The booming business of hair loss

Date:

Abstract

The need for effective hair loss treatments has fostered research and the emergence of several biotechnology companies. Pharmacological approaches, although competitive, have been surpassed by cell-based therapies, which remain clinically immature. But are the current efforts enough for the hairy goal, or will additional strategies be required?

Keywords

A hairy context

Hair loss is acknowledged as an age-related physiologic process, and much has been described on the evolution of human ‘hairlessness’ [

1.

  • Jablonski N.G.
The naked truth.

]. But lifestyle changes and anxiety that dominate the lives of millennials and young generations have contributed to the early onset of androgenic alopecia (AGA) [

2.

  • Agaoglu E.
  • et al.
Prevalence of early-onset androgenetic alopecia and its relationship with lifestyle and dietary habits.

]. AGA is the most common nonscarring pathological hair loss disorder. It affects 50 million men and 30 million women in the USA. This has led to an unprecedented demand for both preventive and therapeutic interventions. The global alopecia market size was valued at $7.6 billion in 2020 and is expected to reach $13 billion by 2028i. However, the high cost of AGA treatments and their limited efficacy fail to meet the needs and expectations of patients. Currently, hair transplant is the most effective therapy for AGA. However, this procedure is limited by the available number of hair follicles (HFs) in the donor area. In addition, only minoxidil (potassium channel agonist) and finasteride (α5-reductase inhibitor) have been approved by the FDA as pharmacological treatments, but these drugs are only marginally effective and have side effects [

3.

Hair restoration surgery: Challenges and solutions.

]. Intriguingly, no other FDA-approved drug has been marketed in over 40 years of research.

The recent understanding of HF biology and cycling has triggered the development of novel therapeutics aiming to reverse HF miniaturization or even to promote HF regeneration. Tissue engineering strategies have made possible the generation of cycling HFs in animal models. With the prospect of a hair loss cure and its business, biotechnology companies have begun to develop more effective treatments for AGA. Here, we benchmark those biotechs, highlighting the most innovative therapeutic strategies and/or those with scientific evidence, and we discuss promising steps to consider in the future.

Drug therapies

Traditional pharmacological approaches, such as nutricosmetics, are not discussed here. Drug therapies are still the most explored route to treat AGA, and they act by (i) blocking androgens’ action or (ii) stimulating hair growth by either delaying catagen onset or promoting anagenic growth (Box 1). This is likely due to the well-established effect of dihydrotestosterone (DHT) on the conversion of terminal hair to miniaturized vellus hair via progressive shortening of anagen [

4.

  • Whiting D.A.
Male pattern hair loss: Current understanding.

]. However, other drugs targeting distinct hair cycle phases (e.g., exogen and ketogen) could be advantageous in hair loss (anagen effluvium) as well as in hair shedding (telogen effluvium).

Box 1

Biotechs on boosting growth

Embryonic conserved signaling pathways that have been consistently associated with hair cycle regulation and trichogenicity are Wingless (Wnt), Sonic hedgehog (Shh), Hairy and enhancer of split 1 (Hes1), fibroblast growth factor 7 (FG7), and keratinocyte growth factor (KGF). The Wnt/β-catenin signaling pathway has a key role in hair morphogenesis and cycling during both the embryonic stage and adult life. Therefore, pharmacological activation of the Wnt/β-catenin signaling has been explored for a long time to promote hair regeneration. Samumed (now Biosplice) was the first company to develop a topical solution for Wnt signaling activation in the balding scalp. Biosplice managed to value $12 billion in 2018, but earlier this year, upon conclusion of a phase 3 clinical trial, Biosplice canceled dalosirvat from clinical development.

Interestingly, other hair growth stimulators have been unintentionally discovered. For example, prostaglandins’ role in hair growth was discovered in patients with glaucoma undergoing latanoprost and bimatoprost [synthetic prostamide (PG)F2α analogs] treatment who presented with increased length and number of eyelashes [

13.

  • Johnstone M.A.
Hypertrichosis and increased pigmentation of eyelashes and adjacent hair in the region of the ipsilateral eyelids of patients treated with unilateral topical latanoprost.

]. Bimatoprost, marketed by Allergan (now AbbVie), is FDA approved for eyelash hypotrichosis but awaits clinical validation for AGA. Similarly, Dermaliq Therapeutics is exploring a topical formulation (DLQ01) containing PGE2.

Another unintended discovery arose during preclinical studies ascertaining the inflammatory role of osteopontin on atherosclerosis. Mice injected with an osteopontin-modified protein exhibited augmented hair growth. On the basis of this finding, a Swedish biotech company, Follicum, was founded in 2011, but the FOL-005 treatment was discontinued after a phase 2 trial in 2021.

Pharmacological inhibition of catagen drivers is another approach to stimulating hair growth. Hope Medicine is testing a prolactin receptor blocking antibody because prolactin promotes catagen [

14.

  • Foitzik K.
  • et al.
Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.

,

15.

  • Foitzik K.
  • et al.
Human scalp hair follicles are both a target and a source of prolactin, which serves as an autocrine and/or paracrine promoter of apoptosis-driven hair follicle regression.

]. Clinical testing is underway with high expectation because this antibody almost doubled the number of terminal hairs in aged stump-tailed macaques with 6 months treatment.

The most explored treatment route is androgen signaling blockage. However, the systemic off-target effects of DHT blockage have led to the design of antiandrogenic approaches that locally target the androgen receptor (AR) in the balding scalp. Moogene Medi is the first company to use the CRISPR/Cas9 gene-editing technology to target the SRD5A2 gene that codes for steroid 5-alpha-reductase 2, an enzyme responsible for converting testosterone into DHT. The approach uses nanoliposome-microbubble conjugates containing the Cas9 protein and a guide RNA targeting SRD5A2. Direct Cas9/single-guide RNA delivery could mitigate the DHT effects on HFs undergoing miniaturization [

5.

  • Ryu J.Y.
  • et al.
Ultrasound-activated particles as CRISPR/Cas9 delivery system for androgenic alopecia therapy.

]. But gene-editing systems still encounter safety, delivery, and off-target issues. OliX Pharmaceuticals is conducting clinical studies on the topical treatment OLX104. OLX104 is a cell-penetrating asymmetric small interference RNA platform technology that targets the expression of SRD5A1, SRD5A2, and AR. This strategy benefits from the selection of multiple targets for efficient androgen blockage in the scalp and has shown reduced off-target effects.

In Table 1, we summarize emergent companies that explore therapies for AGA. Drug-based therapies, which are relevant in the early stages of alopecia development, have rapidly moved into clinical trials, raised funds, and given rise to vigorous biotech business, but they have limited effectiveness at later stages of overt hair loss.

Table 1Biotech companies developing breakthrough therapies for AGAii,iii,

a

Companies whose clinical trials failed or whose products are completely unknown were not included. Y, Yes; N, no.

Cell-based therapies

Over the last decade, advances in stem cell biology and tissue engineering have prompted research on novel strategies to treat hair loss. Both researchers and investors are now more conscious of the power of regenerative medicine to rejuvenate or even to clone HFs (i.e., bioengineering miniorgans for transplant to obtain an unlimited number of HFs).

The HF rejuvenation approach (i.e., restoring miniaturized HFs back to cycling terminal HFs) and regeneration (i.e., inducing HF neogenesis) has been used to recover the signaling center that regulates hair formation and cycling – the dermal papilla (DP). The HairClone company is developing an autologous DP cell-based therapy to rejuvenate miniaturized HFs. Methodology has been developed to specifically select androgen-resistant DP cells from an in vitro culture and to inject them on the balding scalp. The procedure is expected to rescue HF miniaturization upon repeated treatments with androgen-resistant DP cells. Remarkably, HairClone has also established the first HF biobank, envisioning the cryopreservation of patients’ HFs while healthy for their use in regenerative treatments years later. Although the efficacies of HF cryopreservation and DP cell therapy have not been validated yet, the HairClone corporate approach has engaged patients and clinicians in a prospective therapy that feeds its own business model and research. Another company developing an autologous cell therapy to rejuvenate the thickness and growth of hair fibers undergoing miniaturization is RepliCel Life Sciences. Here the concept is to deliver androgen-insensitive dermal sheath cup cells (DSCCs) into the scalp to restore the normal HF cycle. The RCH-01 product consists of a large number of DSCCs retrieved from the patients’ occipital HFs and expanded in vitro.

A different DP cell-based product is EPI-001 from Epibiotech. The goal of that effort is to develop an ‘off-the-shelf’ allogeneic therapy, taking advantage of the immune-privileged property reported for DPs (i.e., nonself DP cells are tolerated without eliciting an inflammatory immune response) [

6.

Effective and economical cell therapy for hair regeneration.

]. The advantages are no requirement for patients’ own HFs and the unlimited supply of donor DP cells.

Other approaches are under development that aim to reach the ‘holy grail’ of hair cloning independently of the patient’s age, sex, or disease stage. TissUse is a German biotech company that has developed a Smart Hair Transplant technology. Neopapillae, HF equivalents generated in vitro, are embedded into full-thickness skin bioprints to produce microfollicles for transplant into patients. Stemson Therapeutics has developed a preclinical stage cell therapy using iPSC-based technology that, upon reprogramming of patient somatic cells (e.g., skin cells) into iPSCs, subsequently transdifferentiates expanded iPSCs into folliculogenesis cells. This technology was adapted from findings at the Terskikh laboratory that elucidated the molecular and cellular mechanisms underlying self-renewing and differentiation and led to the discovery of a process that converts human iPSCs into DP cells [

7.

  • Pinto A.
  • Terskikh A.V.
The rise of induced pluripotent stem cell approach to hair restoration.

].

Finally, a Silicon Valley biotech startup, dNovo, has developed an approach that directly reprograms (i.e., skips the pluripotency induction step) fat or blood cells collected from patients into hair stem cells that can be injected into the scalp.

Numerous biotechs but few strategies

Despite the number of emergent biotech companies fully committed to developing an efficient therapy for AGA, all the approaches are based on two concepts: (i) to attenuate the effect of androgens on HF miniaturization or (ii) to use DP (or induced DP-like cells) to rejuvenate/regenerate HFs.

For those seeking the ultimate hair loss cure, innovative reversive strategies (i.e., that restart hair growth) are still missing. Where is the field now? Cellular reprogramming approaches are becoming increasingly promising, but this methodology is at an immature stage and has safety and delivery concerns. HF bioengineering (functional HFs lab-grown by tissue engineering methodologies) has significantly advanced in recent years, but its applicability is far from being clinically and aesthetically appealing. The architectural and functional complexity of this miniorgan makes it considerably more difficult to reconstruct than other larger organs. Findings from animal models have been encouraging [

8.

  • Takagi R.
  • et al.
Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model.

,

9.

  • Kageyama T.
  • et al.
Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction.

,

10.

  • Abaci H.E.
  • et al.
Tissue engineering of human hair follicles using a biomimetic developmental approach.

], but human specificities have constrained its translation to clinical practice [

11.

  • Castro A.R.
  • et al.
The emergent power of human cellular vs mouse models in translational hair research.

].

Concluding remarks

Nowadays, faster time-to-market pharmacological approaches will primarily fulfill the growing needs of the AGA market. To maximize market share, biotech companies might opt to codevelop both faster drug-based and slower cell-based therapies.

Importantly, direct-to-consumer (DTC) medical treatment is the market trend nowadays, and hair loss stakeholders should take it into account. Patients with AGA seek more convenient and more cost-effective preventive self-screening and self-treatment solutions, and this will impact the development of new hair loss therapies. Although more complex therapeutic solutions may require a business-to-consumer strategy, where patients with AGA visit clinical centers regularly to be monitored by a multidisciplinary team (clinicians and biomedical engineers), DTC therapies will nevertheless continue to answer the increasing demand for self-service and healthcare consumerism.

Because epigenetic alterations are major determinants of postnatal phenotypes, we envision that cellular reprogramming toward the native scalp trichogenic signaling holds the key to hair loss cure. Chemical reprogramming of human somatic cells to pluripotency was recently disclosed [

12.

  • Guan J.
  • et al.
Chemical reprogramming of human somatic cells to pluripotent stem cells.

], and other drug-based therapies resetting the HF epigenome might arise in the future. Noteworthy, the age of digitalization has triggered data mining and machine learning for human therapeutic purposes. Digital biotech companies (e.g., Life Code) streamlining genomics, metabolomics, and epigenomics data might well disclose unanticipated therapeutic targets and potential solutions for the hair loss.

In summary, new therapeutic solutions will continuously emerge in the future to thrive in the fast-paced AGA market, but a definitive cure for AGA in coming years may be delayed by the typical gap between new discoveries and their successful clinical application, unless an unscheduled therapeutic approach arises.

Acknowledgments

This work was supported by FEDER (Fundo Europeu de Desenvolvimento Regional) funds through COMPETE 2020 (POCI; Programa Operacional Competividade e Internacionalização) and Portugal 2020 in the framework of the project 70201-SI I&DT EMPRESAS EM COPROMOÇÃO. E.L. was supported by CEECIND/00654/2020 grant from FCT – Fundação para a Ciência e a Tecnologia, I.P.

Declaration of interests

A.R.C. is a research assistant at Saúde Viável. E.L. is scientific advisor/consultant for Saúde Viável, which provides clinical treatments for hair loss. C.P. is the Chief Clinical Officer at Insparya Hair Center.

Resources

References

    • Jablonski N.G.

    The naked truth.

    Sci. Am. 2010; 302: 42-49

    • Agaoglu E.
    • et al.

    Prevalence of early-onset androgenetic alopecia and its relationship with lifestyle and dietary habits.

    Ital. J. Dermatol. Venerol. 2021; 156: 675-680

  1. Hair restoration surgery: Challenges and solutions.

    Clin. Cosmet. Investig. Dermatol. 2015; 8: 361-370

    • Whiting D.A.

    Male pattern hair loss: Current understanding.

    Int. J. Dermatol. 1998; 37: 561-566

    • Ryu J.Y.
    • et al.

    Ultrasound-activated particles as CRISPR/Cas9 delivery system for androgenic alopecia therapy.

    Biomaterials. 2020; 232119736

  2. Effective and economical cell therapy for hair regeneration.

    Biomed. Pharmacother. 2022; 157113988

    • Pinto A.
    • Terskikh A.V.

    The rise of induced pluripotent stem cell approach to hair restoration.

    Plast. Reconstr. Surg. 2021; 148: 39S-46S

    • Takagi R.
    • et al.

    Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model.

    Sci. Adv. 2016; 2e1500887

    • Kageyama T.
    • et al.

    Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction.

    Sci. Adv. 2022; 8: eadd4603

    • Abaci H.E.
    • et al.

    Tissue engineering of human hair follicles using a biomimetic developmental approach.

    Nat. Commun. 2018; 9: 5301

    • Castro A.R.
    • et al.

    The emergent power of human cellular vs mouse models in translational hair research.

    Stem Cells Transl. Med. 2022; 11: 1021-1028

    • Guan J.
    • et al.

    Chemical reprogramming of human somatic cells to pluripotent stem cells.

    Nature. 2022; 605: 325-331

    • Johnstone M.A.

    Hypertrichosis and increased pigmentation of eyelashes and adjacent hair in the region of the ipsilateral eyelids of patients treated with unilateral topical latanoprost.

    Am J. Ophthalmol. 1997; 124: 544-547

    • Foitzik K.
    • et al.

    Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.

    Am. J. Pathol. 2003; 162: 1611-1621

    • Foitzik K.
    • et al.

    Human scalp hair follicles are both a target and a source of prolactin, which serves as an autocrine and/or paracrine promoter of apoptosis-driven hair follicle regression.

    Am. J. Pathol. 2006; 168: 748-756

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