FDA Drug Approvals: Health Care Practitioners — Year in Review 2018

Mary L Windle, PharmD


January 18, 2019

Other New Drugs

Annovera (segesterone/ethinyl estradiol)

Segesterone/ethinyl estradiol is a reusable vaginal ring contraceptive that can be used for an entire year. The ring is inserted vaginally and should remain in place for 21 days, and then removed for 7 days, during which a withdrawal bleed occurs. The placement and removal cycle is repeated every 4 weeks for 13 cycles. Segesterone/ethinyl estradiol vaginal ring has not been adequately studied in women with a body mass index greater than 29 kg/m2.

Two 1-year multicenter trials (n >2000) were conducted in healthy and sexually active women with regular menstrual cycles. The pooled pregnancy rate, evaluated by the Pearl Index, was 2.98 pregnancies per 100 woman-years of use. (Annovera prescribing information)

Orilissa (elagolix)

Elagolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist. It inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones estradiol and progesterone. It is indicated for moderate-to-severe pain associated with endometriosis.

Approval of elagolix was based on two replicate phase 3 clinical trials (n=872). Improvement of dysmenorrhea was reported in 43.4-46.4% of women in the lower-dose elagolix groups and 72.4-75.8% in the higher-dose elagolix groups, compared with 19.6-22.7% in the placebo groups (P <.001 for all comparisons). Nonmenstrual pelvic pain improvement was reported by 49.8-50.4% of women in the lower-dose elagolix groups and 54.5-57.8% in the higher-dose groups, compared with 36.5% in the placebo groups (P=.003 and P <.001, respectively). (N Engl J Med. 2017 Jul 6;377(1):28-40)

Both elagolix doses are associated with hypoestrogenic adverse effects, including hot flushes, elevated serum lipids, and greater decreases from baseline in bone mineral density compared with women who received placebo. Because of this, treatment duration recommendations are specified for each dosage regimen.

Lokelma (sodium zirconium cyclosilicate)

Sodium zirconium cyclosilicate is a potassium binder indicated for adults with hyperkalemia. Nonabsorbed zirconium silicate preferentially captures potassium in exchange for hydrogen and sodium, resulting in increased fecal potassium excretion by binding and reducing the free potassium concentration in the GI lumen. Because of its delayed onset of action, it is not indicated for emergency treatment of life-threatening hyperkalemia.

Sodium zirconium cyclosilicate preferentially captures potassium in exchange for hydrogen and sodium, which reduces the free potassium concentration in the lumen of the GI tract and thereby lowers the serum potassium level. Like patiromer, sodium zirconium cyclosilicate should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.

Approval was based on the HARMONIZE clinical trial in patients with serum potassium levels of 5.1 mEq/L or higher. In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours. Median time to normalization was 2.2 hours, with 84% of patients achieving normokalemia by 24 hours and 98% by 48 hours. In the randomized phase, serum potassium was significantly lower during days 8-29 with all three zirconium cyclosilicate doses versus placebo (4.8 mEq/L, 4.5 mEq/L, and 4.4 mEq/L for 5 g, 10 g, and 15 g, respectively; 5.1 mEq/L for placebo; P <.001 for all comparisons).

The HARMONIZE trial also included patients with heart failure who were maintained on renin-angiotensin-aldosterone system inhibitors (RAASi), which are known to cause elevated serum potassium levels. Compared with placebo, all three zirconium cyclosilicate doses lowered potassium and effectively maintained normokalemia for 28 days in patients with heart failure without the need to adjust RAASi regimens. (JAMA. 2014 Dec 3;312(21):2223-33)

Sodium zirconium cyclosilicate transiently increases gastric pH, which can change the absorption of coadministered drugs that exhibit pH-dependent solubility, potentially leading to altered efficacy or safety of these drugs when coadministered. In general, administer pH-dependent medications either 2 hours before or after sodium zirconium cyclosilicate. (Eur J Heart Fail. 2015 Oct;17(10):1050-6)

Motegrity (prucalopride)

Prucalopride, a selective serotonin type 4 (5-HT4) receptor agonist, elicits prokinetic actions that simulate colonic peristalsis, which increases bowel motility. It is indicated for adults with chronic idiopathic constipation (stirCIC).

Approval for CIC was based on an integrated analysis of six main clinical trials lasting a minimum of 12 weeks (n=2484). Results showed significantly more patients treated with prucalopride achieved an average of three or more spontaneous, complete bowel movements per week over 12 weeks than those given placebo (27.8% vs 13.2%; P<.001). A rapid response was seen with prucalopride as early as week 1, with improvements maintained throughout 12 weeks of treatment. (Motegrity (prucalopride) prescribing information)

Gamifant (emapalumab)

Emapalumab is indicated for patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent, or progressive disease, or who are intolerant to conventional HLH therapy. It is a human monoclonal antibody that binds to and neutralizes interferon-gamma, which is thought to be hypersecreted in patients with HLH.

Approval was based on a phase 2/3 trial of 27 patients with refractory, recurrent, or progressive HLH. Results showed 63% achieved a complete response, a partial response, or HLH improvement with emapalumab plus dexamethasone. Additionally, 70% of trial participants were able to continue on to hematopoietic stem cell transplantation. (Medscape Medical News. November 20, 2018)

Palynziq (pegvaliase)

Pegvaliase is indicated to reduce blood phenylalanine concentrations in adults with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations above 600 μmol/L on existing management. Pegvaliase is a pegylated phenylalanine ammonia lyase, which is an enzyme that catalyzes phenylalanine to ammonia and trans-cinnamic acid.

Approval of pegvaliase was based on two phase 3 studies, PRISM-1 and PRISM-2, which evaluated efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. Of 261 participants who received pegvaliase, 72% reached 1 year or more of treatment and 32.6% reached 2 years or more of study treatment, and 65% are still actively receiving treatment. Mean (standard deviation) blood phenylalanine was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. (Mol Genet Metab. 2018 May;124(1):27-38)

Crysvita (burosumab)

Burosumab is indicated for adults and children with X-linked hypophosphatemia. Burosumab is a recombinant fully human monoclonal IgG1 antibody against the phosphaturic hormone, fibroblast growth factor 23 (FGF23). X-linked hypophosphatemia is a bone disease characterized by phosphate-wasting due to excess activity of FGF23, which results in suppression of renal tubular phosphate reabsorption and renal production of 1,25 dihydroxy vitamin D.

Approval for children was based on a 64-week, randomized, open-label study in 52 patients aged 5-12 years, which showed that treatment with burosumab improved rickets, increased serum phosphorus levels, decreased serum alkaline phosphatase activity, and increased growth. The indication is also supported by 40-week data from an open-label study in 13 patients aged 1-4 years. In these patients, burosumab improved rickets and lower-limb deformity, increased serum phosphorus levels, and decreased serum alkaline phosphatase activity. (N Engl J Med. 2018 May 24;378(21):1987-1998)

Approval in adults with X-linked hypophosphatemia (n=134) was supported by a randomized, double-blind, placebo-controlled study. Burosumab treatment resulted in a higher proportion of patients achieving serum phosphorus levels above the lower limit of normal compared with placebo (P<.0001). A higher rate of complete healing of active fractures and pseudofractures was also observed compared with placebo. (J Bone Miner Res. 2018 Aug;33(8):1383-1393)

Revcovi (elapegademase)

Elapegademase is indicated for adults and children with adenosine deaminase severe combined immune deficiency (ADA-SCID). Elapegademase provides an exogenous source of ADA enzyme that catalyzes the hydrolytic deamination of adenosine or deoxyadenosine to inosine or deoxyinosine. Maintaining a low level of 2'-deoxyadenosine and adenosine is crucial for proper number and function of immune cells, as well as decreasing the frequency of opportunistic infections.

For years, patients with ADA-SCID have been treated with pegademase (Adagen), which is bovine derived. Elapegademase is a new pegylated recombinant adenosine deaminase (rADA) that does not need to be sourced from animals.

Takhzyro (lanadelumab)

Lanadelumab is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE). It is a human monoclonal antibody (IgG1 kappa-light chain) that targets plasma kallikrein and inhibits proteolytic activity to control excess bradykinin generated with HAE. In patients with HAE caused by C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks.

Approval was based on the HELP clinical trial, which investigated the efficacy and safety of lanadelumab for long-term prophylaxis against angioedema attacks in HAE. Of 125 patients, 113 completed the trial. All lanadelumab dosing regimens significantly reduced the mean monthly attack rates of HAE compared with placebo (P<.001) over the 26-week duration of the study. The regimen of 300 mg SC every 2 weeks reduced attacks by 92.8% from baseline in patients with fewer than two attacks per month and by 88.2% in patients whose baseline was two to fewer than three attacks per month. (JAMA. 2018 Nov 27;320(20):2108-2121)

Oxervate (cenegermin)

Cenegermin is recombinant nerve growth factor approved for neurotrophic keratitis.

Approval was based on the REPARO study (n=156). Patients were randomized 1:1:1 to cenegermin 10 mcg/mL, cenegermin 20 mcg/mL, or vehicle.

At week 4, 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) compared with 54.9% receiving cenegermin 10 mcg/mL (+35.3%; 97.06% CI, 15.88-54.71; P<.001) and 58% receiving cenegermin 20 mcg/mL (P <.001).

At week 8, 43.1% of vehicle-treated patients achieved corneal healing compared with 74.5% receiving cenegermin 10 mcg/mL (P=.001) and 74% receiving 20 mcg/mL (P=.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between cenegermin and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled cenegermin treatment remained recurrence free during 48-week follow-up. (Ophthalmology 2018 Sep;125(9):1332-1343)

Lucemyra (lofexidine)

Lofexidine is indicated as short-term therapy for mitigation of withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. It is a nonopioid, centrally acting alpha2-agonist that binds to receptors on adrenergic neurons, thereby reducing norepinephrine release.

Approval was based on two randomized, double-blind, placebo-controlled clinical trials; an open-label study; and clinical pharmacology studies with concomitant administration of methadone, buprenorphine, or naltrexone. Data showed that compared with patients given placebo, participants treated with lofexidine experienced less severe withdrawal symptoms and were significantly more likely to complete a 7-day opioid discontinuation treatment. (Drug Alcohol Depend. 2017 Jul 1;176:79-88; J Psychopharmacol. 2017 Aug;31(8):1046-1055)

Omegaven (fish oil triglycerides)

Fish oil triglycerides are a parenteral emulsion indicated as a source of calories and fatty acids in pediatric patients with parenteral nutrition–associated cholestasis (PNAC).

Effectiveness was established in two open-label clinical trials of 82 pediatric patients (aged 3-42 weeks), including preterm neonates with estimated gestational age of older than 24 weeks at birth.

Olumiant (baricitinib)

Baricitinib is indicated for adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. It is a Janus kinase (JAK) pathway inhibitor. JAK consists of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor receptor interactions on the cellular membrane to influence cellular processes of hematopoieses and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression. Since baricitinib inhibits JAKs, phosphorylation and activation of STATs are prevented.

Approval of baricitinib was supported by the RA-BUILD, RA-BEYOND, and RA-BEACON phase 3 clinical trials. The RA-BUILD study was a double-blind 24-week study that included 684 biologic disease-modifying antirheumatic drug (DMARD)–naive patients with RA and inadequate response or intolerance to one or more conventional synthetic DMARDs. More patients achieved American College of Rheumatology 20% improvement criteria (ACR20) response at week 12 with baricitinib 4 mg (62%) compared with placebo (39%) (P≤.001). (Ann Rheum Dis. 2017 Jan;76(1):88-95)

The RA-BEYOND study showed that radiographic progression at 24 and 48 weeks was statistically significantly lower for either baricitinib 2 mg or 4 mg compared with placebo. However, only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomized to placebo when observed at week 48. (RMD Open. 2018 May 8;4(1):e000662)

Ilumya (tildrakizumab)

Tildrakizumab is indicated for moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.

Approval was supported by two phase 3 trials, reSURFACE 1 and 2 (n=926). Both studies demonstrated significant clinical improvement with tildrakizumab compared with placebo when measured by at least a 75% reduction in Psoriasis Area and Severity Index (PASI 75) score and Physician Global Assessment (PGA) score of "clear" or "minimal" at week 12 after 2 doses.

In the reSURFACE 1 study, 74% of patients achieved PASI 75 at week 28 after three tildrakizumab doses, and 84% of patients who continued on the drug maintained PASI 75 at week 64 compared with 22% of patients who were re-randomized to placebo. In reSURFACE 2, 61% of patients who received tildrakizumab 100 mg achieved PASI 75, compared with 6% of the placebo group, and 48% of the etanercept group at week 12. (Lancet. 2017 Jul 15;390(10091):276-288)


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