FOL-005 -a novel peptide drug regulates hair growth in a …...2018/05/18 · FOL-005 Baseline 13...
1
FOL-005 - a novel peptide drug regulates hair growth in a Phase I/IIa study Hair loss with subsequent alopecia comes in a wide range of clinical manifestations with androgenetic alopecia being the most frequently observed entity, affecting up to 80% of men and 50% of women 1 . Even though this disorder is known to cause substantial psychological distress to many patients, therapeutic options are limited. The multitude of signalling pathways involved in hair growth suggests that different classes of molecules could be successful candidates for growth stimulation. Still, the number of actives reaching convincing evidence in clinical trials is low. FOL-005 is a well-characterized osteopontin derived peptide that binds specifically to hair follicles (HFs). Osteopontin, a multifunctional immunomodulatory glycoprotein, has been shown to exert multiple roles in skin physiology and pathology 2, 3, 4 and is significantly expressed in human HFs 5 . The hypothesis that osteopontin-derived fragments may modulate human hair growth, has been tested in preclinical studies and FOL-005 was shown to give rise to a potent increase in hair growth in an experimental mice model. In addition, FOL-005 has undergone a standard battery of toxicological tests without signs of any overt toxicity. Recently the first clinical study with FOL-005, “Investigation of FOL-005 on Clinical Safety and Effect on Hair Growth” at CRC for Hair and Skin Science, Charité-Universitätsmedizin, Berlin, Germany was successfully completed. Introduction and Objective Experimental Preclinical studies FOL-005 is a 15 amino acid fragment of the human protein Osteopontin, modified to optimize hair growth stimulating properties. • The hair growth stimulation properties were investigated in young C57Bl/6 mice in stable telogen (resting) phase of hair growth. The animals were carefully shaved and treated with sc injections of FOL- 005 or placebo on the back. The hair growth was visually inspected and scored on a daily basis. • In vitro studies on human facelift skin and ex vivo studies on human scalp skin xenotransplanted to SCID mice were performed at higher doses. • The binding of FOL-005 was studied in sections of human fresh-frozen skin. Sections were incubated with FOL-005 and the binding was analysed using immunofluorescence detection. • An extensive tox/safety program, including 3 months repeat dose studies in the mouse and the pig as well as a sensitization study (Local Lymph Node test) was carried out. Clinical phase I/IIa study The clinical trial was a single centre, randomized, double-blind, placebo-controlled safety trial. In order to study several different treatments on the same subject, the study was performed on six separate areas on the forefront of the thighs of healthy volunteers. The study was divided in two parts, a single ascending dose (SAD) part, and a multiple dose (MD) regime part. Five of the areas were treated with either placebo or one of four doses of FOL-005 in a double-blinded manner and one area was left untreated. FOL-005 and placebo were administered as intradermal injections. The subjects were monitored continuously for safety signals during the study. The number of hairs at the separate areas were manually counted according to a standardized procedure. References: 1 Kelly et al., 2016; 2 Kothari et al., 2016; 3 Scatena et al., 2007; 4 Wei et al., 2017; 5 Chang et al., 2008 About Follicum Follicum is a Swedish biotechnology company working with development of new pharmaceuticals to control hair growth. If you would like to discuss collaboration with Follicum please contact : Jan Alenfall, PhD (CEO). Phone : +46 709 315 115. Email : [email protected] Address : Follicum AB, Scheelevägen 22, SE-223 63 Lund, Sweden Web : www.follicum.com Investigation of FOL-005 on Clinical Safety and Effect on Hair Growth – a phase I/IIa study Figure 4: Example photographs, hair count before and after 13 weeks of treatment The hair growth stimulatory effect was assessed by counting the number of hairs prior to treatment and after 13 weeks of treatment. An overall significant effect was seen at the second lowest dose, with a median increase in hair density of 8% (p=0.016) while for the placebo group a decrease of 5% (p=0.513) was detected. Conclusions Preclinical FOL-005 potently induced hair growth in a mouse model with a rapid onset and a complete, dense fur within 16 days. In both human and mouse skin, FOL-005 was found to be distributed specifically to certain structures within the hair follicle but not to surrounding tissues. Clinical In the clinical study, FOL-005 was very well tolerated and a hair growth stimulating effect was observed. At the second lowest dose a significant increase in hair density of 8% was observed and the response rate was high (about 75%) after 3 months of treatment. Currently a Phase IIa study with FOL-005 administered to minizones on the scalp of alopecia subjects is ongoing. Jan Alenfall 1 , Maria Ekblad 1 , Jan Kottner 2 , Annika Vogt 2 , Ulrike Blume-Peytavi 2 . 1) Follicum AB, Lund, Sweden, 2) Charité-Universitätsmedizin Berlin, Germany Figure 2. Immunofluorescence detection of FOL-005 binding to structures within the hair follicle in human fresh-frozen skin. Binding of FOL-005 to hair follicles in human skin after in vitro incubations of 14µm sections, longitudinal section to the left and cross section to the right. FOL-005 (pink/red) was found to be distributed only to specific areas within the hair follicle but not to the surrounding tissue. Actin filaments (green), and DAPI staining (blue). FOL-005 binds to specific areas of the hair follicle and not to surrounding tissues FOL-005: day 16 Control: day 16 Animals treated with three injections of 25µl, 60 nM FOL-005, obtained full, dense, normal coat hair within 16 days of treatment. Mean (+SEM). Figure 1. Regulation of hair growth in vivo. FOL-005 potently increased hair growth on shaved back in C57Bl/6 mouse model Figure 3: Design of FOL-005 Phase I/IIa study Results FOL-005 in C57Bl/6 model: • Rapid onset of hair growth • Complete hair growth on whole clipped area • Median hair growth score for FOL-005 was 3 versus ~0 for vehicle • In the same model, a marketed Minoxidil solution resulted in score 3 obtained at day 39 (data not shown). A: 2x weekly B: 3x weekly Multiple Dosing 30 volunteers, 3 months Six Treatment Areas 1. No Treatment 2. Placebo 3. Dose 1 4. Dose 2 5. Dose 3 6. Dose 4 • Intradermal injections on the thighs • Administrations controlled and done at clinic • All subjects received all doses • Two groups, 2 or 3 times weekly • 3 months follow-up Placebo Baseline 13 weeks *Fotofinder Device, 20x magnification FOL-005 Baseline 13 weeks A significant increase in hair density of +8% was observed at Dose 2 of FOL-005. Placebo showed a decrease of -5%. In some subjects, FOL-005 treatment induced up to 60% increase in hair density compared to baseline. Hair growth score Days after first treatment 0 0,5 1 1,5 2 2,5 3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 FOL-005 (60 nM) Vehicle Inj 1 Inj 2 Inj 3 As there were no safety concerns in the SAD part the MD part was initiated. Hair density was assessed prior to treatment and after 13 weeks of treatment by photography and manually hair counting by two separate investigators. FOL-005 showed no adverse reactions in toxicology studies • The studies showed that there should be no or minimal risk for any toxicity with the administration of FOL-005 in clinical studies as no adverse reaction occurred in any of the studies performed. • No systemic exposure to intact peptide could be detected and FOL-005 was considered a non-sensitizer in the Local Lymph Node study. • Absence of anti drug antibodies suggested that the immunogenic potential is extremely low. Hair growth scoring and grading criteria Observation Score No hair growth, pink skin 0 Skin colour change from pink to grey without visible hair growth 0.5 Skin colour change from pink to grey or black, without visible hair growth, indicating onset of anagen 1.0 Sparse hair growth 1.5 Sparse or diffuse short hair growth 2.0 Moderate hair growth 2.5 Dense, normal coat 3.0
Transcript of FOL-005 -a novel peptide drug regulates hair growth in a …...2018/05/18 · FOL-005 Baseline 13...
-
FOL-005 - a novel peptide drug regulates hair growth in a Phase I/IIa study
Hair loss with subsequent alopecia comes in a wide range of clinical manifestations with androgenetic alopecia being the most frequently observed entity, affecting up to 80% of men and 50% of women1. Even though thisdisorder is known to cause substantial psychological distress to many patients, therapeutic options are limited. The multitude of signalling pathways involved in hair growth suggests that different classes of moleculescould be successful candidates for growth stimulation. Still, the number of actives reaching convincing evidence in clinical trials is low.
FOL-005 is a well-characterized osteopontin derived peptide that binds specifically to hair follicles (HFs). Osteopontin, a multifunctional immunomodulatory glycoprotein, has been shown to exert multiple roles in skinphysiology and pathology2, 3, 4 and is significantly expressed in human HFs5. The hypothesis that osteopontin-derived fragments may modulate human hair growth, has been tested in preclinical studies and FOL-005 wasshown to give rise to a potent increase in hair growth in an experimental mice model. In addition, FOL-005 has undergone a standard battery of toxicological tests without signs of any overt toxicity.
Recently the first clinical study with FOL-005, “Investigation of FOL-005 on Clinical Safety and Effect on Hair Growth” at CRC for Hair and Skin Science, Charité-Universitätsmedizin, Berlin, Germany was successfullycompleted.
Introduction and Objective
Experimental
Preclinical studies
FOL-005 is a 15 amino acid fragment of the human protein Osteopontin, modified to optimize hair growthstimulating properties.• The hair growth stimulation properties were investigated in young C57Bl/6 mice in stable telogen
(resting) phase of hair growth. The animals were carefully shaved and treated with sc injections of FOL-005 or placebo on the back. The hair growth was visually inspected and scored on a daily basis.
• In vitro studies on human facelift skin and ex vivo studies on human scalp skin xenotransplanted toSCID mice were performed at higher doses.
• The binding of FOL-005 was studied in sections of human fresh-frozen skin. Sections were incubatedwith FOL-005 and the binding was analysed using immunofluorescence detection.
• An extensive tox/safety program, including 3 months repeat dose studies in the mouse and the pig aswell as a sensitization study (Local Lymph Node test) was carried out.
Clinical phase I/IIa study
The clinical trial was a single centre, randomized, double-blind, placebo-controlled safety trial. In order tostudy several different treatments on the same subject, the study was performed on six separate areas onthe forefront of the thighs of healthy volunteers.The study was divided in two parts, a single ascending dose (SAD) part, and a multiple dose (MD) regimepart.Five of the areas were treated with either placebo or one of four doses of FOL-005 in a double-blindedmanner and one area was left untreated. FOL-005 and placebo were administered as intradermalinjections.The subjects were monitored continuously for safety signals during the study. The number of hairs at theseparate areas were manually counted according to a standardized procedure.
References: 1Kelly et al., 2016; 2Kothari et al., 2016; 3Scatena et al., 2007; 4Wei et al., 2017; 5Chang et al., 2008
About Follicum
Follicum is a Swedish biotechnology company working with development of new pharmaceuticals to control hair growth.
If you would like to discuss collaboration with Follicum please contact:
Jan Alenfall, PhD (CEO). Phone: +46 709 315 115. Email: [email protected] Address: Follicum AB, Scheelevägen 22, SE-223 63 Lund, Sweden Web: www.follicum.com
Investigation of FOL-005 on Clinical Safety and Effect on Hair Growth – a phase I/IIa study
Figure 4: Example photographs, hair count before and after 13 weeks of treatment
The hair growth stimulatory effect was assessed by counting the number of hairs prior to treatment and after 13 weeks of treatment. An overallsignificant effect was seen at the second lowest dose, with a median increase in hair density of 8% (p=0.016) while for the placebo group adecrease of 5% (p=0.513) was detected.
Conclusions
Preclinical
FOL-005 potently induced hair growth in a mouse model with a rapid onset
and a complete, dense fur within 16 days.
In both human and mouse skin, FOL-005 was found to be distributed
specifically to certain structures within the hair follicle but not to surrounding
tissues.
Clinical
In the clinical study, FOL-005 was very well tolerated and a hair growth
stimulating effect was observed. At the second lowest dose a significant
increase in hair density of 8% was observed and the response rate was high
(about 75%) after 3 months of treatment.
Currently a Phase IIa study with FOL-005 administered to minizones on the
scalp of alopecia subjects is ongoing.
Jan Alenfall1, Maria Ekblad1, Jan Kottner2, Annika Vogt2, Ulrike Blume-Peytavi2. 1) Follicum AB, Lund, Sweden, 2) Charité-Universitätsmedizin Berlin, Germany
Figure 2. Immunofluorescence detection of FOL-005 binding to structures within the hair follicle in human fresh-frozen skin.
Binding of FOL-005 to hair follicles in human skin after in vitro incubations of 14µm sections, longitudinal section to the left and cross section tothe right. FOL-005 (pink/red) was found to be distributed only to specific areas within the hair follicle but not to the surrounding tissue. Actinfilaments (green), and DAPI staining (blue).
FOL-005 binds to specific areas of the hair follicle and not to surrounding tissues
FOL-005: day 16Control: day 16
Animals treated with three injections of 25µl, 60 nM FOL-005, obtained full, dense, normal coat hair within 16 days of treatment. Mean (+SEM).Figure 1. Regulation of hair growth in vivo.
FOL-005 potently increased hair growth on shaved back in C57Bl/6 mouse model
Figure 3: Design of FOL-005 Phase I/IIa study
Results FOL-005 in C57Bl/6 model:
• Rapid onset of hair growth
• Complete hair growth on whole clipped area
• Median hair growth score for FOL-005 was 3
versus ~0 for vehicle• In the same model, a marketed Minoxidil
solution resulted in score 3 obtained at day
39 (data not shown).
A: 2x weekly
B: 3x weekly
A: follow-up
B: follow-up
Multiple Dosing 30 volunteers, 3 months
No Treatment3 months
single dose
SAD 10 v3 weeks
Six Treatment Areas1. No Treatment2. Placebo3. Dose 14. Dose 25. Dose 36. Dose 4
• Intradermal injections on the thighs
• Administrations controlled and done at clinic
• All subjects received all doses
• Two groups, 2 or 3 times weekly
• 3 months follow-up
Placebo
Baseline 13 weeks
*Fotofinder Device, 20x magnification
FOL-005
Baseline 13 weeks
A significant increase in hair density of +8% was observed at Dose 2 of FOL-005. Placebo
showed a decrease of -5%.
In some subjects, FOL-005 treatment induced up to 60% increase in hair density compared
to baseline.
Hair growth score
Days after first treatment0
0,5
1
1,5
2
2,5
3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
FOL-005 (60 nM)
Vehicle
Inj 1
A: 2x weekly
B: 3x weekly
A: follow-up
B: follow-up
Multiple Dosing 30 volunteers, 3 months
No Treatment3 months
single dose
SAD 10 v3 weeks
Six Treatment Areas1. No Treatment2. Placebo3. Dose 14. Dose 25. Dose 36. Dose 4
Inj 2 Inj 3
As there were no safety concerns in the SAD part the MD part was initiated. Hair density was assessed prior to treatmentand after 13 weeks of treatment by photography and manually hair counting by two separate investigators.
FOL-005 showed no adverse reactions in toxicology studies
• The studies showed that there should be no or minimal risk for any toxicity with the administration of FOL-005 in clinical studies as no adverse reaction occurred in any of the studies performed.
• No systemic exposure to intact peptide could be detected and FOL-005 was considered a non-sensitizer in the Local Lymph Node study.
• Absence of anti drug antibodies suggested that the immunogenic potential is extremely low.
Hair growth scoring and grading criteria
Observation Score
No hair growth, pink skin 0
Skin colour change from pink to grey withoutvisible hair growth
0.5
Skin colour change from pink to grey or black, without visible hair growth, indicating onset of anagen
1.0
Sparse hair growth 1.5
Sparse or diffuse short hair growth 2.0
Moderate hair growth 2.5
Dense, normal coat 3.0
