Novartis to Add Lutathera to Portfolio in Planned $3.9-Billion Deal

Bruno Strigini

Novartis has announced a planned $3.9-billion acquisition of Advanced Accelerator Applications (AAA), a radiopharmaceutical company that develops, produces, and commercializes Molecular Nuclear Medicines.

AAA manufactures Lutathera (lutetium [177Lu] oxodotreotide), a first-in-class RadioLigand Therapy (RLT) product for neuroendocrine tumors (NETs). The EU approved Lutathera for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in September. In addition to Lutathera, the company has also developed the companion diagnostics NETSPOT and SomaKit TOC. AAA had sales of €109 million in 2016.

AAA’s board of directors has already approved a memorandum of understanding stating that Novartis will make a cash offer of $41 per ordinary share of AAA and $82 per American Depositary Share, each representing 2 ordinary shares, subject to certain conditions. This offer values the company at $3.9 billion.

Novartis plans to fund the deal through external short- and long-term debt. The pharmaceutical giant said the deal would boost its oncology presence with “both near-term product launches as well as a new technology platform with potential applications across a number of oncology early development programs.¹

“Novartis has a strong legacy in the development and commercialization of medicines for neuroendocrine tumors where significant unmet need remains for patients,” Bruno Strigini, CEO, Novartis Oncology, said in a press release. “With Lutathera, we can build on this legacy by expanding the global reach of this novel, differentiated treatment approach and work to maximize Advanced Accelerator Applications broader RLT pipeline and an exciting technology platform.”

The FDA is currently reviewing a new drug application (NDA) for Lutathera for patients with GEP-NETs. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a final approval decision by January 26, 2018.

UPDATE 1/26/2018: FDA Approves Lutathera for GEP-NETs

The FDA had granted a priority review designation to the NDA for Lutathera in June 2016, and had been scheduled to make its final decision by December 28, 2016. However, on December 21, 2016, Advanced Accelerator Applications, reported that the FDA had issued a complete response letter (CRL) informing the company that the NDA for Lutathera would need to be resubmitted.

The CRL, which followed a discipline review letter issued in November 2016, requested new subgroup data, a safety update, and that revisions be made to the previously submitted data. The letter did not request the initiation of additional studies of Lutathera.

The NDA is based on the phase III NETTER-1 trial, which compared Lutathera with high-dose octreotide LAR for patients with grade 1 or 2 metastatic midgut NETs.2 In this trial, there was a 79% reduction in the risk of progression or death with Lutathera compared with octreotide.

Patients with midgut NETs who progressed on standard-dose octreotide (30 mg) were randomized to Lutathera (n = 116) or high-dose octreotide (n = 113). Four doses of Lutathera were administered at 7.4 GBq every 8 weeks in combination with octreotide at 30 mg for symptom control. In the control arm, patients received octreotide LAR at 60 mg every 4 weeks.

Baseline characteristics were well balanced between the two arms. The mean age of patients in the investigational arm was 63 years (±9) and the mean BMI was 25 (±5). The primary tumor site was the ileum (74%) and the most common sites of metastasis were the liver (84%), lymph nodes (66%), and other locations (35%). All patients had somatostatin receptor-positive tumors, the majority of which were grade 4 on the Krenning scale (60%).

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints focused on objective response rates (ORR), overall survival (OS), and safety.

Median PFS had not been reached in the Lutathera arm compared with 8.4 months in the high-dose octreotide arm (HR, 0.21; 95% CI, 0.13-0.33; P <.0001). The estimated median PFS was approximately 40 months with Lutathera.

The ORR with Lutathera was 18% versus 3% with octreotide (P = .0008). There was 1 complete response with Lutathera and 17 partial responses. The stable disease rate with Lutathera was 66% versus 62% with octreotide.

At the interim analysis of OS there was a 60% reduction in the risk of death seen with Lutathera versus octreotide (HR, 0.398; 95% CI, 0.21-0.77; P = .0043); however, the prespecified P value for statistical significance at the interim analysis was <.000085. Eighty-eight percent of patients in the Lutathera arm remained alive versus 77% in the octreotide group.

An adverse event (AE) of any grade was experienced by 96% of those in the Lutathera arm versus 86% of those in the octreotide group. Eighty-six percent and 31% of patients, in the Lutathera and octreotide groups, experienced treatment-related AEs, respectively. Treatment related serious AEs were experienced by 9% of patients treated with Lutathera versus 1% in the octreotide arm. Five patients discontinued the study due to Lutathera-related AEs.

The most common grade 3/4 AEs in the Lutathera group versus high-dose octreotide, respectively, were lymphopenia (9% vs 0%), vomiting (7% vs 0%), nausea (4% vs 2%), diarrhea (3% vs 2%), abdominal pain (3% vs 5%), fatigue (2% vs 2%), and thrombocytopenia (2% vs 0%). Grade 3/4 liver enzyme increases were seen in those treated with Lutathera that were not apparent in the high-dose octreotide arm, including AST increase (4% vs 0%), ALT increase (4% vs 0%), and bilirubin increase (2% vs 0%).

References

1. Novartis announces the planned acquisition of Advanced Accelerator Applications to strengthen oncology portfolio. Novartis. http://bit.ly/2yVFRVo. Accessed October 30, 2017.
2. Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: Efficacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE. J Clin Oncol. 2016;34 (suppl; abstr 4005).