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How the drug works

A proprietary small peptide designed for topical use

The drug candidate FOL005 is a small peptide designed for hair growth regulation through topical administration with a unique proprietary formulation (Figure 4A).

Figure 4A) Schematic 3D model of FOL005

The small peptide is based on a modified part of the endogenous human structural protein osteopontin, a glycoprotein expressed by many tissues, among these also the hair follicle, bone and involved in inflammatory processes.

The sequence is based on natural amino acids and was slightly modified to optimize the hair growth stimulating properties and binds specifically to neuropilin-1 (NRP-1), with a stimulating (agonistic) activity.

Studies in mice with systemic administration of FOL005 showed accumulation of FOL005 in the hair follicles (Figure 4B).

Figure 4B) In vivo studies showing high affinity of FOL005 to hair follicles after systemic administration in mice.

A unique topical formulation with FOL005 applied once daily induces hair growth comparable to minoxidil applied twice daily (Figure 5A). However, only in the FOL005-group full hair growth was achieved with FOL005 as compared to minoxidil and control groups (Figure 5B & 5C).

Figure 5, A) topical administered once daily showed a similar hair growth stimulation potential as topical minoxidil when administered twice daily, B) and only in the FOL005 group full hair growth score was achieved, C) representative images of FOL005, minoxidil and control groups.
References: Runnsjö A, et al., J Pharm Sci. 2022 May;111(5):1309-1317. Alam M, et al., Br J Dermatol. 2020 Jun;182(6):1404-1414.

Novel and cosmetically attractive formulation

A novel patent protected formulation has been developed for FOL005 securing good skin penetration and distribution of FOL005 in the epidermis and hair follicles. The cosmetic properties are suitable for application on the scalp and can be used in both men and women. The formulation type is a light ointment with pharmacopoeia excipients, with cream-like or lotion-like feeling and has an attractive perception and easiness of use.

In the formulation FOL005 is stable at room temperature up to 2 years.

The background of Follicum AB and the drug candidate

In 2004 the founders of Follicum among others prof. Anna Hultgårdh Nilsson discovered, in connection with research on arteriosclerosis, that a modified protein increased hair growth in mice. The modified protein FOL005 was derived from the human glycoprotein osteopontin (OPN). OPN is an extracellular matrix glycoprotein with diverse immunomodulatory functions that has been associated with inflammation and fibrosis, but some publications also report OPN to be present in hair follicles in a hair cycle dependent manner. FOL005 has currently proof-of-concept in Phase IIa clinical study and a Phase IIb clinical study is planned.

Androgenetic Alopecia a slowly developing disease

In men androgenetic alopecia is a genetically predetermined disorder due to an excessive response to androgens. However, the commonality between men and women is likely due to the muscle supporting the hair follicle (the arrector pili muscle), where a loss of attachment between the muscle and hair follicle bulge is associated with irreversible or partially reversible hair loss.

A key driver for this is likely diminished blood flow to the muscle. Androgenetic alopecia develops slowly over time and it is caused by the hair follicle becoming smaller and, in the end, it is ultimately inactive and is not able to grow new hair, a process called miniaturization. Each hair originates in a hair follicle, and a cyclic process known as the hair growth cycle, that consists of four phases:

  1. The growth (anagen) phase, (2 to 7 years),
  2. The transition (catagen) phase, (2 weeks),
  3. The resting (telogen) phase where old hair is removed, (12 weeks), and
  4. The release (exogen) phase, which is the release phase of the telogen hair.

 

Miniaturization occurs at some point between the late catagen or early anagen phase, affecting the dermis (dermal papilla) and the tissue surrounding the hair follicle (dermal sheath), resulting in a smaller follicle and a reduced anagen phase (Figure 3A).

References: Runnsjö A, et al., J Pharm Sci. 2022 May;111(5):1309-1317. Martinez-Jacobo L, et al., Indian J Dermatol Venereol Leprol. 2018 May-Jun;84(3):263-268. Cardoso CO, et al., Clin Cosmet Investig Dermatol. 2021 May 12;14:485-499. Man XY et al., Clin Exp Dermatol. 2009 Apr;34(3):396-401. Sinclair R, Torkamani N, Jones L. F1000Res. 2015 Aug 19;4(F1000 Faculty Rev):585. Follicum data on file
Figure 3A, Progression of AGA, notice the regression of the supportive blood vessels underneath the hair follicle

The role of neuropilin-1 in the skin and hair follicle

FOL005 has a unique and novel mode-of-action binding specifically to neuropilin-1 (NRP-1), with a stimulating effect (agonistic activity). NRP-1 is highly expressed in endothelial cells, fibroblasts and outer root sheath cells identified in hair follicles (Figure 2A, 2B) and plays a key role in reactivating the hair follicle likely through stimulation of stem cells in the hair follicle (outer and inner root sheath cells), stimulation of the supportive tissue with new blood vessels (endothelial cells), stimulating the muscle cells supporting the hair follicle (smooth muscle cells), and regeneration of the tissue (fibroblasts).

 
New blood vessels often form by branching off from existing vessels. One key protein that stimulates this branching process is vascular endothelial growth factor (or VEGF for short). To activate VEGF several ‘receptor’ proteins found on the outside of cells must bind to VEGF. NRP-1 is one and with FOL005 an activation of VEGF is happening to form new blood vessels. However, not only formation of new blood vessels can be caused by VEGF, but also an activation of anagen hair follicles likely causing stimulation of hair growth and increase in hair follicle and hair size.

References: The Human protein atlas Yano K, Brown LF, Detmar M. Control of hair growth and follicle size by VEGF-mediated angiogenesis. J Clin Invest. 2001 Feb;107(4):409-17.

Man XY, et al., Expression and localization of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 in human epidermal appendages: a comparison study by immunofluorescence. Clin Exp Dermatol. 2009 Apr;34(3):396-401. Follicum data on file

Figure 2A) section of normal skin, epidermis is the upper layer of the skin, dermis is the lower layer of the skin, the basement membrane is dividing these two skin layers with stem cells. In the dermis the skin is vascularized with vessels. The blue arrows show the brown color of NRP-1
Figure 2B) expression of NRP-1 in specific cells. The highest expression is found in vessel cells, fibroblasts and cells in and around the hair follicle (highlighted in orange)

A specific mode of action through activation of NRP-1

The target receptor for FOL005 is neuropilin-1 (NRP-1). NRP-1 is a co-receptor to many growth factor receptors and important proteins (semaphorins). NRP-1 must bind to a protein in the cell membrane for a signal to occur and hence to have a function (it is a so-called co-receptor).

FOL005 has shown to specifically to bind NRP-1 and act as a co-receptor, and one of the important proteins that can be activated is VEGF, resulting in development of new blood vessels, stimulation of stem cells in the hair follicle, and stimulation of fibroblasts, resulting in stimulation of hair growth, tissue regeneration and anti-fibrotic properties.

In conclusion, FOL005 binds strongly to the outer and inner root sheath cells within the hair follicle, stimulate vessel formation and acting anti-fibrotic resulting in tissue regeneration and activation of hair growth (Figure 3B).

Figure 3B, suggested mode-of-action of FOL005 in AGA

Completed clinical trials

Completed clinical trials

Three clinical trials have been conducted (FCS-001, FCS-002, and FCS-003), with subcutaneous (s.c.) and topical formulations (Table 2A). The FOL005 s.c. and topical formulations were both found to be safe and tolerable, and efficacy in growth of the number of hairs was further shown in all studies.

*FCS-001: A randomized, double-blind, placebo-controlled phase I/IIa trial of FOL005 to investigate clinical safety and effect on hair growth in healthy volunteers

**FCS-002: A randomized, double-blind, placebo-controlled phase IIa trial of FOL005 to investigate efficacy on hair growth on scalp skin in alopecia subjects

***FCS-003: A randomized, double-blind, vehicle-controlled, dose-finding, multi-center, phase IIa trial of FOL005 topical formulations to investigate hair growth potential and safety in healthy male volunteers

****In total 199 patients were treated per protocol, of which 89 patients (45%) had a hair density below 255 hairs/cm2

*****Timeline impact due to COVID-19 pandemic

Table 2A, Overview of completed (FCS-001-003)

In the FCS-003 study in a sub-population of patients with a hair density of less than 255 hair/cm2 a dose response effect was observed for FOL005. Furthermore, FOL005 1.5% dose was on par with treatment effect reported for minoxidil and finasteride with a growth of 12 hairs/cm2 after 4 months of treatment (Figure 7A), however with more than 60% of subjects responding to treatment (Figure 7B) compared to competitors where 40% responders effect is previously documented after 4 months (Table 4).

Figure 7A) Dosis-dependent effect
Figure 7B) Responders to treatment.

Clinical efficacy as compared to existing therapies

FOL005 has been shown to be safe and tolerable, and in the phase IIa clinical trial (FCS-003), the drug demonstrated efficacy with once daily topical administration on par with long term treatment with the competitors minoxidil and finasteride (Table 4).
Table 4, Overview of existing efficacy data on competitors compared with FOL005.

Key benefits

  • First hair loss product with well-defined and novel Mode of Action
  • Efficacious and safe hair growth stimulator in men and women
  • Equal or better efficacy than existing marketed products
  • Higher number of responders than minoxidil and finasteride
  • An attractive topical formulation initially for the Rx market with OTC switch possible
  • Less frequent administrations than minoxidil

Next clinical trial designed to demonstrate the full potential

Future studies planned include a phase IIb, where the final treatment dose is confirmed, furthermore NRP-1 as a biomarker for responders will be included, and a sub-group of women (non-child birth potential or using contraceptives) will be also included. If the signal in women is positive an equal distribution of men and women is planned in phase III.

The treatment duration will also be prolonged up to 6 or 9 months, hence an extended preclinical tolerability study is planned in 2023 (Table 2B).

Table 2B) Overview of planned clinical studies (FCS-004-007)

Potential in the treatment of chronic wounds

FOL005 is based on a modified part of the protein osteopontin, which is upregulated during wound healing. Osteopontin has been shown in vitro to stimulate the migration of stem cells (mesenchymal) to a skin wound and cause the stem cells to differentiate into keratinocytes and endothelial cells.

Furthermore, novel human in situ data on topical application of FOL005 on wounds has shown to induce significant effects on wound healing. A significant re-epithelization was demonstrated by increase in the wound tongue length and area (Figure 6).

Impaired healing in diabetes is the result of a complex disease involving components like decreased cell growth and vascularization. The latter results in the immune cells not being to enter the area not being able to fight bacterial, fungal and viral infections in the wound, hence often serious infections may occur.

Figure 6, FOL005 topical administered once daily showed wound healing in biopsies from patients, bar 50um

Next clinical trial designed to demonstrate the full potential

Diabetic patients have a 15–25% lifetime risk of developing diabetic foot ulcers, of which 40–80% become severely infected, and a high number of the severe cases require hospitalization and surgical intervention with amputation of the affected body part. In addition, the rate of recurrence of a foot ulcer is greater than 50% after 3 years from the first episode.

For this reason, impaired wound healing in diabetic patients represents a major healthcare issue and a significant economic burden. Notably, costs for diabetic foot ulcerations treatment are additive with general costs for diabetes care and are on the rise with the increased incidence and prevalence of the disease. The total medical cost for the management of diabetic foot disease in the United States (US) ranges from US$9 to US$13 billion in addition to the cost for management of diabetes alone.

The treatment options are limited, and safe and effective drugs used are minimal, hence a large unmet need for safe and effective treatments are warranted.

In conclusion there is a strong rational to further develop FOL005 for diabetic wounds. A phase IIa clinical study in diabetic foot ulcers stage 1-2 is hence planned to show that FOL005 is safe and shows signs of effectiveness. The mode-of-action is likely to be stimulation of cell proliferation and re-vascularization, leading to direct healing but also secondary effects on infectious parameters as infiltrating immune cells may clear up the local infection in patients.

Figure 8) Different stages of diabetic foot ulcers

Researchers and publications

Current and previous World Leading Scientific Advisors and Collaborators

FOL005 was developed by Professor Anna Hultgårdh Nilsson, Lund University in collaboration with LU Bioscience AB. Furthermore, Professor Jan Nilsson is active in progressing the mode-of-action of FOL005 at Lund University and in collaboration with Shanghai Changzheng Hospital, China. Furthermore, the topical formulation is very unique being able to ensure peptide delivery to the skin, recently published (Runnsjö, 2022). This work is supported by strong global patents in place and with protection to 2039. Over time several world leading scientists has been involved in the work with FOL005 (Table 3).

Reference: Runnsjö A, et al., A Novel Microparticle Based Formulation for Topical Delivery of FOL-005, a Small Peptide. J Pharm Sci. 2022 May;111(5):1309-1317.

Professor Anna Hultgårdh Nilsson

Professor Anna Hultgårdh Nilsson Lund University. She holds a PhD in Medical Cell Biology from the Karolinska Institute. After a post doc position at Cedars-Sinai Medical Centre, University of California Los Angeles she returned to the Karolinska Institute where she studied the importance of the vascular smooth muscle cell in the onset of atherosclerosis. In 1998 Professor Hultgårdh Nilsson moved to Lund University and has continued to analyze cell and molecular mechanisms in the atherosclerotic process.

Dr Jan Nilsson

Dr Jan Nilsson has been a Professor of Medicine at the Department of Clinical Sciences, Lund University since joining their faculty in 1998. Throughout his scientific career, his research has focused on the regulation of smooth muscle cell proliferation and the inflammatory response of the vascular wall to oxidized lipoprotein and mechanical injury. In recent years, his main research projects have focused on the role of immune responses against oxidized LDL antigens in atherosclerosis. He has published over 300 papers in vascular cell biology and atherosclerotic research. He is currently a member of the editorial board for Atherosclerosis, Thrombosis and Vascular Biology and was elected member of the Royal Swedish Academy of Sciences in 2015.

Professor Ralf Paus

Professor Ralf Paus is currently the Head of Experimental Dermatology at the University of Luebeck, Germany, and Professor of Cutaneous Medicine at the University of Manchester, UK. Professor Paus has studied the biology and pathology of the hair follicle for many years and is a world leader in this field. Professor Paus is particularly interested in understanding the molecular mechanisms that control hair follicle function in the development of diseases such as alopecia.

Dr Maria Kasper

Dr Maria Kasper is a research scientist at the Karolinska Institute in Sweden. Her research is focused on hair follicles, where she and her team study the molecular mechanisms behind the regulation of cell division. It is an excellent model for understanding both how cancer arises and how skin wounds heal. Dr Kasper has received several awards for her research, such as the Ragnar Söderberg’s Institute and the Cancer Foundation’s prize “Young Investigator Award”.

Professor Amos Gilhar

Professor Amos Gilhar is Professor Emeritus at the Department of Medicine at the Technion Israel Institute of Technology. Professor Gilhar has worked in the field of immune dermatology for the last three decades, where he has been successful in developing humanized mouse models. These are used today in the pre-clinical trials for testing the efficacy of new drugs, especially in relation to the modulation of hair growth. His area of expertise includes research on skin autoimmune diseases such as alopecia areata.

Dr Ulrike Blume-Peytavi

Dr Ulrike Blume-Peytavi is Professor and Executive Medical Director at the Department of Dermatology and Allergy, and a Director of the Clinical Research Centre for Hair and Skin Science (CRC) and the Pediatric Dermatology Unit at the Charité-Universitätsmedizin in Berlin, Germany. Her clinical research interests include contemporary dermatotherapy, hair disorders associated with hormonal dysregulation and pediatric dermatology. Principal investigator in Follicum clinical studies, FCS-001, FCS-002 and FCS-003.

Dr Gerd Lindner

Dr Gerd Lindner is a renowned hair-biology-expert at the Technische Universität Berlin, where he heads a hair and skin biology project group. His research focuses on the generation and characterization of human in-vitro organ models, with a recent emphasis on the integration of hair follicles into human skin. Dr Lindner’s research is in the area of hair growth disorders, where he is studying the science and applications of stem cells in the skin and other organs.