Second part: on #ProventionBio #Provention $PRVB #anti-CD3 monoclonal antibody #teplizumab under #FDA consideration for the “delay of clinical #Type1Diabetes #T1D in at-risk individuals”.
Upcoming questions cont’d:
Upcoming questions cont’d:
(4) If risk/benefit is acceptable, which target population is deemed suitable by the FDA? There were proponents of 3 options in EMDAC: (a) Stage 1 + 2, (b) Stage 2, or (c) Stage 2 + family Hx of T1D (= inclusion criteria of TN-10).
(a) is unlikely, I think, my vote is with (b). With regards to age, I think >8 years (as in TN-10) will be a requirement, given the SEs associated with teplizumab.
(5) The next steps in Europe: PRVB have PRIME designation by EMA and Innovation Passport designation by the UK’s MHRA. PRVB have said they will communicate on the way forward after PK/PD results and interactions with FDA.
*More on Teplizumab*
As mentioned, teplizumab is a humanised Fc-mutated anti-CD3 mAb that turns autoreactive T-cells into exhausted T-cells and is said to do other “resetting the tolerigenic mechanism” magic.
(picture from creativebiolabs)
As mentioned, teplizumab is a humanised Fc-mutated anti-CD3 mAb that turns autoreactive T-cells into exhausted T-cells and is said to do other “resetting the tolerigenic mechanism” magic.
(picture from creativebiolabs)
Invented at Columbia; in 2007, Lilly and Macrogenics partnered to develop teplizumab for the Tx of autoimmune diseases. In 2010, Lilly pulled out after failing the co-primary 12-month EP of lowered insulin dose + HbA1c in the phase 3 Protégé trial in recent-onset T1D.
In 2018, PRVB in-licensed teplizumab from Macrogenics just before their $64M IPO. Macrogenics are due a bunch of milestone payments around approval for a 1st ($42.5M) and 2nd ($22.5M) indication, plus $225M sale-tied, if I get these numbers right.
Completed/terminated trials:
TN-10 study (delay in Stage 2 at-risk individuals) + 5 phase 2/3 trials in recent-onset T1D
(picture from FDA EMDAC slides )
TN-10 study (delay in Stage 2 at-risk individuals) + 5 phase 2/3 trials in recent-onset T1D
(picture from FDA EMDAC slides )
On-going trials:
- TN-10 extension study (single-arm OL, TN-10 completers with new T1D)
- PROTECT trial (phase 3 RCT in <6wks-diagnosed T1D, primary EP is C-peptide preservation), including its long-term safety extension study
- TN-10 extension study (single-arm OL, TN-10 completers with new T1D)
- PROTECT trial (phase 3 RCT in <6wks-diagnosed T1D, primary EP is C-peptide preservation), including its long-term safety extension study
The 14-day IV treatment outpatient treatment course with Teplizumab used in TN-10 (and hence, the BLA) is not for the faint-hearted. About 10% discontinue the 14-day course due to AEs and there’s also a small procedure-related risk
(a 25yo F in Protégé had a subclavian VT due to her PICC placement). Apart from lymphocytopenia in almost 80%, the 14-day treatment can be associated with e.g. rash (5/10), raised liver enzymes (3/10), pruritus (2/10), thrombocytopenia (1/10), pyrexia (2/10), and
a low risk of cytokine release syndrome (CRS), an acute inflammatory reaction experienced by some patients receiving Tx with immune effector cells and T-cell engagers.
Fortunately, most of these AEs are transient and resolve after the 14-day treatment course without long-term consequences.
With regards to notable longer-term AEs, the FDA (in preparation for EMDAC) noted in the safety dataset of about 1000 patients (~770 got teplizumab) a surprisingly higher rate of DKA in teplizumab vs. placebo.
(There is some suggestion of this partially being due to potential unblinding of investigators and due to the recruitment of patients with very poorly controlled HbA1c at baseline in a South Asian country in one of the older trials)
In the EMDAC discussion, a need for long-term safety data was further emphasized due to the unknown risks of malignancy (too short follow-up in the trials), which is always a concern with immunomodulatory drugs.
PRVB is partially addressing this with the PROTECT extension study (NCT04598893) with a total of 5 years’ follow-up for AEs.
Regarding risk/benefit: remember that PRVB are seeking approval for Tx of children and young adults who are still healthy but at high risk of developing T1D (85% risk of T1D by 18yrs with ≥ 2 islet antibodies)
with the promise of potentially delaying the onset of T1D by at least 2 years (if we trust the small TN-10 study).
To wrap up the discussion during the EMDAC meeting: It’s not quite correct, by my overarching impression was that most attendees/panellists with a very personal connection to T1D (self/close family) really pushed for recommending approval,
whilst everyone else thought the evidence from TN-10 just didn’t suffice (the C-peptide preserving effects in the old T1D trials were largely ignored as different endpoint and population than target indication).
Everyone agreed on the huge unmet need (no approved disease-modifying Tx exists in T1D) and that more safety & efficacy data was needed (disagreement though if pre/post-approval).
Delaying T1D onset by 2 yrs doesn’t sound much but can be very, very important, esp. for children: more time to reach milestones without disease burden (school, exams, sports), avoid DKA risk, delay insulin Tx (burdensome + risk of iatrogenic hypos),
lower lifetime burden of T1D with better QoL and lower micro/macrovascular risks, older age at diagnosis being associated with lower HbA1c & better cognitive functioning etc.
But against all that, one needs to weigh the risks and safety concerns of treating healthy at-risk persons with IV Teplizumab, and about 1 in 10 will have to discontinue Tx due to AEs.
(two more tweets in 3rt thread)
(two more tweets in 3rt thread)
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