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
]. But lifestyle changes and anxiety that dominate the lives of millennials and young generations have contributed to the early onset of androgenic alopecia (AGA) [
]. 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 [
]. 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
]. 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).
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.
]. 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.
,
]. 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.
]. 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.
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.
]. The advantages are no requirement for patients’ own HFs and the unlimited supply of donor DP cells.
].
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.
,
,
], but human specificities have constrained its translation to clinical practice [
].
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.
], 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
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Published online: January 18, 2023
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