The FDA issued Provention a CRL that focuses on a single low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in health volunteers.
The U.S. Food and Drug Administration (FDA) issued Provention Bio a Complete Response Letter (CRL) for its Biologics License Application (BLA) for teplizumab. The drug is being developed to delay clinical type 1 diabetes (T1D) in people at risk for the disease.
The CRL, which the company received on July 2, 2021, focused on a single low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in health volunteers. The study compared teplizumab with another drug “originating from drug substance manufactured for historic clinical trials.” In that study, teplizumab did not demonstrate PK comparability.
The CRL stated, “As PK remains the primary endpoint for demonstration of comparability between the two products, you will need to establish PK comparability appropriately between the intended commercial product and the clinical trial product or provide other data that adequately justify why PK comparability is not necessary.”
Provention Bio indicates the additional PK/PD data is being collected from a PK/PD substudy during an ongoing Phase III PROTECT trial in newly diagnosed T1D patients later this quarter. These patients are receiving 12 days of therapy.
To protect the integrity of the placebo-controlled study, the data will be analyzed by independent, unblinded third parties. Once that is reviewed, Provention will decide if they can submit the data to the FDA with other relevant data.
The FDA also had some problems with product quality that came from a recent inspection of a manufacturing facility the company uses. Provention believes it has either already addressed those issues in amendments it already sent to the FDA or can be quickly addressed. The agency had indicated it had not reviewed several amendments the company already sent in response to requests about specific Chemistry, Manufacturing and Controls (CMC).
Otherwise, there did not appear to be any problems with the clinical efficacy and safety data submitted.
Teplizumab is an anti-CD3 monoclonal antibody. In the pivotal TN-10 Study, 14 days of the drug delayed insulin-dependent, clinical-stage TD1 by a median of at least two years in presymptomatic patients with Stage 2 T1D compared to placebo. Some adverse events were transient and predictable, including lymphopenia, transaminase elevations, rash, and cytokine release.
Teplizumab has received Breakthrough Therapy Designation by the FDA and PRIME designation by the European Medicines Administration.
Type 1 diabetes affects more than 1.6 people in the U.S. It is an autoimmune disease caused by the destruction of pancreatic beta cells. It is typically diagnosed in children and young adults, although it can occur at any age after symptoms appear when an individual’s pancreas doesn’t manufacture enough insulin. But the disease itself starts long before symptoms and can be detected via a blood test.
“We want to recognize the patients, their families, study investigators, clinicians and T1D 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,” said Ashleigh Palmer, co-founder and chief executive officer of Provention Bio.
“We also want to acknowledge the efforts of Drs. Yanoff and Unger and the review team at the FDA, who have worked so closely and transparently with us throughout the priority review of our BLA for the Breakthrough Therapy Drug.”
