FDA APPROVALS

New FDA Drug Approvals in 2018 by Indication - Part 2

December 21, 2018

INFECTIOUS DISEASES

SYMFI LO (efavirenz; lamivudine; tenofovir disoproxil fumarate)

Manufacturer: Mylan Pharmaceuticals

Approval Date: February 5, 2018

FDA approved the single-tablet regimen Symfi Lo, new antiretroviral (ARV) combination tablet, as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg.

The tablet contains only 400 milligrams of efavirenz, which is associated with numerous troublesome side effects, compared with the typical 600 mg used in other approved combination tablets.

A recent study conducted among first-timers to HIV treatment found that treating the virus with tenofovir and emtricitabine was comparably effective whether participants also received 400 mg or 600 mg of efavirenz.

 

BIKTARVY (bictegravir sodium; emtricitabine; tenofovir alafenamide fumarate)

Manufacturer: Gilead Sciences Inc

Approval Date: February 7, 2018

FDA approved Biktarvy, a once-daily single tablet regimen, as a complete regimen for the treatment of HIV-1 infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Biktarvy.

The approval of Biktarvy is supported by data from four ongoing phase 3 studies: Studies 1489 and 1490 in treatment-naïve HIV-1 infected adults, and Studies 1844 and 1878 in virologically suppressed adults. 

Biktarvy met its primary objective of non-inferiority at 48 weeks across all four studies. Through 48 weeks, no participants in any of the four studies failed Biktarvy with treatment-emergent virologic resistance, no patients discontinued Biktarvy due to renal adverse events, and there were no cases of proximal renal tubulopathy or Fanconi syndrome.

The most common adverse reactions in patients taking Biktarvy were diarrhea, nausea and headache. Biktarvy has a Boxed Warning in its product label regarding the risk of post treatment acute exacerbation of hepatitis B.

No dosage adjustment of Biktarvy is required in patients with estimated creatinine clearance greater than or equal to 30 mL per minute. Biktarvy does not require testing for HLA-B*5701, has no food intake requirements, and has no baseline viral load or CD4 count restrictions. Prior to or when initiating treatment with Biktarvy, healthcare providers should test for hepatitis B virus (HBV) infection and renal function and monitor renal function as clinically appropriate during therapy.

 

CIMDUO (lamivudine; tenofovir disoproxil fumarate)

Manufacturer: Mylan Labs

Approval Date: February 28, 2018

FDA approved Cimduo, a two-drug combination regimen, in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult and pediatric patients weighing at least 35 kg. It is not approved for use as pre-exposure prophylaxis (PrEP).

Cimduo is a once-daily combination of two nucleo(t)side reverse transcriptase inhibitors.

 

TROGARZO (ibalizumab-uiyk)

Manufacturer: Taimed Biologics

Approval Date: March 6, 2018

FDA approved Trogarzo, a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).

The safety and efficacy of Trogarzo were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with 10 or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after Trogarzo was added to their failing antiretroviral regimens. After 24 weeks of Trogarzo plus other antiretroviral drugs, 43% of the trial’s participants achieved HIV RNA suppression.

A total of 292 patients with HIV-1 infection were exposed to Trogarzo IV infusion. The most common adverse reactions to Trogarzo were diarrhea, dizziness, nausea, and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).

Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications.

 

SYMFI (efavirenz; lamivudine; tenofovir disoproxil fumarate)

Manufacturer: Mylan Labs

Approval Date: March 22, 2018

FDA approved Symfi as a complete regimen for the treatment of HIV-1 infection in adults and children weighing ≥40kg. 

Symfi contains the same triple combination ingredients found in Symfi Lo but with a 600-mg dose of efavirenz vs 400-mg.

Safety findings from the ENCORE 1 study showed the 600 mg combination dose of efavirenz was found to have a slightly higher rate for most adverse events than the 400 mg dose including abnormal dreams (11.3% vs 8.7%), insomnia (6.5% vs 6.2%), somnolence (3.9% vs 3.1%), depression (1.6% vs 3.1%), and dizziness (35% vs 27%). 

 

MOXIDECTIN (moxidectin)

Manufacturer: MDGH

Approval Date: June 13, 2018

FDA approved Moxidectin is an anthelmintic indicated for the treatment of onchocerciasis (river blindness) due to Onchocerca volvulus in patients aged 12 years and older.

The approval of Moxidectin was based on data from two randomized, double blind, active controlled clinical studies. Each study met its respective primary endpoints, showing a statistically significant superiority of moxidectin over the current standard of care, ivermectin, in suppressing the presence of the microfilariae in skin.

Moxidectin may cause serious side effects including decrease in blood pressure when standing, worsening of the disease, and a type of severe allergic reaction called Mazzotti reaction. The most common side effects are increase in type of white blood cells called eosinophils, itching, muscle or bone pain, and headache.

 

ZEMDRI (plazomicin sulfate)

Manufacturer: Achaogen Inc

Approval Date: June 25, 2018

FDA approved Zemdri, an aminoglycoside antibacterial indicated for the treatment of patients 18 years of age or older with complicated urinary tract Infections (cUTI) including pyelonephritis, caused by certain Enterobacteriaceae in patients who have limited or no alternative treatment options. 

The approval of Zemdri is supported in part by data from the EPIC (Evaluating Plazomicin In cUTI) clinical trial, which was the first randomized controlled study of once-daily aminoglycoside therapy for the treatment of cUTI, including pyelonephritis.

In the phase 3 EPIC cUTI trial, Zemdri demonstrated non-inferiority to meropenem for the co-primary efficacy endpoints of composite cure (clinical cure and microbiological eradication) in the microbiological modified intent-to-treat (mMITT; N=388) population at Day 5 and test-of-cure (TOC) visit (Day 17 + 2). Composite cure rates at Day 5 were 88.0% (168/191) for Zemdri vs 91.4% (180/197) for meropenem (difference -3.4%, 95% CI, -10.0 to 3.1). Composite cure rates at TOC were 81.7% (156/191) for Zemdri vs 70.1% (138/197) for meropenem (difference 11.6%, 95% CI, 2.7 to 20.3). Composite cure at the TOC visit in patients with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the Zemdri group and 56.5% (13/23) of patients in the meropenem group.

The most common side effects (≥1% of patients treated with Zemdri) were decreased kidney function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension.

Zemdri is an intravenous infusion, administered once daily.

 

TPOXX (tecovirimat)

Manufacturer: Siga Technologies

Approval Date: July 13, 2018

FDA approved Tpoxx, an inhibitor of the orthopoxvirus VP37 envelope wrapping protein, for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg.

Tpoxx is the first drug with an indication for treatment of smallpox. Though the World Health Organization declared smallpox, a contagious and sometimes fatal infectious disease, eradicated in 1980, there have been longstanding concerns that smallpox could be used as a bioweapon.

Tpoxx’s effectiveness against smallpox was established by studies conducted in animals infected with viruses that are closely related to the virus that causes smallpox and was based on measuring survival at the end of the studies. More animals treated with Tpoxx lived compared to the animals treated with placebo. Tpoxx was approved under the FDA’s Animal Rule, which allows efficacy findings from adequate and well-controlled animal studies to support an FDA approval when it is not feasible or ethical to conduct efficacy trials in humans.

The safety of Tpoxx was evaluated in 359 healthy human volunteers without a smallpox infection. The most frequently reported side effects were headache, nausea, and abdominal pain.

 

SYMTUZA (cobicistat; darunavir ethanolate; emtricitabine; tenofovir alafenamide fumarate)

Manufacturer: Janssen

Approval Date: July 17, 2018

FDA approved Symtuza, a single-tablet regimen (STR) for the treatment of HIV-1 in adults who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

Symtuza received FDA approval based on data from two 48-week, non-inferiority, pivotal phase 3 studies that assessed the safety and efficacy of Symtuza versus a control regimen in adults with no prior ARV history (AMBER) and in virologically suppressed adults (EMERALD).

AMBER compared Symtuza to darunavir/cobicistat (D/C) plus emtricitabine/tenofovir disoproxil fumarate (F/TDF). The results demonstrated similar viral suppression rates (HIV-1 RNA <50c/mL at 48 weeks – per FDA Snapshot analysis) between the darunavir-based STR vs. control (91.4% vs 88.4% respectively) and low virologic failure rates (HIV-1 RNA ≥50 c/mL; 4.4% vs. 3.3%) at 48 weeks.

Overall, Symtuza was well-tolerated, with fewer discontinuations due to an adverse event (2% vs 4%) versus control, only one grade 3 adverse reaction and no grade 4 adverse reactions. The most frequent adverse reactions reported in ≥2% of subjects were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence.

The EMERALD study compared Symtuza to continuing treatment with a boosted protease inhibitor (bPI) plus emtricitabine and TDF. The trial found there were low virologic failure rates (HIV-1 RNA ≥50 c/mL; 0.8% vs 0.5%) and high virologic suppression rates (HIV-1 RNA <50 c/mL; 94.9% vs 93.7%) at Week 48, with no patients discontinuing the study due to virologic failure. 

The safety profile was similar to that of those patients with no prior ARV treatment history, and the percentage of participants who discontinued due to adverse events, regardless of severity, was 1%. Symtuza has a Boxed Warning regarding the risk of post-treatment acute exacerbation of hepatitis B. 

The recommended dosage of Symtuza is one tablet taken once-daily with food. Symtuza is not recommended in patients with creatinine clearance below 30 mL per minute or those with severe hepatic impairment.

 

KRINTAFEL (tafenoquine succinate)

Manufacturer: GlaxoSmithKline

Approval Date: July 20, 2018

FDA approved single-dose Krintafel an antimalarial for the radical cure (prevention of relapse) of Plasmodium vivax (P. vivax) malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection.

The approval was based on efficacy and safety data from a comprehensive global clinical development P. vivax radical cure program. Thirteen studies in healthy volunteers and patients directly supported the program. The primary evidence for the clinical efficacy and safety of the 300 mg single-dose, to which more than 800 subjects were exposed, was provided by three randomized, double-blind studies: DETECTIVE Part 1 and Part 2 and GATHER.

Noted adverse reactions (incidence ≥1%) include: headache, dizziness, back pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT), motion sickness, insomnia, depression, abnormal dreams and anxiety.

Tafenoquine should not be administered to: patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency or have not been tested for G6PD deficiency, patients who are breastfeeding a child known to have G6PD deficiency or one that has not been tested for G6PD deficiency, or patients who are allergic to tafenoquine or any of the ingredients in tafenoquine or who have had an allergic reaction to similar medicines containing 8-aminoquinolines.

 

XERAVA (eravacycline dihydrochloride)

Manufacturer: Tetraphase Pharmaceuticals

Approval Date: August 27, 2018

FDA approved Xerava, a fluorocycline antibacterial within the tetracycline class of antibacterial drugs, for the treatment of complicated intra-abdominal infections (cIAI) in patients aged 18 years and older.

Efficacy of Xerava was demonstrated in two phase 3, randomized, double-blind, active-controlled, multinational, multicenter trials in adult patients hospitalized with cIAI. The drug was well-tolerated and achieved high clinical cure rates in patients with cIAI, demonstrating statistical non-inferiority to two widely used comparators – ertapenem and meropenem.

The most common adverse reactions (incidence ≥ 3%) to Xerava are infusion site reactions, nausea, and vomiting. The use of Xerava may also cause tooth discoloration and enamel hypoplasia, inhibition of bone growth, and clostridium difficile-associated diarrhea. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with Xerava, and use of the product should be discontinued if an allergic reaction occurs. The product is contraindicated for use in patients with known hypersensitivity to Xerava, tetracycline-class antibacterial drugs, or to any of the excipients.

The recommended dosage of Xerava approved by the FDA is 1 mg/kg by intravenous infusion over approximately 60 minutes every 12 hours for a total duration of 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Xerava and other antibacterial drugs, the product should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Xerava is not indicated for the treatment of complicated urinary tract infections.

 

PIFELTRO (doravirine)

Manufacturer: MSD Merck Co

Approval Date: August 30, 2018

FDA approved Pifeltro, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral medicines for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience.

The FDA approval of Pifeltro was based on findings from the pivotal, randomized, multicenter, double-blind, active controlled phase 3 trial DRIVE-FORWARD, evaluating the efficacy and safety of Pifeltro, respectively, in participants infected with HIV-1 with no antiretroviral treatment history. In the trial, 766 participants with no antiretroviral treatment history were randomized and received at least one dose of either Pifeltro once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily, each in combination with emtricitabine (FTC)/TDF or abacavir (ABC)/3TC selected by the investigator.

Pifeltro demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to DRV+r, each in combination with FTC/TDF or ABC/3TC (84% in the Pifeltro group achieved viral suppression of HIV-1 RNA <50 copies/mL vs. 80% in the DRV+r group; treatment difference: 3.9%, 95% CI: -1.6, 9.4).

Of the 20% of study participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77% in the Pifeltro group and 74% in the DRV+r group achieved HIV-1 RNA <50 copies/mL at Week 48.

The rate of discontinuation of therapy due to adverse events in either treatment group was low (2% in the Pifeltro group and 3% in the DRV+r group). Clinical adverse reactions of all grades occurring in ≥5% of participants in the Pifeltro treatment group included nausea (7%), headache (6%), fatigue (6%), diarrhea (5%) and abdominal pain (5%). No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥2% of participants treated with Pifeltro.

Pifeltro can be co-administered with a wide range of antiretroviral agents. Pifeltro cannot be co-administered with enzalutamide, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, mitotane, or St. John’s wort. If Pifeltro is co-administered with rifabutin, patients need to increase the Pifeltro dosage to one tablet twice daily approximately 12 hours apart. Use of Pifeltro with efavirenz, etravirine, or nevirapine is not recommended.

Pifeltro is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Pifeltro.

Pifeltro is administered orally once daily with or without food.

 

DELSTRIGO (doravirine; lamivudine; tenofovir disoproxil fumarate)

Manufacturer: MSD Merck Co

Approval Date: August 30, 2018

FDA approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg), for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience.

The FDA approval was based on findings from a pivotal, randomized, multicenter, double-blind, active controlled phase 3 trial. In DRIVE-AHEAD, 728 participants with no antiretroviral treatment history were randomized and received at least one dose of either Delstrigo or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC 200 mg/TDF 300 mg) once daily.

Delstrigo demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to EFV/FTC/TDF (84% in the Delstrigo group achieved viral suppression of HIV-1 RNA <50 copies/mL vs. 81% in the EFV/FTC/TDF group; treatment difference: 3.5%, 95% CI: -2.0, 9.0). Of the 21% of study participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77% in the Delstrigo group and 72% in the EFV/FTC/TDF group achieved HIV-1 RNA <50 copies/mL at Week 48.

The rate of discontinuation of treatment due to adverse events was lower in the Delstrigo treatment group than in the EFV/FTC/TDF treatment group (3% and 6%, respectively). Clinical adverse reactions of all grades occurring in ≥5% of participants in the Delstrigo treatment group included dizziness (7%), nausea (5%) and abnormal dreams (5%). No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥2% of participants treated with Delstrigo.

Delstrigo can be co-administered with a wide range of non-antiretroviral agents. Delstrigo cannot be co-administered with enzalutamide, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, mitotane or St. John’s wort. If Delstrigo is co-administered with rifabutin, patients should take one tablet of Delstrigo once daily, followed by one tablet of doravirine approximately 12 hours after the dose of Delstrigo.

Delstrigo contains a Boxed Warning regarding post-treatment acute exacerbation of hepatitis B (HBV) infection. Delstrigo is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Delstrigo. Delstrigo is contraindicated in patients with a previous hypersensitivity reaction to 3TC.

 

NUZYRA (omadacycline)

Manufacturer: Paratek Pharms Inc

Approval Date: October 3, 2018

FDA approved Nuzyra for the treatment of adults with community-acquired bacterial pneumonia (CABP) and acute skin and skin structure infections (ABSSSI). Nuzyra, a modernized tetracycline, is a once-daily IV and oral antibiotic that exhibits activity across a spectrum of bacteria, including Gram-positive, Gram-negative, atypicals, and drug resistant strains. 

The approval of Nuzyra is supported by multiple clinical trials within the company’s global development program. Nearly 2,000 adult patients received Nuzyra and it was found to be efficacious and generally safe and well tolerated.

The most common adverse reactions (incidence ≥2%) are nausea, vomiting, infusion site reactions, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertension, headache, diarrhea, insomnia, and constipation.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Nuzyra and other antibacterial drugs, Nuzyra should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

 

XOFLUZA (baloxavir marboxil)

Manufacturer: Shionogi Inc 

Approval Date: October 24, 2018

FDA approved Xofluza for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

The safety and efficacy of Xofluza, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 patients where participants were assigned to receive either Xofluza, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms.

In both trials, patients treated with Xofluza had a shorter time to alleviation of symptoms compared with patients who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received Xofluza and those who received the other flu treatment.

The most common adverse reactions in patients taking Xofluza included diarrhea and bronchitis.

 

AEMCOLO (rifamycin)

Manufacturer: Cosmo Technologies, Ltd

Approval Date: November 16, 2018

FDA approved Aemcolo, an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), that is not complicated by fever or blood in the stool.

The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo. 

The safety of Aemcolo, taken orally over 3 or 4 days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions seen with Aemcolo treatment were headache and constipation. 

Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients.

Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (eg, rifaximin), or any of the components in Aemcolo.

 

NEUROLOGY

AIMOVIG (erenumab-aooe)

Manufacturer: Amgen Inc

Approval Date: May 17, 2018

FDA approved Aimovig for the preventive treatment of migraine in adults. The treatment is given by once-monthly self-injections. Aimovig is the first FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide, a molecule that is involved in migraine attacks.

The effectiveness of Aimovig for the preventive treatment of migraine was evaluated in three clinical trials. The first study included 955 participants with a history of episodic migraine and compared Aimovig to placebo. Over the course of 6 months, Aimovig-treated patients experienced, on average, one to two fewer monthly migraine days than those on placebo. The second study included 577 patients with a history of episodic migraine and compared Aimovig to placebo. Over the course of 3 months, Aimovig-treated patients experienced, on average, one fewer migraine day per month than those on placebo. The third study evaluated 667 patients with a history of chronic migraine and compared Aimovig to placebo. In that study, over the course of three months, patients treated with Aimovig experienced, on average, 2.5 fewer monthly migraine days than those receiving placebo.

The most common side effects that patients in the clinical trials reported were injection site reactions and constipation.

 

EPIDIOLEX (cannabidiol)

Manufacturer: GW Research

Approval Date: June 25, 2018

FDA approved Epidiolex oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome.

Cannabidiol (CBD) is a chemical component of the Cannabis sativa plant, more commonly known as marijuana. However, CBD does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC).

Epidiolex’s effectiveness was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex, taken along with other medications, was shown to be effective in reducing the frequency of seizures when compared with placebo.

The most common side effects that occurred in Epidiolex-treated patients in the clinical trials were sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor-quality sleep; and infections.

Epidiolex must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. As is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks. Epidiolex also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine.

 

DIACOMIT (stiripentol)

Manufacturer: Biocodex SA

Approval Date: August 20, 2018

FDA approved Diacomit for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam.

The FDA approval of Diacomit was based on two multicenter placebo-controlled trials similar in terms of disease characteristics and prior treatment of patients, STICLO France and STICLO Italy. The primary efficacy endpoint in both trials was the responder rate, with a responder defined as a patient who experienced a greater than 50% decrease in the frequency (per 30 days) of generalized clonic or tonic-clonic seizures during the double-blind treatment period compared to the 4-week baseline period. In STICLO France, the responder rate for patients receiving Diacomit was 71% (95% CI: 52, 91), compared to 5% (95% CI: 0, 15) for patients receiving placebo. In STICLO Italy, the responder rate for patients receiving Diacomit was 67% (95% CI: 40, 93), compared to 9.1% (95% CI: 0, 26) for patients receiving placebo.

The most common adverse reactions, occurring in at least 10% of Diacomit-treated patients and more frequently than on placebo, included somnolence (67%), decreased appetite (45%), agitation (27%), ataxia (27%), weight decreased (27%), hypotonia (24%), nausea (15%), tremor (15%), dysarthria (12%), and insomnia (12%). There were 2 patients in whom adverse reactions led to discontinuation of Diacomit treatment: one patient had an adverse reaction of status epilepticus; the second patient had drowsiness, balance impaired, and sialorrhea.

 

AJOVY (fremanezumab-vfrm)

Manufacturer: Teva Pharmaceuticals

Approval Date: September 14, 2018

FDA approved Ajovy injection for the preventive treatment of migraine in adults. Ajovy, a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine with quarterly (675 mg) and monthly (225 mg) dosing options.

Ajovy was evaluated in two phase 3, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period.

The most common adverse reactions (≥5% and greater than placebo) were injection site reactions.

 

EMGALITY (galcanezumab-gnlm)

Manufacturer: Eli Lilly And Co

Approval Date: September 27, 2018

FDA approved Emgality injection for the preventive treatment of migraine in adults. 

The efficacy and safety of Emgality was demonstrated in two phase 3 clinical trials in patients with episodic migraine (EVOLVE-1 and EVOLVE-2) and one phase 3 clinical trial in patients with chronic migraine (REGAIN). EVOLVE-1 and EVOLVE-2 were six-month, double-blind, placebo-controlled studies that enrolled adult patients with episodic migraine (defined as 4-14 migraine headache days [MHDs] per month). REGAIN was a 3-month, double-blind, placebo-controlled study that enrolled adult patients with chronic migraine (defined as at least 15 headache days per month with at least 8 MHDs per month). In all three studies, patients were randomized to receive once-monthly placebo, Emgality 120 mg after an initial loading dose of 240 mg, or Emgality 240 mg. The primary endpoint was the mean change from baseline in the number of monthly MHDs over the double-blind treatment period in the intent-to-treat study population.

The safety of Emgality was evaluated in three clinical trials that included more than 2500 patients. Hypersensitivity reactions (eg, rash, urticaria and dyspnea) have been reported with Emgality in clinical studies, can occur days after administration and may be prolonged. The most common adverse reactions (incidence ≥2% for Emgality and at least 2% greater than placebo) associated with Emgality treatment (120 mg vs placebo) were injection site reactions (18% vs 13%).

The recommended dose for Emgality is 240 mg (two consecutive subcutaneous injections of 120 mg each) once as a loading dose, followed by monthly doses of 120 mg injected subcutaneously.

 

SYMPAZAN (clobazam) Oral Film

Manufacturer: Aquestive Therapeutics

Approval Date: November 1, 2018

FDA approved Sympazan oral film for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. Sympazan is the first and only oral film FDA-approved to treat seizures associated with Lennox-Gastaut syndrome. Previously, clobazam was marketed as ONFI and offered in two formulations – either tablet or oral suspension.

In a phase 3, randomized, double-blind, placebo-controlled study of 238 LGS patients, clobazam tablets significantly reduced the frequency of drop seizures (which involve falls) compared to baseline by 41% (low dose) to 68% (high dose) vs 12% for placebo (P < .05 for all doses vs placebo). Multiple pharmacokinetic studies were conducted to compare Sympazan with ONFI. Based on the studies, Sympazan oral film was demonstrated to be bioequivalent to clobazam tablets and have comparable safety profiles.

Sympazan oral film is berry flavored and offered in 5 mg, 10 mg, and 20 mg dosages.

 

ONCOLOGY

LUTATHERA (lutetium Lu 177 dotatate)

Manufacturer: Advanced Accelerator Applications USA, Inc

Approval Date: January 26, 2018

FDA approved Lutathera, a radiolabeled somatostatin analog, for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

Lutathera, which received orphan drug designation from the FDA, is a first-in-class drug and the first available FDA-approved peptide receptor radionuclide therapy, a form of treatment comprising of a targeting molecule that carries a radioactive component.

Approval was based on data from NETTER-1, a randomized, multicenter, open-label, active-controlled trial in 229 patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors. Patients were randomized (1:1) to receive either Lutathera (7.4 GBq [200 mCi] every 8 weeks for up to 4 administrations; maximum cumulative dose of 29.6 GBq) with long-acting octreotide (30 mg by intramuscular injection every 4 weeks) or high-dose long-acting octreotide (60 mg by intramuscular injection every 4 weeks). Lutathera was co-administered with an amino acid solution as a renal protectant. In the US, patients enrolled in NETTER-1 received Aminosyn II 10%, a commercially available solution of amino acids.

The major efficacy outcome measure was progression-free survival (PFS) determined by a blinded IRC using RECIST 1.1. The median PFS was not reached for Lutathera and was 8.5 months in the high-dose long-acting octreotide arm (HR: 0.21; 95% CI: 0.13, 0.32; P <.0001).

The efficacy of Lutathera was also assessed in a subset (n=360) of 1214 patients enrolled in the ERASMUS Medical Center (MC) study with GEP-NET tumors who were assessed according to RECIST criteria. At the ERASMUS MC, Lutathera was initially provided as expanded access under a general peptide receptor radionuclide therapy protocol at a single site in the Netherlands. Lutathera (7.4 GBq [200 mCi]) was administered every 6 to 13 weeks for up to 4 doses. The ORR was 16% (n=58), including 3 CRs in this subset of 360 patients with GEP-NETs who were assessed according to RECIST criteria.

In the NETTER-1 study, the most common grade 3-4 adverse reactions occurring with a greater frequency (at least 4%) among patients receiving Lutathera with long-acting octreotide compared to patients receiving high-dose octreotide alone included lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea and elevated AST (5% each), and increased ALT, hyperglycemia, and hypokalemia (4% each). In NETTER-1, with a median follow-up of 24 months, myelodysplastic syndrome was reported in 2.7% of patients receiving Lutathera with long-acting octreotide; no patients receiving high-dose octreotide LAR developed myelodysplastic syndrome.

The recommended dose of Lutathera is 7.4 GBq (200 mCi) as an intravenous infusion over 30 minutes every 8 weeks for a total of 4 doses.

 

ERLEADA (apalutamide)

Manufacturer: Janssen Biotech Inc

Approval Date: February 14, 2018 

FDA approved Erleada for patients with non-metastatic castration-resistant prostate cancer (NM-CRPC). This is the first FDA-approved treatment for this indication.

Approval was based on a multicenter, double-blind, clinical trial (SPARTAN) randomizing 1207 patients with NM-CRPC (2:1) to receive either Erleada, 240 mg orally once daily in combination with ADT (medical castration or surgical castration) (n=806), or placebo once daily with ADT (n=401).

The major efficacy endpoint was metastasis-free survival (MFS). MFS was defined as the time from randomization to the time of first evidence of distant metastasis (new bone or soft tissue lesions or enlarged lymph nodes outside the pelvis), or death due to any cause, whichever occurred first. The estimated median MFS was 40.5 months for patients receiving Erleada and 16.2 months for those receiving placebo (HR: 0.28; 95% CI: 0.23, 0.35; P < .0001).

The most common adverse reactions in at least 10% of patients were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

The recommended Erleada dose is 240 mg (four 60 mg tablets) administered orally once daily.

 

AKYNZEO (fosnetupitant chloride hydrochloride; palonosetron hydrochloride) injection

Manufacturer:  Helsinn Healthcare

Approval Date: April 19, 2018

FDA has approved Akynzeo, an IV formulation of NEPA (a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg), in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (CINV).

Oral NEPA was previously approved by the FDA as a fixed combination oral agent in 2014 for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. The approval provides an alternative route of administration.

The bioequivalence of Akynzeo with the oral formulation of netupitant was demonstrated, and the safety of Akynzeo was established, through a repeated dose safety study in cancer patients to potentially uncover adverse drug reactions that may appear during subsequent clinical practice. No anaphylactic and injection site reactions related to Akynzeo were reported in this study.

Akynzeo has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy.

 

BRAFTOVI and MEKTOVI (encorafenib and binimetinib)

Manufacturer: Array BioPharma Inc

Approval Date: June 27, 2018

FDA approved Braftovi and Mektovi in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Approval was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Patients were randomized (1:1:1) to receive Mektovi 45 mg twice daily plus Braftovi 450 mg once daily, Braftovi 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

The major efficacy measure was PFS using RECIST 1.1 response criteria and assessed by blinded independent central review. The median PFS was 14.9 months for patients receiving Braftovi and Mektovi, and 7.3 months for the vemurafenib monotherapy arm (HR 0.54, 95% CI: 0.41, 0.71, P < .0001). ORRs assessed by central review were 63% and 40%, respectively. Median response duration was 16.6 months vs. 12.3 months, respectively.

The most common (≥25%) adverse reactions in patients receiving the combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia. Discontinuation of therapy due to adverse reactions occurred in 5% of patients receiving the combination; the most common reasons were hemorrhage and headache.

FDA also granted approval of the THxID BRAF Kit (bioMérieux) as a companion diagnostic for these therapeutics.

The recommended doses are Mektovi 45 mg orally twice daily and Braftovi 450 mg orally once daily.

 

AZEDRA (iobenguane I 131)

Manufacturer: Progenics Pharmaceuticals, Inc

Approval Date: July 30, 2018

FDA approved Azedra for adult and pediatric patients (12 years and older) with iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL) who require systemic anticancer therapy. This is the first FDA-approved drug for this use.

Approval was based on Study IB12B, an open-label, single-arm, multicenter clinical trial in patients 12 years and older with iobenguane scan-positive, unresectable, locally advanced or metastatic PPGL. Of the 68 evaluable patients, 17 (25%; 95% CI: 16%, 37%) experienced a 50% or greater reduction of all antihypertensive medication for at least six months. Overall tumor response (RECIST 1.0) occurred in 15 patients (22%; 95% CI: 14%, 33%), with 53% achieving a response duration of at least 6 months.

The most common grade 3-4 adverse reactions (≥10%) were lymphopenia, neutropenia, thrombocytopenia, fatigue, anemia, increased international normalized ratio, nausea, dizziness, hypertension, and vomiting. In the pooled safety population, 6.8% of patients who received a therapeutic dose of Azedra developed myelodysplastic syndrome or acute leukemia. 

Azedra is administered in an initial dosimetric dose, followed by two therapeutic doses that are adjusted based on dosimetry. The recommended therapeutic dose is 18,500 MBq (500 mCi) for patients weighing more than 62.5 kg and 296 MBq/kg (8 mCi/kg) for patients 62.5 kg or less.

 

VIZIMPRO (dacomitinib)

Manufacturer: Pfizer Pharmaceutical Company

Approval Date: September 27, 2018

FDA approved Vizimpro for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.

Approval was based on a randomized, multicenter, open-label, active controlled trial (ARCHER 1050) comparing the safety and efficacy of Vizimpro to gefitinib in 452 patients with unresectable, metastatic NSCLC. Patients were required to have no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic non-EGFR TKI-containing therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and EGFR exon 19 deletion or exon 21 L858R substitution mutations. Patients were randomized (1:1) to receive either Vizimpro 45 mg orally once daily or gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity.

The trial demonstrated a significant improvement in progression-free survival; no improvement in overall response rate or overall survival were demonstrated. The median progression-free survival, as determined by an independent review committee. was 14.7 and 9.2 months in the Vizimpro and gefitinib arms, respectively (HR 0.59; 95% CI: 0.47, 0.74; P < .0001).

The prescribing information contains warnings and precautions for interstitial lung disease (ILD), diarrhea, and dermatologic adverse reactions. Of 394 patients who received Vizimpro, serious adverse reactions occurred in 27%. The most common adverse reactions resulting in discontinuation of Vizimpro were diarrhea and ILD. The most common (>20%) adverse reactions of Vizimpro were diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus).

The recommended Vizimpro dose is 45 mg orally once daily with or without food.

 

LIBTAYO (cemiplimab-rwlc)

Manufacturer: Regeneron Pharmaceuticals Inc

Approval Date: September 28, 2018

FDA approved Libtayo for patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation.

Libtayo is the third anti-PD-1 approved in the US, and it is the first and only treatment specifically approved and available for advanced CSCC.

Approval was based on clinically meaningful and durable ORR observed in patients with advanced CSCC who were treated with Libtayo in two clinical trials: R2810-ONC-1423, an open-label, multi-center, dose-finding trial with expansion cohorts in patients with various advanced solid tumors; and R2810-ONC-1540, an open-label, multi-center, non-randomized, multicohort trial in patients with metastatic or locally advanced CSCC regardless of prior treatment, for whom surgery or radiation was not recommended.

ORR was assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for patients with metastatic CSCC. A composite response assessment incorporating clinical response criteria using digital photography and RECIST 1.1 was used for those with locally advanced CSCC.

Among 108 patients with advanced CSCC, including metastatic (N=75) or locally advanced (N=33) disease, the ORR was 47% (95% CI: 38, 57), with 4% complete and 44% partial response rates. The ORR was 47% (95% CI: 35, 59) for the 75 patients with metastatic CSCC and 49% (95% CI: 31, 67) for those with locally advanced disease. The median response duration was not reached (range: 1.0 to 15.2+ months), and 61% of responses were durable for 6 months or longer. Response rates and durability results were consistent across the advanced CSCC subtypes. For patients with locally advanced CSCC, radiographic response rate correlated with clinically relevant shrinkage of visible and often disfiguring tumors demonstrated in the photographic data.

Safety data were evaluated in 534 patients who received Libtayo in both trials. Serious adverse reactions are immune-mediated adverse reactions (eg, pneumonitis, hepatitis, colitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes mellitus and nephritis) and infusion reactions. The most common adverse reactions were fatigue, rash, and diarrhea.

The recommended Libtayo dose and schedule is 350 mg as an intravenous infusion over 30 minutes every 3 weeks.

 

TALZENNA (talazoparib)

Manufacturer: Pfizer Inc

Approval Date: October 16, 2018

FDA approved Talzenna, a PARP inhibitor, for patients with deleterious or suspected deleterious gBRCAm, HER2 negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on an FDA-approved companion diagnostic for Talzenna.

Approval was based on EMBRACA, an open label trial randomizing 431 patients (2:1) with gBRCAm HER2-negative locally advanced or metastatic breast cancer to receive Talzenna (1 mg) or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). All patients were required to have a known deleterious or suspected deleterious gBRCA mutation and must have received no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease. Patients were required to have received treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting.

The primary efficacy outcome was PFS according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by blinded independent central review. Estimated median PFS was 8.6 and 5.6 months in the Talzenna and chemotherapy arms, respectively (HR: 0.54; 95% CI: 0.41, 0.71; P < .0001).

The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. Most common (≥20%) adverse reactions of any grade were fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite.

FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify patients with breast cancer with deleterious or suspected deleterious gBRCAm who are eligible for Talzenna. The effectiveness of the BRACAnalysis CDx test was based on the EMBRACA trial population for whom deleterious or suspected deleterious gBRCAm status was confirmed with either prospective or retrospective testing with BRACAnalysis CDx.

The recommended Talzenna dose is 1 mg taken as a single oral daily dose, with or without food.

 

LORBRENA (lorlatinib)

Manufacturer: Pfizer Inc

Approval Date: November 2, 2018

FDA granted accelerated approval to Lorbrena for patients with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease.

Approval was based on a subgroup of 215 patients with ALK-positive metastatic NSCLC, previously treated with one or more ALK kinase inhibitors, enrolled in a non randomized, dose-ranging and activity-estimating, multi cohort, multicenter study (Study B7461001). The major efficacy measures were ORR and intracranial ORR, according to RECIST 1.1, as assessed by an independent central review committee.

The ORR was 48% (95% CI: 42, 55), with 4% complete and 44% partial responses. The estimated median response duration was 12.5 months (95% CI: 8.4, 23.7). The intracranial ORR in 89 patients with measurable lesions in the CNS according to RECIST 1.1 was 60% (95% CI: 49, 70) with 21% complete and 38% partial responses. The estimated median response duration was 19.5 months (95% CI: 12.4, not reached).

Most common adverse reactions (incidence ≥20%) in patients receiving Lorbrena were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. The most common laboratory abnormalities were hypercholesterolemia and hypertriglyceridemia.

The recommended Lorbrena dose is 100 mg orally once daily.

 

VITRAKVI (larotrectinib)

Manufacturer: Loxo Oncology Inc and Bayer

Approval Date: November 26, 2018

FDA granted accelerated approval to Vitrakvi for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.

This is the second tissue-agnostic FDA approval for the treatment of cancer.

Approval was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001, SCOUT, and NAVIGATE. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were ORR and response duration, as determined by a blinded independent review committee according to RECIST 1.1.

Efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials.  All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Twelve patients were less than 18 years of age. A total of 12 cancer types were represented, with the most common being salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%).

ORR was 75% (95% CI: 61%, 85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached. Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients. 

The safety of Vitrakvi was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions (≥20%) with Vitrakvi were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea.

The recommended Vitrakvi doses are 100 mg orally twice daily for adults and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients.