gantenerumab product analysis · swot analysis. datamonitor healthcare pharma intelligence | 9...

Gantenerumab Product Analysis

Ref Code: DMKC0149882Publication Date: 02/09/2016Author: Maha Elsayed

Datamonitor HealthcarePharma intelligence |


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gantenerumab Product Analysis DMKC0149882 | Published on 02/09/2016

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Reference: DMKC0149882 First published: 02/09/2016

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TABLE OF CONTENTS

LIST OF FIGURES

LIST OF TABLES

4 PRODUCT PROFILES4 gantenerumab : Alzheimer's disease

8 Figure 1: Gantenerumab for Alzheimer’s disease – SWOT analysis9 Figure 2: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s

disease10 Figure 3: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s

disease

4 Table 1: Gantenerumab drug profile5 Table 2: Gantenerumab Phase III data in Alzheimer’s disease6 Table 3: Gantenerumab Phase III trials in Alzheimer’s disease


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PRODUCT PROFILES gantenerumab : Alzheimer's disease PRODUCT PROFILE Analyst Outlook

Despite gantenerumab’s (Roche/MorphoSys) failure to demonstrate clinical efficacy in prodromalAlzheimer’s disease, a study examining efficacy in patients with mild Alzheimer’s disease (MargueriteRoAD) is ongoing. While Roche remains confident in gantenerumab’s disease-modifying potential,Datamonitor Healthcare’s expectations for the Marguerite RoAD trial are dim unless changes in thedosing regimen can be applied to influence clinical outcomes. Drug Overview

Gantenerumab is a fully humanized centrally and N-acting monoclonal antibody (MAb) that primarilytargets fibrillar amyloid-beta (Alzforum, 2014). It acts by preventing amyloid-beta plaque formation,promoting microglia-mediated clearance (Bohrmann et al., 2012). This binding and clearance isessential as amyloid-beta accumulation is a hallmark feature of Alzheimer’s disease (Roche, 2014).

Gantenerumab is currently in Phase III development for the treatment of mild Alzheimer’s disease andfor individuals prone to developing Alzheimer’s disease due to the presence of a genetic mutation(Biomedtracker, 2015; Medtrack, 2015). In December 2014, SCarlet RoAD, a Phase III study evaluatinggantenerumab in prodromal patients, was discontinued (Biomedtracker, 2015).


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DEVELOPMENT OVERVIEW

In December 2014, following a pre-specified futility analysis and upon the recommendation of theindependent Data Monitoring Committee, Roche announced its decision to discontinue SCarlet RoAD,a Phase III trial examining the clinical effects of gantenerumab in prodromal Alzheimer’s disease.Marguerite RoAD, a Phase III trial initiated in March 2014, will nevertheless continue to investigatethe efficacy and safety of gantenerumab in patients with mild Alzheimer’s disease (ClinicalTrials.govidentifier: NCT02051608). Gantenerumab is also involved in the ongoing DIAN TU (DominantlyInherited Alzheimer Network Trials Unit) trial, which is investigating treatment options for individualswho are at risk of dominantly inherited Alzheimer's disease (Biomedtracker, 2015; ClinicalTrials.govidentifier: NCT01760005; Trialtrove, 2016).

The discontinued Phase III study is summarized in the table below.

Table 1: Gantenerumab drug profile

Molecule gantenerumab

Phase of development Phase III

Mechanism of action Passive immunization against amyloid-beta

Originator MorphoSys

Marketing company Roche/MorphoSys

Targeted indication Mild Alzheimer’s disease

Formulation Subcutaneous injection

Pricing strategy Expected to be comparable to the average price of Enbrel, Humira,

Remicade, and Stelara

Dosing frequency Every four weeks

Estimated approval date Q2 2019

Alternative names RG1450, RO4909832

Source: Biomedtracker; Medtrack


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Ongoing Phase III trials are summarized in the table below.

Table 2: Gantenerumab Phase III data in Alzheimer’s disease

Trial Sample size Target patients Study design Dosing tested

and duration

Results Reference

SCarlet RoAD

(NCT01224106)

(Phase III)

799 Patients with

prodromal

Alzheimer’s disease

Randomized,

parallel-assignment,

double-blind,

placebo-controlled

Arm 1:

gantenerumab

225mg SC

Arm 2:

gantenerumab

105mg SC

Arm 3: placebo SC

Duration and

frequency: every

four weeks for 104

weeks

Arm 1 or Arm 2

versus Arm 3: No

difference in CDR-

SB;

Mean % change

from baseline in

cortical composite

SUVR at week 100:

Arm 1: -5.37%

Arm 2: +0.19%

Arm 3: -1.11%

Biomedtracker;

Alzheimer’s

Association, 2015

CDR-SB = Clinical Dementia Rating Scale – Sum of Boxes; SC = subcutaneous; SUVR = standardized uptake value ratio

Source: various (see above)


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SCarlet RoAD study discontinued following negative pre-futility analyses

Table 3: Gantenerumab Phase III trials in Alzheimer’s disease

Trial Sample size Target patients Study design Treatment arms Primary

endpoints

Start

date/primary

completion date

Marguerite RoAD

(NCT02051608)

(Phase III)

1,000 Patients with mild

Alzheimer’s disease

Randomized,


double-blind,

placebo-controlled

Arm 1: 105/225mg

gantenerumab SC

every four weeks

Arm 2: placebo SC

every four weeks

Duration: 104 weeks

Mean change from

baseline in ADAS-

Cog13 scores at

week 104

Mean change from

baseline in ADCS-

ADL scores at week

104

Change from

baseline in brain

amyloid load over

time at week 104

March 2014/July

2018

DIAN TU

(NCT01760005)

(Phase II/III)

210 Patients who are at

risk, with

dominantly

inherited

Alzheimer's disease

Randomized,


double-blind,

placebo-controlled

Arm 1:

gantenerumab

225mg SC every

four weeks

Arm 2: placebo SC

Arm 3: solanezumab

400mg IV every four

weeks

Arm 4: placebo IV

Duration: 208 weeks

Change from

baseline in the DIAN

TU cognitive

composite score at

week 52, 104, 156,

and 208

December

2012/September

2019

ADAS-Cog13 = Alzheimer's Disease Assessment Scale – Cognitive Subscale (13-item subscore); ADCS-ADL = Alzheimer's Disease Cooperative Study

– Activities of Daily Living; DIAN TU = Dominantly Inherited Alzheimer Network Trials Unit; IV = intravenous; SC = subcutaneous

Source: Trialtrove; ClinicalTrials.gov


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In November 2010, Roche initiated SCarlet RoAD, a global pivotal Phase III study to measure theeffects of gantenerumab in patients with prodromal Alzheimer’s disease (Mini-Mental StateExamination scores of ≥24). SCarlet RoAD was the first Phase III study to test the therapeutic efficacyof a disease-modifying therapy in patients with prodromal Alzheimer’s disease. Roche decided to stopthe study based on the results of its pre-planned futility analyses. While gantenerumab exerted adose-dependent reduction of brain amyloid load, cerebrospinal fluid tau, and total tau – the firstreported treatment effect on both hallmark biomarkers – this did not translate into a clinical response.The lack of effect, along with the recommendation by the independent Data Monitoring Committee,prompted Roche’s decision to discontinue the study (Biomedtracker, 2015; Alzheimer’s Association,2015; CTAD abstract OC4, 2015; CTAD abstract OC5, 2015). With regards to safety, there wereincidences of amyloid-related imaging abnormalities involving hemosiderosis and edema rangingbetween 6.6–19.2% (CTAD abstract OC4, 2015). Gantenerumab was well tolerated overall by patientswith prodromal Alzheimer’s disease.

Roche presented an exploratory analysis of the SCarlet RoAD study at the 2015 Clinical Trials onAlzheimer’s Disease annual meeting, suggesting that patients with rapidly progressing Alzheimer’sdisease may have had a treatment benefit with high-dose gantenerumab. Approximately one-third ofpatients were identified as fast progressors according to a model developed by Delor et al. (2013)based on the Alzheimer’s Disease Neuroimaging Initiative observational study. The cognitive functionof fast-progressor subjects with high gantenerumab plasma concentrations declined less on theAlzheimer's Disease Assessment Scale – Cognitive Subscale (median change = 2.66) than those withlow concentrations (median change = 4.83), medium concentrations (median change = 4.00), orplacebo (median change = 6.00) at week 104. This suggests that there was an exposure-dependenteffect, particularly among the more vulnerable subset of patients (CTAD abstract OC4, 2015). Ongoing Marguerite RoAD and DIAN TU trials are assessing gantenerumab in differentstages of the disease

Despite the SCarlet RoAD failure, Roche is committed to another global pivotal Phase III study,Marguerite RoAD. This trial is examining the clinical effects of gantenerumab in mild Alzheimer’sdisease patients at the same doses as those used in SCarlet RoAD. The study is expected to be fullycompleted in March 2019 (Biomedtracker, 2015).

Gantenerumab is also being explored alongside Eli Lilly’s amyloid-beta antibody solanezumab in theDIAN TU study. This trial, funded by the National Institute of Health and conducted by WashingtonUniversity, will enroll cognitively normal patients with inherited mutations in a critical gene thatalmost guarantee that they will go on to develop early-onset Alzheimer’s disease later in life, as wellas healthy controls (Washington University, 2012). The aim of the DIAN TU study is to gauge thepreventative efficacy of the drug treatments over a two-year time period. Comparisons will not bemade between the two MAbs. SWOT ANALYSIS


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CLINICAL AND COMMERCIAL ATTRACTIVENESS

The figures below depict Datamonitor Healthcare’s drug assessment summary of gantenerumab forAlzheimer’s disease in relation to the comparator product, Aricept (donepezil; Eisai/Pfizer).

Figure 1: Gantenerumab for Alzheimer’s disease – SWOT analysis

Source: Datamonitor Healthcare


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Figure 2: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s disease


Figure 3: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s disease



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Despite SCarlet RoAD setback, Roche retains gantenerumab as a disease-modifying drug

In July 2015, Roche announced the failure of its SCarlet RoAD study to meet its primary clinicalendpoints. This news did not impact the other ongoing Phase III studies, particularly gantenerumab’sMarguerite RoAD trial. Since the drug was found to be overall safe and well tolerated, Roche iscontinuing to examine gantenerumab’s therapeutic benefit in patients with a more advanced stage ofthe disease. Signs of potential efficacy in crenezumab, Roche’s other amyloid-beta antibody, in mildAlzheimer’s disease might have supported the decision to continue with Marguerite RoAD. However,despite the confidence Roche displays in gantenerumab, Datamonitor Healthcare’s outlook on theMarguerite RoAD study’s potential for success is dim, unless dose escalation can be carried out.

When comparing the various clinical trials conducted for the other amyloid-targeting MAbs that haveeither hinted at or indicated efficacy, the doses used in SCarlet RoAD were particularly low (themaximum dose for gantenerumab was 225mg versus 800mg for aducanumab for an average 80mg/kgsubject). While the lower dose was motivated by safety reasons, it may have been insufficient to reachbiological efficacy. In addition, it seems optimistic to expect to obtain a clinical efficacy response inmild patients when there was no response achieved in a prodromal pool of patients. With amechanism targeting the earlier forms of Alzheimer’s disease pathology, it is unlikely thatgantenerumab will be able to demonstrate clinical efficacy in a more advanced form of the diseaseunless the dose is scaled up.

“I think the major possibilities [for the failure of the SCarlet RoAD study] would include that the drugsimply does not work or that it was dosed too low, and one wonders about dosing too low now inlight of Biogen’s data [of aducanumab] [...] The other possibility is that they looked at the wrongsubjects, but most of the emerging data are that mild or prodromal patients may be the most likely toshow a benefit with these drugs, and they did indeed look at biomarker-positive prodromal patients.So, it does not seem as though they missed the boat on the patient population.”

US key opinion leader Bibliography

Alzforum (2014) End of the RoAD for Gantenerumab? Roche Declares Prodromal Alzheimer’s TrialFutile. Available from: http://www.alzforum.org/news/research-news/end-road-gantenerumab-roche-declares-prodromal-alzheimers-trial-futile [Accessed 29 September 2015].

Alzheimer’s Association (2015) Biomarker Results from Phase 3 Gantenerumab (Roche) Trial in EarlyAlzheimer’s. Available from: http://www.alz.org/aaic/_downloads/Wed-7am.pdf [Accessed 10September 2015].

Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, RauchenbergerR, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loestscher H (2012)Gantenerumab: a novel human anti-A antibody demonstrates sustained cerebral amyloid- binding andelicits cell-mediated removal of human amyloid-. Journal of Alzheimer’s Disease, 280(1), 46–9<DOI>10.3233/JAD-2011-110977</DOI>.


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CTAD abstract OC4 (2015) Efficacy and safety of gantenerumab from the Phase 3 Scarlet Road trial, astudy of gantenerumab in patients with prodromal AD. Available from: http://www.ctad-alzheimer.com/sites/ctad.prod/files/files/ABSTRACTS%20CTAD2015.pdf [Accessed 6 November 2015].

CTAD abstract OC5 (2015) CSF and amyloid Pet biomarker data from the Phase 3 Scarlet Road trial, astudy of gantenerumab in patients with prodromal AD. Available from: http://www.ctad-alzheimer.com/sites/ctad.prod/files/files/ABSTRACTS%20CTAD2015.pdf [Accessed 6 November 2015].

Delor I, Charoin J-E, Gieschke R, Retout S, Jacqmin P (2013) Modeling Alzheimer’s disease progressionusing onset time and disease trajectory concepts applied to CDR-SOB scores from ADNI. CPTPharmacometrics Systems Pharmacology, 2(10) <DOI>10.1038/psp.2013.54</DOI>.

Roche (2014) Roche provides update on gantenerumab development programme. Available from:http://www.roche.com/media/store/releases/med-cor-2014-12-19b.htm [Accessed 10 September2015].

Roche (2015) Expected registration filing date. Available from:http://www.roche.com/research_and_development/who_we_are_how_we_work/pipeline.htm[Accessed 10 September 2015].

Washington University (2012) Investigational drugs chosen for major Alzheimer’s prevention trial.Available from: http://news.wustl.edu/news/Pages/24400.aspx [Accessed 24 September 2015].

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