Antibody-related news from Janice M. Reichert, Editor-in-Chief, mAbs
July - Aug 2015
First marketing approvals granted for two anti-PCSK9 antibody therapeutics
Two human antibodies targeting proprotein convertase subtilisin/kexin type 9 have been granted first marketing approvals. On July 17, 2015, evolocumab (Repatha®), a human IgG2 antibody, was approved in the EU to lower high levels of cholesterol in the blood of people who are unable to control their cholesterol despite taking optimal doses of statins or who cannot take statins, and to treat homozygous familial hypercholesterolemia. Alirocumab (Praluent®), a human IgG1 antibody, was approved by the US Food and Drug Administration (FDA) on July 24, 2015 for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol. FDA also approved evolocumab on August 27, 2015.
Total of eight novel antibody therapeutics in EU or US regulatory review
The number of antibody therapeutics recently granted first approvals in the EU and US will increase substantially if the 8 antibodies currently in regulatory review in these regions are granted marketing approvals. Three of these antibodies target cancerous cells. Necitumumab, a human IgG1 antibody targeting epidermal growth factor receptor, is undergoing review as a treatment for squamous non-small cell lung cancer. In July 2015, a majority of the FDA’s Oncologic Drugs Advisory Committee agreed that necitumumab shows some promise in the first-line treatment of the disease. The anti-CD38 antibody daratumumab is under FDA review for multiple myeloma; the drug has Breakthrough Therapy and Fast Track designations for this indication. Elotuzumab, which targets the signaling lymphocyte activation molecule SLAMF7, is undergoing regulatory review in the EU for multiple myeloma. The European Medicines Agency (EMA) has granted an accelerated assessment of the marketing application.
An additional five antibodies are potential treatments for non-cancerous conditions. Two antibody therapeutics that target interleukin (IL)-5, mepolizumab and reslizumab, are undergoing review in the EU and US for asthma. Ixekizumab, which targets IL-17A, is being evaluated by EMA as a treatment for psoriasis. The protective antigen of B. anthracis exotoxin is the target of obiltoxaximab, which is undergoing review in the US for anthrax infection. Obiltoxaximab has Fast Track designation for this indication. The anti-dabigatron antibody idarucizumab is in US and EU review for reversal of dabigatron-induced anticoagulation; the drug has Breakthrough Therapy designation and its application will receive a priority review in the US.
Median review times in Japan decrease substantially in past decade
In the recent report “New Drug Approvals in ICH Countries 2005-2014”, the Centre for Innovation in Regulatory Science has shown that, in 2014, Japan's the Pharmaceuticals and Medical Devices Agency was the fastest regulatory agency, with a median approval time of 306 days for new active substances (NASs) compared to medians of 343 and 418 days for the FDA and EMA, respectively. Over the past decade, approval times at FDA and EMA have remained relatively stable, but Japan's approval times have decreased substantially, e.g., from ˜800 days in 2005 and 2006 to 306 days in 2014. A marketing application for brodalumab, which targets IL17 receptor, was recently submitted for review in Japan. Brodalumab is undergoing evaluation as a treatment for plaque psoriasis, psoriatic arthritis, pustular psoriasis, psoriatic erythroderma.
April - May 2015
European Medicines Agency recommends approval of 4 new antibody therapeutics
The European Medicines Agency’s Committee for Medicine Products for Human Use (CHMP) has recommended that marketing authorizations be granted for four antibody therapeutics, evolocumab, pembrolizumab, nivolumab and dinutuximab. Evolocumab is a first-in-class, human IgG2 antibody targeting proprotein convertase subtilisin/kexin type 9, and CHMP recommended it to lower high levels of cholesterol in the blood of people who are unable to control their cholesterol despite taking optimal doses of statins or who cannot take statins, and to treat homozygous familial hypercholesterolaemia. Pembrolizumab and nivolumab both target PD1, and they were recommended to treat advanced (unresectable or metastatic) melanoma, and to treat adults with squamous non-small cell lung cancer, respectively. Dinutiximab, a chimeric antibody targeting GD2, was recommended for the treatment of high-risk neuroblastoma.
American Society of Clinical Oncology Annual meeting
The American Society of Clinical Oncology’s Annual meeting was held May 29-June 2, 2015 in Chicago. The meeting features an extensive program of presentations on cancer therapies. Data for numerous antibodies, including avelumab, bavituximab, ensituximab, HuMax-Axl-ADC, OBT357/MEN1112, MEDI4736, MEDI0680, PF-05082566, NI-1701, SEA-CD40, REGN1979, and the CEA-directed BiTE MEDI-565/AMG 211 were made available in abstracts. The meeting abstracts can be accessed at: here.
Collaboration to develop brodalumab halted
Amgen announced that it commenced termination of a collaboration with AstraZeneca to develop brodalumab, a human IgG2 mAb targeting IL-17 receptor. Amgen recently presented data from three Phase 3 clinical trials evaluating brodalumab in patients with moderate-to-severe plaque psoriasis, and in connection with the presentation, suicidal ideation and completed suicides in the brodalumab program were noted. According to the company, the evidence to date does not suggest a causal association between IL-17 inhibition and suicidal ideation and behavior, but the events likely would necessitate restrictive labeling.
February - March 2015
FDA abbreviated licensure pathway yields first biosimilar product
The abbreviated licensure pathway (section 351(k) of the Public Health Service Act), which was created in 2009 to allow regulatory review of biosimilars, has yielded the US Food and Drug Administration’s (FDA) first approval of such a product. Zarxio (filgrastim-sndz; Sandoz, Inc.) is biosimilar to Amgen Inc.’s Neupogen (filgrastim), which was first licensed in 1991. Zarxio is approved for the same indications as Neupogen, and can be prescribed for patients with cancer receiving myelosuppressive chemotherapy; patients with acute myeloid leukemia receiving induction or consolidation chemotherapy; patients with cancer undergoing bone marrow transplantation; patients undergoing autologous peripheral blood progenitor cell collection and therapy; and patients with severe chronic neutropenia.
The FDA is evaluating a marketing application for CT-P13, Celltrion’s biosimilar infliximab. An Arthritis Advisory Committee meeting to discuss biologics license application 125544 for CT-P13 was scheduled for March 17, 2015, but FDA postponed the meeting. According to FDA, the postponement is due to information requests pending with the sponsor of the application. A future meeting date will be announced in the Federal Register. FDA intends to make background material available to the public no later than 2 business days before the meeting.
Supplemental approval for nivolumab in non-small cell lung cancer
FDA has granted a supplemental approval that allows anti-PD1 nivolumab (Opdivo; Bristol-Myers Squibb) to be prescribed for patients with advanced squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Nivolumab was first approved in the US in December 2014 for treatment of patients with unresectable or metastatic melanoma who no longer respond to other drugs. The product is also undergoing evaluation in Phase 3 studies of patients with non-squamous cell NSCLC, recurrent glioblastoma, squamous cell carcinoma of the head and neck, advanced renal cell carcinoma and gastric cancer.
Marketing applications for idarucizumab submitted
Boehringer Ingelheim has submitted marketing applications to regulatory agencies in the US, European Union and Canada for idarucizumab, an antidote for the oral anticoagulant dabigatran etexilate (Pradaxa®; Boehringer Ingelheim). According to the company, Boehringer Ingelheim is pursuing accelerated procedures with all three regulatory authorities. Idarucizumab, a humanized Fab, received a breakthrough therapy designation from FDA in June 2014.
Ublituximab enters Phase 3 study
The first Phase 3 study of ublituximab, sponsored by TG Therapeutics, Inc., began recruiting patients. The study (NCT02301156) evaluates the addition of ublituximab to ibrutinib compared to ibrutinib alone in previously treated chronic lymphocytic leukemia (CLL) patients with high-risk cytogenetic features. A type 1 chimeric IgG1, ublituximab targets a unique epitope of CD20 and is glycoengineered for enhanced antibody-dependent cell-mediated cytotoxicity.
Banner year for approvals in 2014
A total of 7 monoclonal antibody therapeutics were granted their first marketing approval in 2014, which is the most ever approved in a single year. Of the 7 products, 5 (vedolizumab, siltuximab, ramucirumab, pembrolizumab, blinatumomab) were first approved in the United States and 2 (nivolumab, secukinumab) was first approved in Japan. As of January 1, 2015, authorizations for marketing for only 2 (vedolizumab, siltuximab) of the 7 products have been given in the European Union, while applications for the other 5 products remain in regulatory review or have decisions by the European Commission pending. Two of the products, pembrolizumab and nivolumab, target programmed death (PD)-1, and both were approved as treatments for melanoma. Blinatumomab targets CD19 and CD3, and it is the first bispecific antibody therapeutic to gain approval from the Food and Drug Administration.
mAbs in first US or EU regulatory review
As of mid-January 2015, marketing applications for 6 mAb therapeutics not yet approved in either the US or EU are undergoing regulatory review in these regions. Four (secukinumab, mepolizumab, evolocumab, alirocumab) are for non-cancer indications, while 2 (dinutuximab, necitumumab) are for various types of cancer. Evolocumab and alirocumab inhibit proprotein convertase subtilisin/kexin type 9, and these mAbs have been evaluated in numerous clinical studies of patients with elevated cholesterol. Based on the timing of the submissions, the Food and Drug Administration may take action on the applications by the end of the third quarter of 2015. A table of the antibody therapeutics in regulatory review or approved in the US or EU is available on the Society’s web site (www.antibodysociety.org/news/approved_mabs.php).
Comprehensive list of investigational mAbs in Phase 3
A comprehensive list of 39 investigational (i.e., as yet unapproved) mAb therapeutics undergoing evaluation in Phase 3 studies as of late 2014 is now available (www.tandfonline.com/doi/full/10.4161/19420862.2015.988944#.VL_lWdg5B2s). First marketing application submissions for at least 4 (reslizumab, ixekizumab, ocrelizumab, obiltoxaximab) of these “antibodies to watch” are expected in 2015. The 4 mAbs have been evaluated in studies of respiratory conditions (reslizumab), immune-mediated disorders (mepolizumab, ixekizumab, ocrelizumab) and infectious disease (obiltoxaximab). As of January 2015, one additional mAb therapeutic (ublituximab) entered a first Phase 3 study. The study will evaluate the addition of ublituximab to ibrutinib compared to ibrutinib alone in previously treated chronic lymphocytic leukemia patients with high-risk cytogenetic features.
August - September 2014
First approval for pembrolizumab
Pembrolizumab (Keytruda®) was granted an accelerated approval for the treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs by the US Food and Drug Administration (FDA) on September 4, 2014. FDA’s accelerated approval program allowed pembrolizumab to be approved based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. Clinical trials confirming the effect will need to be conducted. Pembrolizumab, a humanized IgG4, targets programmed death receptor-1 (PD-1), and it is the second anti-PD-1 antibody therapeutic to be approved for marketing in any country. The first approval of an anti-PD-1 antibody was granted by Japanese regulatory authorities to nivolumab (Opdivo®), a human IgG4, in July 2014. Nivolumab was approved in Japan for treatment of unresectable melanoma.
First biosimilar antibody enters US regulatory review
A 351(k) application for Remsima®, an infliximab biosimilar product, was submitted to the FDA in August 2014. The application is the first for an antibody, and the second ever, to be submitted under the pathway for the approval of biosimilar products created by the Biologics Price Competition and Innovation Act of 2009. Clinical data for three products, originator product sold in the US, originator product sold in Europe and Remsima®, were included in the application. Remsima® was approved in Europe in 2013, and the product is also approved in numerous other countries, including Canada and Japan.
First PCSK9-targeting antibody enters regulatory review
A biologics license application for evolocumab was submitted to the FDA in August 2014. Evolocumab, a human IgG2, inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver's ability to remove low-density lipoprotein cholesterol from the blood. Evolocumab has been evaluated in at least 10 Phase 3 studies that evaluated the safety and efficacy of drug in patients with elevated cholesterol on statins with or without other lipid-lowering therapies; patients who cannot tolerate statins; patients with heterozygous familial hypercholesterolemia; and patients with homozygous familial hypercholesterolemia, a rare and serious genetic disorder. Two other anti-PCSK9 antibody therapeutics, alirocumab and bococizumab, are currently being evaluated in Phase 3 studies.
April - May 2014
First approvals for three novel antibody therapeutics
A total of three monoclonal antibody (mAb) therapeutics were granted their first approval in April or May 2014. Ramucirumab (Cyramza®), siltuximab (Sylvant®) and vedolizumab (Entyvio™) were approved by the Food and Drug Administration (FDA) on April 21, April 23 and May 20, 2014, respectively. Ramucirumab, which targets human vascular endothelial growth factor receptor-2, is indicated for the treatment of advanced gastric cancer or gastro-esophageal junction adenocarcinoma, as a single-agent after prior fluoropyrimidine or platinum-containing therapy. Ramucirumab is undergoing regulatory review by the European Medicines Agency (EMA); it has orphan drug designation in the European Union (EU) for treatment of gastric cancer and hepatocellular carcinoma. Ramucirumab is undergoing evaluation in Phase 3 studies that are active but not recruiting patients with non-small cell lung cancer (NCT01168973), hepatocellular carcinoma (NCT01140347), colorectal cancer (NCT01183780) or breast cancer (NCT00703326).
Anti-interleukin (IL)-6 siltuximab is indicated in the US for treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. On March 20, 2014, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, which recommended the granting of a marketing authorization for siltuximab for the treatment of adult patients with MCD who are HIV negative and hHHV-8 negative. A decision on the EU marketing application by the European Commission is normally issued 67 d from adoption of the CHMP opinion. Siltuximab received orphan drug designation as a treatment for MCD in both the US and EU.
Vedolizumab is approved to treat adult patients with moderate to severe ulcerative colitis (UC) and adult patients with moderate to severe Crohn disease (CD) when one or more standard therapies (corticosteroids, immunomodulators, or tumor necrosis factor blocker medications) have not resulted in an adequate response. The humanized IgG1 mAb, which targets α4β7 integrin, is Fc-engineered to silence effector functions. On March 20, 2014, CHMP adopted a positive opinion for vedolizumab for the treatment of adult patients with moderately to severely active UC who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor antagonist and adult patients with moderately to severely active CD who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor antagonist.
February - March 2014
Positive opinion for siltuximab and vedolizumab in EU
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted positive opinions for the marketing applications of two monoclonal antibody products (Siltuximab, Vedolizumab) and have recommended the granting of authorizations by the European Commission (EC). The EC normally issues a decision 67 days from adoption of the opinion, which occurred on March 20, 2014.
Siltuximab (Sylvant) is an anti-IL-6 chimeric mAb that reduces tumor burden and improves symptoms in patients with multicentric Castleman’s disease (MCD). In November 2007, the mAb received an orphan medicinal product designation in the EU for MCD. Vedolizumab (Entyvio), a humanized mAb targeting the human lymphocyte integrin α4β7, was evaluated by CHMP as a treatment of adult patients with moderately to severely active ulcerative colitis and adults patients with moderately to severely active Crohn’s disease.
Three novel antibodies enter first Phase 3 studies
The first Phase 3 studies for three antibodies (dupilumab, MPDL3280A, SA237) were initiated in February or March 2014. A Phase 3 study (NCT01949311) of dupilumab (REGN668, SAR231893), an anti-IL-4 receptor alpha human IgG4 antibody, started enrolling atopic dermatitis patients by invitation only in February 2014. The multicenter, open-label extension study will assess the long-term safety and efficacy of repeat doses of dupilumab in adults with moderate-to-severe atopic dermatitis who have previously participated in controlled studies of dupilumab. The study’s primary completion date is October 2016.
MPDL3280A, an Fc-optimized, human antibody targeting programmed cell death-1 ligand 1, is undergoing evaluation in the randomized Phase 3 “OAK” study (NCT02008227) of patients with second- or third-line metastatic non-small cell lung cancer. The mAb is an IgG1, but the Fc region has been modified so that neither antibody-dependent cytotoxicity nor complement-dependent cytotoxicity are induced. The safety and efficacy of MPDL3280A will be compared to docetaxel in the study, which has a primary completion date of June 2018.
SA237 is designed to have pH-dependent binding to soluble IL-6 receptor, which allows the mAb to release bound IL-6R in lysosomes and then be recycled via FcRn. A Phase 3 study (NCT02028884) of SA237 as add-on therapy for neuromyelitis optica (NMO) and NMO Spectrum Disorder started in February 2014. A second Phase 3 study (NCT02073279) of SA237 as monotherapy of NMO and NMO Spectrum Disorder is scheduled to start in June 2014. These studies have primary completion dates in August and September 2016, respectively.
Record number of antibody therapeutics in first regulatory review
As of late January 2014, a total of 7 monoclonal antibody (mAb) therapeutics were undergoing their first regulatory review. The submission of first marketing applications for vedolizumab, siltuximab and ramucirumab have already been discussed in The Antibody Society’s news in 2013. In addition to these, first marketing applications have also been submitted for secukinumab, dinutuximab, nivolumab, and lambrolizumab.
Marketing applications for secukinumab and dinutuximab are undergoing review by the European Medicines Agency (EMA). Secukinumab, a human IgG1 targeting interleukin-17a, has undergone evaluation in Phase 3 studies for immune-mediated disorders such as psoriasis, and EMA is considering an application for use of the mAb as an immunosuppressant. Dinutuximab, a chimeric IgG1 targeting GD2, has undergone evaluation in Phase 3 studies of neuroblastoma. Dinutuximab is designated as an orphan medicinal product in the European Union for treatment of neuroblastoma; EMA is considering an application for use of the mAb as an antineoplastic medicine.
Ono Pharmaceutical Co., Ltd. announced in December 2013 that it had filed an application to obtain manufacturing and marketing approval for nivolumab, a human IgG4 targeting the immune checkpoint inhibitor PD-1, as a treatment for malignant melanoma. Nivolumab received orphan drug designation for malignant melanoma from Japan’s Ministry of Health, Labour and Welfare in June 2013.
On January 13, 2014, Merck announced that rolling submission of a biologics license application for lambrolizumab, a humanized IgG4 targeting PD-1, had been initiated in the US. A rolling submission allows completed portions of the application to be submitted and reviewed by the Food and Drug Administration on an ongoing basis. The submission is expected to be complete in the first half of 2014.
First approvals for two biosimilar trastuzumab products
Biosimilar trastuzumab products developed by Biocon/Mylan and Celltrion were recently approved for marketing in India and Korea, respectively. Canmab™ was approved in December 2013 in India for the treatment of HER2-positive breast cancer. The price of Canmab™, which was co-developed in a joint venture between Biocon and Mylan, is projected to be ~25% lower than the reference product Herceptin®.
Celltrion announced in January 2014 that Herzuma™ had been approved for marketing by the Ministry of Food and Drug Safety in Korea for treatment of early and advanced HER2-positive breast cancer and advanced stomach cancer. The initiation of marketing is expected in mid-2014. Price has not yet been announced, but the price for the reference product is automatically reduced to 70% of the original price when the first biosimilar enters the Korean market. Celltrion’s biosimilar infliximab product, Remsima™, was approved in the European Union in 2013.
October - November 2013
Obinutuzumab approved in the US
On November 1, 2013, obinutuzumab (Gazyva®), a glyco-engineered antibody that targets CD20, was approved by the Food and Drug Administration for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL). Obinutuzumab is the first product with Breakthrough Therapy designation to be approved. The designation is intended to facilitate the drug development and approval process, and FDA can confer the designation if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. Obinutuzumab’s approval was based on a study of 356 CLL patients in which the antibody in combination with chlorambucil demonstrated a significant improvement in progression free survival (average of 23 months vs. 11.1 months with chlorambucil alone).
Ado-trastuzumab emtansine approved in the EU
Ado-trastuzumab emtansine (Kadcyla®) was approved in the European Union for use in the treatment of HER2-positive metastatic breast cancer in November 2013. The product was approved in the US and Japan in February and September 2013, respectively. The product is an antibody-drug conjugate comprising the HER2-targeting trastuzumab, which has been marketed since 1998, conjugate to the cytotoxic drug DM1. It is approved for use in patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab and a taxane chemotherapy, separately or in combination.
FDA advisory panel recommends new approval for alemtuzumab
Approval in the US of alemtuzumab (Lemtrada™) for multiple sclerosis (MS) was recommended by an FDA advisory board. The anti-CD52 antibody, under the brand name Campath®, was first approved in the US in 2001 as a treatment for patients with B-cell chronic lymphocytic leukemia who have been treated with alkylating agents and who have failed fludarabine therapy. The product is no longer marketed to cancer patients. Alemtuzumab was approved in the EU for the treatment of adult patients with relapsing remitting multiple sclerosis with active disease defined by clinical or imaging features in September 2013. An action by FDA on the marketing application of Lemtrada™ is expected by the end of 2013.
July - September 2013
Biosimilar antibody products approved in EU
Marketing applications for two biosimilar infliximab products, Remsima (Celltrion Healthcare Hungary Kft) and Inflectra (Hospira UK Limited), as treatments for rheumatoid arthritis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, pediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis were approved by the European Commission in September 2013. Launch of the products may be delayed until February 2015 because of a recent extension to the EU patent on the reference product (Remicade®, Johnson & Johnson). Celltrion received approval to market Remsima in Korea In July 2012.
Additional biosimilar products are already in regulatory review. Celltrion Inc. announced in June 2013 that it submitted a marketing application for biosimilar trastuzumab to the Ministry of Food and Drug Safety in Korea. The company is seeking approval of the biosimilar product for breast cancer and metastatic gastric cancer.
Marketing applications submitted for siltuximab
Janssen Research & Development, LLC indicated on September 3, 2013 that marketing applications were filed in the US and EU for siltuximab for the treatment of patients with multicentric Castleman disease (MCD) who are HIV-negative and human herpes virus-8-negative. Siltuximab (CNTO 328), a chimeric IgG1 that targets interleukin-6, has orphan drug status in the US and EU for MCD, which is a lymphoproliferative disorder. The marketing applications included data from a Phase 2 randomized, double-blind, placebo-controlled study (NCT01024036) in which MCD patients were administered 11 mg/kg siltuximab or placebo intravenously every three weeks. The primary outcome measure for the study was the number of patients who achieved a tumor and symptomatic response up to 48 weeks after the last patient began study treatment.
EMA recommends approval of alemtuzumab for multiple sclerosis
The European Medicines Agency recommended that the marketing application for alemtuzumab (Lemtrada) as a treatment for relapsing remitting multiple sclerosis (MS) be granted. The anti-CD52 alemtuzumab had been approved for chronic myeloid leukemia in 2001, but the product is no longer marketed for this indication. The mechanism of its immunomodulatory effects in MS is not fully understood, but appears to involve depletion and repopulation of lymphocytes.
May - June 2013
Marketing applications submitted for ramucirumab and obinutuzumab
Eli Lilly and Company announced that they received Fast Track designation from the US Food and Drug Administration (FDA) for ramucirumab, a human IgG1 that targets vascular endothelial growth factor receptor-2, and that they initiated a rolling submission of a licensing application of the mAb as monotherapy in second-line gastric cancer. Fast Track designation is given to drugs intended to treat serious diseases and fill an unmet medical need. The FDA’s evaluation of Fast Track drugs can be expedited by a rolling review in which completed sections of the application are reviewed by FDA as they are submitted, i.e., FDA does not wait for the entire application to be submitted before beginning the review. Lilly expects to complete the submission process by the end of 2013.
In mid-May 2013, Roche announced that obinutuzumab had been granted breakthrough therapy designation by FDA, and that marketing applications had been submitted in the US and European Union. Obinutuzumab is a type II anti-CD20 IgG1 antibody with reduced fucosylation. The marketing applications were based on data from the 3-arm, Phase 3 CLL11 study (NCT01010061), which compared the combination of either obinutuzumab or rituximab and chlorambucil to chlorambucil alone in patients with previously untreated chronic lymphocytic leukemia. Obinutuzumab is also undergoing evaluation as a treatment for lymphoma.
Breakthrough designations granted to three mAbs
As of mid-June 2013, three companies have announced that Breakthrough Therapy designations had been granted for their investigational mAb therapies for cancer. The mAbs are anti-CD38 daratumumab (Genmab), anti-PD1 lambrolizumab (Merck), and anti-CD20 obinutuzumab (Roche). To qualify for the designation, preliminary clinical evidence that demonstrated that the mAb may provide substantial improvement over available therapy on at least one clinically significant endpoint was required. The benefits of the breakthrough therapy designation includes all those provided by the fast track program (e.g., rolling review), but also more intensive FDA guidance on the drug’s development program.
Updates on Celltrion’s biosimilar trastuzumab and biosimilar infliximab
Celltrion announced in June 2013 that it submitted a marketing application for biosimilar trastuzumab to the Ministry of Food and Drug Safety in Korea. The company is seeking approval of the mAb for breast cancer and metastatic gastric cancer. In July 2012, Celltrion received approval to market biosimilar infliximab (Remsima™) in Korea, and a marketing application for the product is undergoing regulatory review in Europe. If approved in Europe, launch of Remsima™ may be delayed until February 2015 because of a recent extension to the European patent on the reference product (Remicade®, Johnson & Johnson).
March - April 2013
2012 global sales of antibody-based therapeutics exceeded USD50 billion
Global sales of antibody-based therapeutics exceeded USD50 billion in 2012. Genetic Engineering Biotechnology News reported that 6 of the top 12 selling drugs in 2012 were antibody-based.
The 6 products are: #1 adalimumab (Humira®), with sales of USD9.265 b; #3 rituximab (Rituxan®), with sales of USD 7.285 b; ); #5 trastuzumab (Herceptin®), with sales of USD 6.397 b; #7 infliximab (Remicade®), with sales of USD 6.139 b; #8 bevacizumab (Avastin®), with sales of USD 6.260 b; and #11 etanercept (Enbrel®) with sales of USD 4.236 b.
Marketing authorization application for vedolizumab submitted in Europe
Takeda Pharmaceutical Company submitted a marketing authorization application to the European Medicines Agency for vedolizumab, an anti-α4β7 humanized mAb, in early March 2013. If approved, vedolizumab would be marketed in the European Union for the treatment of adults with moderate-to-severe active ulcerative colitis and Crohn's disease. The mAb was evaluated in four Phase 3 studies (GEMINI I, II, III, and GEMINI LTS) of patients with these diseases.
Pertuzumab approved in European Union
Roche/Genentech announced that pertuzumab (Perjeta®) was approved in the European Union in March 2013. The product is approved in combination with trastuzumab (Herceptin®) and docetaxel for patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. Pertuzumab is a humanized mAb that targets the extracellular dimerization domain (subdomain II) of HER2 and blocks heterodimerization of HER2 with other HER family members. The product was approved by the US Food and Drug Administration in 2012 for the same indication.
January - February 2013
Trastuzumab emtansine receives a marketing approval in the US
On February 22, 2013, trastuzumab emtansine (Kadcyla; Genentech/Roche) was approved by the US Food and Drug Administration as a treatment for HER2-positive metastatic breast cancer. Trastuzumab emtansine is an antibody-drug conjugate (ADC) composed of trastuzumab (Herceptin®; Genentech/Roche) linked to ImmunoGen’s DM1 maytansinoid drug. The ADC is the third anti-HER2 mAb on the US market. The parental trastuzumab, which was approved in the US in 1998, and pertuzumab (PERJETA™; Genentech/Roche), which targets a distinct epitope compared to trastuzumab and was approved in the US 2012, are marketed as treatments for HER2-positive metastatic breast cancer. Trastuzumab was approved in the European Union in 2000, pertuzumab received a positive opinion from the European Medicines Agency (EMA) in December 2012, and trastuzumab emtansine is undergoing EMA review. A complete list of approved mAbs in the EU or US is available on our website: find here.
Itolizumab receives a marketing approval in India
Biocon announced that it received authorization from the Drugs Controller General of India to market itolizumab (Alzumab) for the treatment of moderate-to-severe psoriasis. The humanized mAb recognizes the membrane-distal domain (SRCR1) of CD6, and was evaluated in a Phase 3 study (CTRI/2009/091/001009) that evaluated administration of the mAb to patients with active moderate to severe psoriasis. In combination with methotrexate, itolizumab has also been evaluated in a clinical trial (CTRI/2008/091/000295) in patients with active rheumatoid arthritis.
Phase 3 studies of KHK4827 are started
Two Phase 3 studies of KHK4827 (Kyowa Hakko Kirin), a human anti-IL17R IgG2 mAb, were initiated in February 2013. One Phase 3 study (NCT01782924) is evaluating administration of KHK4827 to patients with moderate-to-severe plaque psoriasis who completed the preceding 12-week Phase 2 study (NCT01748539). The second Phase 3 study (NCT01782937) is evaluating administration of KHK4827 to patients with pustular psoriasis and psoriatic erythroderma. KHK4827 joins a group of at least 29 other mAb product candidates that are in Phase 3 studies (read in mAbs Journal).
November - December 2012
Raxibacumab receives a marketing approval in the US
The US Food and Drug Administration (FDA) approved raxibacumab (Human Genome Sciences) to treat inhalational anthrax, a rare and lethal infectious disease caused by breathing in the spores of the bacterium Bacillus anthracis. Raxibacumab, a human IgG1 that targets the protective antigen of anthrax, is the first mAb approved under FDA’s Animal Efficacy Rule, which allows efficacy findings from adequate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct trials in humans. The safety of raxibacumab was evaluated in 326 healthy human volunteers.
Brentuximab vedotin is approved in the European Union
The European Commission has granted conditional marketing authorization for brentuximab vedotin (Adcetris; Seattle Genetics, Millennium) for two indications: (1) the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). Brentuximab vedotin is a chimeric IgG1 antibody-drug conjugate that targets CD30, which is expressed at high levels on activated lymphocytes. The drug comprises Seattle Genetics’ cAC10 antibody (SGN-30) conjugated to the anti-tubulin agent monomethyl auristatin E through a peptide linker that is selectively cleaved after internalization into cells.
Trastuzumab emtansine receives a priority review in US
Genentech’s licensing application to the US Food and Drug Administration (FDA) for trastuzumab emtansine as a treatment for patients with HER2-positive, unresectable locally advanced or metastatic breast cancer has received a priority review. The deadline for a first decision letter by FDA is February 26, 2013. Roche submitted a licensing application to the European Medicines Agency (EMA) for the same indication. Trastuzumab emtansine is an antibody-drug conjugate composed of trastuzumab and the chemotherapy DM1.
September - October 2012
Trastuzumab emtansine undergoing regulatory review in US and EU
Genentech submitted a licensing application to the US Food and Drug Administration (FDA) for trastuzumab emtansine as a treatment for patients with HER2-positive, unresectable locally advanced or metastatic breast cancer. Roche submitted a licensing application to the European Medicines Agency (EMA) for the same indication. Trastuzumab emtansine is an antibody-drug conjugate composed of trastuzumab and the chemotherapy DM1. Phase 3 study results showed that people with previously treated HER2-positive metastatic breast cancer survived significantly longer when treated with trastuzumab emtansine compared to those who received the combination of lapatinib and capecitabine (median overall survival: 30.9 months vs. 25.1 months). Adverse events were consistent with those seen in previous studies, with fewer people administered trastuzumab emtansine experiencing Grade 3 or higher adverse events compared with those who received lapatinib plus capecitabine (40.8 percent vs. 57.0 percent).
Review of alemtuzumab for multiple sclerosis delayed in the US
The review of data for alemtuzumab as a treatment for multiple sclerosis has been delayed as the FDA has refused to file the supplemental licensing application because the presented data needs reorganization. The humanized IgG1 alemtuzumab targets CD52 and was first approved in the US and EU in 2001 under the brand names Campath® and MabCampath®, respectively, as a treatment for chronic myeloid leukemia. Genzyme, a Sanofi company, announced in June 2012 that the company submitted a supplemental licensing application to FDA and a marketing authorization application to EMA seeking approval of alemtuzumab under the brand name LEMTRADA™ for treatment of relapsing multiple sclerosis. Genzyme is developing alemtuzumab in MS in collaboration with Bayer HealthCare.
Mixed results for solanezumab in Alzheimer disease
Results from the EXPEDITION trials, which consisted of two Phase 3, double-blind, placebo-controlled studies evaluating solanezumab treatment in patients with mild-to-moderate Alzheimer disease, showed that the primary endpoints, both cognitive and functional, were not met; however, in a pre-specified secondary analysis of pooled data in patients with mild Alzheimer's disease, a statistically significant slowing of cognitive decline was shown. Independent analyses of the EXPEDITION studies conducted by an academic research consortium were generally similar to top-line study results reported in August 2012 by Lilly. The company will determine the next steps for solanezumab after discussions with regulators.
July - August 2012
Biosimilar infliximab approved in Korea
Celltrion, Inc. announced the approval by the Korean Food and Drug Administration of Remsima™ on July 23, 2012. The product, previously known as CT-P13, is a biosimilar version of anti-tumor necrosis factor infliximab, which was first approved in the US in 1998 as Remicade®. Remsima™ was approved in Korea for the same indications as Remicade®, including rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease and psoriatic arthritis. Celltrion submitted a marketing application to the European Medicines Agency; the company is planning to launch the product in over 100 countries.
Two mAbs for Alzheimer’s disease fail to meet Phase 3 study endpoints
Anti-amyloid beta IgG1 solanezumab did not meet primary endpoints in its EXPEDITION 1 and 2 Phase 3 studies in Alzheimer's patients, but seemed to slow decline in those with mild disease, according to developer Eli Lilly. In EXPEDITION 1 and 2, patients with mild-to-moderate Alzheimer's disease who received 400 mg solanezumab intravenously every 4 weeks for 80 weeks were compared to patients who received placebo. Complete study results will be released at the 2012 American Neurological Association’s annual meeting in Boston on October 8, 2012.
Anti-amyloid beta IgG1 bapineuzumab (Pfizer, JANSSEN Alzheimer Immunotherapy Research & Development) failed to meet primary endpoints in two Phase 3 studies, one of mild-to-moderate Alzheimer's disease patients who were ApoE4 gene carriers and one of patients with did not carry ApoE4. Results showed that bapineuzumab failed to change cognitive and functional performance compared to placebo. Patients in these two studies were administered bapineuzumab intravenously; bapineuzumab formulated for subcutaneous administration is undergoing evaluation in Phase 2 studies.
Progress in development of anti-anthrax PA mabs
The development programs of raxibacumab and ETI-204, mAbs that both target the protective antigen of B. anthracis, have progressed. The biological license application for raxibacumab (Human Genome Sciences) has been resubmitted to the US Food and Drug Administration; the agency is due to take action on the application by December 15, 2012. Raxibacumab is intended for use in the event of life-threatening inhalation anthrax disease. Elusys received funding for development of ETI-204 for pre- and post-exposure prophylaxis use via intramuscular injection. The mAb is intended for prevention and treatment of inhalational anthrax following a biowarfare attack.
New research on anti-influenza B mAbs published in Science
Building on their previous work with broadly neutralizing antibodies against influenza A viruses, researchers at Scripps Research Institute and Crucell have now published results for three anti-influenza B mAbs that protect mice against lethal challenge. CR8033 and CR8071 were found to recognize distinct conserved epitopes in the head region of the influenza B hemagglutinin (HA), while CR9114 bound a conserved epitope in the HA stem and protected against lethal challenge with influenza A and B viruses. The authors suggested that the antibodies may inform on development of mAb–based treatments and a universal flu vaccine for all influenza A and B viruses.
GlaxoSmithKline acquires Human Genome Sciences
GlaxoSmithKline (GSK) announced the completion of its acquisition of Human Genome Sciences for US$3.6 billion on an equity basis (approximately US$3 billion net of cash and debt). With completion of the deal, GSK’s portfolio gains belimumab (Benlysta®), as well as raxibacumab, mapatumumab and the fusion protein HGS1036. Raxibacumab targets the protective antigen of anthrax and is undergoing US regulatory review; mapatumumab is agonistic to TRAIL-R1 and is being evaluated in Phase 2 clinical studies of cancer patients; HGS1036 comprises the extracellular domain of FGFR-1C fused to IgG1 Fc and a Phase 1 study of it in combination with chemotherapy in subjects with advanced solid malignancies is not yet open for participant recruitment.
May - June 2012
Pertuzumab approved by FDA
Pertuzumab (Perjeta®; Genentech), a humanized IgG1 mAb that targets human epidermal growth factor receptor (HER) 2, was approved by the US Food and Drug Administration on June 8, 2012. The mAb was approved as a treatment for HER2-positive metastatic breast cancer when given in combination with trastuzumab and docetaxel. Prior to approval, Pertuzumab was evaluated in two Phase 3 studies of mAb combinations: 1) the MARIANNE study (NCT01120184) of the combination of pertuzumab and trastuzumab-DM1; and 2) the CLEOPATRA study (NCT00567190), which evaluated the safety and efficacy of the combination of pertuzumab, trastuzumab and docetaxel compared to the combination of trastuzumab, docetaxel and a placebo in adult patients (18 years or older) with previously untreated HER2-positive metastatic breast cancer.
New study of crenezumab for the prevention of Alzheimer’s disease
A potentially ground-breaking study of crenezumab (MABT5102A) in the prevention of Alzheimer's disease is due to start soon. Genentech, the Banner Alzheimer's Institute, and the National Institutes of Health are collaborating to evaluate the IgG4, anti-(human 1-40-β-amyloid/human 1-42-β-amyloid) mAb in cognitively healthy individuals who are likely to develop Alzheimer’s disease because of their genetic history. The study will include ~300 Colombian participants who share a rare genetic mutation that typically triggers Alzheimer’s symptoms around age 45. The results may substantially change the way the disease is treated or open new possibilities for targets.
Biosimilar infliximab in European review
The European Medicines Agency is reviewing the first marketing application submitted in either the European Union or United States for a biosimilar infliximab. The application is reported to be from Celltrion, a South Korean company that previously declared positive results of their biosimilar infliximab study. The company has several biosimilars mAbs in their pipeline, including rituximab and trastuzumab. The biosimilar trastuzumab is undergoing evaluation in a Phase 3 study [NCT01084876] of 383 patients with metastatic breast cancer; as of May 2012, Phase 1 clinical studies of rutuximab for diffuse large B-cell lymphoma and rheumatoid arthritis are listed on clinicaltrials.gov as not yet open for patient recruitment.
Marketed therapeutic antibodies compendium published
Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As more mAbs become available to physicians and patients, keeping track of the number, types, production cell lines, antigenic targets, and dates and locations of approvals has become challenging. Data are presented for 34 mAbs that were approved in either Europe or the United States (US) as of March 2012, and nimotuzumab, which is marketed outside Europe and the US. The compendium can be freely downloaded at:
March - April 2012
Glyco-engineered mogamulizumab approved in Japan
Kyowa Hakko Kirin announced that it received marketing approval for mogamulizumab (POTELIGEO®) as a treatment for patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma (ATL) from the Ministry of Health, Labor and Welfare (MHLW) in Japan. Mogamulizumab is a humanized, defucosylated IgG1 that targets CCR4 produced using POTELLIGENT®, a technology to produce antibodies with enhanced ADCC activity developed by Kyowa Hakko Kirin. This product is the first glyco-engineered antibody that has received marketing approval. Mogamulizumab was also granted an orphan drug designation for the treatment of CCR4-positive ATL by the MHLW.
Trastuzumab emtansine Phase 3 study results
Topline results of EMILIA, the first randomized Phase 3 study of the antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1, trastuzumab-MCC-DM1; Genentech/ImmunoGen) were announced by Genentech. Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) who had previously received treatment with trastuzumab (Herceptin®) and a taxane chemotherapy were enrolled. Those who received trastuzumab emtansine lived significantly longer without disease progression (progression-free survival) compared with those who received lapatinib plus capecitabine (Xeloda®). The safety profile of trastuzumab emtansine was consistent with that seen in previous studies. Genentech also announced that it plans to submit marketing applications in both the United States and Europe in 2012 for trastuzumab as a treatment for HER2-positive mBC.
Trastuzumab emtansine is a humanized IgG1 ADC. Naked trastuzumab, i.e., the unconjugated antibody, was first approved by the US Food and Drug Administration for treatment of HER2-positive mBC in 1998. Trastuzumab was conjugated to the maytansinoid cytotoxin DM1 to form the ADC, which is internalized, undergoes proteolytic degradation in the lysosome, and releases lysine-MCC-DM1 as a major active metabolite.
Pertuzumab application receives priority review from FDA
The biologics license application for pertuzumab has been given a priority review rating by the US Food and Drug Administration. The FDA’s deadline for a first action on the application is June 8, 2012. Pertuzumab (RO4368451, rhMAb 2C4; Genentech), a humanized anti-HER2 IgG1 mAb that targets HER2, has undergone evaluation as a combination with other drugs in two Phase 3 studies in patients with HER2-postive metastatic breast cancer, i.e., the Phase 3 MARIANNE study (NCT01120184) of the combination of pertuzumab and trastuzumab-DM1 and the Phase 3 CLEOPATRA study (NCT00567190) of the combination of pertuzumab, trastuzumab and docetaxel. Pertuzumab and trastuzumab bind to domain II and IV, respectively, of HER2. Preclinical experiments with the combination of pertuzumab and trastuzumab indicated that the two mAbs can bind simultaneously to HER2-positive tumor cells in vivo and they do not compete for binding.
EMA lists applications in review
To improve transparency in the regulatory review process in Europe, information on validated applications for centralized marketing authorization for human medicines that the European Medicines Agency has received for evaluation is being made public. The EMA now makes available lists that include the international non-proprietary names (INN) and therapeutic areas for all new innovative medicines under evaluation by the Committee for Medicinal Products for Human Use (CHMP). For generic and biosimilar medicines, it includes the INN (active moiety only) and therapeutic area. For the March 2012 list, which includes pertuzumab and brentuximab vedotin, find the list here.
January - February 2012
Amgen agrees to acquire Micromet
Amgen has entered into a definitive agreement to acquire Micromet. The acquisition will include blinatumomab, a bispecific T cell Engager (BiTE) antibody in Phase 2 clinical development for acute lymphoblastic leukemia. According to the agreement, Micromet's site in Germany will operate as an Amgen R&D center of excellence. The $1.16 billion transaction is expected to close in the first quarter.
FDA decision on pertuzumab application due by June 8, 2012
The US Food and Drug Administration (FDA) granted a priority review for pertuzumab, a humanized anti-HER2 IgG1 mAb. In a pivotal clinical trial, breast cancer patients administered pertuzumab in combination with trastuzumab (Herceptin®) and a chemotherapy agent lived for an average of 18.5 months without progression of their disease, compared with 12.4 months for those who received only trastuzumab and the chemotherapy agent. FDA’s deadline date for a first decision on the application is June 8, 2012.
Ipilimumab approved in Canada
Ipilimumab (Yervoy®) has been approved for marketing in Canada for treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease. The product is a human IgG1 mAb targeting CTLA4 that was approved in the US and Europe in 2011. Kaplan-Meier survival rate results indicate that one- and two-year survival rates for patients administered ipilimumab were almost doubled compared with patients treated with gp100 cancer vaccine (46% and 24% one- and two-year survival rates for ipilimumab, respectively, vs. 25% and 14% one- and two-year survival rates for gp100, respectively).
Results for Alzheimer’s mAb therapy studies expected in 2012
Solanezumab (LY2062430; Eli Lilly), a humanized IgG1 mAb that targets soluble amyloid beta, is undergoing evaluation as a treatment for mild-to-moderate Alzheimer disease. In binding its target, the mAb may alter the equilibrium between amyloid beta in the blood and central nervous system. The safety and efficacy of solanezumab administration in Alzheimer disease patients is currently being evaluated in two Phase 3 studies, Expedition and Expedition 2 (NCT00905372 and NCT00904683, respectively). In each study, adults (55 years and older) with mild-to-moderate Alzheimer disease are administered 400 mg solanezumab or placebo once iv every 4 weeks for 80 weeks. The primary outcome measures are the change from baseline to week 80 in the Alzheimer disease assessment scale-cognitive subscore (ADAS-Cog11) and the Alzheimer disease cooperative study-activities of daily living (ADCS-ADL) inventory. The estimated enrollment in each study is 1,000 patients; the estimated study completion dates are April 2012 and June 2012 for the Expedition and Expedition 2 studies, respectively.
November - December 2011
FDA approval and Phase 3 results for aflibercept
The US Food and Drug Administration (FDA) approved aflibercept (EYLEATM), a fusion protein comprising the extracellular domains of the vascular endothelial growth factor receptors (VEGFR)-1 and -2 fused to the Fc of a human IgG1, on November 18, 2011. Aflibercept binds to VEGF-A isoforms as well as placental growth factor and is designed to interfere with angiogenesis. The product was approved as a treatment for neovascular age-related macular degeneration (wet AMD) at a recommended dose of 2 mg every four weeks for the first 12 weeks, followed by 2 mg every eight weeks.
Results from an integrated analysis of two randomized, double masked, active controlled Phase 3 studies (VIEW 1 and VIEW 2) in patients with wet AMD indicated a visual acuity gain from baseline in the aflibercept 2 mg every eight week group at week 96 was 7.6 letters compared to 8.4 letters at week 52, with an average of 11.2 injections over two years and 4.2 injections during the second year. The visual acuity gain from baseline in the monthly ranibizumab (Lucentis®) group at week 96 was 7.9 letters compared to 8.7 letters at week 52, with an average of 16.5 injections over two years and 4.7 injections during the second year.
Regulatory review and Phase 3 results for pertuzumab
Pertuzumab is a humanized anti-HER2 IgG1 mAb that targets HER2 undergoing evaluation in combination with other drugs Phase 3 studies in patients with HER2-postive metastatic breast cancer. Pertuzumab and trastuzumab (Herceptin®) bind to domain II and IV, respectively, of HER2. Preclinical experiments with the combination of pertuzumab and trastuzumab indicated that the two mAbs can bind simultaneously to HER2-positive tumor cells in vivo and they do not compete for binding.
The Phase 3 CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) study evaluated the efficacy and safety profile of pertuzumab combined with trastuzumab and chemotherapy compared to trastuzumab and chemotherapy alone in 808 people with previously untreated HER2-positive metastatic breast cancer. Patients who received pertuzumab in combination with trastuzumab and chemotherapy experienced a 38 percent reduction in the risk of their disease worsening or death (progression-free survival, or PFS), (HR=0.62; p-value=<0.0001). The median PFS improved by 6.1 months from 12.4 months for trastuzumab and chemotherapy to 18.5 months for pertuzumab, trastuzumab and chemotherapy. Overall survival (OS) data are currently immature, with a trend in favor of the pertuzumab combination. Marketing applications for pertuzumab as a treatment of HER2-positive metastatic breast cancer have been submitted in the US and Europe.
Setback for bevacizumab
The US FDA has revoked marketing approval of bevacizumab (Avastin®) used in combination with the paclitaxel for patients who have not been treated with chemotherapy for HER2-negative, although bevacizumab remains on the market for treatment of certain types of colon, lung, kidney and brain cancer. Based on results of one study, bevacizumab was approved for metastatic breast cancer in February 2008 under the FDA’s accelerated approval program, which allows a drug to be approved based on data that are not sufficiently complete to permit full approval. Post-marketing data from two additional clinical trials suggested that the benefit/risk ratio was unfavorable, e.g., small effects on tumor growth without evidence that patients lived any longer or had a better quality of life compared to taking standard chemotherapy alone.
News from FDA on their biosimilar review process
The FDA has proposed performance goals and procedures for authorization of biosimilar biological products on their website.
Second supplemental approval in the US for cetuximab
The US Food and Drug Administration has approved cetuximab (Erbitux® ) for first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-fluorouricil. Cetuximab is a chimeric, epidermal growth factor receptor (EGFR)-targeting mAb that was first approved in the US in 2004 for use with irinotecan for treatment of EGFR-expressing metastatic colorectal cancer patients who are refractory to irinotecan-based chemotherapy and as a single agent in EGFR-expressing metastatic colorectal cancer patients who are refractory to irinotecan-based chemotherapy. The drug received a supplemental approval in 2006 for use in combination with radiation therapy for treatment of non-metastatic squamous cell carcinoma of the head and neck or as a single agent for treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy failed.
Four novel mAbs enter the clinical pipeline
Novel mAbs from Xencor, Circadian Technologies Limited/Vegenics Pty, Amgen, and Theraclone Sciences have entered the clinical pipeline. XmAb5871 (Xencor) is a humanized anti-CD19 mAb with an Fc domain that has been engineered to bind Fc?RIIb with high affinity, thereby promoting the co-engagement of Fc?RIIb with the BCR complex and inhibiting B cells. The mAb has potential as an immunosuppressant in patients with autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis.
VGX-100 (Circadian Technologies Limited/Vegenics Pty) is a human mAb targeting vascular epidermal growth factor (VEGF)-C. Circadian plans to evaluate VGX-100 as a treatment for cancers, particularly glioblastoma and metastatic colorectal cancers; the mAb may also be studied as an agent to treat front-of the-eye diseases.
ImmunoGen announced that an investigational new drug application filed by Amgen to initiate clinical study of a novel anticancer compound that utilizes ImmunoGen’s Targeted Antibody Payload technology is now active. Additional details regarding the candidate have not yet been released.
TCN-032 (Theraclone Sciences) is now undergoing evaluation in a randomized, double-blind Phase 1 dose-escalation study [NCT01390025] in healthy adult volunteers. The human mAb targets a conserved epitope of the amino-terminal extracellular domain of the influenza A virus matrix protein 2, and is intended for use as an antiviral agent for the treatment of disease caused by type A influenza viruses. Treatments within the study will consist of single ascending dose-escalation ranging from 1 to 40 mg/kg; the estimated study completion date is July 2012.
First Phase 2 study for SAR3419
Sanofi has initiated the first Phase 2 study of SAR3419, an anti-CD19 antibody-drug conjugate (ADC). In the Phase 2 study [NCT01440179], SAR3419 will be administered as a single agent by intravenous infusion in patients with relapsed or refractory acute lymphoblastic leukemia. SAR3419 was created by ImmunoGen and licensed to Sanofi prior to initiation of any clinical studies. The ADC has been evaluated in two Phase 1 studies that are active but not recruiting patients: NCT00796731, a dose-escalation, safety and pharmacokinetic study of SAR3419 administered as a single agent by intravenous infusion once weekly in patients with relapsed/refractory CD19-positive B cell non-Hodgkin's lymphoma (NHL); and NCT00549185, an open-label multi-dose-escalation, safety and pharmacokinetic study of SAR3419 administered as a single agent by intravenous infusion every 3 weeks in patients with relapsed/refractory B cell NHL.
EMA plans to revise existing guidelines on biosimilar therapeutics
The European Medicine Agency’s guideline on similar biological medicinal products containing biotechnology derived proteins as active substance, which discussed non-clinical and clinical issues, came into effect in June 2006. Given the trend toward development of increasingly complex biosimilar products, including antibodies, EMA has proposed the re-evaluation of some topics. These include selection of relevant species for non-clinical studies, need for clinical equivalence studies and other issues of the design of pivotal clinical studies, role of biomarkers, amount of immunogenicity data needed and the possibility to extrapolate to other indications. Comments may be submitted to EMA until the end of December 2011; EMA expects a draft revised guideline to be released in the first quarter of 2012.
Brentuximab vedotin approved in US
The U.S. Food and Drug Administration approved brentuximab vedotin (Adcetris; Seattle Genetics) to treat Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). Brentuximab vedotin is a chimeric IgG1 antibody-drug conjugate that targets CD30, which is expressed at high levels on activated lymphocytes. The drug comprises Seattle Genetics’ cAC10 antibody (SGN-30) conjugated to the anti-tubulin agent monomethyl auristatin E through a peptide linker that is selectively cleaved after internalization into cells.
The product, the first new FDA-approved treatment for HL since 1977 and the first specifically indicated to treat ALCL, is to be used in patients with HL whose disease has progressed after autologous stem cell transplant or after two prior chemotherapy treatments for those who cannot receive a transplant or in patients with ALCL whose disease has progressed after one prior chemotherapy treatment. Brentuximab vedotin received an accelerated approval, which allows FDA approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit but Seattle Genetics is required to submit additional clinical information post-approval to confirm the drug’s clinical benefit.
Target date for FDA action on aflibercept in November 2011
The FDA’s target date for action on aflibercept (Eylea; Regeneron Pharmaceuticals, Inc), which was scheduled for August 2011, has been extended to November 18, 2011. The extension will allow FDA time to review information submitted in response to their questions regarding the chemistry, manufacturing, and controls section of the marketing application. Aflibercept is human fusion protein consisting of portions of VEGF receptors 1 and 2 that bind all forms of VEGF-A, as well as placental growth factor. The product is undergoing FDA review as a treatment for neovascular age-related macular degeneration (wet AMD).
Anti-CCR4 mogamulizumab undergoing regulatory review in Japan
The Japanese Ministry of Health, Labor and Welfare is reviewing a marketing application for mogamulizumab (KW-0761, AMG761) for the treatment of adult T-cell leukemia-lymphoma (ATL). Anti-C-C chemokine receptor type 4 (CCR4) IgG1 mogamulizumab was developed by Kyowa Hakko Kirin Co., Ltd. using their POTELLIGENT® technology, which produces defucosylated antibodies with enhanced antibody-dependent cell-mediated cytotoxicity. The product was granted orphan drug designation in Japan for CCR4-positive ATL.
Clinical study results for canakinumab in systemic juvenile idiopathic arthritis
Positive results of the first Phase 3 study of anti-IL1 beta canakinumab (Ilaris, ACZ885; Novartis Pharmaceuticals) in patients with systemic juvenile idiopathic arthritis (SJIA), a rare and serious childhood auto-inflammatory disease, were presented at the 2011 European Pediatric Rheumatology Congress in Bruges, Belgium. All primary and secondary endpoints of the study were met; of the patients who received the drug, most (83.7%) experienced at least a 30% improvement in symptoms (vs. 9.8% for placebo; p<0.0001) and a third (32.6%) achieved a 100% improvement (vs. 0% for placebo; p=0.0001). Canakinumab is marketed in the United States and European Union as a treatment for cryopyrin-associated periodic syndromes.
Rise of the Fc-fusion proteins
As of July 2011, a total of 6 Fc-fusion products have been approved, and one (aflibercept) is undergoing regulatory review in the US, European Union and Japan, with approval in the US possible by August 20, 2011. The most recently approved Fc-fusion product is belatacept (Nulojix), which is composed of the extracellular domain (EDC) of CTLA-4 fused to human IgG1 Fc. Belatacept was approved for marketing by the US Food and Drug Administration (FDA) on June 15, 2011 to prevent acute rejection in adult patients who receive a kidney transplant. The product differs from abatacept (Orencia), which was FDA-approved in 2008 for rheumatoid arthritis, by two amino acid substitutions (L104E, A29Y) in the CTLA-4 region.
Aflibercept (Eylea), composed of the ECDs of VEGF receptors 1 and 2 fused to human IgG1 Fc, binds VEGF-A and placental growth factor, thereby inhibiting angiogenesis. The product is undergoing FDA review as a treatment for wet age-related macular degeneration (AMD); on June 17, 2011, FDA's Dermatologic and Ophthalmic Drugs Advisory Committee voted unanimously to recommend approval of aflibercept ophthalmic solution for this condition.
Farletuzumab studied as lung cancer treatment
Farletuzumab is being evaluated in a new multi-center Phase 2 study (NCT01218516) of patients with adenocarcinoma of the lung. Farletuzumab, a humanized IgG1 that binds folate receptor-alpha, is being administered with one of three standard platinum-containing doublets (carboplatin and paclitaxel, carboplatin and pemetrexed, or cisplatin and pemetrexed) that are approved and recommended for first-line metastatic lung cancer patients. Farletuzumab is also in a Phase 3 study (NCT00849667) in patients with platinum-sensitive ovarian cancer in first relapse.
MORAb-004 enters Phase 2 study
A Phase 2, open label, dose selection, proof-of-concept study (NCT01335009) to assess progression free survival in metastatic melanoma patients treated with MORAb-004 has been initiated. MORAb-004, a humanized IgG1, targets endosialin/tumor endothelial marker-1 (TEM-1), a cell surface glycoprotein that is expressed on cells involved in tumor vasculature and on fibroblast cells that are part of the tumor stroma. The antibody will be tested as a single agent therapy comparing its safety and therapeutic activity at doses of 2 or 4 mg/kg administered intravenously on Days 1, 8, 15, and 22 (4 administrations per cycle). Additional cycles will continue without interruption or change in dose until disease progression occurs.
Fc-fusion protein sotatercept enters first Phase 2/3 study
A Phase 2/3 clinical study (NCT01284348) of sotatercept as a treatment of chemotherapy-induced anemia metastatic non-small cell lung cancer patients treated with first-line platinum-based chemotherapeutic regimens has been initiated. Sotatercept is a soluble receptor fusion protein comprised of ECD of the human activin receptor type IIA (ActRIIA) fused to a human IgG1 Fc; blocking signaling through ActRIIA may be a way to increase red blood cell production, promote bone formation and inhibit tumor growth and metastasis. Three doses (15, 30, 45 mg) of sotatercept administered subcutaneously every 42 days, up to 4 doses/cycles, are being evaluated.
US Congress starts PDUFA V process
Discussion of possible provisions in US legislation that will reauthorize the landmark Prescription Drug User Fee Act of 1992 (PDUFA) for the fourth time have started. The US Senate Health, Education, Labor and Pensions Committee scheduled a hearing on PDUFA V with FDA Commissioner Margaret Hamburg on July 28, 2011. FDA plans to release its PDUFA V proposal on September 1, 2011. Topics likely to be discussed include FDA’s conflict of interest rules applied to experts for advisory committees, possible methods to reduce regulatory uncertainty and risk-aversion, and pathways to expand access to investigational drugs. The current PDUFA legislation is due to expire on June 30, 2012.
First action by FDA on brentuximab vedotin applications due August 30, 2011
The marketing applications for brentuximab vedotin (Seattle Genetics/Millennium) have been granted priority review by the US Food and Drug Administration (FDA). Brentuximab vedotin is undergoing FDA review as a treatment for relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma. Under provisions of the Prescription Drug User Fee Act, FDA’s goal for time to first action on a priority reviewed application is six months. A decision on the application is due by August 30, 2011. Brentuximab vedotin was designated a US orphan drug for both Hodgkin and anaplastic large cell lymphomas.
Brentuximab vedotin is a chimeric IgG1 antibody-drug conjugate that targets CD30, which is expressed at high levels on activated lymphocytes. The drug comprises Seattle Genetics’ cAC10 antibody (SGN-30) conjugated to the anti-tubulin agent monomethyl auristatin E through a peptide linker that is selectively cleaved after internalization into cells.
Bevacizumab vs. ranibizumab trial in AMD results in a tie
Results from the Comparison of AMD Treatments Trials: Lucentis-Avastin Trial (NCT00593450), sponsored by the National Eye Institute, indicate that bevacizumab (Avastin® Genentech) and ranibizumab (Lucentis®; Genentech) are equally effective as treatments for age-related macular degeneration (AMD). Both products are humanized antibodies that target vascular epithelial growth factor (VEGF); bevacizumab is a full-size antibody whereas ranibizumab is an antigen-binding fragment (Fab). Bevacizumab was developed as a cancer drug and was first approved in 2004 and 2005 in the US and Europe, respectively. Ranibizumab was specifically developed for AMD, and was approved in 2006 and 2007 in the US and Europe, respectively, for this indication. Bevacizumab use in AMD is off-label, i.e., it has not been approved for marketing as a treatment for AMD, but is used by physicians for this use.
Initiated in February 2008, the purpose of the study is to evaluate the relative efficacy and safety of treatment of neovascular AMD with ranibizumab on a fixed schedule, bevacizumab on a fixed schedule, ranibizumab on a variable schedule, and bevacizumab on a variable schedule. Study results were reported for 1,185 patients enrolled in one of the four treatment regimens: 1) Lucentis® on a fixed schedule of 0.5 mg (0.05 mL) intravitreal injection every 4 weeks for 1 year; at 1 year, re-randomization to Lucentis® every 4 weeks or to variable dosing; 2) Avastin® on a fixed schedule of 1.25 mg (0.05 mL) intravitreal injection every 4 weeks for 1 year; at 1 year, re-randomization to Avastin® every 4 weeks or to variable dosing; 3) Lucentis® on a variable dosing schedule for 2 years; i.e., after initial treatment with a 0.5 mg (0.05 mL) intravitreal injection, monthly evaluation for treatment based on signs of lesion activity; 4) Avastin® on a variable dosing schedule for 2 years; i.e., after initial treatment with a 1.25 mg (0.05 mL) intravitreal injection, monthly evaluation for treatment based on signs of lesion activity.
The primary outcome measure is change in visual acuity; study results indicate improvement was virtually identical (within one letter difference on an eye chart) for either drug administered monthly. No difference was found in the percentage of patients who had an important gain or loss in visual function. When administered on a variable dosing schedule, no difference (within one letter) was observed between patients who received the drugs. Variable dosing required four to five fewer injections per year than monthly treatment, and visual gains were about two letters less compared with monthly treatment. The study is on-going and due for completion in February 2012.
Upcoming joint EMA/FDA meeting on PML
Progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease that affects the brain, is caused by a polyomavirus that infects 70-80% of adults, but which is normally kept in check by the immune system. AIDS, leukemia and lymphoma patients are known to be at greater risk of developing PML, as are patients who receive certain drugs, e.g., natalizumab, rituximab, alemtuzumab. The European Medicines Agency (EMA) will host a workshop co-chaired with the US Food and Drug Administration in London on July 25-26, 2011 to discuss drug-related PML. The workshop’s objectives include finding a common understanding of the priorities for research in PML; mapping ongoing research and identifying gaps in PML; fostering funding and partnerships to conduct research to fill knowledge and research gaps in the field; agreeing on a mechanism to ensure information-sharing and regular stock-taking of research results, knowledge and knowledge gaps.
FDA proposes user fees for biosimilar products
Although no guidelines are yet available from FDA for development of biosimilar protein products, e.g., monoclonal antibodies, the agency may issue these by the end of 2011 and it has already proposed a fee structure for review of the applications. The user fees are also intended to fund support activities that occur early in the development cycle. FDA has proposed four fees that amount to ~US$2 million based on FDA’s current FY2011 user fee schedule for innovator products.
During the development period, an annual user fee of $150,000 would “support the ongoing scientific, technical, and other regulatory activities associated with biosimilar development, including milestone meetings and the application data reviews required to provide advice for the next steps in development.” The sum of all of the previously paid annual biosimilar product development fees associated with the biosimilar product would be subtracted from application fees if a marketing application is filed.
Three other fees associated with the review and marketing of the biosimilar products would be equivalent to those paid by innovators, i.e., one-time marketing application fee of $1,542,000 for a marketing application requiring clinical data; annual establishment (site at which one or more prescription drug products are manufactured in final dosage form) fee of $497,200; annual product fee of $86,520. [Note: dollar values listed here are based on FDA’s FY2011 user fees.]
Bispecific antibody as potential Alzheimer’s disease treatment?
Yu et al. reported progress on a new approach to an Alzheimer’s disease treatment using bispecific antibodies in Science Translational Medicine (25 May 2011). They generated an antibody with low affinity to the transferring receptor, which allowed receptor-mediated trancytosis across the blood-brain barrier in mice, and high affinity to beta-secretase, which is involved in amyloid-beta production. The bispecific antibody was shown to accumulate in mouse brain and reduce brain amyloid-beta to a greater extent compared with a monospecific antibody targeting beta-secretase.
FDA approves rituximab as a treatment for 2 orphan diseases
The US Food and Drug Administration approved rituximab (Rituxan®, Genentech/Biogen Idec) in combination with glucocorticoids for the treatment of patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). The two disorders, which cause blood vessel inflammation, are considered to be "orphan" diseases because fewer than 200,000 people in the US are affected. Rituximab’s safety and efficacy were demonstrated in a single study of 197 WG or MPA patients who received glucocorticoids with either rituximab or oral cyclophosphamide. After six months of treatment, complete remission was achieved by 64% and 53% of patients treated with rituximab and cyclophosphamide, respectively. Rituximab, a chimeric mAb that targets CD20 on B cells, is also marketed as a treatment for non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. The first marketing approvals for rituximab were granted in 1997 and 1998 in the US and EU, respectively.
Two new anti-cancer mAbs enter first clinical studies
The first-in-humans studies of IMC-3C5 (Circadian Technologies/ ImClone Systems) and KB004 (KaloBios Pharmaceuticals) started in April 2011. IMC-3C5, a human IgG1 that targets vascular endothelial growth factor receptor (VEGFR)-3, is undergoing evaluation in patients with advanced solid tumors refractory to standard therapy or for which no standard therapy is available. The Phase 1 study [NCT01288989] will determine the safety and maximum tolerated dose, with a proposed dose range of 5 mg/kg to 30 mg/kg, of IMC-3C5 administered intravenously on a weekly or biweekly basis. Enrollment is estimated at 40 patients and the estimated study completion date is March 2013.
The first patients were dosed in the first Phase 1 study [NCT01211691] of KB004, a Humaneered™ anti-EphA3 IgG1K mAb, in patients with EphA3-expressing hematologic malignancies, which include acute myelocytic leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, dysmyelopoietic syndromes and myeloproliferative neoplasms (MPN). The study will evaluate safety and determine a possible maximum tolerated dose; use of 4 doses (20, 70, 200 and 700 mg) infused once weekly during a 21-day cycle is planned. Patients may receive up to 17 cycles. Enrollment is estimated at 39 patients and the estimated study completion date is December 2012.
New Phase 1 study of MM-111 initiated
The first patients were dosed in a new Phase 1 study [NCT01304784] of MM-111 (Merrimack Pharmaceuticals, Inc.), an anti-ErbB2/HER2 bispecific single chain variable fragment. The study will evaluate safety and pharmacokinetics of MM-111 when administered to patients with HER2-positive solid tumors as part of three different combination treatments. Specifically, the combinations are MM-111 with 1) cisplatin, capecitabine, and trastuzumab; 2) lapatinib and trastuzumab; or 3) paclitaxel and trastuzumab. Enrollment is estimated at 24 patients and the estimated primary completion date is January 2012. MM-111 is also undergoing evaluation in a Phase 1/2 study [NCT00911898] as monotherapy in patients with HER2-positive cancers and a Phase 1/2 study [NCT01097460] of the combination of MM-111 with trastuzumab in patients with advanced HER2-positive breast cancer.
Positive results from Phase 2 study of AMG 785/CDP7851
In a Phase 2 study [NCT00896532] in postmenopausal women with low bone mineral density, AMG785/CDP7851 (Amgen/UCB) met the primary endpoint by demonstrating a significant change from baseline at month 12 in bone mineral density at the lumbar spine for the AMG785 groups and pooled placebo arms. The study contained 4 arms: 1) AMG 785 70mg or 140mg or 210mg administered subcutaneously (SC) or placebo SC every month; 2) AMG785 140mg or 210mg SC or placebo SC every three months; 3) teriparatide 20ug SC every day; 4) alendronate 70mg PO every week. AMG 785 compared positively with teriparatide and alendronate. The overall incidence of adverse events was generally balanced between groups. AMG 785, a humanized mAb that targets sclerostin, is also undergoing evaluation in Phase 2 studies designed to assess healing in patients with fresh unilateral hip fracture (post surgical fixation), and skeletally mature adults with a fresh unilateral tibial diaphyseal fracture (post a definitive fracture fixation with an intramedullary nail).
First US approvals for two novel antibodies
The US Food and Drug Administration approved two novel antibodies, belimumab and ipilimumab, in March 2011. Belimumab (Benlysta®, Human Genome Sciences/GlaxoSmithKline) was approved on March 9, 2011 for the treatment of patients with active, autoantibody-positive systemic lupus erythematosus who receive standard therapy, e.g., corticosteroids, antimalarial agents, immunosuppressives and non-steroidal anti-inflammatory drugs. Ipilimumab (Yervoy®, Bristol-Myers Squibb) was approved on March 25, 2011 as a treatment for metastatic melanoma. Marketing applications for belimumab and ipilimumab are undergoing review at the European Medicines Agency.
Belimumab is a human IgG1 mAb that targets B lymphocyte stimulator (BLyS). A member of the tumor necrosis factor cytokine family, the soluble ligand BLyS binds to any of three receptors on B lymphocytes, and contributes to differentiation, homeostasis and selection of these cells. The antigen is over-expressed in SLE patients and changes in BLyS concentration correlate with increased disease activity. Ipilimumab is a human IgG1 mAb that targets cytotoxic T-lymphocyte antigen 4; the product has been ,or is being, evaluated in over 50 clinical studies of patients with a variety of cancers, including prostate, pancreatic, urothelial, lung, brain, breast, colorectal, and renal cancer, as well as lymphoma and chronic myeloid leukemia. In melanoma patients, ipilimumab was studied as a single agent and in combination with gp100 vaccine. Clinical benefit appears to be associated with "immune-related adverse events" that often affect the skin and gastrointestinal tract. Ipilimumab was approved with a Risk Evaluation and Mitigation Strategy due to the severe side effects.
First marketing applications submitted for two novel antibody-based therapeutics
First marketing applications for brentuximab vedotin (Seattle Genetics/Millennium) and aflibercept (VEGF Trap; Regeneron/sanofi-aventis/Bayer) were submitted to the US Food and Drug Administration (FDA). Sponsors of both product candidates requested priority review, which, if granted, indicates that the FDA should issue decisions on the applications within 6 months. Brentuximab vedotin will be reviewed as a treatment for relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma. Aflibercept will be reviewed as a treatment for the neo-vascular form of age-related macular degeneration.
Brentuximab vedotin is a chimeric IgG1 immunoconjugate that targets CD30, which is expressed at high levels on activated lymphocytes. The immunoconjugate comprises Seattle Genetics’ mAb cAC10 (SGN-30) conjugated to the anti-tubulin agent monomethyl auristatin E through a peptide linker that is selectively cleaved after internalization into cells. Aflibercept is composed of the extracellular domains of the vascular endothelial growth factor receptors (VEGFR)-1 and -2 fused to the Fc of a human IgG1, and binds to VEGF-A isoforms as well as placental growth factor. Designed to interfere with angiogenesis, aflibercept is also in Phase 3 studies as a potential treatment for non-small cell lung [NCT00532155], colorectal [NCT00561470] and prostate cancer [NCT00519285]. Results announced in March 2011 for the study of non-small cell lung cancer patients indicated that aflibercept failed to meet its primary endpoint of improving overall survival.
Setback for otelixizumab
Otelixizumab did not meet the primary efficacy endpoint of change in C-peptide at month 12 in patients with new-onset type 1 (autoimmune) diabetes mellitus in the Phase 3 DEFEND-1 study [NCT00678886], according to results announced in March 2011. Otelixizumab (TRX4, ChAglyCD3) is a humanized IgG1 that targets CD3 on T cells. The mAb contains a humanized gamma1 heavy chain and a rat/human chimeric lambda light chain, and has no glycosylation site in the Fc domain, which limits its Fc-mediated functions. The mAb is also undergoing evaluation in a Phase 1 study of thyroid eye disease [NCT01114503] and two Phase 2 studies [NCT01077531 and NCT01101555] of patients with rheumatoid arthritis.
Investigational new drug application filed for novel mAb therapeutic
VX15/2503, a humanized antibody targeting semaphorin 4D (SEMA4D), will be evaluated in a Phase 1 clinical study of patients with advanced solid tumors. By blocking the activity of SEMA4D, VX15/2503 may inhibit the growth of primary tumors and limit metastases. The candidate is sponsored in clinical studies by Vaccinex, Inc., which intends to also pursue evaluation of VX15/2503 in patients with multiple sclerosis.
First-in-human studies initiated for novel mAb therapeutic
OncoMed Pharmaceuticals initiated a Phase 1 dose-escalation study (NCT01277146) of OMP-59R5, a mAb targeting Notch receptors. These receptors have been implicated in the activity and survival of cancer stem cells. Patients with previously treated solid tumors will be administered 0.5, 1, 2.5, 5, and 10 mg/kg of OMP-59R5 administered intravenously weekly for 9 doses; safety, immunogenicity, pharmacokinetics, biomarkers, and efficacy will be assessed.
Setback for necitumumab
One of two Phase 3 studies of necitumumab has been halted due to safety concerns related to blood clots. Necitumumab (IMC-11F8) is a human IgG1 mAb that targets epidermal growth factor receptor (EGFR). The Phase 3 INSPIRE study (NCT00982111), an open label, randomized, active control study of necitumumab administered in combination with pemetrexed-cisplatin chemotherapy compared to pemetrexed-cisplatin chemotherapy in adult patients with advanced non-squamous Stage IIIb or IV NSCL cancer, has been halted. The open label, randomized Phase 3 SQUIRE study (NCT00981058) is continuing and will evaluate the safety and efficacy of necitumumab and gemcitabine-cisplatin as first-line treatment of patients with Stage IV squamous non-small cell lung cancer.
Setback for briakinumab
Abbott Laboratories has withdrawn marketing applications filed in the US and EU for briakinumab. The human IgG1 mAb targets the p40 subunit that is common to both IL12 and IL23. The safety and efficacy of the mAb in patients with moderate-to-severe chronic plaque psoriasis were evaluated in four Phase 3 studies. Major adverse cardiovascular (CV) events were observed in one of these four studies and in an ongoing open-label extension, although the data indicated that all patients experiencing these events had identifiable underlying CV risk factors. Regulators indicated additional analyses were needed and that potentially more studies might be required. Abbott has indicated that resubmission may occur at a later date.
Another human mAb enters clinical studies
An application to enter clinical studies has been filed by Centocor Ortho Biotech Inc. for a human mAb derived from Morphosys’ HuCAL platform. The antibody is intended as a treatment for inflammatory and autoimmune diseases; the target has not been disclosed. Human therapeutic mAbs comprise a quickly growing class, with over 50 novel mAbs entering clinical study during 2000-2004, but nearly 100 entering study during 2005-2009. A total of seven human mAbs are currently approved for marketing (adalimumab, panitumumab, golimumab, canakinumab, ustekinumab, ofatumumab and denosumab). All four mAb candidates (raxibacumab, belimumab, ipilimumab and briakinumab) currently undergoing review by the US Food and Drug Administration are human mAbs.
Aflibercept meets COPERNICUS Phase 3 study endpoint
Aflibercept (VEGF Trap, AVE-0005, BAY86-5321; Regeneron/Sanofi-aventis/Bayer) is composed of the extracellular domains of the vascular endothelial growth factor receptors (VEGFR)-1 and -2 fused to the Fc of a human IgG1, and binds to VEGF-A isoforms as well as placental growth factor. Designed to interfere with angiogenesis, the candidate is in Phase 3 studies as a potential treatment for a variety of cancers and ocular disorders. Two on-going Phase 3 studies (COPERNICUS and GALILEO) are evaluating the safety, efficacy and tolerability of repeated intravitreal administration of aflibercept in patients with macular edema due to central retinal vein occlusion (CRVO). In the COPERNICUS study (NCT00943072), adult patients (18 years and older) received monthly 2.0 mg injections of aflibercept or placebo until evaluation at week 24. The primary outcome measure was improvement in visual acuity on the Early Treatment Diabetic Retinopathy eye chart compared to baseline after 6 months of treatment. Visual acuity was improved by at least 15 letters in 56.1% and 12.3% of patients who received aflibercept and control treatment, respectively (p<0.0001).
Setback for motavizumab
AstraZeneca has requested withdrawal of the biologics license application (BLA) filed with the US Food and Drug Administration (FDA) for motavizumab, which was undergoing review for prevention of serious respiratory syncytial virus infection in infants. The BLA was filed in January 2008, a complete response letter was issued by FDA in November 2008 and the sponsor response was filed in December 2009. The application was reviewed by the FDA’s Antiviral Drugs Advisory Committee in June 2010, which expressed concern regarding the risk/benefit ratio of palivizumab compared with the first-generation anti-RSV palivizumab (Synagis®). Palivizumab showed a 3-fold increase in nonfatal hypersensitivity adverse reactions, including urticaria, compared with palivizumab. The panel also expressed confusion regarding the positioning of motavizumab as non-inferior to palivizumab. In a second complete response letter issued in August 2010, FDA requested evidence from an additional clinical trial of motavizumab that supports a satisfactory risk/benefit profile in the population(s) for which the prophylaxis indication was being requested. AstraZeneca indicated that motavizumab will continue to be developed for other serious RSV indications.
Setback for four anti-nerve growth factor antibodies
Clinical studies of four anti-nerve growth factor (NGF) antibodies have been placed on hold, suspended or terminated due to safety concerns after patients in some studies experienced worsening of disease or developed joint damage. The four antibodies are tanezumab (Pfizer), REGN475/SAR164877 (Regeneron Pharmaceuticals Inc, Sanofi-Aventis SA), fulranumab (Johnson&Johnson) and MEDI-578 (MedImmune/AstraZeneca). Studies of tanezumab were the first to be halted in June 2010. The mAbs were being studied in a variety of indications involving chronic pain, including chronic pain associated with osteoarthritis, low back pain, and diabetic peripheral neuropathy. A fifth anti-NGF antibody, PG110 (Abbott), remains in clinical studies as of December 2010.
Supplemental approval for denosumab
Denosumab (Xgeva®, Prolia®; Amgen) has received marketing approval from the US Food and Drug Administration for prevention of skeletal-related events in patients with bone metastases from solid tumors. The human IgG2 mAb targets receptor activator of nuclear kappa-B (RANK) ligand, an osteoclast regulatory protein, and was first approved in June 2010 with the trade name Prolia® for treatment of postmenopausal women with osteoporosis at high risk for fracture. Results of a Phase 3 study comparing effects of denosumab with zoledronic acid (Zometa®) in delaying or preventing skeletal-related events in breast cancer patients with bone metastases were published in the Journal of Clinical Oncology in November 2010 (published online before print November 8, 2010, doi: 10.1200/JCO.2010.29.7101). The trade name of denosumab when administered for the supplemental indication will be Xgeva®.
Belimumab receives favorable vote from FDA panel
In a final vote of 13-2, the Arthritis Advisory Committee of the US Food and Drug Administration has advised approval of belimumab (Benlysta®; Human Genome Sciences, GlaxoSmithKline). The human mAb targets B lymphocyte stimulator protein (BLyS) and is under consideration as a treatment for autoantibody-positive patients with active systemic lupus erythematosus (SLE). The panel indicated the safety profile observed in the clinical studies was acceptable for the patient population studied, long-term follow-up of patients would be necessary and that the label should exclude patient populations that were not included in the Phase 3 studies, e.g., patients with severe lupus nephritis or central nervous system manifestations of the disease. Following the meeting, FDA requested additional information from Human Genome Sciences and extended its target decision date from December 9, 2010 to March 10, 2011.
BI-204 enters Phase 2 study
A Phase 2 study of BI-204 (BioInvent International, Genentech) has been cleared for initiation by the US Food and Drug Administration. The human mAb targets oxidized low-density lipoprotein (LDL) and is undergoing evaluation for secondary prevention of cardiovascular events in patients with acute coronary syndrome. The Phase 2 study will enroll approximately 120 patients; top-line results are expected to be ready for release by the second quarter of 2012. BI-204 was demonstrated to be safe and well-tolerated in a Phase 1 study in 80 healthy volunteers with elevated levels of LDL. The mAb has been administered either intravenously or subcutaneously in single and multiple doses. BI-204 was isolated from BioInvent’s n-CoDeR semi-synthetic library of antibody fragments and was not affinity matured.
First human dosing initiated for MOR208
The first Phase 1 study of anti-CD19 XmAb®5574 (MOR208; Xencor, MorphoSys) has been initiated. The study will assess the safety, tolerability, pharmacokinetic profile and preliminary antitumor activity of XmAb®5574 administered to patients with relapsed or refractory chronic lymphocytic leukemia. The open-label, multi-dose, single-arm, dose-escalation study [NCT01161511] will enroll an estimated 30 patients. The final data collection date for primary outcome measure is estimated to be September 2011.
Briakinumab enters regulatory review
Abbott announced that in the 2010 third quarter it filed marketing applications in the United States and Europe for approval of briakinumab (ABT-874) as a treatment for moderate to severe chronic plaque psoriasis. The human IgG1 mAb targets the p40 subunit that is common to both IL12 and IL23. The company also announced results from 4 separate Phase 3 studies (NCT00679731, NCT00570986, NCT00691964, NCT00710580) that compared the safety and efficacy of briakinumab to results for placebo-, etanercept- or methotrexate-treated psoriasis patients. Patients who were administered briakinumab achieved 75% or better skin clearance rates compared to those treated with the other study agents. Differences in the clinical results for the briakinumab-treated patients vs other cohorts were statistically significant. If approved, briakinumab would compete with ustekinumab, which also targets the IL12/IL23 p40 subunit, and the anti-tumor necrosis factor fusion protein etanercept. Both of these biologic agents are already are approved for the treatment of psoriasis.
Clinical study of ASG-5ME antibody-drug conjugate started
A Phase 1 clinical study (NCT01228760) of ASG-5ME as a treatment for patients with castration-resistant prostate cancer has been initiated by Agensys, which is an affiliate of Astellas Pharma Inc., in collaboration with Seattle Genetics. ASG-5ME is a XenoMouse-derived, human IgG2k conjugated to monomethyl auristatin E, with an average of 3.7 drug molecules per antibody. The antigen target is SLC44A4, which is overexpressed in epithelial cancers such as prostate, pancreatic and gastric cancers. ASG-5ME is also undergoing evaluation in a Phase 1 study (NCT01166490) of patients with pancreatic adenocarcinoma.
Teplizumab misses primary efficacy endpoint in diabetes study
Teplizumab [MGA031, hOKT3 1 (Ala-Ala)], which is in development by MacroGenics and Eli Lilly, is a humanized IgG1 mAb that targets CD3 on mature T lymphocytes and has been engineered to have reduced binding to FcR. The candidate was undergoing evaluation in a 4-arm, controlled Phase 2/3 study (PROTÉGÉ; NCT00385697) in children and adults with recent on-set type 1 diabetes. The study’s data monitoring committee evaluated one-year safety and efficacy data and concluded that the primary efficacy endpoint, which was an assessment of total daily insulin usage and HbA1c levels over 12 months, was not met. Further enrollment and dosing in the PROTÉGÉ study, as well as two other ongoing studies in patients with type 1 diabetes have been suspended.
Trastuzumab indications expanded
The US Food and Drug Administration has approved a supplemental marketing application for trastuzumab (Herceptin®) for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease. In January 2010, the product was approved in the EU in combination with chemotherapy for use in patients with HER2-positive metastatic gastric cancer. Trastuzumab is also approved in both the US and EU for treatment of patients with a various types of breast cancer.
SAR566658 enters first clinical study
SAR566658 (huDS6-DM4), an immunoconjugate developed by ImmunoGen and Sanofi-aventis, entered its first clinical study in September 2010. The Phase 1 study (NCT01156870) will assess the safety and pharmacokinetics of SAR566658 administered intravenously as a single agent every 3 weeks to adult patients with DS6-positive and refractory solid tumors. The parent molecule (DS6) was a murine antibody raised against human serous ovarian cancer ascites and humanized using resurfacing technology. SAR566658 targets an O-linked tumor-associated sialoglycotope on Muc1.
Belimumab’s review process
The biologics license application for belimumab (Human Genome Sciences) will be discussed at a meeting of the US Food and Drug Administration’s Arthritis Advisory Committee on November 16, 2010. The marketing application for belimumab as a treatment for systemic lupus erythematosus is undergoing a Priority Review and FDA’s first action on the application is due by December 9, 2010.
FDA hearing on biosimilars
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) authorized the Food and Drug Administration (FDA) to approve biosimilar products for marketing in the United States. The FDA is announcing a public hearing scheduled for November 2-3, 2010 to obtain input on specific issues and challenges associated with the implementation of the BPCI Act. Such input will be considered as FDA drafts guidance documents to clarify the criteria needed for approval of biosimilars.
Pivotal Phase 2 results for brentuximab vedotin announced
Top-line results were reported for a pivotal Phase 2 study (NCT00848926) of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma who had previously received autologous stem cell transplants. Patients (12 years and older) were administered 1.8 mg/kg doses of brentuximab vedotin every 3 weeks for up to 16 total doses. Of 102 patients who participated in the study, 75% achieved an objective response. The mean duration of response was greater than 6 months. Brentuximab vedotin (SGN-35; Seattle Genetics, Millennium) is a chimeric IgG1 immunoconjugate that targets CD30, which is expressed at high levels on activated lymphocytes. The immunoconjugate comprises Seattle Genetic’s mAb cAC10 (SGN-30) conjugated to the anti-tubulin agent monomethyl auristatin E through a peptide linker that is selectively cleaved after internalization into cells.
Phase 3 study results for ch14.18
Results of a Phase 3 study (NCT00026312) of the chimeric mAb ch14.18 in combination with granulocyte-macrophage colony-stimulating factor,
interleukin-2 and isotretinoin compared to isotretinoin in patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were reported in the New England Journal of Medicine (Yu et al, NEJM 363:1324-1334). The conclusion was that inclusion of the immunotherapy resulted in significantly superior event-free and overall survival, although also associated with important side effects. ch14.18 targets disialoganglioside (GD2). Initiated October 2001, the study was sponsored by the National Institutes of Health, which also provided the antibody.
Phase 3 studies of zanolimumab restarted
The re-initiation of clinical studies of zanolimumab, a human anti-CD4 antibody, has been announced by TenX Biopharma. The molecule was previously developed, as Humax-CD4, by Genmab, and was out-licensed to TenX Biopharma in February 2010. The Phase 3 study, NCT00127881, is an open label, dose escalation, followed by open label, single arm, multi-center clinical trial of HuMax-CD4, in patients with mycosis fungoides type cutaneous T-cell lymphoma (Stage IB-IVB) or Sezary syndrome who are refractory or intolerant to bexarotene and one other standard therapy. Enrollment was originally started in July 2005, but was suspended in October 2008. The current estimated primary completion date is February 2011.
BAN2401 enters clinical study
The start of the first clinical study of BAN2401, a humanized monoclonal antibody that selectively recognizes Aß protofibrils, has been announced by Eisai. Research on the Arctic mutation of amyloid beta-peptide (Aß), which causes familial Alzheimer's disease and was discovered by Professor Lannfelt at Uppsala University, was the basis for development of the mAb. BAN2401 resulted from a strategic research alliance between Eisai and BioArctic that was initiated in 2005 to identify a potential immunotherapy for Alzheimer's disease. At least 6 other mAbs are in clinical studies as treatments for Alzheimer’s disease: gantenerumab (Hoffmann-La Roche), GSK-933776 (GlaxoSmithKline), MABT-5102A (Genentech), solanezumab (Eli Lilly and Company), ponezumab (Pfizer), and bapineuzumab (Pfizer).
Trastuzumab emtansine remains in Phase 3
The U.S. Food and Drug Administration issued a Refuse to File letter for the marketing application, which requested accelerated approval, of Genentech/Roche Pharma’s trastuzumab emtansine (T-DM1). The immunotoxin targets HER2 and is conjugated to ImmunoGen’s DM1 cytotoxin. The company will continue with the ongoing Phase 3 EMILIA study (NCT00829166), which is a randomized, multicenter, open-label study of the efficacy and safety of trastuzumab-MCC-DM1 compared to capecitabine and lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer who have received prior trastuzumab-based therapy. The expected completion date of the study is August 2013, although a marketing application may be submitted earlier.
Bristol-Myers Squibb plans to acquire ZymoGenetics
Bristol-Myers Squibb has announced plans to acquire ZymoGenetics. As part of its pipeline, ZymoGenetics have four antibody therapeutics at the preclinical phase. An IL-31 mAb is scheduled to enter clinical study in 2011 sponsored by the company. Three other preclinical mAbs are out-licensed: mAbs that target IL20 and IL21 are licensed to Novo Nordisk, and an IL22RA-targeting mAb is licensed to Merck Serono.
This page last modifie7 September, 2015-> by Berend Tolner