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Bracco Imaging Spins Out Blue Earth Therapeutics as 'Sister Company' to Dx Subsidiary


NEW YORK – Blue Earth Therapeutics, a new therapeutics-focused subsidiary of Bracco Imaging, is hoping to soon launch a Phase I/II clinical trial of a prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical for metastatic castration-resistant prostate cancer (mCRPC).

Milan-based Bracco Imaging, which acquired Blue Earth Diagnostics in 2019 and is known for imaging-based tests, is hoping to enter the theranostics space through the new sister company. Blue Earth Therapeutics is still in its infancy and shares most infrastructure with Blue Earth Diagnostics.

The therapeutic firm's investigational radiopharmaceutical, 177Lu-rhPSMA-10.1, is rooted in the same fundamental idea as 177Lu-PSMA-617, Novartis' radiopharmaceutical pending approval with the US Food and Drug Administration for mCRPC. A PSMA-targeting component is attached to a radioactive metal — in this case Lutetium-177 — that emits cell-killing radiation exclusively to PSMA-expressing cells, ideally without harming surrounding healthy tissue.

Blue Earth Therapeutics' radiopharmaceutical, like Novartis', has a diagnostic counterpart that involves a different element linked to the PSMA-targeting molecule — one that is not as toxic to cells but still shows up on a positron emission tomography (PET)-based imaging scan. With this iteration, doctors can diagnose and stage PSMA-expressing cancer cells, and potentially determine if patients are eligible for treatment with the therapeutic version.

While Oxford, UK-based Blue Earth Therapeutics is still ironing out the exact details of its pending Phase I clinical trial and bringing on US-based sites that can ideally begin enrollment this summer, David Gauden, CEO of Bracco's diagnostic and therapeutic subsidiaries, said that researchers will likely use the imaging-based PSMA diagnostic to identify the dozen or so patients they hope to enroll.

"In a nutshell, patients have to have PSMA-expressing lesions [to benefit]," he said. "We don't consider that it would be ethical to treat patients with these doses of radioactivity if they don't have PSMA-expressing cancers."

If PET imaging shows strong uptake of the imaging isotope, Gauden added, it's almost certain that the patient's cancer will also have strong uptake with the therapeutic, lutetium-delivering product.

"One of the advantages of our platform is that the diagnostic agent is extremely closely related structurally to the therapeutic agent," he said, explaining how the imaging agent would serve as a companion diagnostic by identifying patients most likely to respond.

When used in the context of radiopharmaceuticals, the term "companion diagnostic" is more a way to describe the imaging agent's function than an official regulatory designation. While most think that the Novartis 177Lu-PSMA-617 approval is around the corner in the US, it remains to be seen whether the agency will note the need for an "FDA-approved companion diagnostic" in the theranostic's label in the same way it requires such testing with some targeted treatments.

One of the only precedents that companies developing theranostics have is Lutathera (lutetium Lu 177 dotatate), a product sold by Novartis subsidiary Advanced Accelerator Applications for somatostatin-expressing gastro-enteropancreatic neuroendocrine tumors. In the Lutathera label, the agency specified that patients had to have somatostatin-expressing tumors but did not stipulate an FDA-approved imaging test be used to confirm this.

"We'll have to wait and see what the next example shows us with the [Novartis product] approval later this year," Gauden said. "But I think there will be, one way or another, some language that requires patients to have a demonstrated level of PSMA positivity before they receive one of these therapies."

Given the shared structure and inevitably intrinsic ties between the imaging and therapeutic products, the choice to spin Blue Earth into two separate firms, one focused on diagnostics and another on treatment, may seem counterintuitive. But Gauden sees it as the best of both worlds; the two firms will stay closely linked, but the therapeutic company will have the freedom to branch out.

"We have a great founding investor in Bracco for this technology, but the heritage of Blue Earth Diagnostics and Bracco is in imaging mainly … so this gives us some flexibility as to how the new Blue Earth entity grows in the future," he said. "There are so many areas we can invest in, and new products we could develop … it makes sense to have it in a slightly separate spinout."

Competition, advantages

Blue Earth Diagnostics already markets a well-established PET product, fluciclovine (18F)-based Axumin, in Europe and the US for detecting suspected recurrent prostate cancer. However, the firm's PSMA PET imaging product — the one that is structurally the same as the new therapeutic — is in late-stage development but not yet approved by any regulatory bodies.

Currently, Blue Earth Diagnostics is conducting two Phase III clinical trials of this PSMA-based PET imaging diagnostic, 18F-rhPSMA-7.3. The trials, dubbed SPOTLIGHT and LIGHTHOUSE, are assessing the safety and efficacy of the imaging product for patients with recurrent and newly diagnosed prostate cancer. Based on the strength of the evidence to date, Gauden is confident about the diagnostic's market prospects in this setting.

The trajectory of the 18F-rhPSMA-7.3 imaging product is crucial to highlight in the context of its therapeutic counterpart since it forms the backbone of 177Lu-rhPSMA-10.1.

Both the imaging and therapeutic forms consist of a radiohybrid ("rh") PSMA-targeting receptor ligand. This ligand, designed to attach itself to prostate cancer cells, can be radiolabeled, or attached, to either 18F for imaging or isotopes like 177Lu for therapy. Blue Earth Diagnostics licensed the technology for diagnostic use from the Technical University of Munich in 2018 and has held the therapeutic rights since 2020. Blue Earth Therapeutics holds the exclusive worldwide rights to the technology for therapeutic use.

The "radiohybrid" element of this product, according to Gauden, is what differentiates the technology from others like it. By incorporating a metal chelating group to bind to lutetium as well as a third chemical group that has the fluorine-18 binding domain, the product can easily switch from diagnostic to therapeutic. To create the therapeutic version, Gauden said the companies swapped in an inactive, "cold" version of the fluorine, fluorine-19, to silence the PET imaging aspect.

The decision to build the compound as a "hybrid," with binding domains for both the radioactive metal and the fluorine, was deliberate. Some other PSMA PET imaging products, including Telix Pharmaceuticals' 68Ga-PSMA-11 (Illuccix), used to screen for the Novartis Phase III VISION trial, rely on gallium-68 — which can be swapped directly onto the same binding site as the lutetium since it, too, is a metal. In Gauden's view, fluorine-18 is more accessible and better established in the PET imaging space than gallium-68.

"From a logistics and supply perspective, gallium is provided primarily today from a generator system, where you have to install these gallium generators in radiopharmacies … and there have been some historical problems with supply of those," he said. "There have been improvements recently, but [gallium] still doesn't have as robust and mature infrastructure as the fluorine-18 products."

Indeed, as Novartis' radiopharmaceutical has inched closer and closer to commercial approval, some have raised concerns about patient access, and ensuing disparities.

"Particularly in markets like the US, [fluorine-18] is already so embedded," Gauden said. "That's how patients today primarily receive access to PET imaging."

In terms of competitive advantage, Gauden was also eager to point out preclinical data suggesting his companies' product might reduce kidney uptake, therefore lowering the risk of toxicities, but it'll take human trials to know for sure.

Even if the greater availability of fluorine-18 versus gallium makes a significant difference for patient access, and its product does a better job curbing kidney damage, Blue Earth Diagnostics and its sister company have a ways to go to compete with Novartis' radionuclide therapy for PSMA-positive mCRPC. Indeed, the Blue Earth Diagnostics imaging product is not yet on the market, and the therapeutic is only about to enter clinical trials.

But watching a giant drugmaker leading the way in radiopharmaceuticals seems to be galvanizing, rather than deterring, new ventures like Blue Earth. If Novartis' product makes it to market for mCRPC, other companies will have a model to follow in this new space.

According to Gauden, Blue Earth Therapeutics ultimately has ambitions to take its theranostics approach beyond mCRPC, perhaps developing treatments for breast cancers, though no plans are set in stone.

The Blue Earth Therapeutics spinout goes hand-in-hand with what Gauden has called a "renaissance" in radiation. In its external-beam, untargeted form, the therapy has been a mainstay of cancer treatment for well over a century. But the idea of administering it exclusively to cancer cells via systemic injections is seeing newfound interest and investment.

"Radiation is a great, toxic modality for treating cancer cells," Gauden said. "If you can get it sufficiently targeted to the right places, you can really have dramatic effects."