Novartis halts Pluvicto new patient starts, struggles with radiotherapy's supply amid manufacturing expansion

For patients with metastatic castration-resistant prostate cancer (mCRPC) who have failed on prior treatments, Novartis’ radiotherapy Pluvicto offers a novel option. But the drug can be hard to come by these days, with supply constraints dogging existing patients and also delaying treatment for potential new takers.

Pluvicto doses were canceled for one patient for the fifth week in a row, Thomas Hope, M.D., a prostate cancer specialist and nuclear medicine expert at the University of California, said in a Sunday tweet. Some other patients have had their doses canceled twice, he added.

Asking whether others have run into the same issue, Hope soon received about a dozen similar complaints from doctors at other healthcare facilities. Some suggested the supply problem has also affected Novartis’ other radiotherapy, Lutathera, for neuroendocrine tumors.

“Yes, Novartis cancelled all our patients scheduled for this week. They had been waiting for months to receive it,” Shilpa Gupta, M.D., who co-leads the genitourinary oncology program at Cleveland Clinic, responded to Hope in a tweet regarding Pluvicto. In another reply, Nadine Mallak, M.D., a radiologist at the Oregon Health & Science University, noted four Pluvicto cancellations last Friday.

“Very frustrating! In some patients PSA rises in the interval waiting to be rescheduled, while they were initially responding well!!” Mallak tweeted.

PSA level in the blood is an indicator of prostate cancer treatment outcomes, and increasing PSA levels suggest cancer recurrence. Pluvicto, which combines therapeutic radioactive isotopes with cancer cell-directed compounds, is dosed every six weeks for up to six treatments.

Novartis is indeed experiencing challenges in meeting Pluvicto’s current demand, a spokesperson acknowledged in an emailed response to Fierce Pharma.

New patient starts paused

Novartis temporarily stopped accepting new patients as “the difficult but necessary step,” the spokesperson confirmed, until it has “more clarity on the FDA’s approval” of a manufacturing site in Millburn, New Jersey. The facility makes Lutathera and also supplies Pluvicto but only for commercial use in Canada and for clinical trial use. Initiating a new manufacturing site for commercial production of a drug requires a separate FDA signoff.

For Novartis, commissioning the Millburn facility may not be a straightforward process. The FDA previously slapped the site with a Form 483, citing quality control shortfalls. Last May, Novartis voluntarily put production at the facility—and another one in Ivrea, Italy—on hold after noticing potential quality issues. That halt interrupted supplies of both Lutathera and Pluvicto to the U.S.

Although Novartis soon brought the two sites back online, the company is still having trouble ensuring timely supply. One major challenge lies in the logistics of transporting the radioligand therapy, which has a very short shelf-life.

Doses have a five-day window to reach the patient, the company spokesperson explained. And Pluvicto is sourced from a single facility in Ivrea.

“Any interruption in the process, from unplanned manufacturing events, to doses not arriving in time due to shipping delays and challenges associated with importing a nuclear medicine into the U.S. may result in patient doses being rescheduled, which causes a ripple effect for patients in the queue,” the spokesperson added.

Rush for more capacity

During Novartis’ fourth-quarter earnings call, CEO Vas Narasimhan, M.D., acknowledged that the company underestimated the demand among post-taxane patients. “It’s a question of us continuing to expand our capacity to meet what is a much larger interested population than we initially expected,” Narasimhan said.

Novartis is hoping to produce Pluvicto from four sites by the end of this year, instead of the existing single facility, Narasimhan said. The four sites will include three for U.S. commercial supply. Besides Ivrea and Millburn, Novartis aims to have a new automated facility online in Indianapolis with “substantial capacity” later this year, the CEO added.

A facility in Zaragoza, Spain, will handle clinical trial supply outside the U.S. And Novartis is evaluating adding more sites in Asia, he said during the earnings call.

At that time, Narasimhan said Novartis was talking to the FDA about filing the Millburn site and was planning to file the Indianapolis facility in the third quarter. Both submissions will be subject to a four-month review timeline.

Novartis has requested an expedited review from the FDA for Millburn. Pending an FDA green light, Millburn could begin supplying for U.S. patients by this summer, Novartis’ spokesperson said. Before the Millburn and Indianapolis sites become available, “our priority is to supply patients who have received their first doses and are currently in the treatment process,” the Novartis spokesperson said. “This is important to allow patients who have already begun the treatment cycle to appropriately complete their course of therapy.”

Overall, Novartis aims to have an at least 250,000-dose annual capacity for Pluvicto from 2024, Narasimhan said on the call.

A rising star

Pluvicto is a key launch for Novartis and part of the company’s broader interest in radiotherapy. Banking on the potential to move into earlier prostate cancer treatment, Novartis put Pluvicto’s peak sales projection above $2 billion.

And $2 billion could be a very conservative estimate. FDA-approved in March 2022, Pluvicto sales reached $179 million in just the fourth quarter of 2022. That sales figure is already pretty close to the average quarterly haul Pluvicto could generate in its current post-taxane indication based on Novartis’ overall peak sales guidance, Bank of America analyst Graham Parry noted on the fourth-quarter call.

And 250,000 doses would translate into $8 billion of revenue at Pluvicto’s current U.S. price, Parry pointed out. 

Doctors’ experience thus far shows that Pluvicto has yet to reach its full potential in post-taxane mCRPC. In the clinical trial used for its approval, the drug showed it could reduce the risk of death by 38% when added to best standard-of-care in PSMA-positive mCRPC patients who had tried an androgen receptor inhibitor and at least one taxane-based chemotherapy regimen.

And Novartis just reported positive pre-taxane mCRPC data from the phase 3 PSMAfore trial. If approved in that setting, Pluvicto’s eligible patient pool could expand from 27,000 to 42,000 patients, Narasimhan has said. The company is accumulating more data at the FDA’s request, with a plan to file for an approval in the second half of this year. In addition, Novartis is testing Pluvicto in metastatic hormone-sensitive prostate cancer in the PSMAddition trial, which has a primary completion date in 2024.

Novartis’ Pluvicto hiccup reflects the difficulty in manufacturing therapeutics made with novel technologies. Back in 2014, Bayer also temporarily suspended supply of its own prostate cancer radiotherapy, Xofigo, because of a manufacturing quality problem. 

Narasimhan believes the difficult manufacturing process around radiotherapies positions Novartis well in potential upcoming competition. “Other players, of course, are going to come in and try to launch,” the Novartis CEO said on the fourth-quarter call. “A question will be, do they have the same scale and expertise that Novartis does to be able to navigate that complexity and really ensure that they can meet the demand?”

Editor's Note: Annalee Armstrong contributed to the reporting.