FDA issues complete response letter for teplizumab
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The FDA issued a complete response letter for a biologics license application for teplizumab for the delay of type 1 diabetes in high-risk children and adults, stating a study failed to show pharmacokinetic comparability.
In an industry press release, Provention Bio said the FDA stated that a single, low-dose pharmacokinetic/pharmacodynamic bridging study in healthy volunteers to compare the planned commercial product with the drug product originating from drug substance manufactured for historic clinical trials failed to show pharmacokinetic comparability. Provention Bio received the complete response letter July 2, according to the release.
“As pharmacokinetic remains the primary endpoint for demonstration of comparability between the two products, you will need to establish pharmacokinetic comparability appropriately between the intended commercial product and the clinical trial product or provide other data that adequately justify why pharmacokinetic comparability is not necessary,” the FDA stated in the letter.
As Healio previously reported, an FDA advisory panel voted 10-7 in favor of recommending approval of teplizumab (Provention Bio) to delay development of type 1 diabetes in high-risk children and adults, with most committee members expressing some concerns about trial size and safety.
In casting their votes, most members of the Endocrinologic and Metabolic Drugs Advisory Committee said they struggled with whether to recommend approval of teplizumab, a humanized anti-CD3 monoclonal antibody, which was shown in a randomized clinical trial to delay development of type 1 diabetes by a median of up to 2 years in children as young as age 8 years after a single, 14-day course of the drug. Members weighed the importance of reducing the well-known disease burden and complications of type 1 diabetes with questions of efficacy and potential safety concerns.
In the release, Provention Bio said it expects relevant additional pharmacokinetic/pharmacodynamic data to be collected from a pharmacokinetic/pharmacodynamic substudy among participants receiving 12 days of therapy in the ongoing phase 3 PROTECT trial in people with newly diagnosed type 1 diabetes later this quarter.
“These data will be analyzed by independent, unblinded third parties to maintain the integrity of this placebo-controlled trial,” Provention Bio stated in the release. “Upon review of the results from this substudy, the company will determine whether to submit these data to the FDA for its review, along with any other relevant data and analyses based on our ongoing discussions with FDA, to support pharmacokinetic/pharmacodynamic comparability or otherwise justify why pharmacokinetic comparability is not necessary.”
In the complete response letter, the FDA cited several additional considerations related to product quality, according to Provention Bio’s release, which the company said have either been addressed in amendments already submitted to the biologics license application or can be addressed in the short term. The complete response letter acknowledged that the FDA had not reviewed several amendments already submitted by the company in response to certain chemistry, manufacturing and controls information requests.
The FDA also stated that certain deficiencies conveyed during a recent general inspection, not specific to teplizumab, at a fill/finish manufacturing facility used by the company will need to be resolved before approval.
The letter did not cite any clinical deficiencies related to the efficacy and safety data packages submitted to the biologics license application and confirmed the acceptability of the proposed proprietary name for teplizumab. The FDA requested that Provention Bio provide a safety update as part of its biologics license application resubmission.
“We want to recognize the patients, their families, study investigators, clinicians and type 1 diabetes champions that have played such a crucial role in the development of teplizumab and thank our partners and our team of dedicated employees and consultants for their outstanding contributions,” Ashleigh Palmer, co-founder and CEO of Provention Bio, said in the release. “We know the type 1 diabetes community is urgently awaiting therapeutic advancements to address their medical needs and believe our collective passion and commitment will continue to drive us forward to meet this goal. We will continue to work collaboratively with the FDA to hopefully secure approval of teplizumab and bring the first disease-modifying therapy for type 1 diabetes to at-risk patients as soon as possible.”
In a statement, JDRF, which has supported teplizumab research, called the decision unfortunate.
“JDRF is thankful for the FDA’s designation of teplizumab as a breakthrough therapy and ongoing consideration of this drug,” the organization stated in the release. “It is unfortunate that the FDA has not approved teplizumab at this time and instead has requested additional information from the sponsor. We look forward to Provention Bio addressing the issues outlined in the complete response letter and working with the FDA to bring this option to market safely.”
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