NEWER DRUGS APPROVED BY US-FDA: A PRECISE OUTLOOK(PART-1)PRESENTED BY:VISHNU.R.NAIR,4TH YEAR PHARM.D,NATIONAL COLLEGE OF PHARMACY(NCP)

GENERAL INTRODUCTION : ▪ INNOVATION drives PROGRESS▪ As far as INNOVATION regarding DEVELOPMENT of NEW DRUGS and

THERAPEUTIC BIOLOGICAL PRODUCTS is concerned , FDA’s CENTER FOR DRUG EVALUATION and RESEARCH (CDER) supports the pharmaceutical industry at every step of the process

▪ With its understanding of the science used to create new products, testing & manufacturing procedures, & the diseases and conditions that new products are designed to treat, FDA provides SCIENTIFIC & REGULATORY ADVICE needed to bring new therapies to market.

▪ Thus, I am going to present the NEWER DRUGS APPROVED BY US-FDA for the year 2016…………………………………………….

US-FDA APPROVED DRUGS IN 2016……………………………………

1. ELBASVIR+GRAZOPREVIR(ZEPATIER):

- ELBASVIR CLASS : NS5A Inhibitor (Non-structural protein 5A)

- GRAZOPREVIR CLASS : NS3-4A inhibitor (Serine protease)

- APPROVED ON : 28.01.2O16

- INDICATION : To treat patients with CHRONIC HEPATITIS C VIRUS (HCV)

- Effective against HCV GENOTYPES 1 & 4

- Used in adults

- MOA :

Elbasvir targets NS5A Prevents TRANSCRIPTION of HCV RNA Prevents VIRION ASSEMBLY

- GRAZOPREVIR Blocks NS3-4A protease prevents CLEAVAGE OF POLYPROTEINS involved in HCV REPLICATION

- ADRs : Headache, tiredness

- INTERACTION : Drug + RIBAVIRIN LOW RBC COUNT

- DOSE : 50 mg (ELBASVIR) + 100 mg (GRAZOPREVIR) ; OD ; For 12 weeks……………..

2. BRIVIACT (BRIVARACETAM) :- CLASS : RACETAM DERIVATIVE

- It’s a chemical analogue of LEVETIRACETAM

- INDICATION : To treat PARTIAL ONSET SEIZURES in patients aged 16 YEARS OR OLDER with EPILEPSY

- APPROVED ON : 18.02.2016

- MOA :

DRUG Binds to SYNAPTIC VESICLE GLYCOPROTEIN 2A (SV2A) Reduces EXCITATORY NEUROTRANSMITTER ACTIVITY , along with enhancing SYNAPTIC DEPRESSION, during high frequency discharges that occur during epilepsy

- Drug is 20 times more efficient than LEVETIRACETAM

- ADRs : Sleepiness, dizziness, co-ordination problems

- INTERACTIONS:

a. DRUG + CARBAMAZEPINE Increased EXPOSURE to ACTIVE METABOLITE OF CBZ (CBZ-EPOXIDE) Reduces its TOLERABILITY

b. DRUG + PHENYTOIN Increases PHENYTOIN levels

- Maximum dose : 100 mg BID/ day(PO)

- If TOLERABILITY is poor, dose can be tapered to 25 mg BID/day

- Initial dose : 50 mg BID/ day…………………….

3. OBLITOXAXIMAB (ANTHIM) :- APPROVED ON : 18/2/2016

- INDICATION : To TREAT INHALATIONAL ANTHRAX in COMBINATION with APPROPRIATE ANTIBACTERIAL DRUGS

- CLASS : MONOCLONAL ANTIBODY ANTHRAX ANTITOXIN

- Effective against BACILLUS ANTHRACIS

- MOA :

Drug binds to PROTECTIVE ANTIGEN(PA) COMPONENT of ANTHRAX TOXIN Neutralizes toxin prevents toxin’s entry into susceptible cells avoids its proliferation prevents TISSUE DAMAGE

- ADR : Hypersensitivity, anaphylaxis

- DOSE : 16 mg/kg i.v over 90 mins………………………

4. IXEKIZUMAB(TALTZ):- APPROVED ON : 22.03.2016

- INDICATION : To treat adults with MODERATE-SEVERE PLAQUE PSORIASIS

- CLASS : INTERLEUKIN-17 INHIBITOR; HUMANIZED MONOCLONAL ANTIBODY

- MOA :

a. IL-17 Cytokine, that stimulates PROLIFERATION & ACTIVATION of KERATINOCYTES in skin

b. Drug binds to IL-17 blocks its action

c. Action is similar to that of BRODALUMAB

- ADR : Increased rate of infections, injection site pain, oropharyngeal pain

- INTERACTION : Drug + WARFARIN Reduced WARFARIN levels

- DOSE : 160 mg s.c (in the form of two 80 mg injections) then reduce to 80 mg s.c

5. RESLIZUMAB(CINQAIR):- APPROVED ON : 23/3/2016

- CLASS : INTERLEUKIN-5 INHIBITOR; HUMANIZED MONOCLONAL ANTIBODY

- INDICATION: To treat SEVERE EOSINOPHILIC ASTHMA

- MOA:

a. IL-5 is a major cytokine, responsible for GROWTH, DIFFERENTIATION, RECRUITMENT, ACTIVATION & SURVIVAL of EOSINOPHILS Causes increased EOSINOPHIL levels increases AIRWAY INFLAMMATION

b. Drug binds to IL-5 Blocks it reduces EOSINOPHILIC LEVELS

- ADRs:

a. Oropharyngeal pain

b. Muscle fatigue

c. Neck pain

- DOSE : 3 mg/kg i.v every 4 weeks (infuse for 20-50 mins)……

6. DEFIBROTIDE SODIUM (DEFITELIO):- APPROVED ON : 30.03.2016

- INDICATION : To treat adults & children, who develop HEPATIC VENO-OCCLUSIVE DISEASE, with KIDNEY/ LUNG ABNORMALITIES , on receiving HEMATOPOEITIC STEM CELL TRANSPLANTATION (Stem cell transplant, from blood/ bone marrow)

- HEPATIC VENO-OCCLUSIVE DISEASE is also known as SOS (SINUSOIDAL OBSTRUCTION SYNDROME)

- Fatal form of hepatic injury, associated with ABDOMINAL PAIN, PORTAL HYPERTENSION, and INCREASE IN SERUM ENZYME LEVELS

- DRUG CLASS : ANTICOAGULANT

- Derived from COW LUNG/ PORCINE MUCOSA

- MOA:

Drug has 4 actions:

a. Drug increases levels of PGI2 Relaxes smooth muscles of blood vessels prevents PLATELET ADHERENCE

b. Drug increases levels of PGE2 Inhibits PLATELET AGGREGATION

c. Drug increases levels of PROSTACYCLIN Inhibits platelet aggregation

d. Drug increases function of t-PA

- ADRs:

a. Increased bleeding

b. Increased bruising tendency

c. Low B.P

- DOSE: 6.25 mg/kg i.v every 6 hours, infused for 2 hours………………..

7. VENETOCLAX(VENCLEXTA):- APPROVED ON: 11.04.2016

- INDICATION : For CHRONIC LYMPHOCYTIC LEUKEMIA patients, with a SPECIFIC CHROMOSOME ABNORMALITY

- CLASS : BCL-2 INHIBITOR

- MOA:

a. In patients with CHROMOSOME ‘17p’ DELETION(MUTATION) Increases levels of ANTI-APOPTOPIC B-CELL LYMPHOMA-2 (BCL-2) PROTEIN Causes CLL

b. Drugs blocks BCL-2 Causes PROGRAMMED CELL DEATH of CLL CELLS

- ADRs:

a. NEUTROPENIA

b. URTI

c. THROMBOCYTOPENIA

d. FERTILITY PROBLEMS IN MALES

e. TUMOR LYSIS SYNDROME (Metabolic abnormality, that occurs as a complication of CANCER CHEMOTHERAPY, where large amounts of TUMOR CELLS are KILLED OFF(LYSED), simultaneously by the treatment, causing release of their contents into BLOODSTREAM………………….)

- DOSE :

a. For 1st week : 20 mg PO OD

b. For 2nd week : 50 mg PO OD

c. For 3rd week : 100 mg PO OD

d. For 4th week : 200 mg PO OD

e. For 5th week : 400 mg PO OD…………………………..

8. PIMAVANSERIN(NUPLAZID):- APPROVED ON : 29.04.2016

- INDICATION : To treat HALLUCINATIONS & DELUSION associated with PSYCHOSIS, experienced by people with PARKINSON’S DISEASE

- CLASS : NON-DOPAMINERGIC ATYPICAL ANTI-PSYCHOTIC

- MOA:

a. Drug behaves as SELECTIVE INVERSE AGONIST & ANTAGONIST of 5-HT(2A) receptor treats HALLUCINATIONS and DELUSIONS associated with PD

- ADRs : PERIPHERAL EDEMA, CONSTIPATION

- DOSE : 34 mg PO every day…………………………

9. ATEZOLIZUMAB (TECENTRIQ):- APPROVED ON : 18.05.2016

- INDICATION : To treat UROTHELIAL CARCINOMA(Most common type of BLADDER CANCER)

- CLASS : IgG1 ISOTYPE HUMANIZED MONOCLONAL ANTIBODY

- MOA:

a. PD-L1(Programmed cell death ligand-1) highly expressed in some tumors reduces activation of cytotoxic T-cells(that can recognize and attack the cancer)

b. Drug BLOCKS INTERACTION of PD-L1 with PROGRAMMED CELL DEATH PROTEIN-1 (PD-1) & CD-80 Removes INHIBITORY EFFECT of PD-L1 Causes ANTI-TUMOR response…………………………….

- ADRs: Anorexia, URI

- DOSE : 1,200 mg i.v every 3 weeks (as 60 mins. Infusion)…………………………

10. DACLIZUMAB (ZINBRYTA):- CLASS : MONOCLONAL ANTIBODY

- APPROVED ON : 27.05.2016

- INDICATION : To treat MULTIPLE SCLEROSIS & its RELAPSE

- MOA:

a. Drug binds to IL-2 receptor SUBUNIT (CD-25) Blocks its activity

b. CD-25 Expressed in high levels in T-CELLS , which become abnormally activated in MULTIPLE SCLEROSIS

- MULTIPLE SCLEROSIS is a DEMYELINATING DISEASE, in which INSULATING COVERS of NEURONS in BRAIN & SPINAL CORD are DAMAGED Disrupts ability of parts of NERVOUS SYSTEM to inter-communicate results in PHYSICAL, MENTAL, PSYCHIATRIC PROBLEMS, along with DOUBLE VISION , BLINDNESS in 1 eye, etc

- ADRs:

a. NASOPHARYNGITIS (28%)

b. URTI (9-17%)

c. BRONCHITIS (7%)

- DOSE : 150 mg s.c ONCE MONTHLY………………………

11. OBETICHOLIC ACID (OCALIVA):- CLASS : FARNESOID ‘X’ RECEPTOR AGONIST; GASTROINTESTINAL AGENT

- APPROVED ON : 27.05.2016

- INDICATION : To treat CHRONIC LIVER DISEASE

- MOA:

a. FXR is a NUCLEAR RECEPTOR expressed in the LIVER, INTESTINE, KIDNEY & ADIPOSE TISSUE , that regulates TARGET GENES , responsible for the CONTROL OF BILE ACID SYNTHESIS , its TRANSPORT, LIPID METABOLISM & GLUCOSE HOMEOSTASIS

b. Drug increases FXR activation SUPPRESSES SYNTHESIS of BILE ACIDS in HEPATOCYTES

c. Drug also increases TRANSPORT OF BILE ACIDS out of HEPATOCYTES Reduces exposure of the HEPATOCYTES to BILE ACID……………………….

- ADRs:

a. PRURITUS (56-70%)

b. FATIGUE (19-25%)

c. REDUCED HDL-CHOLESTEROL (9-20%)

- DOSE : 5 mg PO every day……………………….

12. FLUCICLOVINE F-18 (AXUMIN):- APPROVED ON : 27.05.2016

- INDICATION : A new DIAGNOSTIC IMAGING AGENT, to detect RECURRENT PROSTATE CANCER

- CLASS : DIAGNOSTIC IMAGING AGENTS

- MOA:

a. SYNTHETIC AMINO ACID

b. It is labelled with RADIO-ISOTOPE F-18 for PET-IMAGING

c. Agent taken up by PROSTATE CANCER CELLS , using TRANSPORTERS (LAT-1, ASCT-2) Helps in determining the levels of the TRANSPORTERS, compared to surrounding normal tissues………………………

- ADRs : Injection site pain, erythema

- DOSE : 370 mBq i.v BOLUS…………………….

13. GALLIUM GA-68 DOTETATE (NETSPOT):- APPROVED ON : 01.06.2016

- INDICATION : DIAGNOSTIC IMAGING AGENT, to detect RARE NEUROENDOCRINE TUMORS

- MOA:

a. Agent binds with HIGH AFFINITY to Cells expressing SOMATOSTATIN RECEPTORS SUBTYPE 2 helps diagnose MALIGNANT CELLS(Which overexpress SSTR-2)

b. Allows PET imaging

- DOSE : 200 mBq , as i.v bolus injection………………………..

14. SOFOSBUVIR & VELPATASVIR (EPCLUSA):- APPROVED ON : 28.06.2016

- INDICATION : To treat all 6 MAJOR FORMS OF HCV

- CLASS : HCV POLYMERASE INHIBITORS; HCV-NS5A INHIBITORS

- MOA:

a. VELPATASVIR Blocks NS5A suppresses HCV replication

b. SOFOSBUVIR Blocks HCV NS5B RNA- dependent POLYMERASE suppresses VIRAL REPLICATION

- ADRs:

a. Anemia (26%)

b. Headache (22%)

c. Insomnia (11%)

- DOSE :

a. FOR PATIENTS , WITH CIRRHOSIS : DRUG (400 MG SOFOSBUVIR + 100 mg VELPATASVIR) + RIBAVIRIN, with FOOD, for 12 weeks

b. FOR PATIENTS, WITHOUT CIRRHOSIS : Same dose of drug(excluding RIBAVIRIN) , for 12 weeks……………….

15. LIFITEGRAST OPHTHALMIC SOLUTION (XLIDRA):- APPROVED ON : 11.07.2016

- INDICATION : To treat signs and symptoms of DRY EYE DISEASE

- DRY EYE DISEASE :

a. It’s a condition, that involves DEFICIENCY OF TEARS

b. Main symptom usually involves SCRATCHY / SANDY feeling , as if something is in the eye

c. Other symptoms include:

• Stinging or burning of eye

• Episodes of EXCESS TEARING, followed by periods of VERY DRY SENSATION

- DRUG CLASS : LFA-1 blocker; OPHTHALMIC AGENT

- MOA :

a. LFA-1 (Lymphocyte function associated antigen-1) is a cell surface protein found in leukocytes

b. LFA-1 Binds to ICAM-1(Intercellular adhesion molecule-1) caused adhesion of ICAM-1 to T-CELLS Causes T-CEL ACTIVATION Causes secretion of INFLAMMATORY CYTOKINES Migration to TARGET TISSUES Causes TISSUE DAMAGE

c. Drug blocks the INTERACTION of LFA-1 with ICAM-1 Prevents T-CELL ACTIVATION IMMUNOMODULATORY ACTION

- ADRs:

a. Instillation site reactions (5-25%)

b. Dysgeusia (5-25%)

c. Reduced visual acuity (5-25%)

- DOSE: Instill 1 gtt (guttae) every 12 hours, into each eye………………..

16. LIXISENATIDE (ADLYXIN):- APPROVED ON : 27.07.2016

- INDICATION : To improve BLOOD SUGAR LEVELS (GLYCEMIC CONTROL)

- CLASS : GLUCAGON-LIKE PEPTIDE-1 AGONIST; ANTI-DIABETIC

- MOA:

a. Drug agonized GLP-I receptor increases GLUCOSE-DEPENDENT INSULIN RELEASE

b. Drug also reduces GLUCAGON secretion

c. Drug slows GASTRIC EMPTYING

- ADRs:

a. NAUSEA (25%)

b. HYPOGLYCEMIA:

• If given with INSULIN +/- SULFONYLUREA 47.2%

• If given with INSULIN + /-METFORMIN 28.3%

• If given with INSULIN GLARGINE +/- METFORMIN +/- THIAZOLIDINEDIONE (22%)

• If given with SULFONYLUREA +/- METFORMIN 14.5%

c. Constipation (2%)

- DOSE :

a. STARTING DOSE : 10 mcg s.c every day for first 14 days increase dose to 20 mg s.c every day(from the FIFTEENTH DAY)……………………………

17. ETEPLIRSEN (EXONDYS 51):- APPROVED ON : 19.09.2016

- INDICATION : To treat patients with DUCHENNE MUSCLE DYSTROPHY

- DUCHENNE MUSCULAR DYSTROPHY(DMD):

a. Best known form of MUSCLE DYSTROPHY

b. Occurs due to a MUTATION in a gene on the X-CHROMOSOME Prevents production of DYSTROPHIN (A normal protein in muscle)

c. DMD affects boys, and very rarely , girls

d. Typically appears at age 2

e. Symptoms include WEAKNESS IN PELVIS & UPPER LIMBS, CLUMSINESS, FREQUENT FALLING, GENERALIZED WEAKNESS, etc

f. Some patients may have MILD MENTAL RETARDATION

g. Most patients with DMD die in their early twenties, due to MUSCLE-RELATED BREATHING & HEART PROBLEMS

h. As DMD progresses a wheelchair may be needed

i. There is no cure for DMD

j. Current treatment is directed towards symptoms, like assisting with MOBILITY, PREVENTING SCOLIOSIS, and providing PULMONARY THERAPY(RESPIRATORY TOILET)

- DRUG CLASS : MORPHOLINO ANTISENSE OLIGOMERS; NEUROLOGICAL AGENTS

- MOA:

a. Drug binds to EXON-51 of DYSTROPHIN PRE- MRNA Causes EXON SKIPPING during MRNA PROCESSING Allows production of INTERNALLY TRUNCATED DYSTROPHIN PROTEIN

b. EXON SKIPPING : Form of RNA SPLICING, that causes cells to SKIP OVER FAULTY SECTIONS of GENETIC CODE, leads to a TRUNCATED, FUNCTIONAL PROTEIN, despite the GENETIC MUTATION

c. TRUNCATED PROTEIN: A protein, SHORTENED BY MUTATION, which specifically induces PREMATURE TERMINATION OF MESSENGER RNA TRANSLATION

- ADRs:

a. BALANCE DISORDER (38%)

b. CONTACT DERMATITIS (25%)

c. Elevated temperature(on days of infusion)

- DOSE : 30 mg/kg i.v once weekly……………………………………….

18. OLARATUMAB (LARTRUVO):- APPROVED ON : 19.10.2016

- INDICATION : To treat adults with certain types of SOFT TISSUE SARCOMA

- CLASS : MONOCLONAL ANTIBODY; ANTINEOPLASTICS

- MOA:

a. PLATELET DERIVED GROWTH FACTOR RECEPTOR-ALPHA(PDGFR-ALPHA) is a TYROSINE KINASE RECEPTOR expressed in MESENCHYMAL CELLS

b. PDGFR- ALPHA signaling plays role in CELL GROWTH, CHEMOTAXIS, & MESENCHYMAL STEM CELL DIFFERENTIATION

c. PDGFR-ALPHA has been detected on some tumor cells (including sarcomas) here, SIGNALLING contributes to CANCER CELL PROLIFERTION, METASTASIS, and MAINTENANCE of TUMOR MICROENVIRONMENT

d. Drug is a HUMAN IgG1 monoclonal antibody binds SPECIFICALLY TO PDGFR-ALPHA Prevents its binding of the RECEPTOR by PDGF-AA, BB , CC ligands prevents its activation prevents its signaling pathways

- ADRs:

a. LYMPHOPENIA (77%)

b. NAUSEA (73%)

c. ALOPECIA (52%)

d. NEUTROPENIA (65%)

e. MUSCULOSKELETAL PAIN (64%)

- DOSE :

15 mg/kg i.v , infused over 1 hour on DAYS ‘1’ & ‘8’ of each 21 day cycle……………………….

19. BEZLOTOXUMAB (ZINPLAVA):- APPROVED ON : 21.10.2016

- INDICATION : To reduce the incidence of CLOSTRIDIUM DIFFICILE infection, in patients, aged 18 years or older

- CLASS : MONOCLONAL ANTIBODY

- MOA:

a. Human monoclonal antibody

b. Drug binds to CLOSTRIDIUM DIFFICILE TOXIN ‘B’ Neutralizes its effects

c. Drug does not bind to toxin ‘A’

- ADRs:

a. HEART FAILURE (12.7%)

b. PYREXIA (5%)

- DOSE:

a. Indicated to reduce RECURRENCE OF CDI in adults, who are receiving antibacterial drug treatment for CDI, & are at high risk of RECURRENCE

b. 10 mg/kg I.V over 1 hour, as a single dose………………………

BIBLIOGRAPHY/ REFERENCE :▪ www.fda.gov/Drugs/DevelopmentApproval Process/DrugInnovation

/ucm483775.htm▪ www.emedicine.net▪ www.healthline.com▪ www.drugs.com▪ www.drugbank.com▪ www.MEDGENERA.com

THANK YOU !!!