eChapter 2016 (Part 3): The Goodman & Gilman Year in Review: New and Noteworthy FDA Approvals

In 2016 the U.S. Food and Drug Administration (FDA) approved 22 new drugs and granted 32 noteworthy biologics licenses. Among the 22 new drugs are:

• Six pharmacological “firsts” (see Part 1);

• Three diagnostic imaging agents for use with PET imaging (see Part 1);

• Three previously unapproved marketed drugs (see Part 2);

• Two entities previously regulated only as a dietary supplements (see Part 2); and

• Eight new molecular entities that are pharmacologically similar to previously approved drugs (see Part 2)

Part 1 looked back at first-in-class drug approvals, breakthrough therapies and orphan indications, important new diagnostic tests, and novel medical devices. “Me-too” drug approvals and other 2016 FDA accomplishments were summarized in Part 2. Throughout the series, orphan, breakthrough, and cancer therapy designations are notated by the symbols †, $, and #, respectively.

The 32 noteworthy biologics approved in 2016 are described here. Among them are:

• Twelve new authorizations expanding the clinical uses for biologics that are already on the market in the United States:

  • Six are marketed biologics licensed for orphan indications, and one of these, ustekinumab (Stelara) ¹, an interleukin (IL)-12 and IL-23 antagonist, was also granted a new non-orphan indication to treat adults with Crohn’s disease;² (see Part 1)

  • Four are marketed biologics designated with breakthrough therapy indications; (see Part 1)

  • OnabotulinumtoxinA (Botox)³, a botulinum toxin—approval was extended to the treatment of lower-limb spasticity in adults

  • Secukinumab (Cosentyx)⁴, a monoclonal antibody that inhibits interleukin-17A—approval was extended to the treatment of active psoriatic arthritis and to the treatment of active ankylosing spondylitis (see also below)⁵

• Six first-to-market monoclonal antibodies⁶ (see Table 7)

• Four new vaccines:

  • An oral cholera vaccine for travelers (see Table 8)

  • Three new quadrivalent influenza vaccines (see Table 8)

• Three biosimilars (adalimumab-atto,⁷ etanercept-szzs,⁸ infliximab-dyyb,⁹ see also below)

• Three recombinant coagulation factors (see Table 8)

• Two new products derived from blood:

  • A fibrin coagulation patch (see Table 8);

  • An immune globulin concentrate formulated for subcutaneous administration (see Table 8)

• One previously marketed biologic approved for a new indication (daclizumab for multiple sclerosis)¹⁰

• A cellular sheet of chondrocytes for autologous implantation (MACI)

An interchangeable biological product is similar to an FDA-approved reference product and also meets additional federal standards for interchangeability. A pharmacist may substitute an interchangeable biological product for the reference product without preauthorization by the prescriber. In 2016 FDA approved three biosimilars. No biosimilars currently approved for use in the United States are approved as interchangeable.

1. Adalimumab-atto (Amjevita)¹¹—Humira¹² (not interchangeable)⁷

2. Etanercept-szzs (Erelzi)¹³—Enbrel¹⁴ biosimilar (not interchangeable)⁸

3. Infliximab-dyyb (Inflectra)¹⁵—Remicade¹⁶ (not interchangeable)⁹

Daclizumab

(Zinbryta)¹⁷—daclizumab is a humanized monoclonal antibody (IgG₁) that binds to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the IL-2 receptor. Originally approved under the brand name Zenapax¹⁸ for prophylaxis against acute rejection in renal transplant recipients, daclizumab has not been marketed in the United States since 2009.¹⁹ Daclizumab was repurposed in 2016 and returned to the U.S. market with the brand name Zinbryta¹⁷ as an immunosuppressant to reduce relapses in patients with multiple sclerosis.¹⁰ In premarket clinical trials, daclizumab was compared to placebo and with an active control, interferon beta-1a (Avonex)²⁰, an agent with a small but established benefit on annualized relapse rate. Daclizumab administration was associated with a 45% lower rate of relapse than the active control and demonstrated a slightly higher benefit (54%) against placebo.²¹ Evidence related to a benefit against disease progression and disability were less clear.²¹ Daclizumab is associated with significant safety concerns and was approved with prescribing restricted to a REMS program.^17,21 Candidates for therapy with daclizumab should have a healthy liver and ideally have already failed other available treatment options. Use of the drug requires liver function tests prior to each monthly dose and for up to 6 months after stopping therapy. The elimination half-life of daclizumab is approximately 21 days.²¹ Postmarketing requirements will assess serious risks for drug-induced liver injury, infections, and immune-mediated disorders; the use of daclizumab during pregnancy; therapeutic failure due to the presence of neutralizing antidrug antibodies; and signals for the development of malignancies.²¹

Autologous cultured chondrocytes on porcine collagen membrane

(MACI)²² is indicated for the repair of symptomatic full-thickness cartilage defects of the knee in adult patients.²³ A cartilage biopsy is needed to harvest the cells to manufacture MACI, and the time between harvest and transplant is generally about 6 weeks.²² The product consists of autologous chondrocytes seeded on a 3×5-cm, resorbable porcine collagen membrane for implantation into the cartilage defect(s). The chondrocytes are propagated in cell culture and seeded at a density of 500,000–1,000,000 cells per cm². The implant is cut to size at the time of implantation, and the collagen membrane is resorbed over a period of 6 months or more. The protocol for implantation is described in the product labeling.²² A physician-prescribed postimplantation rehabilitation program is recommended. The basis for FDA approval of MACI²² was the demonstration of safety and effectiveness evaluated in a 2-year, prospective, multicenter, randomized, open-label, parallel-group study (SUMMIT [Superiority of MACI implant versus Microfracture Treatment in patients with symptomatic articular cartilage defects in the knee]).²⁴ Test subjects were randomized to receive either a one-time treatment with MACI or microfracture. Seventy test subjects completed the MACI study arm. At the end of 2 years, the pain and function outcome measurements between groups significantly (p = 0.001) favored MACI²² and the benefits were sustained for 3 years.²⁵ Excellent reviews of this and other forward-looking options for the repair of bad knees have been published.^25,26

• 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 pathology^5,54 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