Atezolizumab#$ (Tecentriq)27—atezolizumab is an Fc-engineered, humanized, nonglycosylated IgG1 kappa monoclonal antibody that binds to and blocks programmed death ligand 1 (PD-L1).43 Atezolizumab is the third monoclonal antibody acting on the PD-1 pathway to be FDA approved; nivolumab (Opdivo)44 and pembrolizumab (Keytruda)45 are both PD-1 receptor blockers that have been marketed in the United States since 2014 as immunotherapies against cancers. The PD-1 pathway and ligand as targets for cancer therapy have been well characterized.46-48 Atezolizumab received approval as the second-line treatment of metastatic non-small cell lung cancer, and it received accelerated approval as the second-line treatment of locally advanced or metastatic urothelial carcinoma.40 Accelerated approval is associated with ongoing clinical trial commitments for the sponsor that will continue into 2021.49 Atezolizumab is administered as a flat 1200-mg intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Dosage adjustments for treatment-associated immune-mediated toxicities are provided in the labeling.27 Some of these toxicities are characterized as life-threatening. Other side effects include infections, infusion reactions, and impaired fertility or infertility. The half-life of elimination for atezolizumab is approximately 27 days. Due to known risks, effective contraception must be used during treatment and for at least 5 months following discontinuation of therapy. Breakthrough therapy designation for atezolizumab for urothelial carcinoma was based on an overall response rate of 14.8% (95% confidence interval [CI], 11.1–19.3) among 310 patients.49 Among the 46 responders, 43 had duration of responses longer than 6 months.49 The most common adverse reactions noted were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation.49 Fifty percent of patients experienced serious toxicity.49 In its summary review, FDA wrote that atezolizumab represents an important, new therapeutic option to address an unmet medical need and judged the benefit-risk profile for the approved indication to be favorable and in line with other PD-1 pathway therapies.49 The results of longer-term ongoing studies should more clearly indicate the duration of response that can be expected with atezolizumab.
Bezlotoxumab (Zinplava)31—bezlotoxumab is a human monoclonal IgG1 antibody engineered as an antitoxin against C. difficile toxin B. Bezlotoxumab is administered as a single-dose 10-mg/kg infusion at any time during the course of antibiotic therapy for C. difficile infection. Bezlotoxumab is indicated to reduce the risk of recurrence of C. difficile infection in patients who are at a high risk for recurrence.50 Included as a secondary endpoint in premarket studies, a sustained response (initial episode cure and absence of recurrence) was found to be statistically significant only in Study P002 (66.8% vs. 52.1%; p<0.0001).51 More study is needed to determine the validity of this finding. The elimination half-life of bezlotoxumab is approximately 19 days.31 Approval of bezlotoxumab was based on the detection of a significantly lower recurrence rate of C. difficile in two phase 3, placebo-controlled clinical studies.51 Study P001 found that the 386 subjects who received bezlotoxumab were 10% less likely to experience a recurrent infection than the 395 patients who received placebo.51 Study P002 found a similar result: 395 patients were 9.9% less likely to experience a recurrence than the 378 subjects given placebo.51 A total of 1790 patients were exposed to bezlotoxumab prior to marketing.51 The therapy was generally well tolerated but the drug is labeled with a warning regarding heart failure.31 In patients with a history of congestive heart failure, 12.7% (15 of 118) of bezlotoxumab-treated patients and 4.8% (5 of 104) of placebo-treated patients experienced heart failure, and there were more deaths in bezlotoxumab-treated patients: 19.5% (23 of 118) vs.12.5% (13 of 104) during 12 weeks of study.51
Ixekizumab (Taltz)34—Secukinumab (Cosentyx)4 and ixekizumab are both monoclonal antibodies engineered to bind IL-17A and inhibit its interaction with the IL-17A receptor.52 Approved for marketing in 2015, secukinumab is a human IgG subgroup 1 monoclonal antibody whereas ixekizumab is a humanized IgG subgroup 4 monoclonal antibody. Subgroup 1 and subgroup 4 antibodies share many similar physiochemical and biological properties but generally may differ in their binding of C1q to cause complement activation (IgG4 normally does not bind C1q); in their avidity for binding antigen (IgG4 usually exhibits less avid binding); and in the vigor of their signaled immune responses (IgG4 is often associated with a subtle response).53 In patients with psoriasis, elevated levels of IL-17A associated with psoriatic plaques are thought to contribute to the pathology of the disease by triggering the abnormal release of proinflammatory cytokines and chemokines.52 By blocking IL-17A from binding to its receptors, secukinumab and ixekizumab reduce this pathology5,54 and both have won FDA approval for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.4,34 In 2016, the approved indications for secukinumab were extend to treatment of active psoriatic arthritis and active ankylosing spondylitis.5 The recommended dose of ixekizumab for psoriasis is 160 mg (two 80-mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, and then 80 mg every 4 weeks.34 Two prospective, double-blind, multicenter, phase 3 studies (UNCOVER-2 and UNCOVER-3) demonstrated ixekizumab to be superior to placebo and etanercept as evidenced by improvements in static physician global assessment and psoriasis area and severity index scores after 12 weeks of therapy.55Evidence of sustained efficacy and safety through week 60 of therapy also has been reported.56
Obiltoxaximab (Anthim)36—obiltoxaximab is the second monoclonal antibody licensed for the treatment of inhalational anthrax† and the second to be added to the U.S. Strategic National Stockpile for this indication.57-59 The first monoclonal antibody against anthrax, raxibacumab (no brand name), was licensed by FDA in 2012.59 Both antibodies have been engineered as antitoxins to neutralize lethal Bacillus anthracis toxins.58,59 Both bind to the protective antigen component of anthrax toxin, blocking it from binding to receptors and thereby preventing its intracellular spread and curtailing the ensuing tissue damage.58,59 Both obiltoxaximab and raxibacumab were approved under the FDA’s Animal Efficacy Rule with drug safety and pharmacokinetic parameters established in healthy adult volunteers.59-62 Both antibodies against anthrax are designated as orphan drugs, both are formulated for administration as an IV infusion, both require premedications to minimize potential allergic reactions, and both are intended to be used in conjunction with aggressive IV antibiotic therapy to fight the B. anthracis infection.61 The recommended dose of obiltoxaximab in adults is 16 mg/kg given one time.36
Olaratumab#$ (Lartruvo)38—olaratumab is a platelet-derived growth factor receptor alpha (PDGFR-α)63,64 blocking monoclonal antibody that was designated as a breakthrough therapy and granted accelerated approval for the treatment of adult patients with a histologic subtype of soft tissue sarcoma that is amenable to an anthracycline-containing regimen but not amenable to curative treatment with radiotherapy or surgery.65 The accelerated approval of olaratumab is associated with ongoing clinical trial commitments for the sponsor that will continue into 2020.65,66 Olaratumab was approved on the basis of demonstrating a benefit over single-agent doxorubicin for progression-free survival (6.6 months [95% CI, 4.1–8.3) vs. 4.1 months [95% CI, 2.8–5.4]) and median overall survival (26.5 months [95% CI, 20.9–31.7) vs. 14.7 months [95% CI, 9.2–17.1]), an objective response rate of 10–25%, and a 48% reduction (95% CI, 21–66) in hazard of death.66 Olaratumab is administered as a 15-mg/kg intravenous infusion on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.38 It is administered with doxorubicin (75 mg/m2) on day 1 of each of the first eight cycles.38 Combined therapy is necessary to thwart the resistance mechanisms associated with anti-PDGF receptor treatments.68 Toxicity-related dose reduction recommendations are published in the product labeling.38 Effective contraception is advised during treatment and for 3 months after the last dose. Among the 485 patients exposed to olaratumab prior to marketing, the most common adverse reactions of the combined regimen were nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, headache, lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated activated partial thromboplastin time (aPTT), hypokalemia, and hypophosphatemia.66 Patients should be premedicated against infusion-related reactions.38 Olaratumab works by preventing receptor activation and downstream PDGFR-α pathway signaling.66,67 Targeting the PDGFR pathway with monoclonal antibodies, ligand traps, and specific and nonspecific small molecule PDGF receptor kinase inhibitors is the subject of intense research with an impressive number of potential therapeutic applications.68,69 A number of other drugs that directly or indirectly modulate the PDGF pathway are already marketed in the United States, including becaplermin (platelet-derived growth factor BB) and eight receptor kinase inhibitors (axitinib, dasatinib, imatinib, nilotinib, pazopanib, ponatinib, sunitinib, and sorafenib).68
Reslizumab (Cinqair)41—reslizumab70is the second IL-5 antagonist monoclonal antibody approved as an add-on to maintenance treatment for patients with severe asthma and an eosinophilic phenotype.71-75 It is the third monoclonal antibody to be marketed for asthma in the United States.73 Reslizumab is an IgG4 kappa monoclonal antibody approved for administration as a 3-mg/kg IV infusion once every 4 weeks to patients age 18 years or older.41 The first monoclonal antibody to be marketed for this indication, mepolizumab (Nucala)76 is an IgG1 kappa monoclonal antibody approved for administration as a subcutaneous injection once every 4 weeks to patients age 12 years or older. (As noted above in the Ixekizumab monograph: Subgroup 1 and subgroup 4 antibodies share many similar physiochemical and biological properties but generally may differ in their binding of C1q to cause complement activation [IgG4 normally does not bind C1q], in their avidity for binding antigen [IgG4 usually exhibits less avid binding], and in the vigor of their signaled immune responses [IgG4 is often associated with a subtle response]).53 Eosinophilic asthma is not described as a phenotype in published asthma treatment guidelines, and no consensus has been established,77,78 but research and development in this area of therapeutics is intense.78,79 Baseline blood eosinophil levels ≥400 cells/μL were used as the threshold for patients enrolled in reslizumab premarket trials.77,80 The measurement of blood eosinophil levels was used as a surrogate measure for eosinophil-mediated inflammation in the airways.77,80 Omalizumab (Xolair)81, a monoclonal antibody targeted against IgE, is another approved biologic for asthma that is dosed on the basis of serum eosinophil levels. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Reslizumab blocks IL-5 from binding to its receptor on the eosinophil surface and results in a reduction in eosinophil counts.77,78 It has a half-life of elimination of approximately 24 days.41 Reslizumab was approved on the basis that it was associated with roughly 40–50% fewer asthma exacerbations and better FEV1 improvements over time than placebo.41,77 Anaphylaxis was reported in 0.3% of patients exposed to reslizumab during premarket clinical trials.41 Other labeled warnings relate to the observed development of malignancies and helminth infections.41 The malignancy risk in humans from reslizumab is unknown.41,77