Update #ProventionBio #Provention $PRVB #teplizumab. For a summary of AdCom etc. see thread below. I am not involved with the company but have other conflicts of interest. All is based on public information and personal opinion.
https://twitter.com/Chris___Nowak/status/1426514032492691458
Recap: Company has Breakthrough Therapy Designation and Priority Review, an AdCom vote 10-7 in favour for “delay of Type 1 diabetes #T1D”, and got a CRL stating CMC problems and failure to demonstrate PK/PD comparability between the studied Lilly-produced
and to-be commercialized ACG-produced teplizumab drug product (DP). A PK/PD substudy in the ongoing phase 3 PROTECT trial of 2 x 12 days of IV teplizumab 6 months apart in new-onset T1D has been completed (AGC Biologics DP ca. 30 patients, Lilly DP ca. 130 patients).
A fractional single-dose healthy volunteer bridging study submitted with the BLA had failed to meet strict pharmacokinetic (PK) comparability (AUC[0-inf] 80-120% b/w old/new DP) but FDA also opened in CRL for “or convince us why PK comparability not needed to be shown”.
PRVB believe pharmacodynamic (PD) data illustrating similar immunological responses in markers associated with efficacy can do the trick (in case the PROTECT PK substudy should fail to meet straightforward PK comparability).
See PRVB’s slide below illustrating similar responses between both DPs in biomarkers (CD3 binding, CD69 expression, T-cell margination) linked to clinical efficacy in previous studies (e.g. Protégé). 
PRVB will shortly (Q4) have a Type A meeting with FDA to discuss the PK comparability model to be populated with substudy data. After OK from FDA and PK modelling, PRVB may seek another meeting to make sure they’ve got everything required prior to re-submitting their BLA.
BLA re-submission expected to be Class 2 re-submission (not Class 1 = minor administrative, 2-month FDA response) with a 6-month response time. Company thinks FDA may reach decision sooner since so few issues to re-consider.
PRVB are confident that CMC issues and fill-and-finish site inspection problems cited in the CRL are solved. Claim that CMC issues already solved by previous filings that FDA hadn’t reviewed (unclear why?). Hence, believe PK/PD is the only outstanding issue.
Triggers in Q4/2021 – Q1/2022:
1. Q4: Phase I healthy volunteer study read-out (safety + neutralizing antibodies) for Coxsackie Virus B vaccine candidate “PRV-101” (clinicaltrials.gov/ct2/show/NCT04… )
1. Q4: Phase I healthy volunteer study read-out (safety + neutralizing antibodies) for Coxsackie Virus B vaccine candidate “PRV-101” (clinicaltrials.gov/ct2/show/NCT04… )
2. Q4: Press release after Type A meeting with FDA (after receipt of minutes ca. 30 days later) on PK modelling.
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