In the fourth quarter of 2022, these three FDA approval decisions are the most noteworthy

In the fourth quarter of 2022, three U.
S.
FDA decisions to approve are of much concern: teplizumab for type 1 diabetes, sparsentan for IgA nephropathy (IgAN), and adagrasib for non-small cell lung cancer (NSCLC).

Teplizumab: the first immunotherapy to relieve type 1 diabetes

Provention has submitted a Clinical Type 1 Diabetes Biologics Licensing Application (BLA)
to the FDA for the use of the investigational CD3-targeted monoclonal antibody teplizumab for delayed high-risk populations.
Teplizumab has been granted a breakthrough treatment designation and orphan drug designation
by the FDA.

The BLA is the result
of a phase II TN10 trial based on teplizumab.

Provention's rolling submission to teplizumab was completed in November 2020, and although it received a full reply letter (CRL)
from the FDA in July 2021 at an FDA Endocrine and Metabolic Drugs Advisory Committee panel meeting in May 2021, with 10 votes in favor and 7 "against" votes in favor.
In CRL, the FDA said single, low-dose pharmacokinetics/pharmacodynamic bridging studies of teplizumab in healthy volunteers failed to show pharmacokinetic comparability
.

Provention resubmitted the BLA in February 2022 to address the FDA's issue of pharmacokinetics comparability in CRL, agreeing to use a pharmacokinetic/pharmacodynamic model to adjust the 14-day dosing regimen for teplizumab, ensuring that the 90% confidence interval for the relevant pharmacokinetic parameters is in the target range of 80–125
%.
The FDA's decision to date the Prescription Drug User Charge Act (PDUFA) is November 17
.
If approved, teplizumab would be the first disease-relieving immunotherapy
to delay the onset of type 1 diabetes.

Sparsentan: The first non-immunosuppressive therapy for IgA nephropathy

The dual endothelin and angiotensin receptor antagonist sparsentan, developed by Travere Therapeutics, is currently under priority review by the FDA to accelerate approval for treatment
of IgAN.

The submission of the sparsentan New Drug Application (NDA) was supported by the Phase III PROTECT trial, which evaluated the safety and efficacy of
sparsentan in 404 IgAN patients.

The first-line results, published in August 2021, suggest that sparsentan is generally well tolerated, with an average reduction of 49.
8% from proteinuria from baseline, while the general-purpose angiotensin-II receptor blocker irbesartan is reduced by an average of 15.
1%.

The FDA decided that the PDUFA date is November 17
.
In Europe, sparsentan's conditional marketing authorization application was filed in August 2022 for the same indication.

If approved, sparsentan could be the first non-immunosuppressant
to show direct clinical benefit in proteinuria reduction in IgAN patients.

adagrasib: Amgen Kras inhibitors against formidable opponents

Adgrasib, a KRAS-G12C oral small molecule inhibitor developed by Mirati Therapeutics, is being evaluated as monotherapy, as well as in combination with other anti-cancer therapies for advanced KRASG12C-mutant solid tumors
.
In June 2021, the FDA granted adagrasib Breakthrough Therapy designation for the treatment of patients with NSCLC who
carry the KRASG12C mutation after previous systemic therapy.

Mirati filed an NDA with the FDA in the fourth quarter of 2021 to expedite approval of ADAGRASIB in the second-line NSCLC as part of
a real-time oncology review program.

The NDA is based on a Phase II Registered Authorized Cohort Study of KRYSTAL evaluating adagrasib in patients with advanced NSCLC who carried the KRASG12C mutation after prior immunotherapy and chemotherapy therapy
.
The findings suggest that adagrasib monotherapy is well tolerated and demonstrate support for inhibiting the clinical activity
of KRAS-G12C in patients with advanced/metastatic NSCLC.
Adagrasib's objective response rate and disease control rate are higher than those of its main competitor, Sotorasib (Lumakras; Amgen), the latter being the first FDA-approved KRAS-G12C small molecule inhibitor
in 2021.

The PDUFA date for adagrasib is December 14
.
If approved, adagrasib will provide an alternative in
KRASG12C-positive NSCLC applications.

Miyazato J.
Upcoming market catalysts in Q4 2022.
Nat Rev Drug Discov.
2022 Sep 13.
doi: 10.
1038/d41573-022-00155-6.
Epub ahead of print.
PMID: 36100674.