February 03,2014
`
`BY COURIER
`
`Division of Dockets Management
`Food and Drug Administration
`5630 Fishers Lane
`Room 1061, HFA-305
`Rockville Maryland 20852
`
`RE: Use of Non-Enteric Coated Naproxen in Generic Versions of
`VIMOVO® (naproxen/esomeprazole magnesium)
`
`Ladies and Gentlemen:
`
`CITIZEN PETITION
`
`Horizon Pharma, Inc. ("Horizon") submits this Citizen Petition in accordance with the
`Food and Drug Administration's ("FDA's" or the "Agency's") regulations set forth in 21 CFR
`§ 10.30. Horizon requests that the Commissioner of the FDA take the actions described below
`with respect to any Abbreviated New Drug Application ("ANDA") submitted to FDA and listing
`VIMOVO® (naproxen/esomeprazole magnesium) ("VIMOVO") as the reference listed drug
`("RLD"). Horizon is the holder of the NDA for VIMOVO, having licensed the product on
`November 18, 2013 and accepted the NDA transfer on December 16, 2013.
`
`As discussed in greater detail below, VIMOVO is specifically formulated to reduce the
`potential for damage to the gastric mucosal tissue induced by non-steroidal anti-inflammatory
`drugs ("NSAIDs"). VIMOVO consists of an immediate-release esomeprazole magnesium
`(proton pump inhibitor [PPJ]) layer surrounding an enteric-coated naproxen (NSAID) core.
`Naproxen, like other NSAIDs, has been shown to increase the risk of stomach and intestinal
`problems, such as bleeding or an ulcer. I Esomeprazole, however, is a known ga troprotective
`agent that works by inhibiting the secretion of gastric acid thus decreasing the amoW1t of acid in
`the stomach. Because the naproxen component is completely surrounded by enteric coating,
`VIMOVO releases its esomeprazole before the release ofnaproxen. This allows the
`gastroprotective effects of esomeprazole to take hold before naproxen is released, thus reducing
`the potential for gastric ulcers. This significant reduction in gastric ulcers was demonstrated in
`the two VIMOVO six-month clinical endoscopy trials in 854 patients. 2
`
`Horizon has received a notice letter from a generic manufacturer that the manufacturer
`has submitted an ANDA, referencing VIMOVO as the reference listed drug ("RLD"), for a
`generic product that contains a measurable amoW1t ofnaproxen outside of the enteric coating. 3
`
`r Singh G, Mannalithara A, Sostek M, Mitha A, Triadafilopolous G. Naproxen Use Increases the Riskfor Complicated
`Gastroduodenal Ulcers in a Dose-Dependent Fashion, Am J Gastroenterology 2009; 104 (Suppl3) #136.
`2 See VIMOVO Prescribing Information, Section 14.
`3 In its Notice Letter dated November 20,2012, Dr. Reddy's Laboratories, Tnc. ("DRL") described the product which is the
`subject of its Abbreviated New Drug Application Number 204206 as follows:
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`The would-be generic manufacturer has done this not to increase efficacy or reduce safety
`concerns. To the contrary, failure to completely enclose the entire naproxen component in an
`enteric coating specifically obviates VIMOVO's careful design and allows release of a
`measurable amount of naproxen before the gastroprotective benefits of esomeprazole can take
`effect. This could cause that generic product to have more frequent or more severe
`gastrointestinal adverse events than does VIMOVO. Thus, we respectfully suggest that FDA
`take steps to ensure that any proposed generic version ofVIMOVO that does not have all of the
`naproxen enterically coated will have a different GI adverse event profile than VIMOVO.
`
`I.
`
`ACTIONS REQUESTED
`
`Horizon requests that FDA take the following actions:
`
`1. Require that any application listing VIMOVO as the RLD, which seeks approval
`for a generic product that employs less than a complete enteric coating around the
`naproxen component, be supported by either (a) pharmacokinetic data sufficient to
`show that the timing of release ofnaproxen in the generic product is equivalent to
`that ofVIMOVO, or (b) data from clinical trials demonstrating that the proposed
`generic product does not cause more frequent or more severe gastrointestinal
`adverse events than does VIMOVO;
`
`2. If additional clinical trials described above are necessary to support safety of the
`proposed generic product, require that any such application be filed as a 505(b)(2)
`application, rather than as an ANDA; and
`
`3. Refuse to approve any currently pending ANDA for such a product, and require the
`applicant to withdraw its ANDA and resubmit as a 505(b)(2) application,
`accompanied by the additional clinical testing described above.
`
`II.
`
`STATEMENT OF GROUNDS
`
`A.
`
`Factual Background
`
`1.
`
`NSAJDs and Gastrointestinal Adverse Events
`
`NSAID therapy is one of the most common and effective treatments available for
`musculoskeletal diseases such as osteoarthritis.4 Unfortunately, chronic use ofNSAIDs can give
`rise to several serious safety concerns which are clearly outlined in class-labeling assigned to all
`NSAIDs. Among the more prevalent of these is that chronic use ofNSAIDs is associated with
`an increased risk for significant gastrointestinal adverse events. These can range from
`
`"A measurable portion of the entire amount of the naproxen (NSAID) in DRL's proposed product is not
`surrounded by a coating that prevents release at a pH of less than 3.5 but instead is coated in a polymer that
`completely dissolves at a much lower pH, and is released at that pH."
`4 Goldstein J.L., et al. Clinical Trial: the incidence ofNSA1D-associated endoscopic gastric ulcers in patients treated with PN
`400 (naproxen plus esomeprazole magnesium) vs. enteric-coaled naproxen alone, Aliment Pharmacal Ther 2010; 32:401-413.
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`endoscopic gastric ulcers (15-46% ofNSAID users),s to clinically relevant symptomatic ulcers
`and serious ulcer complications. 6
`
`The etiology ofNSAID induced damage to the gastric mucosa is likely multifactorial as
`depicted in Figure 1 below. 7 Although a number of possible mechanisms have been suggested,
`the predominant effect on gastric mucosa induced by SAID systemic exposure is inhibition of
`the enzymes cyclooxygenase 1 and 2. The fonner is predominantly responsible for generating a
`protective barrier to the mucosal surface of the stomach to alleviate tissue exposure to the acidic
`noxious environment of the gastric lumen to allow for normal digestion offood. Once the
`mucosal barrier is compromised by inhibition ofthese enzymes, then local effects become very
`In addition, COX-2 inhibition can lead to
`important; in particular the exposure to gastric acid.
`greater adherence of neutrophils to endothelium and slowed healing of mucosal insults.
`
`Figure 1.
`
`COX-!
`inhibition
`
`+
`
`Decreased
`blood Flow
`
`Tqj:aJ
`llntation
`
`+
`
`Epithelial
`damage
`
`COX-2
`inhibition
`
`+
`
`Neutrophil
`adherence
`
`In addition to the inhibition of cyclooxygenase enzymes, some believe that damage to the
`gastric mucosa is enhanced by the local presence ofNSAIDs, almost all of which are formulated
`as weak organic acids. NSAIDs may locally damage the gastric mucosa by close approximation
`to the mucosal cells leading to superficial cell death leaving holes, which can be widened and
`deepened with ongoing exposure to the acidic environment. The enteric coating of the NSAID in
`VIMOVO prevents that exposure. By contrast, drugs that are not completely enteric coated
`might lead to this effect of increased damage by exposure of the drug in the stomach lumen.
`
`j Geis GS, Stead H, Wallemark CoB, Nicholson PA. Prevalence ofMucosa I Lesions in the Stomach and Duodenum Due to
`Chronic Use ofNSAID in Patients with Rheumatoid Arthritis or Osteoarthritis. and Interim Report on Prevention by Misoprostol
`ofDiclofenac Associated Lesions, J Rheurnatol 1991; (Suppl 28) 18: 11-14.
`6 Goldstein J.L., et a!. Clinical Trial: the incidence ofNSAID-associaled endoscopic gastric ulcers in patients treated with PN
`400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone, Aliment Pharmacol Ther 2010; 32:401-413.
`7 Wallace J, Pathogenesis ofNSAID-induced gastroduodenal mucosal injury, Best Pract. & Res. Clin Gastroenterology 2001;
`15(5):691-703.
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`Regardless of the cause(s) for increased risk ofGI complications, evidence increasingly
`makes clear that raising the pH of the gastric environment has a gastroprotective effect.
`According to Wallace, for example,
`
`While the presence of acid in the lumen of the stomach may not be a primary
`factor in the pathogenesis ofNSAID-induced gastroenteropathy it can make an
`important contribution to the chronicity of these lesions and to bleeding by
`impairing the restitution process, interfering with haemostasis and inactivating
`several growth factors that are important in mucosal defense and repair. 8
`
`Indeed, inhibition of acid secretion, which raises gastric pH, has been directly shown to
`reduce the degree of gastric injury in patients on chronic NSAID therapy. This fact is
`demonstrated, for example, by a study conducted by Shiotani, et aI., investigating whether the
`severity of acute and chronic mucosal inflammation, H pylori density, mucosal IL-8 levels, or
`gastric mucosal and juice nitrite levels had predictive value in relation to the severity of NSAID(cid:173)
`induced gastric mucosal damage. 9 After receiving placebo for three days, volunteers underwent
`upper gastrointestinal endoscopy for histology and determination of IL-8 and nitrite levels.
`Following a three week washout period, each patient then received naproxen (500 mg BID) and
`endoscopy was repeated on day four. Fasting gastric juice pH and nitrite levels were assessed at
`each endoscopy.
`
`As shown in Figure 2, the results of this study clearly demonstrate that gastrointestinal
`complications from NSAID therapy are inversely related to gastric pH:
`
`Figure 2.
`
`ji1_--,:,...--_....,.__--.:_R_=""T-.;....O_._7_7-,.',_P_=_O--,.004)
`
`None Mild Mod Severe Very Severe
`Degree of Gastric Injury
`
`Efforts to reduce gastrointestinal adverse events in chronic NSAID therapy have met with
`mixed results. In light of the well-known risks for gastrointestinal problems, many physicians
`prescribe a gastroprotective agent to patients needing chronic NSAID therapy, and who have an
`increased risk for gastrointestinal complications. Unfortunately, adherence is frequently an
`
`8 Wallace J, Pathogenesis o/NSAID-induced gastroduodenal mucosal injury, Best Praet. & Res. Clin Gastroenterology 200 I;
`15(5):691-703.
`9 Shiotani A, Yamaoka Y, l-Iala M, EI-Zimaity T, Ali Saeed M, Qureshi W, Graham D, NSAID Gastric Ulceration Predictive
`Value 0/Gastric pH, Mucosal Density 0/Polymorphonuclear Leukocytes, or Levels of/L-8 or Nitrite, Digestive Diseases and
`Sciences, 2002, 47(1); 38-43.
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`issue. Recent studies have shown that even when prescribed alongside an NSAID, patients
`adhere to prescribed gastroprotective therapy only half the time. 10
`
`2.
`
`VIMOVO
`
`VIMOVO combines a well-established NSAID (naproxen) with a proven PPI
`gastroprotective agent (esomeprazole magnesium). The addition of the esomeprazole component
`to naproxen is intended to provide gastroprotection. Thus, VIMOVO is indicated to relieve the
`signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and to
`decrease the risk of gastric ulcers in patients at risk of developing such ulcers from treatment
`with NSAIDs. Indeed, in two clinical studies conducted to support approval, VIMOVO showed
`a clear reduction in the incidence of gastric ulcer formation as compared to enteric-coated
`naproxen alone. 11
`
`VIMOVO is specifically formulated to allow esomeprazole (a proton pump inhibitor) to
`achieve its gastroprotective impact before naproxen is released into the system. VIMOVO is a
`single-tablet formulation comprising an enteric coated naproxen core surrounded by an
`immediate release esomeprazole mantle. Proton pump inhibitors, such as esomeprazole, work by
`decreasing the generation of hydrochloric acid in the gastric lumen, which increases the gastric
`pH, thereby protecting the gastric mucosa. VIMOVO's design is intended to produce a
`sequential delivery of gastroprotective esomeprazole before systemic (or local) exposure to
`naproxen.
`
`3.
`
`Generic Versions with Only a Portion ofNaproxen Enteric Coated
`
`Several generic manufacturers recently have filed ANDAs listing VIMOVO as the RLD.
`Horizon understands based on a notice letter received that at least one of those ANDA
`applications is for a product that includes a portion of the naproxen component that is not
`surrounded by an enteric coating. As discussed below, such a product would allow for earlier
`release of potentially significant amounts of naproxen.
`
`B.
`
`Discussion
`
`1.
`
`VIMOVO's Sequential Delivery Mechanism is Essential to Reduction of
`Gastrointestinal Adverse Events
`
`VIMOVO addresses the issue of gastrointestinal adverse events in two ways. First, by
`adding the proton-pump inhibitor esomeprazole, VIMOVO acts to reduce overall gastric acid,
`thereby raising gastric pH. Esomeprazole's impact on gastric pH is clearly demonstrated by a
`study conducted by Miner, et al., which to guide formulation selection for Phase 3 clinical testing
`compared gastric acid suppression at days I and 9 in the following four formulations:
`
`1. EC naproxen 500 mg BID + esomeprazole 30 mg;
`
`10 Van der Linden MW, Gastroprotection among new chronic users ofnon-steroidal anti-inflammatory drugs: a study of
`utilization and adherence in The Netherlands, Current Moo Res Opin. 2009 Jan;25(1 ):195-204.
`)1 See VTMOVO Prescribing Information, Section 14.
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`2. EC naproxen 500 mg BID + esomeprazole 20 mg (VIMOVO);
`
`3. EC naproxen 500 mg BID + esomcprazole 10 mg; and
`
`4. Non-EC naproxen 500 mg BID + EC esomeprazole 20 mg l2
`
`The study measured the percentage of time over 24 hours that intragastric pH was greater
`than 4.0, on days one and nine respectively. The results of the study, set forth in Table 1, show
`that increasing doses of esomeprazole clearly led to raised gastric pH over time. At day 1, for
`example, the mean percentage oftime with intragastric pH of 4.0 or greater was 27.8%, 20.5%,
`] 2.8%, and 21.3% for each of the four listed fonnulations, respectively. By contrast, on day
`nine, these percentages had increased to 76.5%, 71.4%,40.9%, and 59.9%, respectively (see
`Table 1). The various study treatments were well tolerated. No endoscopic assessment was
`perfonned, however, which is a primary efficacy endpoint for evaluating products intended to
`prevent NSAID-associated upper GI toxicity. Further, this was a small study of short duration. 13
`Ultimately, the EC naproxen 500 mg BID + esomeprazole 20 mg fonnulation was chosen for
`VIMOVO to be tested in Phase 3 gastroprotection endoscopy studies of six-months treatment
`duration.
`
`ifahle 1. Percentage of time with gastric pH >4.0 over 24 h on days 9 and 1 (PP population)
`Day 9
`Day 1
`
`Time pH >4.0 (%)
`
`PN400fE30, PN400/E20, PN400fE10, Naproxen+EC
`n = 25
`E20. n = 25
`n - 25
`n ~ 25
`
`PN400fE30, PN400fE20. PN400fEIO, Naproxen+EC
`E20, n = 25
`n =25
`n = 25
`n ~ 25
`
`Mean (s.d.)
`
`Median
`
`% coefficient of
`variation
`
`76.5 (12.3) 71.4 (13.0)
`
`40.9 (22.5)
`
`56.9 (10.1)
`
`27.8 (22.6)
`
`20.5 (16.6)
`
`12.8 (11.1)
`
`21.3 (13.6)
`
`78.8
`
`16
`
`70.4
`
`18
`
`35.8
`
`55
`
`55.1
`
`18
`
`20.0
`
`81
`
`15.3
`
`81
`
`91
`
`87
`
`16.8
`
`64
`
`Range
`
`49.8 95.3
`
`51.8-97.6
`
`10.3-85.3
`
`40.6-75.5
`
`1.8-89.6
`
`4.4-74.4
`
`3.0-53.8
`
`3.2-58.2
`
`LS mean (S. E.)
`
`76.8 (3.0)
`
`71.5 (3.0)
`
`41.1 (3.0)
`
`57.2 (3.0)
`
`27.9 (3.3)
`
`20.6 (3.3)
`
`12.7 (3.4)
`
`21.5 (3.3)
`
`LS mean di fference
`vs. naproxen + EC E20
`(S.E.)
`
`19.5 (3.3)
`
`14.2 (3.3)
`
`-16.1 (3.3)
`
`6.4 (3.2)
`
`·0.92 (3.2)
`
`-8.9 (3.2)
`
`9S%CI
`
`13.0--26.0
`
`7.8-20.7
`
`-(22.3-9.7)
`
`-
`-
`PP, per prolocol; EC, enteric coated; s.d., standard deviation; LS, least-squares; S.E., standard error; CI, confidence interval.
`
`0.0-12.8
`
`-(7.3-5.4)
`
`-(15.3-2.4)
`
`Second, as noted above, VIMOVO is specially formulated to release its esomeprazole
`component prior to release ofnaproxen. VIMOVO is designed for immediate release of the
`esomeprazole component, which is located just underneath the drug's outer shell. By contrast,
`VIMOVO's naproxen component is located in the tablet core, and is completely surrounded by
`
`12 Miner P, Jr., et aI., Clinical trial: evaluation ojgastric acid suppression with three doses ojimmediate-release esomeprazole
`in the ftxed-dose combination ofPN 400 (llaproxeniesomeprazole magnesium) compared with naproxen 500 lIlg and enteric(cid:173)
`coated esomeprazole 2fJ mg: a randomized, open-label. Phase f study in healthy volunteers, AI iment Phannacol Ther 2010;
`32:414-424.
`13 Summary Minutes of Gastrointestinal Drugs Advisory Committee (GIDAC), November 4, 20 IO.
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`an enteric coating. This enteric coating is designed to release naproxen only in a pH ~5.5
`environment. 14 Because the normal pH environment of the stomach typically ranges between 1.5
`to 3.5, this enteric coating ensures that naproxen is not released until the enteric-coated core
`passes through the stomach and reaches the small intestine. Thus, by the time VIMOVO begins
`to release its naproxcn, VIMOVO's esomeprazole has already begun to impact gastric pH. This
`provides a less favorable environment for the development of gastric ulcers. 15 Two Phase 3
`studies subsequently demonstrated the effect of VIMova to decrease the risk of developing
`gastric ulcers in patients at risk of developing NSAID associated gastric ulcers. 16
`
`2.
`
`Non_Enteric Coated Naproxen Would Reduce the Benefit ofSequential
`Release
`
`Horizon understands that at least one ANDA applicant for generic VIMOVO has
`formulated its proposed product with a portion of the naproxen not enteric coated. Although it
`is not known precisely what percentage of the proposed generic product's naproxen is outside the
`enteric-coated core, locating any naproxen outside the enteric-coated core will result in the
`immediate release of at least some portion of the naproxen at the same time as esomeprazole is
`released. 17
`
`Any portion of the generic product's naproxen that is released prematurely in the stomach
`will act both topically and systemically without the benefit of the raised gastric pH produced by
`the esomeprazole component. As noted in Figure 2, the gastric injury that can be caused by
`naproxen is inversely related to gastric pH. In other words, unlike VIMOVO, which releases its
`naproxen component only after its esomeprazole component has begun to raise gastric pH, a
`generic product without all of the naproxen enterically coated would release at least some portion
`of its naproxen in a less gastroprotective environment, before gastric pH has begun to rise.
`
`3.
`
`}<LJA Should Take Steps to Ensure That a Generic Product Does not
`Jeopardize Patient Safety
`
`As FDA knows, the potential for GI adverse events with chronic NSAID therapy in
`patients at risk for gastrointestinal complications is significant. Like all NSAIDs, VIMOVO's
`package insert includes a "black" box warning relating to the potential for "serious
`gastrointestinal adverse events including bleeding, ulceration, and perforation ofthe stomach or
`intestines, which can be fatal.,,18 Thus, a reduction in the enteric coating surrounding the
`naproxen core could subject patients to significantly increased risk ofpotentially fatal side(cid:173)
`effects. As a result, FDA should take steps to ensure that patients taking the proposed generic
`product are not exposed to such an increased risk unnecessarily. This is particularly so where, as
`
`14 See VIMOVO Prescribing Information, Section 12.1.
`15 Roberts DN, Miner PB. SaJety aspects and rational use oJnaproxen + esomeprazole combination in the treatment oj
`rheumatoid disease. Drug, Healthcare and Patient Safety 20 I 1:3 1-8.
`16 See VIMOVO Prescribing Information, Section 14.
`17 Miner P, Plachetka J, Orlemans E, et al. Clinical trial: evaluation ojgastric acid suppression with three doses ojimmediate(cid:173)
`release esomeprazole in the fixed-dose combination ojPN 400 (naproxen/esomeprazole magnesium) compared with naproxen
`500 mg and enteric-coated esomeprazole 20 mg: a randomized. open-label. phase 1 study in healthy volunteers. Aliment
`Pharmacol Ther 20 I0;32 :414-424.
`18 See VIMOVO Prescribing Information (Highlights).
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`here, the increased safety risk is not justified by a commensurate increase in overall
`effectiveness.
`
`At a minimum, we suggest FDA require that any ANDA applicant for a product that lists
`VIMOVO as the RLD, and includes a portion ofnaproxen outside of the enteric coated core,
`includes with its ANDA pharmacokinetic data adequate to show that the timing of release of
`naproxen from the generic product is equivalent to the timing of release of naproxen in
`VIMOVO. 19 Such a demonstration cannot be made with reference to FDA's traditional
`requirements for bioequivalence testing, which measure only maximum concentration (Cmax) and
`area under the concentration-time curve (AUC), but do not address the timing ofnaproxen
`release relative to esomeprazole. For example, a product that contained a portion ofnaproxen
`outside of the enteric-coated core would release naproxen before the esomeprazolc component is
`able to begin raising gastric pH, even though the overall values ofnaproxen are within the
`specified 80-125 confidence interval range for Cmax and AVC.
`
`In the absence of clear pharmacokinetic evidence described above, FDA should require
`that the generic applicant provide data from clinical trials demonstrating that the proposed
`product does not result in more frequent, or more severe, gastrointestinal adverse events than
`does VIMOVO. Of course, where clinical trials are necessary to support approval, an ANDA is
`not the appropriate pathway for approval. As a result, any such product should be required to
`submit its application as a 505(b)(2) application rather than an ANDA. In the case of
`applications already on file with FDA, FDA should require the applicant to withdraw its ANDA
`and resubmit as a 505(b)(2).20
`
`III.
`
`ENVIRONMENTAL IMPACT
`
`Horizon claims a categorical exclusion under 21 C.F.R. § 25.31.
`
`IV.
`
`ECONOMIC IMPACT STATEMENT
`
`Horizon will, upon request by the Commissioner, submit economic impact information,
`in accordance with 21 C.F.R. § 10.30(b).
`
`V.
`
`CERTIFICATIONS
`
`The undersigned certifies that, to the best knowledge and belief of the undersigned, this
`Petition includes all information and views on which the Petition relies, and that it includes
`representative data and information known to Horizon which are unfavorable to the Petition.
`
`19 See VIMOVO Prescribing Infonnation, Section 12.3.
`20 See, e.g., 57 Fed. Reg. 17950, 17953 (April 28, 1992) ("Section 505U) of the act permits ANDAs only for duplicate and related
`versions of previously approved drug products. The ANDA applicant relies on a prior agency finding of safety and effectiveness
`based on the evidence presented in a previously approved new drug appl ication. Ifinvestigations on a drug's safety or
`effectiveness are necessaryfor approval, an ANDA is 1I0t permit/ed. "). (emphasis added). See also 54 Fed. Reg. 28872, 28879
`(1989) ("Such a product would require investigations to show its safety and effectiveness; thus an ANDA would not be
`appropriate.").
`
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`Horizon makes the following certification pursuant to FDC Act § 505(q)(l)(H): I certify
`that, to my best knowledge and belief: (a) this petition includes all information and views upon
`which the petition relies; (b) this petition includes representative data and/or information known
`to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to
`ensure that any representative data and/or information which are unfavorable to the petition were
`I further certify that the information upon which I have based the action
`disclosed to me.
`requested herein first became known to the party on whose behalfthis petition is submitted on or
`about the following date: September 20, 2013 (during product licensing due diligence). If!
`received or expect to receive payments, including cash and other forms of consideration, to file
`this information or its contents, I received or expect to receive those payments from the
`I verify under penalty of perjury that the foregoing
`following persons or organizations: Horizon.
`is true and correct as of the date of the submission ofthis petition.
`
`Respectfully submitted,
`
`Timothy P. Walbert
`Chairman, President and Chief Executive Officer
`
`224.383.3009 - 0
`847.572.1372 - f
`twalbert@horizonphanna.com
`
`DC:4943938
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`520 Lake Cook Road, Suite 520, Deerfield, IL 60015
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`Page 9
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`Dr. Reddy's Exh. 1024
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