graft-versus-host disease – opportunity ...graft-versus-host disease – opportunity analysis and...

REFERENCE CODE GDHC021POA | PUBLICAT ION DATE AUGUST 2014

GRAFT-VERSUS-HOST DISEASE – OPPORTUNITY ANALYSIS AND FORECASTS TO 2018

Graft-Versus-Host Disease – Opportunity Analysis and Forecasts to 2018 2 © GlobalData. This report is a licensed product and is not to be copied, reproduced, shared or resold in any form.


Executive Summary

Key Metrics for Graft-Versus-Host Disease (GVHD) in the Six Major Pharmaceutical Markets, 2013–2018 2013 Epidemiology

First allogeneic HSCTs (men and women) (N) 6MM 15,991

Diagnosed incident cases of aGVHD in first allogeneic HSCTs (men and women) (N), 6MM 8,062

Diagnosed incident cases of cGVHD in first allogeneic HSCTs (men and women) (N), 6MM 7,359

2013 Market Sales

US $209.7m

5EU $86.0m

Total $295.7m

Pipeline Assessment

Number of drugs in Phase I–II 33

Number of first-in-class drugs in Phase I–IIb 26

Key Events (2013–2018) Level of Impact

2014 Food and Drug Administration (FDA) approval and restricted* launch of Prochymal (remestemcel-L) for aGVHD

↑↑

2015 European Medicines Agency (EMA) approval and restricted* launch of Prochymal for aGVHD

↑↑

2016 ATG-Fresenius (EZ-2053) launch ↑↑

2016 Budenofalk (budesonide) EU launch ↑

2018 Launch of Leukotac (inolimomab) ↑↑↑

2018 Launch of Begedina (anti-CD26) ↑↑↑

2018 Market Sales

US $273.0m

5EU $134.0m

Total $407.0m Source: GlobalData For the purposes of this report, the six major pharmaceutical markets = US and 5EU (France, Germany, Italy, Spain, and UK). aGVHD = acute GVHD; cGVHD = chronic GVHD; HSTC = hematopoietic stem cell transplantation

Table above presents the key metrics for graft-

versus-host disease (GVHD) in the six major

pharmaceutical markets (US, France, Germany,

Italy, Spain, and UK) covered in this report during

the forecast period from 2013–2018.

Steady Growth Expected in the US and EU GVHD Markets from 2013–2018

The GVHD market was valued at $297.0m across

the 6MM in 2013, and is expected to increase to

$409.0m in 2018, at a Compound Annual Growth

Rate (CAGR) of 6.61%. Growth is anticipated to be

slowest in the US, as there are fewer market

changes expected during the five-year forecast

period. In contrast, due to the multiple product

launches in Europe, growth in the 5EU is expected

to accelerate towards the end of the forecast

period, posting a CAGR of 9.42% during this

timeframe. In addition, multiple biologic products

will fall off their respective patent cliffs during the

2013–2018 forecast period. However, this will not

impact the present GVHD forecast for two very

important reasons: First, biosimilar versions of key

off-label GVHD biologics, such as Rituxan

(rituximab) and Campath/Lemtrada

(alemtuzumab), are in a very early developmental

stage and to date have failed clinical trials.

Secondly, hematologists across the 6MM are not

expected to use biosimilar versions of branded

biologics in GVHD patients whose health is already

severely compromised. Furthermore, key opinion

leaders (KOLs) interviewed by GlobalData

unanimously agreed that they would prefer for new



Executive Summary

biosimilars to be tested in a GVHD clinical trial

setting before they use them in the clinic.

In total, six products are expected to enter the

market by 2018. Osiris Therapeutics/Mesoblast’s

Prochymal is expected to launch in 2014 (US) and

2015 (5EU), reaching $12.2m in sales from the

6MM in 2018. Dr. Falk Pharma’s Budenofalk is

forecast to enter the European GVHD market in

2017, while in the same year, ATG-Fresenius (also

known as ATG-F) is expected to enter the US

GVHD market, and these two products are

estimated to generate 2018 sales of $11.9m and

$4.5m, respectively. Both Jazz Pharmaceuticals’

Leukotac and Adienne Pharma’s Begedina are

forecast to enter the GVHD market in 2018, with

Leukotac being launched only in the 5EU. Due to

their anticipated premium pricing, Begedina and

Leukotac are expected to add over $18m to the

6MM sales in 2018.

Major drivers of growth in the GVHD market over

the forecast period include:

The launch of new therapies with orphan

designations. Since orphan drugs are entitled

to premium pricing, the aGVHD market will

accrue increased revenue.

Academic publication of more favorable clinical

data on off-label second-line therapies in both

aGVHD and cGVHD, which will lead to

increased uptake of already-established

treatments, such as Roche’s Rituxan and

Bristol-Myers Squibb’s (BMS’) Orencia

(abatacept).

Increasing numbers of HSCT patients.

A trend towards prescribing of biologics and

patented small molecules, which will increase

the GVHD market value.

A high incidence of cGVHD throughout the

2013–2018 forecast period, which will lead to

an increase in expensive long-term

prescriptions.

The release of company-funded randomized

clinical trial data, which can be leveraged by

reimbursement agencies to fund expensive

biologics and patented small molecules.

T-regulatory (T-reg) cell and selective T-cell (T-

lymphocyte) therapies currently developed in

academic institutes, which could be licensed

by pharmaceutical companies and drive their

clinical development.



Executive Summary

Major barriers to the growth of the GVHD market

during the forecast period include:

Reimbursement pressures in the EU could

lead to the funding of generic small molecules

or low-efficacy drugs because the latter are

already in stock. For example, Johnson &

Johnson’s (J&J’s) Remicade (infliximab) is

favored in the UK at the expense of Amgen’s

Enbrel (adalimumab), purely because the

former drug is what can be funded by the

National Health Service (NHS) at the moment,

as it is readily available.

The lack of national treatment guidelines in all

6MM could lead to a significant proportion of

patients being enrolled in clinical trials, thus

dissolving potential future GVHD revenues.

The conservative approach to GVHD treatment

in most EU countries could hinder future drug

uptake.

The complex pathophysiology of the disease

and the lack of adequate GVHD animal models

create significant challenges during drug

development.

Figure below illustrates the global GVHD sales for

the six major markets (6MM) (US and 5EU) for all

three GVHD indications during the five-year

forecast period from 2013–2018.



Executive Summary

Global Sales for GVHD by Region and GVHD Indication, 2013–2018

71%

6%

10%

5%3% 5%

26%

35%

39%

67%

9%

11%

5%3% 5%

US France Germany Italy Spain UK

30%

34%

36%

aGVHD cGVHD Prophylaxis

2013 - Total GVHD sales $295.7m

2018 - Total GVHD sales $407.0m

Source: GlobalData



Executive Summary

Research and Development Strategies will Drastically Shape the GVHD Pipeline Over the Next Five Years

Over the past two decades, the GVHD market has

been evolving, with the introduction of biological

and patented small-molecule immunosuppressive

off-label therapies being added to the treatment

paradigm. The current research and development

(R&D) programs in GVHD are exciting, with novel

therapies (such as Adienne Pharma’s Begedina)

and potential first-in-class treatments (such as

mesenchymal stem cell [MSC] therapies).

However, as a consequence of low funds accrual

(as seen in clinical trial NCT00623012), low patient

recruitment (as seen in clinical trial

NCT00616954), and clinical trial failures (as seen

in clinical trial NCT00720850), the GVHD pipeline

has faced a period of slow development. Currently,

R&D strategies in GVHD are characterized by a

trend towards improving prophylactic regimens,

inhibiting T-cell proliferation and activation, using

treatments adopted from hematologic indications,

and targeting niche subgroups within the GVHD

population.

The current GVHD prophylactic regimens are

tailored to the type of conditioning and transplant

type used for HSCT. However, these therapies

carry a risk of opportunistic infection and provide

inadequate GVHD prophylaxis. As a result, the

R&D focus in GVHD remains partly fixated on

prophylaxis. There are three products in the

pipeline targeting the indication of GVHD

prophylaxis.

In addition to the above strategies, blocking

communication between host antigen-presenting

cells and donor T cells has been a focus of R&D in

GVHD for over two decades. However, most of

these R&D ventures involve academically-run

clinical studies. Targeting niche subgroups within

GVHD, such as steroid-refractory aGVHD and

cGVHD, also emerges as one of the key R&D

strategies in the GVHD pipeline, with 31 pipeline

products targeting these populations.

Unmet Needs Remain Largely Unattained in GVHD Management

GVHD is a market with a substantial number of

unattained unmet needs. This is compounded by

the fact that there are no guidelines in place for the

management of GVHD; instead, there are only

recommendations for several therapies. This is

largely due to the orphan nature of the disease, but

it is mainly because of the lack of randomized

clinical trials and the use of variable clinical trial

endpoints in the studies that have been conducted

to date. This has resulted in clinical data that are

not comparable and/or not directly applicable to all

groups of GVHD patients, which, in turn, means

that guidelines cannot be devised.



Executive Summary

Another crucial unmet need is the lack of GVHD-

specific therapies that induce durable remission.

Although the treatments that are currently used in

the management of GVHD (both acute and

chronic) are established and have a good

reputation regarding their efficacy profiles for their

respective indication, they do not seem to offer

durable remission in the GVHD setting. One

example is the extracorporeal photophoresis (ECP)

system, which does not have toxicities and can

induce a quick response, but this response is long-

lasting in only 20–30% of patients. Also, therapies

with minimal side effects are desired, since GVHD

patients are generally not physically fit and cannot

endure additional physical stress due to

conditioning or prophylaxis drugs, or other drugs,

such as antibiotics, antivirals, and antifungal

therapies, that are used to treat or prevent the

other conditions that they develop.

Focusing on patient segments, the management of

steroid-refractory aGVHD (SR-aGVHD) patients

and GVHD patients with respiratory involvement is

challenging and becomes increasingly difficult with

increasing disease duration.

To some extent, most of the aforementioned unmet

needs can be circumvented with better

prophylactic measures, which could possibly

minimize the manifestation of GVHD. However, the

complex pathophysiology of GVHD, combined with

the challenge of personalized treatment design in

GVHD, renders a perfect prophylaxis unattainable

for the foreseeable future.

In all, despite the ongoing development of products

and/or initiatives for the resolution of each unmet

need, the GVHD market is a difficult one to

introduce rapid changes into, as any changes

could affect the survival outcomes for patients. As

such, the highest priority is for more randomized

clinical trials to be conducted.

The GVHD Market Provides an Abundance of Opportunities

There is a large opportunity for pharmaceutical

companies to conduct randomized clinical trials on

immunosuppressive therapies that are being used

off-label in the GVHD setting. This opportunity

could be exploited by supporting existing academic

organizations in their efforts to clarify the treatment

algorithm for GVHD in order to offer optimized

treatment outcomes for patients receiving HSCT.

Further incorporation of specific primary endpoints

in the clinical trial setting of aGVHD and cGVHD

remains an opportunity for both academia and the

pharmaceutical industry. Implementing a more

robust set of endpoints will allow drug developers

to generate accurate and comparable data that

physicians can rely upon in order to adjust their

GVHD management protocols.

Although targeted and stratified clinical trials would

likely lead to drugs being approved for narrower

indications within the GVHD market, the upside is

that the medical community could come closer to a

much needed therapy for sclerotic cGVHD

patients. Overall, there is a great need for

therapies with better safety and efficacy profiles



Executive Summary

that are specific to GVHD pathophysiology and

account for the nature of the disease. Still, there is

room in the market for products for sclerotic

cGVHD patients, particularly given the acute and

poor prognosis elements of GVHD.

Rituxan Remains the Protagonist of the GVHD Market

The prophylaxis setting of GVHD is conservative,

and as such, the historic use of calcineurin

inhibitors with a short course of methotrexate

(MTX) will remain the most avidly-used

prophylactic regimen through 2018. Astellas

Pharma’s Prograf (tacrolimus) and anti-thymocyte

globulins (ATGs) are expected to also remain key

products for prophylaxis. They have been widely

used to date and are trusted by hematologists. In

GlobalData’s competitive assessment of the

prophylaxis landscape, Roche’s Rituxan emerged

as the most clinically and commercially attractive

prophylaxis regimen (see figure below). It is a

favored therapy that is used in both aGVHD and

cGVHD prophylaxis due to its growing reputation in

the field. Meanwhile, Sanofi/Genzyme’s

Campath/Lemtrada will remain an essential part of

conditioning regimens, but not prophylaxis, due to

its highly infectious and generally harmful side

effects. Over the 2013–2018 forecast period,

increasing adverse reactions to classic therapy

might give rise to Orencia-based prophylaxis, as

well as MultiStem (modified mesenchymal stem

cells)-based prophylaxis, which promises effective

prophylaxis with only one use.

Figure below provides GlobalData’s competitive

assessment of the GVHD prophylaxis landscape

from 2013–2018.

Competitive Assessment of GVHD Prophylaxis Off-Label Therapies and Late-Stage Pipeline Agents, 2013–2018

Standard of care: CsA+MTX

Rapamune+CsA without MTX

Prograf and Rapamune instead

of CsA

Thymoglobuline based prophylaxis

Lemtrada based prophylaxis

Orencia based prophylaxis

Velcade based prophylaxis

Rituxan based prophylaxis

MultiStem based prophylaxis

ATG-Fresenius based prophylaxis

2.0

2.5

3.0

3.5

4.0

4.5

2.0 2.5 3.0 3.5 4.0 4.5 5.0

CO

MM

ERC

IAL

SC

OR

E

CLINICAL SCORE Source: GlobalData CsA = cyclosporine A MTX = methotrexate

SR-aGVHD prevails as the most urgent and poorly

managed population in the aGVHD setting, and as

such, there are plenty of innovative initiatives

targeting this group. Because of the complexity of

aGVHD pathophysiology, many different

immunotherapies and immunosuppressive small

molecules have and are being used for its

management, giving way to a complex landscape

where establishing reputation among hematology

communities through trial funding and proven

efficacy is key for an aGVHD therapy to move

forward.



Executive Summary

Figure below provides GlobalData’s competitive

assessment of the aGVHD landscape from 2013–

2018.

Competitive Assessment of aGVHD Off-Label Therapies and Late-Stage Pipeline Agents, 2013–2018

Standard of care: CsA + Steroids

MMF

TNFα inhibitor therapies

CD25α inhibitor therapies

mTOR inhibitors

ECP

Nipent

Thymoglobuline

Lemtrada

Rituxan

Begedina

Leukotac

Prochymal

2.0

2.5

3.0

3.5

4.0

4.5

5.0

2.0 2.5 3.0 3.5 4.0 4.5 5.0

CO

MM

ERC

IAL

SCO

RE

CLINICAL SCORE Source: GlobalData X = Clinical Score; Y = Commercial Score CsA = cyclosporine A; ECP = extracorporeal photophoresis; mTOR = mammalian target of rapamycin; TNFα = tumor necrosis factor alpha

The cGVHD market remains stagnant from the

innovation point of view. Initial therapy with

steroids is the mainstay of treatment for cGVHD,

but because of the nature of steroid therapy —

specifically, the severe side effects associated with

its long-term use — it cannot be used chronically.

Therefore, other treatments such as ECP, Rituxan,

Nipent (pentostatin), and Gleevec (imatinib

mesylate), are expected to face unhindered future

growth in the cGVHD setting during the 2013 to

2018 forecast period, and will emerge as the most

clinically and commercially attractive therapies in

GlobalData’s competitive assessment of the

cGVHD landscape, as shown in figure below.

Competitive Assessment of cGVHD Off-Label Therapies and Late-Stage Pipeline Agents, 2013–2018

Standard of care: Steroids

ECP

mTOR inhibitor

MMFRituxan

Nipent Gleevec

CD25α inhibitor therapies

Lemtrada

2.0

2.5

3.0

3.5

4.0

4.5

5.0

2.0 2.5 3.0 3.5 4.0 4.5 5.0

CO

MM

ER

CIA

L S

CO

RE

CLINICAL SCORE

Source: GlobalData ECP = extracorporeal photophoresis; MMF = mycophenolate mofetil; mTOR = mammalian target of rapamycin

What Do Physicians Think?

In regard to which part of GVHD management

requires improvement, KOLs interviewed by

GlobalData offered the following:

“I think the way to move forward [in the

management of GVHD], clearly, is prophylaxis.

That’s the way it is going to get better [in terms of

improved outcomes in HSCT].”

[US] KOL, March 2014

“...actually, the major point in this [GVHD

management] is that when you start tapering

immunosuppressant therapy when you are already

using low doses of prednisone and [a] calcineurin

inhibitor, there is a time point where a subset of

these patients flare again with chronic GVHD.

There is no standard tapering protocol.”

[EU] KOL, March 2014



Executive Summary

Commenting on the management of patients with

toxicities, a KOL said:

“I would say that for MSC therapies, ECP, and

rituximab, I feel quite comfortable regarding [the]

management of their toxicity, and then the rest of

drugs, actually, are hard to manage, and you have

a quite high incidence of infections, which is not

easy when you have a patient with pre-existing or

serious toxicities. You can’t help these patients;

they usually succumb to organ failure.”


Discussing the safety of late-stage pipeline

therapy, Osiris Therapeutics/Mesoblast’s

Prochymal, a KOL said:

“I mean, there are [a] number of potential safety

issues about what their [MSC therapies’] impact is.

I expect Prochymal will receive a black box

warning regarding viral infection or tumor relapse

risk or issues with chimers. The honest truth is, if

you are applying them in a setting of prophylaxis,

that is the most comfortable way — and there are

data out there to support mesenchymal stem cell

therapy in prophylaxis — then the downsides of

having GVHD probably outweigh any potential

perceived risk of the product. If the product

worked, I wouldn’t be concerned about the

potential risks of it, because having a product that

worked in that setting would outweigh any potential

risk, but I don’t think the product worked.”


Discussing the efficacy of the late-stage pipeline

therapy, Therakos’ Uvadex (methoxsalen), an ECP

therapy, a KOL said:

“It’s a very safe treatment if we compare [it] to all

older therapies, because with ECP you have an

immunosuppressive effect, but it’s a progressive

and chronic immunosuppressive effect, not a

drastic one….Probably, it’s important to introduce

very early this kind of treatment, and to not to

prolong [it] if there is no effect. So, it’s important to

do either eight or 10 photophoresis cycles to know

if there is a response or not, and after, to switch to

another therapy. But probably, photophoresis has

an important place in the therapeutic setting in

acute and in chronic [GVHD]. In chronic [GVHD],

it’s definitely effective in cutaneous and ocular

involvement, as well as in mucositis.”


Commenting on the efficacy of Roche’s Rituxan, a

KOL stated:

“I have a good experience with rituximab; that is

very effective for cutaneous involvement and in

sclerosis, which are the most frequent

expression[s] of chronic [GVHD] disease. It [also]

has good results in ocular lesions and mucositis.”




Executive Summary

Discussing the challenges associated with the

available treatment options in the GVHD market, a

KOL said:

“The fact that there is such [a] big array of

immunosuppressive drugs [used off-label to treat

GVHD], it makes it difficult to decide [what

treatment to select, especially as] none of them

have been studied properly [within the GVHD

setting].”

[US] KOL, April 2014


Table of Contents


1 Table of Contents

1 Table of Contents ..................................................................................................................... 12

1.1 List of Tables .................................................................................................................... 19

1.2 List of Figures ................................................................................................................... 23

2 Introduction ............................................................................................................................... 24

2.1 Catalyst ............................................................................................................................. 24

2.2 Related Reports ................................................................................................................ 25

2.3 Upcoming Related Reports ............................................................................................... 25

3 Disease Overview ..................................................................................................................... 26

3.1 Etiology and Pathophysiology ........................................................................................... 26

3.1.1 Etiology ......................................................................................................................... 26

3.1.2 Pathophysiology ............................................................................................................ 28

3.1.3 Classification and Prognosis ......................................................................................... 29

3.2 Symptoms ......................................................................................................................... 31

4 Epidemiology ............................................................................................................................ 33

4.1 Disease Background ......................................................................................................... 33

4.2 Risk Factors and Comorbidities ........................................................................................ 34

4.3 Global Trends ................................................................................................................... 36

4.4 Forecast Methodology ....................................................................................................... 37

4.4.1 Sources Used................................................................................................................ 39

4.4.2 Sources Not Used ......................................................................................................... 45

4.4.3 Diagnosed Incident Cases of HSCTs ............................................................................ 46


Table of Contents


4.4.4 Diagnosed Incident Cases of Autologous HSCTs .......................................................... 48

4.4.5 Diagnosed Incident Cases of Allogeneic HSCTs ........................................................... 49

4.4.6 Diagnosed Incident Cases of aGVHD ........................................................................... 50

4.4.7 Four-Year Diagnosed Prevalent Cases of aGVHD ........................................................ 50

4.4.8 Diagnosed Incident Cases of cGVHD ............................................................................ 51

4.4.9 Five-Year Diagnosed Prevalent Cases of cGVHD ......................................................... 51

4.5 Epidemiological Forecast for GVHD (2013–2023) ............................................................. 52

4.5.1 Diagnosed Incident Cases of HSCTs ............................................................................ 52

4.5.2 Diagnosed Incident Cases of Autologous HSCTs .......................................................... 54

4.5.3 Diagnosed Incident Cases of Allogeneic HSCTs ........................................................... 55

4.5.4 Diagnosed Incident Cases of aGVHD ........................................................................... 57

4.5.5 Four-Year Diagnosed Prevalent Cases of aGVHD ........................................................ 59

4.5.6 Diagnosed Incident Cases of cGVHD ............................................................................ 61

4.5.7 Five-Year Diagnosed Prevalent Cases of cGVHD ......................................................... 62

4.6 Discussion ........................................................................................................................ 64

4.6.1 Epidemiological Forecast Insight ................................................................................... 64

4.6.2 Limitations of the Analysis ............................................................................................. 65

4.6.3 Strengths of the Analysis ............................................................................................... 66

5 Current Treatment Options ....................................................................................................... 67

5.1 Overview ........................................................................................................................... 67

5.2 Product Profiles – Major Therapies ................................................................................... 69

5.2.1 Methylprednisolone (numerous brand and generic names) ........................................... 69

5.2.2 Cyclosporine (numerous brands and generic names).................................................... 73


Table of Contents


5.2.3 Anti-Thymocyte Globulin (ATG) Therapies .................................................................... 78

5.3 Product Profiles – Off-Label Therapies.............................................................................. 83

5.3.1 Biologics (Tumor Necrosis Factor (TNF)α Inhibitors, Interleukin-2 Receptor α (CD25)

Inhibitors, Co-Stimulatory Blockers and Other Biologics) .............................................. 83

5.3.2 Small Immunosuppressive Molecules (mTOR Inhibitors, Solid Organ Transplant

Therapies, and Anti-Neoplastic Therapies) ................................................................. 102

6 Unmet Need and Opportunity ................................................................................................. 117

6.1 Overview ......................................................................................................................... 117

6.2 Lack of Randomized Clinical Trials ................................................................................. 120

6.2.1 Unmet Need ................................................................................................................ 120

6.2.2 Gap Analysis ............................................................................................................... 120

6.2.3 Opportunity ................................................................................................................. 121

6.3 No Consensus Regarding Clinical Trial Endpoints .......................................................... 121

6.3.1 Unmet Need ................................................................................................................ 121

6.3.2 Gap Analysis ............................................................................................................... 121

6.3.3 Opportunity ................................................................................................................. 122

6.4 Optimization of Prophylactic Measures ........................................................................... 122

6.4.1 Unmet Need ................................................................................................................ 122

6.4.2 Gap Analysis ............................................................................................................... 123

6.4.3 Opportunity ................................................................................................................. 123

6.5 Lack of Standardized Protocols for Established and Off-Label Therapies ....................... 124

6.5.1 Unmet Need ................................................................................................................ 124

6.5.2 Gap Analysis ............................................................................................................... 124


Table of Contents


6.5.3 Opportunity ................................................................................................................. 125

6.6 Improved Treatment Outcomes for Patients Who Develop Toxicities .............................. 125

6.6.1 Unmet Need ................................................................................................................ 125

6.6.2 Gap Analysis ............................................................................................................... 126

6.6.3 Opportunity ................................................................................................................. 126

6.7 Desire for Treatments that Exhibit Longer-Lasting Efficacy Profiles ................................ 126

6.7.1 Unmet Need ................................................................................................................ 126

6.7.2 Gap Analysis ............................................................................................................... 127

6.7.3 Opportunity ................................................................................................................. 128

6.8 Management of SR-aGVHD Patients .............................................................................. 128

6.8.1 Unmet Need ................................................................................................................ 128

6.8.2 Gap Analysis ............................................................................................................... 129

6.8.3 Opportunity ................................................................................................................. 129

6.9 Management of Sclerotic cGVHD Patients ...................................................................... 129

6.9.1 Unmet Need ................................................................................................................ 129

6.9.2 Gap Analysis ............................................................................................................... 130

6.9.3 Opportunity ................................................................................................................. 130

6.10 Improved Prognosis for Patients with Lung Involvement ................................................. 131

6.10.1 Unmet Need ................................................................................................................ 131

6.10.2 Gap Analysis ............................................................................................................... 131

6.10.3 Opportunity ................................................................................................................. 132

7 Research and Development Strategies ................................................................................... 133

7.1 Overview ......................................................................................................................... 133


Table of Contents


7.1.1 Improvement of Prophylactic Regimens ...................................................................... 133

7.1.2 Inhibition of T-Cell Proliferation and Activation ............................................................ 134

7.1.3 Adopting Treatments from Hematologic Indications..................................................... 135

7.1.4 Targeting Niche Subgroups Within GVHD ................................................................... 136

7.2 Current Clinical Trial Design ............................................................................................ 137

7.2.1 Current Trial Designs are Dependent on the Stage Within the Treatment Algorithm That

a Product is Targeting ................................................................................................ 137

7.2.2 Lack of Consensus on Clinical Endpoints in Current Trial Designs .............................. 138

7.2.3 Patient Exclusion Issues in Current Trial Designs ....................................................... 138

7.2.4 Current Trial Design of Key Pipeline Products ............................................................. 138

7.3 Future Clinical Trial Design ............................................................................................. 140

7.3.1 Future Trial Designs Need to Incorporate Randomization ........................................... 140

7.3.2 Future Trial Designs Need to Incorporate Conditioning Regimens and Hematological

Patients ...................................................................................................................... 141

7.3.3 Companies Behind Off-Label Therapies Should Strategize to Conduct Randomized

Studies ....................................................................................................................... 141

7.3.4 Design of Early-Phase Clinical Trials for Cellular and Gene Therapy Products

Accommodates 2014 Guidance from the FDA ............................................................ 141

8 Pipeline Assessment............................................................................................................... 142

8.1 Overview ......................................................................................................................... 142

8.2 Promising Drugs in Clinical Development ........................................................................ 143

8.2.1 Leukotac (inolimomab) ................................................................................................ 143

8.2.2 Begedina (BT 5/9) ....................................................................................................... 148

8.2.3 Budenofalk (budesonide) ............................................................................................ 151


Table of Contents


8.2.4 ATG-Fresenius (EZ-2053) ........................................................................................... 154

8.2.5 Prochymal (remestemcel-L) ........................................................................................ 157

8.2.6 MultiStem (modified mesenchymal stem cells) ............................................................ 162

8.2.7 Uvadex (Extracorporeal Photophoresis) ...................................................................... 165

8.2.8 orBec (beclomethasone dipropionate) ......................................................................... 169

8.3 Innovative Early-Stage Approaches ................................................................................ 172

8.3.1 Targeting Regulatory T Cells ....................................................................................... 175

8.3.2 Mesenchymal Stem Cell Therapies ............................................................................. 176

8.3.3 Immunomodulatory Cell Surface Receptor Inhibitors ................................................... 177

8.3.4 IL-6 Inhibitors .............................................................................................................. 178

9 Pipeline and Off-Label Valuation Analysis............................................................................... 179

9.1 Clinical Benchmarking of Key Pipeline and Off-Label Drugs ........................................... 179

9.1.1 GVHD Prophylaxis ...................................................................................................... 179

9.1.2 Acute GVHD................................................................................................................ 182

9.1.3 Chronic GVHD ............................................................................................................ 186

9.2 Commercial Benchmarking of Key Pipeline and Off-Label Drugs .................................... 187


9.2.2 Acute GVHD................................................................................................................ 190

9.2.3 Chronic GVHD ............................................................................................................ 192

9.3 Competitive Assessment ................................................................................................. 194


9.3.2 Acute GVHD................................................................................................................ 195

9.3.3 Chronic GVHD ............................................................................................................ 197


Table of Contents


9.4 Top-Line Five-Year Forecast ........................................................................................... 199

9.4.1 US ............................................................................................................................... 204

9.4.2 5EU ............................................................................................................................. 208

10 Appendix................................................................................................................................. 212

10.1 Bibliography .................................................................................................................... 212

10.2 Abbreviations .................................................................................................................. 231

10.3 Methodology ................................................................................................................... 237

10.4 Forecasting Methodology ................................................................................................ 237

10.4.1 Diagnosed GVHD Patients .......................................................................................... 237

10.4.2 Percent Drug-Treated Patients .................................................................................... 238

10.4.3 Drugs Included in Each Therapeutic Class .................................................................. 238

10.4.4 Launch and Patent Expiry Dates ................................................................................. 239

10.4.5 General Pricing Assumptions ...................................................................................... 239

10.4.6 Individual Drug Assumptions ....................................................................................... 240

10.4.7 Generic Erosion .......................................................................................................... 247

10.4.8 Pricing of Pipeline Agents............................................................................................ 247

10.5 Physicians and Specialists Included in This Study .......................................................... 248

10.6 About the Authors ........................................................................................................... 250

10.6.1 Author ......................................................................................................................... 250

10.6.2 Reviewer ..................................................................................................................... 250

10.6.3 Epidemiologist ............................................................................................................. 251

10.6.4 Global Head of Healthcare .......................................................................................... 251

10.7 About GlobalData ............................................................................................................ 252


Table of Contents


10.8 Disclaimer ....................................................................................................................... 252

1.1 List of Tables

Table 1: Steps Involved in the Development of aGVHD .................................................................................. 28

Table 2: Steps Involved in the Development of cGVHD .................................................................................. 29

Table 3: Grading System of Organ Involvement in aGVHD ............................................................................ 30

Table 4: Classification of Organ Involvement in cGVHD ................................................................................. 31

Table 5: Symptoms of aGVHD ....................................................................................................................... 31

Table 6: Symptoms of cGVHD ....................................................................................................................... 32

Table 7: Risk Factors and Comorbidities for GVHD ........................................................................................ 35

Table 8: 6MM, Sources of HSCT, aGVHD, and cGVHD Data Used for the Forecast ...................................... 39

Table 9: 6MM, Sources Not Used in the Epidemiological Analysis of GVHD ................................................... 46

Table 10: 6MM, Diagnosed Incident Cases of HSCTs, Both Sexes, All Ages, N, 2013–2023 .......................... 53

Table 11: 6MM, Diagnosed Incident Cases of Autologous HSCTs, Both Sexes, All Ages, N, 2013–2023 ....... 54

Table 12: 6MM, Diagnosed Incident Cases of Allogeneic HSCTs, Both Sexes, All Ages, N, 2013–2023 ......... 56

Table 13: 6MM, Diagnosed Incident Cases of aGVHD in Diagnosed Incident Cases of First Allogeneic HSCTs,

Both Sexes, All Ages, N, 2013–2023 .............................................................................................. 58

Table 14: 6MM, Four-Year Diagnosed Prevalent Cases of aGVHD in Diagnosed Incident Cases of First

Allogeneic HSCTs, All Ages, Both Sexes, N, 2013–2023 ................................................................ 60

Table 15: 6MM, Diagnosed Incident Cases of cGVHD in Diagnosed Incident Cases of First Allogeneic HSCTs,

All Ages, Both Sexes, N, 2013–2023 .............................................................................................. 61

Table 16: 6MM, Five-Year Diagnosed Prevalent Cases of cGVHD in Diagnosed Incident Cases of First

Allogeneic HSCTs, All Ages, Both Sexes, N, 2013–2023 ................................................................ 63

Table 17: Product Profile – Methylprednisolone ............................................................................................. 70

Table 18: Efficacy of Methylprednisolone in GVHD Studies ............................................................................ 71


Table of Contents


Table 19: SWOT analysis – Methylprednisolone, 2014................................................................................... 73

Table 20: Product Profile – Cyclosporine ....................................................................................................... 75

Table 21: Efficacy of Cyclosporine in GVHD Studies ...................................................................................... 76

Table 22: SWOT Analysis – Cyclosporine, 2014 ............................................................................................ 77

Table 23: Product Profiles – ATG Therapies .................................................................................................. 80

Table 24: Efficacy of ATG Therapies in GVHD ............................................................................................... 81

Table 25: SWOT Analysis – ATG Therapies, 2014 ......................................................................................... 82

Table 26: Product Profile – Biologics – TNFα Inhibitors .................................................................................. 85

Table 27: Efficacy of Anti-TNFα Therapies in GVHD ...................................................................................... 86

Table 28: Product Profiles – Biologics – IL-2Rα (CD25) Inhibitors .................................................................. 89

Table 29: Efficacy of IL-2Rα (CD25) Inhibitor Therapies in GVHD .................................................................. 90

Table 30: Product Profile – Biologics – Co-Stimulatory Blockers .................................................................... 93

Table 31: Efficacy of Co-Stimulatory Blocker Therapies in GVHD ................................................................... 94

Table 32: Product Profile – Other Biologics (Campath/Lemtrada and Rituxan) ............................................... 96

Table 33: Efficacy of Other Biologic Therapies (Campath/Lemtrada and Rituxan) in GVHD ............................ 97

Table 34: Safety Profile – Off-Label Biologics Used in GVHD, 2014 ............................................................... 99

Table 35: SWOT Analysis – Biologics – TNFα Inhibitors, 2014 ..................................................................... 100

Table 36: SWOT Analysis – Biologics – IL-2Rα (CD25) inhibitors, 2014 ....................................................... 101

Table 37: SWOT Analysis – Biologics – Co-Stimulatory Blockers, 2014 ....................................................... 101

Table 38: SWOT Analysis – Biologics – Others, 2014 .................................................................................. 102

Table 39: Product Profile – Small Immunosuppressive Molecules – mTOR Inhibitors ................................... 104

Table 40: Efficacy of mTOR Inhibitors in GVHD ........................................................................................... 105

Table 41: Product Profile – Small Immunosuppressive Molecules – SOT Therapies ..................................... 106

Table 42: Efficacy of SOT Therapies in GVHD ............................................................................................. 107


Table of Contents


Table 43: Product Profile – Small Immunosuppressive Molecules – Anti-Neoplastic Therapies..................... 110

Table 44: Efficacy of Anti-Neoplastic Therapies in GVHD ............................................................................. 111

Table 45: Safety Profile – Small Immunosuppressive Molecules .................................................................. 113

Table 46: SWOT Analysis – Small Immunosuppressive Molecules – mTOR Inhibitors, 2014 ........................ 114

Table 47: SWOT Analysis – Small Immunosuppressive Molecules – SOT Therapies, 2014 .......................... 115

Table 48: SWOT analysis – Small Immunosuppressive Molecules – Anti-Neoplastic Therapies, 2014 .......... 116

Table 49: Unmet Need and Opportunity in GVHD ........................................................................................ 119

Table 50: Clinical Trial Design of Key Pipeline Drugs for GVHD, July 2014 .................................................. 139

Table 51: GVHD – Late Stage Pipeline, 2013 .............................................................................................. 143

Table 52: Product Profile – Leukotac (inolimomab) ...................................................................................... 145

Table 53: Efficacy of Leukotac in GVHD ...................................................................................................... 147

Table 54: SWOT Analysis – Leukotac (inolimomab), 2014 ........................................................................... 148

Table 55: Product Profile – Begedina (BT 5/9) ............................................................................................. 149

Table 56: Efficacy of Begedina in GVHD ...................................................................................................... 150

Table 57: SWOT Analysis – Begedina (BT 5/9), 2014 .................................................................................. 151

Table 58: Product Profile – Budenofalk (budesonide) ................................................................................... 152

Table 59: SWOT Analysis – Budenofalk, 2014 ............................................................................................. 153

Table 60: Product Profile – ATG-Fresenius (EZ-2053) ................................................................................. 155

Table 61: Efficacy of ATG-Fresenius in GVHD (EZ-2053) ............................................................................ 156

Table 62: SWOT Analysis – ATG-Fresenius, 2014 ....................................................................................... 157

Table 63: Product Profile – Prochymal (remestemcel-L) ............................................................................... 160

Table 64: SWOT Analysis – Prochymal (remestemcel-L), 2014 .................................................................... 162

Table 65: Product Profile – MultiStem (modified mesenchymal stem cells) ................................................... 163

Table 66: SWOT Analysis – MultiStem (modified mesenchymal stem cells) ................................................. 164


Table of Contents


Table 67: Product Profile – Uvadex (Extracorporeal Photophoresis) ............................................................. 167

Table 68: Efficacy of Uvadex in GVHD ......................................................................................................... 168

Table 69: SWOT Analysis – Uvadex (Extracorporeal Photophoresis) ........................................................... 169

Table 70: Product Profile – orBec (beclomethasone dipropionate)................................................................ 171

Table 71: SWOT Analysis – orBec (beclomethasone proprionate), 2014 ...................................................... 172

Table 72: Early-Stage Pipeline Products for GVHD, July 2014 ..................................................................... 174

Table 73: Clinical Benchmarking for GVHD Prophylaxis, 2014 ..................................................................... 181

Table 74: Clinical Benchmarking for aGVHD, 2014 ...................................................................................... 185

Table 75: Clinical Benchmarking for cGVHD, 2014 ...................................................................................... 187

Table 76: Commercial Benchmarking for GVHD Prophylaxis, 2014 .............................................................. 189

Table 77: Commercial Benchmarking for aGVHD, 2014 ............................................................................... 191

Table 78: Commercial Benchmarking for cGVHD, 2014 ............................................................................... 193

Table 79: Top-Line Sales Forecasts ($m) for GVHD, 2013–2018 ................................................................. 201

Table 80: Key Events Impacting Sales for GVHD, 2013–2018...................................................................... 203

Table 81: Global GVHD Market – Drivers and Barriers, 2013–2018 ............................................................. 204

Table 82: Key Launch Dates, GVHD, 2013–2018 ........................................................................................ 239

Table 83: Key Patent Expiries, GVHD, 2013–2018....................................................................................... 239


Table of Contents


1.2 List of Figures

Figure 1: Schematic of HSCT ...................................................................................................................... 27

Figure 2: Schematic Flow Chart of the Derivation of the aGVHD and cGVHD Patient Population in the 6MM

.................................................................................................................................................... 37

Figure 3: 6MM, Diagnosed Incident Cases of HSCTs , Both Sexes, All Ages, N, 2013–2023 ....................... 53

Figure 4: 6MM, Diagnosed Incident Cases of Autologous HSCTs, Both Sexes, All Ages, N, 2013–2023 ...... 55

Figure 5: 6MM, Diagnosed Incident Cases of Allogeneic HSCTs, Both Sexes, All Ages, N, 2013–2023 ...... 57

Figure 6: 6MM, Diagnosed Incident Cases of aGVHD in Diagnosed Incident Cases of First Allogeneic

HSCTs, Both Sexes, All Ages, N, 2013–2023 ............................................................................... 59

Figure 7: 6MM, Four-Year Diagnosed Prevalent Cases of aGVHD in Diagnosed Incident Cases of First

Allogeneic HSCTs, All Ages, Both Sexes, 2013–2023................................................................... 60

Figure 8: 6MM, Diagnosed Incident Cases of cGVHD in Diagnosed Incident Cases of First Allogeneic

HSCTs, All Ages, Both Sexes, N, 2013–2023 ............................................................................... 62

Figure 9: 6MM, Five-Year Diagnosed Prevalent Cases of cGVHD in Diagnosed Incident Cases of First

Allogeneic HSCTs, All Ages, Both Sexes, N, 2013–2023 .............................................................. 63

Figure 10: Trends in aGVHD Management in the 6MM, 2014......................................................................... 68

Figure 11: Trends in cGVHD Management in the 6MM, 2014 ......................................................................... 69

Figure 12: Competitive Assessment of GVHD Prophylaxis Off-Label Therapies and Late-Stage Pipeline

Agents, 2013–2018 .................................................................................................................... 195

Figure 13: Competitive Assessment of aGVHD Off-Label Therapies and Late-Stage Pipeline Agents, 2013–

2018 ........................................................................................................................................... 197

Figure 14: Competitive Assessment of cGVHD Off-Label Therapies and Late-Stage Pipeline Agents, 2013–

2018 ........................................................................................................................................... 199

Figure 15: Global Sales for GVHD by Region and GVHD Indication, 2013–2018 .......................................... 202



Introduction

2 Introduction

Graft-versus-host disease (GVHD) is an orphan indication with a poor prognosis and high mortality

rates. It is a complication of hematopoietic stem cell transplantation (HSCT), and takes different

forms, depending on the time of disease manifestation and organ localization. As GVHD

pathogenesis remains largely elusive, the current treatments used for its management are not

GVHD-specific, but rather, are off-label therapies borrowed from immunological and hematological

indications. However, the GVHD pipeline is rich and diverse, and promises a big change in the

landscape of the GVHD market.

2.1 Catalyst

Despite the vast array of available off-label therapies (approximately 30) for the treatment and/or

prevention of GVHD, very few of these therapies have been tested in large randomized clinical

trials. This has resulted in vague treatment recommendations and many patients being enrolled in

institutional clinical trials. The only available standard of care is intravenous (IV)

methylprednisolone. However, it fails to produce a complete response (CR) in more than 50% of

treated patients. As a result, steroid-refractory patient subgroups face a poor prognosis, with a

deteriorating quality of life (QoL). This problem is further compounded by the fact that second- and

third-line treatments can vary from country to country across the six major markets (6MM) (US,

France, Germany, Italy, Spain, and UK), and also between different medical institutions in the

same country.

Over GlobalData’s 2013–2018 forecast period, the main drivers of growth in the GVHD market

include the increasing numbers of allogeneic HSCTs and the increasing use of marketed and off-

label biologic therapies across the 6MM.

Sanofi/Genzyme is a key player in the GVHD market, with EU-approved Thymoglobulin (anti-

thymocyte globulin [rabbit]) and the off-label biologic therapy, Campath/Lemtrada, which infiltrate

the prophylaxis, acute GVHD (aGVHD), and chronic GVHD (cGVHD) setting. Still, Johnson &

Johnson’s (J&J’s) Remicade (infliximab) has gained a significant share of the aGVHD patient

group, as it is one of the few drugs that is effective in GVHD with gastrointestinal (GI) involvement.

Meanwhile, gaining more and more ground in the cGVHD setting is Roche’s Rituxan (rituximab),

which GlobalData estimates will be one of the best-selling biologics by value in GVHD, in the US by

2018.



Introduction

2.2 Related Reports

GlobalData (2014). EpiCast Report: Graft-Versus-Host Disease – Epidemiology Forecast to

2023, June 2014, GDHCER064-14

GlobalData (2014). OpportunityAnalyzer: Chronic Lymphocytic Leukemia – Opportunity

Analysis and Forecasts to 2018, June 2014, GDHC017POA

GlobalData (2014). PharmaPoint: Ulcerative Colitis – Global Drug Forecast and Market

Analysis to 2022, February 2014, GDHC80PIDR

GlobalData (2014). PharmaPoint: Crohn’s Disease – Global Drug Forecast and Market

Analysis to 2022, January 2014, GDHC77PIDR

GlobalData (2013). OpportunityAnalyzer: Acute Myeloid Leukemia (AML) – Opportunity

Analysis and Forecasts to 2017, August 2013, GDHC003POA

GlobalData (2013). PharmaPoint: Chronic Myeloid Leukemia (CML), Global Drug Forecast and

Market Analysis to 2022, April 2013, GDHC103PIDR

2.3 Upcoming Related Reports

GlobalData (2014). PharmaSphere – Emerging Biotechnologies: Stem Cell Therapy, August

2014, GDHC012PSR

GlobalData (2014). OpportunityAnalyzer: - Non Hodgkin B cell Lymphoma, Opportunity

Analysis and Forecasts to 2018, July 2014, GDHC035POA


Appendix


10.7 About GlobalData

GlobalData is a leading global provider of business intelligence in the healthcare industry.

GlobalData provides its clients with up-to-date information and analysis on the latest developments

in drug research, disease analysis, and clinical research and development. Our integrated business

intelligence solutions include a range of interactive online databases, analytical tools, reports, and

forecasts. Our analysis is supported by a 24/7 client support and analyst team.

GlobalData has offices in New York, San Francisco, Boston, London, India, Korea, Japan,

Singapore, and Australia.

10.8 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, GlobalData.

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