Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Sirukumab in Confirmed Severe or Critical COVID-19 Disease

The purpose of this study is to evaluate the clinical response of sirukumab (administered as a single intravenous dose) plus standard of care (SOC) compared to placebo plus SOC in COVID-19.

Start Date24 Apr 2020

Sponsor / Collaborator

Janssen Pharmaceutica NV

NCT02899026

/ WithdrawnPhase 3

A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Sirukumab in Subjects With Polymyalgia Rheumatica

Sirukumab is a human anti-IL-6 monoclonal antibody that selectively binds to the cytokine with high affinity that may have therapeutic benefit in the treatment of polymyalgia rheumatica (PMR) by interrupting multiple pathogenic pathways. Sirukumab inhibits IL-6-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation, resulting in the inhibition of the biological effect of IL-6. This study will evaluate the efficacy and safety of sirukumab to characterize the benefit-to-risk profile of sirukumab in the treatment of active PMR. The study will be conducted in 2 parts (Part A and Part B) and consists of the following phases: Screening phase, Part A: 52-week double-blind treatment phase, Part B: 52-week extension phase with no study drug administration and a 16-week follow-up phase if applicable.
Approximately 150 subjects with a diagnosis of PMR and active disease within 6 weeks of baseline will be randomized into Part A, the 52-week double-blind treatment phase, to receive one of two doses of sirukumab or placebo, each in addition to a pre-specified prednisone taper. The efficacy and safety of sirukumab in sustaining remission will be assessed at Week 52. Subjects completing Part A of the study who are in clinical remission will be eligible to enter Part B, the 52-week extension phase, designed to investigate the long-term maintenance of remission and safety following cessation of sirukumab treatment and to assess long-term corticosteroid use. Subjects will need to have follow-up safety evaluations for at least 16 weeks after receiving the last dose of study drug, applicable for those who have withdrawn prematurely from the study or who have completed Part A but are not eligible for Part B.

Start Date15 Mar 2018

Sponsor / Collaborator

GSK Plc

NCT02794519

/ WithdrawnPhase 2

205076: A Phase II, Multicenter, Randomized, Double-blind (Sponsor-unblind), Placebo- Controlled, Parallel Group Trial to Evaluate the Efficacy and Safety of Sirukumab in Subjects With Severe, Poorly Controlled Asthma

Sirukumab is a fully human anti interleukin (IL)-6 immunoglobulin G1-kappa monoclonal antibody (MAb) which is in development for the treatment of rheumatoid arthritis (RA). The continuing unmet need in subjects with asthma refractory to corticosteroid therapy and increased understanding of asthma pathogenesis have stimulated the development of targeted biologics based on predictive biomarkers. The majority of approaches to date have targeted T Helper 2 (Th2) cytokines or their downstream effects. Targeting IL-6 in severe asthma represents an unprecedented approach that has potential to address non-Th2 drivers of severe asthma. This multicenter, randomized, double-blind (sponsor-unblind), placebo-controlled, parallel group study will investigate the efficacy of sirukumab compared to placebo in subjects having uncontrolled severe asthma despite use of high dose inhaled corticosteroid (ICS) in combination with long-acting Beta-agonist (LABA). The study will employ a variable treatment period for individual subjects. Dosing will continue every 4 weeks until week 44 (inclusive), or until 24 weeks after the final subject has been randomized, whichever the sooner. Upon receiving the final dose of study medicine or placebo, subjects will enter a 16 week Follow Up period. Overall, the duration of participation for subjects who complete the full 44-week treatment period and Follow Up period may be up to 64 weeks. Approximately 175 subjects will be randomized such that 140 evaluable subjects complete the study.

Start Date23 Sep 2016

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with Sirukumab

100 Translational Medicine associated with Sirukumab

100 Patents (Medical) associated with Sirukumab

Literatures (Medical) associated with Sirukumab

01 Dec 2024·JOURNAL OF INFECTION

Corrigendum to “The IL-6 hypothesis in COVID-19: A phase 2, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of free IL-6 sequestration by the monoclonal antibody sirukumab in severe and critical COVID-19” [J Infect 89 (2024) 106241]

Author: Foong, Kap Sum

01 Oct 2024·JOURNAL OF INFECTION

The IL-6 hypothesis in COVID-19: A phase 2, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of free IL-6 sequestration by the monoclonal antibody sirukumab in severe and critical COVID-19

Article

Author: Buelens, Annemie ; Verbrugge, Inge ; De Meyer, Sandra ; Robinson, Philip ; Spak, Cedric W ; Chien, Jason W. ; Opsomer, Magda ; Slim, Jihad ; Chien, Jason W ; Van Landuyt, Erika ; Van Wesenbeeck, Liesbeth ; Cook, Paul ; Deveikis, Audra ; Mo, Wai Ling ; Callewaert, Katleen ; Clement, Meredith ; Zhuang, Yanli ; Gottlieb, Robert L. ; Gottlieb, Robert L ; Foong, Kap Sum ; Spak, Cedric W.

BACKGROUND:

Upregulation of IL-6 has been associated with worse prognosis in COVID-19 patients. Impact on IL-6 signalling has mostly been limited to clinical outcomes in IL-6 receptor antagonist trials.

METHODS:

We performed a phase 2, randomised, double-blind, placebo-controlled trial (NCT04380961) of US-based hospitalised adults (<85 years) with laboratory-confirmed SARS-CoV-2 infection and severe (low levels of supplemental oxygen) or critical disease (high levels of oxygen supplementation). Patients received sirukumab 5 mg/kg or placebo single dose IV on Day 1 plus standard of care. The primary endpoint was time to sustained clinical improvement up to Day 28 based on an ordinal scale. Secondary endpoints included clinical improvement, all-cause mortality, and safety. Following an interim analysis, the protocol was amended to only recruit patients with critical COVID-19.

FINDINGS:

From May 2020 to March 2021, 209 patients were randomised; 112 had critical disease (72 sirukumab, 40 placebo) at baseline. Median time to sustained clinical improvement in critical patients was 17 and 23 days in the sirukumab and placebo groups (HR, 1∙1; 95% CI, 0∙66-1∙88; p > 0∙05). At Day 28, 59∙4% versus 55∙0% of patients achieved clinical improvement with sirukumab versus placebo and rates of all-cause mortality were 24∙6% versus 30∙0%, respectively. Rates of grade ≥3 adverse events were comparable between the sirukumab and placebo groups (25∙9% vs 32∙9%; all patients).

INTERPRETATION:

In critical COVID-19 patients who received sirukumab, there was no statistically significant difference in time to sustained clinical improvement versus placebo despite objective sequestration of circulating IL-6, questioning IL-6 as a key therapeutic target in COVID-19.

01 Jan 2024·European journal of medicinal chemistry

Mitochondria-targeted pentacyclic triterpene NIR-AIE derivatives for enhanced chemotherapeutic and chemo-photodynamic combined therapy

Article

Author: Zhang, Xuewei ; Zheng, Jinhong ; Wang, Xiang ; Wang, Jinzhi ; Dong, Mingming ; Zheng, Guoxing ; Lin, Liyin ; Yan, Kang ; Huang, Zhaopeng

Complexes formed by combining pentacyclic triterpenes (PTs) with Aggregation-Induced Emission luminogens (AIEgens), termed pentacyclic triterpene-aggregation induced emission (PT-AIEgen) complexes, merge the chemotherapeutic properties of PTs with the photocytotoxicity of AIEgens. In this study, we synthesized derivatives by connecting three types of triphenylamine (TPA) pyridinium derivatives with three common pentacyclic triterpenes. Altering the connecting group between the electron donor TPA and the electron acceptor pyridinium resulted in increased production of reactive oxygen species (ROS) by PT-AIEgens and a red-shift in their fluorescence emission spectra. Importantly, the fluorescence emission spectra of BA-3, OA-3, and UA-3 extended into the near-infrared (NIR) range, enabling NIR-AIE imaging of the sites where the derivatives aggregated. The incorporation of the pyridinium structure improved the mitochondrial targeting of PT-AIEgens, enhancing mitochondrial pathway-mediated cell apoptosis and improving the efficiency of chemotherapy (CT) and chemo-photodynamic combined therapy (CPCT) both in vivo and in vitro. Cellular fluorescence imaging demonstrated rapid cellular uptake and mitochondrial accumulation of BA-1 (-2, -3). Cell viability experiments revealed that BA-1 (-2), OA-1 (-2), and UA-1 (-2) exhibited superior CT cytotoxicity compared to their parent drugs, with BA-1 showing the most potent inhibitory effect on HeLa cells (IC₅₀ = 1.19 μM). Furthermore, HeLa cells treated with BA-1 (1 μM), BA-2 (1.25 μM), and BA-3 (1 μM) exhibited survival rates of 2.99 % ± 0.05 % μM, 5.92 % ± 2.04 % μM, and 2.53 % ± 0.73 % μM, respectively, under white light irradiation. Mechanistic experiments revealed that derivatives induced cell apoptosis via the mitochondrial apoptosis pathway during both CT and CPCT. Remarkably, BA-1 and BA-3 in CPCT inhibited cancer cell proliferation in an in vivo melanoma mouse xenograft model. These results collectively encourage further research of PT-AIEgens as potential anticancer agents.

News (Medical) associated with Sirukumab

01 Dec 2023

·synapse.patsnap.com

Deciphering IL-6 Inhibitors: Your Guide to Rapidly Accessing the Newest Advances

IL-6, or Interleukin-6, is a cytokine that plays a crucial role in the human body's immune response and inflammation regulation. It is produced by various cells, including immune cells, and acts as a signaling molecule to stimulate the immune system during infection or injury. IL-6 also plays a role in the development and differentiation of immune cells, such as B cells and T cells. However, excessive or prolonged IL-6 production can lead to chronic inflammation and contribute to the pathogenesis of various diseases, including autoimmune disorders and certain cancers. Therefore, understanding and regulating IL-6 levels is of great importance in the pharmaceutical industry for the development of targeted therapies. IL-6 Inhibitors is relevant to many inflammatory diseases and cancers. The first approved medication in this class was tocilizumab (Actemra), an antibody directed against the IL-6 receptor. This was followed by siltuximab (Sylvant), which is directed against IL-6 itself. Sarilumab was approved by the US FDA in 2017 for rheumatoid arthritis. Several other agents are in clinical trials, including olokizumab (CDP6038), elsilimomab, clazakizumab (BMS-945429, ALD518), sirukumab (CNTO 136), levilimab (BCD-089), and CPSI-2364. Looking ahead, IL-6 inhibitors are expected to continue to play a significant role in the treatment of various diseases. They have shown promising results in treating serious COVID-19 cases2 and are also used widely for the treatment of rheumatoid arthritis2. The IL-6 inhibitors market is projected to grow at a CAGR of 10.9%, increasing from US$ 33.3 Billion in 2023 to US$ 93.3 Billion by 20333. However, the emergence of resistance and the lack of an effective reversal drug when bleeding occurs are challenges that need to be addressed. Ongoing research and development efforts are focused on addressing these issues and expanding the clinical applications of IL-6 inhibitors. Based on the analysis of the data, the current competitive landscape for target IL-6 is characterized by the presence of multiple companies with varying stages of development and a wide range of indications. Bristol Myers Squibb Co. stands out as the company with the highest stage of development, with multiple approved drugs and ongoing clinical trials. Small molecule drugs, molecular glues, and monoclonal antibodies are the most rapidly progressing drug types under the target IL-6. The United States, European Union, and China are the leading countries/locations in terms of development, with China showing significant progress. Overall, the target IL-6 presents a competitive landscape with diverse players and promising future development potential. How do they work?IL-6 inhibitors are a type of medication that target and inhibit the activity of interleukin-6 (IL-6), a cytokine involved in the immune response and inflammation. From a biomedical perspective, IL-6 inhibitors are used in the treatment of various inflammatory conditions such as rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman's disease. These inhibitors work by blocking the binding of IL-6 to its receptor, thereby reducing the inflammatory response mediated by IL-6. By inhibiting IL-6, these medications help alleviate symptoms and reduce disease progression in patients with IL-6-mediated inflammatory disorders List of IL-6 InhibitorsThe currently marketed IL-6 inhibitors include: SiltuximabPomalidomidePirfenidoneLenalidomideOlokizumabSirukumabSodium PyruvateClazakizumabRO-7200220ZiltivekimabFor more information, please click on the image below. What are IL-6 inhibitors used for?IL-6 inhibitors are used in the treatment of various inflammatory conditions such as rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman's disease. For more information, please click on the image below to log in and search. How to obtain the latest development progress of IL-6 inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of IL-6 inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

17 Oct 2017

·www.biospace.com

J&J Terminates Two Drugs From Pipeline

J&J Terminates RA and Leukemia Drug From Pipeline Buried in its third-quarter financial announcement, J&J indicated it was dropping two of its pipeline drugs with little or no explanation. Buried in its third-quarter financial announcement , Johnson & Johnson indicated it was dropping two of its pipeline drugs with little or no explanation. The company otherwise had plenty of good news. J&J announced sales of $19.7 billion for the quarter, up 10.3 percent compared to the same period last year. Operational sales increased 9.5 percent and domestic sales increased 9.7 percent. International sales grew 10.9 percent. When you exclude acquisitions and divestures, domestic and international sales each grew 3.8 percent. Deeper into the statement were two sentences: “The Company has made a decision not to pursue global approvals of sirukumab for the treatment of moderately to severely active rheumatoid arthritis. In addition, the clinical trial for talacotuzumab, an investigational compound being studied in patients with acute myeloid leukemia, has been discontinued.” John Carroll, writing for Endpoints News , said , “The writing was already on the wall months ago for sirukumab, once a top prospect for rheumatoid arthritis until its partners at GlaxoSmithKline suddenly walked out. Earlier this year, though, a panel of outside experts voted down the marketing application, fretting over an unexplained imbalance in deaths in the study. The inevitable formal rejection followed.” However, J&J dropping talacotuzumab (JNJ-56022473/CSL362) wasn’t expected. There’s no explanation for why the company gave up on it. Carroll notes that this news is undoubtedly unwelcome, because J&J “has been struggling on the revenue side, leaving some prominent analysts wondering if it can continue to grow pharma sales.” Joaquin Duato , J&J’s global chairman for pharmaceuticals, said in May that the company planned for its branded drug market to continue with a 5 percent annual growth rate through 2020, despite what executives always refer to as “stiff headwinds” on prices. It expected three drugs to be approved this year and four more next year. Carroll writes, “These new drugs were part of one leg of the company’s three-leg strategy for growing revenue, with a promise that it can improve significantly on existing drugs—like Stelara, Invokana and Xarelto—while beefing up on a new core focus on pulmonary arterial hypertension through the Actelion buyout.” J&J also revised its full-year forecast, largely on the basis of strong sales for new cancer drugs. The drugs, specifically Darzalex and Imbruvica, as well as high-margin drugs for rare diseases from its acquisition of Actelion, are expected to be the impetus for future growth. “We are convinced that the pharma pipeline remains robust and more meaningful contributions will kick in beyond 2017,” Joshua Jennings , an analyst with Cowen & Co. wrote in a note to clients. Although those areas are going strong, sales of Remicade for rheumatoid arthritis slowed as biosimilars for the drug hit the market. For its projections for 2017, it increased its profit forecast of $7.12 to $7.22 per share to $7.25 to $7.30 per share. It increased its revenue forecast from $75.8 billion to $76.1 billion to between $76.1 billion and $76.5 billion. HealthBlogger, with Seeking Alpha , writes , “I believe Johnson & Johnson is one of the best positioned companies in the pharmaceuticals space and worthy of long-term investment. However, I think some profit taking on the name would make sense at this time. In fact, after the strong performance in the last two months and a 19 percent move up year-to-date, a valuation check suggests that the risk/reward is much less compelling than a few months ago.”

AcquisitionFinancial StatementClinical Trial Failure

25 Sep 2017

·www.biospace.com

FDA Rejects Johnson & Johnson’s RA Drug Sirukumab, More Safety Data Needed

September 25, 2017 By Alex Keown , BioSpace.com Breaking News Staff HORSHAM, Penn. – The regulatory rejection for Janssen ’s rheumatoid arthritis drug sirukumab is complete. On Friday, the U.S. Food and Drug Administration issued the company a Complete Response Letter calling for additional clinical data to evaluate the safety of the drug. The FDA rejection was not unexpected. In August, an FDA advisory panel overwhelmingly rejected the rheumatoid arthritis drug in a 12 to 1 vote. The rejection followed the release of an FDA briefing document raised concerns over the safety of sirukumab . In that document posted at the end of July, the review said there was a clear imbalance in deaths and malignancies among the patients who took the drug over a 52-week period. The panel noted there have been more deaths associated with patients taking the drug than those taking placebo. Newman Yielding , head of Janssen’s immunology development program, called the rejection disappointing. He said the company believes the data accumulated during the clinical trials “support the efficacy and safety of sirukumab” in treating patients with rheumatoid arthritis. “We believe sirukumab represents an important therapeutic option for patients living with rheumatoid arthritis, especially for those individuals who cycle through multiple treatments and continue to struggle to find an effective option for a potentially disabling disease. We are reviewing the details of the complete response letter and plan to have a follow-up discussion with the agency to gain a full understanding of FDA requirements for U.S. approval,” Yielding said in a statement. In its briefing document issued earlier this summer, the FDA said the deaths associated with sirukumab were typically related to major adverse cardiac events (MACE), infection, and malignancy. Sirukumab was associated with increased risk of serious infection, and there were reports of opportunistic infection and tuberculosis. Sirukumab treatment was associated with laboratory abnormalities including neutrophil count decrease, liver function test values increase, and increase in lipid parameters of LDL, HDL, and triglyceride,” the FDA said in its briefing document . There are already two RA drugs on the market that are in the same class as sirukumab, including the recently approved Kevzara, which was co-developed by Sanofi and Regeneron. Sirukumab, which would be marketed as Plivenzia if approved, is a human anti-interleukin (IL)-6 monoclonal antibody in development for the treatment of adults with moderately to severely active rheumatoid arthritis. Rheumatoid arthritis is a chronic inflammatory condition characterized by pain, swelling of the joints, stiffness and disability. There are approximately 1.5 million people in the United States who have been diagnosed with RA, according to Janssen. Janssen is also seeking regulatory approval for sirukumab in Europe and Japan. Janssen isn’t the only company to be stymied with bringing a new RA drug to market. In April, the FDA rejected RA drug baricitinib, which is being developed by Eli Lilly and partner Incyte Corporation . In July, the two companies announced there would be a significant delay in refiling for approval of the drug. The FDA raised concerns over blood clots. Shares of Johnson & Johnson , Janssen’s parent company, are down slightly this morning, trading at $131.13 as of 9:59 a.m.

Drug ApprovalAccelerated Approval

100 Deals associated with Sirukumab

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KEGG	Wiki	ATC	Drug Bank
D10080	Sirukumab	L04AC15	DB11803

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Polymyalgia Rheumatica	Phase 3	-	GSK Plc	15 Mar 2018
Giant Cell Arteritis	Phase 3	United States	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	Australia	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	Belgium	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	Bulgaria	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	France	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	Germany	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	Hungary	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	Italy	GSK Plc	16 Oct 2015
Giant Cell Arteritis	Phase 3	Netherlands	GSK Plc	16 Oct 2015

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04380961 (CTgov)	Phase 2	COVID-19	212	Sirukumab (Sirukumab + SOC)	vnnfoxmlnk(vdxzfmlmug) = vsaxbumtmu wojubicurv (aavjhnobyf, fwvhvkiurk - cvkmoxljdk) View more	-	21 Jun 2022
				Placebo (Placebo + SOC)	vnnfoxmlnk(vdxzfmlmug) = ulyqgxgrue wojubicurv (aavjhnobyf, joyeygfxvv - rmqpwuzyno) View more
NCT02531633 (Pubmed \| Rheumatol Ther) Manual	Phase 3	Giant Cell Arteritis	161	Sirukumab	hiiduobrep(hduumpqcwg) = tlcbmbfoob oyqhiitpor (lteeoyjewt )	Positive	01 Dec 2020
				Placebo	hiiduobrep(hduumpqcwg) = vbhgvvndid oyqhiitpor (lteeoyjewt )
NCT02473289 (CTgov)	Phase 2	Depressive Disorder, Major	193	Placebo	ttfepdqlkk(aveirhxjvb) = ycqnhekthb ytdldenegr (zusrairsqd, 1.43) View more	-	11 Jun 2019
NCT01856309 (SIRROUND-LTE, CTgov)	Phase 3	Rheumatoid Arthritis	1,820	Placebo (Placebo to 50 mg q4w Due to EE/LE/CO)	fjoqaemjlv = actxcnpemb doukgtdiox (lchnghanxo, mqbzyvmrjm - qiekoiurot) View more	-	06 May 2019
				Placebo (Placebo to 100 mg q2w Due to EE/LE/CO)	fjoqaemjlv = sqobmyopcj doukgtdiox (lchnghanxo, sydecpyvgk - oksumgszbi) View more
NCT02019472 (SIRROUND-H, Pubmed \| Ann Rheum Dis)	Phase 3	Rheumatoid Arthritis	-	Sirukumab 100mg every 2 weeks	iwwuleldek(jfovvqwfks) = dqkyhrsgko kyaywybdmt (bhcejwvmiv )	Positive	01 May 2018
				Sirukumab 50mg every 4 weeks	iwwuleldek(jfovvqwfks) = kdqzebvufi kyaywybdmt (bhcejwvmiv )
NCT01689532 (Pubmed \| J Rheumatol \| Arthritis Res Ther) Manual	Phase 3	Rheumatoid Arthritis	122	Sirukumab (50 mg once every 4 weeks)	qtjjhtesgd(jmogvrvvep) = zyfgxrqpci hyrtokkiht (rlyqbrqlgx )	Positive	07 Mar 2018
				Sirukumab (100 mg once every 2 weeks)	qtjjhtesgd(jmogvrvvep) = ajrusgtlcq hyrtokkiht (rlyqbrqlgx )
NCT01604343 (SIRROUND-D, CTgov)	Phase 3	Rheumatoid Arthritis	1,670	Sirukumab	acwnoqytkg = byrdcvtojv xcgjfxozxk (qvoywrblid, qdgorlqarf - vzkppifaeb) View more	-	11 Jan 2018
NCT01604343 (SIRROUND-D, Pubmed)	Phase 3	Rheumatoid Arthritis	1,670	Sirukumab 100mg every 2 weeks	sffqocicyb(liowwcvkac) = fbvquugjof xidpgchhtq (kfdsedahqs )	Positive	01 Dec 2017
				Sirukumab 50mg every 4 weeks	sffqocicyb(liowwcvkac) = yugmavketu xidpgchhtq (kfdsedahqs )
ACR2017	Not Applicable	Arthritis	-	Biological DMARDs	zqhhegrqvw(drokrcibqm) = vahfybektw abpmujlprf (pwrnppukwc, [-0.6 - -0.08])	Positive	06 Nov 2017
NCT02019472 (SIRROUND-H, CTgov)	Phase 3	Rheumatoid Arthritis	559	Adalimumab (Adalimumab 40 mg)	yvdilqaoko(yhbcywddpv) = cwoddrgixx dtatygbmzj (zufbyyomao, 0.851) View more	-	14 Sep 2017
				Sirukumab (Sirukumab 50 mg)	yvdilqaoko(yhbcywddpv) = ibniizyupk dtatygbmzj (zufbyyomao, 0.881) View more

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