The Right Horse

To reach this point, Sofer and his team have had to surmount numerous obstacles. But he displays the grit and stoicism Israelis are famed for, and is matter-of-fact about roadblocks and disappointments that inevitably crop up in a project like this.

“We’ve had nothing disappointing to deal with so far,” he declares confidently. “Our expectation is that it’s a process, and we are doing whatever we need to do. The most important thing is that we’re getting good results. We just published our first pilot study in the US, in which we got a 100 percent complete response rate. Everything is going according to the plan right now, baruch Hashem.”

Uzi Sofer’s own background, like the company he founded, personifies the Israeli story. He was born in Djerba, the island Jewish community off the coast of Tunisia dating back to Bayis Rishon, and at the age of three he moved with his family to Be’er Sheva, where he grew up and attended yeshivah. He showed an early aptitude for private enterprise, helping his parents in their shoe business. By sixth grade, he had determined that he wanted to go into business for himself.

After completing his army service, he moved to Jerusalem, where he met his wife, Toni. (They now have six children and are already grandparents.) He earned his accounting degree at the Jerusalem College of Technology and gradually worked his way into the business world — starting with “low-tech” investments, and then becoming CFO or chairman in different private or public companies.

Then 20 years ago, he founded a company called BrainsWay, which produced a medical device to treat mood disorders. He served as CEO there for 12 years, and the company still exists today.

The work with BrainsWay represented a substantial pivot from his previous work, Sofer recounts. “I left everything, and I decided to focus on health care. I gained a lot of experience at BrainsWay — we built everything from scratch. We entered a big market and had to get approvals from agencies all around the world — in Europe, the US, Brazil, and Japan.”

That experience would stand him in good stead when he was introduced to two cancer researchers from Tel Aviv University who had invented an intriguing treatment using alpha radiation. They had attempted to bring their idea to market before, but the effort had run aground. Still, they had maintained faith in their idea, and now it seemed to both sides that they had a dream match.

Sofer says the credit goes to the two professors who invented the technology and to the team leading the company today. “We’ve treated more than 100 lesions around the world, and we have a 97 percent overall response rate.”

Dr. Michael Zelefsky recalls hearing about the technology soon after it was first developed — but he says it then slipped off the radar screen for a long time.

“In truth, I heard about this product maybe 20 years ago,” he says. “It came out of a discovery at Tel Aviv University taking a very potent form of radiation and formulating it in a way to allow treatment to be done in a very focused and safe fashion. And it’s to the credit of this current CEO, who really galvanized this project again. Because in the prior situation, they never followed up with clinical trials to scientifically validate the effectiveness of this treatment. The only way to know if it works is to carry out a properly designed clinical trial.”

After the first clinical study was done at Israel’s Beilinson Hospital, the product began gaining credibility and momentum. The study was performed with patients who had recurrent skin cancers; some had cancers that had disappeared and then came back, and some had had prior treatments. In many cases, their other option was “mutilating surgery” — the medical term for surgical excision of the cancerous area, which often leaves significant damage to healthy tissue.

“These patients ultimately got this product, with very, very good results,” says Dr. Zelefsky.

Cluster Bomb

The cancer treatment developed by Alpha Tau uses a discovery first made 120 years ago that could only be made applicable with the advancement of technology. Alpha DaRT irradiates cancer cells internally — a form of radiation treatment called brachytherapy (pronounced “breaky-therapy”). But the way it does so is revolutionary.

The primary current treatment for localized cancer is often surgery, yet there are situations when surgery is either impossible or impractical. The next option is radiation therapy — most commonly, external beam radiation therapy. The patient is placed in a large machine that works something like an X-ray, bombarding the area of the tumor with beta or gamma radiation from several directions.

But this treatment has its downsides as well.

“We hit the tumor from every side until we finish it off,” Sofer says. “But when beta or gamma radiation passes through the body, it ruins everything in its path.”

Radiation therapy until now has used beta or gamma rays, precisely because they are powerful enough to penetrate deep into the body and destroy tumors and lesions. But that same power is its own disadvantage; it doesn’t distinguish between healthy cells and cancerous cells, and damages both. And occasionally, tumors are resistant to these forms of radiation or are able to recover from the damage that’s been inflicted. In those cases, the beta or gamma radiation therapy cannot be used again, because of the damage to healthy tissue that has already resulted.

“Furthermore,” says Sofer, “if the tumor is located next to a major blood vessel or a sensitive organ, then we can’t use the radiation. It’s too broad a beam — it hits too wide an area.”

Medical researchers have long sought to apply a different form of radiation against cancer that is less destructive to healthy cells: alpha rays. In fact, Marie Curie, the Polish scientist who pioneered the study of radiation, discovered back in 1902 that the alpha particles emitted by radium destroyed tumor-forming cells faster than they did healthy cells, and she conjectured that radium would one day provide the cure for cancer.

“Alpha radiation is very special,” says Uzi Sofer. “It’s a very heavy particle. If beta and gamma particles are like ping-pong balls, then an alpha particle is like a bowling ball.”

Alpha particles have been shown to consistently destroy the DNA in cancer cells more thoroughly than beta or gamma radiation; the alpha particles smash both helixes of the genetic molecules, while beta and gamma radiation frequently only break one helix, which can allow the DNA to repair itself.

The problem was that no one knew how to use alpha particles. Beta and gamma radiation can penetrate most surfaces, and they work over distances that make them practical for therapeutic use. Alpha particles, on the other hand, will not even penetrate human skin. They also have a very short range — they can only travel about 20 or 30 microns (a micron being one-millionth of a meter).

But the two Tel Aviv University professors — Dr. Yona Keisari and Dr. Itzhak Kelson, now Alpha Tau’s chief scientific officer and chief physics officer, respectively — hit upon the ideal alpha particle delivery system in 2003.

“They found a naturally occurring isotope, a radioactive element that Hashem created in nature, called radium-224,” Sofer explains. “This isotope, as it sheds atoms during its radioactive decay, emits alpha particles.”

Professors Keisari and Kelson developed a way to coat a very small, seed-sized grain of metal with radium-224. This seed is then implanted directly into the tumor, where it delivers alpha particles into the cancerous cells at point-blank range. And because radium-224 has a very short half-life — that is, the amount of time it takes for an isotope’s radioactivity to drop to half its original value — the risk to health is minimal.

“So now you have, basically, a cluster bomb,” says Sofer. “We call this seed the Alpha DaRT. Since the half-life of this isotope is 3.7 days, after two weeks, there is minimal remaining radioactivity. And during that time, the ‘dart’ is designed to release alpha particles that may shrink the tumor dramatically, potentially even until it disappears entirely.”

This technology turns the alpha particle’s short range into an advantage. Deploying radium-224 in small amounts strategically throughout the tumor focuses the alpha particle’s destructive power on the cancer cells, out of the range of the healthy cells. There is also a treatment-planning software that helps determine where exactly to implant the seed in order to cover the entire tumor.

Sofer points out that the results in the testing phase so far have been remarkable.

“We’ve had fantastic results using this to treat superficial tumors such as squamous cell carcinomas and basal carcinomas, in the ear, the nose, the cheek, the oral cavity, or on the skin,” he says. “All those are very simple because the tumor is very accessible, and it’s easy to implant the seed to eradicate the entire tumor. We have had near 100 percent response using this treatment on these cancers. The tumors shrink, and in many cases disappear. And there are no serious side effects observed from the treatment.”

Dr. Zelefsky says he’s been impressed with the results so far in clinical trials. “It was designed in a certain way to allow it to be safe, and allow it to distribute its radiation in a very, very finite way,” he says. “And that’s why the side effects have been minimal. They published their early results from studies both in Israel and the US, showing very promising results in this group of patients.”

Like a Cancer Vaccine

Alpha Tau has developed a three-pillared strategy for getting this treatment to the front lines in the war on cancer — three market sectors where the company believes the Alpha DaRT therapy could make an immediate impact.

The first is the “localized and unresectable” category. This includes localized tumors that are not candidates for surgery and recurrent tumors that are resistant to radiation therapy, such as tumors of the prostate, head and neck, skin cancer, and squamous cell carcinoma. “We’re talking about thousands of patients in the US alone, every year,” says Sofer. “So this is the first market we’re targeting, the first pillar.”

The second market segment is those cases where there are poor first-line treatment alternatives. “For example,” Sofer elaborates, “There are no great options for glioblastoma in the brain today. Nor for pancreatic cancer. We’re talking about hundreds of thousands of people in the Western countries — in the US alone, 60,000 new cases every year.”

The third targeted segment is also Alpha Tau’s most ambitious: metastatic patients, those suffering late-stage cancer, who until now have been considered the hardest cases, basically facing a death sentence.

“This was really the vision for the company,” says Sofer.

The goal here, he elaborates, is to try to use Alpha DaRT to induce the body’s own immune system to respond to metastatic tumors. Alpha DaRT would be applied in conjunction with another cancer therapy called “checkpoint inhibitors.” Sofer explains that tumors evade immune system detection by setting up a “disguise” that allows cancer cells to masquerade as normal cells. The checkpoint inhibitors basically tear off the disguise. They seem to work well in conjunction with Alpha DaRT, because the alpha particle therapy may leave the immune cells in the normal, healthy tissue surrounding the tumor intact — unlike other radiation therapies, which harm the surrounding tissue along with the tumor.

“What we saw in testing on both animals and people was that since the healthy tissue around the tumor stays healthy, the immune system gets into the tumor after the DaRT crushes it,” says Sofer. “Then the body itself — the natural response that Hashem created — acts against the tumor with the immune system.  The body employs anti-tumor immunity, and — look how smart Hashem made our bodies — then the body starts looking for other lesions, elsewhere in the body, from the same exact tumor. And it kills them, because now it recognizes that this is a tumor. So all metastasis in the body — from the worst cancers out there — could be killed by the new system.”

This outcome is called the “abscopal effect:” When one lesion is treated, there is a simultaneous improvement in other lesions. Alpha Tau’s researchers have observed this effect in their tests of the therapy.

“In Italy,” says Sofer, “we treated a woman who had two lesions, one in the right leg and one in the left. We started treating the one in the left leg, and we saw that the one in the right leg disappeared. We knew it couldn’t be from the radiation, because alpha particles can travel less than 100 microns. We believe it’s from the systemic immune effect.”

The effect was also observed in laboratory tests with animals, when Alpha Tau researchers introduced colon cancer cells into mice. The research team then treated the mice with Alpha DaRT, and the mice responded to the treatment. After the mice were cured, the researchers left them alone — for a while.

“We left them to eat cheese and play with their toys, and after a few months, we came back and rechallenged them with colon cancer,” Sofer says. “And this time, they didn’t develop colon cancer. We challenged them with breast cancer, and they did develop breast cancer. So then we concluded that the immune system had come up with a response, but a very specific one — to colon cancer, but not to breast cancer.”

The researchers then took splenocytes (white blood cells, a chief part of the immune system arsenal) from the mice, and gave them to mice that had not yet been exposed to any cancer cells.

“We tried to challenge those mice with the splenocytes,” says Sofer. “And they didn’t develop cancer. It seemed to function like a vaccine for cancer.”

The Breakthrough?

The blood, sweat, and tears expended on the research and development of a new treatment are often only the beginning of the long path before doctors can use it with patients. The treatment must undergo legal review and a lengthy approval process in every national jurisdiction where it will be used. And even after all that, there remains the critical step of getting buy-in from the medical community.

But that hasn’t stopped Sofer’s team from moving forward. There’s a factory in Israel, one in Lawrence, Massachusetts, and they’re even building one in Japan. But he’s not mitigating the long licensing process.

“In general, it’s very, very challenging. First of all,” says Sofer, “you need to have the technology, and you need to believe in the technology. You need to know that your technology is something that can yield a huge benefit for the patient, something that can really change the world — but it also needs to be something you can protect under intellectual property law.”

The process then moves from the conceptual to the more practical, Sofer says. “You need to see how you can build it. You need to know how to raise money and how to recruit the right personnel to do the special work that’s required at the beginning. The professors are geniuses, they’re the top in their field, but when you’re forming the company, you need different people — you need R&D people, you need the physics people, you need the logistics people, all different kinds of employees.”

After all that, it’s forward march into the bureaucratic arena, a challenge all its own.

“In our field, we have two regulatory protocols,” Sofer explains, “one for radioactive materials and one for medical devices. But this is handled differently in various parts of the world — Europe is different from Japan, Japan and Europe are different from Canada, and all of them are very, very different from the FDA in the US.”

Once all the regulatory approvals are secured, he says, the company can enter a more rational mode of business operation. Staff can begin conducting clinical trials, compiling safety data, building up the production process, and soliciting feedback from doctors to modify the product to fit their needs.

Alpha Tau’s adamant insistence on thorough review gives Sloan Kettering’s Dr. Zelefsky cautious optimism that the company is heading in the right direction. He’s been down this road before.

“I remember some of these ‘cancer breakthroughs’ that became promulgated, even from Israel, and everybody started making their own conclusions — there was a frenzy about it,” Dr. Zelefsky says. “This company is committed to evaluating this  treatment in a very rigorous, scientific fashion so that it’s carefully done, it’s FDA-evaluated, and then the appropriate trials are done, the appropriate timelines are evaluated… And then it becomes, yes, a breakthrough, potentially, for patients with recurrent cancers of the skin or the soft tissue. And now, the Alpha Tau group is exploring this in other diseases, diseases that are notoriously resistant to standard treatments, and they’re taking this on.

“So yes, could this be a potential breakthrough? It looks very encouraging. I think everybody would say that the excellent results or responses that have been seen so far are impressive, and that’s why these trials will continue.”

Once all these steps have been completed and there is a deliverable product ready for the market, there still remains one more critical stage: buy-in from the medical community.

“You need to be sure that you can transfer this technology to the doctors,” Sofer cautions. “All doctors, all over the world, in every field, are very, very conservative. And if you come to them and say this is going to change the world, and then it comes out mediocre, it will be very hard to change their minds. They know exactly what they are doing, and to convince them to switch to something new is very hard. You need to have something that is very strong and very simple to transfer.”

Sofer is referring to the process by which an invention or innovation is turned into a product or service that benefits society. He believes in the transferability of the Alpha DaRT therapy because of its very simplicity.

“What’s so beautiful about this ingenious invention is that it’s so, so simple to transfer — the methodology and the technology can be transferred to other doctors in this field,” he says, but there’s one more ingredient for success. “You need to be very optimistic, but the bottom line is that you need to have siyata d’Shmaya.”

It’s in Our DNA

Meanwhile, the regulatory process grinds on, and Alpha Tau is so far continuing to clear the hurdles.

“We’ve already started a trial in Hadassah, for advanced metastatic patients with cancers of the head and neck and skin,” Sofer says. “We started with the first patient two or three months ago. For the first pillar, we are now in the last trial for approval with the FDA — we’re going to run that in 2022. There is going to be a pivotal trial run with the most distinguished medical centers in the US this year. This is the last step. For the first US trial, we saw 100 percent complete response, so now we are doing the last step.”

Sofer says his executive team’s success can be traced to more than just logistical experience and knowledge of government protocols.

“As Jews, we have strong will to survive,” Sofer says. “This is in our DNA. This is what enables us to build something from scratch and enter into the market, to save lives all around the world, and to give hope to a lot of people suffering from cancer where treatments are no longer effective. This is precisely for them.”

Sofer is quick to extend credit to the entire workforce at Alpha Tau, and especially COO Amnon Gat and chief technology officer Ronen Segal — both of whom joined him from BrainsWay as critical team members; his CFO, Raphi Levy, is originally from the US and joined the company from Goldman Sachs;  Dr. Robert Den, the chief medical officer who’s taken the reins to push the clinical trials forward, is a Harvard-trained physician originally from the Philadelphia suburb of Bala Cynwyd, and serves as an associate professor at Jefferson University; and of course, they’d be nowhere without professors Kelson and Keisari.

Although the majority of Alpha Tau’s workforce is secular, Sofer imposed a rule for employees that there would be no emails sent on Shabbos — and no emails sent to recipients in the US on Motzaei Shabbos. And he insists that he has never been confronted with dilemmas in his work that would conflict with his Torah observance.

“Just the opposite,” he says. “I’ve never come up against anything bad because I’m a religious Jew. It’s my emunah and inborn DNA for Jewish survival that gives me the koach to rise in the face of challenges.”

And that extends as well to his identity as an Israeli. Despite the anti-Israel rancor found in academic environments in America, Sofer says he has only encountered warm professional courtesy and acceptance in all such quarters.

“I think that it’s the opposite,” he says. “We’re making a kiddush Hashem here — we’re developing ways to treat patients around the world, without regard to race, nationality, or religion. We’re utilizing radioactive material to save lives, not build bombs. We work with many universities around the world, and I think they appreciate that this technology is coming from Israel.”

The Alpha Tau executive team gets high marks from external observers as well. Dr. Zelefsky says he’s personally encouraged that the company has set an ambitious program for itself, and that Uzi Sofer is enthusiastic and passionate about it.

That’s one reason Mark Hager, the tech start-up investor, liked what he saw. “When I look at a company, I have an initial meeting with the founders,” he says. “After the first meeting, I say to myself, ‘Did they pass the smell test? Did they get through passport control?’ Meaning, do I really like them? Do I really feel comfortable investing in them? Because I’m not involved in the day-to-day business operations. Do I feel comfortable giving them a lot of money and letting them run on their own? They already came highly recommended before I met them. And when I met Uzi in person, I felt comfortable that I’m betting on the right horse.”

In a field where the drive to implement a vision is just as important as the original scientific research, Sofer’s energy is a powerful engine behind the company’s success. It’s clear he draws a great deal of personal satisfaction from what he’s doing.

“I work 24-6, and I have personal sippuk every second,” he says. “You know, we are doing well by doing good.”

(Originally featured in Mishpacha, Issue 898)