Treatment Of Papulopustular Rosacea With Ivermectin

  • Published: Apr 13, 2017
  • Earliest Priority: Jul 08 2013
  • Family: 45
  • Cited Works: 0
  • Cited by: 0
  • Cites: 4
  • Additional Info: Full text
This following text has been automatically extracted from the original PDF supplied by the patent office.  Please refer to the original PDF document to view the text in its original format.
AU 2014287422 B2
(12) STANDARD PATENT (11) Application No. AU 2014287422 B2
(19) AUSTRALIAN PATENT OFFICE
(54) Title
Treatment of papulopustular rosacea with ivermectin
(51) International Patent Classification(s)
A61K 31/7048 (2006.01) A61K 47/14 (2006.0 1)
A61K 9/00 (2006.01) A61P 17/00 (2006.01)
A61K 47/10 (2006.01) A61P 17/10 (2006.01)
(21) Application No: 2014287422 (22) Date of Filing: 2014.07.08
(87) WIPO No: W015/006319
(30) Priority Data
(31) Number (32) Date (33) Country
61/919,208 2013.12.20 US
61/927,717 2014.01.15 us
14/209,958 2014.03.13 us
61/843,540 2013.07.08 us
(43) Publication Date: 2015.01.15
(44) Accepted Journal Date: 2017.04.13
(71) Applicant(s)
Galderma S.A.
(72) Inventor(s)
Jacovella, Jean;Chappuis, Jean-Paul;Kaoukhov, Alexandre;Graeber, Michael;Salin,
Laurence;Poncet, Michel;Briantais, Philippe
(74) Agent / Attorney
AJ PARK, GPO Box 2600, Sydney, NSW, 2001, AU
(56) Related Art
US 5,952,372 A
WO 2004/093886 Al
US 6,133,310 A
WO 2014/049298 Al

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property
Organization
International Bureau
(10) International Publication Number
(43) International Publication Date W O 2015/006319 A1
January 2015 (15.01.2015) W IPO I PCT
(51) International Patent Classification: (74) Agents: HSING, Weihong et al.; Panitch Schwarze Belis-
A61K31/7048 (2006.01) A61P 17/10 (2006.01) ario & Nadel LLP, One Commerce Square, 2005 Market
A61K 9/00 (2006.01) A61K 47/10 (2006.01) Street, Suite 2200, Philadelphia, PA 19103 (US).
A6P 17/00 (2006.01) A61K 47114 (2006.0 1) (81) Designated States (unless otherwise indicated, for every
(21) International Application Number: kind of national protection available): AE, AG, AL, AM,
PCT/US2014/045739 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
) .a BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,(22) International Filng Date: DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT,8 July 2014 (08.07.20 14) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
(25) Filing Language: English KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,(26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
(30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM,
61/843,540 8 July 2013 (08.07.2013) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
61/919,208 20 December 2013 (20.12.2013) US ZW.
61/927,717 15 January 2014 (15.01.2014) US (84) Designated States (unless otherwise indicated, for every
14/209,958 13 March 2014 (13.03.2014) US kind of regional protection available): ARIPO (BW, GH,
(71) Applicant: GALDERMA S.A. [CH/CH]; Zugerstrasse 8, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
CH-6330 Cham (CH). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
(71) Applicant (for MG only): GALDERMA R & D [US/US]; EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
Cedar Brook Drive, Suite 1, Cranbury, NJ (US). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
(72) Inventor: JACOVELLA, Jean; 2400 Routes Des Colles, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
BP 87, F-06902 Sophia Antipolis (FR). KM, ML, MR, NE, SN, TD, TG).
Published:
- with international search report (Art. 21(3))
(54) Title: TREATMENT OF PAPULOPUSTULAR ROSACEA WITH IVERMECTIN
Figure 5C
* p<.01, ** p<.001
Baseline Week 2 Week 4 Week 8 Week 12
-10
-20J20 -16.5
-540 -44.4
) -- 50
-60
-70 -64.7
-80 3-76
-0-lvermectin 1% ||||||Vehice **
(57) Abstract: Methods and compositions for safe and effective treatment of papulopustular rosacea in a subject are described. The
O methods involve topically applying to an affected skin area a topical composition containing ivermectin and a pharmaceutically ac -
ceptable carrier. Treatment with ivermectin represents an innovative therapy that is more robust and effective than the conventional
treatments.

TITLE OF THE INVENTION
[0001] Treatment of Papulopustular Rosacea with Ivennectin
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] This application claims priority from U.S. patent application Ser. No. 14/209,958,
filed March 13, 2014, which is entitled to priority pursuant to 35 U.S.C. § 119(e) to U.S.
Provisional Patent Application No. 61/843,540, filed July 8, 2013, U.S. Provisional Patent
Application No. 61/919,208 filed December 20, 2013, and U.S. Provisional Patent
Application No. 61/927,717, filed January 15, 2014, the disclosure of each of which is hereby
incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0003] Papulopustular rosacea (PPR) is a chronic inflammatory disorder characterized by
facial papules, pustules, and persistent erythema. 1 It is highly prevalent and associated with
adverse impact on quality of life and depression.2 The etiology of rosacea is multifactorial. In
addition to neurovascular dysregulation, the facial skin of patients with rosacea is affected by
augmented proinflammatory immune responses. 3 The principal active cathelicidin peptide
(LL-37) is highly concentrated in skin affected by rosacea and can contribute to acute
inflammation.4 Moreover, PPR is characterized by the presence of inflammatory infiltrates
that accompany flares, along with a heightened immune response involving neutrophilic
infiltration and increased gene expression of IL-8.5 In addition to exogenous factors (including
UV light, heat and alcohol), it may be triggered by Demodex folliculorum mites. 3 Some
studies of PPR observed higher mite densities compared to controls.6-7 Therefore, a multitude
of factors can activate neurovascular and/or immune responses, and consequential
inflammation leading to flares of rosacea. 3
[0004] Inflammatory lesions of rosacea, particularly moderate to severe PPR, are difficult
to treat. Only a few therapeutic alternatives currently exist in the treatment of inflammatory
lesions of rosacea. In the United States, only three FDA-approved treatments are indicated for
the reduction of inflammatory lesions of rosacea, including two topical treatments. A recent
Cochrane review noted some evidence supporting the effectiveness of topical metronidazole
and azelaic acid in the treatment of moderate to severe rosacea, 8 yet it is clear that not all
patients respond to these medications. In a national survey of current rosacea medication
users, 46% of patients had previously changed medications, usually due to a lack of
improvement. 9
[0005] Ivermectin is an anti-parasitic drug derivative from the macrocyclic lactones
family approved for human use for treatment and chemoprophylaxis of onchocerciasis and
strongyloidiasis since 1996 in the USA and since 1988 in France. In addition, it has been
approved in France for the treatment of human scabies. Oral ivennectin in human and animal
demodicidosis was effective in reducing Demodex folliculorum and improving demodicidosis.
Moreover, when administered orally, ivermectin combined with a subsequent weekly
application of topical permethrin showed treatment efficacy in a patient presenting chronic
rosacea-like demodicidosis (14).
[0006] U.S. Pat. No. 5,952,372 discloses a method of treating rosacea in humans
involving orally or topically administering ivennectin. However, according to U.S. Pat. No.
5,952,372, because of the skin barrier effect, topical treatment with ivennectin would be
anticipated to require once- or twice-daily applications for as long as four weeks to achieve
sufficient follicle penetration and effective miticidal activity. It further describes that after
ivermectin carries out its miticidal activity on skin Demodex folliculorum organisms,
inflammatory responses to them begin to diminish but remnants of the dead mites still elicit
some flushing and lesion formation until the cleanup processes of the body remove them, a
process that requires six to eight weeks. It suggests to employ conventional anti-rosacea
medications, such as oral tetracycline and topical metronidazole, to suppress early flareups
and to give early clinical response during the initial phase of ivennectin administration. U.S.
o Pat. No. 5,952,372 contains no specific disclosure on topical treatment of PPR.
[0007] U.S. Pat. No. 6,133,310 and U.S. Pat. No. 8,415,311 also disclose a method of
treating acne rosacea by topical application of ivermectin. However, they contain no specific
disclosure on treating inflammatory lesions of rosacea or PPR.
[0008] Accordingly, treatments demonstrated to have a greater efficacy in treating PPR,
particularly moderate to severe PPR, than the currently available compositions, such as
metronidazole compositions, are still needed to provide greater, longer lasting, or more rapid
relief to those in need of the treatment. There is a need for improved or alternate effective
treatment of PPR, particularly moderate to severe PPR. Such need is met by the present
invention; and/or at least provides the public with a useful choice.
[0008A] In the description in this specification reference may be made to subject matter
that is not within the scope of the claims of the current application. That subject matter should
be readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the claims of this application.
BRIEF SUMMARY OF THE INVENTION
[0009] It is now demonstrated that topical administration of ivermectin provided more
rapid relief of papulopustular rosacea as well as longer period of time that is free of relapse as
compared to the currently available treatments, such as the topical treatment with 0.75% by
weight of metronidazole.
[0010] In one general aspect, embodiments of the present invention relate to a method of
treating papulopustular rosacea in a subject in need thereof, comprising topically
administering, once daily, to a skin area affected by the papulopustular rosacea a
therapeutically effective amount of a pharmaceutical composition comprising ivermectin and
a pharmaceutically acceptable carrier, wherein the treatment results in a significant reduction
in inflammatory lesion count in the subject as early as two weeks after the initial
administration of the pharmaceutical composition.
[0011] Another general aspect of the present invention relates to a method of treating
inflammatory lesions of papulopustular rosacea in a subject in need thereof, comprising
topically administering, once daily, to a skin area affected by the inflammatory lesions of
papulopustular rosacea a pharmaceutical composition comprising ivermectin and a
pharmaceutically acceptable carrier, wherein the treatment results in a significant reduction in
inflammatory lesion count in the subject as early as two weeks after the initial administration
of the pharmaceutical composition. In a preferred embodiment of the present invention, the
pharmaceutical composition useful in the invention comprises about 0.5% to 1.5% by weight
ivermectin.
[0012] In another preferred embodiment of the present invention, the subject has moderate
to severe papulopustular rosacea before the treatment.
[0013] In yet another preferred embodiment of the present invention, the subject has at
least 10, preferably at least 12 and more preferably at least 15, inflammatory lesions of
papulopustular rosacea, before the treatment.
[0014] According to embodiments of the present invention, once daily topical treatment
with ivermectin is significantly superior than twice-daily topical treatment with metronidazole
in treating papulopustular rosacea.
[0014A] The invention also relates to a use of a composition comprising ivermectin and a
pharmaceutically acceptable carrier in the manufacture of a medicament for the treatment of
papulopustular rosacea in a subject in need thereof to thereby obtain a significant reduction in
inflammatory lesion count in the subject as early as two weeks after the initial administration
of the medicament, wherein the medicament is to be topically administered, once daily, to a
skin area affected by the papulopustular rosacea.
[0014B] The invention also relates to a use of a composition comprising ivermectin and a
pharmaceutically acceptable carrier in the manufacture of a medicament for the treatment of
inflammatory lesions of papulopustular rosacea in a subject suffering from moderate to severe
papulopustular rosacea to thereby obtain a significant reduction in inflammatory lesion count
in the subject as early as two weeks after the initial administration of the medicament, wherein
the medicament is to be topically administered, once daily, to a skin area affected by the
papulopustular rosacea.
[0015] Other aspects, features and advantages of the invention will be apparent from the
following disclosure, including the detailed description of the invention and its preferred
embodiments and the appended claims.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0016] The foregoing summary, as well as the following detailed description of the
invention, will be better understood when read in conjunction with the appended drawings.
For the purpose of illustrating the invention, there are shown in the drawings embodiments
which are presently preferred. It should be understood, however, that the invention is not
limited to the precise embodiments shown in the drawings.
[0017] Figure 1 shows the median percentage change from baseline in lesion counts (ITT-
LOCF population) in a dose range study, after various topical treatments;
[0018] Figure 2 illustrates subjects' response to the statement "the product improves my
rosacea" after various topical treatments (ITT Observed);
[0019] Figure 3 shows subject disposition in 2 clinical studies on the safety and efficacy
of ivermectin topical treatment;
[0020] Figure 4 illustrates proportions of subjects achieving IGA success ("clear" or
"almost clear"): (A) at week 12 in studies 1 and 2; (B) at weeks 2, 4, 8 and 12 in study 1; and
(C) ) at weeks 2, 4, 8 and 12 in study 2, wherein SOOLANTRA is a 1% ivermectin cream;
[0021] Figure 5 shows the change from baseline in inflammatory lesion counts (ITT-
LOCF): (A) mean absolute change (± standard error) in study 1; (B) mean absolute change (
standard error) in study 2; (C) median percent change in study 1; and (D) median percent
change in study 2, wherein SOOLANTRA is a 1% ivermectin cream;
[0022] Figure 6 show subjects' rating of rosacea improvement in (A) Study 1 and (B)
Study 2 at week 12;
[0023] Figure 7 are photographs of a patient at Baseline and Week 12 (standard light);
[0024] Figure 8 shows subject disposition in a clinical study comparing the topical
treatments with ivermectin and metronidazole;
[0025] Figure 9 illustrates the mean percent change from baseline in inflammatory lesion
counts (ITT-LOCF) after the topical treatments with ivermectin and metronidazole, * p<05,
** p<.001;
[0026] Figure 10 shows the success rate based on IGA of "clear" or "almost clear" after
the topical treatments with ivermectin and metronidazole, * p<.05, ** p<.001;
[0027] Figure 11 shows subjects' rating of rosacea improvement after the topical
treatments with ivermectin and metronidazole; and
[0028] Figure 12 shows time to first relapse defined as first re-occurrence of IGA>2 after
the successful treatments with ivermectin (CD5024) and metronidazole.
DETAILED DESCRIPTION OF THE INVENTION
[0029] Various publications, articles and patents are cited or described in the background
and throughout the specification; each of these references is herein incorporated by reference
in its entirety. Discussion of documents, acts, materials, devices, articles, or the like which
have been included in the present specification is for the purpose of providing context for the
present invention. Such discussion is not an admission that any or all of these matters form
part of the prior art with respect to any inventions disclosed or claimed.
[0030] Unless defined otherwise, all technical and scientific terms used herein have the
same meaning as commonly understood to one of ordinary skill in the art to which this
invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the
specification. All patents, published patent applications and publications cited herein are
incorporated by reference as if set forth fully herein. It must be noted that as used herein and
in the appended claims, the singular forms "a," "an," and "the" include plural references
unless the context clearly dictates otherwise.
[0030A] The term "comprising" as used in this specification means "consisting at least in
part of'. When interpreting each statement in this specification that includes the term
"comprising", features other than that or those prefaced by the term may also be present.
Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.
[0031] Ivermectin is a member of the avermectin class, which has been shown in
immunopharmacological studies to exert anti-inflammatory effects by inhibiting
lipopolysaccharide-induced production of inflammatory cytokines, such as tumor necrosis
factor alpha and interleukin (IL)- lb, while upregulating the anti-inflammatory cytokine IL-
1010. It is a semi-synthetic derivative isolated from the fermentation of Streptomyces
avermitilis, that belongs to the avermectin family of macrocyclic lactones. Ivermectin is a
mixture containing 5-0-demethyl-22,23-dihydroavennectin Ala plus 5-0-demethyl-25-de(1-
methylpropyl)-25-(l-methylethyl)-22,23-dihydroavermectin Ala, generally referred to as
22,23-dihydroavermectin Bla and Blb or H2Bla and H2B1b, respectively. The respective
empirical formulas of H2B la and H2B 1b are C 4 8H74 0 14 and C47H72O 1 4 with molecular
weights of 875.10 and 861.07 respectively.
[0032] Ivennectin is a macrocyclic lactone derivative, its therapeutic effect is thought to
be prominently due to its anti-inflammatory properties, similar to that of other macrolides.
Avermectin has been reported to exert anti-inflammatory effects by inhibiting
lipopolysaccharide-induced production of inflammatory cytokines. In addition to its anti-
inflammatory mode of action, ivennectin possesses antiparasitic properties. Its predecessor,
avermectin, is an antiparasitic agent of agricultural importance first isolated in 1974.13 Several
studies support ivermectin's role in the effective oral treatment of cutaneous demodicidosis
(in combination with topical permethrin cream) and scabies, as well as topical treatment of
head lice. 14-16 Ivennectin causes death of parasites, primarily through binding selectively and
with high affinity to glutamate-gated chloride channels, which occur in invertebrate nerve and
muscle cells. This leads to the interruption of nerve impulses, causing paralysis and death of
parasitic organisms. Ivermectin is known to act on Demodex mites in localized and
generalized demodicidosis in animals and in humans.
[0033] In the present invention, studies were conducted to evaluate the efficacy and safety
of ivermectin in treating papulopustular rosacea (PPR). It was discovered that, as early as 2
weeks after the initial topical administration of a pharmaceutical composition comprising 0.5
to 1.5% (w/w) ivermectin to the subject, a significant reduction in inflammatory lesion count
was observed.
As used herein, a "significant reduction" refers to a reduction that is statistically significant,
not due to chance alone, which has a p-value of 0.05 or less. A "significant reduction" can
have a p-value of less than 0.05, 0.04, 0.03, 0.01, 0.005, 0.001, etc. As used herein,
"inflammatory lesion count" refers to the number of inflammatory lesions associated with
rosacea or PPR. Inflammatory lesions can be papules and/or pustules. A papule is a small,
solid elevation less than one centimeter in diameter, and a pustule is a small, circumscribed
elevation of the skin, which contains yellow-white exudates.
[0034] The lesions can be, e.g., papules and/or pustules of any sizes (small or large). For
example, at two weeks after the initial treatment, about 30% (p<0.001) and 27.3% (p<0.01)
median reduction of the inflammatory lesion counts were observed from patients treated with
ivermectin in two separate clinical studies using methods of the present invention. These
reductions are statistically significant because they had p values less than 0.01 or even less
than 0.001.
[0035] This early onset of significant effectiveness is unexpected and surprising in
comparison with the conventional treatments. For example, significant treatment differences
were only observed from week 4 or week 8 forward in two phase III studies for the topical
treatment of moderate PPR using twice-daily 15% azelaic acid (Thiboutot et al., 2003, J. Am
Acad Dermatol, 48 (6): 836-845), while no statistically significant difference with respect to
the median inflammatory lesion counts or the median percentage change in inflammatory
lesion counts was observed at any evaluation time during the study (P > .29) of topical
treatment of moderate to severe PPR using once-daily 0.75% or 1.0% metronidazole (Dahl et
al., 2001, J. Am Acad Dermatol, 45 (5): 723-730).
[0036] This early onset of significant effectiveness is also unexpected and surprising in
view of the prior teaching, that topical treatment with ivermectin would be anticipated to
require once- or twice-daily applications for as long as four weeks to achieve sufficient
follicle penetration and effective miticidal activity; and that after ivermectin carries out its
miticidal activity on skin Demodex folliculorum organisms, remnants of the dead mites still
elicit some flushing and lesion formation until the cleanup processes of the body remove
them, a process that requires six to eight weeks; and that conventional anti-rosacea
medications, such as oral tetracycline and topical metronidazole, are suggested to be
employed to suppress early flareups and to give early clinical response during the initial phase
of ivermectin administration (see, e.g., U.S. Pat. No. 5,952,372).
[0037] Side-by-side clinical studies in the present invention also showed that methods
according to embodiments of the present invention result in more effective treatment of PPR
as well as longer time for the relapse of PPR to occur than the conventional topical treatment,
such as that with metronidazole. In addition, methods according to embodiments of the
present invention also result in less frequent adverse skin reactions than the conventional
topical treatments.
[0038] While not wishing to be bound by the theory, it is believed that the mechanism of
action of ivermectin in treating papulopustular rosacea may be linked to anti-inflammatory
effects of ivermectin as well as the death of Demodex mites that have been reported to be a
factor in inflammation of the skin. Because ivermectin has both anti-inflammatory and anti-
parasitic activities, treatment of PPR with ivermectin represents an innovative therapy
addressing these relevant pathogenic factors in PPR, thus a novel addition to the current
treatment armamentarium.
[0039] Described is a method of treating papulopustular rosacea in a subject in need
thereof, comprises topically administering to a skin area affected by the papulopustular
rosacea a pharmaceutical composition comprising ivermectin and a pharmaceutically
acceptable carrier.
[0040] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically
acceptable vehicle or diluent comprising excipients and auxiliaries that facilitate processing of
the active compounds into preparations which can be used pharmaceutically.
[0041] The pharmaceutical compositions useful according to the invention are suited for
treating the skin. They can be in liquid, pasty or solid form, and more particularly in the form
of ointments, creams, milks, pomades, powders, impregnated pads, syndets, towelettes,
solutions, gels, sprays, foams, suspensions, lotions, sticks, shampoos or washing bases. They
can also be in the form of suspensions of microspheres or nanospheres or of lipid or polymeric
vesicles or of polymeric patches and of hydrogels for controlled release. These compositions
for topical application can be in anhydrous form, in aqueous form, or in the form of an
emulsion.
[0042] Described is a pharmaceutical composition formulated as an emulsion, the topical
pharmaceutical emulsion comprises ivermectin, and one or more other ingredients selected
from the group consisting of: an oily phase comprising dimethicone, cyclomethicone,
isopropyl palmitate and/or isopropyl myristate, the oily phase further comprising fatty
substances selected from the group consisting of cetyl alcohol, cetostearyl alcohol, stearyl
alcohol, palmitostearic acid, stearic acid and self-emulsifiable wax; at least one surfactant-
emulsifier selected from the group consisting of glyceryl/PEG100 stearate, sorbitan
monostearate, sorbitan palmitate, Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; a
mixture of solvents and/or propenetrating agents selected from the group consisting of
propylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate; one or more gelling
agents selected from the group consisting of carbomers, cellulose gelling agents, xanthan
gums, aluminum magnesium silicates but excluding aluminum magnesium silicate/titanium
dioxide/silica, guar gums, polyacrylamides and modified starches; and water.
[0043] In a preferred embodiment, the pharmaceutical composition useful in the invention
comprises 0.5-1.5% (w/w) ivennectin, more preferably, about 1% (w/w) ivermectin, and a
pharmaceutically acceptable carrier.
[0044] In another preferred embodiment, the pharmaceutical composition useful in the
invention comprises about 1% (w/w) ivermectin, and one or more inactive ingredients
selected from the group consisting of carbomer, such as carbomer copolymer type B; cetyl
alcohol; citric acid monohydrate; dimethicone 20 Cst; edetate disodium; glycerin; isopropyl
palmitate; methyl paraben; oleyl alcohol; phenoxyethanol; polyoxyl 20 cetostearyl ether;
propylene glycol; propyl paraben; purified water; sodium hydroxide; sorbitan monostearate
and stearyl alcohol.
[0045] As used herein, the term "subject" means any animal, preferably a mammal, most
preferably a human, to whom will be or has been administered compounds or topical
formulations according to embodiments of the invention. Preferably, a subject is in need of, or
has been the object of observation or experiment of, treatment or prevention of papulopustular
rosacea.
[0046] As known to those skilled in the art, an "intent-to-treat population" or "ITT
population" refers to all subjects who are randomized in a clinical study and to whom the
study drug is administered. "ITT- LOCF" refers to the ITT population using the Last
Observation Carried Forward (LOCF) method, a standard method of handling missing data,
which imputes or fills in values based on existing data. "ITT- MI" refers to the ITT population
using the multiple imputations (MI) method based on all the data available in the model,
another method for processing data known to those skilled in the art. A "per protocol
population" or "PP population" refers to subjects of the ITT population in a clinical study who
have no major deviations from the protocol of study.
[0047] In one embodiment, "treatment" or "treating" refers to an amelioration,
prophylaxis, or reversal of a disease or disorder, or of at least one discernible symptom
thereof. In another embodiment, "treatment" or "treating" refers to an amelioration,
prophylaxis, or reversal of at least one measurable physical parameter related to the disease or
disorder being treated, not necessarily discernible in or by the mammal. In yet another
embodiment, "treatment" or "treating" refers to inhibiting or slowing the progression of a
disease or disorder, either physically, e.g., stabilization of a discernible symptom,
physiologically, e.g., stabilization of a physical parameter, or both. In yet another
embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder.
[0048] Success of treating PPR can be measured using methods known in the art, such as
by the reduction of inflammatory lesion count from the baseline before treatment, by an
improvement from the baseline in an investigator's global assessment (IGA) score, or by both
the reduction of inflammatory lesion count and the IGA score.
[0049] The IGA score is determined by a trained medical professional evaluating the skin
condition of a patient utilizing an investigative global assessment of the skin condition.
Typically, such global assessments assign a value to the degree of rosacea exhibited by the
skin. In addition to the assessment made by the medical professional, the patient's input and
observations of their skin condition and responses to various inquiries (e.g., stinging or
burning sensations) also play a role in determining the IGA score that is assigned. For
example, the IGA score for rosacea (Table 1) can range, for example, from 0 (clear) to 1
(almost clear) to 2 (mild) to 3 (moderate) to 4 (Severe), including values between these
numeric gradings, such as 1.5, 2.6, 3.4 etc. (e.g., intervals of 0.1).
[0050] Table 1. Investigator's Global Assessment of Rosacea Severity
Grade Score Clinical Description
Clear 0 No inflammatory lesions present, no erythema
Almost Clear 1 Very few small papules/pustules, very mild erythema present
Mild 2 Few small papules/pustules, mild erythema
Moderate 3 Several small or large papules/pustules, moderate erythema
Severe 4 Numerous small and/or large papules/pustules, severe erythema
[0051] In view of the present disclosure, a skin area that is affected by papulopustular
rosacea can be identified using any diagnostic signs or means known in the art, and can be
treated by methods according to embodiments of the present invention. Patients can have
papulopustular rosacea at different stages, from mild to severe.
[0052] In a preferred embodiment, the patient has moderate to severe papulopustular
rosacea. As used herein, a patient having "moderate to severe papulopustular rosacea" has at
least moderate facial erythema and at least 10 papulopustular lesions before treatment. For
example, the patient can have an IGA of rosacea of 3 or 4, and at least 10, 15, 20, 25 or more
papulopustular lesions before treatment.
[0053] According to embodiments of the present invention, the papulopustular rosacea is
treated by topically applying to a skin area affected by the papulopustular rosacea a
pharmaceutical composition comprising ivermectin and a pharmaceutically acceptable carrier,
and the treatment results in a reduction in the inflammatory lesion count from the baseline
number of PPR lesions (before treatment) by at least 1 to 100 lesions or more, such as at least
1,2, 3,4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 35, 40, 50, 60, 70, 80, 90 or 100 lesions or more. According to embodiments of the
present invention, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%
reduction in inflammatory lesion count is observed after the treatment. Depending on the
number of inflammatory lesions, and other factors, such as the conditions of the patient, the
treatment can last as long as it is needed, such as 4 to 12 weeks.
[0054] According to other embodiments of the present invention, the treatment reduces
the IGA score in the treated subject. As used herein, the "success rate" in a clinical study
refers to the percentage of subjects in the study having an IGA of 0 ("clear") or 1 ("almost
clear") after the treatment.
[0055] The pharmaceutical composition can be topically administered once or twice daily,
preferably once daily.
[0056] According to embodiments of the present invention, after the initial successful
treatment with ivermectin, i.e., to an IGA of 0 or 1, it takes a longer time to relapse, i.e., to an
IGA of 2 or above, as compared to the conventional treatments, such as topical treatment with
0.75% by weight metronidazole. For example, treatment with ivermectin (1%) once daily
(QD) resulted in a statistically significant extended remission (e.g., delayed time to first
relapse, and increase in the number of treatment free days) of rosacea when compared to
metronidazole 0.75% BID in subjects who were successfully treated (IGA 0 or 1) for 16
weeks. There was also a numerical trend in favor of ivermectin 1% QD for the relapse rates.
[0057] As used herein, "time to first relapse" is defined as the time elapsed between initial
successful treatment to an IGA of rosacea of 0 or 1 to the first reoccurrence of the IGA to 2 or
more in a subject. According to embodiments of the present invention, the median time to first
relapse is about 110, 115, 120, 125, 130, 135, 140, 145 or 150 days or more in subjects treated
with ivermectin, with a p value of 0.05 or less.
[0058] Also described is a method of treating inflammatory lesions of papulopustular
rosacea in a subject in need thereof, comprising topically administering to a skin area affected
by the inflammatory lesions of papulopustular rosacea a pharmaceutical composition
comprising ivermectin and a pharmaceutically acceptable carrier.
[0059] Preferably the subject has moderate to severe PPR before the treatment. More
preferably, the subject has at least 15 inflammatory lesions of PPR before the treatment.
[0060] In another preferred embodiment, at two weeks after the initial treatment, about
27% or more median reduction of the inflammatory lesion counts is observed from subjects
treated with ivennectin, with a p value of 0.01 or less.
[0061] Preferably, the pharmaceutical composition comprises 0.5% to 1.5% by weight
ivermectin, more preferably about 1% by weight ivermectin.
[0062] In an embodiment of the present invention, as early as 2 weeks after the initial
administration of the pharmaceutical composition to the subject, significant reduction in the
inflammatory lesion count in the subject is observed. In other embodiments of the present
invention, the method results in more reduction of the inflammatory lesion count and longer
relapse-free time of the inflammatory lesions of rosacea in the subject in comparison to that
achieved by topically administering to the subject a second pharmaceutical composition
comprising 0.75% by weight metronidazole.
[0063] This invention will be better understood by reference to the non-limiting examples
that follow, but those skilled in the art will readily appreciate that the examples are only
illustrative of the invention and the claims which follow thereafter.
[0064] Unless otherwise indicated, all percentages of the ingredients in the present
application are percentages by weight (w/w).
[0065] Example 1: Topical ivermectin compositions
[0066] Examples of pharmaceutical compositions that can be used in the present invention
are described in U.S. Pat. No. 8,415,311 and US Pat. No. 8,470,788, which are incorporated
herein by reference. Compositions useful in the present invention include, but are not limited
to, the following:
[0067] Composition 1
% by weight relative to
the total weight of the
Ingredients Composition
Ivermectin 1.00
Glycerol 4.0
Aluminum magnesium silicate 1.0
Methyl para-hydroxybenzoate 0.2
Disodium EDTA 0.05
Citric acid monohydrate 0.05
Isopropyl palmitate 4.0
Glyceryl/PEG 100 stearate 3.0
Self-emulsifiable wax 2.0
Palmitostearic acid 2.5
Steareth-20 3.0
Sorbitan stearate 2.0
Dimethicone 20 0.5
Propyl para-hydroxybenzoate 0.1
Propylene glycol 4.0
Glyceryl triacetate 1.0
Phenoxyethanol 0.5
10% sodium hydroxide qs pH
Water qs 100
[0068] Composition 2
% by weight relative to
the total weight of the
Ingredients Composition
Ivenrectin 1.00
Glycerol 4.0
Acrylate C10-30 alkyl acrylate 0.15
Crosspolymer
Methyl para-hydroxybenzoate 0.2
Disodium EDTA 0.05
Citric acid monohydrate 0.05
Isopropyl myristate 4.0
Cetyl alcohol 3.0
Stearyl alcohol 2.0
Self-emulsifiable wax 0.8
Palmitostearic acid 0.5
Steareth-20 2.0
Sorbitan palmitate 1.0
Dimethicone 20 0.5
Propyl para-hydroxybenzoate 0.1
Propylene glycol 4.0
Glyceryl triacetate 1.0
Phenoxyethanol 0.5
10% sodium hydroxide qs pH
Water qs 100
[0069] Composition 3
% by weight relative to
the total weight of the
Ingredients Composition
Ivenrectin 1.00
Glycerol 4.0
Aluminum magnesium
1.0
silicate
Methyl para- 0.2
hydroxybenzoate
Disodium EDTA 0.05
Citric acid
0.05
monohydrate
Isopropyl palmitate 4.0
Glyceryl/PEG 100
3.0
stearate
Self-emulsifiable wax 2.0
Palmitostearic acid 3.0
Steareth-20 3.0
Sorbitan palmitate 2.0
Dimethicone 20 0.5
Propyl para- 0.1
hydroxybenzoate
Propylene glycol 4.0
Glyceryl triacetate 1.0
Phenoxyethanol 0.5
10% sodium hydroxide qs pH
Water qs 100
[0070] Composition 4
% by weight relative to
the total weight of the
Ingredients Composition
Ivenrectin 1.00
Glycerol 4.0
Acrylate C10-30 alkyl acrylate 0.2
Crosspolymer
Methyl para-hydroxybenzoate 0.2
Disodium EDTA 0.05
Citric acid monohydrate 0.05
Isopropyl palmitate 4.0
Cetyl alcohol 3.5
Stearyl alcohol 2.5
Oleyl alcohol 2.0
Ceteareth-20 3.0
Sorbitan monostearate 2.0
Dimethicone 200 20 cs 0.5
Propyl para-hydroxybenzoate 0.1
Propylene glycol 2.0
Phenoxyethanol 1.0
10% sodium hydroxide qs pH
Water qs 100
[0071] Composition 5
% by weight relative to
the total weight of the
Ingredients Composition
Ivermectin 1.4
Glycerol 4.0
Acrylate C10-30 alkyl acrylate 0.2
Crosspolymer
Methyl para-hydroxybenzoate 0.2
Disodium EDTA 0.05
Citric acid monohydrate 0.05
Isopropyl palmitate 4.0
Cetyl alcohol 3.5
Stearyl alcohol 2.5
Oleyl alcohol 2.0
Ceteareth-20 3.0
Sorbitan monostearate 2.0
Dimethicone 200 20 cs 0.5
Propyl para-hydroxybenzoate 0.1
Propylene glycol 2.0
Phenoxyethanol 1.0
10% sodium hydroxide qs pH
Water 
qs 100
[0072] Example 2: Dosage study on topical treatment of PPR with ivermectin
[0073] A phase II, randomized, investigator-blinded, parallel-group, active-and vehicle-
controlled study was conducted to determine the optimal concentration and dose regimen of
topical ivermectin cream for the treatment of inflammatory lesions of rosacea, and evaluate
efficacy and safety.
[0074] Eligible subjects were adults with PPR. The majority of the subjects had at least
facial inflammatory lesions and at least mild facial erythema based on IGA of rosacea
severity. Table 2 shows the demographic and baseline clinical characteristics (ITT population)
of the subjects:
[0075] Table 2
Ivermectin Ivermectin Ivermectin Ivermectin Metronidazole Vehicle
1% BID 1% QD 0.3% 0.1% 0.75% BID QD
(N=48) (N=52) (N=47) (N=51) (N=48) (N=50)
Gender n (%)
Female 39 (81.3) 33 (63.5) 29 (61.7) 31 (60.8) 34 (70.8) 35 (70.0)
Male 9 (18.8) 19 (36.5) 18 (38.3) 20 (39.2) 14 (29.2) 15 (30.0)
Age, year
Mean ± SD 50.9 ± 12.3 50.4 ± 14.5 53.4 ± 14.5 52.7 ± 13.8 52.2 ± 15.9 52.2 ± 14.4
Phototype, n
(%)
I 7 (14.6) 4 (7.7) 6 (12.8) 4 (7.8) 3 (6.3) 7 (14.0)
II 28 (58.3) 27 (51.9) 20 (42.5) 26 (51.0) 29 (60.4) 28 (56.0)
III 12 (25.0) 14 (26.9) 17 (36.2) 18 (35.3) 14 (29.2) 15 (30.0)
IV 1(2.1) 7(13.5) 4(8.5) 3(5.9) 2(4.1) 0
Inflammatory
lesion, n (%)
Mean ±SD 37.3 ±39.0 35.8 ± 18.2 35.1 ± 20.5 31.1± 15.0 37.4± 23.9 35.8 ± 19.9
Min, max 16, 270 16, 93 14, 108 15, 79 15, 153 15, 120
IGA, n (%)
1=Almost 2(4.2) 0 1(2.1) 1(2.0) 1(2.1) 1(2.0)
Clear
2=Mild 15(31.3) 20 (38.5) 15(31.9) 18 (35.3) 18 (37.5) 12 (24.0)
3= Moderate 28 (58.3) 24 (46.2) 21(44.7) 29 (56.9) 21(43.8) 28 (56.0)
4=Severe 3(6.3) 8(15.4) 10(21.3) 3(5.9) 8(16.7) 9(18.0)
[0076] The subjects were randomized to receive one of the following six (6) regimens for
12 weeks: ivermectin 0.1 % (w/w) once-daily (QD), ivermectin 0.3% (w/w) QD, ivermectin
1% (w/w) QD, ivermectin 1% (w/w) twice-daily (BID), metronidazole gel 0.75% (w/w) BID,
or vehicle QD. The 6 groups were comparable in terms of demographic and baseline disease
characteristics (Table 2): majority were female, Caucasian, with a skin phototype II and a
mean age of 51.9 ± 14.2 years. On average, the subjects had 35.4 ± 23.8 inflammatory
lesions, and the majority (51.0%) had an IGA of 3 (moderate).
[0077] Inflammatory lesion (sum of papules and pustules) counts, rate of success [%
subjects "clear" or "almost clear" based on Investigator's Global Assessment (IGA), a scale
from 0 (clear) to 4 (severe)], erythema [from 0 (none) to 3 (severe)], telangiectasia [from 0
(none) to 3 (severe)], adverse events, and satisfaction questionnaire (at the end of the study)
were determined during the study.
[0078] Figure 1 shows the median percentage change from baseline in lesion counts (ITT-
LOCF population).
[0079] At week 12, both ivermectin 1% (w/w) QD and BID were significantly more
effective than vehicle QD in the ITT-LOCF analysis based on the percentage change from
baseline in inflammatory lesion counts (median: -78.3% and -78.9% vs. -60.6%; both p<.05)
(Figure 1); this was also confirmed in the PP analysis. Although ivermectin 1% (w/w) BID
was significantly more efficacious than vehicle, its magnitude of effect was not greater than
ivermectin 1% (w/w) QD. A numeric trend favoring ivennectin 1% QD compared with
metronidazole 0.75% BID was also observed in terms of median % change from baseline in
inflammatory lesion counts [-78.3% vs. -69.2% at Week 12 (ITT-LOCF)]; the sample size
was not large enough to detect differences between these groups.
[0080] All ivennectin dose regimens led to a significantly greater success rate than
vehicle (70.8%, 65.4%, 63.8% and 62.7% for ivermectin 1% BID, 1% QD, 0.3% QD and 0.1
% QD, respectively, vs. 42.0% for vehicle at Week 12; all p<0.05). Furthermore, the success
rate for Metronidazole was 62.5%. No difference was observed in the change in erythema or
telangiectasia between the active and control groups.
[0081] All regimens were safe and well-tolerated, with similarly low incidence of adverse
events. There were no serious related AEs. The majority of related AEs were mild, transient
and dermatologic in nature, the most frequent for the ivennectin groups being skin discomfort
(4 subjects), skin burning sensation (4 subjects), and worsening of rosacea (3 subjects).
[0082] Figure 2 illustrates subjects' response to the statement "the product improves my
rosacea" (ITT Observed). With increasing dosage of ivennectin, more subjects agreed with
the statement "the product improves my rosacea" (Figure 2) and were satisfied with the
product (data not shown). The result was superior in ivennectin 1% QD and BID groups
compared to the metronidazole 0.75% BID group. The majority of subjects in all Ivennectin
groups considered that the product was easy to use (at least 95.5%), pleasant to use (at least
77.3%), and did not irritate the skin (at least 70.2%).
[0083] Topical administration of all tested ivennectin dose regimens (1% BID, 1% QD,
0.3% QD and 0.1 % QD) led to a significantly greater success rate in treating PPR than
vehicle; the result was superior in ivermectin 1% QD and BID groups compared to the
metronidazole 0.75% BID group; and once daily topical administration of 1% (w/w)
ivermectin was considered the optimal dose regimen, because it was safe, well tolerated, and
provided significantly greater efficacy than vehicle for the treatment of PPR. Once daily
topical administration is further preferred because it promotes better patient compliance.
[0084] Example 3: Efficacy and safety study of ivermectin 1% cream
[0085] To demonstrate the efficacy and safety of once-daily ivermectin 1% (w/w) cream
in subjects with PPR, two identically designed randomized, double-blind, controlled studies
were conducted (hereafter designated Study 1 and Study 2). Both studies were conducted in
accordance with the ethical principles of the Declaration of Helsinki and Good Clinical
Practices, and in compliance with local regulatory requirements.
[0086] Each study had three parts. In the first part of the study, subjects with PPR were
treated with ivermectin 1% cream (IVM 1%) or vehicle once daily at bedtime for 12 weeks. In
the second part of the study, subjects initially treated with IVM 1% once daily at bedtime
continued the same treatment, while subjects treated with the vehicle once daily switched to
topical treatment with azelaic acid 15% gel twice daily, in the morning and evening. The
third part of the study consisted of 4 weeks safety follow-up, without treatment.
[0087] Eligible subjects were 18 years or older, with moderate or severe papulopustular
rosacea as noted by an IGA of 3 ("several small or large papules/pustules, moderate
erythema") or 4 ("numerous small and/or large papules/pustules, severe erythema"), and
presenting with 15-70 facial inflammatory lesions (papules and pustules). A total of 683
subjects with moderate to severe PPR were randomized in Study 1 (IVM 1%: 451, vehicle:
232), and 688 subjects in Study 2 (IVM 1%: 459, vehicle: 229) (Figure 3).
[0088] Eligible subjects received either ivermectin cream 1% cream (once daily every day
at bedtime) or vehicle cream (once daily every day at bedtime) on the entire face for 12
weeks. They were instructed to apply a thin film of cream on the entire face (right and left
cheeks, forehead, chin and nose), e.g., in a pea-size amount of the cream, avoiding the upper
and lower eyelids, lips, eyes and mouth. Subjects were also instructed to avoid rosacea
triggers, such as sudden exposure to heat, certain foods, and excessive sun exposure. Study
visits during the first study were as follows: screening visits, baseline, weeks 2, 4, 8, and 12
after the initial administration.
[0089] Efficacy assessments at each visit were the IGA of disease severity, and
inflammatory lesion counts (papules and pustules) on each of the five facial regions (forehead,
chin, nose, right cheek, left cheek). Safety assessments included adverse events (AEs)
throughout the study, local tolerance parameters (stinging/burning, dryness, itching) at each
study visit evaluated on a 4-point scale [from 0 (none) to 3 (severe)], and laboratory
parameters (hematology and biochemistry) measured before and after treatment. Other
assessments included the subject's evaluation of their rosacea improvement at the end of the
study (week 12) compared to their condition at baseline, and two quality of life (QoL)
questionnaires [a dermatology-specific instrument, the Dermatology Life Quality Index
(DLQI)],17 and a rosacea-specific instrument, the RosaQoLTM 8 completed at baseline and
week 12.
[0090] The co-primary efficacy endpoints in both studies were the success rate based on
the IGA outcome and absolute change from baseline in inflammatory lesion counts at the end
of week 12 of the studies. The success rate based on IGA score [% of subjects who achieved
"clear" or "almost clear" ratings on the IGA scale at week 12 (ITT-LOCF)] was analyzed by
the Cochran-Mantel-Haenszel (CMH) test stratified by analysis site, using the general
association statistic. The absolute change in inflammatory lesion counts from baseline to week
12 (ITT-LOCF) was analyzed by analysis of covariance (ANCOVA). Missing data at week 12
in the ITT population were imputed by the LOCF approach. Also, sensitivity analyses were
conducted to impute missing data in order to assess the robustness of the primary efficacy
results. The secondary efficacy endpoint was percent change in inflammatory lesion counts
from baseline at week 12 (ITT-LOCF). The QoL questionnaires were analyzed using the
Wilcoxon rank sum test, and other variables were descriptively analyzed. High mean scores
from the QoL questionnaires indicated a low quality of life.
[0091] In Studies 1 and 2, the vast majority of subjects completed the study (91.4% and
92.6%, respectively). The treatment groups were similar at baseline in terms of demographics
and baseline disease characteristics, with about 31-33 inflammatory lesions on average and
the majority having moderate rosacea (Table 3). Most subjects were female (68.2% and
66.7% in Studies 1 and 2, respectively) and Caucasian/white (96.2% and 95.3%), with a mean
age of 50.4 and 50.2 years, respectively. Additionally, treatment groups were comparable
regarding rates/reasons for early study discontinuation (Figure 3).
[0092] Table 3. Demographic and baseline clinical characteristics (ITT population)
Study 1 Study 2
Total Total
(n=683) (n=688)
Age, years Mean ± SD 50.4 ± 12.09 50.2 ± 12.29
Min, Max 19,88 18, 89
Gender, n (%) Female 466 (68.2%) 459 (66.7%)
Male 217(31.8%) 229(33.3%)
Race White 657 (96.2%) 656 (95.3%)
Black or African 9 (1.3%) 10 (1.5%)
American
Asian 6 (0.9%) 15 (2.2%)
Other 11(1.6%) 7(1.0%)
Inflammatory lesion Mean ± SD 30.9 ± 14.33 32.9 ± 13.70
counts
IGA 3 = Moderate 560 (82.0%) 403 (83.3%)
4 = Severe 123 (18.0%) 81(16.7%)
[0093] The proportion of subjects achieving IGA success ("clear" or "almost clear") at
week 12 for Studies 1 and 2 were 38.4% and 40.1%, respectively for IVM 1% compared to
11.6% and 18.8% for vehicle (both p<.001; Figures 4A). A significant difference between
treatment arms in both studies was observed based on IGA since week 4 (10.9% and 11.8%
versus 5.6% and 5.7%, respectively; both p<.05), and was sustained until Week 12 (Figures
4B and 4C).
[0094] For inflammatory lesion counts, the mean difference between IVM 1% and vehicle
from baseline to week 12 was -8.13 lesions for Study 1 and -8.22 for Study 2 (both p<0.001
versus vehicle), with a 95% CI of [-10.12, -6.13] and [-10.18, -6.25], respectively (Fig. 5A
and 5B). A mean reduction of 9 lesion counts was observed at week 2 in both studies when
treated with IVM 1% (Fig. 5A and 5B). Median reduction from baseline in inflammatory
lesion counts for both studies was 76.0% and 75.0%, respectively, versus 50.0% for both
vehicle groups at week 12 (p<.001), with significant difference observed by week 2 at a
median reduction of 30% and 27.3% (Figure 5C and 5D). This significant reduction in
inflammatory lesion counts as early as week 2 was exceptional when compared with similar
data from treatment with metronidazole or azelaic acid.
[0095] Table 4 summarizes efficacy outcomes of both studies at the end of the first part
12 week studies
IVM 1% Vehicle IVM 1% Vehicle
(N=451) (N=232) (N=459) (N=229)
IGA
Number (%) of Subjects 173 (38.4) 27(11.6) 184 (40.1) 43(18.8)
Clear or Almost Clear in
the IGA at Week 12
Inflammatory Lesions
Mean inflammatory lesion 31.0 30.5 33.3 32.2
count at baseline
Mean inflammatory lesion 10.6 18.5 11.0 18.8
count at Week 12
Mean Absolute Change -20.5 -12.0 -22.2 -13.4
(%) in Inflammatory (-64.9) (-41.6) (-65.7) (-43.4)
Lesion Count from
Baseline at Week 12
[0096] The incidence of AEs was comparable between Studies 1 and 2 (40.5% and 36.5%
for IVM 1% versus 39.4% and 36.5% for vehicle, respectively). Fewer subjects in IVM 1%
groups tended to report related AEs than in vehicle groups (4.2% and 2.6% versus 7.8% and
6.5%, respectively), as well as for related dermatologic AEs (3.5% and 1.5% versus 6.9% and
5.7%) and related AEs leading to discontinuation (1.3% and 0.2%, versus 1.7% for both
vehicle groups). A similarly low proportion of subjects reported serious AEs for IVM 1% and
vehicle groups (0.7% and 1.5% versus 0.4% and 1.7%). There were no related serious AEs.
The most common related AE in Study 1 was sensation of skin burning: 8 (1.8%) in IVM 1%
subjects versus 6 (2.6%) for vehicle. For Study 2, the most common related AEs for IVM 1%
were pruritis and dry skin (3 subjects each (0.7%)) compared to 0 and 2 subjects (0.9%) for
vehicle, respectively. In addition, laboratory tests did not demonstrate clinically significant
abnormalities.
[0097] At baseline before treatment application, a large proportion of subjects presented
with local cutaneous symptoms consistent with rosacea, especially mild or moderate dry skin
(for Studies 1 and 2, 63.0% and 57.0% for IVM 1%, and 59.3% and 60.0% for vehicle,
respectively) and mild or moderate itching (57.3% and 49.4% for IVM 1%, and 45.4% and
49.1% for vehicle). At week 12 (last available data observed), the majority of subjects had
none of the 2 cutaneous symptoms. A trend was observed in terms of absence of dryness in
83-86% of IVM 1% subjects versus 72-76% for vehicle, as well as for absence of itching in
82-85% for IVM 1% versus 70-78% for vehicle.
[0098] Improvement after treatment was rated by subjects as "excellent" or "good" by
69% and 66.2% for IVM 1% compared to 38.6% and 34.4% for vehicle (p<.001), respectively
(Figure 6). "Excellent" improvement was reported by 34.3% and 32.0% for IVM 1% versus
9.5% and 7.3% for vehicle.
[0099] After 12 weeks of treatment, improved QoL scores were observed for subjects in
the IVM 1% compared to vehicle groups. For the DLQI, it is of note that no difference
between treatment groups was observed at baseline. At the end of each study, more subjects in
the IVM 1% group (about 53%) than vehicle (about 35%) considered that their disease had no
effect on their overall QoL (p<.001). For RosaQoLTM, improvement in QoL from baseline
was higher in both studies for IVM 1% (-0.64 ± 0.7 and -0.60 ± 0.6 versus -0.35 ± 0.5 for both
vehicle groups (p<.001 and p=.001 for Studies 1 and 2, respectively). This result indicates that
a higher proportion of subjects felt that their quality of life was not negatively impacted by
rosacea in the group treated with IVM, compared to the control group treated with vehicle.
[0100] IGA was assessed during the second part of the studies (40 weeks). The
percentages of subjects treated with IVM 1% achieving an IGA score of 0 or 1 continued to
increase up to week 52, the end of the second part of the studies. The success rate (IGA = 0 or
1) at week 52 was 71.1% and 76% in studies 1 and 2 respectively. In both studies, the
incidences were comparable in the 2 groups of subjects treated by IVM 1% cream QD and
azelaic acid 15% gel BID across the categories of related AEs, dermatologic AEs, serious
AEs, related AEs leading to discontinuation, and AEs of special interests. There was no
serious related AEs.
[0101] In the follow up third part of the studies, subjects treated with IVM 1% cream QD
and azelaic acid 15% gel BID during the second part of the studies were comparable in
reporting AEs. No subjects reported related serious AEs, related AEs leading to
discontinuation.
[0102] The most frequent (>0.5% in any arm) AEs were skin disorders, and were less
frequent with IVM 1% cream QD than azelaic acid 15% gel BID in both studies.
[0103] These two pivotal studies demonstrated the efficacy and safety of topical
ivermectin 1% cream in the treatment of inflammatory lesions of rosacea with reproducibility.
The effect was robust and highly significant (p,0.001) in all primary and secondary endpoints
at week 12 (ITT-LOCF). Onset of treatment effect was observed at week 4 in each study
based on both IGA and lesion counts. Onset of treatment effect was observed at week 2 in
each study based on lesion counts. The ivennectin 1% cream was well tolerated and safe in
both studies. No notable difference was observed between the ivennectin 1% cream QD and
corresponding vehicle and azelaic acid 15% gel BID. The most frequent (>0.5% in any arm)
AEs were skin disorders, and were less frequent with IVM 1% cream QD than with the
respective comparator. In addition, the continued daily application of the Ivermectin 1%
Cream QD up to 1 year is well tolerated, with no unexpected safety findings associated with
chronic use.
[0104] In conclusion, ivennectin, such as 1% ivennectin cream, was effective and safe in
treating papulopustular rosacea.
[0105] Example 4: Comparison of the efficacy and safety of ivennectin 1% cream vs.
metronidazole 0.75% cream
[0106] This was an investigator-blinded, randomized, parallel group study comparing the
efficacy and safety of ivermectin (hereafter designated IVM) 1% (w/w) cream vs.
metronidazole 0.75% (w/w) cream with a 16-week period A and a 36-week period B to study
recurrence. Study visits during Period A were as follows: a screening visit, and at baseline,
weeks 3, 6, 9, 12 and 16.
[0107] Eligible subjects were 18 years or older, with moderate or severe papulopustular
rosacea as noted by an IGA of 3 ("several small or large papules/pustules, moderate
erythema") or 4 ("numerous small and/or large papules/pustules, severe erythema"), and
presenting with 15-70 facial inflammatory lesions (papules and pustules).
[0108] Subjects were randomized in a 1:1 ratio to receive either IVM 1% cream (once
daily, QD, at bedtime) or metronidazole 0.75% cream (twice daily, BID, as per labelling at
morning and bedtime) for 16 weeks. Study drugs were applied in a thin film on the entire face
(right and left cheeks, forehead, chin and nose), avoiding the upper and lower eyelids, lips,
eyes and mouth. The subjects were instructed to maintain a consistent lifestyle throughout the
study regarding rosacea triggers (i.e. avoiding environmental factors, certain foods, and
excessive sun exposure).
[0109] Efficacy assessments at each visit were inflammatory lesion counts (papules and
pustules) counted on five facial regions (forehead, chin, nose, right cheek, left cheek), and the
Investigator's Global Assessment (IGA) of disease severity. Safety assessments included
adverse events (AEs) throughout the study, local tolerance parameters (stinging/burning,
dryness, itching) at each visit evaluated on a 4-point scale (from 0 (none) to 3 (severe)), and
laboratory parameters measured at baseline, weeks 9 and 16. Other assessments included the
subject's evaluation of rosacea improvement compared to their condition at baseline, and
subject's appreciation questionnaire at the end of the study (regarding satisfaction with the
study drug). Lastly, a quality of life questionnaire (Dermatology Life Quality Index (DLQI))
was completed at baseline and at the end of the study (week 16).
[0110] The ITT population included all subjects who were randomized and to whom the
study drug was administered. The safety population included all subjects who received the
study medication. The primary efficacy endpoint, percent change in inflammatory lesion
counts from baseline to week 16, was analyzed using the CMH test stratified on center, with
ridit transformation and row mean score difference statistic. Secondary efficacy endpoints
included success rate (percent of subjects with IGA rated 0 ("clear") or 1 ("almost clear")
(analyzed by CMH test stratified on center using general association statistic), IGA and
absolute change in lesion counts (analyzed using ANCOVA, including treatments and
analysis center as factors, and baseline as covariate). LOCF was the primary method for
imputation of missing data, and multiple imputations (MI) method was used for sensitivity.
Other variables were descriptively analyzed.
[0111] A total of 1,034 subjects were screened and 962 randomized to receive IVM 1%
cream (n=478) or metronidazole 0.75% cream (n=484); 902 (93.8%) completed the study
(Figure 8). Treatment groups were comparable at baseline in terms of demographics and
baseline disease characteristics, with about 32 inflammatory lesions on average and the
majority having moderate rosacea (83.3% with an IGA of 3) (Table 5). As expected, the
quantity of product applied in the metronidazole group (BID applications) was nearly twice as
much as the product applied in the IVM 1% group (QD), with a mean of 1.31 g vs. 0.72 g,
respectively.
[0112] Table 5. Demographic and baseline clinical characteristics (ITT population)
Metronidazole
Ivermectin 1% 0.75% Total
(n=478) (n=484) (n=962)
Age, years Mean SD 51.22± 13.40 51.87 ±13.24 51.54± 13.32
Min, Max 18, 85 18,90 18,90
Gender, n (%) Female 311 (65.1%) 316 (65.3%) 627 (65.2%)
Male 167 (34.9%) 168 (34.7%) 335 (34.8%)
Race Asian 3 (0.6%) - 3 (0.3%)
White 475 (99.4%) 484 (100.0%) 959 (99.7%)
Skin Phototype I 18 (3.8%) 17 (3.5%) 35 (3.6%)
II 245 (51.3%) 234 (48.3%) 479 (49.8%)
III 178 (37.2%) 213 (44.0%) 391 (40.6%)
IV 36 (7.5%) 19 (3.9%) 55 (5.7%)
V 1 (0.2%) 1 (0.2%) 2 (0.2%)
Inflammatory lesion Mean ± SD 32.87 ± 13.95 32.07 ± 12.75 32.46 ± 13.36
Counts
Investigator Global 3 = Moderate 398 (83.3%) 403 (83.3%) 801 (83.3%)
Assessment 4 = Severe 80 (16.7%) 81(16.7%) 161 (16.7%)
[0113] Regarding the primary endpoint, at week 16 (ITT-LOCF), IVM 1% cream was
significantly superior to metronidazole 0.75% cream in terms of percent reduction from
baseline in inflammatory lesion counts (83.0% vs. 73.7%; p<.001; Figure 9). This difference
was observed as early as week 3 (ITT-LOCF) (as soon as week 6 with ITT-MI), and this
continued through week 16 (all p-values <.04). It should be noted that in this study, there was
no study visit or assessment prior to Week 3, thus the differences in treatment could have
been observed earlier than week 3 if the first study visit was conducted earlier. Similar results
were found for the IGA success rate (subjects rated "clear" or "almost clear"): 84.9% for IVM
1% cream vs. 75.4% for metronidazole 0.75% cream at week 16 (ITT-LOCF) (p<.001). As
illustrated in Figure 10, the difference in IGA was the highest at week 12 (14.9% superior for
ivermectin).
[0114] About 13% more subjects were rated as "clear" in terms of IGA for IVM 1% than
metronidazole 0.75% (34.9% vs. 21.7%, respectively). Furthermore, in a subgroup analysis of
success rate according to IGA severity, about 20% more subjects with severe rosacea at
baseline in the IVM 1% group achieved success (82.5% vs. 63.0%).
[0115] The incidence of adverse events (AEs) was similar between groups (32.4% vs.
33.1% of subjects in the IVM 1% and metronidazole 0.75% groups, respectively), as well as
for related AEs (2.3% vs. 3.7%). Furthermore, a comparably low number of subjects
experienced a related dermatologic AE (9 subjects (1.9%) in the IVM 1% group and 12
(2.5%) in the metronidazole 0.75% group). The most common related AE was skin irritation
(3 subjects (0.6%) vs. 4 subjects (0.8%) for IVM 1% and metronidazole 0.75%, respectively).
Thirteen subjects reported serious but unrelated AEs. A total of 3 subjects (0.6%) in the IVM
1% group experienced related adverse events leading to discontinuation (due to skin irritation
and hypersensitivity), compared to 10 (2.1%) subjects in the metronidazole 0.75% group (due
to skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritis, and general
disorders (hot feeling)).
[0116] In terms of local tolerance, the incidence of worsening from baseline was higher in
the metronidazole 0.75% group for stinging/burning (15.5% vs. 11.1%), dryness (12.8% vs.
10.0%), and itching (11.4% vs. 8.8%). Laboratory tests did not demonstrate clinically
significant abnormalities.
[0117] At the end of period A of this study, the majority (85.5%) of subjects in the IVM
1% group rated their global improvement as "excellent" or "good" compared to 74.8% in the
metronidazole 0.75% group. Furthermore, more subjects receiving IVM 1% reported an
"excellent" improvement of their rosacea (52.3% vs. 37.0%, respectively; Figure 11).
Regarding the subject's appreciation questionnaire, more subjects in the IVM 1% group were
satisfied with the study drug (76.0% vs. 61.3% in the metronidazole 0.75% group). In
addition, more subjects treated by IVM 1% tended to consider the product easy to use and that
the time needed for application was satisfactory, whereas more subjects found metronidazole
0.75% to be irritating (data not shown).
[0118] At baseline, the mean DLQI scores were similar between groups (6.95 for IVM
1% and 6.05 for metronidazole 0.75%, respectively). Patients treated with IVM 1% showed a
higher numerical decrease in their DLQI score than patients treated with metronidazole 0.75%
(-5.18 vs. -3.92; p<.01), indicating a higher improvement in quality of life. At the end of the
study, 71% of patients treated with IVM 1% reported no effect at all on their quality of life
(vs. 64% for metronidazole 0.75%), which means that a higher proportion of subjects felt that
their quality of life was not negatively impacted by rosacea in the group treated with IVM,
compared to the group treated with metronidazole. The study drugs diverged in favor of IVM
1% in the symptoms and feelings sub-scale (level of itching, soreness, pain or stinging: "not at
all" for 78.7% vs. 63.0% in the metronidazole 0.75% group; level of embarrassment or self-
consciousness: "not at all" for 70.3% vs. 60.1%, respectively).
[0119] Topical metronidazole 0.75% (w/w) has been one of the most frequently used
therapies in the treatment of papulopustular rosacea. In this study, IVM 1% cream was
significantly superior to metronidazole 0.75% cream in terms of percent reduction from
baseline in inflammatory lesion counts, with an onset of efficacy (first difference vs.
metronidazole 0.75%) as early as 3 weeks (or even earlier) that continued through 16 weeks.
The findings show that ivermectin is more efficacious than metronidazole, with a tendency
even in patients with higher lesion counts.
[0120] An overall good safety profile was observed for IVM, and it was well-tolerated in
comparison with metronidazole. It is not surprising that for both products, patients
experienced a similarly low number of related adverse events, particularly since the
tolerability of metronidazole is known to be satisfactory. Metronidazole's higher incidence of
worsening from baseline concerning stinging/burning, dryness, and itching may be attributed
to the usual signs and symptoms of rosacea. Nevertheless, this affected the level of quality of
life as measured by the DLQI, as more patients in the metronidazole group reported itching,
soreness, pain or stinging.
[0121] Patient-reported outcomes for IVM 1% cream were consistent with its superior
efficacy results. More patients using IVM indicated that the product was easy to use and that
the time needed for application was satisfactory, implying that the daily application is more
convenient than metronidazole's twice-daily regimen. Related to quality of life measures,
fewer patients using IVM considered themselves to be embarrassed or self-conscious. Thus,
ivermectin appears to be adapted to the complex etiology of rosacea, and in the study IVM 1%
cream demonstrated superiority to metronidazole 0.75% cream in terms of inflammatory
lesion reduction. As noted in the afore-mentioned Cochrane review, few robust studies have
compared topical metronidazole with another rosacea treatment and in three identified studies,
topical metronidazole was either non-significantly different or less effective than azelaic
acid.8 While metronidazole has been used in the past as a reasonable treatment for the papulo-
pustular lesions of rosacea, its efficacy is surpassed by that of ivermectin along with the
advantage of once-daily dosing.
[0122] The relapse among subjects successfully treated at the end of the Period A was
studied during the treatment free Period B (36 weeks). At the end of Period A, only subjects
with an IGA of "0" or "1" (clear or almost clear) were eligible for entering Period B. Then,
their study treatment was discontinued and the subjects were followed for up to 8 months (36
weeks). In case of reoccurrence of an IGA of at least "2" (mild) at any time during Period B,
the subjects were retreated with the same treatment received during the Period A. The re-
treatment was stopped as soon as the IGA was back to "0" or "1" (clear or almost clear). The
maximum duration of re-treatment was 16 consecutive weeks to mimic the Period A treatment
duration. In order to characterize the relapses, the following parameters were assessed: (1)
time of first relapse (time elapsed between Week 16 and first reoccurrence of IGA at "2", "3"
or "4" inducing a retreatment course), (2) relapse rate (percentage of subjects with
reoccurrence of IGA at "2", "3' or "4" after a period free of study treatment) and (3) number
of days free of treatment.
[0123] At the start of Period B, treatment groups were comparable with respect to the
demographic. Of the total 757 subjects included in Period B (399 in Ivermectin 1% and 358 in
Metronidazole 0.75% groups, respectively), 504 (66.6%) were female, 754 (99.6%) were
Caucasian and the mean age was 51.9 years. In terms of disease characteristics, the means
inflammatory lesion counts were similar in both groups (median 2.0). But, the proportion of
subjects with an IGA of 0 was higher in Ivermectin group than in Metronidazole group
(41.6% versus 29.1%) due to the higher efficacy of Ivermectin treatment from Period A.
[0124] Table 6 End of Period A disease characteristics of subjects entering Period B
Ivermectin Metronidazole TOTAL
Inflammatory N 399 358 757
lesion counts Mean 2.58 2.96 2.76
SD 3.20 3.42 3.31
Median 2.00 2.00 2.00
Min-Max 0-19 0-24 0-24
P25-P75 0-4 0-4 0-4
Investigator N 399 358 757
Global Assessment 0 = Clear 166 (41.6%) 104 (29.1%) 270 (35.7%)
1 = Almost Clear 233 (58.4%) 254 (70.9%) 487 (64.3%)
Nodules N 399 358 757
397 (99.5%) 357 (99.7%) 754 (99.6%)
1 2 (0.5%) 1 (0.3%) 3 (0.4%)
Papules N 399 358 757
Mean 2.27 2.56 2.40
SD 2.77 2.83 2.80
Median 2.00 2.00 2.00
Ivermectin Metronidazole TOTAL
Min-Max 0-16 0-17 0-17
P25-P75 0-4 0-4 0-4
Pustules N 399 358 757
Mean 0.32 0.40 0.36
SD 0.91 1.20 1.06
Median 0.00 0.00 0.00
Min-Max 0-9 0~12 0~12
P25-P75 0-0 0-0 0~0
[0125] The time to first relapse, defined as time elapsed between Week 16 and first
reoccurrence of IGA at "2", "3" or"4" was analyzed following 2 definitions: (1) the first one
was based on IGA only; and (2) the second one took also into account any major deviations
by imputing relapse the day of first major deviation. For each definition, a sensitivity analysis
was performed by imputing relapse 4 weeks after discontinuation for all subjects who
discontinued early from Period B without relapse. Relapse rates followed the same
convention analyses as the time to relapse.
[0126] The median times to first relapse were 115 days for ivermectin 1% QD and 85
days for Metronidazole 0.75% BID (p =0.0365), the relapse rates were 62.7% and 68.4%
respectively (Table 7). See also Figure 12. When conducting the sensitivity analysis by
imputing relapse 4 weeks later to subjects who discontinued early without relapse, the
medians were 114 days and 85 days (p=0.0594) and the relapse rates were 66.2% and 70.4%,
respectively. Similar results were obtained when taking also into account the day of first
major deviation.
[0127] Table 7
IVM 1% Metronidazole p-value (1)
N 399 358 0.0365
Median and 95% Confidence Interval 115.0 [113; 165] 85.0 [85; 113] -
Mean ± Standard Error 147.0± 4.66 133.6± 5.13
Relapse is based on IGA only
(1) Logrank test
[0128] Number of days free of treatment was defined for each subject enrolled in period B
as the time interval between a visit where IGA is assessed as 0 or 1 and the next visit. The
number of treatment-free days is the summation over all visits of period B meeting this
criterion. An additional analysis was also performed by subtracting from the days free of
treatment any time interval between visits when the subject while being IGA 0 or 1 had a
major protocol deviation.
[0129] Based on IGA score showed a mean days free of treatment of 183 days for
ivermectin 1% QD versus 170 days for metronidazole (p =0.026). When taking into account
the protocol deviations the mean days free of treatment remained nearly the same 181 days
versus 168 days (p=0.021) in favor of ivermectin 1% QD.
[0130] Ivennectin 1% cream QD treatment resulted in a statistically significant extended
remission (i.e. delayed time to first relapse, and increase in the number of treatment free
days) of rosacea when compared to Metronidazole 0.75% BID in subjects who were
successfully treated (IGA 0 (clear) or 1 (almost clear)) for 16 weeks. There was also a
numerical trend in favor of Ivermectin 1% cream QD for the relapse rates (62.7% and 68.4%
in the Ivermectin 1% group and Metronidazole 0.75% group, respectively). It should be noted
that the differences observed in favor of Ivermectin 1% in Period B are presumably the
consequence of the higher efficacy of Ivermectin compared to Metronidazole observed at the
end of Period A, with a higher proportion of subjects with an IGA=0 in the Ivennectin group
(41.6% and 29.1% in Ivermectin and Metronidazole, respectively).
[0131] The overall pharmacoeconomic benefit of Ivennectin 1% cream QD versus
Metronidazole 0.75% cream BID over the one year duration of the study (Period A & B), is
considerable when viewed as the sum of the following elements: benefit of Ivermectin over
Metronidazole observed at the end of Period A (84.9% of success in Ivermectin group Vs.
75.4% in Metronidazole group), time to first relapse (115 Vs. 85 days), relapse rate (62.7%
Vs. 68.4%) and number of days free of treatment (183.4 Vs. 170.4) .
REFERENCES
1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the
National Rosacea Society Expert Committee on the classification and staging of
rosacea. J Am Acad Dermatol 2002; 46:584-587.
2. Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity of rosacea and depression:
an analysis of the National Ambulatory Medical Care Survey and National Hospital
Ambulatory Care Survey- Outpatient Department data collected by the U.S. National
Center for Health Statistics from 1995 to 2002. Br J Dermatol 2005; 153(6):1176-81.
3. Del Rosso JQ, Gallo RL, Tanghetti E, Webster G, Thiboutot D. An evaluation of
potential correlations between pathophysiologic mechanisms, clinical manifestations,
and management of rosacea. Cutis 2013; 91(3 Suppl):1-8.
4. Del Rosso JQ, Gallo RL, Kircik L, et al. Why is rosacea considered to be an
inflammatory disorder? The primary role, clinical relevance, and therapeutic
correlations of abnormal innate immune response in rosacea-prone skin. J Drugs
Dermatol 2012; 11:694-700.
5. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in
the pathophysiology of rosacea. J Investig Dermatol Symp Proc 2011; 15:2-11.
6. Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case-control study
using standardized skin-surface biopsy. Br J Dermatol 1993; 128(6):650-9.
7. Karincaoglu Y, Bayram N, Aycan 0, Esrefoglu M. The clinical importance of
demodex folliculorum presenting with nonspecific facial signs and symptoms. J
Dermatol 2004; 31(8):618-26.
8. van Zuuren EJ, Kramer SF, Carter BR, Graber MA, Fedorowicz Z. Effective and
evidence-based management strategies for rosacea: summary of a Cochrane systematic
review. Br J Dermatol 2011; 165(4):760-81.
9. Elewski BE. Results of a national rosacea patient survey: common issues that concern
rosacea sufferers. J Drugs Dermatol 2009; 8(2):120-3.
10. Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N, et al. Avermectin exerts anti-inflammatory
effect by downregulating the nuclear transcription factor kappa-B and mitogen-
activated protein kinase activation pathway. Fundam Clin Pharmacol 2009;
23(4):449-55.
11. Yanagihara K, Kadoto J, Kohno S. Diffuse panbronchiolitis- pathophysiology and
treatment mechanisms. Int J Antimicrob Agents 2001; 18 Suppl 1:S83-7.
12. Ianaro A, Ialenti A, Maffia P, Sautebin L, Rombola L, Carnuccio R, et al. Anti-
inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000;
292(1):156-63.
13. Campbell WC. History of avermectin and ivermectin, with notes on the history of
other macrocyclic lactone antiparasitic agents. Curr Pharm Biotechnol 2012;
13(6):853-65.
14. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral
ivermectin and topical permethrin cream. J Am Acad Dermatol 1999; 41: 775-7.
15. Trendelenburg M, BUchner S, Passweg J, Ratz Bravo AR, Gratwohl A. Disseminated
scabies evolving in a patient undergoing induction chemotherapy for acute
myeloblastic leukaemia. Ann Hematol 2001;80(2):116-8.
16. Pariser DM, Meinking TL, Bell M, Ryan WG. Topical 0.5% ivermectin lotion for
treatment of head lice. N Engl J Med 2012; 367(18):1687-93.
17. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical
measure for routine clinical use. Clin Exp Dermatol 1994; 19(3): 210-6.
18. Nicholson K, Abramova L, Chren MM, Yeung J, Chon SY, Chen SC. A pilot quality-
of-life instrument for acne rosacea. J Am Acad Dermatol 2007; 57(2):213-21.
19. Zhang X, Song Y, Ci X et al. Ivermectin inhibits LPS-induced production of
inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res
2008; 57:524-9.
20. Gerber PA, Buhren BA, Steinhoff M, Homey B. Rosacea: The cytokine and
chemokine network. J Investig Dermatol Symp Proc 2011; 15(1):40-7.
21. Wolstenholme AJ, Rogers AT. Glutamate-gated chloride channels and the mode of
action of the avermectin/milbemycin anthelmintics. Parasitology 2005; 131
Suppl:S85-95.
22. Damian D. Demodex infestation in a child with leukemia: treatment with ivermectin
and permethrin. Int J Dermatol 2003; 42:724-6.
23. Filho PA, Hazarbassanov RM, Grisolia AB et al. The efficacy of oral ivennectin for
the treatment of chronic blepharitis in patients tested positive for Demodex spp. Br J
Ophthalmol 2011; 95: 893-5.
24. Powell FC. Rosacea and the pilosebaceous follicle. Cutis 2004; 74 (3 Suppl): 9-12.
25. Marks R. The enigma of rosacea. J Dermatol Treat 2007; 18:326-8.
26. Forton FMN. Papulopustular rosacea, skin immunity and Demodex: pityriasis
folliculorum as a missing link. J Eur Acad Dermatol Venereol 2012; 26:19-28.
27. Reinholz M, Ruzicka T, Schauber J. Cathelicidin LL-37: An antimicrobial peptide
with a role in inflammatory skin disease. Ann Dermatol 2012; 24(2):126-135.
28. Millikan L. Rosacea as an inflammatory disorder: a unifying theory? Cutis 2004;
73(suppl 1): 5-8.
It will be appreciated by those skilled in the art that changes could be made to the
embodiments described above without departing from the broad inventive concept thereof. It
is understood, therefore, that this invention is not limited to the particular embodiments
disclosed, but it is intended to cover modifications within the spirit and scope of the present
invention as defined by the appended claims.
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A method of treating papulopustular rosacea in a subject in need thereof, comprising
topically administering, once daily, to a skin area affected by the papulopustular rosacea a
therapeutically effective amount of a pharmaceutical composition comprising ivermectin and
a pharmaceutically acceptable carrier, wherein the treatment results in a significant reduction
in inflammatory lesion count in the subject as early as two weeks after the initial
administration of the pharmaceutical composition.
2. A method of treating inflammatory lesions of papulopustular rosacea in a subject in
need thereof, comprising topically administering, once daily, to a skin area affected by the
inflammatory lesions of papulopustular rosacea a pharmaceutical composition comprising
ivermectin and a pharmaceutically acceptable carrier, wherein the treatment results in a
significant reduction in inflammatory lesion count in the subject as early as two weeks after
the initial administration of the pharmaceutical composition.
3. The method of claim 1 or 2, wherein the subject has moderate to severe papulopustular
rosacea before the treatment.
4. The method of any one of claims 1-3, wherein the subject has 15 or more of the
inflammatory lesions before the treatment.
5. The method of any one of claims 1-4, wherein the pharmaceutical composition
comprises about 0.5% to 1.5% by weight ivermectin.
6. The method of any one of claims 1-5, wherein the pharmaceutical composition
comprises about 1% by weight ivermectin.
7. The method of any one of-claims 1-6, wherein the pharmaceutical composition further
comprises one or more ingredients selected from the group consisting of: an oily phase
comprising dimethicone, cyclomethicone, isopropyl palmitate and/or isopropyl myristate, the
oily phase further comprising fatty substances selected from the group consisting of cetyl
alcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic acid, stearic acid and self-
emulsifiable wax; at least one surfactant-emulsifier selected from the group consisting of
glyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate, Steareth-20, Steareth-2,
Steareth-21 and Ceteareth-20; a mixture of solvents and/or propenetrating agents selected
from the group consisting of propylene glycol, oleyl alcohol, phenoxyethanol and glyceryl
triacetate; one or more gelling agents selected from the group consisting of carbomers,
cellulose gelling agents, xanthan gums, aluminum magnesium silicates but excluding
aluminum magnesium silicate/titanium dioxide/silica, guar gums, polyacrylamides and
modified starches; and water.
8. The method of any one of claims 1-7, wherein once daily topically administering to the
subject the pharmaceutical composition results in a greater reduction in inflammatory lesion
count in the subject in comparison to that achieved by topically administering to the subject,
twice daily, a second pharmaceutical composition comprising 0.75% by weight
metronidazole.
9. The method of any one of-claims 1-8, wherein once daily topically administering to the
subject the pharmaceutical composition results in longer relapse-free time of the
inflammatory lesions in the subject in comparison to that achieved by topically administering
to the subject, twice daily, a second pharmaceutical composition comprising 0.75% by weight
metronidazole.
10. The method of any one of claims 1-9, wherein the subject is human.
11. Use of a composition comprising ivermectin and a pharmaceutically acceptable carrier
in the manufacture of a medicament for the treatment of papulopustular rosacea in a subject in
need thereof to thereby obtain a significant reduction in inflammatory lesion count in the
subject as early as two weeks after the initial administration of the medicament, wherein the
medicament is to be topically administered, once daily, to a skin area affected by the
papulopustular rosacea.
12. Use of a composition comprising ivermectin and a pharmaceutically acceptable carrier
in the manufacture of a medicament for the treatment of inflammatory lesions of
papulopustular rosacea in a subject suffering from moderate to severe papulopustular rosacea
to thereby obtain a significant reduction in inflammatory lesion count in the subject as early as
two weeks after the initial administration of the medicament, wherein the medicament is to be
topically administered, once daily, to a skin area affected by the papulopustular rosacea.
13. The use of claim 11 or claim 12, wherein the composition comprises about 1% by
weight ivermectin.

Sign in to the Lens

Feedback