FDA approves Ninlaro, new oral medication to treat multiple myeloma.

November 20, 2015

The U.S. Food and Drug Administration approved ixazomib (NINLARO, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib is the first approved oral proteasome inhibitor.

Proteasomes are enzymes found in cells that help the cell break down old or unwanted proteins. These proteins are split into amino acids which can then be recycled to make new proteins. Cancer cells depend on the proteasome to provide this protein metabolism (turnover) function to regulate their growth and survival. Ixazomib disrupts a cancer cells’ ability to survive by blocking the proteasome and disrupting protein metabolism. Myeloma cells may be uniquely sensitive to proteasome inhibitors because they make large amounts of protein (called M-protein) and need this recycling function to survive.

This approval is the third drug for multiple myeloma approved this year and provides patients with a new oral treatment that slows disease progression when other therapy has failed.” The FDA approved Farydak (panobinostat)in February and Darzalex (daratumumab) earlier this month.

NINLARO (ixazomib) is an antineoplastic agent. Ixazomib citrate, a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib. The chemical name of ixazomib citrate is 1,3,2-dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5­dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo- and the structural formula is:

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IXAZOMIB CITRATE

 

 

Clinical Pharmacology

Mechanism of Action

Ixazomib is a reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.

Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model.

 

CLINICAL STUDIES

The efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study.

A total of 722 patients were randomized in a 1:1 ratio to receive either the combination of NINLARO, lenalidomide and dexamethasone (N=360; NINLARO regimen) or the combination of placebo, lenalidomide and dexamethasone (N=362; placebo regimen) until disease progression or unacceptable toxicity. Randomization was stratified according to number of prior lines of therapy (1 versus 2 or 3), myeloma International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor (exposed or naïve). Twenty three percent (N=166) of the A total of 722 patients were randomized patients had light chain disease and 12% (N=87) of patients had free light chain-measurable only disease.

 

Indication

NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

 

DOSAGE AND ADMINISTRATION 

  •  Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 28-day cycle.
  •  Dose should be taken at least one hour before or at least two hours after food.

DOSAGE FORMS AND STRENGTHS 

  • Capsules: 4 mg, 3 mg, and 2.3 mg

 

WARNINGS AND PRECAUTIONS 

  • Thrombocytopenia: Monitor platelet counts at least monthly during treatment and adjust dosing, as needed.
  • Gastrointestinal Toxicities: Adjust dosing for severe diarrhea, constipation, nausea, and vomiting, as needed.
  • Peripheral Neuropathy: Monitor patients for symptoms of peripheral neuropathy and adjust dosing, as needed.
  • Peripheral Edema: Monitor for fluid retention. Investigate for underlying causes, when appropriate. Adjust dosing, as needed.
  • Cutaneous Reactions: Monitor patients for rash and adjust dosing, as needed.
  • Hepatotoxicity: Monitor hepatic enzymes during treatment.
  •     Embryo-Fetal Toxicity: NINLARO can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) are diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain.

 

The FDA granted priority review and orphan drug designations for Ninlaro. Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

Ninlaro is marketed by Takeda Pharmaceuticals based in Osaka, Japan. 

Reference:

FDA News

FDA Label