ANTECIP EXHIBIT 2005
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2019-00028
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`EUROPEANMEDICINES AGENCY
`SCLENCE MEDICINES HEALTH
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`& December 2012
`
`ak
`&
`EMA/COMP/S95031/2012
`Committee for Orphan Medicinal Products
`
`EMA/COMP summaryreport.
`On an application for orphan medicinal product designation
`
`Zoledronic acid
`Treatment of complex regional pain syndrome
`EMA/OD/125/12
`Sponsor: Axsome Therapeutics Limited
`
`
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`7 Westferry Circus s Canary Wharf « London £14 4H e United Kingdom
`Telephone +44.(0)20 7418 8400 Facsimile +44 (0)20 7523 7040
`E-mail info@ema.curcpa.cu Website wivw.ema.curopa.eu
`
`
`An agency of the European Union
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`pharmacological action by binding te the bone matrix, to osteablasts and te osteoclasts, They directly
`inhibit osteoclastactivity, formation and recruitment, and can cauSe osteoclast apeptosis. Nitrogren
`containing bisphosphonates, such as zoledronic acid, alse inhibit the mevalonate pathway In the
`osteoclast thereby interrupting normal osteoclast function £12],
`
` Plausibility of the erphan condition; rationale for use of the medicinal product
`
`.. The scientific rationale for the use of zoledronic acid in the treatment of CRES is as follows:
`
`a} A key feature of CRPS is patchy osteoporosis and bone marrow edema which are the result of
`osteoclast hyperactivity [1-4]. Zoledronicacid is a potent inhibitor ofbone resorption and
`osteoclast activity (12-13, 31-32],
`b} Pain is the primary symptorn of CRPS [1-4], Zoledronic acid has bean shown to relieve pain in
`other disease settings both clinically as well as in animat models FL4-19],
`c).Zoledronic acid has been used te successfully treat CRPS‘patients in a controlled study and
`
`| Case report (21, 22],
`
`CRPS is associated with localized bane resorption and bone marrow edema In the affected fimb which
`are the result of osteoclastic hyperactivity. Consequently, Investigators have theorized that
`bisphosphonates might be beneficial in the treatment of CRPS since these compoundsinhibit bone
`resorption and have analgesic efficacy [20]. As will be discussed below, inal clinical reports aré
`supportive of the potential efficacy of zoledronic acid In the treatment of CRPS (21, 23}.
`The analgesic eMcacy of zoledronic acid has been demonstrated in patients with bone pain associated
`with both malignant and non-malignant disorders [14-19]. Animal studies, as reviewed by Yanow et af,
`[19] have dernonstrated the antinociceptive effects of zoledronic acid and other bisphosphonates in
`non-bone-related pain. These clinical and prectinical observations support the potential analdesic
`activity of zoledronic acid in CRPS.
`
`The mechanism by which bisphosphonates provide pain relief in CRPS is unknown but may invalve
`inhibition of osteoclast activity as well as inhibition of prostaglandin E2, proteolytic enzymes, and lactic
`acid [7, 19]. Activated osteoclasts produce an acidic microenvironment in bone thereby activating acid-
`sensing nociceptors, and release nerve growth factor (NGE} which is also thought to contribute to
`hyperalgesia [19].
`oo
`Clinical Experience with Zoledronic Acid in the Treatment of CRPS
`
`,
`
`.
`
`Zoledronic acid has been successfully used to treat patients with CRPS as reported in a controlled
`study and case report (21, 22], These reports are summarized in Table 4
`
`Zaspel et al. tested zoledronic acid ina prospective active control study of 24 patients with CRPS [21].
`Patients in the treatrnent group received a 5 mg single infusion of zoledrenic acid while these in the
`contro! group received methylprednisoione. Patients were followed for-six months, and pain was
`measured using the VAS (visual analog pain scale}. The zoledronic acid group experienced a 70%
`reduction in pain, an effect that was maintained over the entire sh-month observation period.
`Furthermore this effect was statistically significant versus control (p-<0.001). The control group,in
`contrast, showed only transient pain relief through month 1 versus baseline. Ne reduction in pain was
`seen in the contro! at other time points.
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` Trial and Case Report Investigating the Use of Zoledronic Acid for Complex Regional Pain
`Syndrome
` Sahiaremnecneneama
`
`
`
`Dosage,
`
`
`
`Study administration|Outcomes follow-up duration
`
`
`Results
`,
`|
`: eed eatennnerneeanneerencea
`
`
`Zaspef at
`| amg IV single
`24patients (16
`| VAS, dystrophic
`
`
`70%pain reduction
`ms
`al,, 2007 symptoms, edema,ijzoledronic acid, 14infusion
`
`
`
`with zeledronic acid
`:
`methylpredniscions},
`i [24]
`suderneter activity
`"|
`lasting 6 months,
`statist. signif. versus
`6 months
`control. Tendency
`towards improvement
`
`of dystrophic
`
`
`SYMONS.
`aa a
`31-year old patient
`Total regression of pain
`de Castro
`Sing IV single
`with CRPS-T for 16
`and edema with no
`infusion
`et al.,
`
`:
`years refractory to
`recurrence for 6
`2014 [22]
`multiple treatments,|months.
`
` Tnnnnearernee:
`& months
`2
`
`
`
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`|
`
`fo
`
`WN, intravenous; VAS, Visual Analog Pain Scale
`
`reported the successful use of zoledronic acid in & 34-yearold patient whe had
`de Castro et al,
`suffered from CRPS for 16 years [22]. This patient presented with severe pain and had fail
`ed multiple
`therapeutic interventions including steroids, NSAIDs, amitriptyline, other antidepressants;
`carbarnezapine, other anti-convulsants, sympatheticnerve blocks with lidocaine and bupivacaine,
`opioids, neuromuscular blockers, dexmedetomidine, magnesiurn sulfate and chlorpromazine over a>
`two-year period. Given the lack of response fo these measures, the patient was treated with a S mg
`infusion of zoledronic acid, The result was total regression of pain and edema lasting six months.
`Correborating the potential for zoledranic acid in this disease setting are the positive results from,
`several randomized controlled studies using other bisphosphonates te treat CRES {23-35}. These
`reports are surmmarized in Table 5,
`
`a
`
`|
`
`
`
`Trials Investigating the Use of other Bisphosphonates for Complex Regiona
`i Pain Syndrome
`|
`Patients and
`Study
`
`Brug studied|Type of study , follow-up duration
`
`
`Results
`
`‘Manicourt
`
`Alendronate
`RCT, double-blind,
`39 patients (19 drug,
`
`
`20 placebo), 12
`40mg oral
`placebo-centrolled
`,
`daily for 8
`weeks
`Weeks
`
`et al,
`2004 [23]
`
`
`
`Pamidronate
`RCT, double-blind,
`60mg IV, one
`placebo-controfled
`time
`
`
`
`Statist. signif.
`improvement in
`Spontaneous pain,
`pressure tolerance, and
`
`
`_Joint mability.
`.
`Statist. signif,
`improvernerit In pain
`score, global
`assessment of disease
`
`
`Severity score, and
`
`
`
`i physical function,
`Clodronate
`
`RCT, double-blind,
`Statist. signif,
`i 17 placebo), 40 days
`300mg TV for
`al., 2000
`placebo-contrelied
`
`improvement in pain
` peeeitnannneeee
`10 days
`
`score and clinical global
`-
`2.
`
`
`
`
`Robinson
`
`et al,
`2004 [24]
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`EMA/COMP summary ragort
`EMA/COMP/SSSO312042 CURRENTFinal4.9
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`Patients and
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`follow-up duration|Results
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`Drug studied Type of study
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`most potent inhibitorof asteoclast-mediated bane resorption 124. For example, by some in vitro
`measures if is approximately 20 times as potent as alendronate (Fosamax) and over 60 times as
`potent as pamidronate (Aredia} (12). This increased potency has translated into more rapid, more
`complete and more sustained clinically therapeutic effects than other bisphosphonates [13], Therefore
`soledronic acid may potentially provide greater efficacy, faster onset of action, and less frequent
`dosing than other bisphasohonates in the treatment of CRBS.
`As a whole, we believe the signals of efficacy from these reports support the development ofthis
`potentially promising therapy fora debilitating, difficultte--treat condition with few safe and effective
`treatrnent options, and for which there is currently no medicinal product authorized in the £.U.
`
`Comment eg .
`Zoledronic acid (zoledronate)} belongs to the class of bisphosphonates; motecules used for the
`{ treatment of osteoporesis and other osteoclastic conditions based on thelr inhibition of osteoclastic
`bone resorption. The spansor is applying for orphan designation of zoledronic acid for oral use, and {as
`described in. section E1} is developing zoledronic acid as disodium satt. The sponsor states that
`i zoiedronate is currently available as an intravenous formulation only. The companyis in the process of
`completing the initial manufecture of the sadiurn salt.
`The sponsor proposes the product forthe treatment of CRPS base.on the potentialto treat some of the
`clinical features of CRPS, namely patchy osteoporosis and bene marrow oedema. In addition, the
`sponsor claims that zoledronic acid has been able to reduce pain associated to different diseases, and
`the reduction of pain could be extrapolated to the proposed condition.
`The sponsor provides only 2 citations directly related to the use of Intravenous zolédronic acid in CRPS,
`The first of these references (Zaspel et 31, 2007}, is.a meeting abstract that apparently has not been
`“subsequently published as a full paper: As reperted in this abstract, 24 patients with CRPS (type I,
`early stage) received treatment either with zaledronic acid (10 patients} or methylpredriscione (14
`: patients). The spansor reports that zoledronic acid seemed to Induce reduction of pain as compared to
`i
`methyiprednisolone. However the authors stated also that “over the entire period, compared to the
`bisphosphonate, cortisone showed 3 significant (p <0.001) impact on the improvement ofdystrophic—|
`symptomsssuch as oedema and sudomotor activity®. From this study it seems that the product would
`beactive an pain but not necessarily on oedema. In addition, being the the study reported as a short
`communication and not published in a peer-reviewed Journal, it lacks relevant information that would
`be necessary for an in-depth assessment of the results -
`The other reference is a single case report published in Revista Dor (Brasil), which fs a regional peer-
`reviewed pain journal. The description of the case is lacking details that would beuseful for the
`evaluation of the efficacy ofthe product, e.g. thereis no rnentoniag of any initiating noxious event,
`
`s
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`Lk
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`i i
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`which is atypical criterion for CRPS,
`
`Even though there are more relevant references to published studies on other bisphosphonates in
`CRPS, the sponsor provides no specific data or discussion as to whether such data can be extrapolated
`to thelr product.
`
`
`AICOMP summary report
`-MA/COMP/S9503 1/2022 CURRENT,Finai4.0
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` The COMP questioned the scientific rationale of using bisphosphonates, and in particular the proposed
`
`product, in CPRS, and on the available clinical data. It is also not clear fromthe description ofthe
`condition provided by the sponsor in section Al, how relevant and frequent bone reabsorption (the
`main target of treatment with bisphosphonate) is in CRPS, andthis might need better clarification in
`order te justify the use of the prapased product In this condition.
`
`The Committee also asked the sponsor te provide more specific information on the development of the
`product, which apparently is ata very @arly stage. Since zoledronic acid is knawn to be poorly
`‘absorbed via the oral‘route,
`the sponsor was also asked to discuss the expected low bioavailability
`using the oral formulation (see List of Questions).
`neemnmrnirrommncnnnnnnnrErereEReee
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`mimary report
`GRMCOMP/SS5031/2012 CURRENT,Final.4.0
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` COMP discussion and request for a list of issues
`
`On the basis of the assessrnent of the application as reflected in the different parts of this summary
`report, and according to the discussion held at the COMP meeting, the COMP requests the sponsor to
`_ answer the following lst of issues.
`:
`Written responses to the outstanding issues should be addrassed to the EMA Co-ordinator by 26
`November 2042. The sponsor will be invited to an oral explanation before the COMPat thelr meeting
`on 5-6 December 2012.
`
`
`
`S28 Medical plausibility
`
`
`To establish correctly ifthere exists a scientific rationale for the development ofzaledronic acid for the
`treatment of CRPS, the sponsorIs invited to further elaborate on:
`-the extent and relevance of bone reabsorption and other osteaclastic mechanisins in CRPS;
`~ the mathodology, the sclantific validity and relevance of the two cited references on zoledronic acid in
`CRPS, as the only study on 24 CRPS patients has been published as an abstract (Zaspal et al}, and
`neveras a full article;
`~ the characteristics of the patients that responded to treatment with zolendranic acid |in the abstract
`from Zaspel et al, and in particular on whether the responders had local or generalized osteoporosis;
`~ the extrapolation of data from conditions ether than CRPS in relation to the proposed action of the
`product in reducing pain;
`
`- the possihle extrapolation to zolendronic acid of data from other bisphosphonates tested In CRPS,
`in addition the sponser is invited to comment on the expected low bioavailability using the oral route
`of administration, and how this would influence the expected action of the product on pain and om bone
`
`reabsorption in CRPS.
`
`Prevalence —
`
`in order to correctly establish the prevalence of CRPS In the El the sponsor is invited to elaborate on:
`
`wore 4
`Pee
`
`ae
`
`
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`i(
`i.
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`
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`Development of Medicinal Product
`
` i
`If appears unclear to what extent zoledronic acid Is developed into a medicinal product for oral
`| administration. As yet the pharmacautical formulation is briefly described it prospected terras.
`t
`
`+0BYOvice8Gescriptionofthe medicinalproductasthisseaeeeedevelopedat
`
`
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`EMASCOMP
`summary report
`EMASCOMP/S95033/2012 CURRENT,Final,4.G
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`» Randomized, double-blind, placebo-controlled trials of bisphosphonates in CRPS
`
`
`
`Drug studied
`
`Manicourt
`
`Alendronate
`
`Patients and
`
`follow-up duration
`39patients (19 drug,
`20 placebo}, 12
`weeks
`
`Type of study
`RCT, double-blind,
`placebo-controlled
`
`RCT, double-blind,
`placebo-controlled
`
`RCT, double-blind,
`nlacebo-cantratied
`
`32 patients (15 drug,
`L? placebo), 40 days
`
`
`
`
`
`
`Statist. signif,
`improvement in sain
`score and Clinical global
`assessrnent.
`Statist. signif.
`improvement in ‘pain,
`tenderness, swelling,
`
`
`
`
`etal.,
`2004 [5]
`
`40mg oral
`dally for $
`weeks
`
`| Robinson
`atal,
`2004 [22]
`
`Parnidronate.
`S0mg TY, one
`time
`
`
`
`
`Statist.signif.
`improvement in
`spontaneous pain,
`pressure tolerance, and
`rraceteere:
`__
`joint mobility.
`27 (14 drag, 13
`Statist. signif,
`placebo}, 3 months
`improvement in pain
`score, global
`assessment of disease
`severity score, and
`anttneee
`| Varenna et Cladronate
`al., 2006
`300mg Ty for
`[Ss]
`Lddays
`ponnnnerte
`
`
`
`
`
`
`
`Adarni et
`al., 1997
`{23]
`
`Alendronate
`
`7.arig IV daily .
`for 3 days
`
`RCT, double-blind,
`placebo-controlled
`
`20 patients (10 drud,
`10 placeba}, 2 weeks
`
`RCT, randemized controlled trial: IV, intravenous
`
`-
`
`
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`EMA/COMP. summary report
`EMA/COMP/593031/2012 CURRENT,Final.4.0
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`Comments ta the ssponser’sresponse and surnmary of theoralexplanation:
`
`Thefirst question from the COMP addressed the proposed mechanism of action of zoledronte acid in
`CRPS, with particular regard to the extent and relevance of osteoporosis in this specific condition, as
`esteoporosis is one of the main targets of bisphosphonate treatment.
`The sponsor cited in the written response and the oral explanation some publications ta support the
`role of bone reabsorption and osteoclastic activity in CRES.
`From the sources cited by the sponsor, Rha 2002 Is a review article stating that osteoporosis can occur
`but no insights are provided in the publication aboutthe pathophysiologic and clintcal relevance of
`osteoporosis in CRPS, which would support its rationale as therapeutic target in CRPS,
`
`i.
`
`
`
`
`
`The second article, from Raja 2062, is another review on CRPS but it does not mention osteoporesis.
`The only brief mention to. osteopenia is on page 1256and reads: “Yhe subgroup ofpatients wha
`exhibited CRPS features, including motor or trophic changes and osteopenia, had the briefest disease
`duration", The article fromBickerstaff et al (1991, ref. 2 in the sponsar’s responses to the List of
`_ Questions} concludes that the radiographic appearances of algodystrophy“are not specific for the
`disorder butare qualitatively similar to those which follow fracture and immobilisation”, though the
`radiographic changes In patients with Colles’ fracture were more marked in those patients who
`developed algodysirophy. The authors concluded that there might be a common, pathogenesis to the
`two conditions, which is accelerated by algodystrophy. Even though this article provides insights ints
`loss of bone density in agodystrophy, it does not provide any information which has been considered
`by the Committe ag supporting the extent and relevance of osteoporosis in thecondition. In addition,
`osteoporosis is not listed in the IASP ner In the Budapest diagnostic criteria, which are the recognized
`} diagnostic criteria of the condition as stated by the sponsor in the original application {see section Al}.
`Other artictes cited by the sponsor in the written answer to this question do not seem to be relevant to
`the discussion. The article from Bickerstaff 1994 (ref. 28) daes not address osteoporosis as a feature oF}
`CRRS, and the one from Leitha 1995 (ref, 3) is net conclusive and does not provide information on the
`role of osteoparosis as target of treatment in CRPS. The study fromAtkins 1989 (ref, 33) addresses
`dolorimetry, and it is not understood how the results of this study coutd be extrapolated to therole of
`asteaporasis/asteoclast activity/bone reabsorption in CRS,
`The article fram Maincourt 2004.(ref. 5 in the sponsors’ responses to the List of Questions} provides
`theoretical discussion into the possible role of osteaclasts and bone reabsorption in CRPS in relation to
`the therapeutic action of alendronate, a product belonging te the class of bisphosphonates. The
`sponsor did not present or discuss any of the bibographic references relevant te such discussion cited
`by Manincourt et al. The evidence of ostecporasis reported at baseline in the study of Manincourt could
`have been further elaborated by the sponsor for supporting the plausibility of zoledronic acid treatment
`in CRPS. These baseline data indicate that osteoparasis is present but do nat per se support its
`relevanceas therapeutic target.
`,
`
`1
`
`In conclusion, even though the COMP acknowledged the presence of asteoporasis in CRPS, the written
`answers and the discussion provided by the sponser during the oral explanation were not considered
`by the COMP sufficient to satisfactorily justify the relevance of bone reabsorption and other osteoclastic
`mechanisms in CRPS te support the scientific rationale forthe development of zaledronic acid in CRPS.
`The second question from the Committee was focused on the two main references prrasented by the
`Sponsor as data supporting the plausibility of zoledronic acid in the CRPS, Le., the abstract from Zaspel|
`at al. and the case study from de Castro et al.
`
`;
`
`‘The COMP was of the opinion that an abstract which has never been published and that therefore has
`not been subject to review by other experts In the field does not constitute a valid source of evidence,
`
`
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`The sponsor arqued that some peer review is expected alse for the acceptance of an abstract at a
`conference. However the COMP was of the opinion that evenif this principle would be accepted, by
`being verybrief by nature the abstract is not tailored to provide sufficient information for supporting
`the validity of its methodology and results. The COMP considered that necessary information was
`missing in the abstract regarding the study population (e.g. diagnostic criteria, main features of CRPS,
`patient’s age, presence of regional and/ordiffuse asteoporosis,), the study methadology (e.g.
`treatment schedule, dosage, methodology usedfor evaluating pain), the endpoints besides pain, and
`the results (e.g. complete overview of the endpoints, figures of the effect -only p values are provided},
`among others.
`in absence of more extensive information on this study, which would have been
`provided in a full article or a study report, the COMP considered that such abstract cannot be
`considered as containing conclusive information.
`:
`A case report, such as the one presented by the sponsor from deCastro et al (Rev Dor Sao Pauto,
`| 2021) is usually considered by the COMP as supportive data rather than a main argument for
`establishing the medical plausibility of a proposed treatment. The COMP considered that information
`} Was missing in the report of this case which would have been relevantfor the evaluation of the efficacy
`
`| ofzoledronicacid inthe proposed condition, such as e.g. the method forthe establishmentofthe
`primary diagnosis, the description of the diagnostic criteria in the clinical history, and the quantification |
`of the different signs and symptoms pre and past-treatinent, among others. Further, the discussion in
`|
`
`i the oral explanation was focused on the possibility of extrapolating data from: other bisphasphonates fo
`} the use of zoledronic acid for thetreatment of CRPS. The sponsor had cited in the written responses
`four published clinical trials where bisphosphonates were used in CRPS (Manincourt 2004; Adami
`1997; Robinson 2004; Varenna 2000}.
`
`i
`
`i
`
`.
`
`a,
`
`73
`Len
`
`In two of these studies the product was alendronate, in one study it was pamidronate, and In one
`study clodronate. In all stugies, the bisphosphonates were administered intravenously, similarly to
`zoledronic acid in the case report of de Castro et al, while the sponsoris proposing the development of
`an oral formulation of zoledronic acid for orphan designation in the present application.
`The sponsor presented the conclusions of the studies but did not perform a critical review of such
`studies neither.in the written responses mot during the discussion, even thoughthis was requested by
`the Committee. A critical discussion of the trials would have been useful for the purpose of evaluating
`their relevance to the extrapolation of the results to zofendr.onic acid in the treatment of CRPS. This
`would have inchided ¢.g.:
`
`~ discussion on the patient population of these trials and how the results on this population could be
`extrapolated to the condition fer which the sponsorIs seeking designation. Arnona the four trials
`presented, two addressed only CRPS tyoe I, and two refer to reflex sympatheticdystrophy (which
`would Hkely nowadays encompass type I and type Il CRPS according te some authors, or only to CRPS
`type I accarding to other authors namely Varenna et al, the authors of one of the clinical trials
`presented by the sponsor).
`Systematic reviews on clinical trials in CRPS have indicated the need of
`USING uniform diagnostic criteria in order to allow evaluation of treatrnent efficacy of bisphosphonates
`and in general of treatments for CRPS (Tran et al, Can J Anesth 2010: 57:149-166; Brunner et al Eur 3
`Pain 2009;123.-(2) 17-21), and the discussion on the different diagnostic criteria in Uve different studies
`would havebeen appropriate, being the present a bibllegraphic-only application.
`
`~ discussion on the methodology and the study endpoints, in relation te the proposed mechanism of
`action of zoledronic acid and the relative relevance of pain and osteoporosis in the study population,-
`and the endpoints and outcome in these studies. For example, a discussion. on.the comparability of
`endpoints of reversal of trophic changes and of improvernentof functionality across the studies would
`have been useful to the evaluation of the possibility to geeneralize the results of these trials te the
`whole class of bisphosphonates. Of note, Tran et al noted in the systematic review that future bials
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`are neededfor better understanding oftreatment efficacy in CRPS, namely trialsincluding sample size i
`justification, and endpoints of functionality and reversal of trophic changes.
`~ dear reasoning on the extrapolation of data obtained using bisphasphonates intravenously te the aral
`use proposed by the sponser in the present application. OF nate, in the abstract from Zaspel et af. and
`the case report from de Cashro presented by the sponsor, zoledronic acid had-been always used
`intravenously,
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`in additionit isto be noted that the aforernentioned two different systematic reviews (Brunner et al,
`and Tran et al) reached different conclusions on the efficacy of bisphosphonates in the treatment of
`CRPS, and a discussion on these condusions, thelr meaning and thelr relevance would have been,
`useful ta the evaluation of the medical plausibility of zoledronic acid inthe treatment of CRPS. The —
`sponsor did not present any of these two systematic reviewsin the bibliography provided for this
`pplication, although systematic reviews are considered to be at one of the highest levels in the scate
`of scientific. evidence. Gne of the systernatic reviews considered the four clinical trials to be of
`moderate quality, and a discussion on this point would have alse bean appropriate from the side of the
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`sponser.
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`Conclusion
`The COMP considered that the data provided by the sponsor were not robust enough to satisfactorily
`astablish the intention to treat the condition. In particular the sponsor did not provide adequate
`justificationste support the pharrnacological action of zoledranic acid in the proposed condition (La.
`CRPS) and to clarify the roleof its pathophysiolagic target in the syndrome,
`The sponsor did not present own generated data in the propased condition CAPS, The bibliographic
`data presented in the proposed condition CRPS were considered by the COMP as not containing
`sufficient level of detail to be fully evaluable, due to the lack of essential information and relevant
`details for data evaluation.
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`The four bibliographic clinical trials presented by the sponser where other bisphosphonates were used
`were not considered by the COMP suffiicienfly discussed and elaborated by the sponsor to the aim of -
`Supporting the possible extrapolation of the data to the use of zoledronic acid In its intention to treat
`CRPS,
`For this reasons the COMP adopted a negative opinion on the orphan designation ofzoledranic acid for
`the treatment of CRPS,
`vevvrerertnneneenennnnnnets--wenewrrennnctaennentcaerneeweenineenceeeemennen=s
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`The sponsor has established that the condiition was affecting approximately nat more than 3in 16,006
`| persons in the European Union, at the time the application was made. The prevalence estimate was
`| based on relevant international literature.
`| The sponsor has established that the conditionis chronically debilitating in those caseswhich do not
`undergo spontaneous resolution. In thase cases, the chronically debilitating nature of the disease is
`| due to symptoms such ag pain, cedema, motor, sensorial, and vasomotor disturbances in the affected
`region. Continuous disabling pain has been described as the halimaric of the disease; it is
`:
`| the pain often spreads beyond theaffected limb. Autonomic symptoms and motordysfunction can
`'|disproportionateto the inciting event and lasts beyond the healing period. As the disease progresses,
`| develap, including dystonia, tremor, myoclonus and muscle weakness.
`The Committee has considered that the sponsor has not established that the product is intended for
`the treatmentof the proposed condition dsrequired for orphan designation under Article 3(1}fa) of
`‘Regulation (EC} Ne 1441/2000. The intention to treat the candition with the above-mentioned prod
`us
`ck
`has been considered by the Committee not to be suffiidientlyjustified by the sponser. The sponsor did
`not provide a satisfactory discussion of the pharmacological action of the product in the proposed.
`condition, In addition, the Committee was of the opinion that the sponsor.did not provide suffident
`data to suppert the potential clinical use of the product jin complex regional pain syndrome. The data
`presented by the sspensor, based on a single non-sponsor generated abstract (Zaspel et al, 2007,
`never published as a full article} were not considered sufficient to justify the intentionto treat the
`condition, Similarly, the biiblographic case report (De Castro et al, 20113 presented by the sponsor was
`considered to flack sufficient details for evaluation. Further, the sponsor did nat sufficiently justify the
`extrapolation of data from clinical trials of other bisphassphonates in complex regional pain syndrome,
`to the proposed product,
`There is at present rio Satisfactorytreatmentthat has been authorised in the European Union for
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`Grounds for the opinion on orphan medicinal product
`designation
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`The sponser Axsome Therapeutics Limited - UK, submitted on 38 August 2012 an application for
`designation as an orphan medicinal product te the European Medicines
`Agency fer zoledronic acid for
`treatment of complex regional pain syndrome.
`Whereas, the Committee for Orphan Medicinal Products {COMP}, having examined the application,
`conchided:
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`*
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`complex regional pain syndrome (hereinafter referred to as “the condition’) was estimated to be
`affecting net more than 3 in 18,000 persons in the European Union, at the time the application
`was made. The prevalence estimate was based on relevant international Hterature,
`the condition is chronically debilitating in those cases which do not undergo spontaneous
`resolution. In those cases, the chronically debilitating nature of the disease is due to syraptomes
`such as pain, oedema, motor, sensorial, and vasomotor disturbances in the affected region.
`Continuous disabling pain has been described as the hatimark of the disease; it is disproportionate
`tethe inciting event and lasts beyond the healing period. As-the disease progresses, the pain often
`Spreads beyond the affected flmb. Autonomié symptoms and motor dysfunction can develop,
`including dystonia, tremor, myoclonus and muscle weakness.
`* However, the intention to treat the condition with the above-mentioned product has been
`considered by the Commitkee not to be sufficiently justified by the sponsor. The sponsor did not
`provide a satisfactory discussion of the pharmacological action of the product in the proposed
`condition. In addition, the Cornmittee was ofthe opinion that the sponser did not provide sufficient
`data to support the potential clinical use ofthe product in cornplex regional pain syndrome. The
`data presented by the sponsor, based on a single non-sponsor generated abstract (Zaspel ef al,
`2007, never published as a full article) were not considered sufficient to justly the intention to
`treat the condition. Similarly, the bibliographic case report (De Castro et al, 2011) presented by
`the sponsor was considered to lack suffident detailsfor evaluation. Further, the sponsor did not
`sufficiently justify the extrapolation of data from clinical trials of other bisphosphonates jn complex
`regional pain syndrome, to the proposed praduect.
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`the Committee has therefore considered that the sponsor has not established that the product is
`intended for the treatment of the proposed condition as required for orphan designation under
`Article 3(1}(a) of Requlation (EC) No i41/2000;
`the sponsor has demonstrated, as required under Artide 3(1\(b}, Regulation (EC) Noe 1412/2000 of
`16 Decernber 1999, that there exists na satisfactory rnathod of treatment of the condiMen in
`question that has been authorised in the European Union. Therefore a demonstration of Significant
`benefit has not been required.
`7
`The Committee for Grphan Medicinal Products has recommended the refusal of the granting of the
`designation of zoledronic acid as an orphan medicinal product for treatment of cornplex regional pain’
`syndrome.
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`BAREEEL Pe A RE EEME
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`Comments to thessponser’s groundsfor appeal and.summary of the eral explanation: