A quick look!

*For medical professionals only, what is the target of action of the new drug? Why was it approved? What are the characteristics? The "New Drugs Are Coming" column has been updated! Recently, a variety of new drugs and new therapies in the field of neurology have been approved by the FDA for clinical treatment, which is gratifying! This article briefly introduces three of them
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Two injections a year, powerful lipid-lowering, siRNA drug Inclisiran has been approved for the treatment of hyperlipidemia.
According to a large amount of evidence-based medical evidence, reducing LDL-C levels is the primary goal of lipid-lowering treatment for ischemic stroke patients.
The most commonly used treatment drugs
.

However, statin lipid-lowering drugs have many limitations: a.
6% effect of statins (the further reduction of LDL-C is only about 6% when the dose of any statin is doubled); b.
High-dose statins will increase adverse drug reactions; c.
Partially Patients with statin intolerance, mainly manifested as elevated transaminases, elevated muscle enzymes, myalgia, fatigue and so on
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PCSK9 (preprotein convertase subtilisin/kexin9) is a serine protease encoded by the PCSK9 gene, mainly produced by the liver, and is considered to be a new target for lowering LDL-C
.

Low-density lipoprotein receptor (LDLR) is the main receptor for clearing LDL in plasma, and PCSK9 can mediate the degradation of LDLR in the liver, reduce the number of LDLR, and reduce the clearance of LDL-C in the liver [1]
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Inhibition of PCSK9 expression increases LDLR and decreases serum concentrations of LDL-C
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At present, two PCSK9 inhibitors (eloyumab and alizumab) have been approved in China for the treatment of familial hypercholesterolemia in adults
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Ilocumumab is a human monoclonal IgG2 against human PCSK9, and alicumab is a fully human cloned monoclonal antibody against PCSK9, IgG1, both of which can bind to PCSK9 and inhibit the binding of PCSK9 to LDLR, thereby Block PCSK9-mediated degradation of LDLR, allowing LDLR to recycle to the surface of hepatocytes
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In addition to their lipid-lowering advantages, these two drugs are long-acting blood lipid-lowering drugs, which can be injected once every 2 weeks or once a month, which greatly improves the convenience of patients' medication
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In recent years, RNA interference (RNAi) technology has become more and more mature, and small interfering RNA (siRNA) drugs developed based on this technology are also gradually used in clinical practice.
siRNA drugs can target and bind to mRNA, by inhibiting mRNA translation or mRNA degradation.
Knock out (silence) the downstream protein expression of the disease-causing gene, so as to achieve the purpose of treating the disease
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Compared with traditional small molecules and antibodies that act at the protein level, the advantages of small nucleic acid drugs are that they can intervene in the expression of pathogenic genes at the genetic level, silence pathogenic genes, and have rich targets, small molecular weight, and specificity.
It has the characteristics of strong sex and long half-life
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On December 22, 2021, Novartis announced that the U.
S.
FDA has approved inclisiran, which is the first and currently the only siRNA drug for LDL-C lowering in the world
.

The drug's approval was based on the results of the ORION-9, ORION-10, and ORION-11 Phase III clinical trials, which enrolled 3,457 patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia Hyperemia (HeFH) patients who received maximal tolerated doses of statin therapy without significant reductions in LDL-C levels
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Figure 1 ORION-9 results show that Inclisiran significantly reduces LDL-C and PCSK9 levels
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ORION-9 is a double-blind, randomized, placebo-controlled Phase III clinical study involving 482 adult patients with HeFH
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The results showed that, compared with the placebo group, Inclisiran could significantly reduce LDL-C levels and PCSK9 levels in HeFH patients (Figure 1).
The results of the study have been published online in the journal N Engl J Med [2]
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Figure 2 ORION-10 and ORION-11 results show that Inclisiran significantly reduces LDL-C levels
.

The ORION-10 trial was conducted in the United States, while the ORION-11 trial was conducted in Europe and South Africa
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These two clinical trials mainly included patients with ASCVD who received lipid-lowering therapy but still had LDL-C higher than 70 mg/dL
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The results showed that at month 17 in the trial, inclisiran effectively and consistently reduced LDL-C by up to 52% compared to placebo (Figure 2), and the incidence of adverse reactions was approximately the same in the inclisiran-treated and placebo groups , the findings were also published in the journal N Engl J Med [3]
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The FDA recommends that inclisiran be administered by subcutaneous injection, administered at 3-month intervals after the first dose, every 6 months thereafter, and only twice a year for the maintenance period
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Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, the main clinical manifestations are memory dysfunction, abnormal behavior and daily life Decreased ability to live
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In recent years, transdermal administration has become the third largest route of administration after oral administration and injection, and has formed a brand-new medication trend
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It is reported that the main advantages of transdermal administration are: a.
Drug absorption is not affected by factors such as pH, food, and transit time in the digestive tract; b.
Avoid liver first-pass effect; c.
Absorption is too fast to produce adverse reactions caused by high blood drug concentration; d.
Continuously control the administration speed and flexibly administer it, which can provide a long-term administration method, and the administration can also be stopped at any time
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On March 14, 2022, Corium announced that the FDA approved Adlarity for the treatment of patients with mild, moderate or severe AD.

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Adlarity is the first approved prescription drug to use Corium's proprietary CORPLEX transdermal technology and is currently the first donepezil drug delivered via a patch, which avoids the adverse gastrointestinal side effects of oral donepezil
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The FDA approved the Adlarity patch to be administered at 5mg/day or 10mg/day, which can be applied continuously for 7 days and has consistent adhesion, reducing the inconvenience of daily oral administration
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Heavy! GABA receptor allosteric modulator ganaxolone approved for the treatment of CDD-related seizures CDKL5 Deficiency Disorder (CDD) is an X-linked dominant genetic disorder caused by a rare neurological disorder caused by mutations in the CDKL5 gene developmental disease
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Patients mainly present with early-onset epilepsy, cognitive, motor, language and visual dysfunction caused by neurological developmental delay
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The incidence of CDKL5 deficiency is about 1:40,000 to 1:60,000 in neonates, mostly female
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On March 18, 2022, Marinus Pharmaceuticals announced that the FDA has approved its new drug ganaxolone oral suspension for the treatment of CDD-related seizures in people two years of age and older
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Before this drug, there was no approved treatment specifically for CDD
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Gamma-aminobutyric acid A (GABAA) is the most important inhibitory neurotransmitter receptor in the central nervous system, and ganaxolone is a positive allosteric modulator of GABAA receptors, which can bind to GABAA receptors and enhance their activity, thereby Mediates sedative, anxiolytic, anticonvulsant, and antiepileptic effects
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The approval of Ganaxolone is based on the results of the Phase III clinical trial, the Marigold study
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The results showed that Ganaxolone significantly reduced the frequency of motor seizures compared with the placebo group (30.
7% in the Ganaxolone group and 6.
9% in the placebo group, P=0.
0036) (Figure 3)
.

In terms of safety, the most common adverse events were somnolence, fever, salivary gland hypersecretion and seasonal allergies [4]
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Figure 3: Ganaxolone can significantly reduce motor seizure frequency Reference source: [1]Reiss,AB,et al.
,PCSK9 in cholesterol metabolism:from bench to bedside.
Clin Sci(Lond),2018.
132(11):p.
1135 -1153.
[2]Ray,KK,et al.
,Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.
N Engl J Med,2020.
382(16):p.
1507-1519.
[3]Raal,FJ, et al.
,Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.
N Engl J Med,2020.
382(16):p.
1520-1530.
[4]CDD MARIGOLD TOPLINE DATA from https://s25.
q4cdn.
com/443656056/files /presentation/2022/03/Corporate-Deck-March-FINAL-no-appendix-BK-1.
pdf