Point looks to turn the tables on Novartis

Conventional wisdom says manufacturing takes second place to clinical development, but Point turned that on its head, and now a big catalyst approaches.

Radiopharmaceuticals are a different beast versus traditional drugs. Just ask Novartis, which has endured problems supplying first Lutathera and now Pluvicto, issues that have marred an otherwise hugely successful launch of the latter drug and are set to keep it away from new patients for months.

In contrast, Point Biopharma tells Evaluate Vantage that it decided early on to focus on manufacturing before even building a pipeline – a controversial move that Novartis’s troubles seem to have vindicated. Now the two companies are heading for a showdown, with rival studies in prostate cancer set to read out in the second half.

Point’s lead asset, PNT2002, is the subject of the Splash study, whose readout was recently delayed from mid-2023 to the second half. Like Pluvicto PNT2002 is a Lu-177 labelled anti-PSMA molecule for prostate cancer; having already toplined Pluvicto’s PSMAfore trial as positive, Novartis will also present full data in the second half, possibly at Esmo.

Pluvicto’s approved use, in post-chemo prostate cancer, brought $211m in first-quarter sales, Novartis said yesterday, but Splash and PSMAfore both look at the pre-chemo setting in patients who have undergone androgen deprivation. One obvious thing investors will want to know is how PNT2002 might be positioned versus Pluvicto.

Insufficient manufacturing

A more immediate differentiator will be each company’s ability to manufacture. Point was founded on the premise that there was insufficient radiopharmaceutical production capacity, something attested by Novartis’s inability to meet Pluvicto demand.

“Manufacturing is the core of the business, with construction of our commercial-scale facility beginning even before initiation of phase 3,” Point’s chief of staff, Ari Shomair, tells Vantage. “In our early days people accused us of over-allocating to manufacturing supply chain, suggesting that a junior biotech shouldn’t be buying physical assets, that it should be focusing on increasing the value of intellectual property.”

But in March Pluvicto went on the FDA’s short supply list, and Novartis told doctors that it was unable to meet manufacturing demand, being unable to take any new Pluvicto orders until it brought more sites on stream.

The problem is not the supply of the lutetium-177 isotope, but rather Novartis’s reliance on a single facility in Italy to serve the entire US market – bearing in mind that Pluvicto’s half-life gives only a five-day window to get each dose to a patient. Last week the FDA approved a new facility in Milburn, NJ, but this will not contribute “meaningfully” until the third quarter.

Such apparently fundamental problems persist largely because radiopharmaceuticals is an immature, non-commoditised business, lacking back-up production. “Because there haven’t been that many approved radiopharmaceuticals you haven’t had a wide variety of companies attacking that problem,” says Shomair.

In addition each isotope has a half-life that limits how far it can be shipped. “The nature of manufacturing radiopharmaceuticals [is] fundamentally different from 95% of other treatments,” says Shomair. “It's much easier to make something [to] sit on the shelf than have to get it to the patient in under seven days. It’s a very unusual constraint to be working with.”

It is puzzling that Novartis had not foreseen such issues when it was buying Advanced Accelerated Applications and Endocyte, and before Pluvicto was approved. The Swiss firm has struck several other radiopharmaceuticals-focused deals, and in December bought Clovis’s FAP-2286 for $50m as its maker entered Chapter 11 proceedings.

Source: Novartis investor presentation, 25 April 2023.

Like Novartis, Point is not stopping at lutetium-177, a beta emitter used in its lead assets. The biotech wants to repeat the manufacturing trick with the alpha-emitter actinium-225, which features in several earlier-stage molecules but is in short supply.

Crucially, there is no common manufacturing method between the two isotopes, necessitating entirely separate supply chains. And, while earlier this month Point struck an actinium-225 supply deal, Shomair admits: “We’re hedging by working with multiple vendors, each using different production methodologies and input materials so we have multiple shots on goal.”

Among Point’s Ac-225 labelled assets is PNT2001, which like PNT2002 targets PSMA, and a separate question is how different isotopes might be used in molecules that have the same target. Shomair believes that there is space for both alpha and beta emitters, the former’s toxicity and short half-life giving it applicability in micrometastases, and the latter having promise in large tumours.

There are differences between projects with the same isotope and same target too; PNT2002 and Pluvicto both emerged from German academia, and use the same PSMA-binding domain, but comprise different molecules with different linkers. PSMAfore and Splash will make for some interesting cross-trial comparisons.

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