ADIS R&D PROFILE
`
`Drugs R D 2008; 9 (4): 261-269
`1174-5886/08/0004-0261/$48.00/0
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Aflibercept
`AVE 0005, AVE 005, AVE0005, VEGF Trap – Regeneron,
`VEGF Trap (R1R2), VEGF Trap-Eye
`
`Abstract
`
`Aflibercept is a fully human recombinant fusion protein composed of the
`second Ig domain of VEGFR1 and the third Ig domain of VEGFR2, fused to the
`Fc region of human IgG1. Aflibercept is in clinical development with Regeneron
`Pharmaceuticals and sanofi-aventis for the treatment of cancer, while Regeneron
`and Bayer are developing the agent for eye disorders. Aflibercept binds to all
`VEGF-A isoforms as well as placental growth factor (PIGF), thereby preventing
`these factors from stimulating angiogenesis. Blockade of VEGF can also prevent
`blood vessel formation and vasuclar leakage associated with wet age-related
`macular degeneration (AMD). Aflibercept is a member of Regeneron’s proprieta-
`ry family of ‘Trap’ product candidates that catch, hold and block (i.e. trap) certain
`harmful cytokines or growth factors.
`Regeneron and Bayer HealthCare entered into a collaboration agreement in
`October 2006 to develop and commercialize aflibercept for the treatment of eye
`disorders outside the US. The companies will share equally in profits from this
`market, while Regeneron will retain exclusive commercialization rights and
`profits from sales in the US.[1]
`Regeneron and sanofi-aventis amended their aflibercept collaboration agree-
`ment to include Japan. Under the terms of the amended agreement, reported in
`December 2005, the two companies will jointly develop and commercialize
`aflibercept worldwide in all indications, except for intraocular delivery to the eye.
`sanofi-aventis paid $US25 million to Regeneron for the inclusion of Japan and
`will pay milestone payments linked to Japanese regulatory approvals, plus royal-
`ties on Japanese sales. sanofi-aventis will lead Japanese development and will pay
`all development costs; however, Regeneron will repay 50% of these expenses out
`of profits generated through the commercialization of aflibercept.[2]
`sanofi-aventis reaffirmed its commitment to the aflibercept programme in
`oncology in January 2005, while the exclusive rights to develop and commercial-
`ize the agent for eye diseases through local delivery systems reverted to Regener-
`on. A $US25 million clinical development milestone payment to Regeneron was
`also triggered in connection with this agreement.[3]
`Aventis (now sanofi-aventis) and Regeneron entered into a global (excluding
`Japan) agreement in September 2003 to jointly develop and commercialize
`aflibercept. Under the terms of the agreement, Aventis was to pay Regeneron
`$US125 million and fund development costs. An additional early clinical mile-
`stone payment of $US25 million was also outlined in the agreement. The two
`companies will share promotional rights equally, and profits globally. Aventis
`will also pay Regeneron up to $US360 million at identified milestones related to
`the receipt of marketing approvals for up to eight indications in Europe and the
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 1
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`Joining Petitioner: Apotex
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`262
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`Adis R&D Profile
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`US. The companies initially agreed to jointly develop aflibercept in oncology,
`ophthalmology and possibly in other indications.[4]
`Originally, aflibercept was being developed under a research and development
`alliance between Regeneron and Procter & Gamble. However, in 2000 this
`agreement was restructured and Regeneron regained all rights.
`An NCI-sponsored phase II trial (NCT00407654) of aflibercept, involving 80
`patients with previously treated metastatic colorectal cancer, is also underway in
`the US and Canada. The trial was initiated in October 2006 and is evaluating the
`efficacy of aflibercept in this patient group, as measured by objective tumour
`response and progression-free survival at 4 months.
`In September 2006, a phase II trial in 82 patients with locally advanced,
`unresectable or metastatic gynaecological soft tissue sarcoma was initiated by
`NCI and Regeneron in the US and Canada. This ongoing trial (NCT00390234)
`will evaluate the efficacy of aflibercept, as measured by progression-free survival
`and tumour response rate.
`Regeneron and sanofi-aventis are conducting a phase II trial of intravenously
`(IV) administered aflibercept in patients with advanced ovarian cancer who have
`recurrent symptomatic malignant ascites (SMA). The trial (NCT00327444) began
`in July 2006 and was continuing to recruit a total of 54 patients at centres in the
`US, Canada, India and the EU (Austria, Belgium, Hungary, Spain and the UK) in
`April 2007.
`In October 2006, the companies initiated a second small phase II trial of
`aflibercept (NCT00396591) in 15 patients with malignant ascites associated with
`ovarian cancer. The study will assess the efficacy, safety, pharmacokinetics and
`immunogenicity of aflibercept IV given every 2 weeks in the US and EU (Italy
`and Sweden) and was recruiting patients in May 2007.
`Regeneron and sanofi-aventis are also conducting a single-agent phase II study
`of aflibercept in non-small-cell lung adenocarcinoma (NSCLA). The open-label,
`single-arm study (NCT00284141) has completed enrolment of approximately 100
`patients with platinum- and erlotinib-resistant, locally advanced or metastatic
`NSCLA to receive aflibercept (4.0 mg/kg IV) in the US, France and Canada.
`Results from the first 37 evaluable patients have been reported showing
`aflibercept was generally well tolerated and two partial reponses were noted.[5,6]
`Regeneron has completed an open-label phase I trial in patients with solid
`tumours and non-Hodgkin’s lymphoma (NHL) at three sites in the US. The study
`enrolled 38 patients with incurable, relapsed or refractory solid tumours who
`received subcutaneous injections. In total, the trial enrolled patients with 15
`different types of cancer who were treated with seven subcutaneous doses of
`aflibercept over 10 weeks. In June 2004, Regeneron presented results from this
`study showing that the aflibercept was well tolerated and had a good safety
`profile. The maximum tolerated dose was not established. The company has not
`conducted any further trials in this indication with aflibercept as a monotherapy,
`although the NCI has ongoing trials of aflibercept in patients with solid tumours
`and NHL (e.g. NCT0008283).[7]
`In May 2005, Regeneron announced initiation of a phase I safety and tolerabili-
`ty study with aflibercept in combination with the FOLFOX-4 regimen (oxalipla-
`tin, 5-fluorouracil and leucovorin) in patients with advanced solid tumours. As at
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`
`Joining Petitioner: Apotex
`
`

`

`Aflibercept
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`263
`
`August 2006, the maximum tolerated dose had not been reached and dose-
`escalation was continuing in this study.[8,9]
`The NCI/Regeneron trial in patients with metastatic or unresectable kidney
`cancer began in September 2007 with continued recruitment in April 2008. This
`trial (NCT00357760) is anticipated to recruit 120 patients in the US to evaluate
`the efficacy of two doses of aflibercept.
`Regeneron and Bayer inititiated a phase III trial of aflibercept in approximately
`1200 patients with the neovascular form of wet AMD in August 2007. The non-
`inferiority, VIEW 1 (VEGF Trap: Investigation of Efficacy and safety in Wet age-
`related macular degeneration) study will evaluate the safety and efficacy of
`intravitreal aflibercept at doses of 0.5 mg and 2.0 mg administered at 4-week
`dosing intervals, and 2.0 mg at an 8-week dosing interval, compared with 0.5 mg
`ranibizumab administered every 4 weeks. The randomized, double-blind trial will
`be conducted at more than 200 centres throughout the US and Canada, pursuant to
`a Special Protocol Assessment (SPA) issued by the the US FDA. Patients will
`continue to be treated and followed for an additional year, after the first year of
`treatment. The VIEW 1 study is the first in a phase III global development
`programme in wet AMD, which is expected to be conducted in the US, Europe
`and other nations. Regeneron received a $US20 million milestone payment from
`Bayer HealthCare in August 2007 following dosing of the first patient.[10,11]
`A second phase III trial (VIEW 2) in wet AMD began with the first patient
`dosed in May 2008. The VIEW 2 trial will enrol approximately 1200 patients from
`the EU, Asia Pacific, Japan and Latin America. This study will evaluate the safety
`and efficacy of aflibercept at 0.5 mg and 2.0 mg administered at 4-week intervals
`and 2.0 mg at an 8-week dosing interval, including one additional 2.0 mg dose at
`week 4. Patients randomized to the ranibizumab arm of the trial will receive a
`0.5 mg dose every 4 weeks. The primary endpoint will be the proportion of
`patients treated with aflibercept who maintain vision at the end of 1 year
`compared with ranibizumab patients.[12,13]
`Regeneron has completed a 12-week, phase II trial in patients with wet AMD,
`to evaluate the safety and efficacy of intravitreal aflibercept using different doses
`and dose regimens. Two patient groups received monthly doses of 0.5 or 2.0 mg,
`and three groups received quarterly doses of 0.5, 2.0 or 4.0 mg (baseline and
`week 12). Analysis of data demonstrated that all five doses of aflibercept met the
`primary study endpoint of a statistically significant reduction in retinal thickness
`after 12 weeks and 32 weeks of treatment compared with baseline. The study
`commenced in April 2006 and enrolled 157 patients at sites in the US. Preliminary
`phase I trial results in 21 patients have also been presented.[14-16]
`Additionally, Regeneron has conducted a phase I trial of aflibercept in five
`patients with diabetic macular oedema (DME) in the US. Results presented in
`May 2007 indicated that a single 4 mg injection resulted in a marked decrease in
`mean central retinal thickness and mean macular volume throughout the 6-week
`observation period. The VEGF Trap-Eye was generally well tolerated, and there
`were no drug-related serious adverse events.[17] Regeneron plans to conduct
`advanced studies of the VEGF Trap-Eye in DME.
`Previously, sanofi-aventis and Regeneron had been collaborating on the devel-
`opment of aflibercept for eye diseases through local delivery systems. However,
`the exclusive rights to develop and commercialize aflibercept for eye diseases
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 3
`
`Joining Petitioner: Apotex
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`

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`264
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`Adis R&D Profile
`
`through local delivery systems reverted to Regeneron in January 2005. Addition-
`ally, Regeneron chose to pursue intravitreal inection as a route of administration,
`instead of systemic delivery.[18]
`Results from an earlier phase I trial assessing the safety and tolerability of
`intravenous infusions of aflibercept in patients with wet AMD have been reported.
`Preliminary results from the trial showed that the efficacy endpoint was met.
`Furthermore, systemic delivery of aflibercept was associated with a dose-depen-
`dent increase in blood pressure.[19]
`
`862111-32-8
`A10X (Other Drugs Used in Diabetes)
`S01X (Other Ophthalmologicals)
`L01 (Antineoplastic Agents)
`A10X (Other Drugs Used in Diabetes)
`S1X (Other Ophthalmologicals)
`L1 (Antineoplastics)
`Regeneron Pharmaceuticals: USA
`Bayer HealthCare: world; sanofi-aventis: world
`Phase III (World)
`
`Vascular endothelial growth factor A antagonists
`Halts new blood vessel growth and stopped leakage from existing blood vessels
`in mice; inhibits VEGF and abolishes mature, pre-existing vasculature of tumours
`in mice; inhibits development of ascites and decreases tumour burden in animal
`models of ovarian cancer
`IV
`
`est dose groups or 800 µg/kg once or twice weekly.
`In the trial patients received one or two initial doses
`of VEGF Trap followed 4 weeks later by six weekly
`or twice-weekly doses. Seven dose groups were
`evaluated in the trial ranging from 25 to 800 µg/kg
`weekly or 800 µg/kg twice weekly. Values for tmax,
`Cmax, t1/2, AUC28 and CL/F were 84 ± 60 hours,
`3 ± 1 µg/mL, 25.3 ± 9.3 days, 1304 ± 256 µg (cid:127) h/mL
`and 0.4 ± 0.1 mL/h/kg, respectively.[21]
`
`Table I. Features and properties
`
`CAS number
`WHO ATC code
`
`EphMRA ATC code
`
`Originator
`Licensee companies
`Highest development phase
`
`Properties
`Mechanism of action
`Pharmacodynamics
`
`Route
`
`1. Profile
`
`1.1 Pharmacokinetics
`
`Clinical studies: Preliminary results of an open-
`label, phase I trial of a single dose of subcutaneous
`VEGF Trap (25, 50, 100 or 200 µg/kg) followed
`4 weeks later by six weekly doses in patients with
`solid tumours or lymphoma showed that VEGF Trap
`binds to VEGF in plasma and has an apparent elimi-
`nation half-life (t1/2) of ≈17 days.[20]
`Solid tumours: Results of a phase I, open-label,
`dose-escalation trial of VEGF Trap in 38 patients
`Results of a phase I, open-label, dose-escalation
`trial of 38 patients with relapsed or refractory solid with relapsed or refractory solid tumours showed
`that the drug had a good safety profile and was well
`tumours showed that VEGF Trap has a long t1/2 and
`binds to both VEGF 121 and VEGF 165 in patient
`tolerated overall. The maximum tolerated dose was
`plasma. Plasma VEGF Trap levels that were asso-
`not reached in the study, which reached the highest
`planned dose level of 800 µg/kg twice weekly. The
`ciated with antitumour activity in animal models
`were approached in patients receiving the two high- majority of adverse events reported were grade 1 or
`
`1.2 Adverse Events
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 4
`
`Joining Petitioner: Apotex
`
`

`

`Aflibercept
`
`265
`
`Table II. Drug development history
`
`May 2000
`Nov 2001
`Nov 2001
`Jun 2003
`Jun 2003
`Jun 2003
`Sep 2003
`Mar 2004
`Apr 2004
`Aug 2004
`Feb 2005
`Feb 2005
`
`May 2005
`
`May 2005
`Jul 2005
`Jul 2005
`Dec 2005
`Dec 2005
`Dec 2005
`Dec 2005
`May 2006
`May 2006
`Jun 2006
`Jun 2006
`Jun 2006
`Jun 2006
`Jul 2006
`Jul 2006
`Jul 2006
`Jul 2006
`Aug 2006
`Sep 2006
`Sep 2006
`Oct 2006
`
`Oct 2006
`Oct 2006
`
`Oct 2006
`Nov 2006
`Dec 2006
`Jan 2007
`Jan 2007
`
`Preclinical development for Cancer in the US (Unknown route)
`Phase-I for Non-Hodgkin’s lymphoma in the US (Unknown route)
`Phase-I for Solid tumours in the US (Unknown route)
`Prein Age-related macular degeneration in the US (IV)
`Prein Eye disorders in the US (Intravitreous)
`Prein Wilms’ tumour in the US (Intraperitoneal)
`Aflibercept has been licensed to Aventis worldwide (excluding Japan)
`Phase-I in Age-related macular degeneration in the US (IV)
`Regeneron has initiated enrolment in a phase I trial for cancer in the US
`Aventis has merged with Sanofi-Synthelabo to form sanofi-aventis
`Aflibercept received Fast Track designation for Malignant ascites [IV] in the US
`Discontinued – Phase-I for Age-related macular degeneration in the US (IV-
`infusion)
`Regeneron has initiated the safety and tolerability study with VEGF Trap in
`combination with the FOLFOX-4 regimen (oxaliplatin, 5-fluorouracil and folinic
`acid) in patients with advanced tumours
`Phase-I in Solid tumours in the US (IV)
`Phase-I in Age-related macular degeneration in the US (Intravitreous)
`Prein Eye disorders in the US (Intravitreous)
`Regeneron has licensed aflibercept to sanofi-aventis in Japan
`Phase-II in Non-small cell lung cancer in France (IV)
`Phase-II in Non-small cell lung cancer in Canada (IV)
`Phase-II in Non-small cell lung cancer in the US (IV)
`Phase-I in Diabetic macular oedema in the US (Intravitreous)
`Phase-II in Age-related macular degeneration in the US (Intravitreous)
`Phase-II in Ovarian cancer in the US (IV)
`Phase-II in Ovarian cancer in Australia (IV)
`Phase-II in Ovarian cancer in Canada (IV)
`Phase-II in Ovarian cancer in Europe (IV)
`Phase-II/III in Malignant ascites in India (IV)
`Phase-II/III in Malignant ascites in the US (IV)
`Phase-II/III in Malignant ascites in Canada (IV)
`Phase-II/III in Malignant ascites in Europe (IV)
`Phase-II in Glioma in the US (IV)
`Phase-II in Sarcoma in Canada (IV)
`Phase-II in Sarcoma in the US (IV)
`Aflibercept has been licensed to Bayer HealthCare for the treatment of eye
`disorders
`Phase-II in Colorectal cancer in Canada (IV)
`Regeneron and sanofi-aventis initiate enrolment in a second phase II trial in
`Malignant ascites in the EU and US
`Phase-II in Colorectal cancer in the US (IV)
`Phase-II in Bladder cancer in the USA (IV)
`Phase-II in Multiple myeloma in the US (IV)
`Phase-II in Gynaecological cancer in the US (IV)
`Phase-II in Breast cancer in the US (IV)
`
`Continued next page
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`Joining Petitioner: Apotex
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`

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`266
`
`Table II. Contd
`
`Mar 2007
`
`Mar 2007
`Jun 2007
`
`Jun 2007
`
`Jun 2007
`Jul 2007
`Jul 2007
`Aug 2007
`Aug 2007
`
`Aug 2007
`Aug 2007
`Aug 2007
`Aug 2007
`Aug 2007
`Aug 2007
`Aug 2007
`Aug 2007
`Aug 2007
`Aug 2007
`Oct 2007
`
`Dec 2007
`Dec 2007
`Dec 2007
`Dec 2007
`Dec 2007
`Apr 2008
`May 2008
`
`Adis R&D Profile
`
`Interim results from a phase II clinical trial in wet Age-related macular
`degeneration added to the Eye Disorders therapeutic trials section
`Phase-I in Cancer in Japan (IV)
`Final results from a phase I clinical trial in patients with diabetic macular
`oedema added to the adverse events and Eye Disorders therapeutic trials
`sections
`Data presented at the 43rd Annual Meeting of the American Society of Clinical
`Oncology (ASCO-2007) added to the adverse events and Cancer therapeutic
`trials sections
`Phase-II in Malignant melanoma in the US (IV)
`Suspended – Phase-II for Colorectal cancer in Canada (IV)
`Suspended – Phase-II for Colorectal cancer in the US (IV)
`Phase-III in Age-related macular degeneration in the US (Intravitreous)
`Regeneron initiates patient dosing in a phase III trial for Age-related macular
`degeneration in the US
`Phase-III in Prostate cancer in the US (IV)
`Phase-III in Prostate cancer in Canada (IV)
`Phase-III in Prostate cancer in European Union (IV)
`Phase-III in Prostate cancer in Switzerland (IV)
`Phase-III in Prostate cancer in South Africa (IV)
`Phase-III in Prostate cancer in South America (IV)
`Phase-III in Prostate cancer in Asia (IV)
`Phase-III in Non-small cell lung cancer in the US (IV)
`Phase-III in Non-small cell lung cancer in France (IV)
`Phase-III in Prostate cancer in Australia (IV)
`Results from a phase II clinical trial in age-related macular degeneration added
`to the Eye Disorders therapeutic trials section
`Phase-III in Pancreatic cancer in World (IV)
`Phase-III in Colorectal cancer in World (IV)
`Phase-III in Non-small cell lung cancer in World (IV)
`Phase-III in Prostate cancer in World (IV)
`Suspended – Phase-II for Breast cancer in the US (IV)
`Interim efficacy data from a phase II trial in wet AMD released by Regeneron
`Bayer and Regeneron initiates enrolment in the VIEW 2 trial for Age-related
`macular degeneration in EU, Asia Pacific, Japan, and Latin America
`
`2, including fatigue, nausea and vomiting. Observed
`grade 3 and 4 adverse events that were potentially
`drug related were grade 3 leukopenia, afebrile neu-
`tropenia and proteinuria, and grade 3 and 4 thrombo-
`embolic events including a transient cerebral ischae-
`mia and a pulmonary embolism. Dose-related ad-
`verse events included hypertension and grade 1
`hoarseness and anorexia. All patients who discontin-
`ued participation in the extension study withdrew
`due to disease progression, except one patient who
`developed grade 3 hypertension and proteinuria and
`was withdrawn after 22 weeks.[21]
`
`The VEGF Trap administered intravenously eve-
`ry 2 weeks was generally well tolerated in a phase I,
`open-label, dose-ascending study in 27 patients with
`advanced solid tumours. The maximum tolerated
`dose has not been reached. The most frequently
`reported adverse events included fatigue, pain and
`constipation. The majority of adverse events were
`mild to moderate by nature. Occasional adverse
`events, including hypertension, were manageable
`and reversible. There were no anti-VEGF Trap anti-
`bodies detected.[9]
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 6
`
`Joining Petitioner: Apotex
`
`

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`Aflibercept
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`
`1.3 Pharmacodynamics
`
`1.3.2 Eye Disorders
`Preclinical studies: Administration of VEGF
`Trap (either subcutaneously or directly into the eye)
`resulted in significantly less new blood vessel
`growth, and also blocked leaking of blood vessels
`usually caused by VEGF, in two groups of mice. In
`the first group, mice with laser-induced rupture of
`Bruch’s membrane received a single intravitreous
`injection of VEGF Trap. In the second group, mice
`genetically engineered to express VEGF in the reti-
`na received subcutaneous injections of VEGF Trap.
`No adverse effects were observed in these stud-
`ies.[24]
`
`1.4 Therapeutic Trials
`
`ascites in the OVCAR-3 model was also significant-
`ly lower in the VEGF Trap group, compared with
`1.3.1 Cancer
`controls. In fact, VEGF Trap completely inhibited
`Preclinical studies: VEGF Trap inhibited VEGF
`the development of measurable ascites. Further-
`and destroyed mature, pre-existing vasculature in more, tumour burden was reduced by 56% in the
`nude mice bearing established Wilms’ tumour (SK- VEGF Trap group, compared with the controls.[23]
`NEP-1) xenografts. This could provide an alterna-
`tive therapeutic option for patients with bulky, meta-
`static cancers. Destruction of blood vessels was
`followed by marked tumour regression that included
`regression of lung micrometastases. The size of
`pulmonary metastases was significantly smaller in
`the lungs of VEGF Trap-treated animals compared
`with controls. These observations indicated that
`VEGF inhibition by VEGF Trap had interrupted cell
`signalling of the endothelial-vascular wall essential
`for the protection of tumours from apoptosis. Thus,
`it was concluded that even low levels of VEGF
`could be critical to the integrity of blood vessels and
`the maintenance of even the smallest tumour mass-
`es.[22]
`VEGF Trap inhibited the development of ascites
`and decreased tumour burden in animal models
`of ovarian cancer. Findings
`indicated
`that
`VEGF Trap’s activity was facilitated by inhibition
`of tumour angiogenesis as well as reduction in vas-
`cular permeability. In the first model, SKOV-3 ova-
`rian carcinoma cells were engineered to overexpress
`VEGF (SKOV-VEGF) and then injected into the
`peritoneum of female nude mice. The animals were
`then administered subcutaneous (SC) VEGF Trap
`25 mg/kg or control solution twice weekly until they
`had lost >10% of bodyweight or had persistent
`ascites. In the second model, OVCAR-3 ovarian
`cancer cells were injected into the peritoneum
`of athymic Balb/C nude mice. Fourteen days later,
`twice-weekly treatment with subcutaneous VEGF
`Trap 25 mg/kg or control solution was initiated and
`continued for 5 weeks. Ascites developed considera-
`1.4.2 Eye Disorders
`bly earlier in control animals injected with SKOV-
`Age-related macular degeneration (AMD): At
`VEGF cells, compared with those injected with un-
`32 weeks, the 157 patients receiving either 0.5 or 2.0
`altered SKOV-3 cells. In contrast, the majority of
`mice administered VEGF Trap did not develop asci- mg followed by as-needed (PRN) dosing achieved
`tes, and those that did develop ascites had much mean improvements in visual acuity of 8.0 and 10.1
`lower volumes of fluid, compared with controls,
`letters, respectively, and mean decreases in retinal
`according to the researchers. The mean volume of
`thickness of 141 and 162 microns, respectively.
`
`1.4.1 Cancer
`Ovarian cancer: Preliminary results of an open-
`label, phase I trial of a single dose of subcutaneous
`aflibercept (25, 50, 100 or 200 µg/kg) followed
`4 weeks later by six weekly doses in patients with
`solid tumours or lymphoma (n = 14 treated to date)
`showed stable disease in patients with renal cell
`carcinoma (up to 15 weeks) and colon cancer.[20]
`Preliminary efficacy data of the aflibercept ad-
`ministered intravenously every 2 weeks showed the
`reduction of tumour size and prolonged stable dis-
`ease in some patients. A partial response with disap-
`pearance of ascites has been achieved in one patient,
`two patients had minor responses, and a stable dis-
`ease was maintained in one patient for more than
`11 months.[9]
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 7
`
`Joining Petitioner: Apotex
`
`

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`268
`
`Adis R&D Profile
`
`While PRN dosing also maintained the improve-
`ments versus baseline following a fixed dosing regi-
`men (quarterly dosing at baseline and week 12), the
`results achieved were generally not as robust as
`those achieved with initial fixed monthly dosing.
`After the last fixed-dose administration at week 12,
`patients from all dose groups required on average
`only one additional injection over the following
`20 weeks to maintain visual acuity gain achieved.
`Fifty-five percent of patients receiving 2.0 mg
`monthly for 12 weeks did not require any additional
`treatment throughout the next 20-week PRN dosing
`period.[14]
`Preliminary results from a phase I trial in 20
`patients with wet AMD have shown rapid, substan-
`tial and prolonged (≥4 weeks) reductions in retinal
`thickness with single-dose intravitreal injections of
`VEGF Trap. Ninety-five percent of patients had
`stabilization or improvement in visual acuity.[16,25]
`Preliminary results from a phase I trial in 25
`patients with advanced AMD showed a statistically
`significant decrease in excess retinal thickness with
`VEGF Trap (0.3, 1.0 and 3.0 mg/kg) compared with
`placebo.[19]
`
`References
`1. Bayer HealthCare, Regeneron Pharmaceuticals Inc. Bayer
`HealthCare and Regeneron to Collaborate on VEGF Trap for
`the Treatment of Eye Diseases. Media Release: 18 Oct 2006.
`Available from URL: http://www.bayer.com
`2. Regeneron Pharmaceuticals Inc. Sanofi-Aventis and Regeneron
`Pharmaceuticals Expand Their VEGF Trap Oncology Collabo-
`ration to Japan. Media Release: 22 Dec 2005. Available from
`URL: http://www.sanofi-aventis.com
`3. sanofi-aventis. Sanofi-aventis and Regeneron Pharmaceuticals
`Reaffirm Development Commitment. Media Release: 10 Jan
`2005. Available from URL: http://www.sanofi-aventis.com
`4. Aventis, Regeneron Pharmaceuticals Inc. Aventis and Regener-
`on Enter Global Partnership to Develop and Commercialize
`the VEGF Trap. Media Release: 8 Sep 2003. Available from
`URL: http://www.aventis.com
`5. Massarelli E, Miller VA, Leighl NB, et al. Phase II study of the
`efficacy and safety of intravenous AVE0005 (VEGF Trap)
`given every 2 weeks in patients with platinum- and erlotinib-
`resistant adenocarcinoma of the lung. Journal of Clinical On-
`cology 25 (Suppl.): 416 (plus poster) abstr. 7627, No. 18, Part
`1, 20 Jun 2007
`6. Regeneron Pharmaceuticals Inc. Regeneron Reports Fourth
`Quarter and Full Year 2005 Financial and Operating Results.
`Media Release: 24 Feb 2006. Available from URL: http://
`www.regeneron.com
`7. Regeneron Pharmaceuticals Inc. Regeneron Reports Positive
`Preliminary Results from Phase 1 Study of the VEGF Trap in
`
`Patients with Advanced Solid Tumors. Media Release: 6 Jun
`2004. Available from URL: http://www.regn.com
`8. Regeneron Pharmaceuticals Inc. Regeneron Reports Second
`Quarter Financial and Operating Results; BLA Filing for Auto-
`Inflammatory Diseases Planned for Early 2007; Two Antibody
`Candidates from VelocImmune(R) Program to Enter Clinical
`Trials Each Year Beginning in 2007. Media Release: 3 Aug
`2006. Available from URL: http://www.regeneron.com
`9. Regeneron Pharmaceuticals Inc. Regeneron’s VEGF Trap Dem-
`onstrates Positive Preliminary Results from Single-Agent
`Phase 1 Trial in Patients with Advanced Cancer; Results
`Presented at ASCO Annual Meeting on May 16, 2005. Media
`Release: 16 May 2005. Available from URL: http://ww-
`w.regeneron.com
`10. Regeneron Pharmaceuticals Inc. Regeneron Receives $20 Mil-
`lion Milestone Payment for Initiation of Phase 3 Study of
`VEGF Trap-Eye in Wet AMD. Media Release: 14 Aug 2007.
`Available from URL: http://www.regeneron.com
`11. Regeneron Pharmaceuticals Inc, Bayer HealthCare. Regeneron
`and Bayer HealthCare Initiate Phase 3 Global Development
`Program For VEGF Trap-Eye In Wet Age-Related Macular
`Degeneration (AMD). Media Release: 3 Aug 2007. Available
`from URL: http://www.regeneron.com
`12. Bayer HealthCare AG. Bayer and Regeneron start additional
`Phase 3 Study for VEGF Trap-Eye in Wet Age-related Macu-
`lar Degeneration. Media Release: 8 May 2008. Available from
`URL: http://www.bayerscheringpharma.de
`13. Bayer HealthCare AG, Regeneron Pharmaceuticals Inc. Bayer
`and Regeneron Dose First Patient in Second Phase 3 Study for
`VEGF Trap-Eye in Wet Age-Related Macular Degeneration.
`Media Release: 8 May 2008. Available from URL: http://
`www.bayerhealthcare.com
`14. Regeneron Pharmaceuticals Inc, Bayer HealthCare AG.
`Regeneron and Bayer HealthCare Announce Encouraging
`32-Week Follow-Up Results from a Phase 2 Study of VEGF
`Trap-Eye in Age-Related Macular Degeneration. Media Re-
`lease: 29 Apr 2008. Available from URL: http://www.regener-
`on.com
`15. Regeneron Pharmaceuticals Inc. Regeneron Announces Positive
`Primary Endpoint Results from a Phase 2 Study of VEGF
`Trap-Eye in Age-related Macular Degeneration. Media Re-
`lease: 1 Oct 2007. Available from URL: http://www.regener-
`on.com
`16. Regeneron Pharmaceuticals Inc. Regeneron Reports Positive
`Phase 1 Data for the VEGF Trap in Age-Related Macular
`Degeneration; Preliminary Results Show Improvements in
`Vision and Retinal Swelling; VEGF Trap Was Well Tolerated
`at All Dose Levels. Media Release: 1 May 2006. Available
`from URL: http://www.regeneron.com
`17. Regeneron Pharmaceuticals Inc. VEGF Trap-Eye Phase 2 Wet
`AMD Results Reported at ARVO Annual Meeting. Media
`Release: 10 May 2007. Available from URL: http://ww-
`w.regeneron.com
`18. Regeneron Pharmaceuticals Inc. Regeneron Reports Fourth
`Quarter and Full Year 2004 Financial and Operating Results.
`Media Release: 22 Feb 2005. Available from URL: http://
`www.regeneron.com
`19. Regeneron Pharmaceuticals Inc. Clinical and Pre-Clinical Stud-
`ies of the VEGF Trap Show Potential for the Treatment of
`Neovascular Eye Diseases. Media Release: 3 May 2005.
`Available from URL: http://www.regeneron.com
`20. Dupont J, Camastra D, Gordon MS, et al. Phase 1 study of
`VEGF Trap in patients with solid tumors and lymphoma. 39th
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 8
`
`Joining Petitioner: Apotex
`
`

`

`Aflibercept
`
`269
`
`Annual Meeting of the American Society of Clinical Oncolo-
`gy: 194, 31 May 2003
`21. Dupont J, Schwartz L, Koutcher J, et al. A phase I and pharma-
`cokinetic clinical trial of subcutaneous VEGF Trap in ad-
`vanced solid tumor patients. EJC Supplements 2: 43 (plus
`poster) abstr. 132, 29 Sep 2004
`22. Huang J, Frischer JS, Serur A, et al. Regression of established
`tumors and metastases by potent vascular endothelial growth
`factor blockade. Proceedings of the National Academy of
`Sciences of the United States of America 100: 7785-7790, 24
`Jun 2003
`23. Byrne AT, Ross L, Holash J, et al. Vascular endothelial growth
`factor-trap decreases tumor burden, inhibits ascites, and causes
`
`dramatic vascular remodeling in an ovarian cancer model.
`Clinical Cancer Research 9: 5721-5728, No. 15, 15 Nov 2003
`24. Johns Hopkins’ Wilmer Eye Institute. Injection Prevents Blind-
`ing Blood Vessel Growth in Mice. Media Release: 17 Jun
`2003. Available from URL: http://www.hopkinsmedicine.org
`25. Regeneron Pharmaceuticals Inc. Regeneron’s VEGF Trap Dem-
`onstrates Positive Preliminary Results in Patients with Age-
`Related Macular Degeneration; Phase 1 Preliminary Results to
`Be Presented at the Angiogenesis 2006 Meeting Sponsored by
`Bascom Palmer Eye Institute. Media Release: 2 Feb 2006.
`Available from URL: http://www.regeneron.com
`
`© 2008 Adis Data Information BV. All rights reserved.
`
`Drugs R D 2008; 9 (4)
`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 9
`
`Joining Petitioner: Apotex
`
`

`

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`
`Mylan Exhibit 1007
`Mylan v. Regeneron, IPR2021-00880
`Page 10
`
`Joining Petitioner: Apotex
`
`