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Alpha-emitting Radiation Therapy Could Create a Paradigm Shift in Cancer Treatment

As the new Chief Medical Officer of Alpha Tau Medical, I passionately believe that the success of our new alpha-emitting radiation therapy, Alpha DaRT, has the potential to create a paradigm shift in cancer care. Despite advances in conventional therapies, there are still many patients who succumb to their disease or who are unable to tolerate existing treatments. I am proud to be part of an Israeli startup company that is working to expand cancer care for millions of patients worldwide.

Looking to make a global impact in improved patient care

As I began my medical career, I chose to specialize in radiation oncology. This field specifically attracted me because it blends together three important passions of mine – cancer biology, radiation physics, and patient care. Many of my patients share their deepest dreams and hopes with me, at a vulnerable time in their lives. This influenced me as a physician to make a contribution to medicine by improving treatment outcomes and quality of life.

I decided to pursue a research career in academia, as Associate Professor of Radiation Oncology, Urology, and Cancer of Biology at Thomas Jefferson University in Philadelphia. One of my primary goals was to do translational research combining radiation therapy with new biologic agents to improve the efficacy of cancer therapy, while reducing its toxicity. I was exposed to many new developments in radiation oncology and novel targeted therapies. One of the new drugs I have used with my patients was an alpha radiation therapy called Xofigo (Radium-233). This work made me aware of the growing potential of alpha radiation, as an alternative to conventional radiotherapy. The decision to shift my focus from academia to industry was catalyzed by my interest in improving care for patients on a global level.

When Alpha Tau CEO Uzi Sofer approached me with an offer to become CMO and lead the company’s clinical research program, I responded with an enthusiastic yes. I was very impressed by Uzi and the entire management team at Alpha Tau. In particular, I was quite appreciative of their willingness and encouragement for me to continue to practice clinical medicine at Jefferson, as they understood the importance of direct patient interactions in my professional and personal growth.

I am a strong believer in the significance of the “startup nation”. In spite of its small size, Israel has an amazing impact on the world of technology and medicine that is recognized globally. I feel great pride to be able to contribute to the startup nation through my leadership role in our pioneering company Alpha Tau.

I firmly believe that alpha-emitting radiation therapy has the potential to make a profound impact on the field of radiation oncology. Our challenge at Alpha Tau is to provide more evidence of the clinical benefits of this new technology across different indications.

Alpha DaRT may fill important unmet needs in current radiation therapy

Radiation therapy is one of the three core modalities of cancer treatment, along with surgery and chemotherapy. Radiation treatment planning and delivery has evolved significantly with the use of inverse treatment planning, real-time imaging, and adaptive planning allowing for dose escalation and reduction in toxicity. For external beam therapy, we have a plethora of options such as photons, electrons, protons, and carbon, each with unique properties and advantages. However, we have not had the same level of advancement in radiation isotope selection for internal sources of radiation therapy, which has limited its clinical use. A new treatment incorporating an alpha-emitting isotope could meaningfully expand the use of internal, localized radiotherapy in treating cancer, and would thus have a major impact on the field.

From my experience, there are three major clinical challenges in radiation therapy: (1) the trade-off between dosage and toxicity for effective treatment, (2) the decreased efficacy of radiation for management of recurrent disease, and (3) the challenge of improving healthcare delivery associated with radiation therapy, including improved access for elderly patients and those who live far from large medical centers.

Alpha DaRT has the potential to overcome these challenges. Our clinical trials program is designed to demonstrate that the Alpha DaRT can provide the following clinical advantages:

1. Increasing the potency of radiation treatment for tumors without causing intolerable toxicity.

Radiation therapy is used today mainly to treat primary, localized tumors. High radiation doses are often necessary to kill tumors before they become metastatic, and impossible to cure. However, sometimes it is impossible to escalate the radiation dose to the level required to eradicate a tumor, because of normal tissue tolerance.

We believe Alpha DaRT may be capable of eradicating most tumors, even those that require high doses of radiation. The reasons for this are twofold. Alpha radiation has a higher relative biological effectiveness than other radiation types. This means it can cause greater damage to a tumor cell at a lower radiation dose than, for example, gamma or beta radiation. On the other hand, alpha radiation also has a short path length, leading to a rapid drop in radiation exposure to nearby tissues. In certain areas like the pelvis, this may be key, because traditional radiotherapy has limited use due to its toxic effect on the small intestine.

2. Addressing the problem of radiation-resistance in recurrent tumors.

Patients often receive radiation as a first-line treatment, but when tumors recur, they are usually at least partially, if not fully, resistant to repeat radiation therapy with gamma or beta emitters. Once a tumor recurs, it must be treated with a higher dose than was used before, because of this resistance, and often the radiation level is too toxic for a patient to tolerate.

Data from a recent clinical trial with squamous cell carcinoma (SCC) patients suggest that Alpha DaRT may be a very effective solution for recurrent tumors. Over 60% of the patients had been previously treated, including over 40% with radiation. And yet, the overall response rate was 100%, and the complete response rate was about 78%.

This means that the SCC patients responded to Alpha DaRT regardless of whether they had gone through previous treatment or not. Even those that had received prior radiation therapy responded partially or fully. This is quite exceptional.

3. Radiation toxicity can make treatment unsuitable for elderly patients.

Lastly, we recognize that as life expectancy continuously increases, more people will be diagnosed with cancer. Conventional clinical trials typically exclude older patients, so there is lack of robust data on treatments that are appropriate for elderly patients. For this geriatric population, the toxicity of cancer therapy is a more important consideration than in the general population because their ability to tolerate the standard regimen is generally lower.

We believe that Alpha DaRT will be suitable for elderly patients currently being excluded from clinical trials, due to its high relative biological effectiveness and minimal collateral toxicity. Our clinical trial data so far have shown that elderly patients (median age ~80 years) had no increase in adverse events as compared to younger patients.

Patient population in the SCC trial was heavily pretreated, including with radiation, yet displayed an overall response rate of almost 80%.

Alpha DaRT may also help to overcome obstacles in delivery of quality healthcare

Alpha DaRT may also be able to overcome current obstacles in healthcare delivery for patients who could benefit from radiation therapy but are not receiving it. For example, utilization of Alpha DaRT as a one-time, outpatient procedure could potentially have huge appeal to patients who cannot visit a hospital frequently, as is required for EBRT (External Beam Radiation Therapy). Also, for patients who live far from major medical centers that possess the resources to purchase equipment for EBRT, the use of Alpha DaRT at a local clinic would greatly expand treatment possibilities compared to what exists at present. Convenient access to treatment is a major factor influencing the quality of life and employment status of cancer patients.

In addition, for geriatric patients in nursing homes, Alpha DaRT could be a game-changer. By dispensing of the need for multiple treatment sessions and potentially even bringing radiation therapy directly to the patient, we could minimize or eliminate the need to transport immobilized nursing home patients to medical centers for treatment.

Where radiation oncology is headed and what role Alpha DaRT can play

In the near future, I think we will continue to see the expansion of radiation therapy for oligometastases (i.e. metastases that are limited to one or several localized and treatable tumors). There is great potential to combine radiation therapy with immunotherapy to convert tumors from “cold” to “hot”, thereby enabling the immune system to clear cancer systemically. So far, no ideal protocol has been developed to combine radiation with immunotherapy. Lots of research is being done in this area currently, including Alpha Tau’s preclinical work (see paper here). The results we have produced by treating a mouse model of colon cancer with DaRT and immunotherapy are particularly exciting and suggest that we could potentially expand utilization of Alpha DaRT well beyond its current use as a monotherapy.

We are now in the early stages of understanding the full potential of the Alpha DaRT, as a tool for treatment of human patients. Nonetheless, when I go to conferences in every region of the world, I see the excitement of clinical investigators about Alpha DaRT. Alpha DaRT should not be pigeon-holed into one indication or one stage of cancer. Alpha DaRT can potentially be used across the entire cancer spectrum from primary tumors to regionally advanced tumors, to oligometastases, and finally to metastatic cancer.

Four types of tumors that may be treated with Alpha DaRT: early-stage and localized, locally advanced, oligometastatic, and polymetastatic.

In terms of indications, all solid tumors are potentially treatable by Alpha DaRT. One of our first clinical indications will be in skin and head and neck cancer, spurred by the promising data we obtained in our first clinical trial.

However, we anticipate that the use of Alpha DaRT for breast, prostate, lung, and pancreatic cancer are close on the horizon, pending the outcomes of our ongoing and planned trials. Physicians tend to follow where the data leads them, and this is especially true in oncology. Many types of physicians can be trained to use Alpha DaRT – radiation oncologists, surgeons, interventional radiologists, dermatologists, and other specialties.

Alpha DaRT appears to be effective in all cell types that we have tested in preclinical research. This means that it could conceivably have a broad impact on the whole field of oncology, if these results are confirmed in human patients.

Alpha DaRT appears to be effective in all cell types that we have tested in preclinical research. This means that it could conceivably have a broad impact on the whole field of oncology, if these results are confirmed in human patients.

Alpha Tau is evolving from an exclusive focus on R&D to include clinical care

I only recently arrived at Alpha Tau, but I am very impressed with the company; with the professionalism and dedication to the work, and from the warm welcome I received. There is an obvious spirit of collaboration and cooperation among the staff. Even while we move to concentrate more on patient care, I know there is a robust commitment to continuing research. We are looking at different ways to use Alpha DaRT in terms of tumor types and in combination with other types of therapy, such as immunotherapy and chemotherapy.

If you had asked me a few years ago whether it would be possible to successfully utilize alpha particle therapy in clinical practice as a form of brachytherapy, I would have replied, it’s a nice dream but an impossible feat.

At Alpha Tau, it doesn’t matter what obstacles and challenges exist, we will find a way of reaching our goals. We are a startup company in the startup nation, and in Israel, dreams have a way of becoming realities.

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