Novel Biological Therapies in Dermatology: Mechanisms of Action, Indications of Usage and Side Effects Part-I
Tara Bardawil1, Joanna Khalil2, Ossama Abbas1, Abdul Ghani Kibbi1, Mazen Kurban1,3,4*
1Department
of Dermatology, American University of Beirut, Lebanon
2Department
of Internal Medicine, American University of Beirut, Lebanon
3Department
of Biochemistry and Molecular Genetics, American University of Beirut, Lebanon
4Department of Dermatology, Columbia University Medical Center, USA
*Corresponding author: Mazen Kurban, Department of Dermatology, Columbia University, USA. Tel: +961-1-3500007919; Fax: +961-1-745320; Email: mk104@aub.edu.lb
Received Date: 28 October, 2017; Accepted Date: 18 November,
2017; Published Date: 27 November, 2017
In recent years,
research interest in biologic therapy for the treatment of various dermatologic
entities has been growing. Multiple drugs have already been approved by the FDA
and are rapidly becoming the mainstay in the treatment of a number of cutaneous
diseases, namely psoriasis, psoriatic arthritis, melanoma, basal cell
carcinoma, and many more. In this review, based on a detailed search of
the literature via PubMed, we discuss novel biologic drugs recently approved by
the FDA, their mechanism of action, indications, dosage, side effects and
safety in pregnancy. We also present some of the newer biologics that are
currently being investigated, along with promising fields of research in the
treatment of numerous cutaneous diseases. The biologics discussed in part 1 of
our review include interleukin inhibitors andBRAF and MEK inhibitor
combinations. Part 2 discussesSmoothened inhibitors, JAK/STAT pathway
inhibitors, PI3K-AKT-mTOR pathway inhibitors, Toll-like receptor 9 agonists,
and other tyrosine kinase inhibitors.
Keywords: BRAF;
Interleukin inhibitors; JAK/STAT; MEK; Psoriasis
1. Introduction
In recent years, research interest in biologic therapy for the
treatment of various dermatologic entities has been growing. Multiple drugs
have already been FDA approved and are rapidly becoming the mainstay in the
treatment of these cutaneous diseases, namely psoriasis, psoriatic arthritis,
melanoma, basal cell carcinoma, and many more. The FDA defines biologics as
medical products made from natural sources, whether human, animal or
microorganism, that are intended to treat diseases and medical conditions. This
review explores novel biologic drugs recently approved by the FDA, their
mechanism of action, indications, dosage, side effects and safety in pregnancy.
It also presents some of the newer biologics that are currently being
investigated, along with promising fields of research in the treatment of
numerous cutaneous diseases.
2. Methods
A detailed, comprehensive search of the literature was
accomplished via PubMed searches of biologic therapies used in dermatologic
diseases. Reviews, case reports, case series, clinical trials, randomized
controlled trials, prospective and retrospective studies were analyzed and
inspected.
2.1. Ustekinumab
2.1.1. Year of introduction
Ustekinumab (Stelara) was approved by the FDA in 2009 for the
treatment of moderate to severe plaque psoriasis. It was also approved in 2013
for the treatment of adult patients with active psoriatic arthritis, alone or
in combination with methotrexate [1].
2.1.2. Mechanism of action
A fully human monoclonal antibody of the IgG1 class directed
against the shared p40 subunit of cytokines IL-12 and IL-23, inhibiting their
pro-inflammatory effect [1].
2.1.3. Formulation
Injectable solution for intravenous or subcutaneous
administration [1].
2.1.4. Uses/indications
2.1.4.1. Plaque Psoriasis and Psoriatic arthritis
Multiple studies have assessed the use of ustekinumab in the
treatment of psoriasis and psoriatic arthritis; indeed, this drug received FDA
approval for the treatment of psoriasis in 2009 and psoriatic arthritis in 2013
[1].
2.1.4.2. Acrodermatitis continua of Hallopeau (ACH)
ACH is a variant of pustular psoriasis that is often very
difficult to treat. Almost all anti-psoriatic agents have been used in the
treatment of ACH. Adisen et al. present the case of a 50-year-old male with ACH
resistant to anti-tumor necrosis factor-α agents.
Initial therapy with ustekinumab achieved a sustained response; however, after
seven months of interruption, retreatment resulted in a slower and poorer
response than the initial regimen.
2.1.4.3. Palmoplantar Pustular Psoriasis
Buder et al demonstrated evidence for the effectiveness and
tolerability of ustekinumab in the treatment of palmoplantar postural psoriasis
in a case series of nine patients who were treated with ustekinumab, with
resultant improvement in symptoms and minimal side effects (local injection
site reactions and mild infections). However, long-term efficacy, safety, and
therapeutic benefit are yet to be validated [2].
2.1.5. Side effects/contraindications/warnings
The most common reported side effect is upper respiratory tract
infection, which primary care physicians must warn patients about and be on the
lookout for. Other less common side effects include nasopharyngitis, back pain,
cellulitis, depression, diarrhea, fatigue, headache, myalgias, and antibody
formation [1].
2.1.6. Use in pregnancy, breastfeeding, and spermatogenesis
Pregnancy Category: B
Lactation: use caution [1].
· IL-17 inhibitors (Figure 1)
2.2. Brodalumab
2.2.1. Year of introduction
Brodalumab (Siliq) was FDA approved in February 2017 for the
treatment of moderate-to-severe plaque type psoriasis [3].
2.2.2. Mechanism of action
Brodalumab is a human IgG2 monoclonal antibody that binds with
high affinity to IL-17 Receptor A and inhibits its activity by decreasing its
downstream effect and the release of pro-inflammatory cytokines and chemokines [4].
2.2.3. Formulation
Injections administered subcutaneously.
2.2.4. Uses/indications
It was FDA approved for the treatment of moderate to severe
plaque-type psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic
erythrodermain adult patients who are candidates for systemic
therapy/phototherapy and have failed to respond to other systemic therapies [5].
The recommended dosage is 210 mg in 1.5 ml solution
subcutaneously at weeks 0, 1 and 2, and then every 2 weeks [6].
2.2.4.1. Moderate-to-severe plaque psoriasis
The AMAGINE-1 trial, a phase-3, double-blind,
placebo-controlled, randomized trial, showed that PASI75 was achieved in 83.3%
of patients treated with 210 mg of Brodalumab, and in 60.3% of patients treated
with 140 mg versus placebo. Clinical improvements were maintained through weak
52. PASI100 was also noted in 23.3% of patients in the 140-mg group and 41.9%
of the 210 mg group [7].
Furthermore, the AMAGINE-2 and AMAGINE-3 trials evaluated the
efficacy and safety of Brodalumab compared to placebo. These trials showed that
86% of patients treated with Brodalumab achieved PASI75 after 12 weeks compared
to 8.1% of patients treated with placebo [8].
2.2.4.2. Generalized pustular psoriasis (GPP) and psoriatic
erythroderma (PsE)
An open-label, multicenter, long-term phase III study in
assessed the efficacy of brodalumab 140 mg at day 1 and weeks 1 and 2, and then
every 2 weeks until week 52 Japanese patients with GPP and PsE. Brodalumab
significantly improved the symptoms of patients with GPP and PsE throughout the
52 weeks, and demonstrated favorable safety profiles [9].
2.2.4.3. Psoriatic arthritis
A phase II RCT was conducted in 2014 comparing brodalumab (140
mg or 280 mg) vs. placebo in the treatment of psoriatic arthritis was stopped
in May 2015 due to potentially increased risk of depression and suicidal
ideation associated with Brodalumab [10].
2.2.5. Side effects/contraindications/warnings
The most frequently reported adverse events that treating
physicians should look out for include nasopharyngitis, upper respiratory tract
infection, headache and mild, treatable cases of candidiasis and Tinea
infection [7].
As with most immune modulatory drugs, patients are at an
increased risk for opportunistic infections, including reactivation of latent
tuberculosis. If serious infections occur, the drug should be immediately
discontinued. Patients should also be evaluated for TB infection prior to
initiating treatment with Brodalumab.
Brodalumab is contraindicated in patients with Crohn’s disease. Overexpression
of IL-17 is implicated in the pathogenesis of Crohn’s disease [11]. A
randomized, double blind, placebo-controlled study conducted to evaluate the
safety, tolerability, and efficacy of was terminated early due to worsening of
Crohn’s disease in patients in the treatment arm compared to the
control [11, 12].
Brodalumab has also been associated with an increased risk of
suicide behavior but this was no significant according to Chiricozzi et al. [12].
2.2.6. Use in pregnancy, breastfeeding, and spermatogenesis
Human IgG are known to cross the placenta, however there are no
human studies to determine whether Brodalumab is transmitted from mother to
fetus or whether it is distributed in breast milk.
2.3. Ixekizumab
2.3.1. Year of introduction
Ixekizumab (Taltz) was FDA approved in March 2016 for the
treatment of moderate-to-severe plaque psoriasis [13].
2.3.2. Mechanism of action
Humanized IgG4 monoclonal antibody that selectively binds IL-17A
and inhibits the release of proinflammatory cytokines and chemokines [14].
2.3.3. Formulation
Injections, administered subcutaneously.
2.3.4. Uses/indications
The recommended dose ofIxekizumab is 160 mg given subcutaneously
once, followed by 80 mg at weeks 2, 4, 6, 8, 10 and 12, and then 80 mg every 4
weeks [15].
2.3.4.1. Moderate to severe psoriasis
UNCOVER-2 and UNCOVER-3 are prospective, double-blind,
multicenter, phase-3 studies in which patients with moderate to severe plaque
type psoriasis received subcutaneous placebo, etanercept (50 mg twice weekly)
or ixekizumab 160 mg starting dose followed by 80 mg every 2 weeks or every 4
weeks. This study demonstrated that 90% of patients receiving ixekizumab every
2 weeks achieved PASI75 at week 12 with rapid onset of efficacy. A higher
percentage of patients receiving Ixekinumab every 2 weeks achieved PASI90 at 12
weeks compared to every 4 weeks (71% vs. 60% in UNCOVER-2, and 68% vs. 65% in
UNCOVER-3). In comparison, only 19% (UNCOVER-2) and 26% (UNCOVER-3) of patients
achieved PASI90 at 12 weeks with etanercept therapy [14].
2.3.4.2. Psoriatic arthritis
SPIRIT-P2 is randomized, double-blind, placebo-controlled phase
3 trial in which patients with psoriatic arthritis who have had inadequate
response to TNF-inhibitors were randomly assigned to receive ixekizumab every 4
weeks, ixekizumab every 2 weeks, or placebo. ACR-20 was achieved in 53% of
patients in the ixekizumab every 4 weeks group, compared to 40% of patients in
the ixekizumab every 4 weeks group and 20% of placebo patients [16].
2.3.5. Side effects/contraindications/warnings
Refer to Bordalumab side effects above.
2.3.6. Use in pregnancy, breastfeeding, and spermatogenesis
Similar toBrodalumab.
2.4. Secukinumab
2.4.1. Year of introduction
Secukinumab(Cosentyx) was FDA approved in January 2015 for the
treatment of plaque psoriasis. It was later approved in January 2016 for the
treatment of patients with ankylosing spondylitis and psoriatic arthritis [17,18].
2.4.2. Mechanism of action
Secukinumab is a monoclonal antibody that selectively binds to
and inhibits the pro-inflammatory cytokine interleukin IL-17A [17].
2.4.3. Formulation
Lyophilized powder or solution for subcutaneous injection [17].
2.4.4. Uses/indications
2.4.4.1. Psoriasis and Psoriatic Arthritis
Recent studies have highlighted the importance of T helper
17 cells and associated pathologic enhanced expression of the cytokine
interleukin-17A (IL-17A). As integral players in the pathogenesis of psoriasis
and psoriatic arthritis. Novel biologic therapies targeting the IL-17
pathway have been found to be highly effective.
In treating patients with moderate-to severe plaque psoriasis
and psoriatic arthritis in clinical trials [19]. Of those, only secukinumab has received Health Canada and
US Food and Drug Administration approval for treatment
of moderate-to-severe psoriasis, as well as the US Food and Drug Administration approval for treatment of
psoriatic arthritis and ankylosing spondylitis (but not pustular
psoriasis).
In head-to-head studies, secukinumab has been found to be more
effective than etanercept and ustekinumab, particularly in achieving Psoriasis
Area and Severity Index (PASI) 90/100 and achieving PASI 50/75 as early as week
4[20].
In summary, secukinumab is an effective and safe treatment option
that attains high clearance rates up to PASI 90 and 100 as monotherapy in cases
of moderate-to-severe psoriasis. It may be particularly helpful in patients
with psoriasis who have formed antidrug antibodies or failed other biologic
agents and in patients with psoriatic arthritis or ankylosing spondylitis [20].
2.4.4.2. Pityriasis Rubra Pilaris (PRP)
The use of secukinumab has been reported in a 33-year-old female
with a 9-year history of PRP, who had failed or relapsed after multiple
therapeutic modalities including topical corticosteroids, acitretin,
photochemotherapy, immune modulators, and biologics. After treatment with 5
subcutaneous 300-mg weekly injections of secukinumab, followed by once a month
injection, in association with cyclosporine and 10mg of prednisone, a
significant and prompt clinical response and quality-of-life improvement were observed
[21].
2.4.5. Side effects/contraindications/warnings
Physicians should inform their patients that 10-30% of patients
may report infections and nasopharyngitis. Less common side effects include
diarrhea, upper respiratory tract infection, rhinitis, oral herpes, rhinorrhea,
and urticarial [17].
According to Malakouti et al. safety data for secukinumab is
comparable to available biologics.
2.4.6. Use in pregnancy, breastfeeding, and spermatogenesis
Pregnancy category: B.
Lactation: unknown [17].
· BRAF and MEK inhibitor combinations (Figure 2)
The Ras-regulated RAF/MEK/ERK pathway is involved in the
pathogenesis of melanoma. This pathway regulates cell proliferation, migration,
differentiation, angiogenesis etc. In tumors that are BRAF mutation
positive. Administering selective BRAF or MEK inhibitors was associated with
increased overall survival in melanoma patients [22].
2.5. Trametinib and dabrafenib
2.5.1. Year of introduction
Trametinib (Mekinist) was FDA approved in 2013 for treatment of
unresectable or metastatic melanoma with a positive BRAF V600E/K mutation. FDA
approved in 2014 in combination with dabrafenib (Tafinlar), a BRAF inhibitor [23].
2.5.2. Mechanism of action
Trametinib: selective inhibitor of MEK1/1
Dabrafenib: BRAF inhibitor
2.5.3. Formulation
Both are available in oral formulation given at dose of 2 mg
daily (Trametinib) and 150 mg twice daily (Dabrafenib) [24].
2.5.4. Uses/indications
2.5.4.1. Metastatic/unresectable melanoma
The METRIC study is a Phase III, randomized, open-label,
multisite study in which patients with advanced or metastatic BRAF V600E/K
mutation-positive melanoma were randomized to receive trametinib vs.
chemotherapy (dacarbazine or paclitaxel). After 6 months, trametinib
demonstrated a significantly higher overall survival compared to chemotherapy
(81% vs. 67%, P=0.01) [22].
Trametinib in combination with dabrafenib showed significant
benefit in the treatment of melanoma as compared to Trametinib monotherapy. A
multicentre, double-blind, phase 3 randomized controlled trial comparing the
combination vs.monotherapy and placebo concluded that overall survival was
significantly higher in the combination group compared to the dabrafenib group
at 1 year (74% vs. 68% respectively) and at 2 years (51% vs. 42%) with a higher
median progression-free survival (11vs. 8.8 months) [25].
2.5.5. Side effects/contraindications/warnings
Adverse events were generally similar in trametinib monotherapy
and combination of trametinib and dabrafenib. Physicians should inform their
patients that they might experience rash, diarrhea, gastrointestinal
disturbances and edema [24]. However, the trametinib-dabrafenib
combination was associated with significantly higher rates of pyrexia,
hyperkeratosis, arthralgia [25]and major hemorrhagic events and venous
thromboembolism.
2.5.6. Follow-up and screening
Treating physicians should perform a baseline CBC and liver
function testing on their patients with periodic follow up along with an
echocardiogram, repeated 1 month after therapy initiation, and then at 2- to
3-month intervals as the drugs were associated with
cardiomyopathy [24].
2.5.7. Use in pregnancy, breastfeeding, and spermatogenesis
Pregnancy category D.
It is unknown whether these drugs are also excreted in
breastmilk.
2.6. Vemurafenib and cobimetinib
2.6.1. Year of introduction
Vemurafenib (Zelboraf) was FDA approved in August 2011 for the
treatment of late stage/unresectable melanoma [26].FDA approved in
combination with Cobimetinib(Cotellic) in November 2015[27].
2.6.2. Mechanism of action
Vemurafenib: selective inhibitor of mutant BRAF V600E
Cobimetinib: MEK inhibitor.
2.6.3. Formulation
Both are available in oral formulation given at dose of 960 mg
every 12 hours (Vemurafenib)and 60 mg daily (Cobimetinib) for 21 out of 28 days
of the treatment cycle [28].
2.6.4. Uses/indications
2.6.4.1. Metastatic or Unresectable melanoma
Larkin et al. conducted a randomized phase 3 study in which 495
patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation positive
melanoma were randomly assigned to receive combination therapy with
vemurafenib+cobimetinib, or vemurafenib+placebo.
The group receiving combination therapy showed a significant
increase in progression-free survival compared to the control group (9.9 vs.
6.2 months) and a higher rate of complete or partial response (68% vs. 45%).
The combination was however associated with increased toxicity [29].
2.6.5. Side effects/contraindications/warnings
Vemurafenib was associated with the development of new primary
cutaneous malignancies and new non-cutaneous squamous cell carcinomas. A
frequent dermatologic evaluation is recommended for up to 6 months following
discontinuation of the drug. The combination was associated with lower rates of
squamous cell carcinoma compared to monotherapy (2%vs. 11%) [29]. Physicians
should also inform their patients of other side effects including arthralgia,
fatigue, rash, photosensitivity, hepatotoxicity, severe hypersensitivity
reactions including DRESS syndrome [28].
2.6.6. Follow-up and screening
Similarto trametinib and dabrafenib.
2.6.7. Use in pregnancy, breastfeeding, and spermatogenesis
Vemurafenib and cobimetinib can cause fetal harm. Placental
transfer of vemurafenib to the fetus has been reported.
2.7. Encorafenib and Binimetinib
2.7.1. Year of introduction
This combination is currently being studied in trials for the
treatment of melanoma
2.7.2. Mechanism of action
Encorafenib: BRAF inhibitor
Binimetinib: MEK inhibitor.
2.7.3. Formulation
Binimetinib is given at a dose 45 mg orally twice daily.
Encorafenib is currently being tested at different oral doses (400, 450, or 600
mg once daily) in various studies [30].
2.7.4. Uses/indications
2.7.4.1. BRAF-mutant melanoma
The combination of encorafenib and binimetinib is currently
being studied in a phase 3 trial for the treatment of BRAF mutant melanoma. The
COLOMBUS trial is an ongoing randomized, open label, multi-center, parallel
group, phase III study comparing the combination of encorafenib and binimetinib
to vermurafenib and to encorafenib monotherapy in patients with locally
advanced, Unresectable or metastatic BRAF V600 mutation positive patients. It
demonstrated that the combination of encorafenib and binimetinib significantly
improved progression free survivalcompared to vemurafenib and encorafenib
monotherapy (14.9 vs. 7.3 vs.9.6 months respectively) [30].
2.7.5. Side effects/contraindications/warnings
The safety profile was more favorable in patients receiving the
combination therapy compared to vemurafenib or encorafenib monotherapy. The
most common side effects that physicians should expectinclude elevations in
transaminases, nausea, vomiting, pyrexia and increased creatinine phosphokinase
[30].
2.7.6. Use in pregnancy, breastfeeding, and spermatogenesis
Precautions to avoid during pregnancy and breastfeeding.
3. Conclusion
Our review (parts 1 & 2) is not all-inclusive. Ongoing
research is-and will keep-revealing new indications for existing biologics as
well as new biologic agents. We have described a few biologic therapies that
have recently been used as dermatologic treatments. With the promising fields
of research in the treatment of numerous cutaneous diseases, we look forward to
the exploration of new agents and indications.
Figure 1: Showing the site
of action of the four different drugs that inhibit the IL-17 signaling pathway.
Figure 2: Showing the site
of action of the six different medications in inhibiting the BRAF pathway
whether at the level of the BRAF itself or downstream at the level of MEK.
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