Lind, Tore
`Leff, Richard L
`Levine, Doug; Magner, David; Sostek, Mark
`513112006 8:11:39 AM
`RE: Platinum (confidential)
`
`From:
`To:
`GG:
`Sent:
`Subject:
`
`HiRich,
`
`I've seen the comments in several mails this week and find them adequate although sometimes speculative which also is
`adequate as long as we dont hare adequate data.
`I've touched base with Kerstin Röhss, our clinical pharmacology epert. I did a couple of studies in the mid 80th on omeprazole
`and "cytoprotection" with no such signs and we have at least three additional ir¡house studies of interest incl. uncoated
`omeprazole. We are chasing these reports.
`According to timelines addressed in your previous mail, a phase 3 program with Nexium-Meloxicam (l've not seen any timelines
`for a Naproxen-combo except for inthe US program, studystart mid 20011) could start at the earliest late 2010, probablythe
`year after. /tore
`
`--:-Or¡g¡nal Message--
`From: Leff, Richard L
`Sent: 31 maj 2006 03:01
`To: Lind, Tore
`Cc: Levine, Doug; Magner, David; Sostek, Mark
`Subject: FW: Platinum (confi dential)
`Sensitivity: Confidential
`
`Tore,
`
`Mark Sostek and David Magner went to do some information gathering on Friday last week, and yesterday (Monday) wa9 a
`holiday in the US. Their DRAFT notes are below.
`
`Basically, there was variable PK and PD withotf buffering or enteric coating the PPI for lanzoprazole 15 ng + EC-naproxen
`500 mg BID given for up to 14 days lo normalvolufteers (l think administered fasting).
`
`The Medical Science view coming from that visit is thus that withotf some protection of the PPl, a combination with Naproxen
`(or any NSAID) would be inferior to buffered or enteric coasted PPl. Withotf such formulation, the combination would
`probably be superior to naproxen alone, but on a background of LDA compared to celecoxib it is not as certain. Arthritis and
`other pain patients usually take their NSAID with food. Also, in the realworld patients don't take their NSAID every day (even
`if told to do so by their physician, which technically is not the FDA's recommendation); thus, for those takirg the combination
`once a day or sometimes skipping a few days, we're thinking that an optimal formulation of the PPI is best. Which, from
`what I understand, is consistent with the Neium rationale and messaging.
`
`lf you have any questions, please let Mark and/or I know
`
`I 1
`
`6
`
`IIa
`
`Take care.
`
`Rich
`
`----Original Message----
`From: Magner, David
`Sent: Saturday I May 27 t 2006 1:42 PM
`Tor Sostek, Mark; Helm, Jim
`Cc: Levine, Doug; Watson, Chr¡s; Goode, Denise E; Anson, Lisa LMi Gibbs, Mike; Leff, Richard L; Jones, Derek
`Subject: RE:
`Sens¡t¡vity: Conf¡dential
`
`Mark,
`
`Thanks for the summary of our meeting with Pozen. I'd just like to add a couple of other comments, specific to dose ard the
`comparators in their studies.
`
`Their pilot study (for each PPI) compared the PN product to naproin and the PPI (l'll call it N+P) given separately. The PN
`product had the adr,antage, by design, of delivering the PPI twice, whereas the N+P only had the PPI given in the am. Given
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`Mark's comments relative to availability of the PPI from the PN product, this looks a lot like a comparison of a "half dose" of
`the PPI in the PN formualtion, given bid, as compared to the "full dose" of the PPI in the N+P dose. They claim that
`differences between PN and N+P are due to the localeffect of the PPI (as Mark stated, there is no clear evidence of that
`currently). lt may also be possible that it is due to a bid dosing regimen of the PPl, and that being unprotected is not
`necessary at all. lf they are right, and there is a localeffect, it is good fortheir product. lf there is no localeffect though, it
`may be possible to get a similar effect with bid dosing for naproin and a PPl.
`
`We spoke a little about a potential eso POC study, if we are to more fonvard with eso. They would propose a study similar
`to the ome and lanso POC studies. We should consider if using a bid eso dose in the N+P arm would be justified - it could
`either prove/dispror,e the need for the unprotected eso.
`
`I believe that there is also a risk regarding the dose. The piolt studies were run in healthy volunteers and for 14 days.
`Ext rapolating that to 6 months in patients is not without risk. Pozen's position is that they may not have the best dose, but
`they are confident of positive resufts since the FDA has allowed them to move forurard with a single dose. lf we mo\€
`forward with this project, I think we should consider the risks and rewards of adding a second (higher) dose to the Phase 3
`studies. ll may be that a higher dose is needed either for 1)patients, as opposed to l-lVs, or 2) to keep patients ulcer free for
`6 months, as opposed to 14 days.
`
`Dave
`
`---Original Message---
`From: Sostek, Mark
`Sent: Saturday, May 27,2006 10:10 AM
`To: Helm, Jim
`Cc: Magner, Dav¡d; Lev¡ne, Doug; Watson, Chris; Goode, Denise E; Anson, Lisa LM; Gibbs, Mike; Leff, Richard L; lones, Derek
`Subject:
`Importance: High
`Sensitivity: Confi dential
`
`Dear Jim:
`
`Dave ard I spent a very interesting day at Pozen yesterday. We look forward to discussing further with you on Tuesday
`I thought that I would send you a few "top line" bullets that we came away with regarding the Pozen formulation and
`planned development program.
`
`The CEO, Marty Reese and some of their other top executives were gracious enough to answer all of our questiors and
`allowed us to look at anything we requested.
`
`Here are some points we learned
`
`The "unprotected" immediate PPI release formulation results in approximately 50-ô0% of lhe PPI being degraded in
`the stomach on DAY 1, before it is absorbed. \Â/rth each successive day as the gastric pH is increased
`somewhal less gets degraded on each successive day. By steady state approximately 30o/o is being degraded.
`So the pharmacodynamic efficacy gradually increases on each successive day until steady state is reached
`
`The steady state pharmacodynamics of the PPI in the Pozen formulation is therefore equivalent to less than the
`initialdose (e.9. lansoprazole 15 mg gets degraded to the point where its acid control is perhaps equivalent to
`only 10 ng). The bid dosing o\ercornes this somewhat...bnt omeprazole 20 mg bid in this formulation is probably
`more consistent with omeprazole 10 or 15 bid.
`
`The current Pozen formulation with omeprazole will be unproven for treating GERD symptoms (due to degradation
`of parent compound), therefore this formulation may be suboptimal for patients who need to be treated for
`GERD
`
`POZEN is postulating that a "local" non acid inhibitory effect is paflially responsible for the ulcer protection that they
`har,e seen. Specifically they cite the possibilÍty that the PPI could acl as a local free radical scavenger on lhe
`gastric mucosa. However there is no good, recent or solid data to support this and therefore at this point this
`can only be categorized as pure speculation.
`
`The postulated "beneficial impact" of the PPI being released first before the naprosyn will only matter if there is a
`"local PPI effect". Since this is unproren, I doubt this could be promoted. Although data displays of the
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`pharmacokinetics withorf attached claims could be possible.
`
`They have nol done any studies in actual patients, reflecting the true target population and hare not done any pilot
`studies longer than 14 days duration. Therefore the results of the pivctal studies of 6 months duration and in a
`different population are not necessarily a slam dunk...although I believe it is better than 50:50 that they would be
`successful.
`
`I think that it is clear, that the current formulation is l'.lOT optimal from an acid suppression standpoint (because of
`PPI is degradation in the stomach), brf they characterize it as a good first attempt, with fulher refinements and
`modifications possible later
`
`The Gl black box will still be present for this product, as well as the CV black box.
`
`It could be difficult to erplain to physicians why PPI 'protection' is not necessary for this product unlike all other
`PPls.
`
`Kind Regards,
`
`Mark
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