Case 1:22-cv-00061-TSK-JPM Document 505-28 Filed 05/26/23 Page 1 of 6 PageID #:
`40584
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`Exhibit 24
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`Case 1:22-cv-00061-TSK-JPM Document 505-28 Filed 05/26/23 Page 2 of 6 PageID #:
`40585
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`Date:
`Subject:
`From:
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`Thursday, March 29 2007 03:59 PM
`Thoughts on Phase 3 AMD Design
`Robert Terifay
`Leonard Schleifer <Leonard.Schieifer@regeneron.com>; George Yancopoulos
`<George.Yancopoulos@regeneron.com >; Neil Stahl <Neil.Stahi@regeneron.com>; Murray Goldberg
`<Murray.Goldberg@regeneron.com >; Peter Powchik <Peter.Powchik@regeneron.com >; Avner Ingerman
`<Avner.Ingerman@regeneron.com >; William Roberts <William.Roberts@regeneron.com >; Jesse
`Cedarbaum <Jesse.Cedarbaum@regeneron.com >;
`Caroline Saxton <Caroline. Saxton@regeneron.com >; Kremena Simitchieva
`cc:
`<Kremena.Simitchieva@regeneron.com
`Attachments: Thoughts on VEGF Trap.doc
`Ihave summarized my thoughts on the VEGF Trap-Eye Phase 3 AMD study design based upon market needs (physician and patient),
`efficacy considerations, payer considerations, partner considerations, and company considerations in the attached document. It is
`important that we consider this information as we debate phase 3 design.
`
`To:
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`I look forward to our discussions.
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`Regards,
`
`Bob Terifay
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`CONFIDENTIAL
`
`RGN-EYLEA-MYLAN-00526134
`
`

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`Case 1:22-cv-00061-TSK-JPM Document 505-28 Filed 05/26/23 Page 3 of 6 PageID #:
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`Thoughts on VEGF Trap-Eye Phase 3 Development Plan
`
`e
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`e
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`Ph 3 Development Goals
`Ensure that clinical development plan secures FDA and EMEA approval with
`minimal regulatory risks.
`Institute study designs that are relevant to treating physicians and their patients in
`the U.S. and E.U.
`e Differentiate VEGF Trap from its competitors (ie, Lucentis and, by inference,
`Avastin) to allow for:
`o Ability to seize market share and grow the AMD market.
`o Pricing per year oftherapy at least comparable to that for Lucentis even if
`dosing schedules vary.
`e Minimize time to approval.
`e Carefully manage development costs.
`
`Lucentis Profile
`Studies have been shown that Lucentis initially improves visual acuity over the
`e
`first 3 months of monthly administration and maintains that improvement over
`time with monthly injections. Lucentis is recommended for use as a once-monthly
`injection at an average sales price (ex-factory) of $ 1,950 per injection per eye or
`$ 23,400 per year per eye.
`e After a 3-month monthly injection schedule in which overall visual acuity was
`improved, patients treated with quarterly injections of Lucentis were shown to
`lose the initial visual acuity gained over the subsequent 9 months.
`This dosing schedule is allowed in the U.S. for patients for whom monthly
`In the E.U., a PRN dosing schedule is allowed after
`injections are not feasible.
`the initial first 3 months of dosing.
`Genentech estimates that the average patient will receive 5 to 7 Lucentis
`injections per year per eye at a cost of$ 9,750 to $ 13,650 per year per eye.
`e All patients are monitored monthly during the first few months oftherapy
`regardless of dosing schedule. From a cost-of-care perspective, patients in the
`U.S. who receive quarterly injections of Lucentis are reported by physicians to
`require one additional office visit per quarter to ascertain maintenance of visual
`acuity (8-10 visits per year). There is a need for a drug that can predictably
`provide maintenance of visual acuity for a period longer than 1 month which does
`not require costly and time-consuming interim office visits to verify maintenance
`of visual acuity.
`The E. U. labeling recommends monthly office visits to verify maintenance of
`visual acuity (12 visits per year), making PRN dosing with Lucentis unattractive
`from a cost-of care perspective and inconvenience to the physician and patient..
`
`CONFIDENTIAL
`
`RGN-EYLEA-MYLAN-00526135
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`

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`Case 1:22-cv-00061-TSK-JPM Document 505-28 Filed 05/26/23 Page 4 of 6 PageID #:
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`Opportunities for VEGF Trap-eye
`e VEGF Trap needs to optimize the improvement in visual acuity initially
`achieved ( even if that requires monthly dosing for a period of time) and then
`predictably maintain that effect on a chronic dosing schedule that is less
`frequent than every 4 weeks and does not require interim monitoring.
`e Due to better binding affinity and the potential to administer higher doses that will
`increase the effective elimination half-life, VEGF Trap has the opportunity to
`initially improve visual acuity at least as well as Lucentis and maintain that
`improvement in visual acuity with less frequent chronic dosing than Lucentis.
`Less frequent chronic dosing is desirable to patients for comfort and convenience
`reasons and to physicians from a scheduling and liability perspective.
`e Equally important to physicians is that the maintenance of effect with chronic
`VEGF Trap therapy may be predictable over the dosing interval, eliminating the
`need for interim office visits. From a scheduling and cost-of-care perspective, less
`frequent visits are desirable to physicians, patients, and payers.
`
`e
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`Phase 2 Interim Results
`Initial monthly dosing with VEGF Trap appears to offer rapid improvement in
`e
`visual acuity at least as well as historical data indicate for Lucentis. However, a
`dose response between 0.5 mg, 2 mg, and 4 mg doses is not readily discernable.
`The maintenance of improvement in visual acuity with VEGF Trap appears
`longer than that seen with Lucentis. However, questions exist as to whether an 8-
`week fixed dosing interval is more appropriate than a 12-week dosing interval in
`maintaining effect.
`U.S. Pricing Considerations
`e Pricing decisions will be based upon the phase 3 clinical findings and market
`conditions at that time. Phase 3 study design, however, must not restrict the
`company’s pricing flexibility.
`Lucentis is currently reimbursed at $ 1,950 per injection for up to 12 injections
`per eye per year or $ 23,400. This should be considered a reasonable annual price
`cap VEGF Trap that will be acceptable to payers.
`e VEGF Trap will be used by physicians based upon clinical data according to the
`chronic dosing schedule that maintains improvement in visual acuity on the most
`convenient dosing schedule whether this is reflected in the Prescribing
`Information or not.
`Payers, however, will set annual reimbursement caps for VEGF Trap based upon
`its recommended Dosing and Administration included in the Prescribing
`Information. In order for the less frequent dosing interval to be included in the
`Dosing and Administration section of the labeling, it must be studied in the
`Pivotal Phase 3 studies, reviewed by the FDA, and considered clinically
`meaningful and relevant.
`If the labeling reflects the clinical utility of dosing VEGF Trap chronically at an
`interval longer than every 4 weeks versus Lucentis administered monthly (non-
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`e
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`e
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`CONFIDENTIAL
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`RGN-EYLEA-MYLAN-00526136
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`

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`Case 1:22-cv-00061-TSK-JPM Document 505-28 Filed 05/26/23 Page 5 of 6 PageID #:
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`inferiority), a reimbursement argument could be made to command a higher price
`per dose of VEGF Trap than Lucentis due to the likelihood of fewer injections per
`year. At the extreme where VEGF trap is dosed quarterly, a price per dose of $
`5,850 could be feasible if the labeling reflects this information.
`Alternatively, if the labeling only reflects non-inferiority for monthly dosing with
`VEGF Trap versus Lucentis, pricing per dose will likely be capped at $ 1,950 by
`payers. The problem with this scenario is that if data arise indicating that less
`frequent dosing is acceptable for VEGF Trap, physicians will adopt the less
`frequent dosing schedule. Revenues per patient will be significantly lowered;
`pricing can not be renegotiated upward.
`It should be noted that a positive clinical study comparing longer dosing intervals
`of VEGF Trap to sham will likely be sufficient for physicians to decide to dose
`the drug less frequently than monthly. However, unless the longer interval is
`shown to be non-inferior to Lucentis on a monthly schedule, payers will be
`unlikely to consider the less frequent dosing schedule in their reimbursement
`decisions.
`
`e
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`E.U. Considerations
`The Lucentis E. U. labeling allows for PRN dosing after a 3-month initial
`e
`monthly treatment period. Due to the lack of predictability for maintenance of
`effect with Lucentis, patients are to be monitored monthly, increasing the cost of
`care and decreasing physician and patient convenience versus a fixed dosing
`interval.
`This has led to the recommendation that one phase 3 study should evaluate VEGF
`Trap versus Lucentis, both dosed on a quarterly dosing schedule after an initial 3-
`month monthly treatment period. If VEGF Trap is proven to be non-inferior to
`Lucentis in this scenario, reimbursement authorities will limit pricing per dose to
`levels similar to Lucentis. Only a demonstration of the superiority of VEGF Trap
`dosed quarterly versus Lucentis dosed quarterly will lead to better reimbursement.
`e VEGF Trap could be differentiated from Lucentis if a chronic dosing interval
`could be established that is longer than every 4 weeks that doesn’t require interim
`office visits; VEGF Trap needs to be shown to offer predictable maintenance of
`effect with chronic fixed interval dosing less often than every 4 weeks. This effect
`should be demonstrated to be consistent with Lucentis on a monthly schedule to
`ensure fair reimbursement per dose.
`Implications for Phase 3 Design
`e Regulatory needs to clarify whether the same dose at the same dosing interval
`needs to be studied in two phase 3 clinical studies to ensure inclusion in the
`Dosing and Administration section of the labeling.
`e Dependent upon the above response, one or two studies including VEGF Trap
`studied at a longer chronic dosing interval compared to an FDA-approved active
`control (ie, Lucentis on a monthly dosing schedule) need to be included in the
`phase 3 plan. A comparison of a VEGF Trap extended-dosing interval to Lucentis
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`CONFIDENTIAL
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`RGN-EYLEA-MYLAN-00526137
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`

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`Case 1:22-cv-00061-TSK-JPM Document 505-28 Filed 05/26/23 Page 6 of 6 PageID #:
`40589
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`dosed on a quarterly dosing schedule may be too risky due to the need to show
`superiority.
`e Based upon interim phase 2 data, it needs to be determined whether we are more
`confident in an 8-week or 12-week dosing interval or whether both intervals need
`to be assessed in phase 3 testing.
`It should be noted that given MD preference for a dosing regimen that
`optimally improves visual acuity and then maintains that effect and
`treatment patterns which naturally lead to monthly visits for the first few
`months after initiation of drug therapy, monthly injections of VEGF Trap
`are recommended for the first three months of treatment, regardless of the
`chronic dosing schedule.
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`e
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`e
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`e
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`e
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`Preferred Phase 3 Design
`Lucentis 0.5 mg q4 wk vs. VT 0.5 mg q4wk vs VT 2 mg q4wk vs. VT 2 mg
`q4wks X 3, then q8wks
`Lucentis 0.5 mg q4wk vs. VT 0.5 mg q4wk vs VT 2 mg q4wk (+/- VT 2 mg
`q4wks X 3, then q8wks, or VT 4 mg q4wks X 3, then q12wk, dependent upon
`clinical assessment and regulatory feedback)
`e Medical Affairs study exploring other interval options (not for labeling). This may
`be where q12 wk dosing is studied.
`Implications for Commercialization
`Ifthe plan is successful, VEGF Trap initially dosed monthly would be shown to
`be non-inferior to Lucentis dosed monthly on initial improvement in visual acuity
`(and hopefully trend better).
`e Moreover, g8wk chronic dosing with VEGF Trap would be shown to be non-
`inferior to Lucentis q4wk on maintenance of effect.
`This outcome would afford physicians and patients a more convenient, yet
`predictable treatment option versus Lucentis.
`Payers will favorably respond to the cost savings of fewer office visits for
`injections due to the less frequent dosing schedule and elimination of the need for
`interim check-up visits due to the predictability of response with a fixed dosing
`schedule.
`e Moreover, the flexibility to price VEGF Trap at an annual cost similar to that for
`Lucentis and at a price per dose higher than Lucentis will be retained.
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`e
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`e
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`CONFIDENTIAL
`
`RGN-EYLEA-MYLAN-00526138
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