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EvaluatePharma and BioPharm International highlight the antibody-based therapeutics that may gain United States Regulatory approval in 2017.
In 2016, 7 of the 22 new molecular entity (NME) and new therapeutic biological product approvals by FDA were antibody-based medications: Merck’s Zinplava (bezlotoxumab), Eli Lilly’s Lartuvo (olaratumab), Biogen’s Zinbryta (daclizumab), Genentech’s Tecentriq (atezolizumab), Teva’s Cinqair (reslizumab), Eli Lilly’s Taltz (ixekizumab), and Elusys’ Anthim (obiltoxaximab) (1). Although that is fewer monoclonal antibodies (mAbs) than were approved in 2015 (9 mAbs approved)-when considered as a percentage of the total approvals-there was a larger percentage of antibody-based products in 2016 than in 2015; antibody-based therapeutics were approximately 32% of NME approvals in 2016. For 2017, life-science commercial intelligence firm Evaluate, in collaboration with BioPharm International, predicts that FDA may grant marketing approval to somewhere in the range of 8–16 antibody-based investigational candidates.
The first portion of mAbs that we highlight for 2017 are those that have concrete Prescription Drug User Fee Act (PDUFA) dates in 2017. These dates have been disclosed by the companies developing the drugs, and the forecasted approval dates are drawn directly from company-disclosed information (e.g., press releases, company presentations). As such, there may be products that are filed or in Phase III that are not included in this article, due to the lack of information regarding approval/launch dates.
In the second section of this article, the mAbs highlighted are those that have 2017 launch dates based on broker models for these products, which show 2017 as the first year of forecasted sales for the products. All of the products in the second section are in Phase III trials-and may be eligible for regulatory approval in 2017-but may not have publically announced PDUFA dates.
Although drug efficacy was not an inclusion requirement in the selection of mAbs that were likely to gain approval, BioPharm International did review and include some efficacy findings from clinical trials, wherever they were applicable.
Brodalumab-This mAb that binds to the IL-17 receptor for the treatment of psoriasis got some bad press in May 2015 when Amgen dropped out of the co-development project with AstraZeneca after clinical-trial results suggested that the drug was associated with suicidal ideation in patients. Valeant took over the United States commercialization and development of the project in September 2015. IL-17 inhibitors have been shown to clear plaques more efficiently than anti-tumor necrosis factor (TNF) therapies, which are first-line therapies for psoriasis (2). Other FDA-approved IL-17 inhibitors include secukinumab and ixekizumab. Although Brodalumab had an original PDUFA date of Nov. 16, 2016, its new date is Feb. 16, 2017. In July 2016, an FDA panel recommended the therapy for approval (3).
Ocrelizumab-Roche’s ocrelizumab, which will go by the trade name Ocrevus if approved, is being developed to treat relapsing multiple sclerosis (MS) and primary progressive MS (PPMS). FDA granted the product a Breakthrough Therapy designation in February 2016 (4). In clinical trials, ocrelizumab was shown to be superior to interferon beta-1a, a widely used treatment for relapsing forms of the disease. There are currently no approved treatments for the progressive form of the disease. Ocrelizumab is designed to selectively target CD20-positive B cells that are thought to contribute to myelin and axonal damage. It works by binding to CD20 cell-surface proteins on B cells and blocking their action. Because ocrelizumab does not bind to stem cells or plasma cells, Roche says the immune system will remain somewhat intact following the elimination of mature B cells. FDA extended review of the application for ocrelizumab so that Roche could provide extra data on the commercial manufacture of the investigational agent.
Dupilumab-Sanofi and Regeneron’s first-in-class dupilumab in under investigation for the treatment of eczema/atopic dermatitis, for which it received Breakthrough Therapy status from FDA in 2014 (5, 6). The companies are also investigating the drug for the treatment of asthma, chronic sinusitis, and eosinophilic esophagitis. The drug, approved by the European Medicines Agency (EMA) as Dupixent, is an IL-4Rα antagonist that inhibits the biological effects of both IL-4 and IL-13, two cytokines responsible for eliciting an immune response (7). In clinical trials, dupilumab was shown to provide significant improvement in the clinical signs and symptoms of atopic dermatitis compared with existing topical treatments or placebo (8, 9).
Durvalumab-AstraZeneca/MedImmune’s durvalumab was granted a Breakthrough Therapy status from FDA in February 2016 and a Priority Review status in December 2016 for the treatment of urothelial cancer in patients whose disease has progressed following treatment with platinum-based chemotherapy (10). Durvalumab is also being tested in combination with other products for the treatment of non-small cell lung cancer (NSCLC), head and neck cancers, gastric cancer, pancreatic cancer, hepatocellular carcinoma, and blood cancers in more than 30 ongoing clinical trials. This anti-PD-L1 IgG1 investigational therapy works by blocking the interaction of PD-L1 with both PD-1 and CD80 on T cells, effectively blocking the “cloaking” mechanism that tumor cells use to evade detection by T cells. If approved, durvalumab may compete with Opdivo (nivolumab), which received approval for the treatment of metastatic urothelial cancer on Feb. 2, 2017.
Avelumab-This investigational anti-PD-L1 mAb is being investigated for its efficacy in treating metastatic Merkel cell carcinoma (MCC) and bladder cancer. It is being co-developed by Merck KGaA and Pfizer. It has the potential to be the first treatment for MCC, and has received Breakthrough Therapy, Fast Track, and Orphan Drug designations from FDA for this indication. (11). For the bladder cancer indication, avelumab is a potential competitor to Tecentriq (atezolizumab)-although unlike Tecentriq, avelumab is thought to have a dual mechanism of action, and is thought to preserve antibody-dependent cell-mediated cytotoxicity (ADCC) and help white blood cells find and attack tumors (12). Although the medication is also under investigation to treat NSCLC, ovarian cancer, stomach cancer, renal cell carcinoma, and other cancers, the first potential indications that are expected to launch in 2017 are the MCC and bladder cancer indications.
Romosozumab-UCB and Amgen are backing this mAb, which will serve as an alternate therapy to existing osteoporosis treatments Fosmax (alendronate) and Forteo (teriparatide). Romosozumab was developed to inhibit the production of the protein sclerostin and help increase bone mineral density, especially in the spine and hip regions. In Phase III trials, romosozumab reduced the risk of new vertebral fractures in post-menopausal women after 12 months of treatment (13, 14). "We are pleased to see nearly 15 years of sclerostin antibody research reinforced with these Phase III data," said Sean E. Harper, MD, executive vice-president of research and development at Amgen, in a company press release (15). "Romosozumab, with its dual effect as a bone builder and anti-resorptive, has the potential to play a distinct and important role in the treatment of women with postmenopausal osteoporosis at increased risk of fracture” (15).
Sirukumab-Co-developed by GlaxoSmithKline and Johnson & Johnson subsidiary Janssen Biotech, sirukumab is a human anti-interleukin IL-6 mAb for the treatment of rheumatoid arthritis (RA). It is being investigated as a second-line therapy in five different studies for patients who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs), were intolerant to tumor necrosis factor (TNF) inhibitors, or for those who failed treatment with methotrexate or sulfasalazine.
The companies are seeking approval for the drug in both prefilled syringes and in an autoinjector, which may give the drug a competitive advantage over other market contenders. Roche/Chugai's Actemra (tocilizumab)-the existing first-in-class product that targets the IL-6 receptor in RA-is typically infused in an outpatient office or hospital setting.
Sirukumab could also compete with investigational candidate sarilumab, as well as with popular TNF inhibitors for RA such as Humira (adalimumab). Clinical trial results comparing sirukumab to Humira suggested sirukumab was more effective at achieving one of the co-primary endpoints-significantly greater improvement in Disease Activity Score (DAS28)-but both drugs performed about the same for the study’s second co-primary endpoint, which was improvement in the signs and symptoms of RA (16).
Guselkumab-Guselkumab is a mAb that targets a particular subunit alpha (p19 subunit) of IL-23. Janssen is developing the therapy for the treatment of plaque psoriasis, which is interesting because Janssen also holds the rights to Stelara (ustekinumab), an older anti-IL-12/23 p40 mAb that could serve as a competitor to guselkumab. Another anti-IL-23 mAb in the pipeline with an indication for plaque psoriasis is Sun Pharma's tildrakizumab, which is still in clinical trials. Recently approved mAbs to treat psoriasis, such as Taltz (ixekizumab) and Cosentyx (secukinumab), might also serve as competitors, although these therapies target the IL-17 cytokine.
When compared head-to-head with Humira for 16 weeks, guselkumab was able to produce almost complete skin clearance in a significantly higher proportion of patients (17, 18). Humira was administered ten times during the treatment period, whereas guselkumab was only administered three times during the treatment period, which could make guselkumab an attractive alternative to existing therapies. Results from the NAVIGATE study-which evaluated the efficacy of guselkumab for psoriasis patients who had an inadequate response to ustekinumab-will be presented at upcoming scientific meetings.
1. FDA, “Novel Drug Approvals for 2016,” www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775.htm, accessed Feb. 1, 2017.
2. P.S. Yamauchi and J. Bagel, J. Drugs Dermatol. 14 (3) 244–253 (March 2015).
3. Valeant, "FDA Advisory Committee Recommends Approval Of Brodalumab For Treatment Of Moderate-To-Severe Plaque Psoriasis," Press Release, July 19, 2016.
4. Roche, "U.S. FDA grants Breakthrough Therapy Designation for Roche's investigational Medicine Ocrelizumab in Primary Progressive Multiple Sclerosis," Press Release, Feb. 17, 2016.
5. Regeneron, "Regeneron and Sanofi Announce Positive Dupilumab Topline Results from Two Phase 3 Trials in Inadequately Controlled Moderate-to-Severe Atopic Dermatitis Patients," Press Release, Apr. 1, 2016.
6. Regeneron, "Regeneron and Saofi Announce that Dupilumab Has Received FDA Breakthrough Therapy Designation in Atopic Dermatitis," Press Release, Nov. 20, 2016.
7. Sanofi, "Regeneron and Sanofi Announce Marketing Authorization Application for Dupixent (dupilumab) Accepted for Review by the EMA," Press Release, Dec. 8, 2016.
8. D. Thaçi et al., The Lancet 387, pp. 40–52 (2016).
9. E.L. Simpson et al., N. Engl. J. Med. 375, pp. 2335–2348 (Dec. 15, 2016).
10. AstraZeneca, "US FDA Accepts First Biologics License Application for AstraZeneca’s Durvalumab in Bladder Cancer," Press Release, Dec. 9, 2016.
11. Pfizer, "FDA Accepts the Biologics License Application for Avelumab for the Treatment of Metastatic Merkel Cell Carcinoma for Priority Review," Press Release, Nov. 29, 2016.
12. Personal communication, Sally Beatty, Media Relations at Pfizer
13. Amgen, "Results from Phase 3 FRAME Study of Romosozumab Showed Significant Reductions in Both New Vertebral and Clinical Fractures in Postmenopausal Women with Osteoporosis," Press Release, Sept. 18, 2016.
14. M.R. McClung et al., N. Engl. J. Med. 370, pp. 412–420 (Jan. 30, 2014).
15. GlaxoSmithKline, "GSK Announces US Regulatory Submission for Sirukumab in Rheumatoid Arthritis," Press Release, Sept. 23, 2016.
16. Johnson & Johnson, "New Phase 3 Monotherapy Study of Sirukumab Versus Humira and Sirukumab Data in an Anti-Tnf Refractory Population Reported in the Treatment of Moderately to Severely Active Rheumatoid Arthritis," Press Release, Nov. 16, 2016.
17. Janssen, "New Phase 3 Data Show Efficacy Versus Placebo and Superiority of Guselkumab Versus Humira in Treatment of Moderate to Severe Plaque Psoriasis," Press Release, Oct. 1, 2016.
18. BioPharm International Editors, "Guselkumab Superior to Humira in Phase III Trial," www.biopharminternational.com/guselkumab-superior-humira-phase-iii-trial-0, accessed Feb. 1, 2017.
19. J.S. Smolen et al., Ann. Rheum. Dis. Published Online First: Jan. 13, 2017, doi: 10.1136/annrheumdis-2016-209831.