By Randi Hernandez
Of the 45 new molecular entities and new therapeutic biological products approved by FDA in 2015, nine products were monoclonal antibodies (mAbs). And there may be many more of these types of proteins on the horizon—as many as 14 are projected to hit the market in 2016, according to data compiled by EvaluatePharma, in collaboration with BioPharm International (*).
mAbs in development
Most of the products listed below are in Phase III trials; however, a few are in earlier stages of development. Although the pharmaceutical manufacturers developing these mAbs will likely seek various indications for their products, the preliminary indications include treatments for various cancers, multiple sclerosis, psoriasis, asthma, HIV, and exposure to anthrax. Most of the emerging large-molecule drugs in the asthma pipeline are interleukin inhibitors targeting inflammatory pathways and are indicated for patients who have a reduced sensitivity to corticosteroids, although the specific targets vary somewhat by product.
Ixekizumab—Eli Lilly’s ixekizumab is an interleukin-17 drug that works by targeting the IL-17 ligand. This mAb is being developed for the treatment of psoriasis and psoriatic arthritis, and may directly compete with Novartis’ Cosentyx (secukinumab) and AstraZeneca/Valeant’s brodalumab. Brodalumab, however, will work a bit differently—it is an antibody that binds to the IL-17 receptor, whereas secukinumab and ixekizumab focus on the IL-17 ligand. In clinical trials, ixekizumab demonstrated superiority over Enbrel (etanercept) for clearing skin plaques.
Brodalumab—Valeant and AstraZeneca’s IL-17 therapy, brodalumab, 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. In September 2015, however, Valeant stepped in and agreed to be responsible for the commercialization and development of the project. Brodalumab was shown in clinical trials to clear the scaly skin patches associated with psoriasis more efficiently than Johnson & Johnson’s Stelara (ustekinumab).
Obiltoxaximab—Elusys Therapeutics’ mAb, obiltoxaximab, which will go by the trade name Anthim, differs significantly from the rest of the mAb pack. The investigational agent for the treatment of inhalational anthrax infection is supported by the Biomedical Advanced Research and Development Authority (BARDA), which is part of the US Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response (HHS ASPR). Even before the product’s approval by FDA, BARDA granted Elusys its first delivery procurement order for Anthim so that the agency could add Anthim to its Strategic National Stockpile (SNS) as a countermeasure against a potential bioterrorist attack. Elusys has already received more than $220 million in grants from government agencies to develop the mAb. The drug, meant to be used as both a treatment after anthrax exposure and as an anthrax prophylactic, is being investigated as an intravenous treatment as well as an emergency injectable. Obiltoxaximab was granted Fast-Track status and Orphan Drug Designation by FDA, according to the company.
Atezolizumab—This fully humanized mAb immunotherapy is the product of a collaboration between Roche and Genentech. The PD-L1 checkpoint inhibitor is being investigated for the treatment of various solid tumors, including indications for non-small cell lung cancer (NSCLC), bladder cancer, renal cell carcinoma, and breast cancer. The medication is meant for patients whose tumors express high levels of PD-L1. In clinical trials, treatment with atezolizumab corresponded to an average 7.7 month-extension of life when compared with those who received docetaxel chemotherapy; this represents a statistically significant survival benefit. If approved, atezolizumab will likely compete with Merck's Keytruda (pembrolizumab), Bristol-Myers Squibb's Opdivo (nivolumab), and AstraZeneca's durvalumab, which is being investigated in Phase II and III trials.
Reslizumab—Teva is gunning for FDA approval in 2016 for its biologic reslizumab (trade name Cinquil), which targets IL-5. Although the company will first seek an approval for the medication for the treatment of eosinophilic asthma, it is also researching the drug’s efficacy in the treatment of eosinophilic esophagitis. Reslizumab is in the same class as AstraZeneca’s Nucala (mepolizumab). In late 2016 or early 2017, AstraZeneca's benralizumab may also prove to be a competitor to reslizumab; although like mepolizumab, benralizumab will be a subcutaneous injection, while reslizumab is an intravenous drug. According to Teva, a decision from FDA on reslizumab is expected by March 2016.
Dupilumab—Sanofi and Regeneron’s dupilumab is currently in late-stage development for asthma and eczema/atopic dermatitis. The drug is promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. It will compete with AstraZeneca’s Nucala (mepolizumab), which was approved by FDA in November 2015, although Nucala works by another mechanism (through IL-5). Other competitors to dupilumab will likely include AstraZeneca’s Xolair (omalizumab), which was approved in the US in 2003 and works by another mechanism as well (by binding to the Ce3 domain of immunoglobulin E). Teva’s IL-5 inhibitor Cinquil (reslizumab, currently in Phase III trials), Roche’s IL-13 inhibitor lebrikizumab (in Phase II trials), and AstraZeneca’s IL-13 inhibitor tralokinumab (in Phase III trials for asthma) may also compete for market share in this crowded uncontrolled asthma mAb market. Sanofi/Regeneron will also seek approval for dupilumab for the treatment of eosinophilic esophagitis.
Farletuzumab—Farletuzumab is an investigational humanized IgG1 antibody targeting tumor cell surface protein folate receptor alpha (FRA), which is typically overexpressed in epithelial tissue-derived cancers. Farletuzumab works by blocking the function of FRA. The mAb, which is a radiotherapeutic that is bound to a cytotoxic radioisotope, received Orphan Drug designation in the US, European Union, and in Switzerland for its potential to treat platinum-sensitive ovarian cancer. Although the investigational agent is being developed by Eisai subsidiary Morphotek, the precursor to farletuzumab was originally developed by Dr. Lloyd Old from the Ludwig Institute for Cancer Research.
In November 2015, Morphotek announced it entered into an agreement with the Targeted Alpha Therapy Group (TAT Group) at the University of Gothenburg in Sweden to collaborate on the research and development of farletuzumab as an alpha therapy vector.
Ibalizumab—The medication ibalizumab is believed to be a promising treatment for HIV, as it represents a treatment alternative to traditional antiretroviral therapies (ARTs) and HIV vaccines. It represents a therapy for those who have become resistant to ARTs. Known as a viral-entry inhibitor, the anti-CD4 human mAb of murine origin works by blocking HIV-1 entry in vitro and has demonstrated in clinical trials to reduce HIV viral load.
Clinical-trial supplies of ibalizumab were manufactured at WuXi's biologics manufacturing facilities in China for its partner, developer TaiMed Biologics, according to a WuXi press release. The drug received FDA’s Breakthrough Therapy designation, according to WuXi, but curiously, the drug is not mentioned on the fda.gov website, perhaps because some sources say the drug received this status more than 12 years ago. EvaluatePharma cites Roche, Biogen, and The Aaron Diamond AIDS Research Center as co-developers of the drug.
Inotuzumab ozogamicin—Pfizer’s drug candidate for the treatment of acute lymphoblastic leukemia (ALL) is the only antibody-drug conjugate on the potential approval list for 2016. The drug received a Breakthrough Therapy designation from FDA in October 2015 based on the results of the drug’s performance in clinical trials compared with long-term chemotherapy for patients with relapsed or refractory CD22-positive ALL. Current treatments for ALL include Gleevec (imatinib) and Sprycel (dasatinib), but these are both examples of treatments for patients whose leukemia cells have the Philadelphia chromosome. According to the American Cancer Society, other mAbs that are now being studied for use against ALL include Rituxan (rituximab) and Campath (alemtuzumab). Inotuzumab ozogamicin originated from a collaboration between Pfizer and Celltech, which is now UCB—but Pfizer currently has sole responsibility for all manufacturing and clinical development activities for the medication.
The success of inotuzumab ozogamicin may not be easily gauged until Phase III trials conclude, however. In 2013, Pfizer ended its Phase III study of inotuzumab ozogamicin for the treatment of relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) patients due to futility.
Ocrelizumab—Roche’s ocrelizumab is a mAb being developed to treat relapsing multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS). In clinical trials, ocrelizumab was shown to be was superior to interferon beta-1a, also known as Pfizer/EMD Serono’s Rebif, 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 immune cells—CD20-positive B cells—that are thought to contribute to myelin and axonal damage. Ocrelizimab works by binding to CD20 cell-surface proteins on B cells, blocking their action. Roche’s Chief Medical Officer and Head of Global Product Development Sandra Horning, MD, stated in a company press release that ocrelizumab is the "first investigational medicine to slow a clinically meaningful and statistically significant effect on the progression of disease in primary-progressive MS."
Sarilumab—This IL-6-receptor inhibitor from Sanofi and Regeneron—meant to treat rheumatoid arthritis—was originally projected by some sources to gain regulatory approval in 2015, but is now expected to have a potential approval and launch in late 2016. The mAb 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.
The drug is being tested in clinical trials as a first- and second-line therapy in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs) and also as a monotherapy. Regeneron said in its 2015 investor notes that EULAR guidelines support the use of an IL-6 inhibitor as a monotherapy. Sailumab is likely to compete with such first-line therapies as Bristol-Myers Squibb’s Orencia (abatacept), Genentech’s IL-6 inhibitor Actemra (tocilizumab), and AbbVie’s tumor necrosis factor (TNF)-blocker Humira (adalimumab). The company said it will have clinical trial results comparing sarilumab’s efficacy to adalimumab by 2016.
Tildrakizumab— Another psoriasis drug, you say? This mAb from Merck is in Phase III clinical trials for the treatment of plaque psoriasis and is yet another psoriasis medication that is expected to gain regulatory approval in 2016. Merck licensed the product to Sun Pharma in September 2015; Sun will be responsible for the funding of the molecule through regulatory approval, but Merck will perform the clinical and regulatory duties leading up to approval. Post-approval, Sun will take over all subsequent regulatory duties. Potential competitors that target IL-23 include J&J’s Stelara (ustekinumab) and Janssen’s guselkumab, which is currently in Phase II trials.
Tremelimumab—Tremelimumab is an immune checkpoint inhibitor that prevents the blocking of the action of cytotoxic T-lymphocytes, allowing the immune system to more effectively destroy cancer cells. The fully humanized mAb binds to the protein CTLA-4 on the surface of activated T-lymphocytes, turning off inhibitory immune signals.
The molecule has had somewhat of a troubled developmental past, however, as Pfizer got to Phase III trials with it for the treatment of metastatic melanoma, but failed in this phase to demonstrate the drug’s superiority over chemotherapy. In 2011, AstraZeneca’s MedImmune arm gained worldwide development and commercialization rights to the molecule (although Pfizer will retain rights to tremelimumab for certain combinations of therapies). In the ARCTIC, MYSTIC, and NEPTUNE trials, MedImmune is testing the drug's efficacy in combination with investigational agent durvalumab for the first-line treatment of metastatic non-small cell lung cancer and head and neck cancers. FDA has also granted Fast Track designation to tremelimumab as a monotherapy for the treatment of malignant mesothelioma, an aggressive, rare form of cancer that affects the lining of the lungs and abdomen.
Daclizumab—Daclizumab will join Roche’s ocrelizumab as another treatment for multiple sclerosis that could gain regulatory approval in 2016. Daclizumab, under the trade name Zenapax, was actually approved by FDA in 1997 to prevent organ rejection after transplantation. The drug would be listed under trade name Zinbryta for the treatment of multiple sclerosis, and according to a press release from co-developers Biogen and AbbVie, it demonstrated “superior outcomes” in clinical trials when compared with Biogen’s Avonex (interferon beta-1a). The superior outcome was defined as 45% better relapse reduction than was observed with Avonex. Although daclizumab successfully reduced the relapse rate of disease, it did not significantly improve disease progression after three months when compared with treatment with Avonex.
Unlike investigational agent ocrelizumab, which binds to CD20, daclizumab binds to IL-2 subunit CD25, modulating the activity of IL-2 against abnormally activated T-cells that attack myelin. Zinbryta is believed to modulate the function on IL-2 without disrupting general immune system responses.
Other notable mentions of mAbs to watch in 2016: AstraZeneca's benralizumab, Merck’s avelumab.
*The forecasted approval dates are drawn directly from company-disclosed information (e.g., press releases, company presentations, etc.). As such, there may be products that are filed or in Phase III that are not included in these reports, due to the lack of information regarding approval/launch dates from either of these sources. Similarly, the original data were requested by and provided to BioPharm International by EvaluatePharma in August 2015; therefore, some of the original submissions have been excluded and/or modified by BioPharm International to reflect regulatory changes. As examples, although daratumumab, elotuzumab, and idarucizumab were originally included in EvaluatePharma’s list as mAbs that would gain regulatory approval in 2016, these three molecules actually gained US FDA approval in 2015.