Novartis delays Pluvicto filing as CEO spots industry 'conundrum' with FDA

Novartis entered a new era after spinning off Sandoz earlier in October. As the pure-play innovative medicines company reports strong growth from the business it’s now built on, one product faces a delay.

In the third quarter, Novartis reported sales of $11.8 billion, reflecting a 12% increase over the same period last year. This quarterly figure exceeded the previous projections of Wall Street analysts by 5%.

Breast cancer drug Kisqali and multiple sclerosis med Kesimpta grew by 76% and 124% at constant currencies, respectively, as they separately beat expectations by 6% and 24%.

Kisqali’s $562 million sales in the third quarter came as the CDK4/6 inhibitor has taken 46% of new-to-brand share within its class in metastatic HR-positive, HER2-negative breast cancer, Novartis CEO Vas Narasimhan told investors during a call Tuesday.

In June, Novartis reported positive data from the NATALEE trial, showing Kisqali could significantly reduce the risk of invasive disease recurrence or death when used as an adjuvant therapy after surgery in early-stage breast cancer.

The trial has accumulated additional disease recurrence or death events, and Kisqali’s benefit was consistent with the previous analysis, Narasimhan said. An FDA filing is now planned for later this year. Novartis has put Kisqali’s peak sales potential in the adjuvant setting alone at above $3 billion.

The Swiss pharma is also trying to move its radiotherapy Pluvicto into earlier treatment settings, but that plan has been delayed—again.

Novartis is now looking to file Pluvicto for treating PSMA-positive, metastatic castration-resistant prostate cancer before taxane-based chemotherapy treatment next year rather than this year.

The phase 3 PSMAfore trial supporting that potential application met its primary endpoint in late 2022. But Novartis later said it wouldn’t immediately file with the FDA because the agency requested more mature overall survival data.

Data from the second interim analysis of PSMAfore were presented Monday at the European Society for Medical Oncology 2023 congress. In a mixed showing, Pluvicto improved progression-free survival (PFS) by 57% compared with a change of androgen receptor inhibitor but was linked to a 16% increased risk of death before adjusting for crossover. In the control arm, 84% of patients went on to receive Pluvicto following disease progression. After adjusting for crossover, Pluvicto showed a 20% reduction in the risk of death.

The reported data included 45% of deaths that will trigger a final overall survival (OS) analysis. The trial now continues to its next interim analysis until 75% of death events are reached, and an FDA filing will come after that, Novartis said Tuesday.

“Our belief is that with a 75% information fraction, we’ll have collected adequate data to demonstrate the overall profile of the medicine,” Narasimhan said of Pluvicto’s PSMAfore.

On several occasions, including in prostate cancer specifically, the FDA has made clear that it doesn’t want to see a negative trend in overall survival despite a disease progression benefit. And in some cases, the agency has requested longer-term follow-up to be sure of the overall survival trend.

“We’re a little bit in new territory,” Narasimhan said, “insofar as the FDA, I think, has made a significant shift affecting all cancer drugs with respect to the expectations of OS at the filing with PFS.”

The FDA also encourages patient-friendly cancer studies in which crossover from the control arm onto the experimental therapy is allowed. Companies are now in a bit of a “conundrum” trying to manage that because the FDA doesn’t like crossover-adjusted overall survival analysis, Narasimhan said.

Meanwhile, Pluvicto sales have been growing in the post-taxane setting, albeit at a slower-than-expected pace in the third quarter.

The PSMA-targeted radiotherapy brought in $256 million in sales in the third quarter, up only $16 million from the second quarter. And the number missed consensus by 9%.

In explaining the stall, Narasimhan pointed to a shortage earlier this year. During the shortage, doctors prioritized the limited supply to sicker patients, many of whom didn’t complete the entire Pluvicto treatment, he said. What’s more, because Pluvicto is given six weeks apart, fewer patient starts in the first and second quarters meant a smaller patient base for the third quarter.

The good news is that Novartis saw 50% growth in patient numbers in the third quarter over the second quarter, and Pluvicto remains on track to reach $1 billion this year, Narasimhan said. Supply is not a problem right now, and Novartis is looking to bring online an additional manufacturing site in Indianapolis, which according to Narasimhan will give the company “enough capacity to fully meet the U.S. market.”