Highlights

Ycanth (cantharidin) is a new drug indicated to treat molluscum contagiosum in patients aged 2 years and older.

Ycanth, developed by Verrica Pharmaceuticals, is awaiting approval by the U.S. Food and Drug Administration (FDA), which has until the end of May 2022 to make a decision.

  • On May 25, 2022, the FDA rejected Verrica’s New Drug Application (NDA) due to identified problems at the facilities of Sterling Pharmaceuticals Services, the contract manufacturing organization (CMO) that executes orders for Ycanth. The deficiencies found mainly relate to individual sterile product operations related to serving other customers, while Ycanth’s production does not require sterility. Nevertheless, FDA inspection rules prevent any drugs manufactured at the troubled CMO’s facilities from being approved until any manufacturing issues are resolved. Verrica will continue to engage with the regulator and will search for an alternative CMO. Whatever the case, Verrica’s stock quotes lost two-thirds at once.

Ycanth will be the first drug against molluscum contagiosum to be approved by the U.S. regulator. Currently, the treatment for this skin infection is off-label.

Over time, Ycanth will expand its range of indications to include the treatment of warts, including common warts (verruca vulgaris), genital warts (condyloma acuminatum), and plantar warts (verruca plantaris).

The appearance of Ycanth could have come much sooner, but Verrica has already faced FDA rejection twice. Thus, in July 2020, the regulator refused the New Drug Application (NDA), requesting additional information related to the Chemistry, Manufacturing, and Controls (CMC) section of the NDA. In September 2021, the regulator identified deficiencies at the Sterling’s site unrelated to Ycanth’s production.

Industry observers forecast that demand for Ycanth will cross the quarter-billion-dollar mark in 2026.

 

What is Molluscum Contagiosum

Molluscum contagiosum is a common viral infection affecting the skin and subcutaneous layers and usually appears as single or small groups of painless, flesh-colored, pustular papules 3–5 mm in diameter.

Molluscum contagiosum usually occurs in three population groups: preschool and primary school-age children, sexually active adolescents or young adults, children or adults who are immunocompromised (for example, HIV patients or those who have recently undergone chemotherapy). Children become infected through close physical contact with other infected children or fomites (contaminated objects). Young people are infected through sexual contact. The latter are infected through physical or sexual contact and are characterized by more numerous, diffuse, and large lesions.

Patients with atopic dermatitis are at increased risk of infecting with molluscum contagiosumm.

The worldwide prevalence of molluscum contagiosum in children is estimated to be between 5%–11%. Molluscum contagiosum is the third most common skin infection in children and is one of the top five skin diseases in the world. [1] [2]

Molluscum contagiosum is caused by molluscum contagiosum virus (MCV), a double-stranded DNA-poxvirus belonging to the genus Molluscipoxvirus of the family Poxviridae. At least 4 subtypes of MCV have been identified, with the most common (75%–96% of cases) being subtype 1 (MCV-1), followed by subtype 2 (MCV-2). The latter is associated with immunodeficiency conditions and HIV (it occurs in 60% of cases in HIV patients). Incubation period of MCV is from 2 weeks to 6 months.

The persistence of lesions left untreated for many weeks (usually 6-9 months, but possibly up to 2 years) suggests that molluscum contagiosum virus evades the immune response by expressing a number of proteins that prevent it. For example, MC159 and MC160 inhibit molluscum bodies apoptosis by inhibiting TRAIL and NF-κB; MC54L prevents inflammation by binding interleukin 18; MC148 prevents differentiation of infected keratinocytes; MC80R interferes with MCV-specific peptide presentation and cytotoxicity of infected cells; glutathione peroxidase prevents leukocyte-mediated oxidative damage. [2] [3]

Unlike herpesviruses, which can remain inactive in the body for months or years before reappearing, MCV does not persist in the body after skin lesions disappear. Immunity to MCV is temporary, and reinfection is possible.

In most immunocompetent individuals, molluscum contagiosum does not require any treatment, resolving on its own within 6–13 months. To prevent viral spread, sexual contacts involving the affected areas of the skin should be avoided.

Treatment of molluscum contagiosum is recommended in the following cases: to relieve itching or other symptoms, to eliminate cosmetic problems (including social stigma associated with visible skin lesions, which negatively affects quality of life), to contain self-infection (when scratching, shaving), to prevent transmission to others (especially in genital lesions in sexually active people).

Possible treatment options for molluscum contagiosum are pharmacotherapy (topical and systemic drugs), surgery, and other procedures. [4] [5] [6] [7] [8]

Topical medications proven to be effective in treating molluscum contagiosum include cantharidin, podophyllotoxin, imiquimod.

Surgical and other ways to treat molluscum contagiosum include curettage (puncturing the center of the papule and scraping out its contents), removal of the core with a comedone extractor, and cryotherapy.

  • Treatments for molluscum contagiosum with limited evidence of benefit or associated adverse effects are as follows: potassium hydroxide, salicylic acid, myrtle leaf extract, benzoyl peroxide, combination of povidone iodine and salicylic acid, tretinoin, glycolic acid, silver nitrate, cidofovir, cimetidine, interferon alfa, laser treatments, trichloroacetic acid peels.

There is currently no FDA-approved treatment for molluscum contagiosum in the U.S., and Ycanth should be the first.

 

Ycanth: Mechanism of Action of Cantharidin

Cantharidin is a chemical vesicant (dermal blister) isolated from the blister beetles, which include the well-known Spanish fly (Lytta vesicatoria).

Once cantharidin is absorbed by the lipid membranes of epidermal cells, its mechanism of action involves the activation or release of epidermal serine proteases that degrade desmosomal plaques (cellular structures involved in intercellular adhesion), leading to detachment of tonophilaments (holding cells together). This process is reflected by the loss of cellular connections (acantholysis), eventually causing intraepidermal blistering and inflammation, which promote shedding of infected keratinocytes and viral clearance. [1]

Cantharidin has been widely used in the treatment of molluscum contagiosum and warts since the 1950s. Advantages of cantharidin over other therapies include a rapid onset of therapeutic effect and no seriously pronounced pain during use. After the FDA began requiring efficacy data for approved drugs in 1962, and cantharidin manufacturers failed to provide it, it was withdrawn from the market. In 1997, cantharidin was reintroduced as an approved bulk substance, allowing physicians to use it in clinical practice. However, the ambiguity of the FDA’s status of cantharidin leads to a number of problems including its availability. [2]

Despite broad clinical use and the reported safety of cantharidin, robust clinical trials were needed to conclusively confirm the efficacy and safety of cantharidin with subsequent approval as a treatment for molluscum contagiosum and warts.

Verrica was the first to do so, offering the topical formulation Ycanth, known by the codename VP-102, containing 450 µl of a 0.7% w/v cantharidin solution, and marketed with a single-use applicator with a 1-mm tip. Ycanth contains the dye gentian violet to facilitate the identification of already treated lesions and not yet treated lesions.

 

Ycanth: Efficacy and Safety of Cantharidin in Treating Molluscum Contagiosum

The CAMP-1 (NCT03377790) and CAMP-2 (NCT03377803) phase 3 (randomized, double-blind, placebo-controlled, multicenter) pivotal clinical trials of the same design involved patients (n=528) aged 2 years and older with contagious molluscum.

Participants were mostly within the age range of 2–11 years, males and females were equally represented, the period from diagnosis to initiation of experimental treatment averaged 4.2 months, approximately one-third of patients had previously been treated for molluscum contagiosum, and the number of baseline lesions averaged 21.5.

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Subjects were given placebo or Ycanth, which were applied to all lesions and left for 24 hours. This procedure was repeated up to 4 times at 21-day intervals.

The primary efficacy endpoint for treatment of molluscum contagiosum, defined by the proportion of patients with complete disappearance of all treatable lesions (baseline and new) by day 84, was 46.3% and 54.0% of participants receiving Ycanth in the CAMP-1 and CAMP-2 groups — versus 17.9% and 13.2% in the placebo groups (p<0.0001).

At the end of treatment, the number of lesions (baseline and new) decreased by a mean of 69% and 83% — vs. increases of 20% and 19% (p<0.05).

The use of Ycanth was reflected in the rapid onset of therapeutic effect: a statistically significant difference with the placebo group was observed already after the first course of treatment, continuing to improve with subsequent application of the drug.

When the results of the clinical trials were pooled, 50% of patients treated with cantharidin reached the primary endpoint — vs. 15.6% who received placebo therapy (p<0.0001).

On completion of treatment, the number of lesions (baseline and new) decreased by a mean of 76% — vs. 0.3% (p<0.0001).

Looking at the cure of molluscum contagiosum in the context of the location of the lesions, the results were as follows: lesions completely disappeared on the head/neck in 81.8% of those receiving Ycanth and in 39.6% of those receiving placebo, back/ buttocks in 75.2% vs. 37.4%, chest/abdomen in 71.1% vs. 37.3%, groin in 85.7% vs. 52.0%, upper extremities in 66.5% vs. 33.6%, and lower extremities in 64.0% vs. 33.3%.

Ycanth’s safety profile was characterized by acceptable tolerability, with 93.6% of patients completing treatment completely — versus 95.4% in the control groups. Among the most common treatment-emergent adverse events (TEAEs) were site-specific adverse reactions such as vesicles, itching, pain, erythema, scabs, decoloration, and dryness. All of them were mostly mild-to-moderate in severity.

 

Ycanth: What’s Next

Verrica intends to expand Ycanth’s range of indications to include the treatment of common warts (verruca vulgaris), genital warts (condyloma acuminatum), and plantar warts (verruca plantaris), common skin infections caused by certain types of human papilloma virus (HPV).

Thus, the COVE-1 (NCT03487549) phase 2 clinical trial tested cantharidin in the treatment of common warts. Use of the drug resulted in complete disappearance of the skin lesions in 51.4% of patients.

The CARE-1 (NCT03981822) phase 2 clinical trial evaluated cantharidin in the treatment of genital warts. Administration of the drug provided complete disappearance of skin lesions in an average of 35.1% of patients, and the number of genital warts was reduced by an average of 76.9%.

 

Meanwhile

In the fourth quarter of 2022, Novan intends to submit a New Drug Application (NDA) to the FDA for Kinsolus (berdazimer), a new topical drug for the treatment of molluscum contagiosum.

Berdazimer (SB206), implemented in an isopropyl alcohol–based gel formulation, is a macromolecule consisting of a polysiloxane backbone with covalently bound N-diazeniumdiolate nitric oxide (NO) donors. Immediately prior to application, berdazimer is mixed with a carboxymethyl cellulose–based hydrogel to trigger the local release of NO from the macromolecule by proton-initiated hydrolysis.

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Nitric oxide is an endogenous small molecule with many functions in the body, including vasodilation, neurotransmission, angiogenesis, and modulation of wound healing. Nitric oxide is a major component of innate immunity against virtually any invading pathogen. Nitric oxide stimulates the localized immune response, simultaneously working as a short-acting immunomodulator and a direct broad-spectrum antimicrobial agent. The oxidative and nitroso compounds produced by the action of nitric oxide provide multiple pathways for damage to bacteria, yeast, fungi and viruses. Due to the multitude of biochemical targets for action on pathogens, they have no way of developing resistance to nitric oxide.

The development of topical treatments with nitric oxide is limited by the inability to stably store it, safely deliver it to the site of infection or inflammation, and release it in a controlled manner. Novan solved the problem with its proprietary NITRICIL technology.

In the B-SIMPLE4 (NCT04535531) phase 3 clinical trial, Kinsolus provided complete disappearance of molluscum contagiosum–induced skin lesions in 32.4% of patients after a 12-week course of daily applications. The treatment was characterized by acceptable tolerability.

In the future, Novan intends to offer other drugs based on NITRICIL technology for the treatment of acne vulgaris, genital warts (condyloma acuminata), atopic dermatitis (eczema), plaque psoriasis, tinea pedis (Athlete’s foot), and onychomycosis.

 

Extras

Verrica Pharmaceuticals. Company overview. April 7, 2022. [PDF]

Safety and efficacy of VP-102, a proprietary, drug-device combination product containing cantharidin, 0.7% (w/v), in children and adults with molluscum contagiosum: Two phase 3 randomized clinical trials. JAMA Dermatol. 2020 Dec 1;156(12):1315-1323. [source]

Pooled results of two randomized phase III trials evaluating VP-102, a drug-device combination product containing cantharidin 0.7% (w/v) for the treatment of molluscum contagiosum. Am J Clin Dermatol. 2021 Mar;22(2):257-265. [source]

Safety and efficacy of VP-102 (cantharidin, 0.7% w/v) in molluscum contagiosum by body region: Post hoc pooled analyses from two phase III randomized trials. J Clin Aesthet Dermatol. 2021 Oct;14(10):42-47. [source]

COVE-1: A phase 2, open-label study to evaluate efficacy and safety and the optimal regimen of VP-102, a proprietary drug-device product containing topical cantharidin (0.7% w/v) under occlusion for the treatment of common warts. Dermatol Ther (Heidelb). 2021 Oct;11(5):1623-1634. [source]

Phase II, double-blind, vehicle-controlled study to determine the cantharidin dose regimen, efficacy, safety, and tolerability of VP-102 in subjects with external genital warts. Am J Clin Dermatol. 2021 Nov;22(6):867-875. [source]

Novan. Corporate presentation. March 2022. [PDF]

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Tanya von Reuss

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Tanya has been dedicated to forensic science and molecular pathology for two decades. Her professional interests include thanatology, evidence-based medicine, and holistic medicine.

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