FDA approval activity last week resulted in a new atypical antipsychotic, the return of an early targeted oncologic under a new NDA, and a new claim for a botulinum toxin. Keeping Track also highlights the submission of the first oral proteasome inhibitor for multiple myeloma.

Rexulti Approval Continues Lundbeck CNS Portfolio Rejuvenation

FDA's July 10 approval of Otsuka Pharmaceutical Co. Ltd. and H. Lundbeck AS's Rexulti (brexpiprazole) brings another new molecular entity to the crowded atypical antipsychotic field, and marks another step in the recovery of Lundbeck's CNS portfolio in the face of increasing generic competition to Cipralex (escitalopram), an antidepressant that once accounted for more than half of Lundbeck sales.

Rexulti, approved for treatment of schizophrenia and adjunctive treatment of major depressive disorder, will be available in the U.S. in early August. It will join once-monthly Abilify Maintena (aripiprazole depot) for schizophrenia, also co-marketed with Otsuka, and the antidepressant Brintellix (vortioxetine), both approved by FDA in 2013, in Lundbeck's launch portfolio ([A#14150506001]).

Rexulti is the 17th new molecular entity approved by FDA in 2015. (The FDA Performance Tracker's CDER Novel Approvals chart tracks new molecular entity and novel therapeutic biologic approvals for the year.)

Iressa Returns, This Time With Companion Diagnostic

AstraZeneca PLC's attempt to resuscitate Iressa (gefitinib) by identifying patients with specific mutations who were likely to respond to the kinase inhibitor met with success on July 13, 2015, when FDA approved Iressa as monotherapy for first-line treatment of metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions, as identified through a companion diagnostic test. Qiagen NV's therascreen EGFR RGQ PCR kit was cleared to identify Iressa patients the same day.

Iressa had been one of the first molecularly targeted oncologics to reach the U.S. market, with an accelerated approval in 2002 that did not require associated molecular profiling of patients, but the drug failed to show a survival benefit in a confirmatory trial. Iressa's use was restricted and AstraZeneca pulled the drug from the U.S. market in 2011.

The EGFR marketplace of 2015 will be much more competitive in Iressa's second go-round (see related story, Also see "AstraZeneca’s Iressa, Now Resurrected, Faces Daunting U.S. EGFR Market" - Pink Sheet, 20 July, 2015.).

AstraZeneca has been working on an Iressa companion diagnostic since 2009, when it inked a deal with DxS, a molecular diagnostic firm that was acquired by Qiagen shortly thereafter [See Deal]. Qiagen now estimates it holds more than 50% of the EGFR test market. Its therascreen EFGR kit tests for more than 20 EGFR mutations in multiple cancers, and was cleared as an NSCLC companion diagnostic for Boehringer Ingelheim GMBH's Gilotrif (afatinib) to test for the exon 19 deletion and exon 21 (L858R) substitutions, the same ones specified by the Iressa approval, in 2013.

The FDA-approved therascreen product analyzes tumor tissue, but since 2013 AZ and Qiagen also have been co-developing a "liquid biopsy" test that uses circulating DNA from a blood sample ([A#14140727001]). The therascreen EGFR Plasma RGQ PCR Kit was launched in Europe in January 2015; Iressa remained available in Europe and Asia after the U.S. withdrawal.

Ipsen's Dysport Adds Upper Limb Spasticity Indication

Ipsen's Dysport (abobotulinumtoxinA) strengthened its position in the competitive botulinum toxin market with FDA approval of a new claim for "treatment of upper limb spasticity in adults, to reduce the severity of increased muscle tone in the elbow, wrist and finger flexors" on July 15, 2015. Allergan Inc.'s Botox (onabotulinumtoxinA) recently extended its indication for upper limb spasticity to include two thumb flexor muscles, and Merz GMBH & Co. KGAA submitted a post-stroke upper limb spasticity claim for Xeomin (incobotulinumtoxinA) in April ([A#00150427015]).

The Dysport Phase III trial was "the first registration study to evaluate ULS treatment in adult patients with both stroke and traumatic brain injury," the company stated.

At a July 2 investor day, Ipsen said it was reinforcing its Dysport team to prepare for the U.S. launch of the upper limb spasticity indication with the addition of 20 new employees ([A#14150706001]).

Takeda Buttresses Multiple Myeloma Franchise With Oral Ixazomib NDA

Takeda Pharmaceutical Co. Ltd. submitted the first oral proteasome inhibitor to FDA with an NDA seeking approval of ixazomib for treatment of relapsed or refractory multiple myeloma, the company announced July 14. The NDA sets up ixazomib as part of an all-oral regimen with lenalidomide (Celgene Corp.'s Revlimid) and dexamethasone, based on the TOURMALINE-MM1 trial.

“Continuous treatment is emerging as a standard of care in multiple myeloma with demonstrable improvement in long-term outcomes,” ixazomib clinical program leader Paul Richardson (Dana-Farber Cancer Institute) said. “Proteasome inhibition has become an essential component of treatment, but there are logistical challenges for patients with both intravenous and subcutaneous approaches, and especially in the absence of an effective oral option."

Takeda has long held a key position in multiple myeloma treatment with the pioneering injectable proteasome inhibitor Velcade (bortezomib) from its Millennium Pharmaceuticals Ltd. subsidiary. But Velcade will lose patent protection in the U.S. in 2017, and Takeda is betting on ixazomib to make up for the loss. The TOURMALINE Phase III program is testing the drug in four more indications: for newly diagnosed multiple myeloma, also in combination with lenalidomide and dexamethasone; as maintenance therapy for newly-diagnosed multiple myeloma, both after induction therapy and autologous stem cell transplant and in patients who have not undergone ASCT; and for relapsed or refractory systemic light-chain (AL) amyloidosis, an indication that has been awarded "breakthrough therapy" status by FDA.

Ixazomib will need to fight for a place in an increasingly competitive multiple myeloma marketplace. Amgen Inc. is looking to bring its proteasome inhibitor Kyprolis (carfilzomib), approved for relapsed multiple myeloma, into the first-line setting ([A#00150622010]).

Genmab AS and Janssen Biotech Inc. recently completed a rolling BLA filing for the first-in-class anti-CD38 monoclonal antibody daratumumab for heavily pretreated multiple myeloma patients ([A#00150713010]).

(See the User Fee Goals chart on the FDA Performance Tracker for information on pending applications.)

Keeping Track: Rexulti, Iressa Approved; Takeda Submits Oral Myeloma Drug Ixazomib

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