Takeda's Ninlaro Receives Conditional Approval from EMA, Pioneering Oral Treatment for Multiple Myeloma
First Oral Proteasome Inhibitor in Europe
On November 21, 2016, the European Commission granted conditional approval for Ninlaro (ixazomib citrate) from Takeda Pharmaceutical. Ninlaro is the first oral proteasome inhibitor that reversibly inhibits the beta5 subunit of the 20S proteasome. It is used in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least one prior therapy. The oral triple therapy reduces the burden of visits and administration compared to Velcade (bortezomib) and Kyprolis (carfilzomib), which are administered in a clinical setting, thereby increasing the feasibility of long-term treatment.
Clinical Value Proven by TOURMALINE-MM1
The approval is based on the TOURMALINE-MM1 study, a randomized, double-blind Phase 3 trial involving 722 patients. The median progression-free survival (PFS) in the ixazomib combination group was 20.6 months, compared to 14.7 months in the control group. The hazard ratio (HR) for disease progression or death was 0.742, with a p-value of 0.012. The combination of approximately 6 months of improvement and convenience of administration has created a differentiated treatment option for relapsed patients that maintains the same mechanism of action as injectable proteasome inhibitors.
Conditional Approval Reverses Negative Opinion
The CHMP initially adopted a negative opinion on May 26, 2016, citing uncertainties in demonstrating efficacy. However, after Takeda requested a re-examination, the CHMP recommended conditional approval on September 15, 2016. The EMA required the submission of final overall survival data and additional studies as a condition for approval, balancing early access with the need for further evidence. The U.S. FDA approved the same combination indication on November 20, 2015, and, given the absence of significant public health concerns, did not hold a vote by the oncology advisory committee. Japan's Ministry of Health, Labour and Welfare also approved the drug for relapsed/refractory multiple myeloma after PMDA review on March 30, 2017.
Large Market and Rapidly Evolving Competitive Landscape
The global market for multiple myeloma treatments was estimated at USD 29.24 billion in 2025. However, the focus of competition has shifted to combination therapies, including CD38-targeted antibodies. Current marketed competitors include Darzalex (daratumumab, CD38) from Janssen, Kyprolis from Amgen, Velcade and Revlimid (lenalidomide, CRBN) from Takeda. In newly diagnosed patients, daratumumab- or isatuximab-based quadruplet therapy has become the standard of care. Ninlaro's FY2023 sales were JPY 87.4 billion, a decrease of 5.7% from the previous year, indicating that oral convenience alone may not be sufficient to sustain a competitive advantage. Therefore, the European approval represents a successful platform transition, but its current value depends on its ability to capture market share among relapsed patients who prefer oral treatment and to maintain prescription rates in long-term maintenance therapy.
The European conditional approval commercializes the first oral proteasome inhibitor, which demonstrated a PFS of 20.6 months versus 14.7 months (HR 0.742) in Phase 3, enhancing Takeda's ability to address the patent cliff for Velcade. From a researcher's perspective, the reversal of the initial negative CHMP opinion after re-examination provides a case study of regulatory decision-making between clinical benefit and statistical uncertainty. In the USD 29.24 billion market projected for 2025, the growth of marketed Darzalex, Kyprolis, Velcade, and CD38-based quadruplet standard-of-care therapies defines the competitive landscape. Ninlaro's FY2023 sales of JPY 87.4 billion and a 5.7% decrease suggest that short-term cash generation is supported, but long-term investment value depends on defending market share in relapsed and maintenance therapy by leveraging the convenience of oral administration.
Source: EMA (ema)