The United States Food and Drug Admin­istra­tion (FDA) has approved ixazomib for the treat­ment of multiple myeloma.

The drug will be marketed under the brand name Ninlaro. It should be avail­able in U.S. pharmacies by the middle of next month, according to a spokesperson from Takeda Oncology, the com­pany that developed Ninlaro and will be mar­ket­ing it globally.

Ninlaro is the second new multiple myeloma ther­apy approved by the FDA this week. The agency on Monday announced the approval of Darzalex (dara­tu­mu­mab) for the treat­ment of myeloma patients who have had three prior lines of ther­apy (see related Beacon news).

The FDA approval of Ninlaro is for use in com­bi­na­tion with Revlimid (lena­lido­mide) and dexamethasone (Decadron) to treat multiple myeloma patients who have received at least one prior ther­apy.

There is no require­ment that Ninlaro treat­ment be preceded by any particular pre­vi­ous ther­apy or class of ther­a­pies.

As was the case with Darzalex, the FDA approved Ninlaro several months earlier than ex­pec­ted given U.S. drug review guidelines, and the agency made its decision without formally consulting with its Oncologic Drugs Advisory Committee of outside experts.

These aspects of the drug’s approval suggest that the FDA did not have any sig­nif­i­cant concerns about Ninlaro’s safety and effectiveness, and that the agency believes the drug meets an important medical need.

The FDA has now approved three new myeloma ther­a­pies in 2015. Prior to this week’s approvals of Ninlaro and Darzalex, the FDA in February gave the go-ahead to Farydak (panobinostat) (see related Beacon news). The agency also is reviewing an appli­ca­tion requesting the approval of elotuzumab (Empliciti) as an addi­tional new treat­ment for multiple myeloma.

It has not been, however, a perfect year for myeloma-related FDA drug reviews. The agency last month turned down an appli­ca­tion requesting approval of a new formulation of mel­phalan for use in myeloma patients during stem cell trans­plan­ta­tion (see related press release from Spectrum Pharma­ceu­ticals).

Ninlaro also is being reviewed by the European Medicines Agency (EMA), and its marketing appli­ca­tion was granted accelerated assess­ment this past July (see related press release from Takeda). A decision on the appli­ca­tion is ex­pec­ted by early next year.

The First Oral Proteasome Inhibitor

Ninlaro belongs to the class of drugs known as pro­te­a­some inhibitors, which in­cludes Velcade (bor­tez­o­mib) and Kyprolis (car­filz­o­mib). Proteasome inhibitors work by preventing the breakdown of protein in cancer cells, triggering their death.

Unlike Velcade and Kyprolis, which are admin­istered by injection or infusion, Ninlaro is given orally as a capsule. Another orally-administered pro­te­a­some inhibitor, oprozomib, is being in­ves­ti­gated as a poten­tial myeloma ther­apy, but it is still relatively early in the devel­op­ment process.

Ninlaro shares some chemical similarities to Velcade. However, the two myeloma ther­a­pies are distinctly different drugs, much as Revlimid and thalidomide (Thalidomide) are different drugs despite being chemically similar.

Basis For The FDA Approval Of Ninlaro

Ninlaro’s FDA approval is based on data from the TOURMALINE-MM1 clin­i­cal trial. The Phase 3 trial in­cluded 722 multiple myeloma patients who had received one to three prior ther­a­pies. The trial had few re­stric­tions on specific pre­vi­ous treat­ments patients could have if they wanted to take part in the trial. Patients could not join the trial, however, if their disease was resistant (refractory) to either Revlimid or a pro­te­a­some inhibitor.

Half the patients in the study were treated with Ninlaro, Revlimid, and dexa­meth­a­sone, while the other half were treated with a placebo (sugar capsule), Revlimid, and dexa­meth­a­sone. Treatment was con­tinued until a patient’s disease progressed, or until side effects or tolerability required dis­con­tinu­a­tion.

More patients who received Ninlaro in com­bi­na­tion with Revlimid and dexa­meth­a­sone had at least a partial response to treat­ment compared to patients who received the placebo with Revlimid and dexa­meth­a­sone (78 per­cent versus 72 per­cent, re­spec­tive­ly).

Progression-free survival also was longer in the Ninlaro-treated patients (a median of 20.6 months versus 14.7 months).

There is not at this time, however, a statistically sig­nif­i­cant difference in over­all survival between the two groups of patients.

The side effects ex­peri­enced by the two groups of patients in the trial were similar, although patients treated with Ninlaro were somewhat more likely to ex­peri­ence upper res­pira­tory tract in­fec­tions, periph­eral neu­rop­athy, gastro­in­tes­ti­nal disorders, rash, back pain, and swelling in the feet or hands.

Recommended Ninlaro Dosing And Duration Of Therapy

Ninlaro is admin­istered orally (by mouth) in the form of a capsule. The recommended starting dose is one 4 mg capsule per week for three weeks, followed by a week off. Two lower-dose capsules also are avail­able: 3 mg, and 2.3 mg.

The Revlimid taken in com­bi­na­tion with Ninlaro should be taken daily on a 21-day on / 7-day off schedule, with a recommended starting dose of 25 mg per day. The week off from Revlimid treat­ment should be the same as the week off from Ninlaro treat­ment.

The dexa­meth­a­sone taken with Ninlaro and Revlimid should be taken weekly, with no week off, and on the same day the patient takes Ninlaro in the weeks when Ninlaro is taken. The recommended dexa­meth­a­sone starting dose is 40 mg per week.

There is no fixed number of cycles that patients are advised to be treated with Ninlaro, Revlimid, and dex­a­meth­a­sone. Instead, it is recommended that treat­ment with the three-drug regi­men con­tinue “until disease pro­gres­sion or unacceptable toxicity.”

Ninlaro’s Cost

A Takeda spokesperson has informed The Beacon that the wholesale price of a Ninlaro will be $8,670 per four-week cycle, or $2,890 per Ninlaro capsule. The per-capsule cost of Ninlaro will be the same for each of the three capsule doses.

The $8,670 cost for a four-week cycle of Ninlaro is about the same as the average four-week cost of Velcade when Velcade is admin­istered twice a week for two weeks of a three-week cycle. Ninlaro’s cost is higher than Velcade’s, however, when Velcade is admin­istered less frequently. Velcade admin­istered once a week for three out of every four weeks, for example, costs about $4800 per four-week cycle.

Ninlaro’s cost per four-week cycle is lower, on the other hand, than the cost of Kyprolis, which is about $10,500 per four-week cycle when Kyprolis is admin­istered at its standard dose.

Additional details about the FDA approval of Ninlaro can be found in this press release from the FDA, a related press release from Takeda Oncology, and the full prescribing in­­for­ma­tion for Ninlaro.

Results of the TOURMALINE-MM1 trial have not yet been published in a medical journal or presented at a major medical conference. However, there will be an oral presentation summarizing the trial results at next month’s American Society of Hematology annual meeting (presentation abstract).