Agency says it can’t approve vinorelbine formulation due to concerns about authenticity and CMC issues.

FDA has told Adventrx Pharmaceuticals it can’t approve the firm’s NDA for Exelbine™ (vinorelbine injectable emulsion) based on submitted data, due to concerns about drug authenticity in a previous clinical trial and additional CMC issues. The drug had been submitted for approval as a treatment for non-small cell lung cancer.

In its complete response letter (CRL) to Adventrx, FDA said that based on inspections at clinical sites, the authenticity of Exelbine used in a pivotal bioequivalence trial (study 530-01) couldn’t be verified, and the trial will need to be repeated. FDA also cited CMC concerns, which Adventrx states the agency had flagged earlier in the review cycle, but which had already been addressed individually prior to receipt of the CRL.

The firm admits it is “disappointed” with FDA’s decision, but plans to meet with the agency to discuss the way forward. “However, we believe the authenticity of the drug products used in the pivotal study is verifiable and plan to discuss FDA’s concerns in this regard,” comments Brian M. Culley, Adventrx CEO. “We also will enquire whether FDA has comments to our previously submitted responses,” he adds.

In the meantime, the firm plans to push on with development of its two other clinical-stage candidates, ANX-514 (docetaxel emulsion for injection) and ANX-188 (purified poloxamer 188). “Our cash and equivalents of $40.7 million at July 31, plus cost savings from delaying or potentially discontinuing the Exelbine program, will provide us with the capital to continue to advance both of these programs,” Culley states.

Exelbine has been developed as a bioequivalent formulation of Navelbine® (vinorelbine) that is less likely to cause the injection site reactions commonly occurring after Navelbine administration. The Exelbine formulation emulsifies vinorelbine in a homogeneous suspension of nanoparticles that is designed to reduce the interaction between vinorelbine and the venous endothelium during administration into a peripheral vein, and so reduce irritation associated with administration of the drug.

ANX-514 is detergent-free reformulation of the chemotherapy drug docetaxel (Taxotere), which is solubilized in oil droplets to negate the use of polysorbate 80, the excipient used in current formulations. Adventrx says the oxidation products of polysorbate 80 have been associated with sometimes severe or even fatal hypersensitivity reactions that can occur after Taxotere administration. ANX-514 is currently in late-stage clinical development: protocols for a second safety and bioequivalence study, and a Phase III trial are being planned for submission to FDA.

ANX-188 is a novel, purified, rheologic and antithrombotic compound initially being developed as a first-in-class treatment for pediatric patients with sickle cell disease in acute crisis. Adventrx took over ANX-188 through the share-based acquisition of SynthRx, a deal completed in April. The candidate has been designed to eliminate impurities in a previous formulation of poloxamer 188 used in clinical trials that were associated with renal toxicity. In ANX-188 has been evaluated in multiple clinical studies, including a 255-patient, Phase III study by a prior sponsor. Adventrx plans to meet with FDA to agree on its own Phase III clinical trial protocol for ANX-188 as a treatment for pediatric patients with sickle cell disease in acute crisis.

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