Takeda's Ninlaro Fails in Phase 3 Multiple Myeloma Trial Amid Ongoing $10B Asset Divestment Plan

Compiled by Keke

On September 9, Takeda presented detailed results from the Phase 3 TOURMALINE-MM2 clinical trial at the Society of Hematologic Oncology (SOHO) Annual Meeting. The study evaluated NINLARO™ (ixazomib) in combination with lenalidomide and dexamethasone, compared with placebo plus lenalidomide and dexamethasone, for the treatment of patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplantation. The findings showed that adding NINLARO to the lenalidomide and dexamethasone regimen extended median progression-free survival (PFS) by 13.5 months compared with placebo—35.3 months in the NINLARO group versus 21.8 months in the placebo group (hazard ratio [HR] 0.830; p=0.073). The trial did not meet the threshold for statistical significance and failed to achieve its primary PFS endpoint.

TOURMALINE-MM2 is an international, randomized, double-blind, multicenter, placebo-controlled Phase 3 clinical trial designed to evaluate the efficacy of NINLARO (ixazomib) in combination with lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone in 705 adult patients with newly diagnosed multiple myeloma (MM) who are ineligible for transplantation. Patients in the NINLARO combination arm received single oral doses of ixazomib (4.0 mg) on Days 1, 8, and 15; single oral doses of lenalidomide (25 mg) on Days 1–21; and single oral doses of dexamethasone (40 mg) on Days 1, 8, 15, and 22. Each cycle lasted 28 days, for a total of 18 cycles or until disease progression or unacceptable toxicity, whichever occurred first. After Cycle 18, the doses of ixazomib and lenalidomide were reduced, and dexamethasone was discontinued. The primary endpoint was progression-free survival (PFS), assessed at each cycle during treatment and every 4 weeks post-treatment until disease progression (the median duration of the endpoint assessment period was estimated to be approximately 30 months). Key secondary endpoints included complete response (CR) rate, pain response, overall survival (OS), and median time to progression (TTP).

Key findings from the TOURMALINE-MM2 study include:

In the prespecified high-risk cytogenetic subgroup, the median PFS was 23.8 months in the NINLARO combination group versus 18.0 months in the placebo group (HR 0.690).

In the trial, the incidence of CR, a key secondary endpoint, was 26% in the NINLARO combination therapy group and 14% in the placebo group.

The median follow-up duration was 57.8 months in the NINLARO combination therapy group and 58.6 months in the placebo group; median overall survival (OS) was not reached in either group (HR 0.998).

Compared with the placebo group, the NINLARO combination therapy group had a longer median time to progression (TTP) of 45.8 months versus 26.8 months in the placebo group (HR 0.738).

Furthermore, the safety profile associated with NINLARO in the trial was generally consistent with the existing prescribing information. Specific safety data include:

In the NINLARO combination therapy group, 96.6% of patients experienced treatment-emergent adverse events (TEAEs), compared with 92.6% in the placebo group. The most common clinically significant symptoms in the former group were diarrhea, rash, peripheral edema, constipation, and nausea.

In the NINLARO combination therapy group, 88.1% of patients experienced grade ≥3 treatment-emergent adverse events (TEAEs), compared with 81.4% in the placebo group. Most TEAEs occurred without discontinuation of treatment; the proportions of patients who discontinued treatment due to TEAEs were 35% and 26.9% in the two groups, respectively.

The mortality rates in the NINLARO combination therapy group and the placebo group were 7.6% and 6.3%, respectively.

NINLARO (ixazomib) is an orally administered proteasome inhibitor in capsule form that selectively and reversibly inhibits the β-5 subunit of the proteasome (PSMB5). PSMB5 is a component of the 20S proteasome complex and exhibits chymotrypsin-like enzymatic activity. It induces apoptosis, a form of programmed cell death, in various cancer cell lines. Previous studies have demonstrated that ixazomib acts synergistically with lenalidomide in numerous myeloma cell lines. The drug was first approved by the FDA in November 2015, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. It has currently been approved for marketing in more than 65 countries and continues to be investigated in the field of MM treatment.

Molecular Structure of Ixazomib (Image Source: Wikipedia)

Over the past two years, Takeda has been repaying debt incurred from its $59 billion acquisition of Shire by continuously divesting non-core pharmaceutical assets. Yesterday, Takeda announced a latest agreement to sell several non-core prescription drugs, primarily marketed in Europe and Canada, to Germany-based Cheplapharm for $562 million. Takeda aims to divest $10 billion worth of assets, having consistently shed businesses inconsistent with its new strategic focus—namely gastroenterology, rare diseases, oncology, plasma-derived therapies, and neuroscience—over the past two years. Additionally, the company has implemented personnel adjustments to reduce operational costs. Key measures include:

Shire's ophthalmic drug Xiidra was sold to Novartis;

Surgical hemostatic patch TachoSil sold to Ethicon, a subsidiary of Johnson & Johnson;

Non-core assets in the Middle East and Africa were sold to Switzerland (Read more: To repay acquisition debt, Takeda sells rights to 30 drugs in emerging markets);

Sale of Non-Core Assets in Russia and the CIS Region to German Company Stada;

Resold its Latin American products to Hypera Pharma ($825 million), while relocating its U.S. operations from Chicago to the Greater Boston area and selling its former headquarters for $115 million (Read more: $940 Million! Takeda Continues to Divest Non-Core Assets);

Sold OTC and prescription drugs marketed in the European region to Orifarm Group;

Sold the Asia-Pacific rights to 18 drugs to South Korea’s Celltrion (Read more: $278 Million! Takeda Sells Asia-Pacific Rights to 18 Drugs to Celltrion);

The majority of the generic drug portfolio, along with a joint venture production base controlled in partnership with Teva, was transferred to Nichi-Iko Pharmaceutical;

Takeda offers “early retirement” packages to its sales and administrative staff in Japan (Read more: The $59 billion mega-acquisition’s lingering effects persist as Takeda launches a new round of “downsizing”)

Takeda Consumer Healthcare Company’s OTC Division Sold to U.S. Private Equity Firm Blackstone (Read More: Takeda Plans to Sell Its Japan OTC Business, Multi-Billion Dollar Divestiture Nearing Completion!)

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While actively optimizing its R&D pipeline amid debt repayment, Takeda sees NINLARO, a promising candidate in one of its five key therapeutic areas, as needing to penetrate the first-line treatment market to unlock greater opportunities. However, the failure of this recent study has clearly cast a shadow over the drug’s future prospects.

Reference Source:

1. Wikipedia

2. Takeda Official Website

3.Takeda's Ninlaro Stumbles in Latest Multiple Myeloma Trial

4.IXAZOMIB Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma

Original Title: Takeda’s Ninlaro Fails in Multiple Myeloma Clinical Trial; Previous $10 Billion Asset Divestiture Plan Not Yet Completed