Winlevi™

Winlevi™ is the brand name of our anti-androgen for the treatment of acne. It is a topically delivered small molecule that penetrates the skin to reach the androgen receptors of the sebaceous gland. It aims to be the first effective and safe topical anti-androgen that does not have systemic effects. Unlike other hormonal therapies for acne, Winlevi™ can be used by both male and female patients.

Winlevi™ has completed Phase II clinical trials and Phase III trials are scheduled to commence in H2 2015.

Product Description

Winlevi™'s active pharmaceutical ingredient, or API, is a steroid belonging to the family of cortexolone derivatives. Chemically, this API is cortexolone-17α-propionate. Its chemical formula is C24H34O5, its molecular weight is 402.5, and its CAS number is 19608-29-8.

Figure 6: Chemical Structure of Cortexolone 17α-propionate

Winlevi™ is an opaque, white, homogeneous oil-in-water (O/W) emulsion that can be stored at room temperature.

Mechanism of Action

Acne involves a cascade of four physiological events.

  • Seborrhea. Sebaceous gland cells, or sebocytes, in the skin are androgen-sensitive and contain androgen receptors. When stimulated by androgen hormones, they increase production of sebum, an oily or waxy substance that lubricate and waterproofs the skin and hair.
  • Obstruction. Excessive sebum and keratin debris obstruct the pilosebaceous follicle, which contains both the sebaceous gland and the root of a hair that grows from the follicle. The obstruction and the continued androgen-stimulated excessive sebum production dilate the follicle, resulting in the formation of the acne lesion, known as a comedo and commonly called a "blackhead" or "whitehead".
  • Infection. Bacteria, primarily P. acnes, colonize the obstructed follicle.
  • Inflammation. In presence of bacteria, inflammation occurs and the lesion worsens to papules, which are swollen bumps that contain no visible fluids, and pustules, more severely inflamed swellings that contain fluid. The endpoint of the inflammation process brings to nodules and cysts.

Winlevi™ helps to prevent that cascade of events that leads to acne.

Winlevi™ displaces the androgen hormones from the androgen receptors on the sebaceous gland within the hair follicle. Because the follicle is not obstructed, it does not provide P. acnes with the optimal conditions that it needs to colonize the follicle and cause subsequent inflammation.

Winlevi™ is metabolized completely and quickly to cortexolone, a physiological component of the body’s endogenous pool of corticosteroids.

Safety

No clinically relevant safety issues were noted with any of the concentrations of Winlevi™ tested and no clinically relevant signs of the typical Local Skin Reactions (LSR) generally associated with corticosteroids use were appreciated. In the HPA / PK study only 3 out of 42 subjects resulted borderline in the lab test relevant to HP axis, with no sign of clinical corticosteroid specific adverse events.

Based on safety to date, and low levels of systemic exposure, FDA granted a waiver for the typically required systemic 2-year carcinogenicity study.

Clinical Trials

To date, Winlevi™ has completed four Phase I studies in a total of 92 subjects, being healthy volunteers and acne patients, and three Phase II studies in 477 subjects with acne. Results of Phase II clinical trials were received in June 2014. The end of Phase II meeting has been achieved in January 2015. The FDA is currently evaluating our proposed protocol for a Phase III trial. The next catalysts for Winlevi™ are First Patient Enrolled, which we expect in the second half of 2015, and Last Patient Out, expected in the first half of 2017.

Highlights of Phase I Program

We conducted four Phase I studies in 92 subjects. 84 of these subjects were healthy while eight patients had acne. The results of these trials showed that Winlevi™:

  • was well tolerated;
  • showed no measurable side effects; and
  • permeated the skin and was quantifiable in plasma at very low plasma levels.

Phase II Program

We completed three Phase II trials, two in the United States and one in the European Union, in 2014 with a total of 477 subjects with acne:

  • a Phase II POC (proof-of-concept) study on 72 patients with acne vulgaris, compared to Retin-A and placebo
  • an HPA/PK study in 42 subjects; and
  • a Phase II dose-ranging study (DRS) in 363 subjects.

In the POC study, Winlevi™ has been compared to placebo cream and Retin A 0.05% as active control, with a treatment of 8 weeks: Winlevi™ resulted statistically superior to placebo in all the endpoints dealing with Lesion counts and Acne severity Index, and clinical superior to Retin A cream.

In the DRS study, aimed to identify the best dose and trial conditions for the Phase III studies, Winlevi™ resulted superior to placebo: there was a statistical significant difference in absolute change vs. baseline of Total Lesions count, Inflammatory and Non Inflammatory lesions counts among the treatment groups. The 1% BID (twice daily) cohort had a statistically significant decrease (p<0.05) compared to placebo in all the lesions counts, including Total, Inflammatory and Non Inflammatory lesions. Furthermore, Winlevi™ 1% BID (twice daily) had a greater proportion of subjects than placebo with at least a 2 points improvement in IGA score, that resulted in a statistically significant Odds Ratio comparison (2.89), the standard way to compare binary outcomes, i.e. treatment success:

Figure 9: Positive Phase IIb Results

No clinically relevant safety issues were noted with any of the concentrations of Winlevi™ tested and no clinically relevant signs of the typical LSR generally associated with corticosteroids use were appreciated.

In the HPA/PK study only 3 out of 42 subjects resulted borderline in the lab test relevant to HP axis, with no sign of clinical corticosteroid specific adverse events.

Phase III Program

We submitted our SPA to the FDA in April 2015.

We are planning to treat subjects with facial acne with Winlevi™ 1% cream applied twice daily for 12 weeks. Two pivotal trials are planned, each enrolling 700 patients in two arms, treatment and placebo. We expect to carry out one trial in the United States and the other primarily in the European Union, with some additional patients in the United States. The protocol calls for subjects of nine years of age and older with moderate to severe acne (Grades 3 and 4 on the IGA score system).

We expect to engage Therapeutics Inc. as our CRO provider in the United States and Innopharma Srl as CRO provider in the European Union.

The primary endpoints of the trials are:

  • Change from baseline in absolute total lesion count at week 12
  • Change from baseline in absolute non-inflammatory lesion count at week 12
  • Proportion of subjects with at least a two-point reduction in IGA compared to baseline

In a clinical trial using hierarchic endpoints, all endpoints must be reached, and each earlier endpoint must be reached before attempting to reach the following endpoint.

The secondary endpoints are:

  • Proportion of subjects with at least two-point reduction in IGA and IGA score of 0 (clear) or 1 (almost clear)
  • Change from baseline in inflammatory lesion count at week 12

Our proposed Phase III program also includes a long-term, open label safety trial. This trial would expose 300 or more subjects to Winlevi™ for a cumulative six months and a further 100 subjects for a cumulative twelve months.

We expect data from the Phase III trials to be available during the second half of 2017.

Our IP Rights

Two patent families are protecting Winlevi™ and its API, cortexolone 17α-proprionate, in its polymorphic forms: the first patent family, expiring in United States in 2022/23 and in 2022 in the rest of the world, covers the medical use of the compound for the treatment of acne, alopecia and other diseases; the second patents family covers all the known crystalline forms of the API, the compositions containing the same API and the related medical use in treating acne, AGA and other diseases: this patent family is already issued in United States, Europe, Canada, Japan and other countries, will expire in 2030 in United States and 2028 in the rest of the world.

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