atrial fibrillation – global drug forecast and · pdf filereference code gdhc87pidr |...

REFERENCE CODE GDHC87PIDR | PUBLICATION DATE FEBRUARY 2015

ATRIAL FIBRILLATION – GLOBAL DRUG FORECAST AND MARKET ANALYSIS

TO 2023

Atrial Fibrillation – Global Drug Forecast and Market Analysis to 2023 2 © GlobalData. This report is a licensed product and is not to be copied, reproduced, shared or resold in any form.

ATRIAL FIBRILLATION – GLOBAL DRUG FORECAST AND MARKET ANALYSIS TO 2023

Executive Summary

Table below provides the key metrics for atrial

fibrillation (AF) in the eight major pharmaceutical

markets (8MM) (US, France, Germany, Italy,

Spain, UK, Japan, and Canada) covered in this

report, from 2013 to 2023.

AF: Key Metrics in the 8MM, 2013−2023 2013 Epidemiology

Prevalent population 10.1 million

Treated population 8.7 million

2013 Market Sales

US $2.7bn

5EU $1.4bn

Japan $258m

Canada $243m

Total $4.6bn

Pipeline Assessment

Number of drugs in Phase I–III 10

Number of first-in-class drugs 1

Most Promising Pipeline Drug Peak-Year Sales

Gilead’s ranolazine/dronedarone $315m

Key Events (2014–2023) Level of Impact

Launch of Daiichi Sankyo’s Savaysa* (edoxaban) in 2014 and 2015 ↑↑

Portola Pharmaceuticals launches the factor Xa inhibitor antidote, andexanet alfa, in 2017 ↑↑

Boehringer Ingelheim launches the Pradaxa antidote, idarucizumab, in 2018 ↑↑

Boehringer Ingelheim’s Pradaxa (dabigatran) loses US patent protection in 2018 ↓↓↓

Gilead launches ranolazine/dronedarone in 2022 ↑↑

2023 Market Sales

US $2.4bn

5EU $2.5bn

Japan $535m

Canada $255m

Total $5.7bn

Source: GlobalData *Edoxaban is marketed as in Japan under the brand name Lixiana. 5EU = France, Germany, Italy, Spain, and the UK, 8MM = US, France, Germany, Italy, Spain, UK, Japan, and Canada

Atrial Fibrillation Market Will Peak at $9.4bn in 2020

GlobalData estimates the 2013 sales for AF at

approximately $4.6 billion across the 8MM. The US

dominates the overall size of the AF market,

generating an estimated $2.7 billion in 2013 and

accounting for 59% of the overall size of the

market. This is mainly due to the large prevalent

AF population in the US, early adoption of the new

oral anticoagulants (NOACs), and higher prices for

AF medications in this market.

Since the launch of the first of the NOACs in 2010,

this drug class has experienced substantial uptake,

accounting for $3.2 billion − approximately 70% −

of all AF sales revenue across the 8MM in 2013.

GlobalData anticipates that NOAC uptake will

continue to increase, and will be the main driver in

the growth of the AF market. This growth will be

driven further by the recent launch of a fourth

NOAC, Daiichi-Sankyo’s Savaysa, which now

provides further anticoagulant treatment options for

patients with AF. GlobalData forecasts that the AF

drug market will grow at a Compound Annual

Growth Rate (CAGR) of 2.1% over the 10-year

forecast, resulting in a market value of $5.7 billion

by 2023. However, it is expected that peak sales

will be reached prior to this date, in 2020, when the

AF market will be valued at $9.4 billion. A

subsequent decline in the overall size of the AF

market from this date will be related to the entry of

the first generic versions of the NOACs, starting



Executive Summary

with Boehringer Ingelheim’s anticipated loss of US

patent protection for Pradaxa in 2018.

The antiarrhythmic drugs ranolazine/dronedarone,

developed by Gilead, and Laguna

Pharmaceuticals’ vanoxerine are also forecast to

launch late in the forecast period. However, neither

will reach peak sales by 2023, with only

ranolazine/dronedarone making an early impact as

a potential drug candidate for the maintenance of

sinus rhythm.

Major drivers for the growth of the AF market over

the forecast period will include:

The continued uptake of the NOACs for the

prevention of stroke in patients with AF. Due to

the advances that the NOACs provide in terms

of improved safety and the lack of a need for

routine monitoring, NOAC uptake will continue

to increase, taking market share away from

warfarin.

A shift in AF treatment guidelines to using the

CHA2DS2-VASc score instead of the CHADS2

score for assessing stroke risk, which will

cause a larger proportion of lower risk patients

to receive anticoagulant treatment. (See Table 13 and Table 14 for descriptions of the

CHADS2 and CHA2DS2-VASc abbreviations,

respectively.)

The approval and launch of the first antidotes

for the NOACs will alleviate physician and

patient concerns regarding a lack of a reversal

agent in the event of uncontrolled bleeding,

thereby increasing overall uptake.

Major barriers to the growth of the AF market over

the forecast period will include:

Generic erosion of the NOACs, starting with

Boehringer Ingelheim’s Pradaxa, which will

lose US patent protection in 2018.

Large, costly, and comprehensive clinical trials

required to support regulatory approval of

cardiovascular drugs, which will deter drug

developers wanting to enter the AF market.

Widely available generic antiarrhythmic drugs,

which will make it difficult for any novel rhythm

control agents to gain reimbursement and

wider uptake.



Executive Summary

Figure below provides the sales for AF in the 8MM

from 2013 to 2023.

Sales for AF by Region, 2013–2023

59%

4%

12%

4%

7%

3%6%

5%

2013 Total: $4.6bn

US

France

Germany

Italy

Spain

UK

Japan

Canada

42%

8%15%

7%

10%

4%

9%5%

2023 Total: $5.7bn

Source: GlobalData

The New Oral Anticoagulants Will Drive the Growth and Size of the Atrial Fibrillation Market

Antithrombotic therapy has an important role in the

prevention of stroke in patients with AF, with

vitamin K antagonists such as warfarin historically

being the most widely prescribed drugs and with

antiplatelet drugs playing a more minor role.

However, since 2010, and the launch of the first of

the NOACs, a shift in the treatment of patients with

AF has occurred. There are now four NOACs on

the market indicated for the prevention of AF,

which include Boehringer Ingelheim’s Pradaxa

(dabigatran), Bayer/Janssen’s Xarelto

(rivaroxaban), Bristol-Myers Squibb/Pfizer’s Eliquis

(apixaban), and a fourth NOAC which was only

approved in the US early in 2015, Daiichi-Sankyo’s

Savaysa (edoxaban).

The NOACs represent important advances over

warfarin because they have predictable

pharmacological profiles and do not require routine

blood monitoring or dose adjustments, have fewer

drug–drug interactions, an absence of major

dietary effects, and in terms of efficacy and safety,

have proven to be non-inferior, if not superior,

compared with warfarin, particularly with regard to

a reduced risk of major bleeding. However, uptake

of the NOACs has been slowed due to the

associated cost of these drugs, which are

substantially higher than that of generically

available warfarin and other vitamin K antagonists.

In addition, the lack of an antidote that can be used

in the case of excessive bleeding with NOACs has

also limited their widespread use. GlobalData

believes that as physician familiarity with these

drugs increases, and experience is gained in

selecting the appropriate NOAC based on a

patient’s risk profile, further NOAC uptake will

occur across all markets. The anticipated arrival of



Executive Summary

NOAC reversal agents (antidotes) from 2017 on

are also expected to ease remaining physician and

patient concerns regarding the treatment of

uncontrolled bleeding.

GlobalData anticipates that the NOACs will have

the greatest impact on the AF market within the

forecast period. It is anticipated that the strong

safety and efficacy profile of Eliquis, as

demonstrated in pivotal Phase III clinical trials, will

drive uptake of the drug, despite it being positioned

as the third NOAC to enter the market. It is

forecast that sales of Eliquis will exceed Xarelto by

2018 replacing it as the market leader of the

NOACs. In contrast, the impact of the launch of

Savaysa in the US is expected to be more limited

than initially anticipated, after the US Food and

Drug Administration (FDA) decided that Savaysa

will carry a boxed warning stating that the drug

should not be used in patients with normal renal

function. With the anticoagulant space for the

prevention of stroke becoming increasingly

crowded, it is forecast that Pradaxa will be the

NOAC to lose the most market share as physicians

and patients opt for one of the other NOACs such

as Xarelto and Eliquis, which not only have strong

safety profiles, but also less restrictions on their

use.

Companies Focus on Label Expansion and Intensive Marketing to Differentiate Their Products

Companies attempting to penetrate the AF market

and differentiate their products, particularly those

companies that market NOACs, are doing so with

two main strategies: label expansion to increase

physician brand familiarity, and intensive marketing

to disseminate clinical trial results. Gaining

approval for additional cardiovascular indications

has been a strategy that has worked very well for

Bayer and Janssen, the two companies that jointly

developed and market Xarelto. Positioned as the

second-to-market NOAC, after Pradaxa, Xarelto’s

marketing companies rapidly conducted clinical

trials and filed for regulatory approval for non-AF

indications, such as the treatment and reduction in

risk of recurrent deep vein thrombosis (DVT),

pulmonary embolism (PE), and acute coronary

syndrome (ACS), thereby initially garnering the

approval for more indications than any of the other

NOACs. Boehringer Ingelheim, Bristol-Myers

Squibb, and Pfizer have tried to follow suit, but

have been much slower at expanding the labels of

their own respective NOACs. The competing

companies have had difficulty in keeping up with

the marketers of Xarelto, and Bayer and Janssen

are now also pursuing Xarelto’s approval for

additional patient populations such as chronic

heart failure, and the prevention of symptomatic

venous thromboembolism (VTE) and VTE-related

death in high-risk, medically ill patients.



Executive Summary

In addition to label expansion, marketing has also

played a strong role in the success of certain

NOACs. Bayer and Janssen, for example, heavily

invested in advertising by utilizing journal articles

and direct-to-consumer advertising as a means to

reach physicians and patients, while Bristol-Myers

Squibb and Pfizer have also reported that they

have initiated marketing and outreach campaigns

to disseminate the positive results from the pivotal

Phase III clinical trials with Eliquis. Furthermore,

some companies are using the results from

additional clinical trials or subanalysis studies to

differentiate their NOACs. Bayer and Janssen are

the only companies to have conducted a clinical

trial for a NOAC solely in a Japanese population

(with the J-ROCKET AF study); the companies

have strongly publicized this information, thereby

giving Xarelto an advantage in Japanese clinical

practice. Companies such as Bayer, Janssen, and

Daiichi Sankyo are also conducting studies in

subgroups of the AF population, such as patients

scheduled for cardioversion or catheter ablation, as

a way of differentiating their NOACs and

cementing them as part of the standard of care in

the anticoagulation of patients with AF.

Figure below provides a gap analysis of the major

players in the AF market during the forecast period

Company Portfolio Gap Analysis in AF, 2013–2023

Strength of Pipeline

Low High

Hig

hLo

wStre

ngth

of M

arke

ted

Pro

duct

s

Strength of Pipeline

Source: GlobalData

Safer Antiarrhythmic Drugs Remains Biggest Unmet Need in Atrial Fibrillation Treatment

The overall level of unmet need in the AF market is

moderate, with a number of generics available for

the management of heart rate control, and the

recent arrival and anticipated the launch of several

NOACs for the prevention of stroke. However,

even though there is now adequate therapeutics

available for most AF management strategies, the

biggest unmet need lies in safer antiarrhythmic

drugs for the maintenance of sinus rhythm. Despite

the restoration and maintenance of sinus rhythm

being a common practice in the management of

AF, the antiarrhythmic drugs that are available are



Executive Summary

of modest efficacy and have unfavorable safety

profiles. For example, amiodarone is a widely used

generic antiarrhythmic drug, and even though it is

considered the most effective agent available for

heart rhythm control, it has a number of side

effects, including proarrhythmia as well as thyroid,

liver, skin, and pulmonary complications.

Subsequently, Sanofi’s Multaq (dronedarone) was

developed in the hope it would be an effective and

safer alternative to amiodarone, but it was found to

increase the risk of death in patients with

permanent AF and some subtypes of heart failure.

Antiarrhythmic drug development has been very

slow and there are very few drugs in the current

pipeline that are expected to address this unmet

need during the forecast period. At present, there

are no antiarrhythmic drugs in Phase III clinical

trials; however, there are six drugs in Phase II

development and one drug in Phase I. Of these

agents, the furthest in development is Gilead’s

fixed-dose combination (FDC) of ranolazine and

low-dose dronedarone, which recently completed

Phase II clinical trials for paroxysmal AF. Part of

the reason for the low level of activity in the

pipeline is due to the high risk involved in

developing an antiarrhythmic drug. Large and

costly clinical trials are required to demonstrate

that a drug is safe and effective, and the track

record for those antiarrhythmic drugs that have

reached the market in the past decade has been

disappointing. It is also expected that the

availability of cheaper generic alternatives and the

continuing cost constraints faced by national health

authorities will also make it difficult for drugs to

obtain reimbursement and subsequent addition to

hospital formularies.

Outside of rhythm control strategies, the other key

unmet needs that still exist are related to barriers

to NOAC uptake, which include: antidotes that can

successfully reverse the anticoagulant effect of the

NOACs; improved access and reimbursement of

the NOACs; and increased patient awareness and

physician education on the clinical benefits of

stroke prevention with these drugs.

New Oral Anticoagulant Market Becomes Increasingly Crowded as Antiarrhythmic Drug Pipeline Remains Sparse

The AF therapeutics pipeline can be divided into

two categories of drugs: anticoagulants in

development for the prevention of stroke in

patients with AF, and antiarrhythmic drugs that can

be used for the maintenance of normal sinus

rhythm or to cardiovert patients with AF back to

sinus rhythm. In the anticoagulant market, Daiichi-

Sankyo’s Savaysa (edoxaban) was approved for

stroke prevention in Japan and the US, in

September 2014 and January 2015, respectively,

with regulatory approval in Europe still pending;

making it the fourth NOAC to enter this space.

However, Savaysa will encounter competition from

established brands, such as Pradaxa, Xarelto, and

Eliquis, which for some, have had several years to

increase brand familiarity through indication

expansion, marketing, and a larger collection of



Executive Summary

supportive clinical trial data. Even though, the

Savaysa clinical trials produced solid results that

confirmed its non-inferior efficacy to warfarin, and

significantly reduced bleeding rates, which have

become critical components for advancing a

“warfarin replacement” product to market,

Savaysa’s future in the AF market is now

uncertain. GlobalData initially believed the drug

would be well positioned for those AF patients with

a previous history of bleeding events, as its various

dosages would allow for dose adjustments. In

addition, Savaysa’s convenient once-daily dosing

also made it a very attractive patient option.

However, the FDA’s decision that Savaysa should

not be used in patients with normal renal function

has severely restricted the drug’s patient potential.

GlobalData now believes that Savaysa will struggle

to capture a significant share of the anticoagulant

market. With no other drug candidates presently in

Phase III development for stroke prevention in AF,

GlobalData does not anticipate any major

developments to occur in the anticoagulant

treatment landscape during the forecast period.

In terms of antiarrhythmic drugs, two drug

candidates are forecast to enter the market within

the next decade: Gilead’s FDC of

ranolazine/dronedarone and Laguna

Pharmaceuticals’ vanoxerine, which have both

completed Phase II clinical trials. Based on the

clinical trials required to bring Sanofi’s Multaq

(dronedarone) to market, for Gilead to gain

regulatory approval for ranolazine/dronedarone, it

is expected that an extensive series of Phase III

clinical trials will be required to provide evidence to

support its rhythm control properties and potentially

superior safety profile over existing therapies.

Laguna Pharmaceuticals, on the other hand, is a

very small spin-off company of the pharmaceutical

testing firm, ChanTest, and will require substantial

outside investment in the form of venture capital or

a partnership agreement, if it is to succeed in

bringing its cardioversion drug candidate to market.

Both drug candidates are expected to launch late

in the forecast period and will not reach peak sales

until after 2023.



Executive Summary

Figure below provides a competitive assessment of

the late-stage pipeline agents for AF during the

forecast period.

Competitive Assessment of Late-Stage Pipeline Agents for AF, 2013–2023

Clinical Attributes

Low High

Hig

hLo

w

Com

mer

cial

Attr

ibut

es

Note: Bubble size corresponds to projected sales during peak years.

Gilead’s ranolazine/dronedarone

Laguna Pharmaceuticals’ vanoxerine

Source: GlobalData

What Do the Physicians Think?

Key Opinion Leaders (KOLs) interviewed by

GlobalData highlighted the advancement the

NOACs offer in the anticoagulation of patients for

stroke prevention in AF. It is expected that the

continued uptake of the NOACs will be the main

driver in the growth of the AF market.

“Antithrombotic drugs are certainly the most rapidly

evolving field, because we have several new

drugs, the NOACs, that have come or are coming

into the market and they are revolutionizing the

entire area.”

EU Key Opinion Leader

“I think the NOACs are definitely an advance.

Patients are happy that they do not have to worry

about getting needle pricks, they do not have to

worry about dieting restrictions, and of course, they

can travel. I make sure that they understand that

there is a bleeding risk, but it is not likely that there

is one. In my opinion, there is more bleeding with

warfarin than with the NOACs.”

US Key Opinion Leader

“They are all at least as effective as vitamin K

antagonists and they all are safer; this is why

vitamin K antagonists should no longer be used.”


“I believe the antidotes or the availability of an

antidote would increase the use of NOACs. Further

education of physicians will also play a good part in

increasing NOAC use. So, there are lots of things

which need to be done in the upcoming years to

make the NOACs the number one therapy for

stroke prevention. But, I do believe the drugs do

have the potential for this.”




Executive Summary

KOLs interviewed by GlobalData believe there is

limited clinical need for NOAC antidotes, but that

the significant media attention surrounding the risk

of uncontrolled bleeding events and a lack of

clinical knowledge about the NOACs have fueled

the interest and investment in their development.

“I do think that this desire for a reversal agent is a

little bit overstated, because I do think that we will

end up using antidotes a lot less than people think

we need to.”


“Antidotes are required more to reassure the

physician and patient, rather than an actual unmet

need in clinical practice. In fact, you don’t need an

antidote, that’s what the big randomized clinical

trials tell us.”


“I think it makes sense to have an antidote. The

reason that there are no antidotes was a mistaken

concept from the pharma industry. They thought

that these drugs would be so safe that antidotes

would not be necessary. I think that most people

are concerned about bleeds that will not stop and

would like to have specific antidotes that will stop

bleeding. I don’t think there is much of a need to

use such antidotes very often and it might not

actually be justifiable to develop antidotes, but they

are being developed because most people say

they want them.”


“I am not sure if antidotes will be largely used, but

it’s important and very necessary to have these

antidotes to reassure people who are

anesthesiologists, emergency doctors, and

surgeons – because most of them are telling

everyone that these drugs are dangerous, because

there is no antidote.”


KOLs interviewed by GlobalData agreed that the

biggest unmet need in the management of AF is

safer antiarrhythmic drugs for rhythm control;

however, they state the reason for the low level of

activity in the pipeline is due to the high risk

involved in developing an antiarrhythmic drug.

Large and costly clinical trials are required to

demonstrate that a drug is safe and effective, and

the track record for those antiarrhythmic drugs that

have reached the market has been disappointing.

“I strongly believe that we need better

antiarrhythmic drugs for rhythm control.”


“Of course, for antiarrhythmic drugs, there are still

unmet needs because it’s clear that most [AF]

patients will sometime in their lives be on

antiarrhythmic drugs. But, the problem is that most

companies don’t want to take the risk of developing

an antiarrhythmic drug because they all have been

a failure.”




Executive Summary

“We have had no new antiarrhythmic drugs for

something like 25 years. The last one was

flecainide. We had dronedarone [Multaq], but the

rate of prescription of dronedarone in Europe

remains very low because many countries have

refused to reimburse the drug.”


“To treat AF patients we could use safer rhythm

control drugs, if such a thing could ever exist. We

thought for a long time that dronedarone [Multaq]

was the one, but it turned out that in certain

groups, it will increase the risk of death. So, that

did not work out.”


“Very few companies want to take risk of

developing an antiarrhythmic drug, because that

means a huge cost for development.”


“It is a market which has a large number of AF

patients, but it’s so difficult to demonstrate

something [in a clinical trial]. The problem with AF

is that, of course, it’s a disease with an increased

risk for [shortened] life expectancy, but fortunately,

the rate of complication is very low. So, if you want

to demonstrate something, for example in

anticoagulation, you have to make huge trials with

something like 15,000 patients. So, it’s a huge cost

and it’s too difficult to do. It’s one of the main

reasons why there are no new developments with

antiarrhythmic drugs. And then there is still the

history of dronedarone; it was a failure.”


“I do think that an antiarrhythmic therapy that is

very safe and very effective is needed, it’s just I’m

not optimistic. There has never been a drug that’s

been particularly effective or safe. So, if there

happens to be one, I think that’s great; but I don’t

think that there are very many people in the field

who think that a new great blockbuster

antiarrhythmic drug is around the corner. I don’t

think anyone is holding their breath.”



Table of Contents


1 Table of Contents

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

1.1 List of Tables .................................................................................................................... 20

1.2 List of Figures ................................................................................................................... 25

2 Introduction ............................................................................................................................... 27

2.1 Catalyst ............................................................................................................................. 27

2.2 Related Reports ................................................................................................................ 28

2.3 Upcoming Related Reports ............................................................................................... 28

3 Disease Overview ..................................................................................................................... 29

3.1 Etiology and Pathophysiology ........................................................................................... 29

3.1.1 Etiology ......................................................................................................................... 29

3.1.2 Pathophysiology ............................................................................................................ 30

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

3.3 Classification of Atrial Fibrillation ....................................................................................... 32

3.4 Prognosis .......................................................................................................................... 32

4 Epidemiology ............................................................................................................................ 34

4.1 Disease Background ......................................................................................................... 34

4.2 Risk Factors and Comorbidities ........................................................................................ 35

4.3 Global Trends ................................................................................................................... 37

4.4 Forecast Methodology ....................................................................................................... 39

4.4.1 Sources Used................................................................................................................ 41

4.4.2 Forecast Assumptions and Methods ............................................................................. 47


Table of Contents


4.4.3 Sources Not Used ......................................................................................................... 52

4.5 Epidemiological Forecast for Atrial Fibrillation (2013–2023) .............................................. 53

4.5.1 Diagnosed Prevalent Cases of Atrial Fibrillation ............................................................ 53

4.5.2 Age-Specific Diagnosed Prevalent Cases of Atrial Fibrillation ....................................... 54

4.5.3 Sex-Specific Diagnosed Prevalent Cases of Atrial Fibrillation ....................................... 56

4.5.4 Age-Standardized Diagnosed Prevalence of Atrial Fibrillation ....................................... 58

4.5.5 Diagnosed Prevalent Cases of Atrial Fibrillation by Clinical Subtypes ........................... 60

4.6 Discussion ........................................................................................................................ 61

4.6.1 Epidemiological Forecast Insight ................................................................................... 61

4.6.2 Limitations of the Analysis ............................................................................................. 63

4.6.3 Strengths of the Analysis ............................................................................................... 64

5 Disease Management ............................................................................................................... 65

5.1 Diagnosis and Treatment Overview .................................................................................. 65

5.1.1 Diagnosis ...................................................................................................................... 65

5.1.2 Treatment Guidelines and Leading Prescribed Drugs ................................................... 67

5.1.3 Clinical Practice ............................................................................................................. 69

5.2 US..................................................................................................................................... 83

5.3 France .............................................................................................................................. 85

5.4 Germany ........................................................................................................................... 87

5.5 Italy ................................................................................................................................... 89

5.6 Spain ................................................................................................................................ 91

5.7 UK..................................................................................................................................... 93

5.8 Japan ................................................................................................................................ 95


Table of Contents


5.9 Canada ............................................................................................................................. 98

6 Competitive Assessment ........................................................................................................ 100

6.1 Overview ......................................................................................................................... 100

6.2 Product Profiles – Major Brands, Anticoagulant Agents .................................................. 105

6.2.1 Warfarin (Widely Genericized) ..................................................................................... 105

6.2.2 Pradaxa (dabigatran)................................................................................................... 115

6.2.3 Xarelto (rivaroxaban) ................................................................................................... 129

6.2.4 Eliquis (apixaban) ........................................................................................................ 142

6.2.5 Savaysa (edoxaban) ................................................................................................... 155

6.3 Product Profiles – Major Brands, Antiarrhythmic Drugs ................................................... 167

6.3.1 Multaq (dronedarone) .................................................................................................. 167

6.3.2 Brinavess (vernakalant) ............................................................................................... 179

6.4 Other Therapeutic Classes.............................................................................................. 191

6.4.1 Vitamin K Antagonists Other than Warfarin (Widely Genericized) ................................ 192

6.4.2 Antiplatelets – Aspirin (Widely Genericized) ................................................................ 194

6.4.3 Beta-Blockers – Atenolol, Metoprolol, Propranolol (Widely Genericized) ..................... 195

6.4.4 Calcium Channel Blockers – Diltiazem, Verapamil (Widely Genericized) .................... 196

6.4.5 Cardiac Glycosides − Digoxin (Widely Genericized) .................................................... 197

6.4.6 Potassium Channel Blockers – Amiodarone, Sotalol, Dofetilide (Widely Genericized) . 198

6.4.7 Sodium Channel Blockers – Flecainide, Propafenone (Widely Genericized) ............... 200

7 Unmet Need and Opportunity ................................................................................................. 202

7.1 Overview ......................................................................................................................... 202

7.2 Safer Antiarrhythmic Drugs for the Maintenance of Sinus Rhythm .................................. 203


Table of Contents


7.2.1 Unmet Need ................................................................................................................ 203

7.2.2 Gap Analysis ............................................................................................................... 204

7.2.3 Opportunity ................................................................................................................. 205

7.3 Effective and Rapid Acting Cardioversion Drugs ............................................................. 206

7.3.1 Unmet Need ................................................................................................................ 206

7.3.2 Gap Analysis ............................................................................................................... 207

7.3.3 Opportunity ................................................................................................................. 208

7.4 Antidotes for the New Oral Anticoagulants ...................................................................... 209

7.4.1 Unmet Need ................................................................................................................ 209

7.4.2 Gap Analysis ............................................................................................................... 210

7.4.3 Opportunity ................................................................................................................. 212

7.5 Improved Access to and Reimbursement of the New Oral Anticoagulants ...................... 213

7.5.1 Unmet Need ................................................................................................................ 213

7.5.2 Gap Analysis ............................................................................................................... 216

7.5.3 Opportunity ................................................................................................................. 218

7.6 Increased Physician Education on the Clinical Benefits of the NOACs ............................ 219

7.6.1 Unmet Need ................................................................................................................ 219

7.6.2 Gap Analysis ............................................................................................................... 220

7.6.3 Opportunity ................................................................................................................. 221

7.7 Increased Patient Awareness on the Clinical Benefits of the NOACs .............................. 222

7.7.1 Unmet Need ................................................................................................................ 222

7.7.2 Gap Analysis ............................................................................................................... 223

7.7.3 Opportunity ................................................................................................................. 223


Table of Contents


8 Pipeline Assessment............................................................................................................... 225

8.1 Overview ......................................................................................................................... 225

8.2 Clinical Trial Mapping ...................................................................................................... 226

8.2.1 Clinical Trials by Country ............................................................................................. 226

8.2.2 Clinical Trials by Phase and Trial Status ..................................................................... 227

8.3 Promising Drugs in Clinical Development ........................................................................ 228

8.3.1 Ranolazine/Dronedarone ............................................................................................ 230

8.3.2 Vanoxerine .................................................................................................................. 240

8.4 Other Drugs in Development ........................................................................................... 250

8.4.1 Early-Stage Anticoagulant Pipeline ............................................................................. 250

8.4.2 Early-Stage Antiarrhythmia Pipeline ............................................................................ 256

9 Current and Future Players ..................................................................................................... 261

9.1 Overview ......................................................................................................................... 261

9.2 Trends in Corporate Strategy .......................................................................................... 263

9.3 Company Profiles ............................................................................................................ 265

9.3.1 Boehringer Ingelheim .................................................................................................. 265

9.3.2 Bayer .......................................................................................................................... 268

9.3.3 Janssen (Johnson & Johnson) .................................................................................... 271

9.3.4 Bristol-Myers Squibb ................................................................................................... 274

9.3.5 Pfizer ........................................................................................................................... 277

9.3.6 Daiichi-Sankyo ............................................................................................................ 280

9.3.7 Gilead.......................................................................................................................... 283

10 Market Outlook ....................................................................................................................... 287


Table of Contents


10.1 Global Markets ................................................................................................................ 287

10.1.1 Forecast ...................................................................................................................... 287

10.1.2 Drivers and Barriers – Global Issues ........................................................................... 296

10.2 United States .................................................................................................................. 301

10.2.1 Forecast ...................................................................................................................... 301

10.2.2 Key Events .................................................................................................................. 307

10.2.3 Drivers and Barriers .................................................................................................... 307

10.3 France ............................................................................................................................ 310

10.3.1 Forecast ...................................................................................................................... 310

10.3.2 Key Events .................................................................................................................. 314


10.4 Germany ......................................................................................................................... 318

10.4.1 Forecast ...................................................................................................................... 318

10.4.2 Key Events .................................................................................................................. 323


10.5 Italy ................................................................................................................................. 325

10.5.1 Forecast ...................................................................................................................... 325

10.5.2 Key Events .................................................................................................................. 330


10.6 Spain .............................................................................................................................. 333

10.6.1 Forecast ...................................................................................................................... 333

10.6.2 Key Events .................................................................................................................. 337



Table of Contents


10.7 United Kingdom .............................................................................................................. 339

10.7.1 Forecast ...................................................................................................................... 339

10.7.2 Key Events .................................................................................................................. 344


10.8 Japan .............................................................................................................................. 347

10.8.1 Forecast ...................................................................................................................... 347

10.8.2 Key Events .................................................................................................................. 352


10.9 Canada ........................................................................................................................... 355

10.9.1 Forecast ...................................................................................................................... 355

10.9.2 Key Events .................................................................................................................. 359


11 Appendix................................................................................................................................. 362

11.1 Bibliography .................................................................................................................... 362

11.2 Abbreviations .................................................................................................................. 383

11.3 Methodology ................................................................................................................... 388

11.4 Forecasting Methodology ................................................................................................ 388

11.4.1 Diagnosed Atrial Fibrillation Patients ........................................................................... 388

11.4.2 Percent Drug-Treated Patients .................................................................................... 389

11.4.3 Drugs Included in Each Therapeutic Class .................................................................. 389

11.4.4 Launch and Patent Expiry Dates ................................................................................. 390

11.4.5 General Pricing Assumptions ...................................................................................... 391

11.4.6 Individual Drug Assumptions ....................................................................................... 392


Table of Contents


11.4.7 Generic Erosion .......................................................................................................... 401

11.4.8 Pricing of Pipeline Agents............................................................................................ 401

11.5 Physicians and Specialists Included in this Study ........................................................... 402

11.6 About the Authors ........................................................................................................... 404

11.6.1 Analyst ........................................................................................................................ 404

11.6.2 Therapy Area Director ................................................................................................. 404

11.6.3 Epidemiologist ............................................................................................................. 405

11.6.4 Global Head of Healthcare .......................................................................................... 405

11.7 About GlobalData ............................................................................................................ 406

11.8 Disclaimer ....................................................................................................................... 406


Table of Contents


1.1 List of Tables

Table 1: Common Cardiac and Non-Cardiac Causes of AF ....................................................................... 30

Table 2: Classification of AF...................................................................................................................... 32

Table 3: Clinical Subtypes of AF ............................................................................................................... 34

Table 4: Risk Factors and Comorbidities for AF ......................................................................................... 36

Table 5: Diagnosed Prevalence (%) of AF in the 6MM,* as Reported in Epidemiological Studies ............... 37

Table 6: Total Prevalence (%) of AF in the 7MM,* as Reported in Epidemiological Studies ........................ 38

Table 7: 8MM, Sources of Prevalence Data Used to Forecast the Diagnosed Prevalent Cases of AF ........ 40

Table 8: 8MM, Sources of AF Subtype Data Used to Forecast the Diagnosed Prevalent Cases of AF by

Subtypes ..................................................................................................................................... 41

Table 9: 8MM, Diagnosed Prevalent Cases of AF, Ages ≥40 Years, Both Sexes, N, 2013–2023 ............... 53

Table 10: 8MM, Diagnosed Prevalent Cases of AF, by Age, Both Sexes, N (Row %), 2013......................... 55

Table 11: 8MM, Diagnosed Prevalent Cases of AF, by Sex, Ages ≥40 Years, N (Row %), 2013 .................. 57

Table 12: 8MM, Diagnosed Prevalent Cases of AF, by Clinical Subtypes, Both Sexes, N (Row %), 2013 .... 60

Table 13: CHADS2 Index for Stroke Risk Assessment ................................................................................. 67

Table 14: CHA2DS2-VASc Index for Stroke Risk Assessment ...................................................................... 67

Table 15: Treatment Guidelines for Atrial Fibrillation by Country .................................................................. 68

Table 16: Most Prescribed Drugs or Drug Classes for AF by Country, 2014 ................................................ 69

Table 17: Country Profile − US.................................................................................................................... 84

Table 18: Country Profile − France.............................................................................................................. 86

Table 19: Country Profile – Germany .......................................................................................................... 88

Table 20: Country Profile − Italy .................................................................................................................. 90

Table 21: Country Profile − Spain ............................................................................................................... 92

Table 22: Country Profile − UK.................................................................................................................... 94


Table of Contents


Table 23: Country Profile − Japan ............................................................................................................... 97

Table 24: Country Profile − Canada ............................................................................................................ 99

Table 25: Leading Treatments and Branded Drugs for AF, 2014 ............................................................... 104

Table 26: Product Profile – Warfarin (Widely Genericized) ........................................................................ 108

Table 27: Warfarin (Widely Genericized) SWOT Analysis, 2014 ................................................................ 113

Table 28: Global Sales Forecasts ($m) for Warfarin, 2013–2023 ............................................................... 115

Table 29: Product Profile – Pradaxa (dabigatran) ...................................................................................... 119

Table 30: Pradaxa (dabigatran) SWOT Analysis, 2014 .............................................................................. 126

Table 31: Global Sales Forecasts ($m) for Pradaxa, 2013–2023 ............................................................... 129

Table 32: Product Profile – Xarelto (rivaroxaban) ...................................................................................... 133

Table 33: Xarelto (rivaroxaban) SWOT Analysis, 2013 .............................................................................. 139

Table 34: Global Sales Forecasts ($m) for Xarelto, 2013–2023 ................................................................. 141

Table 35: Product Profile – Eliquis (apixaban) ........................................................................................... 146

Table 36: Eliquis (apixaban) SWOT Analysis, 2014 ................................................................................... 152

Table 37: Global Sales Forecasts ($m) for Eliquis, 2013–2023 .................................................................. 154

Table 38: Product Profile – Savaysa (edoxaban) ....................................................................................... 158

Table 39: Savaysa (edoxaban) SWOT Analysis, 2014............................................................................... 164

Table 40: Global Sales Forecasts ($m) for Savaysa, 2013–2023 ............................................................... 167

Table 41: Product Profile – Multaq (dronedarone) ..................................................................................... 170

Table 42: Overview of the Pivotal Clinical Trials for Multaq ........................................................................ 171

Table 43: Efficacy of Multaq in Patients with Paroxysmal or Persistent AF/AFL in the ATHENA Study ....... 173

Table 44: Efficacy of Multaq in Patients with Permanent AF in the PALLAS Study ..................................... 175

Table 45: Multaq (dronedarone) SWOT Analysis, 2014 ............................................................................. 177

Table 46: Global Sales Forecasts ($m) for Multaq, 2013–2023 .................................................................. 179


Table of Contents


Table 47: Product Profile – Brinavess (vernakalant) .................................................................................. 184

Table 48: Efficacy of Intravenous Brinavess in Pivotal Late-Stage Clinical Trials ....................................... 185

Table 49: Brinavess (vernakalant) SWOT Analysis, 2014 .......................................................................... 189

Table 50: Global Sales Forecasts ($m) for Brinavess, 2013–2023 ............................................................. 191

Table 51: Summary of Widely Genericized Therapeutic Classes, 2014 ..................................................... 192

Table 52: Commonly Used Genericized Vitamin K Antagonists (Excluding Warfarin), by Region* .............. 193

Table 53: Unmet Need and Opportunity in Atrial Fibrillation ....................................................................... 202

Table 54: AF – Clinical Trials by Phase and Status, 2014 .......................................................................... 228

Table 55: Late-Stage Pipeline for AF, 2014 ............................................................................................... 228

Table 56: Therapeutic Classes in Late-Stage Development for AF, 2014................................................... 229

Table 57: Product Profile – Ranolazine/Dronedarone ................................................................................ 233

Table 58: Ranolazine/Dronedarone SWOT Analysis, 2014 ........................................................................ 238

Table 59: Global Sales Forecasts ($m) for Ranolazine/Dronedarone, 2013–2023 ..................................... 240

Table 60: Product Profile – Vanoxerine ..................................................................................................... 243

Table 61: Efficacy of Vanoxerine in Patients with AF/AFL in the Phase IIb COR-ART Study ...................... 244

Table 62: Safety of Vanoxerine in Patients with AF/AFL in the Phase IIb COR-ART Study ........................ 246

Table 63: Vanoxerine SWOT Analysis, 2014 ............................................................................................. 248

Table 64: Global Sales Forecasts ($m) for Vanoxerine, 2013–2023 .......................................................... 250

Table 65: Early-Stage Pipeline Products for Atrial Fibrillation – Anticoagulant Agents ................................ 251

Table 66: Early-Stage Pipeline Products for Atrial Fibrillation – Antiarrhythmic Drugs ................................ 257

Table 67: Key Companies in the AF Market, 2014 ..................................................................................... 262

Table 68: Boehringer Ingelheim’s AF Portfolio Assessment, 2014 ............................................................. 267

Table 69: Boehringer Ingelheim SWOT Analysis, 2014 ............................................................................. 268

Table 70: Bayer’s AF Portfolio Assessment, 2014 ..................................................................................... 270


Table of Contents


Table 71: Bayer SWOT Analysis, 2014 ..................................................................................................... 271

Table 72: Janssen’s AF Portfolio Assessment, 2014 ................................................................................. 273

Table 73: Janssen SWOT Analysis, 2014 ................................................................................................. 274

Table 74: Bristol-Myers Squibb’s AF Portfolio Assessment, 2014 .............................................................. 276

Table 75: Bristol-Myers Squibb SWOT Analysis, 2014 .............................................................................. 277

Table 76: Pfizer’s AF Portfolio Assessment, 2014 ..................................................................................... 279

Table 77: Pfizer SWOT Analysis, 2014 ..................................................................................................... 280

Table 78: Daiichi-Sankyo’s AF Portfolio Assessment, 2014 ....................................................................... 282

Table 79: Daiichi-Sankyo SWOT Analysis, 2014 ....................................................................................... 283

Table 80: Gilead’s AF Portfolio Assessment, 2014 .................................................................................... 285

Table 81: Gilead SWOT Analysis, 2014 .................................................................................................... 286

Table 82: Global* Sales Forecasts ($m) for AF, 2013–2023 ...................................................................... 289

Table 83: Global AF Market – Drivers and Barriers, 2014 .......................................................................... 296

Table 84: Sales Forecasts ($m) for AF in the US, 2013–2023 ................................................................... 304

Table 85: Key Events Impacting Sales for AF in the US, 2014 ................................................................... 307

Table 86: AF Market – Drivers and Barriers in the US, 2013–2023 ............................................................ 307

Table 87: Sales Forecasts ($m) for AF in France, 2013–2023 ................................................................... 312

Table 88: Key Events Impacting Sales for AF in France, 2014................................................................... 314

Table 89: AF Market – Drivers and Barriers in France, 2013–2023 ............................................................ 314

Table 90: Sales Forecasts ($m) for AF in Germany, 2013–2023 ................................................................ 320

Table 91: Key Events Impacting Sales for AF in Germany, 2014 ............................................................... 323

Table 92: AF Market – Drivers and Barriers in Germany, 2013–2023 ........................................................ 323

Table 93: Sales Forecasts ($m) for AF in Italy, 2013–2023........................................................................ 327

Table 94: Key Events Impacting Sales for AF in Italy, 2014 ....................................................................... 330


Table of Contents


Table 95: AF Market – Drivers and Barriers in Italy, 2013–2023 ................................................................ 330

Table 96: Sales Forecasts ($m) for AF in Spain, 2013–2023 ..................................................................... 334

Table 97: Key Events Impacting Sales for AF in Spain, 2014 .................................................................... 337

Table 98: AF Market – Drivers and Barriers in Spain, 2013–2023 .............................................................. 337

Table 99: Sales Forecasts ($m) for AF in UK, 2013–2023 ......................................................................... 341

Table 100: Key Events Impacting Sales for AF in the UK, 2014 ................................................................... 344

Table 101: Asthma Market – Drivers and Barriers in the UK, 2013–2023 ..................................................... 344

Table 102: Sales Forecasts ($m) for AF in Japan, 2013–2023 .................................................................... 349

Table 103: Key Events Impacting Sales for AF in Japan, 2014 .................................................................... 352

Table 104: AF Market – Drivers and Barriers in Japan, 2013–2023 ............................................................. 352

Table 105: Sales Forecasts ($m) for AF in Canada, 2013–2023 .................................................................. 357

Table 106: Key Events Impacting Sales for AF in Canada, 2014 ................................................................. 359

Table 107: AF Market – Drivers and Barriers in Canada, 2013–2023 .......................................................... 359

Table 108: Key Launch Dates ..................................................................................................................... 390

Table 109: Key Patent Expiries ................................................................................................................... 390

Table 110: High-Prescribing Physicians (non-KOLs) Surveyed, By Country ................................................ 403


Table of Contents


1.2 List of Figures

Figure 1: 8MM, Diagnosed Prevalent Cases of AF, Ages ≥40 Years, Both Sexes, N, 2013–2023 ............... 54

Figure 2: 8MM, Diagnosed Prevalent Cases of AF, by Age, Both Sexes, N, 2013 ....................................... 56

Figure 3: 8MM, Diagnosed Prevalent Cases of AF, by Sex, Ages ≥40 Years, N, 2013 ................................ 58

Figure 4: 8MM, Age-Standardized Diagnosed Prevalence (%) of AF, by Sex, Ages ≥40 Years, 2013 ......... 59

Figure 5: 8MM, Diagnosed Prevalent Cases of AF, by Clinical Subtypes, Both Sexes, N, 2013 .................. 61

Figure 6: ESC Guideline Recommendations for Choosing an Anticoagulant ............................................... 72

Figure 7: JCS Guideline Recommendations for Choosing an Anticoagulant ................................................ 74

Figure 8: CCS Guideline Recommendations for Choosing an Anticoagulant ............................................... 75

Figure 9: AHA Guideline Recommendations for Drug Therapy for Ventricular Rate Control ........................ 77

Figure 10: AHA Guideline Recommendations for Rhythm Control in Patients with Paroxysmal and Persistent

AF ............................................................................................................................................... 79

Figure 11: ESC Guideline Recommendations for Rhythm Control According to Underlying Pathology .......... 81

Figure 12: JCS Guideline Recommendations for Rhythm Control ................................................................. 82

Figure 13: Site of Action of the New Oral Anticoagulants in the Anticoagulation Cascade ........................... 101

Figure 14: AF Therapeutics – Clinical Trials by Country, 2014 .................................................................... 226

Figure 15: Competitive Assessment of Late-Stage Pipeline Agents for AF, 2013–2023 .............................. 229

Figure 16: Company Portfolio Gap Analysis in AF, 2013–2023 ................................................................... 263

Figure 17: Global Sales for AF by Country, 2013–2023 .............................................................................. 291

Figure 18: Annual Global Sales for AF by Region, 2013–2023.................................................................... 292

Figure 19: Global* AF Sales by Drug Class, 2013–2023 ............................................................................. 293

Figure 20: Annual Global* Sales for AF by Drug Class, 2013–2023 ............................................................ 294

Figure 21: Annual Global* Sales for the Novel Oral Anticoagulants, 2013–2023 ......................................... 295

Figure 22: Sales for AF in the US by Drug Class, 2013–2023 ..................................................................... 306


Table of Contents


Figure 23: Sales for AF in France by Drug Class, 2013–2023 ..................................................................... 313

Figure 24: Sales for AF in Germany by Drug Class, 2013–2023 ................................................................. 322

Figure 25: Sales for AF in Italy by Drug Class, 2013–2023 ......................................................................... 329

Figure 26: Sales for AF in Spain by Drug Class, 2013–2023 ....................................................................... 336

Figure 27: Sales for AF in the UK by Drug Class, 2013–2023 ..................................................................... 343

Figure 28: Sales for AF in Japan by Drug Class, 2013–2023 ...................................................................... 351

Figure 29: Sales for AF in Canada by Drug Class, 2013–2023 ................................................................... 358



Introduction

2 Introduction

2.1 Catalyst

Various therapeutic options are available to treat patients with atrial fibrillation (AF), and most

patients will receive some form of antithrombotic therapy, a heart rate control agent, and

potentially, an antiarrhythmic drug for rhythm control. All sectors of the AF market have historically

been saturated with generics, with the vitamin K antagonists such as warfarin playing an important

role in stroke prevention in AF. However, since 2010, and the launch of the first of the new oral

anticoagulants (NOACs), a shift in the treatment of patients with AF has occurred. The NOACs

offer a significant advancement in anticoagulation and their continued uptake will be the main driver

of growth in the AF market over the next 10 years.

There are now four NOACs on the market; these include Boehringer Ingelheim’s Pradaxa

(dabigatran), Bayer/Janssen’s Xarelto (rivaroxaban), Bristol-Myers Squibb/Pfizer’s Eliquis

(apixaban), and Daiichi-Sankyo’s Savysa (edoxaban).

In September 2014, Daiichi-Sankyo gained label expansion in Japan for edoxaban to include

the treatment of patients with AF, and it was also approved and launched in the US early in

2015 under the brand name Savaysa.

All major treatment guidelines for the management of AF now include the NOACs as a

treatment option for the anticoagulation of patients with AF, with some giving preference to the

NOACs over vitamin K antagonists. Treatment guidelines also give more focus to identifying

and treating patients with AF that have a low risk of stroke.

The anticipated arrival of NOAC antidotes from 2017 onwards is also forecast to be a major

driver of further NOAC uptake. The availability of NOAC antidotes is expected to ease

remaining physician and patient concerns surrounding the risk of uncontrolled bleeding events.

In contrast, despite a great unmet need for safer antiarrhythmic drugs, developments in this field

are expected to be much slower.

Two potential antiarrhythmic drugs are forecast to enter the market within the next decade:

Gilead’s fixed-dose combination (FDC) of ranolazine and low-dose dronedarone, and Laguna

Pharmaceuticals’ vanoxerine, both of which have completed Phase II clinical trials. Both drug



Introduction

candidates are expected to launch late in the forecast period and will not reach peak sales until

after 2023.

The low level of activity in the pipeline is expected to continue due to the high risk involved in

developing antiarrhythmic drugs.

2.2 Related Reports

GlobalData (2014). Acute Coronary Syndrome − Global Drug Forecast and Market Analysis to

2023, July 2014, GDHC69PIDR

2.3 Upcoming Related Reports

GlobalData (2015). Dyslipidemia − Global Drug Forecast and Market Analysis to 2023,

GDHC110PIDR


Appendix


11.7 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.

11.8 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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