Ixazomib

Ixazomib (trade name Ninlaro) is a drug for the treatment of multiple myeloma,[5] a type of white blood cell cancer,[6] in combination with other drugs. It is taken by mouth in the form of capsules.

Common side effects include diarrhea, constipation and low platelet count. Like the older bortezomib (which can only be given by injection), it acts as a proteasome inhibitor, has orphan drug status in the US and Europe, and is a boronic acid derivative.

The drug was developed by Takeda. In the US, it is approved since November 2015, and in the EU since November 2016.

Medical uses

Ixazomib is used in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in adults after at least one prior therapy.[7] There are no experiences with children and youths under 18 years of age.[8][9]

The study relevant for approval included 722 people. In this study, ixazomib increased the median time of progression-free survival from 14.7 months (in the placebo+lenalidomide+dexamethasone study arm including 362 people) to 20.6 months (under ixazomib+lenalidomide+dexamethasone, 360 people), which was a statistically significant effect (p = 0.012). 11.7% of patients in the ixazomib group had a complete response to the treatment, versus 6.6% in the placebo group. Overall response rate (complete plus partial) was 78.3% versus 71.5%.[9][10]

Side effects

Common side effects of the ixazomib+lenalidomide+dexamethasone study therapy included diarrhea (42% versus 36% under placebo+lenalidomide+dexamethasone), constipation (34% versus 25%), thrombocytopenia (low platelet count; 28% versus 14%), peripheral neuropathy (28% versus 21%), nausea (26% versus 21%), peripheral oedema (swelling; 25% versus 18%), vomiting (22% versus 11%), and back pain (21% versus 16%). Serious diarrhoea or thrombocytopenia occurred in 2% of patients, respectively.[9]

Side effects of ixazomib alone were only assessed in a small number of people. Diarrhea grade 2 or higher was found in 24% of these patients, thrombocytopenia grade 3 or higher in 28%, and fatigue grade 2 or higher in 26%.[12]

Interactions

The drug has a low potential for interactions via cytochrome P450 (CYP) liver enzymes and transporter proteins. The only relevant finding in studies was a reduction of ixazomib blood levels when combined with the strong CYP3A4 inducer rifampicin. The Cmax was reduced by 54% and the area under the curve by 74% in this study.[9][13]

Pharmacology

Chemistry

Ixazomib is a boronic acid and peptide analogue[15] like the older bortezomib. It contains a derivative of the amino acid leucine with the carboxylic acid group being replaced by a boronic acid; and the remainder of the molecule has been likened to phenylalanine.[14] The structure has been found through a large-scale screening of boron-containing molecules.[14]

History

The drug was developed by Takeda. It got US and European orphan drug status for multiple myeloma in 2011, and for AL amyloidosis in 2012. Takeda submitted a US new drug application for multiple myeloma in July 2015.[16] In September 2015, the U.S. Food and Drug Administration (FDA) granted ixazomib combined with lenalidomide and dexamethasone a priority review designation for multiple myeloma.[17] On 20 November 2015, the FDA approved this combination for second-line treatment.[8]

The request for marketing authorisation in Europe was initially refused by the European Medicines Agency (EMA) in May 2016 due to insufficient data showing a benefit of treatment.[18] After Takeda requested a re-examination, the EMA granted a marketing authorisation on 21 November 2016 on the condition that further efficacy studies be conducted. The approval indication is the same as in the US.[9]

Research

As of January 2017, ixazomib is also in Phase III clinical trials for the treatment of AL amyloidosis[19] and plasmacytoma of the bones,[20] and in Phase I/II trials for various other conditions.[21][22]