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Takeda announced the submission of a New Drug Application for ixazomib, the first orally administered proteasome inhibitor for multiple myeloma.

On 14 July 2015, Takeda announced the submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for ixazomib, the first oral proteasome inhibitor for the treatment of patients with relapsed/refractory multiple myeloma. While this approval will be important for Takeda to maintain its strong position in the multiple myeloma market, additional evidence of clinical efficacy will be required if ixazomib is to effectively challenge existing therapies.

The NDA submission was based on data from the pivotal TOURMALINE-MM1 Phase III trial, a randomized, double-blind, placebo-controlled clinical trial of 722 patients evaluating the efficacy of ixazomib plus Revlimid (lenalidomide; Celgene) and dexamethasone compared to placebo plus Revlimid and dexamethasone in patients with relapsed/refractory multiple myeloma. Patients in this trial had a confirmed diagnosis of multiple myeloma, and had received one to three prior therapies. An interim analysis of this Phase III study indicated that ixazomib achieved its primary endpoint of improving progression-free survival (PFS). Patients treated with investigational ixazomib plus Revlimid/dexamethasone lived without their disease worsening for a significantly longer time than patients who received placebo plus Revlimid/dexamethasone.

Ixazomib is a second-generation oral proteasome inhibitor designed to kill cancer cells by blocking the proteasome and by inhibiting protein metabolism. Proteasomes are responsible for the degradation of the majority of regulatory proteins, including proteins that control apoptosis, DNA repair, and cell cycle progression. Disruption of proteasome activity can therefore result in growth arrest and cell death. Ixazomib’s mechanism of action is uniquely suited to multiple myeloma since myeloma cells generally have higher levels of proteasome activity compared to normal cells.

Takeda’s market-leading proteasome inhibitor Velcade (bortezomib) is facing increasing competition in the multiple myeloma space and patent expiry in the US in Q2 2017. A successful approval for ixazomib is therefore important for Takeda as the company tries to maintain its strong position in this market. Velcade’s position as the leading proteasome inhibitor for multiple myeloma is now being challenged by Kyprolis (carfilzomib; Amgen/Ono Pharmaceutical) which, despite its approval as a third-line therapy in the US, has seen impressive growth since its launch in 2012. This growth is set to increase with recently released data from the Phase III ENDEAVOR clinical trial indicating a PFS advantage for Kyprolis over Velcade in relapsed patients (ClinicalTrials.gov identifier: NCT01568866). Top-line results from an interim analysis released in March 2015 demonstrated that relapsed multiple myeloma patients receiving Kyprolis plus dexamethasone had a statistically and clinically significant median PFS of 18.7 months versus 9.4 months for patients treated with Velcade plus dexamethasone. The results from this Phase III trial will likely increase Kyprolis’s uptake in the near future, and Amgen is currently seeking label expansions to include first-line therapy in the US in 2016.

Ixazomib will be the first orally administered proteasome inhibitor to reach the multiple myeloma market, but further evidence of its clinical efficacy will be required to boost its market share. Kyprolis and Velcade are available as intravenous formulations, with Velcade also receiving FDA approval for subcutaneous administration in 2012. Ixazomib’s formulation as a convenient once-weekly, orally administered drug is clinically and commercially attractive. However, the drug’s initial approval will be limited to the relapsed/refractory setting and there is a lack of evidence to suggest that ixazomib is more effective than Kyprolis or Velcade at improving PFS. Thus far, ixazomib has only demonstrated a PFS advantage compared to placebo in relapsed/refractory multiple myeloma. Takeda has also yet to release the full results of the TOURMALINE-MM1 study on which the NDA submission is based, but in the absence of direct comparison trials, the PFS will be compared to the 18.7 months recently achieved by Kyprolis in relapsed patients.

Ixazomib’s approval in the first-line setting will be essential if Takeda wants to maximize drug uptake and secure its position in the multiple myeloma market. The TOURMALINE-MM1 study was the first in a series of five Phase III clinical trials designed to test the efficacy of ixazomib in a variety of patient populations (see table below). Three of the Phase III TOURMALINE studies (MM2, MM3, and MM4) are investigating ixazomib as a treatment for newly diagnosed patients, and these studies will be critical in determining ixazomib’s commercial potential. The drug’s once-weekly oral administration may be preferable for many patients facing continuous long-term treatment with a proteasome inhibitor. If Takeda is able to provide additional evidence of clinical efficacy and gain first-line approval for ixazomib then it could achieve significant revenues. With Velcade projected to lose over $1bn in sales by 2020, Takeda will be hoping that uptake of ixazomib will help to offset threats from Kyprolis and incoming generics.


Table: Phase III TOURMALINE clinical trials investigating the development of ixazomib

Trial name (ClinicalTrials.gov identifier) Sample size  Target patients  Treatment arms  Primary endpoints  Start date/primary completion date
TOURMALINE-MM1(NCT01564537) 722 Relapsed/refractory MM
Arm A: ixazomib + Revlimid + dexamethasoneArm B: placebo + Revlimid + dexamethasone PFS August 2012/December 2014
TOURMALINE-MM2(NCT01850524) 701 Newly diagnosed MM Arm A: ixazomib + Revlimid + dexamethasoneArm B: placebo + Revlimid + dexamethasone PFS May 2013/June 2018
TOURMALINE-MM3(NCT02181413) 652 Newly diagnosed MM following induction therapy and ASCT Arm A: ixazomibArm B: placebo PFS July 2014/February 2018
TOURMALINE-MM4(NCT02312258) 761 Newly diagnosed MM who have not undergone ASCT Arm A: ixazomibArm B: placebo PFS April 2015/December 2018
TOURMALINE-AL1(NCT01659658) 248 Relapsed/refractory AL amyloidosis Arm A: ixazomib + dexamethasoneArm B: physician’s choice of selected regimens Two-year vital organ deterioration and mortality rate; total patients with overall hematologic response
December 2012/May 2018

 AL = amyloid light-chain; ASCT = autologous stem cell transplantation; MM = multiple myeloma; PFS = progression-free survival

 Source: ClinicalTrials.gov; BioMedTracker, Copyright 2015, reprinted with permission

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