as well as worldwide. If dermatologists are interested, please reach out to us directly, and we would be happy to engage them.

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