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).
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).
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).
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:
- The growth (anagen) phase, (2 to 7 years),
- The transition (catagen) phase, (2 weeks),
- The resting (telogen) phase where old hair is removed, (12 weeks), and
- 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).
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
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).
Completed clinical trials
Completed clinical trials
*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
Latest completed clinical trials
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).
Representative trichogram images
Difference in total hair counts 12 hairs/cm2 and non-vellus hair counts 12 hairs/cm2. Baseline counts 200 hairs/cm2 and Day 112 212 hairs/cm2.
Difference in total hair counts 7 hairs/cm2 and non-vellus hair counts 12 hairs/cm2. Baseline counts 252 hairs/cm2 and Day 112 259 hairs/cm2.
Difference in total hair counts 5 hairs/cm2 and non-vellus hair counts 13 hairs/cm2. Baseline counts 245 hairs/cm2 and Day 112 251 hairs/cm2.
Difference in total hair counts 0 hairs/cm2 and non-vellus hair counts -9 hairs/cm2. Baseline counts 223 hairs/cm2 and Day 112 223 hairs/cm2.
Clinical efficacy as compared to existing therapies
- 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).
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.
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.
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).
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
Professor Ralf Paus
Dr Maria Kasper
Professor Amos Gilhar
Dr Ulrike Blume-Peytavi
Dr Gerd Lindner