Antibody-related news from Janice M. Reichert, Editor-in-Chief, mAbs
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.
October-November 2011
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.
August-September 2011
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.
June-July 2011
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.
May 2011
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.
April 2011
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).
March 2011
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.
February 2011
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.
January 2011
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.
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.
November 2010
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.
October 2010
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.
September 2010
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 modifie16 February, 2012-> by Berend Tolner
