Global Data>>
`
`ALLERGIC RHINITIS -
`GLOBAL DRUG FORECAST AND MARKET ANALYSIS TO 2024
`
`Competitive Assessment
`
`Table 42 presents a product profile of Dymista.
`
`,n"'"""~"-=•·• Azelasline hydrochloride/flulicasone propionate (Dymista}
`US- 2012; 5EU-2013; Japan - preregistered, expected launch in 2012
`
`H1 receptor antagonist and corticosteroid
`
`Dygaro (Italy); Azeflu (France); Dymolin (Germany); Dylastine (Germany, Spain); Dyvistanil
`(Germany); Synaze (France, Spain); Xatalin (France); Dymol (Spain), Nycena (Italy)
`- - - -
`- - - - - - - - - - - - -
`
`Cipla
`
`The relief of symptoms of SAR ,md PAR in patients c1ge 12 years and older who require
`treatment with both azelastine hydrochloride and fluticasone propionate for symptomatic relief,
`when each drug alone is not considered sufficient
`Intranasal spray: recommended dose is one spray per nostril twice daily in aduHs and
`adolescents age ~ 12 years.
`
`2023-2026 {US, 5EU)
`
`Source: GlobalData; Dym1sta package insert, 2015; USPTO, 2015
`
`6.5.1.2 Efficacy
`
`The efficacy and safety of Dymista was evaluated in a series of four head-to-head, double-blind
`placebo- and active-controlled studies in over 4,000 patients age 12 years and older with moderate
`to severe SAR (Meltzer et al., 2013). The patients were required to have a minimum two-year
`history of AR-related symptoms and a positive skin prick test to the relevant allergen. The four
`studies took place over two weeks, following a seven-day run-in period during various pollen
`seasons. The primary efficacy endpoint was the patient-reported reflective total nasal symptom
`score (rTNSS) score compared with baseline in 12 hours (AM and PM) assessed over 14 days.
`
`The rTNSS was used as a measure of the symptom severity, as it is the only efficacy endpoint
`accepted by the FDA and EMA. Patients rate four nasal symptoms (nasal congestion, itching,
`rh!norrhea, and sneezing) twice daily, in the morning and evening, for 14 days on a scale of Oto 3,
`with o being symptom free and 3 being severe symptoms, generating a maximum daily score of 24.
`
`Error! Reference source not found. shows the change in baseline in rTNSS in the intent-to-treat
`(ITT) population. In all four studies, Dymista demonstrated superior efficacy compared with
`
`intranasal AH and lNCS delivered as a monotherapy. All four studies were conducted in a similar
`manner, with the exception of MP4001, which used the branded version of the AH, Astelin
`(azelastine). All four drugs were dosed as one spray per nostril twice daily.
`
`Allergic Rhinitis - Global Drug Forecast and Market Analysis to 2024
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`
`ALLERGIC RHINITIS(cid:173)
`GLOBAL DRUG FORECAST AND MARKET ANALYSIS TO 2024
`
`Competitive Assessment
`
`.
`
`.-
`
`. _-' -
`
`,=--- -I
`-
`.
`:. :.,
`
`MP29-02 -FP
`
`MP29-02 -
`
`~
`
`MP29-02 - PLA
`
`0,003
`<0.001
`I <O,OOt
`
`-
`
`'
`
`-5.3
`
`-3 3
`I -3-8
`
`-2.2
`
`-5_5 (5 2)
`
`-4.1 (4.6)
`
`MP29-02- FP
`
`o.o~
`O:.:tm
`
`18.2 (3.2)
`
`- 5.0 (4 .7)
`
`MP29-02 - AZE
`
`I ·1a_6 (3.2)
`
`I 1s_2 (3.3)
`
`1-2.6 (3 .9)
`
`-5.6 (5.2)
`
`MP29-02 • Pl.A I <0.001
`
`I-
`
`1 18-5 (3_ 1)
`
`-4 .4 (4.6)
`
`I MP29-02 - FF'
`
`.etoaa
`
`18.6 (2.9)
`
`- 5.0 (5 .2)
`
`MP29-02 - AZE
`
`Q,.032
`
`I
`
`18.2 (3 .1 )
`
`19.4 (.2 .4}
`
`-2.8 (3 .9)
`
`1-5.6 (5.2)
`
`MP29-02 • PLA
`
`I <O.l'IOJ
`
`19-5 (2 .5)
`
`-4 5 (4 .8)
`
`MP29-02-FP
`
`O.O(i!9
`
`19.4 (2.4)
`
`-5.1 (4 7)
`
`Table 43: Efficacy of Dymista
`~
`-
`
`.
`
`-
`Dymista (N = 153)
`
`-
`
`-
`
`-
`
`.
`
`18.8 (3 .1)
`
`18.1 (3. 7)
`
`18'3 (3_5)
`
`1~ 8.7(3.5}
`
`'18-3(3.0)
`
`18.2 (3.5)
`
`MP4001
`' Astelin (N = 152)
`2007/2008 Texas r
`-
`f Fluticasone (N aa 150)
`Mountain Cedar
`Placebo (N"= 150)
`
`Dymisla (N = 207)
`
`r Azelastine (N = 208)
`
`MP4002
`2008 Spring
`
`MP4004
`2008 Fall
`
`--- -
`
`MP4006
`2009 Spring and
`Summer
`
`Fluticasone
`(N = 207)
`,_ -
`Placebo
`I
`(N =209)
`
`Dymista
`(N = 193)
`~ Azelastine
`(N = 193)
`Flut1casone
`(N = 188)
`~--
`I Placebo
`(N = 199)
`I Oymisla
`(N = 448)
`r Azelastin; -
`
`1N = 443)
`-
`f--
`Fluticasone-
`(N =450)
`
`MP29-02 -AZE
`
`I o.o~
`MP29-02 - PLA I ~ ;oo:-t
`
`19.4 (2.4)
`
`-3.2 (4 .3)
`
`Placebo
`(N = 448)
`NCTD1165138; Meltzer et al,. 2014
`"Least-squares mean obtained from analysfs of variance (ANOVA) model for baseline or analysis of covariance (ANCOVA) ·model for
`overall .
`••p-value for comparison between treatment group for baseline was based on an ANOVA model containing the treatment group and site
`as fixed effects_
`~E = azelastine
`
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`
`ALLERGIC RHINITIS -
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`
`Competitive Assessment
`
`6.5.1.3 Safety
`
`The adverse events associated with Dymista are generally mild and infrequent (Meltzer et al.,
`
`2014). The most common treatment-related adverse events {TRAEs} experienced by SAR patients
`following the 14-day treatment included headache, epitaxis, and dysgeusia.
`
`In two recent controlled trials of Dymista, a total of 4,022 patients were evaluated for safety and
`tolerability. One study, MP4002, was conducted in patients with SAR, in which Dymista was
`compared with fluticasone propionate, azelastine, and placebo during two weeks of treatment
`(Meltzer et al., 2014). The other study, MP 4000, was a long-term study in patients with chronic
`rhinitis (that is, PAR or non-allergic vasomotor rhinitis) in which Dymista was compared with
`
`fluticasone propionate during 52 weeks of treatment (Meltzer et al., 2014).
`
`Table 44 provides the results of these two studies, which showed no appreciable difference
`between the treatment groups in terms of safety. The most common TRAEs in each of the
`
`treatment groups in both studies were dysgeusia, epistaxis, and headache.
`
`Dysgeusia
`
`Epistaxis
`
`Headache
`
`5(2.4%)
`2(1.0%)
`- - -
`-
`1 (0.5%)
`
`2(1 .0%)
`
`5(2.4%)
`
`5 (2.4%)
`
`7(3.4%)
`
`4(1.9%)
`
`1 (0.5%)
`
`1 (0.5%J I
`2 (1.0%)
`-- -
`3 (1.4%)
`
`source. GlobaJData: GSK, NCT0116513!1, Meltzer et al., 2014
`
`5(1.2%)
`--
`-
`4(1 .0%)
`
`10(2.5%) i 1 (0.5%)
`
`1 (0.5%)
`
`9(4.3%)
`
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`
`ALLERGIC RHINITIS(cid:173)
`GLOBAL DRUG FORECAST AND MARKET ANALYSIS TO 2024
`
`Competitive Assessment
`
`6.5.1.4 SWOT Analysis
`
`Table 45 provides a SWOT analysis of Dymista.
`
`Table 45: Dymista SWOT Analysis, 2014
`
`Is rapidly gaining worldwide approval.
`
`Demonstrated superior efficacy in cl inical trials compared wilh azelastine, fluticasone, and placebo over a 14-day period
`when administered as a monotherapy.
`
`Sales have been promising so far, and the company reports that Dym1sta has rapidly gained market share. ------
`
`Dosing (one spray per nostril twice daily) is more convenient than when both agents are admiriistered as a monblherapy.
`This is likely to increase treatment compliance, and therefore, Improve symptom relief.
`
`Rapid onset of action can be effective within mlnutes , and produces a.significant reduction 1n symptoms with in days.
`
`Good safety and toleratiility profile should improve patient adherence.
`
`Trial shows Improvement over INCS alone, wh ich are currently the gold siandard of AR therapy.
`
`Meda has a strong presence in the resp iratory market, with good marketing connections to allergists and asthma specialists.
`
`Gained expanded approval in the US for children age 6-11 years.
`
`Is more expensive than prescribing each therapy individually, am:I considerably more expensive.than the cheaper formulary(cid:173)
`pieferred generic versions of the two individual components.
`Mechanism of action has not been fully-cJetermmed .
`AR IA guidelines support the use of oral over intranasal AHs ·itl adults With $easona·1 or perennial/persls\en"'l AR.
`Clinical trials compared monotherapy with each agent with Dymista rather than against taking the two agents concurrently
`
`Despite a statistically significant reduction in nasal symptoms in patients treated with Dymista compared with placebo and
`monotherapy (p<0.001) , the absolute difference between the treatment arms was small, and might not be clinically relevant
`enough to warrant the higher price associated with the FDC drug for payers.
`
`Carries a safety warning stating that patients cannot consume alcohol while taking Dymista.
`- - - - - - - - - - -
`There is a growing prevalence of moderate to severe AR , and these patients do not find monotherapy with INCS or AH
`effective.
`
`Very few branded prescription-only medicines are avallable, which means there are few choices for people who want to be
`reimbursed by their insurance in the applicable markets. The out-of-pocket cost for symptomatic AR therapies is increasing,
`as more treatments are no longer covered by insurance plans.
`______,
`
`Japan Is second largest AR market, which has yet to be entered.
`
`Nasonex is currently the best-selling product in this patient segment in the US, but ~s patent is due to expire in 2017'.
`However, two high-profile challenges by Teva and Apotex resulted in generic entries in 2014 and 2015, making space for
`
`Dymisla to become a leading product in the branded AR market. ----------------------
`
`Ci p I a has patented intranasal.combinations of'lhe ·AH . azelas\ine, with the corticosteroids mometasone furoate. -ciclesonide",
`and fluticasone propionate.
`
`Despite a
`statistically
`significant
`reduction in nasal
`symptoms in
`patients treated
`with Dymista
`compared with
`placebo and
`mono therapy
`(p<0.001 ), the
`absolute
`difference
`between the
`treatment arms
`was small, and
`might not be
`clinically relevant
`enough to
`warrant the
`higher price
`associated with
`the FDC drug for
`payers.
`
`As there is no clear difference between the various AHs and corticosteroids, it is likely that other combinations will be
`generated to compete for this new patient segment. Should a company with a bigger sales force than Meda enter the race,
`it could see substantial sales.
`
`Many National Health Service (NHS) formularies have released guidance for GPs, instructing them not to prescribe
`Dymista. citing the lack or evidence to support its improved efficacy and safely compared with cheaper monotherapy
`combinations .
`
`Source. Global Data: Oymista package insert. 20l5
`
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`
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`
`Competitive Assessment
`
`6.5.1.5 Forecast
`
`Table 46 presents the global sales forecasts for Dymista from 2014-2024.
`
`US
`
`41.4
`
`67.4
`
`67.6 I 74.4
`
`7.9 - 23:S [27.9
`
`33.6
`
`39.3
`
`Fra~ce T 0.0
`j Germany
`22.6
`22.6
`48.1 ~ -3
`Italy
`r
`~~I 0.0 1~3.6 ~
`1
`UK
`1.3
`10.2
`
`60.9
`54.8
`48.6
`48.5
`48.4
`- 1-
`-6 ~ ~ 28.0 I 28.2
`15.3
`18.0
`18.1
`20.8
`20.9
`
`74.9
`
`28.0
`
`39.2
`
`75.4
`
`32.1
`
`44.7
`
`75.8
`
`32.2
`
`44.7
`
`82.7
`
`36.3
`
`50.1
`
`67.1
`
`31.9
`23.6
`
`-
`
`83.2
`
`40.5
`
`55.6
`
`73.2
`-35.5 t
`26.4
`
`-1-
`2ss.8 I 2s2.1 291.1
`
`83. ~ 84.2 I
`7.3%
`- - - -
`-
`-
`48.9
`61.0 I 66.5
`11.4%
`85-.7
`43.2
`
`44.6
`
`79.3
`
`39.2
`29.f
`
`32.0 --
`
`5.9%
`
`38.1°/~ 1
`
`12.3%
`
`314.4
`
`337.0
`
`360.5
`
`113.4
`Source; Global Data
`CAGR = Compound Annual Growt~ Rate
`
`169.s
`
`209.7 m.3m
`
`.1
`
`6.6 Decongestants
`
`6.6.1 Overview
`
`Decongestants relieve nasal congestion by stimulating alpha-adrenergic receptors or by increasing
`levels or norepinephrine and epinephrine. This induces localized vasoconstriction of the blood
`vessels in the upper respiratory tract including in the nose, throat, and sinuses, thereby reducing
`inflammation and mucus formation . Shrinkage of the nasal mucous membranes helps promote
`nasal drainage and relieves watery eyes, runny nose, and sneezing.
`
`Decongestants can be administered either orally or intranasally. Intranasal decongestants, such as
`
`ephedrine, pseudoephedrine, xylometazoline naphazoline, oxymetazoline, and phenylephrine, are
`widely available generically and OTC. Intranasal decongestants are potent vasoconstrictive agents
`
`that are highly effective in reducing nasal congestion, with a rapid onset of action, working within 10
`minutes after application. The effects of short-acting decongestants can last up to four hours;
`longer-acting formulations can remain effective for up to six to 12 hours. They are available as
`sprays, gels, drops, and vapors, and are relatively inexpensive. However, patients often abuse
`these medications by overusing them, and develop rhinitis medicamentosa after prolonged use.
`This can result in adverse effects such as nasal irritation and increased rhinorrhea. In addition,
`
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`
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`
`abuse of nasal decongestants can result in dependency and rebound nasal congestion as a result
`
`of swelling in the nasal cavity. Therefore, it is advisable to only take nasal decongestants
`
`continuously for a maximum of three days. The ARIA guidelines state that adults with AR and a
`
`severe nasal blockage should use a very short course (a maximum of five days) of an intranasal
`
`decongestant, in combination with other drugs. In addition, they also do not recommend the regular
`
`use of oral decongestants.
`
`Oral decongestants, such as pseudoephedrine and phenylephrine, are only available
`
`in
`
`combination with an AH in some countries. Pregnant women and children are advised not to take
`
`oral or nasal decongestants for AR. Nasal formulations have a faster onset of action than oral
`
`forms, and may not result in as much drowsiness. Nasal and ophthalmic decongestants both lead
`to tachyphylaxis (a diminished response to successive doses), and therefore, long-term use is not
`
`recommended.
`
`While decongestants are widely used in the US and South America, either as a monotherapy or in
`
`combination with an oral AH, they are used less often in other parts of the world, particularly in
`
`Europe. In Italy they are used very rarely (Pawankar et al., 2011 ). This is due to their lack of a
`
`therapeutic advantage and adverse effects when used longer than several days. These medication
`
`are recommended only for short-term use, and are readily accessed by patients OTC.
`
`"l almost never prescribe decongestants. Why? Well, one [reason] is [that] they {patients] can buy
`them over the counter, anyway, and use them before you [even] see them; something like 26% of
`patients [with AR] presenting at the hospital clinic will be on decongestants, some of them very
`regularly, because you get hooked on them. What decongestants do is to squeeze the vasculature
`of the nose and leave it in fact far too open, and a patient gets used to a very clear, unobstructed
`nose, which is actually not good because you need the nasal airway to filter, warm, and humidify.
`and decongestant [use] robs us of quite a lot of its functions. And then, because when they
`{patients] go off {these drugs]. they wear off, [and] you get a rebound {congestion]. so the nose
`blocks up again, {and] they use more. And some of them present with something called rhinitis
`
`they've overused the
`is a completely blocked-up nose, because
`medicamentosa, which
`decongestant. And in order not to get into that situation, f think it's easier not to start on [a]
`decongestant [in the first place]. Now, we used to use, I think, a thing called Dexa-Rhinospray Duo,
`which had a steroid in it which was dexamethasone, and a low dose of decongestant, of
`tramazoline. And that was extremely useful, especially for chronic rhinosinusitis, because it hit the
`osteomeatal complex area and really helped to open it up, and patients could then douche their
`
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`
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`
`nose and make themselves feel much better. But Boehringer-lngelheim no longer market[s] that
`{drug} in the UK. though I think you can get it in places like Germany. So, we don't use it anymore.
`
`But there's a bit of evidence that, if you combine a decongestant with a corticosteroid, you're less
`
`likely to get the sorts of problems of rhinitis medicamentosa, and it might be useful at the start of
`
`therapy to have that combination. I think it's available in the USA."
`
`"Well, patients often use them [decongestants] over the counter as nasal sprays. I don't use the
`combination of [a] intranasal antihistamine plus [an] oral decongestant due to my concerns about
`
`side effects. But there are such combinations available on the German market. And patients can
`buy them over the counter."
`
`EU Key Opinion leader
`
`EU Key Opinion Leader
`
`"I do not prescribe decongestants much. I find [there are] a lot of side effects with systemic
`
`decongestants. Some adults use them. I usually don't prescribe Al/egra-D or Claritin-D to children
`
`because [of} the side effects; they get insomnia, they get hyperactive, and [other] things. I do
`sometimes use the spray, like Afrin, oxymetazoline. I will use that sometimes, like if I have a patient
`that has alfergies, and they are really, really severe. Their nose is totally blocked, and if you spray
`Nasonex up their nose, it runs right back out. One of the ways I sometimes treat that patient is, I'll
`
`open them up with Afrin. And then /'II spray in the Nasonex, the nasal steroid spray. And f will do
`that for the first three or four days of therapy. And then I'll stbp the Afrin and continue the Nasonex.
`And f don't let people use Afrin for more than three or four days at a time because many of them
`
`develop rebound nasal congestion, cafled rhinitis medicamentosa. "
`
`"Decongestants are used, but not by the specfafist. Or, I would say, not even by the GPs. This fuse}
`
`is mainly OTC [by patients themselves]."
`
`US Key Opinion leader
`
`EU Key Opinion leader
`
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`
`6.7
`
`Intranasal Anticholinergics
`
`6.7.1
`
`Overview
`
`lpratropium bromide metered-dose spray is indicated for the symptomatic relief of rhinorrhea
`
`associated with allergic and non-allergic perennial rhinitis in adults and children age six years and
`
`older. Originally developed by Boehringer lngelheim, it was approved as Atrovent in 1996, and is
`
`now available generically.
`
`lpratropium bromide blocks muscarinic cholinergic receptors, inhibiting the action of acetylcholine
`
`at parasympathetic sites in bronchial smooth muscle, causing bronchodilation. It decreases the
`
`contraction of the smooth muscles in the respiratory tract, thereby clearing the respiratory tract and
`
`relieving the symptoms of rhinitis. It has a fast onset of action, within 30 minutes. Although
`
`ipratropium bromide is effective for all types of watery rhinorrhea, it is· unlikely to be beneficial for
`
`the other symptoms of AR, including nasal congestion, sneezing, and postnasal drip.
`
`The ARIA guidelines state that intranasal ipratropium bromide should only be used for the
`
`treatment of rhinorrhea in patients with persistent AR. It is most effective when co-administered in
`
`combination with a nasal corticosteroid. lpratropium bromide is a very effective nasal treatment for
`
`the relief of rhinorrhea, with a good safety profile. However, it has an inconvenient dosing schedule,
`
`requiring three applications daily. Also, its adverse effects, while infrequent, include dry nose,
`
`epistaxis, urinary retention, and glaucoma. lpratropium should not be used by people who have
`
`glaucoma, or by men who have an enlarged prostate gland. The label advises against using the
`
`lpratropium bromide
`is a very effective
`nasal treatment for
`the relief en
`rhinorrhea, with a
`good safety profile.
`However, it has an
`inconvenient dosing
`schedule, requiring
`th/98 applications
`daily.
`
`therapy for more than three weeks.
`
`"I rarely prescribe anticholinergics - maybe once or twice a year."
`
`EU Key Opinion Leader
`
`"I do not prescribe anticholinergics as {a] first-line [treatment] at all; {rather,] usuafly as [a] second(cid:173)
`or third-line [treatment]. /'fl prescribe the anticholinergics in somebody who has allergic rhinitis
`who's not responding to a nasal steroid spray, (even] with good adherence and everything else.
`
`And I usually, if they still have [a] runny nose as their main symptom, and they are not responding
`to a nasaf steroid spray and an antihistamine, f usually add the antichofinergic in. "
`
`US Key Opinion Leader
`
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`ALLERGIC RHINITIS -
`GLOBAL DRUG FORECAST AND MARKET ANALYSIS TO 2024
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`Competitive Assessment
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`"Anticholinergics? Yes, I use those, especially if I think the patient has a mixed rhinitis, with a
`neurogenic element as well as an allergic element, and then ipatropium {bromide] may be ve,y
`useful. I use ipatropium bromide in the nose."
`
`"I just prescribe anticholinergics for hypersecretion. If there are too many secretion{s), it's used;
`otherwise, it's not used. So, ve,y seldom [do I use them]."
`
`EU Key Opinion Leader
`
`EU Key Opinion Leader
`
`6.8
`
`Leukotriene Receptor Antagonists
`
`6.8.1
`
`Overview
`
`LRAs, also known as leukotriene inhibitors and antileukotrienes, are oral treatments prescribed for
`
`patients who have asthma and/or catarrhal inflammation of the mucous membranes in the nose
`and respiratory tract. Merck's Singulair (montelukast sodium) is an LRA approved for the relief of
`
`AR symptoms.
`
`It is a cysteinyl leukotriene receptor 1 (CysL TR1) antagonist, blocking the
`physiologic actions of cysteinyl leukotriene 04 (L TD-4). L TD-4 belongs to the family of cysteinyl
`
`leukotrienes (Cys-L Ts). which are potent inflammatory mediators in both AR and asthma that are
`
`released from a variety of cells, including mast cells and eosinophils (Lee et al., 2009). They bind to
`
`cysteinyl
`
`leukotriene
`
`receptors
`
`(Cysl TRs)
`
`found
`
`in
`
`the human airways,
`
`triggering
`
`bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.
`
`Cys-L T
`
`levels are
`
`increased
`
`in asthmatics, particularty during
`
`the early phase of
`
`bronchoconstriction that follows an allergen challenge. Montelukast binds with high affinity and
`selectivity to the Cysl T1 receptor, which is found in the human airways, including in the smooth
`
`muscle cells and macrophages of the airways. Since Singulair attenuates leukotriene-modulated
`
`signaling, it provides a good alternative to increasing the dose of INCS. The drug is indicated for
`
`the relief of the symptoms of AR: SAR in patients age two years and older, and PAR in patients six
`
`months of age and older. It can be administered orally in the form of tablets (also chewable) and
`oral granules, giving it a competitive advantage over intranasal AR medications, especially in
`pediatric patients.
`
`Antileukotrienes are effective in reducing nasal obstruction, rhinorrhea, and ocular symptoms, in
`
`addition to bronchial symptoms, in patients with AR In the treatment algorithm, they follow lNCS
`
`and AHs in the treatment of patients with mild persistent, moderate to severe AR, if the patient is
`
`Allergic Rhinitis - Global Drug Forecast and Mark:et Analysis to 2024
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`ALLERGIC RHINITIS -
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`Competitive Assessment
`
`asthmatic. However, this class of therapy is not consistently effective, and there have been reports
`of adverse effects, including Churg-Strauss syndrome, headache, gastrointestinal symptoms, and
`
`rash (Greiner et al., 2011). The evidence indicates that for the treatment of SAR, montelukast is
`more beneficial than placebo, but equally effective as loratadine (Claritin). In addition, there is only
`a slight increase in benefit when using montelukast and loratadine in combination, and neither
`formulation was superior to INCS in terms of efficacy (Meltzer et al., 2000; Pullerits et al., 2002).
`Furthermore, a study comparing montelukast With pseudoephedrine demonstrated an equal
`benefit, with no difference in side effects (Mucha et al. , 2006).
`
`Of all the LRAs, only montelukast sodium is approved for use in patients With AR in the US and EU.
`
`Singulair received the FDA approval in 1998; however, it wasn't until January 2002 that it was
`approved for SAR, and in August 2005 for PAR. The drug reached blockbuster status, with $5.5
`billion in sales in 2011. Singulair lost its patent protection in the US in 2012, and has since suffered
`massive generic erosion. There are currently 11 generic manufacturers that market generic
`versions of Singulair in the US, putting Singulair in a very unfavorable position (FDA, 2013).
`Singutair's 2012 revenues reached $3.9 billion, with $2.8 billion coming from the first half of the
`year. Sales of Singulair declined to $1 .2 billion in 2013, and Merck lost nearly all sales of Singulair
`
`iii the US, where they dropped to negligible $60m.
`
`Since their discovery, Cys-L T antagonists have been regarded as candidate drugs for treating AR.
`Generic pranlukast hydrate, originally developed by Ono Pharmaceutical Co., Ltd., is a CysL T1
`receptor antagonist that is widely used in Japan. lt was originally approved in a capsule formulation
`for AR in January 2000, and the dry syrup formulation was approved for AR in December 2011 .
`The dry syrup formulation, Onon Dry Syrup, was approved and launched in 2000, but only for
`pediatric patients with bronchial asthma. It has a Pregnancy B Category rating, making it safe for
`
`use by expectant mothers. In addition to being indicated for patients With AR, it can also be used as
`a treatment for other respiratory conditions -
`namely, asthma and chronic obstructive pulmonary
`disease (COPD).
`
`Allergic Rhinitis - Global Drug Forecast and Mark:et Analysis to 2024
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`ALLERGIC RHINITIS -
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`Competitive Assessment
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`"Singu/air is the onfy one [LRAJ avaifable currently on the German market, but f only can prescribe
`it if the patient has a documented asthma. And it's not {a] first-line treatment for asthma, either. So,
`it would be prescription [prescribed} to a patient who is on an inhaled steroid, has allergic rhinitis,
`and the allergic rhinitis with asthma would not be sufficiently controlfed by a nasal steroid, pfus the
`inhaled steroid sometimes in combination with a beta-2 agonist. So, you can imagine that this is a
`very low proportion of patients that will receive this kind of treatment."
`
`EU Key Opinion Leader
`
`"I see a lot of people with allergic rhinitis and asthma. And if it's on the milder side, I usually will
`prescribe Singufair for both their allergy and their asthma. So yes, I do [prescribe it]. I see a lot of
`children. I particularly believe that that's a good option in children who have allergy and asthma,
`rather than pouring steroids into both air.vays, because we don 't know the safety implications ... [of}
`
`pouring steroids into both airways in children."
`
`US Key Opinion Leader
`
`"There's no doubt that inhaled corticosteroid is superior to antileukotriene. When you look at real
`
`life, actually, antileukotriene does remarkably well, because peopfe like taking a tablet. So, one
`
`does need more real-fife work in this area. "
`
`EU Key Opinion Leader
`
`"No. f don't use antileukotrienes because they're not useful for aflergic rhinitis, although, they are in
`
`the guidelines."
`
`"In Japan, I hear complaints about the cost of /eukotriene antagonists; /eukotriene antagonists are
`very costly. So, I get complaints from patients when I prescribed feukotriene antagonist for a
`
`month or two. "
`
`EU Key Opinion Leader
`
`Japanese Key Opinion Leader
`
`Allergic Rhinitis - Global Drug Forecast and Mark:et Analysis to 2024
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`ALLERGIC RHINITIS -
`GLOBAL DRUG FORECAST AND MARKET ANALYSIS TO 2024
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`Competitive Assessment
`
`6.9 Cromones
`
`6.9.1
`
`Overview
`
`Cromones, such as sodium cromoglycate and nedocromil sodium, are mast cell stabilizers and are
`
`available as both ocular and intranasal preparations for the treatment of allergic conjunctivitis and
`
`rhinitis, respectively. They are more commonly prescribed as an ocular preparation for patients with
`
`allergic conjunctivitis. They are considered less effective than INCS and other treatment options for
`
`AR symptoms, and have a short-lasting effect (Ratner et al., 2002}. The ARIA guidelines
`
`recommend them for the treatment of mild persistent or moderate/severe intermittent AR as an
`
`add-on therapy. The mechanism of action of cromones is poorly understood. As both intranasal
`
`and intraocular cromones have a short duration of action, they require repeated administration,
`
`often four times daily, which can have a negative impact on patient compliance.
`
`Both cromolyn and nedocromil are rated Pregnancy Category B, baseg primarily on their safety in
`
`animal reproduction studies. Intranasal cromones are normally used in the treatment of SAR, but
`
`can also be used to treat mild PAR. As they can take a couple of weeks to become fully effective, it
`
`is recommended that patients start therapy two weeks prior to the beginning of the pollen season.
`
`This is a highly genericized drug class, with many formulations being available OTC, such as
`
`intranasal sodium cromoglycate (Angier et al., 2010). They are rarely prescribed, and therefore,
`
`GlobalData excluded this drug class from the forecast.
`
`"I don't prescribe cromones, no. Except sometimes for eye use, but normally not for nasal use."
`
`EU Key Opinion Leader
`
`"Well, I did prescribe cromones, but now you really can't. Most of them are not available anymore
`because of the CFC {chlorofluorocarbon]-to-HFA [hydrofluoroalkane] propellant change that
`occurred. There's very low cromones used here in the US anymore. The people complained about
`it [the fact that it's no longer available], they loved it, they wished it was back, but l haven't
`I think Nasalcrom [cromofyn sodium] is still available, but it's {now] over-the-counter."
`prescribed -
`
`US Key Opinion Leader
`
`Allergic Rhinitis - Global Drug Forecast and Mark:et Analysis to 2024
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`ALLERGIC RHINITIS -
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`Competitive Assessment
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`"I find cromones useful for small children. I stf/1 some sometimes {use] nedocromil also, in the eyes,
`which is a cromone. There's only twice-a-day use, and that's pretty effective, although I think
`Patanol has largely replaced that.'
`
`"Cromones - no. I don't prescribe them."
`
`6.10 Thromboxane A2 Receptor Antagonists
`
`6.10.1 Overview
`
`EU Key Opinion Leader
`
`EU Key Opinion Leader
`
`The Japanese AR treatment guidelines recommend
`
`the use of a dual
`
`thromboxane A2
`
`(TXA2)/CRTH2 receptor antagonist for patients suffering from nasal blockage as the major
`
`symptom . TXA2 receptor antagonists are considered to be more effective for nasal blockage than a
`
`second-generation AH , and can also improve sneezing and rhinorrhea symptoms when
`administered for more than two weeks. The only approved medication in