Lilly's $1.4B Radiopharmaceutical Ambition Faces Setback as PNT2002 Misses Market Expectations Despite Hitting Phase III Primary Endpoint

On December 18, Point Biopharma announced that the pivotal Phase III SPLASH trial evaluating its core product, 177Lu-PNT2002, for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients previously treated with androgen receptor inhibitors, met its primary endpoint with statistical significance.

Data on PNT2002 have drawn significant attention due to Eli Lilly’s acquisition of POINT Biopharma. The Phase III clinical trial met its primary endpoint, largely aligning with Eli Lilly’s expectations but falling short of analysts’ anticipation. Some analysts expressed disappointment with the PNT2002 results compared to Novartis’s Pluvicto. Importantly, this data release comes at a critical juncture for POINT Biopharma, as its shareholders are resisting Eli Lilly’s takeover offer in hopes of securing a more favorable deal.

Acquisition Delayed for the Third Time: Eli Lilly’s Radiopharmaceutical Strategy Remains Unsettled

On October 3, 2023, Eli Lilly announced that it had entered into a definitive agreement to acquire Point Biopharma for $1.4 billion, at a price of $12.50 per share, payable upon closing in late 2023.

The acquisition price represents a premium of approximately 87% over Point Biopharma’s closing share price on October 2, 2023, and a 68% premium over its 30-day volume-weighted average price. Influenced by the acquisition news, Point Biopharma’s stock surged more than 80% on the day, bringing its market capitalization to approximately $1.3 billion, while Eli Lilly’s shares declined nearly 1%, with its market capitalization standing at $506.3 billion.

At the time, Wall Street analysts praised the deal as a validation of POINT’s portfolio and the long-term value of radiotherapy. Meanwhile,This transaction is also regarded as a pivotal event marking Eli Lilly’s formal entry into the radiopharmaceutical sector.Upon completion of the acquisition, Eli Lilly will gain a full industry chain encompassing research and development, production, manufacturing, and commercialization. In addition to acquiring Point’s radiopharmaceutical pipeline, which can directly compete with Novartis’ Pluvicto, Eli Lilly will also obtain its 17,000-square-meter radiopharmaceutical production campus in Indianapolis, Indiana—the world’s largest dedicated facility for the manufacture of radiopharmaceuticals.

Just as both parties seemed poised for a happy outcome, many investors in POINT Biopharma Global (POINT) had other ideas, rejecting Eli Lilly’s acquisition offer in hopes of securing a better deal. The acquisition has been postponed three times, with deadlines set for November 16, December 1, and December 15. By these dates, Eli Lilly had secured support from only about one-quarter of POINT’s shares. On December 4, when Eli Lilly extended the deadline for its tender offer for POINT shares for the second time, only 24.75% of POINT’s shares had been tendered, even lower than the 26.45% collected by November 16. During the third extension, Eli Lilly set the final deadline for December 15, maintaining the acquisition price at $12.50 per share. However, by the close of trading on December 15, Eli Lilly had garnered support from only 22.81% of POINT’s shares. Throughout this process, that figure has continued to decline.

Why POINT’s Investors Rejected Eli Lilly’s Acquisition Offer: The Role of Novartis’ PSMA Star Radioligand Drug Pluvicto (177Lu-PSMA-617)

At the time Eli Lilly announced its acquisition, Novartis prominently released data from the Phase III PSMAfore study of Pluvicto at the 2023 European Society for Medical Oncology (ESMO) Congress. The results showed:Although Pluvicto demonstrated substantial benefits in delaying tumor progression among patients receiving androgen receptor pathway inhibitors, an initial negative trend in overall survival (OS) was observed.Therefore, Novartis has decided to postpone its application submission to the FDA, pending longer-term follow-up from the PSMAfore trial.

Pluvicto and PNT2002 share a similar mechanism of action and target the same indication; meanwhile, Pluvicto’s Phase III PSMAfore study is also comparable to PNT2002’s Phase III SPLASH study. Therefore,With the release of PSMAfore data, some investors are anticipating superior overall survival results for PNT2002 in the SPLASH trial, believing that PNT2002 holds greater potential than Pluvicto and can effectively compete with it. Should the results demonstrate that PNT2002 outperforms Pluvicto, investors may push Eli Lilly and other potential acquirers to offer higher valuations.

How are the PNT2002 data?

PNT2002, which combines the PSMA-targeting ligand PSMA-I&T with the beta-emitting radioisotope lutetium-177 (Lu-177), is Point Biopharma’s lead radiopharmaceutical product with the most advanced clinical progress. This product is considered a star drug in the radiopharmaceutical sector. In December 2022, Lantheus, an established radiopharmaceutical company, obtained exclusive global commercialization rights for PNT2002 from Point (excluding certain Asian regions). In April 2023, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to PNT2002 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). In October 2023, Eli Lilly announced that it had reached a definitive agreement to acquire Point Biopharma for $1.4 billion.

The SPLASH study announced herein was conducted in the United States, Canada, Europe, and the United Kingdom. This open-label study randomized 412 patients with PSMA-expressing metastatic castration-resistant prostate cancer (mCRPC) in a 2:1 ratio (177Lu-PNT2002 : control group). These patients had experienced disease progression following treatment with novel androgen receptor pathway inhibitors (ARPIs) and either declined or were ineligible for chemotherapy. In the trial, 84.6% of patients in the control group who experienced disease progression subsequently crossed over to receive 177Lu-PNT2002. Among patients enrolled in the SPLASH clinical trial, 80% resided in North America, and approximately 10% of all participants were Black or African American.

Currently, the pivotal Phase III SPLASH trial has met its primary endpoint. The data indicate that the median radiographic progression-free survival (rPFS) was 9.5 months in patients treated with PNT2002, compared with 6 months in those receiving androgen receptor pathway inhibitors (ARPIs) in the control group, representing a statistically significant 29% reduction in the risk of radiographic progression or death (hazard ratio [HR] 0.71; p=0.0088).Interim Overall Survival (OS) Results Are Not Yet Mature(reaching 46% of the target OS events specified in the protocol),Hazard ratio (HR) was 1.11. POINT and Lantheus anticipate that additional follow-up data may become available prior to the submission of the New Drug Application (NDA) to the FDA in 2024.

In terms of safety, PNT2002 demonstrated a favorable safety profile. The incidence rates of Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to discontinuation were lower in the PNT2002 group than in the ARPI group (30.1%, 17.1%, and 1.9% vs. 36.9%, 23.1%, and 6.2%, respectively).

The results of the pivotal Phase III SPLASH study indicate that PNT2002 is well tolerated and has the potential to play a significant role in addressing the needs of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).

Reaching the Endpoint Without Recognition

Based on cross-trial comparisons, the data and efficacy of PNT2002 are broadly comparable to those of Pluvicto.Regarding the overall survival (OS) of widespread concern, the hazard ratio for PNT2002 was 1.11, compared with 1.16 in Novartis’ prior Pluvicto trial.This has met Eli Lilly’s expectations.

For Eli Lilly, the results of the SPLASH trial may not be the focal point. The company has downplayed the necessity of using the SPLASH study to demonstrate PNT2002’s potential superiority over Pluvicto, instead stating that its interest in POINT Biopharma Global is tied to the latter’s manufacturing and research capabilities. “Our interest in POINT is primarily focused on their technology platform,” Dan Skovronsky, Chief Scientific and Medical Officer at Eli Lilly, stated at an investor conference in late November. “I believe now is the optimal time to enter the radiopharmaceutical field.”

However, although the clinical study of PNT2002 met its primary endpoint, analysts and many investors were dissatisfied with the data.

Even before the clinical results were announced, some investors were bearish on the SPLASH data, believing it was more likely to yield outcomes similar to those of Pluvicto’s PSMAfore trial, with immature overall survival data.

A comparison of clinical data between PNT2002 and Pluvicto reveals that PNT2002 is actually inferior to Pluvicto in terms of progression-free survival (PFS). The median PFS was 9.5 months in the PNT2002 cohort versus 6 months in the control group, whereas the corresponding figures from the Pluvicto clinical trial were 12 months and 5.6 months, respectively.

Regarding the latest clinical data, analyst William Blair stated that the SPLASH study underperformed, and clinicians may view PNT2002 as inferior to Pluvicto, lacking strong competitive advantage in clinical practice. “PNT2002 demonstrates efficacy comparable to Pluvicto, suggesting that the goal of launching PNT2002 ahead of Pluvicto for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) may not be achievable.”

As for safety, William Blair is uncertain whether POINT can demonstrate its safety advantage, given that Pluvicto has a lower incidence of severe adverse events compared to other novel hormonal therapies. “We believe that the efficacy of PNT2002 may be inferior to that of Pluvicto, while its tolerability and safety profile do not show substantial advantages,” wrote William Blair.

December 18,Eli Lilly Announces Further Extension of Offer Deadline for Acquisition of POINT to December 22, POINT’s investors will also decide whether to accept Eli Lilly’s acquisition offer based on the latest data. The initial stock price reaction suggests that POINT may now view Lilly’s bid as the best option. In pre-market trading, POINT’s share price fell 11% to $12.47, just a few cents below the acquisition offer. Meanwhile, analysts stated that the deal is likely to be finalized, as it is unlikely that other bidders will emerge.