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Evaluate and BioPharm International highlight the antibody-based therapeutics that may have 2017 launch dates in the United States.
In Part I of this series, the BioPharm International highlighted antibody-based therapeutics that have set 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 were drawn directly from company-disclosed information (e.g., press releases, company presentations).
In Part II of the series, BioPharm International, in collaboration with life-science commercial intelligence firm Evaluate, highlights product candidates that have 2017 launch dates based on broker models for the products, which identify 2017 as the first year in which sales will occur for the products. In short, all of the following products are in Phase III trials-and may be eligible for regulatory approval in 2017-but may not have publically announced PDUFA dates.
The following group of mAbs may also receive regulatory approval in 2017, but because not all companies disclose PDUFA dates, it is unclear when exactly each therapy will be considered for regulatory review. The therapies, however, could be found in company-disclosed estimates of sales earnings and Wall Street forecasts.
Benralizumab-Co-developed by AstraZeneca and Kyowa Hakko Kirin Co., this glycoengineered anti-eosinophil antibody targets cytokine IL-5 and is being investigated for its efficacy in the treatment of severe asthma in patients whose symptoms are not adequately controlled with inhaled corticosteroids or long-acting beta agonists. In a study published in The Lancet, benralizumab successfully reduced asthma exacerbations in patients with high levels of eosinophils in their blood (1).
GlaxoSmithKline’s Nucala (mepolizumab) and Teva’s Cinqair (reslizumab), which are both FDA-approved drugs that inhibit IL-5, are similar to benralizumab. Mepolizumab and reslizumab, however, target the IL-5 molecule directly, whereas benralizumab targets the IL-5 receptor. "By targeting the IL-5 receptor, benralizumab depletes eosinophils directly, and our studies show that eosinophil counts were nearly completely depleted by week 4 of treatment," said Eugene Bleecker, MD, professor at the Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, who served as lead author of the SIROCCO trial investigating benralizumab, in a Lancet press release (1). Mepolizumab and reslizumab are indicated every four weeks; treatment with benralizumab in the four-week cohort reduced eosinophil levels but did not confer reduction of asthma symptoms. There was only a significant reduction in patient-reported asthma symptoms when treatment occurred every eight weeks (compared with placebo at week 48) (2, 3). Although this could be considered a treatment drawback, investigators viewed the eight-week cycle as a potential advantage, saying in a linked comment that lower-dose, less-frequent dosing of IL-5 could be economically advantageous (4).
Depatuxizumab mafodotin (ABT-414)-This investigational agent is actually an antibody-drug conjugate. Developed by AbbVie, it consists of an epidermal growth factor receptor (EGFR) IGg1 mAb (depatuxizumab) conjugated to the tubulin inhibitor monomethyl auristatin F via a stable maleimidocaproyl linker. FDA gave the medication an Orphan Drug status in 2014 for the treatment of glioblastoma multiforme, a type of brain cancer. It also received a Rare Pediatric Disease Designation from FDA for Diffuse Intrinsic Pontine Glioma (DIPG)-a condition characterized by tumors at the base of the brain-based on the proposal of a nested, sub-study of ABT-414 in adults with recurrent EGFR-amplified glioblastoma (5).
Farletuzumab (MORAb-003)-Farletuzumab is a humanized mAb that binds to folate receptor-alpha, which is expressed in 80% to 100% of epithelial ovarian cancers. It is being studied in combination with carboplatin and a taxane for the treatment of platinum-sensitive ovarian cancer. In 2013, farletuzumab did not meet the study’s primary endpoint, which was progression-free survival (PFS) (6). It was revealed in the study that patients with low levels of CA125, a protein produced by cancer cells, responded best to treatment with farletuzumab. In response to this finding, Morphotek initiated a Phase II trial, MORAb-003-011, to further investigate the potential clinical benefit observed in the patients with a low CA125 level (7, 8).
Ibalizumab-Ibalizumab is certainly of interest, if judging by the number of companies that are involved in its development. Three co-developers are counted as cooks in the kitchen, including Theratechnologies, TaiMed Biologics, and The Aaron Diamond AIDS Research Center. Treatment with this anti-CD4 mAb for multidrug-resistant HIV-1 produced a significant reduction of viral load in Phase III clinical trials, and is likely to be reserved for heavily treated patients who have developed extensive resistance to other antiretroviral classes. It is the first mAb-based treatment being investigated in the treatment of HIV. Unlike retroviral medications, which work by inhibiting replication of the HIV virus, ibalizumab binds to the second extracellular domain of the CD4 receptor, preventing the virus from entering the CD4+ immune cells (9). Ibalizumab was granted Breakthrough Therapy designation, an Orphan Drug status, and a Fast Track designation from FDA.
Inotuzumab ozogamicin-Pfizer and UCB’s inotuzumab ozogamicin is an investigational agent for adults with relapsed/refractory acute lymphoblastic leukemia (ALL). It is an antibody-drug conjugate (ADC) composed of a mAb that targets CD22, an antigen found on the surface of cancerous B cells in many patients. The mAb is linked to cytotoxic antibiotic agent calicheamicin. Inotuzumab ozogamicin received a Breakthrough Therapy designation from FDA in 2015 (10).
In 2016, the drug met its primary endpoint (complete response) in the Phase III INO-VATE ALL study and was found to be superior than treatment with standard chemotherapy. But, the drug did not significantly extend overall survival (the secondary study endpoint) compared with chemotherapy. In addition, veno-occlusive liver disease (VOD) occurred more frequently in patients treated with inotuzumab ozogamicin than in the chemotherapy cohort (11% vs. 1%) (11, 12).
Burosumab-In development for the treatment of a disorder involving phosphate metabolism that causes rickets, called X-linked hypophosphatemia, burosumab (KRN-23) is co-owned by Ultragenyx Pharmaceutical Inc. and Kyowa Kirin International. The drug candidate seeks to reduce the activity of FGF23, a hormone instrumental in regulating phosphate excretion by the kidneys. The companies plan to submit a biologics license application (BLA) to FDA for KRN23 in the second half of 2017 (13).
Sarilumab-This IL-6-receptor inhibitor was originally projected by some sources to gain regulatory approval in 2015, and then in 2016, but is now expected to have a potential approval and launch in late 2017. Sarilumab received a Complete Response letter from FDA in 2016 and is currently addressing cGMP manufacturing issues related to that letter (14). Meanwhile, sarilumab was approved by Health Canada on February 2, 2017 under the trade name Kevzara (15).
The mAb from Sanofi and Regeneron works by blocking the binding of IL-6 to its receptor and interrupting the cytokine-mediated inflammatory signaling cascade. Clinical trials with the investigational compound revealed x-ray data that showed 90% inhibition of structural damage to joints.
Sarilumab is likely to compete with Roche/Chugai's IL-6 inhibitor Actemra (tocilizumab) and with the investigational anti-IL-6 mAb sirukumab.
Xilonix- XBiotech's Xilonix is being tested in clinical trials for the treatment of advanced colorectal cancer that is refractory to the current standard of care. The investigational therapy received Fast Track designation from FDA (16).
It consists of MABp1, an antibody that targets interleukin 1α; interleukin 1α is responsible for driving inflammatory signals within the tumor microenvironment. MABp1 is being investigated for its effect on symptoms of colorectal cancer as well as its ability to treat cachexia and the associated muscle loss, fatigue, appetite loss, and pain that is characteristic of patients with colorectal cancer. There are two Phase III trials that are ongoing for the treatment of colorectal cancer: The first is studying Xilonix for a non-traditional endpoint (one measured by combined objective and self-reported measures of symptom control), and the second study is looking at the drug in relation to overall survival (17). For the “novel” endpoint of improving tumor-related symptoms, Xilonix demonstrated a clinical benefit (18). In 2012, Xilonix received a Fast Track designation from FDA for the treatment of wasting syndrome (19).
1. J.M. FitzGerald et al., The Lancet 388 (10056) 2128–2141 (Oct. 29, 2016).
2. E.R. Bleecker et al., The Lancet 388 (10056) 2115–2127 (Oct. 29, 2016).
3. AstraZeneca, "Benralizumab Phase III Trials Show Positive Results in Severe Asthma," Press Release, Sept. 5, 2016.
4. M. Castro and L.B. Bacharier, The Lancet 388 (10056) 2059–2060 (Oct. 29–Nov. 4, 2016).
5. AbbVie, "AbbVie Receives US FDA Rare Pediatric Disease Designation for Investigational ABT-414 for the Treatment of a Type of Pediatric Brain Tumor Known as Diffuse Intrinsic Pontine Glioma (DIPG)," Press Release, July 11, 2016.
6. Eisai, "Eisai Announces Results of Phase III Study of Anticancer Agent Farletuzumab in Patients with Relapsed Platinum-Sensitive Ovarian Cancer," Press Release, Jan. 11, 2013.
7. Morphotek, "Morphotek Announces Publication of Phase 3 Results from MORAb-003-004 Trial in Platinum-Sensitive Ovarian Cancer Patients," Press Release, Apr. 18, 2016.
8. I. Vergote et al., J. Clin. Onc. 34 (19) 2271–2278 (July 2016).
9. Theratechnologies, "Theratechnologies Announces Results from the Last Pivotal Phase III Trial of HIV Long Acting Biologic (LAB) Investigational Antiretroviral Ibalizumab," Press Release, Nov. 10, 2016.
10. Pfizer Oncology, "Inotuzumab Ozogamicin Fact Sheet," www.pfizer.com/files/news/esmo/ESMO2016_Pipeline_Fact_Sheet_Inotuzumab.pdf, accessed Feb. 1, 2017.
11. Pfizer, "Pfizer Announces Final Results from Inotuzumab Ozogamicin Pivotal Phase 3 Study in Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia," Press Release, June 12, 2016.
12. H.M. Kantarjian et al., N. Engl. J. Med. 375, pp. 740–753 (June 12, 2016).
13. Ultragenyx, "Ultragenyx and Kyowa Kirin International Announce Marketing Authorization Application for KRN23 Filed and Accepted for Review by European Medicines Agency," Press Release, Jan. 5, 2017.
14. Sanofi, "Sanofi and Regeneron Receive Complete Response Letter from FDA for Sarilumab, an Investigational Treatment for Rheumatoid Arthritis," Press Release, Oct. 28, 2016.
15. Regeneron, "Regeneron and Sanofi Announce First Approval of Kevzara (sarilumab) for the Treatment of Moderately to Severely Active Rheumatoid Arthritis in Adult Patients by Health Canada," Press Release, Feb. 1, 2017.
16. XBiotech, Inc., NCT02138422, "A Phase 3 Study to Evaluate Xilonix as an Anticancer Therapy in Patients with Symptomatic Colorectal Cancer," https://clinicaltrials.gov/show/NCT02138422, accessed Feb. 1, 2017.
17. XBiotech, Inc., "A Phase III Study of Xilonix in Patients with Advanced Colorectal Cancer (XCITE)," https://clinicaltrials.gov/show/NCT01767857, accessed Feb. 1, 2016.
18. T. Hickish et al., The Lancet 18 (2) 192–201, (February 2017).
19. XBiotech, "XBiotech Receives Fast Track Designation from FDA for Anti-Cachexia Drug Xilonix," Press Release, Oct. 3, 2012.