WO2014006113A1 - Procédé de traitement du cancer par quantités efficaces d'aflibercept - Google Patents
Procédé de traitement du cancer par quantités efficaces d'aflibercept Download PDFInfo
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- WO2014006113A1 WO2014006113A1 PCT/EP2013/064079 EP2013064079W WO2014006113A1 WO 2014006113 A1 WO2014006113 A1 WO 2014006113A1 EP 2013064079 W EP2013064079 W EP 2013064079W WO 2014006113 A1 WO2014006113 A1 WO 2014006113A1
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- aflibercept
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- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Definitions
- Colorectal cancers are among the most frequent tumor types in the western countries, second to breast in women and third to lung and prostate in males.
- the end prognosis is dependent upon the extent of the disease.
- the five year survival rate in early localized stage of about 90% decreased to approximately 60-65% after spread to adjacent organ(s) or lymph nodes and is of less than 10% after spread to distant sites.
- 5-Fluorouracil has remained the mainstay of the chemotherapy in colorectal cancer.
- 5-FU 5-Fluorouracil
- the bimonthly regimen (LV5FU2) of 5-FU given as bolus/infusion over 2 days has been shown to be superior to the monthly 5 day bolus regimen (Mayo regimen) in terms of response rate (RR) (32.6% vs 14.4%), in terms of progression free survival (PFS) (27.6 vs 22.0 weeks), and safety (de Gramont et al, Journal of Clinical Oncology 1997;15(2):808-815).
- Aflibercept (ziv-aflibercept in the US) is the INN of a fusion protein comprising the signal sequence of VEGFR1 fused to the D2 Ig domain of the VEGFR1 receptor, itself fused to the D3 Ig domain of the VEGFR2 receptor, in turn fused to the Fc domain of lgG1 Aflibercept. It is also referred to as VEGF trap, VEGFR1 R2-Fc.DELTA.C1 or Flt1 D2.Flk1 D3.Fc.DELTA.C1 .
- Aflibercept binds to VEGF-A, VEGF-B and PIGF ligands with high affinity in vitro.
- the amino acid sequence (SEQ ID N°1 ) of Aflibercept is illustrated in Figure 1 and is also shown inter alia in FIG. 24 of patent application WO 00/75319.
- Aflibercept is marketed in the EU and in the US under the trade name ZALTRAP®.
- aflibercept-ligand complexes also called bound aflibercept
- bound aflibercept The complex formed by aflibercept and VGEF-A is referred below as "bound aflibercept”.
- Rudge et al (PNAS 2007,104, 18363) performed pre-clinical experiments on mice bearing tumors. They increased doses of aflibercept from 0.5mg/kg to 25mg/kg and concluded that assays of free and bound aflibercept can serve as useful indicators of the proportion of bioavailable VEGF that is bound and neutralized at a given dose.
- 5-fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites.
- Folinic acid or leucovorin is an adjuvant to cancer chemotherapy used in combination with 5-fluorouracil.
- Irinotecan is a drug used for the treatment of cancer.
- Irinotecan is a topoisomerase 1 inhibitor, which prevents DNA from unwinding.
- FOLFIRI is the combination of folinic acid, 5-fluorouracil (5-FU) and irinotecan and will be used throughout the document.
- aflibercept was administered IV in combination with irinotecan (180 mg/m 2 on day 1 ), leucovorin (200 mg/m 2 on day 1 and day 2), and 5- FU (bolus/infusional 400/600 mg/m 2 on day 1 and day 2), every 2 weeks in patients with advanced solid malignancies.
- phase III trial of aflibercept in metastatic pancreatic cancer was discontinued in 2009 and in 201 1 the data of a phase III trial evaluating aflibercept for the second-line treatment of non-small cell lung cancer (NSCLC) showed that adding aflibercept to the chemotherapy drug docetaxel did not meet the pre-specified criteria for the primary endpoint of improvement in overall survival compared with a regimen of docetaxel plus placebo.
- a phase III study evaluating the combination of aflibercept and FOLFIRI for the second line treatment of metastatic colorectal cancer (MCRC) showed improvement in overall survival (OS), progression free survival (PFS) and response rate (ORR). This study formed the basis of regulatory filings and subsequent marketing approvals of aflibercept (ZALTRAP®) in the United States and European Union.
- the invention relates to methods, compositions and articles as disclosed herein.
- the invention provides for a method of treating cancer or cancer symptom in a patient in need thereof, said method comprising the following steps:
- the invention provides for a method of treating cancer or cancer symptom in a patient in need thereof, said method comprising administering to said patient therapeutically effective amounts of aflibercept to patient displaying a ratio free/bound aflibercept comprised between 1 and 4, as measured by ELISA as described in the example 2 below.
- This method comprises the following steps:
- ratio free/bound aflibercept comprised between 1 and 4.
- ratio free/bound aflibercept is around 1.6.
- ratio free/bound aflibercept is comprised between 1 .6 and 3.2.
- ratio free/bound aflibercept is comprised between 1 .5 and 1.8.
- the free/bound ratio may be measured any time during the treatment of a patient.
- the free/bound ratio is determined after the first cycle of treatment of the patient, or after the second cycle of treatment of the patient.
- Free aflibercept concentrations and VEGF:aflibercept complex concentrations are measured in plasma by the methods known by the man skilled in the art.
- Such a method can be an enzyme linked immunosorbent assay (ELISA) method.
- ELISA enzyme linked immunosorbent assay
- the cancer is Colorectal Cancer (CRC).
- the method comprising administering to said patient therapeutically effective amounts of aflibercept and FOLFIRI.
- This method is safe and effective.
- the invention provides a method wherein said patient has already been treated for the CRC or CRC symptom (second-line treatment).
- CRC is a Metastatic Colorectal Cancer (MCRC).
- the said method can be used for treating any other cancer such as lung cancer, gastric cancer, ovarian cancer and any other cancer susceptible to be treated with aflibercept.
- the said method can be used for treating cancer with aflibercept as single agent or with aflibercept in combination with other chemical molecule or biologic molecule of the cancer.
- Such biologic molecule can be for instance an anti-Ang2 antibody.
- the invention provides for a method wherein said patient has previously been treated with chemotherapy, radiotherapy or surgery. In an embodiment said patient has failed chemotherapy, radiotherapy or surgery.
- the invention provides a method wherein said patient has previously been treated with therapy based on oxaliplatin with or without bevacizumab. In an embodiment said patient has failed therapy based on oxaliplatin with or without bevacizumab.
- the invention provides a method wherein folinic acid at a dosage comprised between about 200 mg/m 2 and about 600 mg/m 2 , 5-fluorouracil (5-FU) at a dosage comprised between about 2000 mg/m 2 and about 4000 mg/m 2 , irinotecan at a dosage comprised between about 100 mg/m 2 and about 300 mg/m 2 and aflibercept at a dosage comprised between about 1 mg/kg and about 10 mg/kg are administered to patient.
- 5-fluorouracil 5-FU
- the dosage of folinic acid indicated should be understood as the dosage of the racemate of folinic acid, i.e. comprising the D and L forms. Should only the L form be used the dosage should be half of the dosage indicated for the racemate.
- a dosage of folinic acid of about 200 mg/m 2 as indicated in the present application corresponds to about 200 mg/m 2 of racemate and about 100 mg/m 2 of L form.
- the invention provides a method wherein folinic acid at a dosage of about 400 mg/m 2 , 5-fluorouracil (5-FU) at a dosage of about 2800 mg/m 2 , irinotecan at a dosage of about 180 mg/m 2 and aflibercept at a dosage of about 4 mg/kg are administered to patient.
- the invention provides a method wherein said patient receives intravenous folinic acid at a dosage comprised of about 400 mg/m 2 , intravenous 5- fluorouracil (5-FU) at a dosage of about 2800 mg/m 2 , intravenous irinotecan at a dosage comprised of about 180 mg/m 2 and intravenous aflibercept at a dosage of about 4 mg/kg every two weeks.
- intravenous folinic acid at a dosage comprised of about 400 mg/m 2
- intravenous 5- fluorouracil (5-FU) at a dosage of about 2800 mg/m 2
- intravenous irinotecan at a dosage comprised of about 180 mg/m 2
- intravenous aflibercept at a dosage of about 4 mg/kg every two weeks.
- the invention provides a method wherein said patient receives intravenous folinic acid, intravenous 5-fluorouracil (5-FU), intravenous irinotecan and intravenous aflibercept every two weeks for a period comprised between about 9 and about 18 weeks.
- the invention provides a method wherein said patient receives intravenous folinic acid immediately after aflibercept administration.
- the invention provides a method wherein said patient receives intravenous irinotecan immediately after aflibercept administration.
- the invention provides a method wherein said patient receives intravenous irinotecan immediately after aflibercept administration over almost 90 minutes.
- the invention provides a method wherein said patient receives intravenous 5-fluorouracil (5-FU) immediately after aflibercept administration.
- the invention provides a method wherein said patient receives a first quantity of intravenous 5-fluorouracil (5-FU) immediately after aflibercept administration and a second quantity in continous infusion.
- 5-FU intravenous 5-fluorouracil
- the invention provides a method wherein said patient receives about 400 mg/m 2 of intravenous 5-fluorouracil (5-FU) over about 2 to 4 minutes after aflibercept administration and 2400 mg/m 2 over about 46 hours after aflibercept administration in continuous infusion.
- 5-FU intravenous 5-fluorouracil
- the invention features a composition comprising therapeutically effective amounts of aflibercept in combination with folinic acid, 5-fluorouracil (5-FU) and irinotecan for treating patients with CRC for simultaneous administration.
- the invention features a composition comprising therapeutically effective amounts of aflibercept in combination with folinic acid, 5-fluorouracil (5-FU) and irinotecan for treating patients with CRC for sequential administration.
- the invention features a composition comprising therapeutically effective amounts of aflibercept in combination with folinic acid, 5-fluorouracil (5-FU) and irinotecan for treating patients with CRC for administration that is spaced out over a period of time so as to obtain the maximum efficacy of the combination.
- aflibercept in combination with folinic acid, 5-fluorouracil (5-FU) and irinotecan for treating patients with CRC for administration that is spaced out over a period of time so as to obtain the maximum efficacy of the combination.
- the invention features a composition comprising therapeutically effective amounts of aflibercept in combination with folinic acid, 5-fluorouracil (5-FU) and irinotecan and comprising a pharmaceutically acceptable carrier for treating patients with CRC.
- the patient has liver metastases.
- the invention features an article of manufacture comprising:
- the invention features a kit for treating patients with CRC
- kits indicating that aflibercept is to be used in combination with folinic acid, 5-fluorouracil (5-FU) and irinotecan (FOLFIRI) or folinic acid, 5-fluorouracil (5-FU) and irinotecan (FOLFIRI) is to be used in combination with Aflibercept
- the invention features a kit comprising in separate containers pharmaceutical compositions for combined use in treating CRC in a patient which comprises (1 ) a pharmaceutical composition comprising aflibercept, (2) a pharmaceutical composition comprising folinic acid, (3) a pharmaceutical composition comprising 5-fluorouracil (5-FU) and (4) a pharmaceutical composition comprising irinotecan.
- the invention in another aspect relates to aflibercept for use in treating patients with cancer or cancer symptom wherein the ratio free/bound aflibercept in a biological sample of said patient is measured and the treatment of said patient is adapted based on the ratio free/bound aflibercept.
- the invention relates to aflibercept for use in treating patients with cancer or cancer symptom wherein the ratio free/bound aflibercept in a biological sample of said patient is measured and a therapeutically effective amount of aflibercept is administered to patient displaying a ratio free/bound aflibercept comprised between 1 and 4.
- the production process of aflibercept is typical for a recombinant-Fc fusion protein.
- the upstream process includes expansion of the CHO host cells and expression of recombinant aflibercept.
- the downstream process involves clarification and purification of the protein from the culture medium.
- the manufacturing process is initiated with the thawing and inoculation of one working cell bank (WCB) vial.
- WB working cell bank
- the cell culture is expanded until reaching sufficient density for inoculation into the production bioreactor.
- the downstream process consists of several chromatography steps (protein A affinity chromatography, Cation exchange chromatography, Anion exchange chromatography and Hydrophobic Interaction chromatography), and includes viral inactivation and filtration steps to clear potential adventitious viral agents.
- concentration/diafiltration the drug substance is filled into containers and stored frozen.
- Aflibercept can be formulated as described in WO2006/104852.
- Zaltrap is formulated in vials of 4 ml containing 100 mg of aflibercept (25 mg/ml) or in vials of 8 ml containing 200 mg of aflibercept (25 mg/ml).
- Zaltrap formulation also contains sucrose, sodium chloride, sodium citrate dihydrate, citric acid monohydrate, polysorbate 20, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, sodium hydroxide and/or hydrochloric acid and water for injections.
- aflibercept can be formulated differently if it is intended to be administered by other ways for instance by sub cutaneous administration. If the sub cutaneous administration route is used aflibercept can be formulated as described in US 8,404,638.
- Figures Figure 1 Aflibercept amino acid sequence (SEQ ID NO:1 )
- Figure 2 Overall survival (months) - Kaplan-Meier curves by treatment group- ITT population
- Figure 3 Overall survival (months) - Subgroup analyses (forest plot) - By stratification factors as per IVRS - ITT population
- Figure 4 Overall survival (months) - Subgroup analyses (forest plot) - By patient demographics - ITT population
- Figure 5 Overall survival (months) - Subgroup analyses (forest plot) - By baseline characteristics - ITT population
- Figure 6 PFS based on tumor assessment by the IRC (months) - Subgroup analysis (forest plot) - By stratification factors as per IVRS - ITT population
- Figure 8 VELOUR - OS Kaplan-Meier curves by average free aflibercept AUC
- FIG. 1 Velour - OS KM curves by free/bound aflibercept median ratio
- Figure 15 VELOUR - OS Kaplan-Meier estimates according to Free/Bound aflibercept median ratio (looking at various thresholds)
- EXAMPLE 1 EFC10262 (VELOUR)/ A Multinational. Randomized. Double-blind Study. Comparing the Efficacy of Aflibercept Once Every 2 Weeks versus Placebo in Patients with Metastatic Colorectal Cancer (MCRC) Treated with Irinotecan / 5-FU Combination (FOLFIRI) after failure of an oxaliplatin based regimen
- EFC10262 was designed as a randomized, double-blind, multi-centre study comparing aflibercept at 4 mg/kg to placebo, in combination with Irinotecan and 5 Fluorouracil combination (FOLFIRI) given intravenously every 2 weeks as second line treatment for patients with metastatic colorectal cancer (MCRC) after failure of an oxaliplatin based regimen. Each randomized patient was to be treated until disease progression, death, or unacceptable toxicity.
- EFC10262 The primary objective of EFC10262 was to demonstrate improvement in overall survival (OS) for aflibercept + FOLFIRI compared to placebo + FOLFIRI.
- OS overall survival
- FOLFIRI placebo + FOLFIRI.
- the predefined statistical significance level for this final analysis was 0.0466 after adjusting the type I error spent for the two interim analyses using the O'Brien-Fleming spending function.
- DMC Data Monitoring Committee
- Treatment assignment was stratified according to prior therapy with bevacizumab (yes or no), and ECOG performance status (PS) (0 vs 1 vs 2).
- the enrolment started in November 2007 and was completed in March 2010. A total of 1226 patients were randomized. The efficacy analysis was based on all randomized patients (Intent-to-Treat (ITT) population: 614 in the placebo arm and 612 patients in the aflibercept arm). The safety analysis was based on all treated patients (safety population: 605 and 61 1 patients in the placebo and aflibercept arms, respectively). Treatment arms were evenly balanced for demographics, disease characteristics and prior anti-cancer treatments, including prior exposition to bevacizumab.
- ITT Intent-to-Treat
- Arm A, aflibercept 4 mg/kg was administered IV over 1 hour on Day 1 , every 2 weeks,
- Asian/Oriental 51 (8.3%) 35 (5.7%) 86 (7.0%)
- the median number of aflibercept/placebo infusions was 8.0 and 7.0 in the placebo and aflibercept treatment arms, respectively (Table 5).
- the median relative dose intensity was 83% with aflibercept as compared to 92% with placebo.
- Number of cycles received Number of cycles with at least one dose infusion of aflibercept placebo.
- the median number of irinotecan infusions was 8.0 and 9.0 in the placebo and aflibercept treatment arms, respectively (table 6).
- the median relative dose intensity was 84% in the aflibercept arm as compared to 91 % in the placebo arm.
- two patients did not receive irinotecan; the dose was considered equal to 0 for the calculation of the cumulative dose, actual and relative dose intensity.
- Number of cycles received Number of cycles with at least one dose infusion of irinotecan.
- Number of cycles received Number of cycles with at least one dose infusion of 5- FU.
- Table 8 Overall survival (months) - Kaplan-Meier survival estimates by treatment group- Primary analysis- Stratified according to stratification factors at randomization (IVRS) - ITT population Placebo/Folfiri Aflibercept Folfiri
- Cutoff date 7 FEBRUARY 201 1
- Recto 14.1 (12.71 to 14.3 (12.35 to 1.039 (0.772 to
- Placebo/Folfiri ri P-value Median Median Hazard Ratio for (Months) (Months) (95.34% CI) vs interactio (95.34% CI) (95.34% CI) Placebo/Folfiri n a
- PFS progression free survival
- Table 11 PFS based on tumor assessment by the IRC (months) - Kaplan-Meier survival estimates by treatment group - Stratified according to stratification factors at randomization (IVRS) - ITT population
- Significance threshold is set to 0.0001 .
- PFS Progression free survival
- Medra classification SOC (system organ class), HLT (high level term), PT (Preferred term).
- Grouping grouping of selected PTs
- ⁇ difference in incidence in aflibercept arm compared to placebo
- the safety profile was qualitatively consistent with that of anti VEGF treatment with enhancement of known toxicities of the background chemotherapy (such as diarrhea, stomatitis, infections, neutropenia/neutropenic complications).
- EXAMPLE 2 VELOUR exploratory PK-PD analyses on estimated free and bound aflibercept PK parameters
- Free and bound aflibercept trough concentrations were measured and maintaining free/bound ratio at least >1 in the dosing interval was used as a guide for dose selection in different clinical trials.
- Free aflibercept and VEGF:aflibercept complex concentrations were measured in plasma by validated enzyme-linked immunosorbent assay (ELISA) methods with a LOQ of 0.0156 g/ml_ and 0.0439Mg/ml_, respectively.
- Free aflibercept (unbound aflibercept) concentrations in human plasma were quantified using a validated, direct enzyme-linked immunosorbent assay.
- hVEGF165 aflibercept capture agent
- PBS blocking buffer
- Calibration standards, quality control (QC) samples and subject samples, all in a 10% human CTAD plasma matrix human CTAD plasma diluted with 0.5% bovine serum albumin [BSA] and 0.05% polysorbate 20 [Tween 20] in 1 x Dulbecco's phosphate-buffered saline [PBS]
- BSA bovine serum albumin
- PBS polysorbate 20
- a mouse monoclonal antibody specific to an epitope on the VEGFR1 domain of aflibercept report is bound to the immobilized hVEGF165:aflibercept complex.
- peroxidase-conjugated Affinipure goat anti-mouse IgG Fey report is bound to the immobilized mouse monoclonal antibody-hVEGF165:aflibercept complex.
- a luminol-based substrate specific for peroxidase is added to generate a chemiluminescent signal the intensity of which is directly proportional to the concentration of free aflibercept.
- Human VEGF:aflibercept complex was quantified using a validated direct ELISA.
- a non-blocking goat anti-hVEGF antibody report is adsorbed to the polystyrene surface of the wells of a microtiter plate. Following adsorption of the capture antibody, non-specific protein binding sites on the surface of the wells are blocked with 5% BSA in PBS (blocking buffer) that contained 10 ⁇ g/mL goat IgG.
- Calibration standards, QC samples and subject samples all in a 20% human CTAD plasma matrix (human CTAD plasma diluted with 0.5% BSA, 10 ⁇ g mL goat IgG and 0.05% polysorbate 20 [Tween 20] in 1 x Dulbecco's phosphate-buffered saline [PBS]), are subsequently added and incubated with the surface bound anti-VEGF antibody resulting in the binding of hVEGF:aflibercept complex to the immobilized anti-human VEGF antibody.
- a mouse monoclonal antibody specific to an epitope on the VEGFR1 domain of aflibercept is bound to the immobilized complex.
- a mouse monoclonal antibody, peroxidase-conjugated Affinipure goat anti-mouse IgG Fey is bound to the immobilized mouse monoclonal antibody complex.
- a luminolbased substrate specific for peroxidase is added to generate a chemiluminescent signal the intensity of which is directly proportional to the concentration of the hVEGF:aflibercept complex.
- a population pharmacokinetic analysis of free aflibercept concentrations was performed using data from Phase 1 and Phase 2 patients where aflibercept was administered intravenously every two or three weeks as single agent or in
- the tested covariates were the following: age, gender, weight, race such as Caucasian, Black and Asian, albumin, serum alkaline phosphatase, total bilirubin, aspartate amino transferase, alanine amino transferase, total protein and creatinine clearance.
- Significant covariates were identified during the univariate analysis based on nonlinear mixed effect modeling using the likelihood ratio test to discriminate among alternative models, then incorporated into the model and final model building was accomplished by a backward elimination procedure (POH0253).
- aflibercept undergoes a target- mediated drug disposition (TMDD); a term used to describe the phenomenon in which drug is bound with high affinity to its pharmacologic target such that the interaction is reflected in the PK properties of the drug. Therefore, a mechanism-based PK model for aflibercept was developed in order to characterize its binding to VEGF and its pharmacokinetic properties in healthy subjects and then applied to the Phase 2 & 3 patients' database. No covariates were tested for inclusion in the model.
- TMDD target- mediated drug disposition
- the mechanistic model was used to simulate concentration-time courses of free and bound aflibercept for a typical patient who receives 1 -hour IV infusion of 1 , 2, 4 or 6 mg/kg aflibercept q2w and q3w. After q2w and q3w
- PK-PD analyses were performed to estimate the relationship between aflibercept PK parameters and various measures of efficacy and safety. Free aflibercept
- VEGF:aflibercept complex concentrations were measured in plasma by a validated enzyme linked immunosorbent assay (ELISA) method.
- VEGF- bound aflibercept concentrations were expressed as free aflibercept equivalents using the ratio of molecular weights between free aflibercept and VEGF:aflibercept complex.
- Free aflibercept the following PK parameters were estimated:
- AUC of first cycle i.e, AUCO-336 or AUCO-504 in the q2w or q3w schedule, respectively
- the safety pharmacodynamic parameters used for this analysis included: • Patients with safety events were defined as patients who experienced the events (any grade, unless otherwise specified) at least once during the first 2 cycles of treatment
- PK-PD analyses were performed after submission of regulatory dossiers to FDA and EMA. The primary objective of these PK-PD analyses was:
- Blood samples for free/bound ratio measurement were collected prior to the first administration of aflibercept, then prior to administration of aflibercept of each odd numbered cycle.
- the free/bound ratio for PK/PD analysis was calculated as the median of free/bound values from Cycle 3 to the end of treatment.
- PK parameters defined as categorical variables, dichotomizing patients according to the median PK parameter ( ⁇ median, ⁇ median)
- the additional PK-PD analyses of the VELOUR data suggest that free to bound ratio may be used to administer therapeutically effective amounts of aflibercept to patients with MCRC.
- the free to bound ratio may be measured at any time during the patient's treatment.
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Abstract
L'invention concerne un procédé de traitement du cancer par quantités efficaces d'aflibercept, lequel procédé comprend la mesure du rapport d'aflibercept libre/lié dans un échantillon biologique d'un patient, et l'adaptation du traitement du patient sur la base du rapport d'aflibercept libre/lié.
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EP3363811B1 (fr) | 2015-10-15 | 2023-04-19 | Alteogen, Inc. | Procédé de production de protéine de fusion présentant un domaine fc d'igg |
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JP2021167827A (ja) * | 2016-01-25 | 2021-10-21 | サノフイSanofi | 血漿バイオマーカーのレベルを測定することによる、がんに罹患していることが疑われる患者のアフリベルセプトによる治療の転帰を予測するための方法 |
JP7170096B2 (ja) | 2016-01-25 | 2022-11-11 | サノフイ | 血漿バイオマーカーのレベルを測定することによる、がんに罹患していることが疑われる患者のアフリベルセプトによる治療の転帰を予測するための方法 |
US11912784B2 (en) | 2019-10-10 | 2024-02-27 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
CN117805397A (zh) * | 2024-02-29 | 2024-04-02 | 军科正源(北京)药物研究有限责任公司 | 检测游离vegf的方法 |
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