With the first three months of 2022 now in the rear-view mirror, the FDA has approved 10 new drugs. For these newly approved drugs on the market, this article summarizes information on the molecular structure, target and mechanism, and development company of each drug.

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New FDA Approved Drugs in Q1 2022
With the first three months of 2022 now in the rear-view mirror, the FDA has
approved 10 new drugs (Table 1).
Table 1: FDA Approved Drugs in Q1 2022
For these newly approved drugs on the market, this article summarizes
information on the molecular structure, target and mechanism, and
development company of each drug.
1. Quviviq (daridorexant，Jan 7, 2022)
Quviviq is a dual orexin receptor (OXR) antagonist developed by Idorsia for
the treatment of adult insomnia characterized by difficulties in sleep onset or
sleep maintenance. Quviviq treats insomnia by blocking the binding of the
neuropeptide orexin A/B to the receptors OX1R and OX2R (both GPCR family
receptors), which play an important role in the maintenance of wakefulness.
Prior to this, two orexin receptor antagonist drugs had been approved for
marketing, namely Mercer's Suvorexant (2014) and Eisai's Lemborexant
(2019), but both drugs did not perform as expected in the market.

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FDA approved orexin receptor antagonist drugs
2.Cibinqo (abrocitinib，Jan 14, 2022)
Abrocitinib is a JAK1 inhibitor developed by Pfizer for the treatment of adult
patients with refractory moderate-to-severe atopic dermatitis. Atopic dermatitis
is one of the most common inflammatory skin diseases, with a prevalence of
approximately 5-10% in the U.S. JAK is an intracellular protein kinase
responsible for the downstream transmission of signal stimuli received by
cytokine receptors or growth factor receptors on the cell membrane. First, JAK
phosphorylates and activates STAT molecules, and the phosphorylated STAT
translocates to the nucleus and regulates the transcriptional activation of target
genes. The market for JAK inhibitors is attractive (estimated to be over $10
billion and growing) given the diversity and commonness of disease processes
in which JAK is involved, and several JAK inhibitors are currently approved for
marketing.
JAK-STAT signaling pathway and inhibitors

In 2011, Incyte/Novartis' JAK1/2 inhibitor Ruxolitinib was approved for the
treatment of myelofibrosis. 2021, topical Ruxolitinib cream was approved for
the treatment of vitiligo and mild to moderate atopic dermatitis, and is the only
topical JAK inhibitor currently approved.


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In 2012, Pfizer's Tofacitinib was approved for the following indications: 1)
moderate to severe rheumatoid arthritis (RA); 2) psoriatic arthritis (PsA); 3)
moderate to severe ulcerative colitis ( Ulcerative Colitis (UC) and other
autoimmune diseases.

In 2017, Incyte/Lilly's JAK1/2 inhibitor Baricitinib was launched for the
treatment of moderately severe active rheumatoid arthritis with an inadequate
response to TNF antagonist therapy. Notably, Baricitinib was previously
granted Emergency Use Authorization (EUA) by the FDA for the treatment of
patients with COVID-19, and the new indication for Baricitinib on COVID-19
was discovered by AI pharmaceutical company BenevolentAI, sparking an
instant buzz.

In 2019, Abbvie's JAK1/2 inhibitor Upadacitinib was approved for the treatment
of moderately severe active rheumatoid arthritis.

2019 then saw the development of Fedratinib, a JAK2 inhibitor, finally pushed
to market by Celgene (now acquired by BMS) for the treatment of
myelofibrosis.

With the exception of BMS's Fedratinib, all other molecules have relatively
similar structures. Despite the attractive prospects of JAK inhibitors, studies in
recent years have found that JAK inhibitors increase the risk of severe heart
disease, cancer and blood clots in patients, and the FDA requires related
drugs to add black box warnings to their instructions.
JAK inhibitors currently approved by the FDA
3. Kimmtrak (tebentafusp-tebn，Jan 25, 2022)

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Tebentafusp-tebn, a bispecific protein developed by Immunocore, consists of
a soluble affinity-enhancing T cell receptor fused to an anti-CD3 effector that
confers T cell recognition of gp100-positive tumor cells (gp100 is a
glycoprotein highly expressed in melanocytes and melanoma) for the
treatment of HLA-A *02:01-positive unresectable or metastatic adult uveal
melanoma.
Mechanism of action of tebentafusp-tebn (Figure source: N Engl J Med)
Tebentafusp-tebn binds to uveal melanoma cells and activates polyclonal T
cells to release inflammatory cytokines and cytolytic proteins that induce
apoptosis in tumor cells. The median overall survival (mOS) of patients in the
Tebentafusp-tebn treatment group was 21.7 months, and the median
progression-free survival (mPFS) was 3.3 months.
4. Vabysmo (faricimab-svoa，Jan 28, 2022)
Faricimab-svoa is a bispecific antibody developed by Genentech for the
treatment of wet age-related macular degeneration (AMD) and diabetic
macular edema (DME). Faricimab-svoa blocks both angiopoietin-2 (Ang-2)
and vascular endothelial growth factor-A ( VEGF-A), which are thought to
contribute to vision loss by destabilizing blood vessels, possibly further
causing new leaky vessel formation and increasing inflammation. Preclinical
studies suggest that inhibition of these two pathways has potential
complementary benefits and may be effective in reducing vascular leakage
and inflammation in the macula.

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Structure and target site of Faricimab-svoa
5. Enjaymo (sutimlimab-jome，Feb 4, 2022)
Enjaymo, a lgG4 monoclonal antibody developed by Sanofi, is the
"first-in-class" treatment for Cold Agglutinin Disease (CAD) to reduce the need
for red blood cell transfusions due to hemolysis in adult patients with CAD.
CAD is a rare form of autoimmune hemolytic anemia in which a patient's red
blood cells are "tagged" with cold agglutinin, an antibody active at 3-4°C, which
causes red blood cell clumping and lysis resulting in anemia. The annual
incidence of CAD is about 1 in a million and most patients are 40-80 years old.
Enjaymo inhibits hemolysis in CAD patients by inhibiting the classical
complement pathway and specifically targeting the complement C1s protein (a
serine protease), which prevents the deposition of complement regulators on
the surface of red blood cells.
Mechanism and efficacy of Enjaymo for CAD (Figure source: Blood, 2019)

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6. Pyrukynd (mitapivat，Feb 17, 2022)
Pyrukynd is the "first-in-class" pyruvate kinase (PK) allosteric
activator developed by Agios for the treatment of hemolytic anemia caused by
PK deficiency. Pyrukynd acts by binding to PK tetramers and increasing PK
activity. There are four main PK isozymes in mammals, of which PK-R is
expressed in erythrocytes. PK-R deficiency results in accumulation of the
glycolytic intermediate 2,3-DPG, reduced ATP, shortened erythrocyte life span
and chronic hemolysis.
Mechanism of action of mitapivat
7. Vonjo (pacritinib，Feb 28, 2022)
Pacritinib is an oral JAK2 kinase-selective inhibitor developed by CTI
BioPharma for the treatment of adult patients with moderate or high-risk
primary or secondary (post-geniculocytosis or post-primary thrombocythemia)
myelofibrosis (MF). Pacritinib has activity against wild-type JAK2, mutant JAK2
(V617F) and FLT3, which contribute to the signaling of cytokines and growth
factors associated with hematopoiesis and immunity. Myelofibrosis is usually
associated with dysregulated JAK2 signaling. Pacritinib has higher inhibitory
activity against JAK2 compared to its fellow families JAK1, JAK3 and TYK2.
Pacritinib also exhibits inhibitory activity against other kinase families such as
CSF1R and IRAK1, but its clinical relevance has yet to be investigated.

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Mechanism of action of Pacritinib
8. Ztalmy (ganaxolone，Mar 18, 2022)
Ztalmy is a neuroactive steroidal gamma-aminobutyric acid (GABA) receptor
positive modulator developed by Marinus Pharma for the treatment of seizures
associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency, a severe
and rare genetic disorder characterized by early-onset, uncontrollable seizures
and severe neurodevelopmental disorders. The disease is caused by
mutations in the CDKL5 gene located on the X chromosome, which expresses
a protein important for normal brain development and function. Patients in the
Ztalmy-treated group had a 30.7% median reduction in 28-day major motor
seizure frequency, compared with a 6.9% reduction in the placebo group,
meeting the trial's primary endpoint.

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Classification of antiepileptic drugs (source: CNS Drugs, 2016)
More than 20 antiepileptic drugs have been marketed, most of which reduce
hyperexcitability by decreasing excitability or enhancing inhibitory
neurotransmission. The targets involved include GABA aminotransferase
(GABA-T), GABA transporter protein (GAT), synaptic vesicle protein 2A
(SV2A), GABA receptors, NMDA receptors, AMPA receptors, and the
voltage-gated potassium channel family (KCNQ, also known as the Kv7
family). Among them, Lacosamide, which was launched in 2008 (developed by
the Belgium pharmaceutical company UCB) for the treatment of seizure
epilepsy, is currently the top-selling antiepileptic drug (its sales in 2020 are
$1.883 billion).
9. Opdualag (nivolumab and relatlimab-rmbw，Mar 18, 2022)
Opdualag is a combination therapy of the BMS-developed PD-1 monoclonal
antibody Nivolumab and the LAG-3 monoclonal antibody relatlimab for the
treatment of patients aged 12 years and older with unresectable or metastatic
melanoma.

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Mechanism of action and therapeutic effect of Opdualag
The trial met its primary endpoint, progression-free survival (PFS), and
Opdualag more than doubled the median PFS when compared to nivolumab
monotherapy, 10.1 months (95% Confidence Interval [CI]: 6.4 to 15.7) versus
4.6 months. The Opdualag safety profile was similar to that previously reported
for nivolumab.1,2 No new safety events were identified with the combination
when compared to nivolumab monotherapy.1,2 Grade 3/4 drug-related
adverse events were 18.9% in the Opdualag arm compared to 9.7% in the
nivolumab arm.2 Drug-related adverse events leading to discontinuation were
14.6% in the Opdualag arm compared to 6.7% in the nivolumab arm.
LAG-3 is another popular immune checkpoint target in addition to CTLA-4 and
PD-1, and Relatlimab became the first LAG3-targeting antibody to be
approved for marketing.
10. Pluvicto (lutetium (177Lu) vipivotide tetraxetan，Mar 23, 2022)
Pluvicto is a "first-in-class" radiopharmaceutical developed by Novartis for the
treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC), a
prostate-specific membrane antigen (PSMA). Cancer (mCRPC). PSMA is a
tumor-associated antigen and a type II transmembrane protein that is highly

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expressed in several malignant prostate cancer cells. Pluvicto consists of
PSMA-617, a ligand that targets PSMA, coupled to the radioisotope lutetium
177Lu. Following intravenous administration of Pluvicto, PSMA-617 targets
and binds to the surface of PSMA-expressing tumor cells and enters the cells
during the receptor cycle, followed by the destruction of tumor cells by beta
particles released by decay of 177Lu. Patients treated with Pluvicto + standard
therapy had a 38% lower risk of death compared to patients treated with
standard therapy only.
Mechanism of action of Pluvicto. Image credit: ASCO 2021
Also, the FDA approved Locametz (Ga 68 gozetotide) as a radiological
reagent for PET imaging of PSMA-positive lesions (requires intravenous
injection). Previously, Ga 68 PSMA-11 (available in 2020) and Pylarify
(available in 2021) were both approved by the FDA as diagnostic reagents for
PET imaging of PSMA-positive lesions.
Huateng Pharma is a one-stop contract development and manufacturing
organization (CDMO) to supply researchers and companies with PEG
derivatives and products used across the pharmaceutical value chain
including intermediates, excipients, APIs, and reagents.
References:
.
Paul Nathan et al. "Overall Survival Benefit with Tebentafusp in Metastatic Uveal
Melanoma" Lancet 2021; 398: 803-816.
Novel Drug Approvals for 2022,
https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therape
utic-biological-products/novel-drug-approvals-2022

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.
https://rarediseases.org/rare-diseases/cold-agglutinin-disease/
.
Novel Drug Approvals for 2022,
https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therape
utic-biological-products/novel-drug-approvals-2022
.
https://ir.marinuspharma.com/news/news-details/2022/Marinus-Pharmaceuticals-Announ
ces-FDA-Approval-of-ZTALMY-ganaxolone-for-CDKL5-Deficiency-Disorder/default.aspx
.
https://www.who.int/en/news-room/fact-sheets/detail/epilepsy
.
Wolfgang Löscher et al. CNS Drugs, 2016, 30, 1055–1077.
.
https://news.bms.com/news/corporate-financial/2022/U.S.-Food-and-Drug-Administration
-Approves-First-LAG-3-Blocking-Antibody-Combination-Opdualag-nivolumab-and-relatlim
ab-rmbw-as-Treatment-for-Patients-with-Unresectable-or-Metastatic-Melanoma/default.a
spx
.