New Medicines

Type 1 diabetes mellitus - prevention in very high-risk pts


New molecular entity
Provention Bio
Provention Bio

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Not recommended for approval (Negative approval)
Sep 21When the FDA issued a CRL they expressed concerns about how small the study was and also requested further safety details as part of any resubmission. The biotech expects to be able to offer the drug product data later this quarter from a sub-study underway in the ongoing phase 3 PROTECT trial in newly diagnosed Type 1 diabetes patients. Provention is working hard towards a request and submission [32].
Jul 21The US FDA issued Provention Bio a Complete Response Letter (CRL) for its for teplizumab. They have asked the company to "establish PK comparability between intended commercial product and the clinical trial product or provide other data that adequately justify why PK comparability is not necessary.” The company are collecting additional PK/PD data from the ongoing PIII PROTECT trial. Once that is reviewed, Provention will decide if they can submit the data to the FDA with other relevant data.[31]
May 21The Endocrinologic and Metabolic Drugs Advisory Committee voted 10-7 that the benefits of teplizumab outweighed its risks [20].
May 21Briefing documents from the advisory panel now show that the committee will not review the comparability issue, but instead stick to safety and efficacy question [29].
Apr 21A delay to FDA approval of teplizumab is anticipated due to the FDA requesting further information. The advisory committee is still due to meet in May but final approval may be delayed [28].
Jan 21US FDA grants priority review to BLA [28].
Nov 20Rolling submission of data to support filing to US FDA is now complete. [27]
Apr 20Provention Bio initiate rolling submission of BLA to FDA for teplizumab for delay or prevention of clinical T1D in at-risk individuals [26].
May 18Provention Bio acquires all rights to further development of teplizumab [25].
Jan 18PII NCT01030861 trial ongoing in US, Canada and Germany [18].
Mar 16Remains in PII development for prevention of type 1 diabetes [16].
May 15Teplizumab for the treatment of T1DM is no longer listed on the MacroGenics pipeline and appears to have been discontinued. [15]
Mar 15Still PII for at-risk pts [14].
May 13PII for at-risk pts [10].
Oct 10Lilly terminates its collaboration agreement with MacroGenics for development of teplizumab [9].
Dec 09Regulatory filings planned for 2012 [4].
Aug 09Orphan drug status in US [3].


CD3 antagonist. Proposed to inhibit autoimmune destruction of insulin-producing pancreatic beta cells in patients with type 1 diabetes
Currently, 3.8 million people in the UK are diagnosed with diabetes. Up to 1 million people have type 2 diabetes that is yet to be diagnosed, so the total is estimated to be 4.7 million people at present. This represents 7% of the UK population (1 in every 15 people) having diabetes (diagnosed and undiagnosed). 10% have type 1 diabetes [21]. Incidence is increasing by about 4% each year, particularly in children under five, with a 5% increase each year in this age group [22].
Type 1 diabetes mellitus - prevention in very high-risk pts

Trial or other data

Nov 19Estimated primary completion date of PIII NCT03875729 is May 22 [24].
Jun 19PII (´AT RISK´) study results found teplizumab significantly delayed the onset and diagnosis of clinical T1 Diabetes compared to placebo, by a median of 2 years in children and adults considered to be at high risk. Median time to clinical diagnosis of T1D for teplizumab was 48 months compared with placebo (24 months, p=0.006). During the trial, 72% in the placebo group developed clinical diabetes compared to 43% in those treated with teplizumab [23].
Apr 19First patient dosed in PIII PROTECT trial (NCT03875729) of PRV-031 (teplizumab) in patients with recent onset type 1 diabetes (T1D) [22].
Jan 19Estimated primary completion date of NCT01030861 is now Jan 19 [19].
Jan 18Estimated primary completion date of NCT01030861 is Jan 21 [18].
Feb 16PII At-Risk study (NCT01030861) is still recruiting pts. Collection of primary outcome data are expected to complete Jan 21 [17].
Aug 13Preliminary results from the PII AbATE study published online before print in Diabetes July 8, 2013, doi: 10.2337/db13-0345. In this open-label PII study, 52 new-onset T1DM patients (ages 8 to 30 years old) were randomized to teplizumab (two 14-day courses one year apart) or placebo. In the ITT analysis of the primary endpoint, teplizumab-treated patients had a reduced decline in C-peptide at 2 years (-0.28 vs. 0.46nmol/L; p=0.002), a 75% improvement. A post-hoc analysis found that metabolic (HbA1c and insulin use) and immunologic features distinguished responders to teplizumab from non-responders. The most common AEs were rash, transient upper respiratory infections, headache and nausea. The results suggest teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D [13].
May 13A PII study evaluating teplizumab is currently enrolling pts at risk of developing T1D [10].
Mar 13PROTEGE ENCORE trial was completed in July 2012, in the US, Mexico, the EU, Ukraine, Israel and India [8].
Jan 13The PII At-Risk (NCT01030861) study is expected to complete collection of primary outcome data. The At-Risk study is sponsored by TrialNet & the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). It is designed to evaluate whether teplizumab can help to prevent or delay the onset of T1D in relatives determined to be at very high risk for developing the disease. It will enrol 170 US or Canadian pts & the primary outcome is diabetes onset as defined by the American Diabetes Association (ADA) based on glucose testing or the presence of unequivocal hyperglycemia with acute metabolic decompensation [11,12].
Jun 11Results from the PIII Protégé published online in the Lancet (June 28, 2011; DOI:10.1016/S0140-6736(11)60931-8). Protege is a two-year RCT with 513 patients aged 8–35, recently diagnosed with T1DM. Participants were allocated 2:1:1:1 to receive daily infusions of teplizumab (full dose for 14 days, 1/3 dose for 14 days, or full dose for 6 days) or placebo at baseline and at 6 months. The primary composite primary endpoint, % of patients with insulin use <0.5 U/kg/day and HbA1C <6.5% at 1 year, was not achieved. An exploratory, post-hoc analyses suggest that teplizumab in a 14-day full dose regimen, preserves C-peptide and increases the % of patients requiring very low doses of insulin (< 0.25 U/kg/day) with HbA1C < 7% vs placebo. Protege is ongoing and will complete the 2-year follow-up in 2011. Rash was the most common adverse event reported more frequently with teplizumab than placebo. Mild cytokine release syndrome was infrequent but greater in treatment groups. There were transient increases in some liver function test results and decreases in white cells but no increase in overall infections [6]
Oct 10PROTEGE PIII trial – one year safety & efficacy data showed that the primary endpoint (composite of pts total daily insulin usage and HbA1c level at 12 months) was not met. No unanticipated safety issued identified. Safety monitoring to continue until all administration of teplizumab completed. Further enrollment suspended, as is dosing in 2 other trials (Protege Encore Trial, P3 and SUBCUE trial, PIb). [5]
Jun 09PROTEGE ENCORE (NCT00920582): a PIII global trial in patients with recent-onset type 1 diabetes started in June 2009 and is designed to measure patient-reported outcomes in addition to safety and efficacy information [3].
Jun 09enrollment in PROTEGE trial complete. The main composite outcome for PROTEGE includes the patient´s total daily insulin usage and his/her HbA1c levels at 12 months. Secondary outcomes are assessed at 24 months. Longer term safety and efficacy data from patients who complete the PROTEGE study are being gathered in a separate Phase III trial called the PROTEGE Extension trial. (2)
Nov 08Pivotal multinational Phase II/III clinical trial of teplizumab (the PROTEGE trial) assessing the ability of teplizumab to inhibit the autoimmune destruction of insulin-producing pancreatic beta cells in children and adults with recent onset type 1 diabetes (1)