Is the end near for Minoxidil era?

Medical treatment of Androgenic alopecia has been dominated by two drugs Minoxidil and Finasteride. Treatment with finasteride and minoxidil should be life-long as its interruption is followed by gradual hair loss, with return to the pre-treatment status within 1 year. Though Minoxidil and Finasteride are effective in only about 40% of the patients increasing concentration to achieve results can be disastrous. Minoxidil has compliance issues when used in higher concentration of 5% and 10% with majority experiencing scalp dryness, erythema, dermatitis, headache and potential cardiac symptoms. Finasteride has its own set of potential side effects like Erectile dysfunction, loss of libido gynecomastia etc. Recent studies have shown that these side effects are not transient and may have lasting effect. In view of the latest evidence this could have legal implications and patients may opt out of treatment.

 

” Patients on 5 Alpha reductase inhibitors for more than 6 months, 4.5% developed Erectile dysfunction and 2% had persistent erectile dysfunction which lasted mean of 4.2 years after discontinuing the drug”

Is Prostaglandin D2 (PGD2) the Key to Curing Hair Loss?

For years, it has been widely accepted that dihydrotestosterone (DHT) is the primary cause of male pattern baldness. But in 2012, a groundbreaking medical research paper challenged this previously unchallenged theory. Although DHT does play a part, this new research claimed to have revealed the real cause of hair loss: prostaglandin D2 (PGD2).

 

University of Pennsylvania published a breakthrough study concluding that PGD2 was found in higher levels than normal on the scalp of balding men. It seems that PGD2 prevents the hair follicles from maturing.

The key findings of the study are:

  • PGD2 levels are far higher (around 3x higher) in balding scalps than non-balding scalps
  • Increasing PGD2 levels inhibits hair growth
  • Mice without the GPR44 receptor were not affected by these increased PGD2 levels – they did not lose their hair

The hypothesis from these findings is that disrupting the PGD2-GPR44 pathway will stop hair loss.

Although drugs that block PGD2 signaling or enhance PGE2 are under trial for evaluation of their eicacy and safety in AGA, other prostaglandins also have therapeutic effects. The prostaglandin F2α analogue latanoprost, and prostamide F2α analogue bimatoprost, commonly used in treating glaucoma were serendipitously discovered
to be promoters of hair growth of eyelashes and eyebrows. They result in hair growth through modulatory action on the dermal papilla that results in induction of the anagen phase in telogen hair follicles.

“Bimatoprost is the only FDA-approved topical for hypotrichosis of the eyelashes. Allergan has completed Phase 2 trials of Brimatoprost Topical 1% and 3% solutions shown promising results

Setipiprant

Is a selective oral antagonist to the PGD2 receptor.

PGD2 binds to the GPR44 receptor. When this happens, hair loss occurs.

But Setipiprant blocks PGD2 from binding to prostaglandin receptors. This should, in theory, stop hair loss from progressing. It may even reverse it.

A second benefit of Setipiprant described  is its ability to extend the anagen (growing) phase of hair follicles. Although this won’t stop androgenic alopecia from progressing further, it will have the short term effect of making hair appear thicker. What’s more, this effect could make Setipiprant an effective treatment for the prevention of telogen effluvium.

Advantages of Setipiprant over current hair loss treatments. For one, Setipiprant comes in pill form, which should make it easier to take in comparison to topical solutions such as minoxidil. And by treating hair loss from this unique PGD2 angle, it has the potential to be used in conjunction with other hair loss treatments, improving results. But perhaps the biggest advantage of Setipiprant is that is expected to have zero anti-androgenic effects.

Setipiprant is in Phase 2A clinical trials and unpublished data shows promising results.

CB0301(Breezula ), or cortexolone 17a-propionate, has anti-androgenic effects when applied to the skin.

As we know, androgenetic alopecia (male pattern hair loss) is an effect of the hormone dihydrotestosterone (DHT) on hair follicles.There are already treatments available that stop this process. Finasteride and dutasteride reduce levels of DHT in the body by approximately 70% and 90% respectively.But this isn’t an ideal solution.Ideally, a hair loss treatment would reduce the effects of DHT locally, not systemically. Rather than lowering overall DHT levels, it would be preferable to reduce its effects in the scalp only.

Rather than being ingested orally, CB0301 is a topical treatment. It’s applied to the scalp and should – in theory – negate the hair loss causing-effects of DHT. What’s more, it’s also said to reduce levels of prostaglandin D2 (PGD2).

CB0301 phase 2 trial results

Initial results from the Phase 2 trial for androgenetic alopecia show CB0301 is slightly more effective than minoxidil

Wnt Signaling

A large number of molecular signals are involved in the normal hair cycle. The activation of Wnt/b-catenin/Lef1,Sonic Hedgehog, and signal transducer and activator of transcription (STAT) 3 pathways and down-regulation of bone morphogenetic protein signaling initiate and maintain the anagen phase. Wnt pathway activation alsoinduces endogenous dermal progenitor cells to differentiateinto a hair bulge, leading to the formation of new hairfollicles . In addition, it has been demonstrated that androgens may inhibit Wnt/b-catenin signaling in AGA.

Although the factors that may stimulate and regulate follicular neogenesis are still unknown, there are a number of studies showing that drugs that can act by activating Wnt signaling may be useful.

SM04554

A small molecule—SM04554—shown to activate the Wnt pathway is currently undergoing clinical trials. In a
phase I clinical trial, this topical solution appeared to be safe, well-tolerated, and potentially efficacious.
According to a company report, in phase II trials the SM04554 topical solution (0.15 and 0.25 %) produced a
statistically significant increase for both objective outcome measures: non-vellus hair count (primary outcome measure) and hair density (secondary outcome measure)

Hair Stimulating Complex (HSC)

Hair Stimulating Complex (HSC) is a bioengineered,non-recombinant, human cell-derived formulation containing Wnt7a protein, epidermal growth factors, and follistatin. A study evaluating efficacy of HSC in patients with MAGA showed a significant increase in hair shaft thickness and terminal hair density with no relevant adverse effects. Moreover, a statistically significant increase in total hair count continued to be seen after 1 year .Phase II of this study is currently in progress with no published results available.

Hair cloning

Effective as they may be, current hair loss treatments are only really effective at preventing further balding. A lucky few may experience regrowth, but maintenance is key in the fight against hair loss. For those who’ve already lost ground, hair transplants are an option, but only a finite amount of donor hair will be available to cover balding areas. But a future hair loss treatment promises to address this problem. Hair cloning, and the similar hair multiplication, should provide an unlimited supply of new hair for hair loss sufferers. Culture-expanded follicular cells obtained through a patient’s scalp biopsy can be injected into the bald areas to stimulate hair growth.

Canada based Replicel just released 5-year safety data for “a high-dose of dermal sheath cup cells (DSCC) for patients with pattern baldness due to androgenetic alopecia”, which is basically their RCH-01 product. Since the injected cells are a patient’s own cells (i.e., autologous), the positive safety results are not surprising. According to the RepliCel TM website, results after 6 months in 19 patients showed increased proportions of vellus hair (24.9 %) and terminal hair (14.9 %), increased total hair density (19.2 %), and increased overall hair thickness per area
(15.4 %). The phase IIb trial is in progress and is analyzing different injection regimens .

 

Adipose-derived stem cells (ADSCs)

Adipose-derived stem cells (ADSCs) are a new treatment modality. Adipose tissue was found to have abundant mesenchymal stem cells that can produce growth factors, including VEGF, hepatocyte growth factor, insulin-like growth factor, and PDGF, and may be an emerging therapeutic option in AGA.

A phase II clinical trial using adipose stem cells obtained by liposuction (Kerastem Technologies, LLC,Solana Beach, CA, USA) in 70 patients with early MAGA and FAGA has recently been started.

Hair loss

 

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