2021 First-in-Class Small Molecule Drugs

together with Dr. Naveed Yasin, Dr. Jennifer Huen, Dr. Vinicius Texeira, and Dr. Adrian Parodi

In 2021 there were:

  • 50 novel drugs approved by the FDA
  • 27 that CDER considers first-in-class (FIC)
  • 16 first-in-class small molecules (according to CDER)

These drugs are the first in their therapeutic class to have a particular mechanism of action. While many have novel drug targets and new mechanisms of action (e.g. KRAS inhibitor), some leverage established targets in a new setting (e.g. CDK4/6 to prevent chemotherapy-induced myelosuppression).

Oncology
sotorasib
trilaciclib
pafolacianine
Genetic Conditions
beizutifan 
fosdenopterin
odevixibat
vosotiride
Infectious Diseases
maribavir
ibrexafungerp
Endrocinology
finerenone
Immunology
voclosprorin
avacopan 
belumosudil
Other
difelikefalin
vericiguat
pegcetacoplan

The 16 first-in-class small molecules of 2021 according to CDER are:

  • Brexafemme (ibrexafungerp)
  • Cosela (trilaciclib)
  • Nulibry (fosdenopterin)
  • Empaveli (pegcetacoplan)
  • Lumakras (sotorasib)
  • Kerendia (finerenone)
  • Rezurock (belumosudil)
  • Bylvay (odevixibat)
  • Welireg (belzutifan)
  • Tavenos (avacopan)
  • Voxzogo (vosoritide)
  • Livtencity (maribavir)
  • Cytalux (pafolacianine)
  • Lupkynis (voclosporin)
  • Korsuva (difelikefalin)
  • Verquvo (vericiguat)

How can a CDK4/6 inhibitor be considered first-in-class, you might ask? Read on…

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CoselaTM (trilaciclib):

CoselaTM (trilaciclib) is an injectable CDK4/6 kinase inhibitor approved to be given prior to chemotherapy to decrease the incidence of chemotherapy-induced myelosuppression in ES-SCLC patients. The drug significantly reduces the duration and severity of neutropenia as well as the need for RBC transfusions and G-CSF administration. Though there are several approved CDK4/6 inhibitors for cancer treatment, this is the first CDK4/6 inhibitor for the prevention of cytopenias rather than inhibiting tumors.

It exerts its protective effect for hematopoietic stem and progenitor cells (HSPCs) by inhibiting the CDK4/6 pathway, preventing the healthy stem cells from proceeding into cell cycle stages where they are susceptible to chemotherapy. This is a significantly different purpose from other CDK4/6 inhibitors such as palbociclib, which are intended to attack tumor cells.

It is the first and only multilineage myeloprotection therapy. Previously, there were only reactive treatments for chemotherapy-related myelosuppression targeting individual cell lines (neutrophils, red blood cells, platelets etc.). For example, pegfilgrastim is a bone marrow stimulant given to help restore white blood cell levels after chemotherapy. Instead, this drug provides a proactive, preventative approach for preserving multiple cell lines.

Approximately 90% of patients with ES-SCLC receive one of the chemo regimens evaluated in the trilaciclib trials. G1 Therapeutics had received Breakthrough Therapy Designation in 2019 for positive data from trilaciclib’s phase II trials.

This novel use of a CDK4/6 inhibitor in SCLC is justified for the 93% of patients who have Retinoblastoma (RB) inactivation, as their cancers replicate independently of CDK4/6. But it’s been noted that RB loss-of-function is not universal for SCLC, in which case CDK4/6 inhibitors would likely antagonize the effects of the chemotherapy.

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