American Journal of Clinical Dermatology (2022) 23:125–136

https://doi.org/10.1007/s40257-021-00666-9

LEADING ARTICLE

New Developments in Topical Acne Therapy

Lara Drake1,2 · Sophia Reyes‑Hadsall1,3 · John S. Barbieri1,4 · Arash Mostaghimi1,4

Accepted: 6 December 2021 / Published online: 18 January 2022

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022

Abstract
Acne vulgaris is a common chronic inflammatory disease with a multifactorial pathogenesis. Although myriad acne treat-
ments are available, current options may not be sufficient because of a lack of efficacy, limited tolerability, or burden of
cost to patients. In this review, we highlight recently approved topical acne treatments, as well as those currently in clinical
trials. Novel formulations of tretinoin, tazarotene, and minocycline provide modifications of and improvements to existing
products. Trifarotene, a novel fourth-generation retinoid, has demonstrated improved tolerability compared with existing
topical retinoids. Clascoterone is a novel first-in-class antiandrogen that topically addresses the hormonal etiology of acne.
The late-phase clinical trials pipeline consists of agents with bactericidal and anti-sebum mechanisms. Although it is evident
that acne treatments continue to evolve, it is important to recognize the need for further comparative studies among new and
existing agents to define optimal treatment algorithms that address not only safety and efficacy but also cost-effective care.

Key Points
Some novel formulations or modifications of existing
topical medications, such as tretinoin, tazarotene, mino-
cycline, and trifarotene, have demonstrated improved
side effect profiles compared with existing products,
thereby facilitating adherence.
Clascoterone is a novel first-in-class anti-androgen that
topically addresses the hormonal pathogenesis of acne.
With a robust clinical trials pipeline demonstrat-
ing promising results for agents with bactericidal and
anti-sebum modalities, further comparative studies are
necessary to identify optimal treatment algorithms with a
focus on safety, efficacy, and cost-effective care.
Lara Drake and Sophia Reyes-Hadsall are co-first authors; both
authors contributed equally.
* Arash Mostaghimi
amostaghimi@bwh.harvard.edu
1 II and III) clinical trials. We further aim to highlight their
Department of Dermatology, Brigham and Women’s
Hospital, 221 Longwood Avenue, Boston, MA 02115, USA
2 discuss their place in current clinical practice and potential
Tufts University School of Medicine, Boston, MA, USA
3
University of Miami Miller School of Medicine, Miami, FL,
USA
4
Harvard Medical School, Boston, MA, USA
1 Introduction
Acne vulgaris is a common chronic inflammatory disease
of the pilosebaceous unit. It results from a multifactorial
process consisting of hyperkeratinization of the follicle, bac-
terial colonization with Cutibacterium acnes, and increased
androgen-induced sebum production, which together lead to
inflammation (Fig. 1) [1–4]. In the USA, acne affects 85% of
adolescents and can persist into adulthood at a prevalence of
12% in adult women [5, 6]. In addition to physical discom-
fort, acne may lead to permanent scarring and psychological
effects, including depression and anxiety [2].
A multitude of topical and oral treatments are available
for acne. Current guidelines cite a combination of topical
retinoids, benzoyl peroxide (BPO), and topical antibiotics
as mainstays in topical acne treatment for mild to moder-
ate acne, as severe acne usually requires systemic therapy.
Although current options are effective, they may not be suf-
ficient for many patients because of a lack of efficacy or side
effects, including skin irritation, photosensitivity, and dry-
ness [7, 8]. We aim to review new developments in topical
acne treatments by identifying agents approved within the
past 3 years as well as those currently in late-phase (phase
mechanisms of action and pharmaceutical modifications and
future roles for those currently in development.

Vol.:(0123456789)
126
Fig. 1  Summary of acne pathogenesis (blue) and targets (red) for FDA-approved (bold) and clinical trial investigational drugs. Blue arrows indi-
cate interrelatedness of acne pathogenesis pathways. Red arrows indicate the primary or confirmed targets of the drugs
2 Topical Retinoids
Topical retinoids include tretinoin, tazarotene, and ada-
palene. These drugs are vitamin A derivatives that bind
to different retinoic acid receptors (RARs) and function as
comedolytic and anti-inflammatory agents. American Acad-
emy of Dermatology (AAD) guidelines recommend mono-
therapy use as the first line for primarily comedonal acne and
in combination with antibiotics (topical or oral) for mixed
or inflammatory acne [2]. Use of these agents is limited by
their side effect profile, including skin irritation, dryness,
and photosensitivity [2].
2.1 Tretinoin
Tretinoin historically has been available as a 0.01% and
0.025% gel [9]; 0.08%, 0.06%, 0.04%, and 0.1% gel micro-
sphere [10]; and 0.025%, 0.05%, and 0.1% cream [9]. Its
precise mechanism of action is unknown, but it is believed
to increase mitotic activity, induce follicular epithelial cell
detachment, and increase cell turnover, leading to expulsion
of mature comedones; it is also thought to help prevent the
formation of microcomedones [11, 12].
2.1.1 New Formulation: Tretinoin 0.05% Lotion
A novel formulation of tretinoin 0.05% lotion was approved
by the US FDA in 2018. The lotion formulation aims to
increase efficacy and tolerability [13].
L. Drake et al.
Clinical trial results: Two phase III double-blind, vehi-
cle-controlled 12-week studies in patients with moderate-to-
severe acne showed that tretinoin 0.05% lotion had statisti-
cally significantly greater efficacy than its vehicle control
[13]. The treatment was well-tolerated, with no participants
discontinuing because of adverse side effects [13].
Place in clinical practice: The results indicate favorable
efficacy and tolerability profiles, but this study was limited
as it did not evaluate the novel lotion formulation compared
with other existing generic inexpensive gel or cream coun-
terparts, and further comparative effectiveness studies are
needed.
2.2 Tazarotene
Tazarotene historically has been available as a 0.1% gel,
cream, or foam. Tazarotene binds to all three classes of
RARs—RARɑ, RARβ, and RARγ—with more selectivity
for RARβ and RARγ. Tazarotene may modify gene expres-
sion, but its true mechanism of action is unknown [14].
Of the available topical retinoids, it is reported to have the
greatest potential for cutaneous irritation [15].
2.2.1 New Formulation: Tazarotene 0.045% Lotion
A novel formulation of tazarotene 0.045% lotion was
approved by the FDA in 2019 [16]. This lotion aims to
reduce the irritation seen in existing cream and gel products.
Clinical trial results: In two phase III vehicle-controlled
12-week trials in patients with moderate-to-severe acne,
0.045% tazarotene lotion was found to be superior to placebo
New Developments in Topical Acne Therapy
in reducing acne lesions [15]. Adverse events (AEs) included
site pain, dryness, exfoliation, and erythema [15]. In a phase
II comparative study of tazarotene 0.045% lotion and 0.1%
cream, the efficacy of the lotion formulation was similar
to that of the cream [15, 17]. Additionally, the cream was
associated with more AEs than was the lotion (5.6% with
cream; 2.9% with lotion) [17].
Place in clinical practice: Tazarotene 0.045% lotion
offers similar efficacy and an improved tolerability profile
compared with tazarotene 0.1% cream. Given irritation is a
common limiting side effect for tazarotene cream and gel,
this new lotion formulation offers the potential for improved
adherence and clinical outcomes.
2.3 Adapalene
Adapalene is available as 0.1% and 0.3% gel and 0.1% cream
and lotion. It modulates keratinization and cell differentia-
tion, but the exact mechanism of action in treating acne vul-
garis is unknown. The 0.1% adapalene gel is the first FDA-
approved over-the-counter topical retinoid for acne treatment
in patients aged ≥ 12 years [18].
2.4 New Class of Topical Retinoid: Trifarotene
It is hypothesized that the side effects of topical retinoids
have been attributed to the nonselective RAR antagonist
activity of tretinoin, adapalene, and tazarotene, although this
hypothesis is yet to be confirmed [19]. Trifarotene 0.005%
cream, a novel first-in-class fourth-generation topical reti-
noid that is selective for RAR-γ, was introduced in the USA
in 2019 [20].
Clinical trial results: Two randomized, double-blind,
vehicle-controlled phase III clinical trials (PERFECT 1
and PERFECT 2) were performed to assess both facial and
truncal acne. Success of Investigator’s Global Assessment
(IGA), a validated 5-point severity scale, was achieved in
29.4% (179/612) and 42.3% (255/602) of patients with
facial acne with trifarotene cream compared with 19.5%
(116/596) and 25.7% (157/610) of patients with vehicle
cream in the PERFECT 1 and PERFECT 2 trials, respec-
tively. Additionally, trifarotene was significantly superior
to vehicle control at reducing inflammatory and nonin-
flammatory lesions. Similar results were seen with truncal
acne. Trifarotene has similar tolerability and side effects
as existing topical retinoids [21]. In a phase III 52-week
safety study, 12.6% of patients experienced AEs, including
pruritus, irritation, and photosensitivity [20].
Place in clinical practice: Although clinical trials
showed that trifarotene 0.005% cream had significant effi-
cacy in lesion reduction, no studies to date have evaluated
trifarotene compared with currently available topical reti-
noids. Theoretically, trifarotene’s RAR selectivity has the
127
potential to reduce AEs, but additional comparative studies
are needed to identify its optimal role in clinical practice.
3 Topical Antimicrobials
3.1 Benzoyl Peroxide
BPO is available as a topical antimicrobial wash, foam,
cream, or gel, with strengths ranging from 2.5 to 10%.
The AAD recommends topical BPO as first-line treatment
for mild acne vulgaris as either monotherapy or in combi-
nation with a topical antibiotic, and in combination with
topical retinoid or systemic antibiotics for moderate-to-
severe acne. Its use is limited by its side effects of con-
centration-dependent irritation, staining, fabric bleaching,
and contact allergy [2].
3.2 Topical Antibiotics
Topical antibiotics combat acne with anti-inflammatory
and antibacterial mechanisms. The AAD recommends
their use as first-line treatment of mild acne and in combi-
nation with BPO or retinoids to prevent antibiotic resist-
ance [2]. The agents include clindamycin, erythromycin,
azelaic acid, and dapsone. Common side effects include
dermatitis, erythema, pruritis, and dry skin [2]. Azelaic
acid has skin-lightening effects and can be useful to treat
post-inflammatory dyspigmentation [2] but should also
be monitored closely in patients with darker complexions
[22]. If combined with BPO, dapsone can be oxidized
causing red/orange coloration that can be washed off [2].
3.3 New Formulation: Minocycline Foam
A new minocycline 4% foam was introduced in the USA
in 2019. Like other tetracycline-class antibiotics, mino-
cycline foam is thought to be both antibacterial and
anti-inflammatory.
Clinical trial results: In two phase III randomized vehi-
cle-controlled studies assessing change in inflammatory
lesion count and IGA, minocycline foam was significantly
superior for both primary endpoints. Minocycline foam also
reduced noninflammatory lesions [23]. The foam was well-
tolerated: headache was the most frequently reported AE and
<1% skin-related AEs were reported in the treatment arm,
including application site discoloration, rash, dermatitis, and
local swelling [23].
Place in clinical practice: With the rise in antibiotic
resistance to topical and oral antibiotics used for acne, a
minocycline foam formulation may provide benefit in
128
patients with resistance to other options. However, future
comparative studies are needed to identify the relative role
of minocycline foam compared with other topical antibiotic
options [23].
4 Combination Topical Agents
Many FDA-approved fixed-dose combination products are
available on the market. Although a systematic review found
no evidence that fixed-dose combination therapy is supe-
rior to using the products separately [24], these combina-
tion treatments aim to increase ease of therapy and improve
adherence for patients. Current combinations include antibi-
otic and BPO, antibiotic and retinoid, and retinoid and BPO.
4.1 New Fixed‑Dose Combination Cream: 0.1%
Tretinoin, 3% Benzoyl Peroxide
A novel fixed-dose combination tretinoin/BPO 0.1%/3%
cream was introduced in the USA in 2021 [25]. Previous
retinoid/BPO FDA-approved combinations include ada-
palene 0.1% and BPO 2.5%, and adapalene 0.3% and BPO
2.5%. Both the tretinoin and BPO are microencapsulated to
enhance stability and extend the delivery time.
Clinical trial results: In two multicentered, randomized,
vehicle-controlled double-blind trials, the combination
cream was statistically superior to the vehicle in reduction of
inflammatory and noninflammatory lesions [26]. Side effects
of tretinoin/BPO 0.1%/3% combination cream as reported
in the two clinical trials included mild and moderate appli-
cation-site erythema (37.6 and 42.2%), pigmentation (37.6
and 29.5%), dryness (28 and 27%), scaling (21.2 and 16.8%),
itching (14 and 11.9%), burning (7.6 and 8.6%), and sting-
ing (7.6 and 3.3%), with only 2% of reactions reported as
severe [26].
Place in clinical practice: This product combines two
popular first-line treatments for acne vulgaris, making its
application more convenient for patients. However, whether
this product offers any meaningful advantages over existing
inexpensive generic options such as fixed-dose adapalene
and BPO combinations remains unclear. In addition, treti-
noin is more photolabile than adapalene, limiting application
in the morning, but leave-on BPO products may bleach fab-
rics if applied at night before bed [7, 8]. As a result, without
additional comparative effectiveness data, the role, if any, of
this product in the management of patients with acne also
remains unclear.
L. Drake et al.
5 Other Topicals
5.1 New Class: Clascoterone
A novel topical antiandrogen, clascoterone 1% cream, was
introduced in the USA in 2020 [27]. It is the first topical
product targeting the hormonal pathogenesis of acne vul-
garis that is available to both men and women. Systemic hor-
mone modulation has been effective via oral contraceptive
pills and spironolactone, but both medications have systemic
side effects and are typically only used in female patients.
Mechanism of action: Clascoterone, also known as cor-
texolone 17ɑ-propionate, is a topical steroidal antiandrogen.
Androgen receptors (Ars) are present diffusely throughout
the skin, specifically in sebaceous glands, and androgens
bind to the AR to stimulate sebum production. Clascoterone
exerts its effects by competitively inhibiting the human AR
at the level of the sebaceous gland, thereby minimizing hor-
mone-driven sebum overproduction. Upon absorption, it is
quickly metabolized to free inactive cortexolone, thereby
minimizing systemic antiandrogenic effects [28].
Clinical trial results: Two vehicle-controlled, double-
blind, phase III studies with 1440 total patients with mod-
erate-to-severe facial acne demonstrated the statistically
superior efficacy of clascoterone compared with the vehicle
cream [27]. In these studies, treatment with clascoterone
1% cream resulted in a statistically significant reduction in
both absolute inflammatory (− 19.3 and − 20.0 vs. − 15.5
and − 12.6 with vehicle, respectively) and noninflamma-
tory (− 19.4 and − 19.4 vs. − 13.0 and − 10.8 in vehicle,
respectively) from baseline. At week 12, the treatment suc-
cess rates were 18.4 and 20.3 versus 9.0 and 6.5% compared
with placebo in the two trials. The trials reported that clas-
coterone 0.1% cream was well-tolerated with no systemic
adverse effects. The most frequent local site reactions were
erythema (11.3–13.1%) and scaling/dryness (8.8–12.2%),
which were minimal to mild in severity, with similar rates
noted in the vehicle control arm. In total, 17 patients dis-
continued because of treatment-related AEs, of which 5/722
were receiving clascoterone cream and 12/722 were receiv-
ing the vehicle cream [27]. Although clascoterone cream
is rapidly metabolized to its inactive form, cortexolone, in
serum, thereby minimizing systemic adverse effects, adrenal
dysregulation can still occur. In a phase II trial, asympto-
matic adrenal suppression was observed in 7% of patients
using high amounts of clascoterone, which normalized after
discontinuation [7].
Place in clinical practice: Clascoterone 1% cream is the
first topical anti-androgen acne treatment available for all
sexes [27]. In a randomized, double-blind, parallel-group
pilot study comparing clascoterone, placebo, and tretinoin
0.05% cream, clascoterone was significantly superior to
New Developments in Topical Acne Therapy
placebo in reducing total (P = 0.0017) and inflammatory
(P = 0.0134) lesion counts. However, this study included
relatively few patients, and additional comparative effective-
ness studies are warranted to confirm this finding in larger
populations [28]. Although future studies are needed to iden-
tify the subpopulations with acne that will benefit most from
topical clascoterone, it will likely be a valuable addition to
our treatment options for a wide range of patients. In addi-
tion, its novel mechanism of action means it can be com-
bined with other existing options to expand our possibilities
for combination therapy.
6 Clinical Trials Pipeline
This section focuses on novel topical drugs, targets, formu-
lations, and combinations that are currently in clinical trial
pipelines. A search was performed on clinicaltrials.gov with
the search term “acne vulgaris” to identify all treatments
with acne vulgaris as an indication. The studies were indi-
vidually assessed, and those that were topical were included.
Additionally, only drugs that were still actively being studied
were included below. In other words, drugs whose clinical
trials had been terminated or that had not progressed for over
5 years were not included.
6.1 Novel Targets in Advanced Clinical Trials (Phase
II and Phase III)
Novel targets fall into two broad categories—anti-sebum
agents and antibacterial agents—summarized in Table 1 and
described in the following subsections.
6.1.1 Anti‑Sebum Agents
Hormone-driven sebum production resulting in hyperseb-
orrhea is one of the primary pathophysiologic drivers of
acne. Sebum is composed primarily of triglycerides and fatty
acids, with wax esters, squalene, and cholesterol making up
a smaller proportion [29]. Novel investigational drugs aim
to modulate either sebum production or sebaceous gland
differentiation.
JNJ 10229570-AAA is a melanocortin receptor-5 (MC5R)
antagonist that has completed phase II trials. MC5R is
expressed in human sebocytes. Mouse in vivo studies dem-
onstrated a decrease in both sebum-specific lipid production
and sebaceous gland size and differentiation upon inhibition
of MC5R [30]. Results from a multicenter, double-blind,
vehicle-controlled, phase II study are summarized in Table 1
and indicate that the trial drug performed only slightly bet-
ter than placebo, although statistical analysis to determine
significance is pending.
129
MTC896 is a small-molecule mimetic of α-melanocyte-
stimulating hormone that inhibits melanocortin receptors.
This drug has completed phase I and II clinical trials and
has been evaluated as a 0.75% and 1.5% gel; however, no
results are yet available.
6.1.2 Antimicrobial Agents
Novel investigational drugs aim to target C. acnes to reduce
the inflammatory pathway of acne vulgaris.
SB204 (NVN1000) is a 4% nitric oxide gel currently
being studied in inflammatory acne. Nitric oxide has both
immunoregulatory and antimicrobial properties, inhibit-
ing the growth of C. acnes via oxidative mechanisms and
through its metabolites (e.g., nitrites) [31, 32]. A rand-
omized, double-blind, placebo-controlled, three-arm phase
II study [32] reported significantly superior inflammatory
and noninflammatory lesion reduction in the 1 and 4% arms
when compared with the vehicle arm. AEs were reported
to be mild in severity. A long-term phase III study has been
completed, and results are pending.
B244 is a spray containing a strain of the ammonia-oxi-
dizing bacteria Nitrosomonas eutropha, which is a nitric
oxide-producing bacteria. It is a first-in-class topical for-
mulation designed to repopulate the skin microbiome with
beneficial bacteria that oxidize ammonia into nitrite (anti-
bacterial) and nitric oxide (immunoregulatory and vasodi-
latory). A phase Ib/IIa double-blind, placebo-controlled,
single-center, randomized, sequential, multidose study was
conducted. Table 1 summarizes the preliminary efficacy
results. Reported side effects include dose-dependent reduc-
tions in blood pressure in normotensive subjects in the B244
arm when compared with the placebo arm [33].
BTX 1503 is a topical synthetic cannabinoid that is
reported to have anti-sebum, antimicrobial, and anti-inflam-
matory properties [34]. A phase II randomized, double-
blind, vehicle-controlled study in patients with moderate-
to-severe acne has been completed. No study results are yet
publicly available, but a press release from Botanix Phar-
maceuticals cited FDA support for progression to phase III
clinical trials because of the reported favorable safety and
efficacy data [31].
VB-1953 is a first-in-class topical gel formulation of a
fourth-generation fluoroquinolone that has bactericidal and
anti-inflammatory properties. The small molecule targets
various inflammatory pathways, including toll-like recep-
tors, which activate pathogen-induced inflammatory path-
ways, as well as interfering with DNA gyrase and topoi-
somerase to disrupt bacterial replication [35]. It is being
investigated for use in inflammatory acne. In vitro proof-
of-concept studies demonstrated potent bactericidal activ-
ity of VB-1953 within strains of C. acnes resistant to other
antibiotics. An open-label, single-arm clinical study in

Table 1  Summary of clinical trial data of investigational drugs in late-phase clinical trials.
Clinical trial identifier
JNJ 10229570-AAA​
MTC896
SB204 (NVN1000)
Drug
1.2%, 2.4%, 3.6% melano-
cortin type 5 receptor
antagonist
0.75%, 1.5% concentration
of investigational drug
Nitric oxide 4%
130
Formulation Mechanism of action Phase completed Results Place in clinical practice
Cream Inhibits sebaceous gland Phase II vehicle-controlled Acne lesion reduction with Novel target for inhibition of
differentiation and the trial: NCT01326780 2.4% cream (− 29.4) sebum production
production of sebum- and 3.6% cream (− 33.1)
specific lipids vs. 1.2% cream (− 25.2)
and PL (− 26.0). Results
demonstrate trial drug at
2.4% and 3.6% concen-
tration performed only
slightly better than PL,
and trial drug at 1.2%
concentration demon-
strated similar efficacy
to PL.
Gel Small molecule, first-in- Phase I and II No results posted Anti-sebum agent
class mimetic of α-MSH (NCT02293018)
Gel Inhibits Cutibacterium Phase II (NCT01844752, Phase II: Significantly For use in inflammatory acne
acnes growth and inflam- completed), phase III larger mean absolute
matory response via (NCT02667444) and percent change
oxidative mechanisms in inflammatory and
noninflammatory lesion
counts with the SB204
4% gel (P < 0.05).
SB204 1% demonstrated
statistical significance
for noninflammatory
lesion reduction only
(P < 0.05). Safety results:
ten subjects (19.2%) with
vehicle and 20 (19.8%)
with treatment reported
mild TEAE, including
headache, dysmenorrhea,
and nasopharyngitis
Phase III: SB204 4% used
for study. No results
available
L. Drake et al.
Table 1  (continued)
Clinical trial identifier Drug Formulation Mechanism of action Phase completed Results Place in clinical practice

B244 Ammonia-oxidizing Spray First-in-class topical formu- Phase III completed, No SAEs or difference Topical antibiotic and anti-
bacteria Nitrosomonas lation designed to repopu- Results avail- between treatment and inflammatory
eutropha late the skin microbiome able for phase I and II vehicle groups. Reported
with beneficial bacteria (NCT02656485) dose-dependent reduc-
that oxidize ammonia into tions in BP in normoten-
nitrite (antibacterial) and sive subjects statistically
nitric oxide (regulates significantly decreased vs.
inflammation and vasodi- PL. Preliminary efficacy
lation) results demonstrated
pooled active doses
New Developments in Topical Acne Therapy

achieved an absolute
change from BL in total
number of lesions of − 9.6
vs. − 6.7 in ­PLa
BTX-1503 Synthetic cannabinoid Gel Normalizes excessive Phase II, NCT03573518 No results posted For patients with moderate-
lipid synthesis of human to-severe acne
sebocytes, suppresses cell
proliferation, and provides
an anti-inflammatory
effect to potentially reduce
bacterial infection
VB-1953 Small-molecule fourth-gen- Gel First-in-class topical fluoro- Prospective clinical study, Prospective clinical study: May be a safe and effective
eration fluoroquinolone quinolone small molecule: phase II (NCT03900676) Reduction in mean abso- therapy for moderate-to-
2% TLR-MD2 inhibitor, dual lute inflammatory and severe acne with underly-
inhibitor of DNA gyrase/ noninflammatory lesion ing resistant Cutibacterium
topoisomerase IV counts by 53.1 and 52.2% acnes in subjects who had
(P < 0.0001). Resistant not responded to previous
bacteria reduced by 94.3 antibiotic treatments
± 1%; P < 0.05) within
12 wks
Phase II: pending results
CLS001/MBI 226 (Omi- 1%, 1.75%, 2.5% Gel Topical cationic peptide Phase II (NCT02066545, No results posted Topical antibiotic
ganan) that is the analog of NCT02571998)
indolicidin, which has
bactericidal properties

α-MSH α-melanocyte-stimulating hormone, BL baseline, BP blood pressure, MD2 myeloid differentiation factor 2, PL placebo, SAE serious adverse event, TEAE treatment-emergent adverse
effect, TLR Toll-like receptor, wks weeks
a
No statistical analysis reported
131
 132

Table 2  Summary of clinical trial data for investigational formulations and new uses for existing agents
Clinical Drug Formulation Mechanism of action Phase completed Results Place in clinical practice
trial identi-
fier

IDP-126 Clindamycin 1.2%, benzoyl Gel Triple fixed-dose combi- Phase II (NCT03170388) Safety: Treatment-related AEs were Reduce number of different
peroxide 3.1%, and ada- nation mild–moderate in severity and included products to apply to maintain
palene 0.15% application site pain and dryness an effective acne regimen
Efficacy: Of 741 enrolled pts, 52.5%
achieved treatment success with
IDP-126 vs. 8.1% with vehicle and
27.8–30.5% with dyad combinations (P
≤ 0.001)
DFD-03 Tazarotene 0.1% Lotion Nonselective RAR Phase III (NCT03292640, Safety: AEs reported in 40.7% in tazaro- More potent formulation vs.
agonist NCT03290027), phase tene lotion vs. 53.06% in tazarotene FDA-approved tazarotene
II (NCT03341910, cream (34.62% in vehicle lotion vs. 0.045% lotion
NCT03599193) 42.31% in vehicle cream)
Phase III: Reduced inflammatory and
noninflammatory lesion counts and
treatment success based on IGA score
in DFD-03 0.1% lotion vs. vehicle
lotion were met. Proportion of subjects
with treatment success based on IGA
score: 18.4% in active arm vs. 12.5%
in vehicle arm. Minimal side effects
observed
FCD105 Fixed-dose combination of Foam New fixed-dose combina- Phase II, NCT04104685 By wk 12, 35.9% of treatment group Reduce number of different
3% minocycline and 0.3% tion foam with both of reached IGA success vs. 15.7% of products to apply to maintain
adapalene these commonly used vehicle group (P = 0.0003). Treatment an effective acne regimen
topical acne medica- group demonstrated greater percent
tions decrease in inflammatory lesions
(− 64.1 vs. 50.9%; P = 0.0013) and
noninflammatory lesions (− 51.0 vs.
45.9%) vs. vehicle
L. Drake et al.
Table 2  (continued)
Clinical Drug Formulation Mechanism of action Phase completed Results Place in clinical practice
trial identi-
fier

CD5024 Ivermectin 1% Cream Anti-inflammatory Phase II, NCT03034460 32.5% decrease in total lesion count with Studied and used in rosacea,
and antiparasitic CD5024 cream vs. 34.0% reduction novel use as acne treatment;
via suppression of with CD5024 cream matched PL, phase II results demonstrated
LPS-induced cytokine 50.2% reduction in ADP/BPO gel not as effective as primary
inflammation group, and 27.8% reduction in ADP/ comparator ADP/BPO gel
BPO gel-matched PL. AEs reported by
66.7% of pts with CD5024 vs. 63.6%
with ADP/BPO gel
New Developments in Topical Acne Therapy

GDC 268 Bioequivalent to clindamy- Lotion Phase III, NCT03717506 − 39.3 ± SD 36.10% change in inflam- Bioequivalent to clindamycin
cin phosphate 1% matory lesion count vs. − 40.0% phosphate 1% lotion
reduction with clindamycin phosphate
lotion and − 35.1% reduction with PL.
Safety profile similar for all arms: AEs
reported in 10.7% in treatment arm vs.
8.4% in clindamycin phosphate group
and 11.6% in PL

ADP adapalene, AE adverse event, BPO benzoyl peroxide, IGA investigator global assessment, LPS lipopolysaccharides, PL placebo, pts patients, RAR​retinoic acid receptor, SD standard devia-
tion, wk week
133
134
patients with moderate-to-severe facial acne who had mini-
mal response to prior clindamycin treatment resulted in a
significant reduction of mean absolute inflammatory and
noninflammatory lesions with a reduction in clindamycin-
resistant bacteria [35].
CLS001/MBI 226 (Omiganan) is a novel topical cationic
peptide analog of indolicidin that has bactericidal properties
[36]. It has completed two phase II randomized, double-
blind, vehicle-controlled studies, but no results have yet been
made available.
6.2 New Uses and Variations of Existing Agents
This section highlights novel formulations and combinations
of and indications for existing topical agents (summarized
in Table 2).
IDP-126 is a first-of-its-kind triple fixed-dose topical
combination therapy for the treatment of acne, consisting
of clindamycin 1.2%, BPO 3.1%, and adapalene 0.15% gel.
This triple fixed-dose combination has completed a phase II
study assessing safety and efficacy compared with placebo,
individual components, and other dyad fixed-dose combina-
tions, demonstrating a comprehensive study design. Table 2
summarizes the results from this study, which indicate the
overall superior efficacy of IDP-126 compared with its vehi-
cle and individual components and that the drug was well-
tolerated after 12 weeks of use [37].
DFD-03 (tazarotene 0.1% lotion) was designed with the
intent of serving as a short-contact face and body wash to
minimize irritation. Results are summarized in Table 2.
Notably, the FDA submission was withdrawn in June 2020
[38]. DFD-03 tazarotene 0.1% lotion demonstrates prom-
ise in the landscape of topical retinoids as a short-contact
minimally irritating option contingent upon progression into
subsequent stages.
FCD105 is a fixed-dose combination foam consisting of
3% minocycline and 0.3% adapalene. It is the first combina-
tion retinoid and tetracycline in the clinical trials pipeline. A
phase II study evaluated FCD105 compared with 3% mino-
cycline foam, 0.3% adapalene foam, and a vehicle control
foam; preliminary results are summarized in Table 2 [39]. A
phase III study is currently being planned given the promis-
ing results from the phase II study. FCD105 may contribute
to the topical fixed-dose combination acne therapies, which
help simplify the routine of patients using multiple products.
CD5024 is ivermectin 1% cream. Topical ivermectin is
already used to treat rosacea. It has antiparasitic and anti-
inflammatory properties, and—despite different pathophysi-
ologic mechanisms—it is hypothesized that the anti-inflam-
matory properties may apply clinically to the treatment of
acne [40]. CD5024 has completed a phase II exploratory,
randomized, investigator-blinded, vehicle-controlled study
L. Drake et al.
with adapalene/BPO (ADP/BPO 0.1%/2.5%) gel as a com-
parator, with full study results summarized in Table 2. This
study demonstrated decreased efficacy in lesion count reduc-
tion compared with placebo and ADP/BPO gel with a com-
parable safety profile. These results indicate that CD5024
might not have a clearly defined place in clinical practice.
GDC 268 is a clindamycin phosphate bioequivalent 1%
lotion. Phase III trials evaluating GDC 268 compared with
clindamycin phosphate 1% lotion and placebo showed a
comparable efficacy in inflammatory and noninflammatory
lesion reduction as well as similar side effect profiles. How-
ever, no statistical analysis has been performed on the data,
limiting its interpretation [41].
7 Conclusion
The AAD guidelines recommend a combination of retinoids,
antibiotics, and BPO as first-line topical agents, but new
approaches to topical treatment of acne are emerging. Mino-
cycline foam, tazarotene, and trifarotene are modifications
of and improvements to existing products, and clascoterone
is the first topical antiandrogen to have carved out a new
space in clinical practice. Combined with a robust clinical
trials pipeline, with late-phase agents targeting bactericidal
and anti-sebum modalities as well as novel formulations,
topical treatments for acne vulgaris will continue to evolve
to optimize efficacy and reduce AEs. Further comparative
studies are needed to help define each new agent’s place in
the acne treatment algorithm, with an eye not only towards
safety and efficacy but also cost-effective care.
Declarations
Funding No sources of funding were used to conduct this study or
prepare this manuscript.
Conflict of interest Lara Drake, Sophia Reyes-Hadsall, and John S
Barbieri have no conflicts of interest that are directly relevant to the
content of this article. Dr. Mostaghimi has received royalty payments
from Pfizer for licensing of the ALTO tool; has participated in clinical
trials related to alopecia by Incyte, Lilly, Concert, and Aclaris; and has
received consulting fees from Pfizer.
Availability of data and material Not applicable.
Ethics approval Not applicable.
Consent Not applicable.
Author contributions All authors contributed to the study conception
and design. Lara Drake and Sophia Reyes-Hadsall conducted the litera-
ture search and data analysis and wrote the first draft of the manuscript.
All authors commented on subsequent versions of the manuscript and
read and approved the final manuscript.
New Developments in Topical Acne Therapy 135

References tufts.​edu/​news-​events/​press-​annou​nceme​nts/​fda-​appro​ves-​diffe​
rin-​gel-​01-​over-​count​er-​use-​treat-​acne.
19. Aubert J, Piwnica D, Bertino B, Blanchet-Réthoré S, Carlavan I,
1. Cooper AJ, Harris VR. Modern management of acne. Med J Aust.
Déret S, et al. Nonclinical and human pharmacology of the potent
2017;206(1):41–5. https://​doi.​org/​10.​5694/​mja16.​00516.
and selective topical retinoic acid receptor-γ agonist trifarotene.
2. Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE,
Br J Dermatol. 2018;179(2):442–56. https://​doi.​org/​10.​1111/​bjd.​
Berson DS, et al. Guidelines of care for the management of acne
16719.
vulgaris. J Am Acad Dermatol. 2016;74(5):945-73.e33. https://​
20. Blume-Peytavi U, Fowler J, Kemény L, Draelos Z, Cook-Bolden
doi.​org/​10.​1016/j.​jaad.​2015.​12.​037.
F, Dirschka T, et al. Long-term safety and efficacy of trifarotene
3. Degitz K, Placzek M, Borelli C, Plewig G. Pathophysiology of
50 μg/g cream, a first-in-class RAR-γ selective topical retinoid,
acne. JDDG J der Deutschen Dermatologischen Gesellschaft.
in patients with moderate facial and truncal acne. J Eur Acad
2007;5(4):316–23.
Dermatol Venereol. 2020;34(1):166–73. https://​doi.​org/​10.​1111/​
4. Webster GF. The pathophysiology of acne. Cutis. 2005;76(2
jdv.​15794.
Suppl):4–7.
21. Tan J, Thiboutot D, Popp G, Gooderham M, Lynde C, Del Rosso J,
5. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Der-
et al. Randomized phase 3 evaluation of trifarotene 50 μg/g cream
matol. 2013;168(3):474–85.
treatment of moderate facial and truncal acne. J Am Acad Der-
6. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in
matol. 2019;80(6):1691–9. https://d​ oi.o​ rg/1​ 0.1​ 016/j.j​ aad.2​ 019.0​ 2.​
adults. J Am Acad Dermatol. 1999;41(4):577–80.
044.
7. Barbieri JS. A new class of topical acne treatment address-
22. Azelex (Allergan) (azelaic acid cream) 20% FDA Access Data.
ing the hormonal pathogenesis of acne. JAMA Dermatol.
2003. https://​www.​acces​sdata.​fda.​gov/​drugs​atfda_​docs/​label/​
2020;156(6):619–20. https://d​ oi.o​ rg/1​ 0.1​ 001/j​ amade​ rmato​ l.2​ 020.​
2003/​20428​slr016_​azelex_​lbl.​pdf.
0464.
23. Gold LS, Dhawan S, Weiss J, Draelos ZD, Ellman H, Stuart IA. A
8. Han JJ, Faletsky A, Barbieri JS, Mostaghimi A. New acne ther-
novel topical minocycline foam for the treatment of moderate-to-
apies and updates on use of spironolactone and isotretinoin: a
severe acne vulgaris: results of 2 randomized, double-blind, phase
narrative review. Dermatology and Therapy. 2021;11(1):79–91.
3 studies. J Am Acad Dermatol. 2019;80(1):168–77. https://​doi.​
https://​doi.​org/​10.​1007/​s13555-​020-​00481-w.
org/​10.​1016/j.​jaad.​2018.​08.​020.
9. Retin-A-Tretinoin Cream, Retin-A-Tretinoin Gel Drug Label
24. Yang Z, Zhang Y, Lazic Mosler E, Hu J, Li H, Zhang Y, et al.
Information DailyMed. 2019. https://​daily​med-​nlm-​nih-​gov.​
Topical benzoyl peroxide for acne. Cochrane Database Syst Rev.
ezpro​xy.​libra​r y.​tufts.​edu/​daily​med/​drugI​nfo.​cfm?​setid=​9556d​
2020;3(3):CD011154. https://d​ oi.o​ rg/1​ 0.1​ 002/1​ 46518​ 58I01​ 1154.​
73d-​c573-​4e0a-​9feb-​764ce​2d110​7b.
pub2.
10. Retin-A Micro-Tretinoin Gel DailyMed. 2017. https://​daily​med-​
25. Sol-Gel Technologies Announces FDA Approval of TWYNEO
nlm-​nih-​gov.​ezpro​xy.​libra​r y.​tufts.​edu/​daily​med/​drugI​nfo.​cfm?​
Globe News Wire. 2021. https://​www.​globe​newsw​ire.​com/​news-​
setid=​08ab7​e0c-​1437-​455f-​815c-​98904​d96a2​89.
relea​se/​2021/​07/​27/​22695​61/0/​en/​Sol-​Gel-​Techn​ologi​es-​Annou​
11. Retin-A (Tretinoin) Cream Gel Liquid for Topical Use Only FDA
nces-​FDA-​Appro​val-​of-​TWYNEO.​html.
Access Data. 2002. https://​www.​acces​sdata.​fda.​gov/​drugs​atfda_​
26. Del Rosso J, Sugarman, J., Levy-Hachman, O., Mizrahi, R.
docs/​label/​2002/​16921​s21s2​2s25l​bl.​pdf.
TWYNEO (Microencapsulated benzoyl peroxide 3%, tretinoin
12. Bikowski JB. Mechanisms of the comedolytic and anti-inflam-
0.1%) phase 3 efficacy and safety: results from two randomized
matory properties of topical retinoids. J Drugs Dermatol.
controlled clinical trials. Sol-Gel Technologies. https://​ir.​sol-​gel.​
2005;4(1):41–7.
com/​static-​files/​c1d4a​3ff-​e56d-​4abf-​932b-​53337​d8961​b3.
13. Tyring SK, Kircik LH, Pariser DM, Guenin E, Bhatt V, Pillai
27. Hebert A, Thiboutot D, Stein Gold L, Cartwright M, Gerloni
R. Novel tretinoin 0.05% lotion for the once-daily treatment of
M, Fragasso E, et al. Efficacy and safety of topical clascoterone
moderate-to-severe acne vulgaris: assessment of efficacy and
cream, 1%, for treatment in patients with facial acne: two phase 3
safety in patients aged 9 years and older. J Drugs Dermatol.
randomized clinical trials. JAMA Dermatol. 2020;156(6):621–30.
2018;17(10):1084–91.
https://​doi.​org/​10.​1001/​jamad​ermat​ol.​2020.​0465.
14. Tazorac (tazarotene) gel, 0.05% and 0.1%, for topical use FDA
28. Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G.
Access Data. 2018. https://​www.​acces​sdata.​fda.​gov/​drugs​atfda_​
Cortexolone 17α-propionate 1% cream, a new potent antiandrogen
docs/​label/​2018/​02060​0s010​lbl.​pdf.
for topical treatment of acne vulgaris. A pilot randomized, double-
15. Tanghetti EA, Werschler WP, Lain T, Guenin E, Martin G, Pillai
blind comparative study vs. placebo and tretinoin 0.05% cream.
R. Tazarotene 0.045% lotion for once-daily treatment of moderate-
Br J Dermatol. 2011;165(1):177–83. https://​doi.​org/​10.​1111/j.​
to-severe acne vulgaris: results from two phase 3 trials. J Drugs
1365-​2133.​2011.​10332.x.
Dermatol. 2020;19(1):70–7. https://​doi.​org/​10.​36849/​jdd.​2020.​
29. Picardo M, Ottaviani M, Camera E, Mastrofrancesco A. Seba-
3977.
ceous gland lipids. Dermatoendocrinol. 2009;1(2):68–71. https://​
16. Shari L. Targum M, MPH, FACP, FACC. NDA 211882: NDA
doi.​org/​10.​4161/​derm.1.​2.​8472.
Approval accessdata.fda.gov: FDA U.S. Food & Drug Administra-
30. Eisinger M, Li WH, Anthonavage M, Pappas A, Zhang L, Ros-
tion; 2019. https://w ​ ww.a​ ccess​ data.f​ da.g​ ov/d​ rugsa​ tfda_d​ ocs/a​ pple​
setti D, et al. A melanocortin receptor 1 and 5 antagonist inhibits
tter/​2019/​21188​2Orig​1s000​ltr.​pdf.
sebaceous gland differentiation and the production of sebum-spe-
17. Tanghetti EA, Kircik LH, Green LJ, Guenin E, Harris S, Martin G,
cific lipids. J Dermatol Sci. 2011;63(1):23–32. https://​doi.​org/​10.​
et al. A phase 2, multicenter, double-blind, randomized, vehicle-
1016/j.​jderm​sci.​2011.​04.​001.
controlled clinical study to compare the safety and efficacy of a
31. Botanix Progresses Development Plan for BTX 1503: BiotechDis-
novel tazarotene 0.045% lotion and tazarotene 0.1% cream in the
patch; 2020. https://​biote​chdis​patch.​com.​au/​news/​botan​ix-​progr​
treatment of moderate-to-severe acne vulgaris. J Drugs Dermatol.
esses-​devel​opment-​plan-​for-​btx-​1503.
2019;18(6):542.
32. Baldwin H, Blanco D, McKeever C, Paz N, Vasquez YN, Quiring
18. FDA approves Differin Gel 0.1% for over-the-counter use to treat
J, et al. Results of a phase 2 efficacy and safety study with SB204,
acne: first retinoid approved for over-the-counter use FDA New
an investigational topical nitric oxide-releasing drug for the treat-
Release: FDA.gov; 2016. https://​www-​fda-​gov.​ezpro​xy.​libra​r y.​
ment of acne vulgaris. J Clin Aesthet Dermatol. 2016;9(8):12–8.
136
33. AOBiome Completes Patient Enrollment In Phase 2 Clinical Trial
Of Lead Candidate B244 To Treat Elevated Blood Pressure: First-
in-Class Therapy Designed to Deliver Nitric Oxide for Applica-
tion in Diverse Inflammatory Conditions: AOBiome Therapeutics;
2017. https://​www.​aobio​me.​com/​press​relea​ses/​aobio​me-​compl​
etes-​patie​nt-​enrol​lment-​in-​phase-2-​clini​cal-​trial-​of-​lead-​candi​
date-​b244-​to-​treat-​eleva​ted-​blood-​press​ure/.
34. Our Product Pipeline. Botanix Pharmaceuticals. https://b​ otani​ xpha​
rma.​com/​pipel​ine/.
35. Batra R, Sadhasivam S, Saini S, Gupta S, Bisen RKS, Sinha
M, et al. Efficacy and safety of VB-1953 topical gel in non-
responder acne patients with clindamycin-resistant cutibacterium
acnes. Drugs R&D. 2020;20(2):95–104. https://​doi.​org/​10.​1007/​
s40268-​020-​00299-z.
36. Information NCfB. PubChem Compound Summary for CID
16131446, Omiganan pentahydrochloride. 2021. https://​pubch​
em.​ncbi.​nlm.​nih.​gov/​compo​und/​Omiga​nan-​penta​hydro​chlor​ide.
37. Stein Gold L, Baldwin H, Kircik LH, Weiss JS, Pariser DM, Cal-
lender V, et al. Efficacy and safety of a fixed-dose clindamycin
phosphate 1.2%, benzoyl peroxide 3.1%, and adapalene 0.15% gel
L. Drake et al.
for moderate-to-severe acne: a randomized phase II study of the
first triple-combination drug. Am J Clin Dermatol. 2021.
38. Drug Profile: Tazarotene topical. Dr Reddys Laboratories Adis
Insight: Springer; 2020. https://​adisi​nsight.​sprin​ger.​com/​drugs/​
80004​4869.
39. Weller M. Minocycline, adapalene combination foam shows
good results in acne treatment: Healio; 2021. https://​www.​healio.​
com/​news/​derma​tology/​20210​128/​minoc​ycline-​adapa​lene-​combi​
nation-​foam-​shows-​good-​resul​ts-​in-​acne-​treat​ment.
40. Barańska-Rybak W, Kowalska-Olędzka E. New indications for
topical ivermectin 1% cream: a case series study. Postepy derma-
tologii I alergologii. 2019;36(1):58–62. https://​doi.​org/​10.​5114/​
ada.​2019.​82825.
41. Bioequivalence study of clindamycin phosphate topical lotion,
1% in subjects with acne vulgaris. ClinicalTrials.gov Identifier:
NCT03717506 ClinicalTrials.gov. 2021. https://​clinic​ altr​ials.​gov/​
ct2/​show/​resul​ts/​NCT03​717506?​view=​resul​ts.