duchenne muscular dystrophy and becker muscular dystrophy - … · muscular dystrophy - identifying...

FRONTIER PHARMA

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy - Identifying and

Commercializing First-in-Class Innovation Published: May 2015 Report Code: GBIHC361MR

© GBI Research. This is a licensed product and is not to be photocopied

[Front cover image reference: Cross of thigh muscle from a rat, reproduced under the Creative Commons CC0 1.0 Universal Public Domain Dedication license]

GBIHC361MR / Published MAY 2015

1 Table of Contents

1 Table of Contents ........................................................................2 1.1 List of Tables ....................................................................3 1.2 List of Figures ...................................................................3

2 Executive Summary .....................................................................4 2.1 Highly Innovative and Diverse Pipeline ...........................4 2.2 Alignment of Innovation to Genetics and Disease

Processes .........................................................................4 2.3 Deals Landscape Present Substantial Investment

Opportunities ....................................................................4 3 The Case for Innovation ..............................................................5

3.1 Growing Opportunities for Biologic Products ..................6 3.2 Diversification of Molecular Targets ................................6 3.3 Innovative First-in-Class Product Developments Remain

Attractive ..........................................................................6 3.4 Regulatory and Reimbursement Policy Shifts Favor First-

in-Class Product Innovation .............................................7 3.5 Sustained Innovation ........................................................7 3.6 GBI Research Report Guidance .......................................8

4 Clinical and Commercial Landscape ...........................................9 4.1 Disease Overview ............................................................9 4.2 Disease Epidemiology and Etiology ................................9

4.2.1 Disease Inheritance ................................................ 10 4.3 Disease Pathophysiology ............................................... 10

4.3.1 Hypothesized Pathophysiological Mechanisms of Duchenne Muscular Dystrophy/ Becker Muscular Dystrophy................................................................ 11

4.3.2 Dysfunction in Regeneration and Development of Fibrosis ................................................................... 13

4.4 Disease Symptoms ......................................................... 13 4.5 Complications and Co-morbidities ................................. 14

4.5.1 Respiratory Complications ..................................... 14 4.5.2 Cardiac Complications ........................................... 14 4.5.3 Scoliosis .................................................................. 14

4.6 Diagnosis ........................................................................ 14 4.7 Disease Staging and Prognosis ..................................... 15 4.8 Treatment Options ......................................................... 16

4.8.1 Pharmacological Treatments.................................. 16 4.8.2 Non-pharmacological Treatments.......................... 18 4.8.3 Treatment Algorithm............................................... 19

4.9 Overview of Marketed Products .................................... 21 4.9.1 Glucocorticoids ....................................................... 21 4.9.2 Translarna (ataluren) ............................................... 23 4.9.3 Molecule Type and Target Analysis ....................... 23

4.10 Current Unmet Needs .................................................... 24 5 Assessment of Pipeline Product Innovation ............................. 25

5.1 Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Pipeline by Molecule Type, Phase and Therapeutic Target ......................................................... 25

5.2 Comparative Distribution of Programs between Duchenne Muscular Dystrophy/Becker Muscular

Dystrophy Market, and Pipeline by Therapeutic Target Family ............................................................................. 29

6 Signaling Pathways, Genetics and Innovation Alignment ....... 34 6.1 First-in-Class Target Matrix Assessment ....................... 34 6.2 Repositioning Potential among Muscular Dystrophies . 36

7 First-in-Class Target Evaluation ................................................ 38 7.1 Pipeline Programs Targeting Sarcospan ...................... 38 7.2 Pipeline Programs Targeting Utrophin.......................... 40 7.3 Pipeline Programs Targeting Biglycan .......................... 43 7.4 Pipeline Programs Targeting Laminin-111 ...................... 45 7.5 Pipeline Programs Targeting Hematopoietic

Prostaglandin D Synthase ............................................. 48 7.6 Pipeline Programs which Target G Protein-Coupled

Receptor Mas ................................................................. 50 7.7 Pipeline Programs Targeting Mothers against

Decapentaplegic Homolog 3 ........................................ 52 7.8 Pipeline Programs which Target Myostatin .................. 54 7.9 Pipeline Programs Targeting Dystrophin ...................... 56 7.10 Conclusion ..................................................................... 59

8 Deals and Strategic Consolidations ......................................... 60 8.1 Industry-Wide First-in-Class Deals ................................ 60 8.2 Licensing Deals ............................................................. 61 8.3 Co-development Deals .................................................. 66 8.4 First-in-Class Programs Not Involved in Licensing or Co-

Development Deals ....................................................... 68 9 Appendix ................................................................................... 70

9.1 Abbreviations ................................................................. 70 9.2 References ..................................................................... 70 9.3 Contact Us ..................................................................... 77 9.4 Disclaimer ...................................................................... 77



1.1 List of Tables

Table 1: Stages of Duchenne Muscular Dystrophy, 2015 .......... 15

1.2 List of Figures

Figure 1: Innovation Trends in Product Approvals, 1987–2013 .....5 Figure 2: Sales Performance of First-in-Class and Non-First-in-

Class Products Post Marketing Approval, 2006–2013...7 Figure 3: Schema for Initiation of Glucocorticoid Treatment in

Duchenne Muscular Dystrophy ..................................... 20 Figure 4: Molecular Targets of Marketed Products, 2015............ 24 Figure 5: Developmental Pipeline Overview................................ 26 Figure 6: Developmental Pipeline Overview................................ 28 Figure 7: Molecular Target Category Comparison, Pipeline and

Marketed Products ........................................................ 29 Figure 8: Molecular Target Category Comparison, Pipeline First-

in-Class and Established Molecular Targets ................. 31 Figure 9: Duchenne Muscular Dystrophy and Becker Muscular

Dystrophy, Global, Pipeline, First-in-class Products in the Pipeline .................................................................... 32

Figure 10: First-in-Class Molecular Target Analysis Matrix ............ 35 Figure 11: Data and Evidence for Sarcospan as a Therapeutic

target ............................................................................. 39 Figure 12: Pipeline Programs Targeting Sarcospan ...................... 39 Figure 13: Data and Evidence for Utrophin as a Therapeutic target

....................................................................................... 42 Figure 14: Pipeline Programs Targeting Utrophin ......................... 43 Figure 15: Data and Evidence for Biglycan as a Therapeutic target

....................................................................................... 44 Figure 16: Pipeline Programs Targeting Biglycan .......................... 44 Figure 17: Data and Evidence for Laminin-111 as a Therapeutic

Target ............................................................................ 47 Figure 18: Pipeline Programs Targeting Laminin-111 ...................... 48 Figure 19: Data and Evidence for Hematopoietic Prostaglandin D

Synthase as a Therapeutic target ................................. 49 Figure 20: Pipeline Programs Targeting Hematopoietic

Prostaglandin D Synthase ............................................. 49 Figure 21: Data and Evidence for G Protein-Coupled Receptor

Mas as a Therapeutic target ......................................... 51 Figure 22: Pipeline Programs Targeting G Protein-Coupled

Receptor Mas ................................................................ 51 Figure 23: Data and Evidence for Mothers against

decapentaplegic homolog 3 as a Therapeutic target .. 53 Figure 24: Pipeline Programs Targeting Mothers against

decapentaplegic homolog 3 ......................................... 53 Figure 25: Data and Evidence for Myostatin as a Therapeutic

target ............................................................................. 55 Figure 26: Pipeline Programs Targeting Myostatin ........................ 55 Figure 27: Data and Evidence for Dystrophin as a Therapeutic

target ............................................................................. 57 Figure 28: Pipeline Programs Targeting Dystrophin ...................... 58 Figure 29: Industry-Wide Deals by Stage of Development, 2006–

2014 ............................................................................... 60 Figure 30: Industry Licensing Deal Values by Stage of

Development, 2006–2014 ............................................ 61 Figure 31: Licensing Deals in Duchenne Muscular Dystrophy,

2006–2015 .................................................................... 63 Figure 32: Licensing Deals Global Distribution, 2006–2015 ......... 64

Figure 33: Licensing Deals by Molecule Type, 2006–2015 ......... 64 Figure 34: Licensing Deals by Molecular Target, 2006–2015 ...... 65 Figure 35: Summary of Licensing Deals, 2006–2015 ................... 65 Figure 36: Co-development Deals by Year, 2006–2015 .............. 66 Figure 37: Co-development Deals Global Distribution, 2006–2015

...................................................................................... 66 Figure 38: Co-development Deals by Molecule Type, 2006–2015

...................................................................................... 67 Figure 39: Co-development Deals by Molecular Target, 2006–

2015 .............................................................................. 67 Figure 40: Summary of Co-Development Deals, 2006–2015 ....... 68 Figure 41: First-in-Class Programs with no Recorded Prior Deal

Involvement, 2006–2015 ............................................. 69



2 Executive Summary

2.1 Highly Innovative and Diverse Pipeline

The Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) pipeline consists of XX molecules across all stages of development. It is characterized by a high level of innovation and diversity in terms of molecular targets; XX% of all pipeline programs with disclosed molecular targets are first-in-class. This exceptional first-in-class innovation is largely due to the high number of first-in-class products that solely target the dystrophin gene, which is the primary genetic cause of DMD and BMD. GBI Research’s analyses identified XX first-in-class programs in active development, acting on XX first-in-class targets. Over the last few decades, the market landscape has relied on the use of glucocorticoids, which offer symptomatic benefits in increasing muscle strength and a delay in the loss of ambulation in DMD/BMD patients without altering the genetic cause and dystrophic pathology. Translarna (ataluren), despite being the first approved therapy treating the underlying genetic cause in the EU, is only applicable in XX–XX% of all DMD cases with nonsense mutations. The strong presence of first-in-class products in the pipeline therefore creates a distinctly different landscape due to their disease-modifying potential. While they are most commonly distributed in the Preclinical stage, they are also present in late stages of development. Despite a strong focus on personalized treatments that treat the genetic cause of the disease in the DMD/BMD pipeline, innovation is also concentrated on novel molecular targets that alleviate the dystrophic pathology regardless of gene mutations. This gives them the potential to be translated into therapies that will be used alongside primary treatment intended to repair the mutated gene, halt muscle degeneration, and improve the life expectancy of patients in the future market.

2.2 Alignment of Innovation to Genetics and Disease Processes

DMD, a neuromuscular disease, and BMD, its less severe form, are caused by heritable mutations in the single dystrophin gene, which ultimately lead to progressive muscle weakness and degeneration due to destabilization of the sarcolemma (muscle cell membrane) and the resultant loss of muscle integrity. However, it has become increasingly apparent that the loss of functional dystrophin protein is not the only factor driving the progression of DMD/BMD. Although the exact molecular mechanism remains unclear, secondary pathological processes have been suggested to cause or contribute to the pathological features, such as mechanical stress, deregulated calcium homeostasis, impaired vascular adaptation, inflammation, and fibrosis, thereby reflecting that muscle fiber degeneration is a multifaceted process.

Our proprietary analyses show that the XX first-in-class targets differ substantially in terms of clinical and commercial potential based on how well their functional roles align to either the genetic cause of DMD/BMD or the secondary processes of disease pathophysiology and the strength of evidence in Preclinical studies. Some molecular targets are therefore considered more promising than others due to a stronger potential to be translated

into novel treatments. The most promising targets provide a strong scientific rationale to support their therapeutic development, as indicated by substantial improvement in both muscle histopathology and function in vivo across different animal model systems.

Analysis also indicates opportunities for some of the first-in-class DMD/BMD targets to be repositioned to other MDs. However, the development of successful compounds that benefit a number of MD forms is expected to be challenging, and to take place in the distant future, given the currently limited understanding of the common molecular processes defected across multiple types of MD.

2.3 Deals Landscape Present Substantial Investment Opportunities

Strategic consolidation is relatively uncommon in the DMD/BMD market, as reflected in the low number of licensing and co-development deals between 2006 and April 2015. Only XX first-in-class products that are currently in development have been involved in strategic consolidations. Despite the limited data available, evidence suggests a tendency for first-in-class deals to attract higher average values than non-first-in-class deals. This is supported by the findings from the industry-wide analysis, which show that first-in-class products typically command a higher deal value than non-first-in-class counterparts, especially in the earlier stages of development. This reflects companies’ willingness to invest despite the high-risk profile of first-in-class products and presents a significant industry interest placed on innovation across DMD.

With the XX first-in-class products available for strategic consolidations, a vast number of investment opportunities are available for licensing or co-development deals in DMD/BMD. This will be encouraged by the typically poor disease prognosis and significant unmet needs for disease-modifying treatments that are available for the majority of patients. Among these, some first-in-class products have demonstrated promising Preclinical evidence and have significant potential to become game-changing products by targeting either the primary genetic defects of the disease or the secondary disease pathways, representing high-reward investments.


GBIHC361MR / Published MAY 2015 Page 8

3.6 GBI Research Report Guidance

This report is part of the Frontier Pharma series, which has been designed to identify innovative pipeline programs across a therapy area, with a focus on indications with high levels of R&D activity, strong innovation, a competitive commercial landscape, and high levels of deal activity. Monitoring innovative new product developments is becoming increasingly important, not just for companies looking to acquire technologies, products or companies, or smaller companies that are seeking strategic partnerships, but also as a vital part of competitive intelligence for all market participants. In an entirely evidence- and data-driven approach, GBI Research has identified four immunological indications with the highest number of innovative and promising pipeline products. The primary parameters that were applied to identify innovative first-in-class products were based on comprehensive database analyses on the mechanisms of action, molecular targets, molecule types and routes of administration of molecules. The identified pipeline programs were then assessed on the basis of the available data, secondary academic literature, primary research with relevant experts on the scientific and clinical rationale for each respective approach, and commercial prospects.

The identification and assessment of innovative pipeline products is accompanied by proprietary data analyses on the trends in licensing and co-development deals by phase of development, molecule type, mechanism of action and route of administration. These data analyses provide underlying datasets to assist in the assessment of the value of novel products for both acquisition and out-licensing companies and venture capital firms to optimize the conditions of future deals. Furthermore, this analysis helps identify those novel products that have already been part of a deal and are therefore no longer available for acquisition. Conversely, novel products that have not been part of any deals to date can be identified and could assist clients that are searching for new acquisition targets in pooling potential candidates.



5.2 Comparative Distribution of Programs between Duchenne Muscular Dystrophy/Becker Muscular Dystrophy Market, and Pipeline by Therapeutic Target Family

Currently there are only six pharmacological treatments marketed for DMD, including those addressing the complications associated with the disease and the recently approved drug Translarna, which is intended to treat nonsense mutations in XX–XX% of the DMD population. There is a strong unmet need for more effective disease-modifying treatments for different patient populations carrying specific gene mutations, and treatments that can be used in a larger DMD population, or even all patients. With a high degree of innovation and a diverse array of completely novel target families found in the pipeline, the outlook is considered very promising.

As shown in Figure 7, none of the pipeline products target the serotonin receptor 5-HT 2A receptor, which is targeted by two marketed products available to treat DMD in South Korea. Its role in DMD is not well established and the market approval is limited to a single territory, which explains the lack of research interest in the pipeline.

Given the high level of diversity in molecular targets under development compared with the market landscape, there is strong evidence of a trend towards personalized and mutation-specific therapies in the pipeline of DMD/BMD. Together with the approval of Translarna, this will encourage continual R&D investment in gene therapies. Other disease-modifying therapies that target the pathophysiology underlying the disease without correcting defects in the dystrophin gene are also expected to play a significant role in transforming the future treatment landscape, predominantly due to the larger size of the DMD population they target, meaning they offer a promising commercial prospect.

Figure 7: Molecular Target Category Comparison, Pipeline and Marketed Products

Number of products

Pipeline Marketed

Source: GBI Research, Proprietary Pipeline Products Database and Marketed Products Databases

Number of pipeline products with unknown/undisclosed molecular targets is 19.

5-HT: 5-Hydroxytryptophan; ECM: Extracellular Matrix; MoA: Mechanism of Action; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; PTC: Premature Termination Codon; TGF: Transforming Growth Factor



6 Signaling Pathways, Genetics and Innovation Alignment

GBI Research’s data show that the DMD/BMD pipeline is characterized by a high level of innovation and diverse molecular targets. GBI Research’s proprietary analysis indicates that XX% of the pipeline products with disclosed molecular targets are first-in-class innovation programs (XX% of all pipeline products including disclosed and undisclosed molecular targets). There are XX first-in-class products in active development in the pipeline. The key drivers for this degree of innovation are the generally poor level of survival, and the substantial unmet needs for disease-modifying treatment that is available for the majority of patients, which present opportunities for breakthrough products.

In the DMD/BMD pipeline, GBI Research’s analytics identified XX distinct first-in-class molecular targets. Innovation is concentrated on several novel molecular targets including dystrophin (the genetic determinant of DMD and BMD), those participating in the pro-fibrotic TGF-β signaling pathway, and compensatory proteins such as utrophin and biglycan. Apart from the fact that DMD/BMD is a single-gene disorder, this trend may be a result of a limited understanding of the pathophysiological mechanisms caused by the loss of functional dystrophin in DMD/BMD. This results in a relatively narrow range of molecular targets being selected for innovative drug development in comparison to indications such as breast cancer in which a detailed understanding of disease pathophysiology leads to a larger number of distinct first-in-class pipeline targets. It should be noted that the low number of programs in active development for DMD/BMD also contributes to the relatively lower first-in-class target count compared with other indications, which have larger overall pipelines. Despite this, the DMD/BMD pipeline still represents one of the indications presenting a high diversity of innovation, as reflected by the high percentage of first-in-class programs.

6.1 First-in-Class Target Matrix Assessment

First-in-class molecular targets were integrated into a proprietary matrix that qualitatively assessed the rationale for therapeutic intervention based on a number of factors, combined with an extensive review and validation process (Figure 10). The matrix provides a platform to understand the value and rationale for first-in-class innovation.

GBI Research’s analysis is supported by integrating data to assess whether the first-in-class targets are well-integrated into the indication-specific signaling pathway(s), using one of the best-established human protein–protein interaction databases, Reactome.



8.2 Licensing Deals

A total of XX licensing deals took place for DMD products between 2006 and April 2015. However, some of these deals included multiple products, with one deal in particular being an expansion on a previous deal in order to include more exon-skipping therapies. Furthermore, Cialis (tadalafil), which is now in Phase III, has been involved in distinct licensing deals on two separate occasions. In this analysis, no products involved in licensing deals were currently in development for BMD, and therefore the following analysis is DMD specific.

Of the XX deals, only four had a disclosed total deal value. All disclosed deals were valued at over $XXm, as shown in Figure 31, suggesting high commercial potential within this indication. The highest valued deal, at $XXm, was primarily for GSK to gain the license for the exon-skipping therapy drisapersen. However, the deal also gave GSK access to other exon-skipping therapies developed by Prosensa.

Three of the XX deals with a disclosed value were also first-in-class. One of those is the aforementioned exon-skipping therapy drisapersen, which commanded the highest value at $XXm. The other was the utrophin modulator SMTC-1100, which BioMarin licensed to Summit for an upfront payment of $XXm and further milestone payments up to $XXm, resulting in a total deal value of $XXm. Lastly, ramatercept, an Activin type IIB receptor inhibitor, had a total deal value of $XXm, although clinical development of the drug was discontinued in 2013. There was only one non-first-in-class deal (involving the phosphodiesterase-5 inhibitor Cialis) which had a total deal value of $XXm.



Figure 31: Licensing Deals in Duchenne Muscular Dystrophy, 2006–2015

$100–300m

$301–500m

>$500 million

A) Deals by value

Discovery Preclinical Phase I Phase II Phase III

Num

ber o

f dea

ls

C) Deals by phase

2006 2007 2008 2009 2010 2011 2012 2013 2014

Num

ber o

f dea

ls

B) Deals by year

Number of deals with undisclosed valuesNumber of deals with disclosed values

Source: GBI Research Proprietary Deals Database



9 Appendix

9.1 Abbreviations

6MWT- Six-Minute Walk Test

AAV- Adeno-Associated Virus

ACE- Angiotensin-Converting Enzyme

ActRII- Activin type II Receptor

ALK-5- Activin-Linked Kinase-5

API- Active Pharmaceutical Ingredient

AT-1- Angiotensin II receptor

Bcl-2- B-cell lymphoma 2

BMD- Becker Muscular Dystrophy

CD- Cluster of Differentiation

Cdk- Cyclin-dependent kinase

cGMP- cyclic Guanosine Monophosphate

CTA- Clinical Trial Approval

DAP- Dystrophin-Associated Proteins

DAPC- Dystrophin-Associated Protein Complex

DMD- Duchenne Muscular Dystrophy

DP- D Prostanoid receptor

EBD- Evans Blue Dye

EMA- European Medicines Agency

ERK- Extracellular signal-Regulated Kinase

FAP- Fibro/Adipogenic Progenitors

FDA- Food and Drug Administration

Grb2- Growth factor receptor-bound protein

HGF- Hepatocyte Growth Factor

HGPDS- Hematopoietic PGDS

IL- Interleukin

IND- Investigational New Drug

JNK- c-Jun N-terminal Kinase

LMGD- Limb-Girdle Muscular Dystrophy

LPGDS- Lipocalin PGDS

LT-β- Lymphotoxin-β

MAPK- Mitogen-Activated Protein Kinase

MD- Muscular Dystrophy

MDC1A- Merosin-Deficient Congenital MD

NFAT- Nuclear Factor of Activated T-cells

NF-κB- Nuclear Factor kappa-light-chain-enhancer of activated B cells

NME- New Molecular Entity

nNOS- neuronal Nitric Oxide Synthase

mRNA- messenger RNA

MyoD- Myoblast Determination protein

p70S6K- 70-kDa ribosomal protein S6 Kinase

PAI- Plasminogen Activator Inhibitor

PDGFR- Platelet-Derived Growth Factor Receptor

PG- Prostaglandin

PGDS- Prostaglandin D Synthase

PLC- Phospholipase C

PMO- Phosphorodiamidate Morpholino Oligomers

PTC- Premature Termination Codon

Rac- Ras-related C3 botulinum toxin substrate 1

Rag- Recombination-activating gene

RAS- Renin-Angiotensin System

sGC- soluble Guanylyl Cyclase

SLRP- Small Leucine-rich Repeat Protein

Smad- Sma and mothers against decapentaplegic

SMD- Spinal Muscular Dystrophy

Sos1- Son of sevenless homolog 1

SpO2- oxygen saturation

TGF- Transforming Growth Factor

TIMP- Tissue Inhibitor of Matrix metalloprotease

TNF- Tumor Necrosis Factor

UGC- Utrophin-Glycoprotein Complex

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9.4 Disclaimer

All Rights Reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GBI Research.

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