會場分享—生發黑科技 Report from Conference - Latest Baldness Research

This article is written in Chinese and English.

6月底在Ledge安排下為兩家生物科技公司作了幾場投資洽談會的口譯，其中一家就是在脫髮界已經小有名氣且被寄予厚望的Replicel。今天就來聊聊這個領域的最新進展。（說多了都是淚！）

In June, I was assigned the task to interpret for the investment sessions of a Canadian biological company whose hair loss product is highly expected – Replicel.  This article is aboutthe latest advancement in this field. (Why I bother to talk about it? You guess!)

據說，亞里斯多德曾經注意到太監不會禿頭，因為太監已經過渡到女性的狀態。亞里斯多德的這個觀察在一定程度上也得到了現代醫學的佐證。過去幾十年來，醫學界一個較為成熟的理論是雄性激素在禿頭（脫髮）的過程中起到了非常關鍵的作用。90%的脫髮問題都是雄性激素脫髮（androgenetic alopecia）所引起。當然我們現在知道，女性同樣深受脫髮的困擾。本人就多年來飽受脫髮折磨。（可以想見當時接到這個會口任務的我有多興奮！）脫髮界這幾年的發展，可以說是exciting。多種圍繞新發現開發的新藥物和設備已進經入2期甚至3期臨床試驗，極有可能在接下來幾年面世，也極有可能扭轉脫髮治療領域不盡如人意的局面。

 

真的找不到比脫髮更具有普遍困擾性的問題了。據可靠數據，在亞洲，脫髮發生率高達73%（！！！）（Characteristicsof Androgenetic Alopecia in Asian, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412231/）。哈佛的一篇文章表示有三分之一的女性在人生中的某個時段經歷過脫髮困擾。隨之而來的當然就是大市場了（30多億美元的市場，並且大部分都打水漂了。）（ISHRS 2015 Report,http://www.ishrs.org/）工作那天在會議開始前，我與Replicel的CEO Lee Buckler 溝通的時候向他表達了我的脫髮困擾和對產品的期待，他說道，AGA在亞洲女性群體中尤為嚴重，且比例在上升（這一點我沒有找到數據支撐）。我個人在留意到自己的脫髮問題後，在大街上對女性的頭髮就尤其敏感。我在英國確實沒有看到過女性頭髮稀疏的現象。但在香港和上海的街道和地鐵上都多次看到40+以上的女性頭頂頭髮稀疏，甚至頭皮裸露。（含淚敲完這一段）

 

這些數據乍一看有點駭人聽聞。男性的脫髮問題顯而易見，無須贅述，男性在青春期以後就該好好護理頭髮。女性出現這個問題的年齡要遲很多。這裡要注意的是，雄性脫髮是一個進展性的過程，可能從你某個年齡段開始，頭頂的頭髮開始稀疏，但在很長一段時間你都不會留意到，直到幾年以後，或是中老年以後，你會注意到有頭皮的裸露。（經常埋怨自己掉發多的女性要注意了）。

 

人生已經如此艱難，為什麼還會有雄性脫髮這個問題？

 

人的頭髮從生長到脫落經歷了一個三階段的完整周期。首先是頭發生長初期（anagen），在正常情況下，這一階段會持續長達3 年，頭髮可以長到1m多長，毛幹（hair shaft）厚實。終毛，接著毛囊進入頭發生長中期／退行期（catagen），這個階段通常持續3周，細胞分解。最後是頭發生長休止期（telogen），這個階段持續幾個月，毛囊進入了休眠狀態，頭髮停止生長。隨後再進入頭發生長初期，如此循環。其實脫髮是正常現象，比如有70個毛但是在雄性激素脫髮的症狀中，毛囊過早結束了頭發生長初期，這一階段只持續了幾周甚至幾天，毛囊縮小，毛幹也變得微小脆弱，頭髮脫落。毛囊不斷縮小，直至休眠，不再長出新頭髮，這個過程稱為毛囊萎縮（follicle miniturization）。

© DermNet New Zealand.

http://creativecommons.org/licenses/by-nc-nd/3.0/nz/

醫學界的一個主流理論是睪酮（一種男性荷爾蒙）在2型5α還原酶（5-α reductase 2）的作用下產生二氫睪酮（DHT），而有些人的基因對這種雄性荷爾蒙太過敏感。DHT激活了毛囊的雄激素受體（androgen receptor），這一受體的激活減少了細胞的生長活動，導致毛囊萎縮死亡，引起脫髮。在惟二獲得FDA批准的藥物中，非那雄胺（finasteride）正是通過抑制2型5α還原酶治療脫髮。（另一獲批的藥米諾第爾（minoxidil）的作用機理尚不明確）。

近年來，以賓夕法尼亞大學教授Dr. George Cotsarelis等為主的醫學家孜孜不倦的研究下，人類對雄性脫髮的認識又有了重大的突破。

 

首先，科學家在毛囊中發現了幹細胞，幹細胞存在於隆突部分。賓大的團隊發現男性禿髮區的幹細胞數量相比頭髮區的幹細胞（stem cell）數量並沒有減少。毛囊並沒有死亡，它們只是沉睡了。但是這些幹細胞沒能生成祖細胞，因為他們發現增殖能力比幹細胞強的祖細胞（progenitor cell）數量在禿頭區大大減少。也就是說，存在一種抑制因子阻止毛囊生長，或者缺乏某種激活因子來喚醒沉睡的毛囊。

 

更為重大的發現是，在對男性禿頭區和頭髮區進行基因表達分析之後發現，一種稱為「前列腺素D2（PGD2）」（prostaglandin D2）的脂質在禿髮區的表達大大上升。它極有可能是抑制頭發生長的禍害（之一）。

 

2012年，Dr. George Cotsarelis和他的團隊在Science Translational Medicine期刊第126期發表了一篇題為《前列腺素D2抑制頭發生長，其表達在男性雄性禿頭患者中的禿髮頭皮區大大上升》（Prostaglandin D2 Inhibits Hair Growth and IsElevated in Bald Scalp of Men with Androgenetic Alopecia）的論文，這是繼發現DHT這一雄性禿髮的誘因後，醫學界對雄性禿髮認知的一個重大突破。

 

PGD2是眾多前列腺素中的一種，它是由前列腺素H2通過前列腺素D合酶PTGDS（prostaglandin D2 synthase）轉化而成。通過對男性雄性禿髮患者的禿髮頭皮和非禿髮頭皮內的不同基因表達的對比檢測，科學家發現在禿髮頭皮中，PTGDS合酶和PGD2水平都大大增加（PGD2在禿髮頭皮中的水平高大約3倍）。另外，PGD2的非酶產物15-dPGJ2的水平也在禿髮頭皮中增加。科學家還在對老鼠進行實驗分析後發現前列腺素D合酶PTGDS在頭發生長初期（anagen）的後期達到頂峰，此後毛囊開始衰退，它的酶產物PGD2則是在頭發生長中止期（catagen）達到頂峰。

 

PGD2有兩種受體——PTGDR(DP-1) 和GPR44(DP-2)，為了確定PGD2是通過哪種受體作用於毛囊，科學家對老鼠進行了敲除實驗。實驗中發現敲除了GPR44的老鼠能夠抵抗PGD2的抑制作用，由此確定PGD2是通過GPR44受體抑制頭發生長。自此，GPR44成為了雄性禿髮的一個新的治療耙點。

幸運的是，在此之前，GPR44已經被認為是導致過敏性鼻炎（allergicrhinitis）和哮喘的因素，因此已經有製藥公司開發了幾種GPR44抑制劑，並且進行了臨床試驗。只是這些藥物因為沒有療效而被放棄了，但是已經積累了大量的安全性數據，所以撿起來容易。

 

其中一個很有市場前景的在研藥叫Setipiprant。它是一種口服藥片。它的另一個優勢是，它不會抑制雄性激素，因為非那雄胺的一大副作用就是造成男性性功能障礙。Kythera已經在2015年買下了這個藥，並且買下了賓大的幾個相關專利，Kythera後來又被Allergan收購。目前，ClinicalTrials.gov網站顯示，該藥已經在美國進入2A期臨床試驗（https://clinicaltrials.gov/ct2/show/NCT02781311）。預計在2018年前完成。很快就能看到這個藥物在男性雄性禿髮患者身上的療效。

©Kythera        Source: Kythera shareholder presentation

Aristotlenoticed that eunuchs don’t go bald, because of their transition into female.Aristotle’s observation is validated to a certain extent by modern medicine. An established theory on the pathology of hair loss or baldness is that androgen(male hormone) plays a pivotal role in this process. Most of the baldness isrelated to androgenetic alopecia (AGA). But now we know that females are alsovictimized to AGA, such as me. You can imagine how I feel excited when I wasassigned the task. The past decade has seen what could be described as excitingprogress. There are dozens of pharmaceuticals and devices in pipeline that arebased on the newest findings, and are highly promising to be game-changers inthis unsatisfactory market.

 

You really cannot find a more commonly disturbing problem than hair loss. It is reportedthat the incidence among Asian men and women is up to 73%. （Characteristics of Androgenetic Alopecia in Asian, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412231/). And an article from Harvard tells us that one third of females have such experience at some time in their lives. Acommon problem brings a vast market, 3+ billion dollars at stake, with ineffective treatments. (ISHRS 2015 Report,http://www.ishrs.org/ ).  Before the meeting began on that day, I expressed my own concern and my expectation to the product to Lee Buckler, CEO of Replicel, who told me that Asian women are particularly and increasingly predisposedto AGA (I haven’t found the data to support this statement yet). Since I’m particularly sensitive to hair health of women, I haven’t observed hairthinning  conditions among English womenwhile I’m on the British streets. But I do spot women with hair loss (with barenaked scalp) on repeated occasions in HK and Shanghai subways. (with tears and fears!!!)

 

These data may seem a little bit appalling to you. While AGA is conspicuous among men (as early as right after puberty), its onset on women occurs at much later age. Worth noticing is that, AGA is a progressive process, you might start shedding hairs from a certain age but you won’t realize the severity of it until several years lateror after middle age when you spot naked scalp or gaps. I myself fits into this category. (Ladies who complain about shedding large volume of hairs every day should take it seriously.)

 

So how doesthis AGA come to mess up with our already arduous human lives?

Our hair follicles will go through repeated cycles of three phases. The first stage is called anagen, or growth stage, which would last up to 3 years in normalconditions. The hair can grow as long as 1m with thick hair shaft. Then the hair follicle enters into catagen (cessation phase) for about 3 weeks, during which time, the cells degenerate. The last phase is telogen (quiescence phase)which could last for several months, during which time the hair follicles are dormant and the hairs stop growing. Then the follicles re-enter anagen. The cycle will repeat. However, the tricky problem is that with AGA, the anagen ends much earlier than it should, lasting for only few weeks even few days. The result is that the hair follicles gradually miniaturize, the hair shafts are getting thinner and finer and the hair falls. The miniaturized follicles stopgrowing new hairs.

 

An established theory is that some people are genetically susceptible to a male hormone called dihydrotestosterone (DHT) (a male hormone), which is converted from testosterone (another male hormone) with the catalyst of 5-α reductase 2. DHT initiates the androgen receptor in the follicles, the cell growth activities are reduced, causing the hair follicles to miniaturize. Finasteride,one of the only two drugs treating this syndrome, inhibits 5-α reductase 2. (The biological mechanism for the other one, Minoxidil is unknown.) (Theefficacy for hair loss of these two pharmaceuticals are discovered serendipitously.)

 

The medical community, led by Dr. George Cotsarelis from Pennsylvania University has made huge breakthroughs inunderstanding the pathology of AGA.

 

The scientists discovered that the number of stem cells in the bald areas, which resides in the bulge area of the hair follicle is not much less than in the non-bald areas. Meaning that the hair follicles are not dead, they are just dormant. However, these stem cells fail to produce progenitor cells, because they discover that the number of progenitor cells, which have higher capacity of proliferation is largely reduced in the bald areas. There must be either apresence of inhibitor, supressing the growth of hair follicles, or a lack ofgrowth factor to activate the hair follicles.

 

This research has revealed another piece of the puzzle. The expression of a lipid called Prostaglandin D2 (PGD2) is highly elevated in the bald areas. It is highly likely that PGD2 is (one of )the culprits inhibiting the hair growth.

 

In 2012, Dr. George Cotsarelis and his team announced that they have discovered aninhibitor PGD2 in the paper published in Science Translational Medicine (Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Menwith Androgenetic Alopecia), marking a new breakthrough human made in AGA research after the discovery of DHT.

 

PGD2 is converted from Prostaglandin H2 (PGH2) with the catalyst of prostaglandin D2 synthase (Ptgds). Through the comparison and test of the expression levels ofdifferent genes in the bald scalp and haired scalp in male AGA patients, the scientists found that the level of PTGDS and PGD2 are largely increased (3 times higher for PGD2) in the bald scalp. In the mouse experiment, the scientists also found that Ptgds is at the highest in the late anagen phase and the follicles begin to decay from the point and its enzyme product PGD2 is atthe vertex in catagen.

 

There are two receptors for PGD2 – PTGDR (DP-1) and GPR44 (DP-2). Through knock out experiment on the mice, it is discovered that mice with GPR44 knockout are able to resist the inhibitory effect of PGD2, leading to the conclusion that PGD2 block hair growth through GPR44. GPR44 becomes a new treatment target.

 

GPR44 has already been identified to be the culprit behind allergic rhinitis and asthma. GPR44 inhibitor are already in pipeline. But because of the lack of efficacy, someare abandoned. Now it is easy to pick up these drugs for new direction since there already have clinical data on safety.

 

One most promising drug in pipeline is called Setipiprant. It is an oral pill. And Setipiprant does not supress male hormone (unlike finasteride, causing sexual dysfunction in its side effect.) Kythera, which is acquired by Allergen, snaps upthe rights to Setipiprant in 2015. The drug is now on 2A clinical trial phase (for more information, see https://clinicaltrials.gov/ct2/show/NCT02781311 ). It will not be long before themarket validates its efficacy on male AGA patients.

 

Reference:

1.    ProstaglandinD2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with AndrogeneticAlopecia, George Cotsarelis et al.

2.    Doesprostaglandin D2 hold the cure to male pattern baldness? Ashley Nieves and LuisA. Garza

3.    IsProstaglandin D2 (PGD2) the Key to Curing Hair Loss? https://tophairlosstreatments.com/prostaglandin-d2-pgd2-key-curing-hair-loss/

4.    UltimateGuide to Hair Regeneration

http://www.folliclethought.com/ultimate-guide-to-hair-regeneration/

5.    ClinicalTrials.gov

https://clinicaltrials.gov/ct2/show/NCT02781311

6.    Lateston Setipiprant

https://tophairlosstreatments.com/latest-on-setipiprant/

7.    ProstaglandinD2: Miracle Hair Loss Discovery… Or Just Another Sign of Inflammation?

https://perfecthairhealth.com/prostaglandin-d2-miracle-hair-loss-discovery-or-just-another-sign-of-inflammation/

8.    StemCell Baldness Cures

http://stemcellbaldnesscures.com/grow-hair-2/grow-hair-faster-with-growth-factor-serums/

9.    KytheraShareholder Presentation

http://files.shareholder.com/downloads/AMDA-MFNLA/3961447985x0x808462/68E997C5-DA72-40B4-8BD5-9DFD765BFA2E/KYTHERA%20Investor%20Deck%209FEB15[1].pdf

10. http://www.folliclethought.com/ultimate-guide-to-hair-regeneration/