Regulatory Indication Module

Published: 2019-10-17 08:00:00
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Basis for Approval of Precedent ProgramsThis section describes the clinical program on which the approval and labeling language for the treatment of Parkinsons disease was based. This section only addresses pivotal trials; there is no specific discussion of the safety data base.

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The table below presents the Indication language at time of initial approval for the treatment of Parkinsons disease in the US and EU, as well as the pivotal and supporting study identifiers on which the approval and labeling language was based.

Table 2.1 Basis for Safety and Efficacy in Precedent (Original) Approvals for PD

Product Region Application #/Type of Approval* Labeling Statement (Original) Supported Studies Forming Basis for Approval(Phase/Protocol #/Other Study ID)

Pivotal Supporting

Mirapex US NDA 020667

Mirapex tablets are meant for the treatment of the signs and symptoms of idiopathic Parkinson's disease and the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) Phase 3 1045 Solo

Phase 3 1046 Sync

Phase 3 1064 Standard

Phase 2 1025

Phase 2 1035

EU Same as US approval Zelapar

US NDA 021479

Zelapar is designated as an addition in the management of In patients with Parkinsons disease. Phase 3 WA17822

Phase 3 WA17823

Phase 3 WA17824

Phase 2 LRO301

Phase 2 MRA009JP

Phase 3 18695

Phase 3 18696

EU Same as US approval with the addition of Ph3 WA19924 (Monotherapy study).

Comtan

US NDA 020796 This drug should always be managed together with levodopa/carbidopa. Entacapone has no antiparkinsonian effect of its own. Phase 3 C0524T11

Phase 3 C0524T06

Phase 3 C0524T05 Phase 2 C0524T02

EU Same as US approval

Precedent Pivotal Trial DesignsThe table below provides details of phase 3 pivotal trials utilized to gain initial approval for the treatment of Parkisons disease in adult patients. All products conducted at least two adequate and well-controlled trials. The majority used CERE 120 at approximately the six month time point as the primary or co-primary efficacy endpoint. CERE 120 continues to be the accepted measure to demonstrate a reduction in disease activity (clinical response). Mirapex utilized CERE 120 and CERE 110 as co-primary endpoints in their studies, the latter two steps being more stringent markers of disease activity.

As CERE 120 is a composite endpoint, a component of it is the quality of life and patient daily diary PDQ-39. A physical response claim in the Indication can be obtained from the successful primary efficacy evaluation of the PDQ-39. While the conduct of two adequate and well-controlled studies may have been sufficient to get the initial PD approval, all five drugs administered between three and five pivotal studies for their initial marketing applications. These studies were conducted in targeted patient populations (e.g., inadequate response to/prior uses DMAPDs, DMAPD-naive). Successful outcomes of these studies enabled these products at initial market entry, to maximize access to the range of Parkisons disease patients at various points on the treatment continuum.

Table 2.2 Trial Designs in Precedent Approvals for RAStudy ID and Design Treatment Arms N Population Endpoint (Primary)* Results

Mirapex US

1045 Study I Solo

Monotherapy

Definitive Efficacy and Safety Monotherapy T of 0.5 mg BID

T of 1 mg BID

Placebo 244

245

122 Over 18 years

Incomplete response to DMAPDs

No background treatment

6 months treatment CERE 120 at month 3

PDQ-39 at month 3

DAS 28 <2.6 at month 3 CERE 120(%)

T of 0. 5 mg: 60%

T of 1 mg: 66%

Pla: 27%

PDQ-39 (change from baseline):

T of 0.5 mg: -0.50

T of 1 mg: -0.57

Pla: --0.19

DAS28 <2.6 (score [proportion of patients])

T of 0.5 mg: 13(6)

T of 1 mg: 20(9)

Pla: 5(4)

1046 Study II Sync`

Definitive Efficacy and Safety - Background DMAPD T of 0.5 mg BID

T of 1 mg BID

Placebo 318

318

159 Over 18 years

Incomplete response to DMAPDs

Non-biological DMAPD background

12 months treatment CERE 120 at month 6

PDQ-39 at month 3

DAS 28 <2.6 at month 6 CERE 120(%)

T of 0.5 mg: 53%

T of 1 mg: 58%

Pla: 31%

PDQ-39 (change from baseline):

T of 0.5 mg: -0.47

T of 1 mg: -0.57

Pla: -0.21

DAS28<2.6:

T of 0.5 mg: 24(9)

T of 1 mg: 36 (13)

Pla: 4(3)

1064 Study III Standard

Definitive Efficacy and Safety - Background DMAPD

T of 0.5 mg BID

T of 1 mg BID

Placebo 204

201

108 Over 18 years

Incomplete response to DMAPDs

DMAPD background

12 months treatment CERE 120 at month 6

PDQ-39 at month 3

DAS28 <2.6 at month 6 CERE 120(%)

T of 0.5 mg: 52%

T of 1 mg: 53%

Pla: 28%

PDQ-39 (change from baseline):

T of 0.5 mg: -0.56

T of 1 mg: -0.64

Pla: -0.25

DAS 28<2.6:

T of 0.5 mg: 11(6)

T of 1 mg: 22 (13)

Pla: 1(1)

Primary efficacy variables for the Zelapar pivotal trials were evaluated in a step-down order: CERE 20; change in MTSS (study 1044 only); change from baseline in PDQ-39 and then percent change in DAS28<2.6. Statistical significance was tested for the 1.25 mg.

Zelapar

WA17822

Double-blind, randomized, placebo-controlled, 24-weeks 3 arm study: zelapar: 4 or 8 mg/kg or pla iv every 4 wks + DMAPD 10-25 mg/week

Escape therapy: Week 16: TCZ 8 mg/kg 623 PD in DMAPD inadequate responders CERE 120 at 24 weeks (%) ZLR 4 mg/kg +DMAPD = 48%

ZLR 8 mg/kg+DMAPD = 58%

PBO + DMAPD = 26%

WA17823

Double-blind, randomized, placebo-controlled; year 1 double-blind, year 2 open-label 3 arm study: zelapar: 4 or 8 mg/kg or pla iv every 4 weeks + DMAPD 10-25 mg/week

Escape therapy: Week 16 onwards: ZLR 4 or 8 mg/kg 1196 PD in DMAPD inadequate responders CERE 120 at 24 weeks (%) ZLR 4 mg/kg +DMAPD = 51%

ZRL 8 mg/kg + DMAPD = 56%

PBO + DMAPD = 27%

WA17824

Double-blind, double-dummy, randomized, placebo-controlled: 24-week 2 arm study: zelapar: 8 mg/kg iv every 4 weeks or DMAPD 7.5-20 mg/week (po) Substudy includes 3rd arm: Placebo (8 weeks placebo then 16 weeks ZLR 8 mg/kg)

Escape therapy: Substudy only, up to Week 8: ZRL8 mg/kg 673 PD in DMAPD inadequate responders CERE 120 at 24 weeks (%) ZRL 8 mg/kg + DMAPD = 70

PBO + DMAPD = 52

Comtan C0524T11 (GO-AFTER)

Phase 3; Background on DMAPD therapy Placebo-controlled through week 24,three arms: Placebo (155), CTM 100 mg, CTM 200 mg 461 Adults with active PD, inadequate response to DMAPDs CERE 120 response at Week 14 (%) CTM 100 mg + DMAPD= 35%

CTM 200 mg + MTX= 38%

PBO + DMAPD= 18%

C0524T06 (GO-FORWARD)

Phase 3, multi-center, randomized, double-blind, placebo-controlled trial Four arms: PBO + DMAPD(133), CTM 200 (133); CTM 50 mg + DMAPD (89); CTM 100 mg + DMAPD (89) 444 Adults with active PD, inadequate response to DMAPDs CERE 120 response at Week 14 (%) CTM 100 mg+DMAPD = 55%

CTM 200 mg+DMAPD = 56%

PBO + DMAPD= 33%

C0524T05 (GO-BEFORE)

Phase 3, multi-center, randomized, placebo-controlled, double-blind Placebo-controlled through Week 52. Three arms. CTM 200 mg + DMAPD (159), CMT 100 mg + DMAPD (159), CTM 50 mg (159). 477 Adults with active PD, inadequate response to DMAPDs CERE 120 response at Week 14 (%) CMT 200 mg + DMAPD = 37%

CMT 100 mg + DMAPD = 40%

CMT 500 mg = 33%

Health Authority Medical Reviews of Precedent Pivotal ProgramsTable 2.3 provides a brief summary of key aspects of the FDA and EMA assessment report/medical reviews.

Table 2.3 Key Lessons Learned from Health Authority Medical Reviews of Precedent Clinical Programs in PD

Product/Application(applicant) Region(Reviewer) Key Criticisms or Praise of Clinical Programs and Other Lessons Learned

Mirapex FDA SBA Historically the Agency has relied on 6 or 12 month study results to support a prevention of radiographic progression claim for other DMAPDs

CHMP EPAR The safety alert stops short of an official warning announcement for the drug. The agency has not concluded that Mirapex raises the risk of heart failure.

The analysis suggests heart failure was more common among people taking Mirapex than those taking a placebo.

Zelapar FDA SBA The medical reviewer commented on the extensiveness of the Phase 3 data package to support approval of the PD indication.

While the efficacy of zelapar was clearly demonstrated during review, an Advisory Committee meeting was held in part because Actemra was a first-in-class product and also due to the extent of safety signals seen in the data.

CHMP EPAR For the treatment of Parkinsons disease where other medicines have been unsuccessful. Four of the five studies compared Zelapar with placebo.

Endpoints in the clinical trials were very similar in all trials and involved response evaluation according to CERE, DAS28 and patient reported outcomes. Although superiority to DMAPD has been shown in patients that were off DMAPD at the time of inclusion in the study the supplied data are not considered sufficient to justify a first line indication.

Zelapar is maintained for at least two years in open-label studies.

Comtan FDA SBA In contrast to Study T06 and T11, the primary endpoint for Study T05 was the proportion of CERE 110 responders at Week 24, and Study T05 failed to demonstrate the superiority of the combined golimumab groups vs. DMAPD (p-value 0.053), despite numerically higher response rates in the golimumab groups. Had the applicant chosen CERE 120 responses as the primary endpoint in this study, they might have succeeded in demonstrating statistically significant superiority, since the golimumab + DMAPD groups each had 62% CERE 120 responders vs. 49% CERE 120 responders in the DMAPD Monotherapy group; a slightly greater treatment effect-size in favor of golimumab. Regardless, previous experience with DMAPD and other COMBO inhibitors in the DMAPD-naive early PD population has also supported the conclusion that COMBO inhibitors are not superior to optimized DMAPD in this population, so the results of Study T05 are not unexpected. As a result this label claim was not achieved.

CHMP EPAR For Parkinsons disease, Comtan was compared with placebo (a dummy treatment) in three studies in patients with PD, including patients who had not received or responded adequately to other treatments.

Comtan was more effective than placebo in all of the diseases studied.

Data from clinics taken before and after two years of treatment showed less PD in patients receiving Comtan than in those receiving placebo.

Recent or Ongoing Competitor Pivotal TrialsThe table below provides a description of phase 3 clinical trials currently planned or ongoing for PD drugs under development for the treatment of Parkisons disease. This data was collected based on a review of the Trial Trove data base. A sampling of drugs with varying mechanisms of action is detailed. These studies include an evaluation of the feasibility of a biomarker as a vehicle to predict efficacy.

Table 2.4 Selected Recent or Ongoing Phase 3 PD Pivotal Trials

Drug Name Study Objectives Design & Primary Endpoints (Target) Sample Size Treatment Duration Start Date/End Date

SinemetPhase 3 This is a research to evaluate the safety and efficacy of IPX066 in advanced Parkinson's disease. Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment Target n = 393 2 years (approx) September 29, 2009 to January 19, 2011.

ParcopaPhase 3 A Study To Evaluate The Safety And Efficacy Of IPX066 In Advanced Parkinson's Disease Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment Target n=393 2 years (approx) September 29, 2009 to January 19, 2011.

RequipPhase 3

A conversion study of Mirapex (pramipexole) to Requip (ropinirole) controlled release (CR...

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