Status: Eylea BLA approved in Nov. 2011; Eylea MAA approved in Nov. 2012; Zaltrap BLA in Aug. 2012; Zaltrap MAA in Feb. 2013

Organizations involved:

Regeneron Pharmaceuticals, Inc. – Manuf.; R&D; Tech.; USA mark.

Bayer HealthCare – Intl. mark.

Sanofi S.A. - Manuf. other; World mark.

Genentech/Roche – Patent dispute; Tech.

Cross ref.: See also the entries for VEGF monoclonal antibodies, particularly Lucentis, and IL-1 Trap, rDNA.

Description: Eylea and Zaltrap are formulations of aflibercept, a recombinant fusion protein expressed by unspecified transformed Chinese hamster ovary (CHO) K-1 cells consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 that binds all forms of VEGF-A, along with the related Placental Growth Factor (PlGF). VEGF Trap-Eye is a specific and highly potent blocker of these growth factors. VEGF Trap-Eye is specially purified and contains iso-osmotic buffer concentrations, allowing for injection into the eye. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 96.9 kDa and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.

Eylea is packaged as a preservative-free, sterile, aqueous solution in single-use, glass vial, each providing 0.05 mL (50 microliters) of 40 mg/mL solution for intravitreal injection. Eylea also contains 40 mM sodium chloride, 0.03% polysorbate 20 (Tween 20), and 5% sucrose, at pH 6.2. EYLEA is a sterile, clear, and colorless to pale yellow solution. Each Eylea vial contains 0.278 mg of drug product.

ZALTRAP is supplied in single-use vials of 100 mg per 4 ml and 200 mg per 8 ml formulated as 25 mg/mL ziv-aflibercept in polysorbate 20 (0.1%), sodium chloride (100 mM), sodium citrate (5 mM), sodium phosphate (5 mM), and sucrose (20%), in Water for Injection USP, at a pH of 6.2. The dating period for Zaltrap is 36 months when stored at 2-8˚C (refrigerated). Very unusual, FDA has redacted (censored) the definition of the date of manufacture for the finished product and the dating period for the drug substance when stored at ≤20˚F [How could this information be in any way proprietary, help competitors or otherwise not deserve to be public?]

Aflibercept is apparently manufactured using no animal-derived products (animal origin free/AOF).

Biological.: Aflibercept (VEGF Trap), an anti-angiogenic agent, is a fusion protein specifically designed to bind all forms of Vascular Endothelial Growth Factor-A (VEGF-A). VEGF-A is required for the growth of new blood vessels that are needed for tumors to grow and is a potent regulator of vascular permeability and leakage. In addition, aflibercept binds Placental Growth Factor (PLGF), which has also been implicated in tumor angiogenesis.

“Traps,” as developed by Regeneron, are composed of fusions between two distinct cytokine receptor components and a portion of an antibody molecule called the “Fc region”, resulting in the generation of cytokine blockers with markedly increased affinity over that offered by single component agents.; In simplistic terms, two cytokine-binding receptors have been swapped into or substituted for the immunogen-binding portions of the two arms of an antibody/immunoglobulin molecule. In this respect, IL-1 Trap appears to qualify as an immunoadhesin, i.e., recombinant fusion proteins combining certain structural features of antibodies with high-affinity cell surface receptors [and seems to be covered by the associated dominant patent(s) held by Genentech; See the Monoclonal Antibodies entry no. 300].

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and inhibits the binding and activation of these cognate VEGF receptors.

Nomenclature; VEGF Trap, rDNA [BIO]; VEGF Trap-Eye [TR former]; Eylea [TR for Eylea]; Zaltrap [TR for Zaltrap]; aflibercept [USAN; INN]; des-432-lysine-[human vascular endothelial growth factor receptor 1-(103-204)-peptide (containing Ig-like C2-type 2 domain) fusion protein with human vascular endothelial growth factor receptor 2-(206-308)-peptide (containing Ig-like C2-type 3 domain fragment) fusion protein with human immunoglobulin G1-(227 C-terminal residues)-peptide (Fc fragment)], (211-211':214-214')-bisdisulfide dimer [CAS]; Vascular endothelial growth factor receptor type VEGFR1 (synthetic human immunoglobulin domain 2 fragment) fusion protein with vascular endothelial growth factor receptor type VEGFR2 (synthetic human immunoglobulin domain 3 fragment) fusion protein with immunoglobulin G1 (synthetic Fc fragment), dimer [CAS]; 862111-32-8 [CAS RN]; AVE0005,[SY]; NDC 0024-5840-01; NDC 0024-5840-03; NDC 0024-5841-01 [NDC for Zaltrap]

Note, FDA has arbitrarily (contrary to prior nomenclature conventions and precedents) selected ziv-aflibercept as the U.S. establiished (compendial, generic) non-proprietary name for Zaltrap and its active agent (while, the rest of the world uses 'aflibercept' the established INN and USAN for the active agent). FDA reports it felt it essential for safety to give a different name to Zaltrap and Eylea (despite all prior precedents and nomenclature rules following the convention of naming based on active agent, which is the same with these products). To date, the INN and USAN for the active agent remains aflibercept, while neither USAN nor INN filings have been reported for 'ziv-aflibercept.'

Companies.: Regeneron, CBER/FDA est. no. 1760, East Greenbush =(Rensselaer), NY, manufactures active agent for Eylea and Zaltrap. Final formulated Zaltrap is manufactured, filled, labeled, and packaged at Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany and labeled and packaged at sanofi-aventis, U.S., LLC in Saint Louis, MO.

FDA approval letter cited Est. no. 1760 (Regeneron) as the manufacturer of Eylea, with Est. no. 1752 (Sanofi, Bridgewater, NJ) the manufacturer of Zaltrap (obviously, reflecting product fill-finish operations, with the active agent for both the same and manufactured by Regeneron.

Regeneron and Bayer HealthCare collaborated on the development of VEGF Trap-Eye for the treatment of wet AMD, central retinal vein occlusion, diabetic macular edema, myopic choroidal neovascularisation, and other eye diseases and disorders. Regeneron retains U.S. marketing, while Bayer HealthCare markets VEGF Trap-Eye outside the U.S., where the companies share equally in profits from sales of VEGF Trap-Eye for its ophthalmic markets.

Regeneron and Sanofi have a global collaboration to develop and commercialize aflibercept for non-ophthalmic indications, including Zaltrap for cancer, with Sanofi having exclusive development and marketing rights. Sanofi and Regeneron share equally the global profits of Zaltrap after Regeneron repays its share of development expenses (so earlier post-launch revenue mostly goes to Sanofi).

In July 2012, with sales of Eyelea expanding , Regeneron Pharmaceuticals decided to build an additional 44,000 square feet of manufacturing space and 27,000 square feet for offices at its facilities in East Greenbush, NY.

FDA class: Biologic BLA

Approvals: Date = 20111118, full BLA (BL 125387/0) for Eylea

Date = 20120803, full BLA (BLA 125418/0) for Zaltrap, with Priority Review

Indications: [Full text of the INDICATIONS AND USAGE section of the Eylea product insert/labeling] EYLEA is indicated for the treatment of patients with Neovascular (Wet) Age-Related Macular Degeneration (AMD).

Indications: [Full text of the INDICATIONS AND USAGE section of the Zaltrap product insert/labeling]
ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Status: Regeneron filed its BLA on Feb. 22, 2011 for VEGF Trap-Eye for the treatment of the neovascular form of age-related macular degeneration (wet AMD). Regeneron’s submission rceived Priority Review, shortening the FDA’s targeted goal for review time under PDUFA to six months (vs. the usual 10 months). FDA initially delayed its decision on Aug. 16, 2011 stating that answers Regeneron provided to the agency on its application about manufacturing controls were “a major amendment,” with FDA extending review by 3 months.

On June 20, 2011, the Ophthalmic Drugs Advisory Committee, FDA, voted unanimously to support approval of Eylea.'

In June 2011, Bayer submitted a MAA for EU marketing.

Zaltrap was approved by FDA with a black box warning, including warnings regarding fatal hemorrhage, gastrointestinal (GI) perforation and sSevere compromised wound healing. Zaltrap can also make it more difficult for wounds to heal.

Both Zaltrap and Eylea are exempt from CBER, FDA, lot release requirements.

On Nov. 26, 2012, EMA/EU approved Eylea for marketing by Bayer for the treatment of patients with neovascular age-related macular degeneration.

On Dec. 6, 2012, Bayer filed for supplemental approval of Eylea for the treatment of macular edema following central retinal vein occlusion.

In April 2013, EMA/EU granted approval to Zaltrap for metastatic colorectal cancer.

In Aug. 2013, EMA/EU granted approval to Eylea for treatment of visual impairment due to Macular Edema Secondary to Central Retinal Vein Occlusion (CRVO).

On Nov. 7, 2013, Bayer HealthCare submitted a MAA to EMA seeking approval of VEGF Trap-Eye (aflibercept solution for injection) for the treatment of patients with diabetic macular edema (DME). Regeneron had also submitted a supplemental BLA for VEGF Trap-Eye with FDA.

Tech. transfer: The U.S. product insert for Eylea cites, U.S. Patents 7,306,799, "Use of VEGF inhibitors for treatment of eye disorders." with calculated expiration date of May 23, 2020; 7,531,173, "Ophthalmic composition of a VEGF antagonist," with calculated expiration date of Feb, 2, 2026; 7,608,261, "VEGF antagonist formulations suitable for intravitreal administration," with calculated expiration date of June 14, 2027; 7,070,959; " Modified chimeric polypeptides with improved pharmacokinetic properties," with calculated expiration date of May 23, 2020; 7,374,757; "Modified chimeric polypeptides with improved pharmacokinetic properties," with calculated expiration date of May 23, 2020; and 7,374,758, "Modified chimeric polypeptides with improved pharmacokinetic properties and methods of using thereof," with calculated expiration date of May 23, 2020.

Other U.S. patents include 7,303,746, "Methods of treating eye disorders with modified chimeric polypeptides," expiring in 2024.

Yet ungranted EU-relevant patents include EP12700590/WO2012097019, "USE OF A VEGF ANTAGONIST TO TREAT ANGIOGENIC EYE DISORDERS, assigned to Regeneron, filed in 2011, will expire in 2031. EP2029103, "VEGF ANTAGONIST FORMULATIONS SUITABLE FOR INTRAVITREAL ADMINISTRATION," filed 2006, will expire in 2026. EP1917024, "METHODS OF TREATING DISEASES WITH A VEGF ANTAGONIST, filed in 2006, will expire in 2026. EP1861116, "- VEGF ANTAGONIST FORMULATIONS," filed in 2006, will expire in 2026.

In Jan. 2012, Genentech/Roche and Regeneron partially settled their patent disputes concerning Eylea. Regeneron received a non-exclusive license to certain patents relating to VEGF receptor proteins, known as the Davis-Smyth patents, and other technology patents [Cabilly III?]. Under the terms of the Agreement, Regeneron will make payments to Genentech based on US. sales of Eylea through May 7, 2016. Regeneron will pay $60 million upon cumulative U.S. sales of Eylea reaching $400 million. Regeneron also pays royalties of 4.75 percent on cumulative US sales of Eylea between $400 million and $3 billion and 5.5 percent on any cumulative US. sales of Eylea over $3 billion.

The Davis-Smyth patents continued as the subject of patent litigation between Regeneron and Genentech then pending in the U.S. District Court, Southern District of New York. Patent litigation continued with respect to matters not covered by the Agreement.

Trials: Zaltrap, like Avastin, was shown to be ineffective in treating prostate cancer. It also failed in other studies to improve outcomes in patients with lung and pancreatic cancers.

This approval was based upon the results of two Phase III clinical studies involving 2,412 adult patients. In these studies, Eylea dosed every eight weeks, following three initial monthly injections, was clinically equivalent to the standard of care, Lucentis (ranibizumab injection) dosed every four weeks, as measured by the primary endpoint of maintenance of visual acuity (less than 15 letters of vision loss on an eye chart) over 52 weeks. The most common adverse reactions (frequency of 5% or more) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure. The adverse event profile was similar to that seen with ranibizumab. The most commonly reported side effects in patients receiving Eylea included eye pain, blood at the injection site (conjunctival hemorrhage), the appearance of floating spots in a person's vision (vitreous floaters), clouding of the eye lens (cataract), and an increase in eye pressure.

A broad Phase III development program, initiated in 2007, included three Phase III studies of VEGF Trap (non VEGF Trap-Eye; with Sanofi Aventis) in combination with chemotherapy that are targeted to enroll a total of approximately 3,400 patients. These studies are being conducted in second-line metastatic colorectal cancer, second-line non-small cell lung cancer, and first-line metastatic hormone-refractory prostate cancer. Also, in early 2011, a Phase 2 combination study of aflibercept in first-line metastatic colorectal cancer was in progress.

Regeneron conducted the largest global Phase III clinical program in patients with wet AMD. This demonstrated that patients treated with VEGF Trap-Eye 2 mg every two months, following three loading doses, were able to be dosed with fewer injections over one year (compared to Lucentis).

The VEGF Trap-Eye BLA was based on the positive results from two Phase III trials, the North American VIEW [VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD] 1 trial and the global VIEW 2 trial. In these trials, all regimens of VEGF Trap-Eye, including VEGF Trap-Eye dosed 2 mg every two months (following three loading doses), successfully met the primary endpoint of non-inferiority, compared to the current standard of care, ranibizumab 0.5 mg dosed every month. The primary endpoint analysis was statistical non-inferiority in the proportion of patients who maintained (or improved) vision over 52 weeks compared to ranibizumab (Lucentis). A generally favorable safety profile was observed for both VEGF Trap-Eye and ranibizumab. The ocular adverse events were balanced across all treatment groups in both studies. There were no notable differences in non-ocular adverse events among the study arms.

In clinical testing, people who received the Zaltrap-FOLFIRI combination lived an average of 13.5 months, compared to 12 months with a combination of FOLFIRI and a placebo. An improvement in median survival time was noted with the addition of Zaltrap to FOLFIRI, accompanied by an improvement in response rate and a delay in tumor progression and growth. Zaltrap’s safety and effectiveness was evaluated in a randomized clinical study of 1,226 patients with metastatic colorectal cancer whose cancer grew while receiving oxaliplatin-based combination chemotherapy, or whose cancer was removed by surgery but returned within six months after receiving oxaliplatin-based combination chemotherapy for post-surgery (adjuvant) treatment. Participants received treatment until their cancer progressed or side effects became unacceptable. The study was designed to measure overall survival, or the length of time a patient lived. Patients who were assigned to receive the Zaltrap plus FOLFIRI combination lived an average of 13.5 months compared to an average of 12 months for those receiving FOLFIRI plus placebo. A reduction in tumor size occurred in 20 percent of patients receiving the Zaltrap plus FOLFIRI combination versus 11 percent for those receiving FOLFIRI plus placebo. In addition, the clinical trial demonstrated an improvement in progression-free survival, or the time a patient lived without the cancer progressing. The progression-free survival for patients receiving the Zaltrap plus FOLFIRI combination was 6.9 months compared with 4.7 months for those receiving FOLFIRI plus placebo.

The FDA review of Eylea took 9.0 months, with the PDUFA target date extended by the submission of a late major amendment by the sponsor.

Medical: The recommended dose for Eylea is 2 mg administered by intravitreal injection every four weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg once every eight weeks (2 months). Although Eylea may be dosed as frequently as 2 mg every four weeks (monthly), additional efficacy was not demonstrated when Eylea was dosed every four weeks compared to every eight weeks.

The recommended dose for Zaltrap is 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks, administered prior to any component of the FOLFIRI regimen on the day of treatment. Diluted ZALTRAP solution is administered as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Trials: In its trials for FDA approval, the most commonly reported side effects in patients receiving Eylea include eye pain, blood at the injection site (conjunctival hemorrhage), the appearance of floating spots in a person’s vision (vitreous floaters), clouding of the eye lens (cataract), and an increase in eye pressure. Disease: Regeneron has estimated about 1.5 million people have the wet form of the disease with 200,000 new cases diagnosed each year.

Market: Eylea is the only FDA-approved treatment for wet AMD labeled for less than monthly dosing that has demonstrated clinical equivalence to the monthly standard of care.

Sanofi gets half of the drug's profits, and Regeneron has to repay half of Sanofi's development costs,

Total 2012 sales of Eylea were reported by Regeneron to be $838 million. Arbitrarily estimating Zaltrap 2012 sales at $100 million, this provides estimated $938 2012 revenue.

Regeneron had 2013 sales of ~$1.4 billion, about >50% growth. Some analysts project Eylea sales will hit $4.7 billion by 2018.

Citigroup had projected Eylea peak sales of $1.1 billion in 2021 as its use is expanded to other eye disorders.

Unless approved or adopted for new indications and in new markets, the market may contract. Patients start Eylea on a frequent dosing schedule and then taper down as time goes on.

Despite demonstrating a similar level of efficacy to Lucentis, Eylea is dosed less frequently than Roche’s product – a notable benefit considering these therapies are injected into the eye. Precedents suggest that Regeneron could have launched Eylea at a price premium to Lucentis. However, the decision to launch at a modest discount positioned Regeneron as a cheaper alternative to Lucentis and a notably less expensive alternative to Avastin, given its less frequent administration. This strategy appears to have paid off handsomely, with 2013 sales expected to be about $1.3 billion.

Upon approval, Eylea cost $1,850 per dose. $9,600 per month for a typical patient, or $16,000 for a year’s treatment. For comparison, Lucentis, which has about 40% of the market, costs about $2,000 for each monthly injection, while off-label Avastin use costs about $50/injection (which is why why Avastin had at least 60% of the wet AMD market in 2012).

Upon approval, some analysts projected Zaltrap peak sales for its colorectal indications at $300-$400 million/year.

For colorectal cancer, Zaltrap must compete with Erbitux (BMS) and Avastin (Genentech/Roche). Upon approval, there was no comparative testing or data available.

In Nov. 2012, Sanofi drastically reduced its price for Zaltrap, by 50%. Zaltrap had met price resistance upon U.S. launch, including some major hospital systems, e.g., Memorial Sloan-Kettering Cancer Center, refusing to use and purchase it. Sanofi decided to set up new deals with U.S. cancer treatment providers, to offer Zaltrap at discounts of about 50%. But, technically, the "acquisition price" itself remains the same. The price cut may help Zaltrap compete against Avastin.

VEGF Trap-Eye is the first therapeutic to compete with Lucentis, which has well over $1 billion/year sales (and off-label Avastin). Lucentis has monthly dosing, while Eylea is taken once every two months, making it more convenient for patients, besides Eylea costing less.

In May 2013, the U.K. National Institute for Health and Care Excellence (NICE) reversed its prior rejection of the cost-effectiveness of Eylea after Novartis gave a substantially discounted price. Eylea and Lucentis will be on equal footing approval-wise, with NICE having set similar criteria for patients' eligibility for both treatments.

In June 2013, the U.K. National Institute for Health and Care Excellence (NICE) rejected use of Zaltrap, finding that the benefits din not outweigh its high price. NICE said the agency would not recommend that the National Health Service (NHS) pay for Zaltrap for treating metastatic colorectal cancer that is resistant to, or has progressed after, an oxaliplatin-containing regimen. NICE cited that it had already approved 6 other treatments for various stages of the disease. Although NICE's independent committee had considered aflibercept to be a clinically effective treatment, it could not be considered cost-effective. NICE estimated the cost per "Quality Adjusted Life Year" (QALY) would run from £62,900 to £66,500 ($97,000 to $102,656).

Other FDA-approved treatment options for wet AMD include: Visudyne (verteporfin for injection) approved in 2000, Macugen (pegaptanib sodium injection) approved in 2004, and Lucentis (ranibizumab injection) approved in 2006, considered the standard of care. The much lower administration frequency of VEGF Trap-Eye may give it an advantage over Lucentis. Plus, Avastis is used off-label for wet AMD. Eylea involves fewer injections than either Licentis or Avastin, which gives it one potential edge over the existing competition. And Regeneron has priced Eylea lower than Lucentis: about $100 lower on a per-injection basis, but about $8,000 less for a full year's treatment (using the less-frequent injection schedule).

However, initial sales had been higher than expected, and in Oct. 2012, Regeneron projected first year sales of $700-$750 million, , compared with its previous projections of $500 million to $550 million.

Citigroup has projected Eylea peak sales of $1.1 billion in 2021 as its use is expanded to other eye disorders.

In Aug, 2013, BioTrends reported Eylea's patient share at 26% of surveyed doctors' wet-AMD patients, with this outpacing Lucentis, with about 21% of the surveyed doctors' wet-AMD patients. That means Eylea has overtaken the older Lucentis just two years after approval, despite Roche's having five years to establish Lucentis. Other than price, Eylea is generally considered more convenient for patients, requiring fewer injections for the first two years of wet-AMD treatment, giving it a dosing advantage over both Lucentis and off-label Avastin.

In later 2013, Regeneron plans on filing an NDA for diabetic macular edema (DME), Lucentis and Eyelea will then compete directly for this indication.