Table of contents 

Compound description and mechanism of action

Literature review

Safety Profile Discussion

Compound description and mechanism of action

GT20029 is a proteolysis-targeting chimera (PROTAC) drug, a class of drugs which allow for TPD (targeted protein degradation). What GT20029 allows for in a hair loss context is a completely unique mechanism of action for stopping androgenic alopecia. GT20029 has been modified to target the androgen receptor, leading to its eventual degradation. GT20029 has been administered topically in gel form in clinical trials.

This unique mechanism of action is why GT20029 is, in my opinion, the most promising upcoming hair loss treatment. Other drugs work by inhibiting DHT to cause less DHT to bind to the AR and cause miniaturization (Finasteride, Dutasteride) whereas other drugs work by binding to the AR receptor itself also preventing DHT from binding to the AR (topical antiandrogens, Ru58841, Fluridil, CB0301). However by degrading the AR, GT20029 stops the entire process involved in DHT induced miniaturization from occurring. 

The cause of androgenic alopecia is a process where a hormone called DHT binds to the androgen receptors in the scalp, and this DHT-AR complex signals for the miniaturization of the hair follicle until it eventually stops growing. 

The way it causes AR degradation is as follows. The PROTAC molecule harnesses a system called the ubiquitin-proteasome system, to degrade a target protein (AR receptor in this case). 

The ubiquitin proteasome pathway is an essential process in your body that involves the targeted degradation of proteins that it no longer wants such as cell cycle regulatory proteins, whose degradation is vital for controlled cell division (making PROTAC drugs and treatment for cancer).

These molecules consist of two ligands and a linker. One binds to the desired degradation protein, and the other binds to an E3 Ubiquitin Ligase, causing the ubiquitylation (addition of ubiquitin to a substrate protein – marks it for degradation via proteasome) of the targeted protein. Importantly, after this process occurs the PROTAC is not degraded itself and is recycled to continue this process for other desired proteins. In simpler terms, PROTAC drugs mark desired proteins for degradation, and aren’t destroyed in this process allowing them to mark multiple desired proteins for degradation (allowing for infrequent administration).

The ability for these PROTAC molecules to be recycled has incredible therapeutic promise as classic inhibitors are limited by their one-to-one relationship with the desired protein.

For instance, when RU58841 is applied to the scalp, each molecule binds to one Androgen receptor, therefore inhibiting DHT from binding to the AR, but in order to prevent inhibition of more androgen receptors you have to introduce more RU58841 molecules, so the level of inhibition is dose dependent. That isn’t exactly the case with GT20029. Theoretically, you may only need to apply GT20029 a few times in order to get this inhibitory effect.

The unique qualities of GT20029’s mechanism of action provides many advantages to previous hair loss prevention treatments, in terms of efficacy, method of administration, and side effect profile. As a result many people involved in hair loss communities believe it to be the most promising upcoming treatment. Due to its molecular size, it is believed to be difficult to absorb into the skin when applied topically allowing it to act almost entirely on androgen receptors at the scalp. GT20029 is currently being studied and developed by Kintor Pharmaceuticals in china. 

Interestingly, the first PROTAC molecule was synthesized in 2001 but the first small-molecule PROTAC molecule was reported in 2008. Part of this PROTAC molecule includes a non-steroidal androgen receptor ligand which is a selective androgen receptor modulator (SARM). 

Literature review 

As of this moment there are no published studies on GT20029, but there are some data results about both Phase 1 and 2 trials that Kintor Pharmaceuticals has released. There is also some very difficult to find information published in google patents. 

Preclinical studies

According to one of Kintors interim result announcements GT20029 was tested to treat acne in a testosterone propionate-induced skin hamster flank organ acne model.

Looking through Google Patents, a patent titled ‘Bifunctional compound, preparation method therefor, and use thereof’, mentioned a recently invented compound named A46, so this was its initial named used.

The effectiveness of A46 (GT20029) in promoting hair growth was tested in a mouse model of androgenetic alopecia, using minoxidil as a positive control. The study found that both 1% and 3% concentrations of A46 were comparable in efficacy to 5% minoxidil, while a 0.5% concentration of A46 showed no statistically significant effect .

 

These findings suggest that, at a sufficiently high concentration, A46 (GT20029) may be as effective as minoxidil in promoting hair growth. These efficacy results are needed for pharmaceutical companies to move into human trials.

Clinical studies

In 2021, Kintor released a statement that the NMPA of china (National Medical Products Administration) has accepted its application for GT20029 to treat androgenic alopecia and acne. Later that year Kintor also released a statement that the FDA had given the IND (Investigational new drug) application clearance, allowing Phase 1 human clinical trials to commence in both China and the United States. 

The phase I trials were successful in both the U.S and China. It is important to note that Phase 1 human clinical trials are focused on the drugs safety profile and dose ranges. 

The study in China was a randomized, double-blind, placebo-controlled study involving 92 healthy subjects. Both single and multiple ascending doses were tested (using both methods help determine safety, tolerance, and potential effects before a full clinical trial). 

The results showed that GT20029 was safe and well-tolerated, with limited systemic exposure. After a single dose, no drug was detected in the blood. Then after 14 days of multiple doses, the maximum drug concentration was very low (less than 0.05 ng/mL). 

TRAE stands for treatment related adverse events and is ranked in a 5 grade system. There were no TRAE reported above grade 1 meaning GT20029 was very well tolerated.

The study in the U.S was also a randomized, double-blind, placebo-controlled study that had a parallel group design and included dose escalation, and enrolled 123 healthy subjects, including healthy individuals and those with AGA or acne (as both conditions are androgen-ar related and are treated similarly in clinical evaluations).

 

This trial also found GT20029 to be safe and well-tolerated with limited systemic exposure. In the single ascending dose stage, no drug was detected in the blood of healthy subjects. In the multiple ascending dose stage, the maximum drug concentration after 14 days was still very low (highest observed was less than 0.015 ng/mL). There were no TRAE reports above grade 2 in this study. It should be noted that as the U.S had a larger sample size it is probably more accurate in elucidating the safety profile of GT20029. 

Kintor progressed into phase II clinical trials, with results coming out in April 2024.

This multi-center, randomized, double-blind, placebo-controlled trial enrolled 180 male AGA patients across 12 clinical research centers in China. Participants were divided into QD (once daily) and BIW (bi weekly/twice a week) dosing cohorts. Each had control groups receiving a placebo and experimental groups receiving either 0.5% or 1% GT20029 tincture. 

The length of the study was 12 weeks and it assessed 

non-vellus target area hair count (TAHC).

Personally I find this to be the most accurate way of measuring haircount because Vellus hairs to be a key factor in yielding exaggerated results. Vellus hairs are thin, terminal hairs on your scalp and are basically invisible unless you are using dermatological/trichological equipment, and add no cosmetic benefit. 

The 0.5% QD GT20029 group experienced an increase of 16.80 hairs/cm² from baseline, which was 6.69 hairs/cm² more than the placebo group (P<0.05). The 1.0% BIW GT20029 group showed an increase of 11.94 hairs/cm² from baseline, exceeding the placebo group by 7.36 hairs/cm² (P<0.05). Ultimately indicating GT20029 to be efficacious. The article notes no adverse sexual events were reported, indicating if GT20029 makes it to the market it will probably be advertised to be a more tolerable compound in terms of sexual side effects compared to finasteride in order to create some product differentiation. Based on these findings for phase II it is likely that the 1% BIW dosage is optimal, and will be used in subsequent phase 3 clinical trials.

Safety profile discussion

As elucidated earlier, GT20029 works by degrading the androgen receptor, eliminating the DHT induced androgen receptor signaling that leads to the miniaturization and eventual death of the hair follicle. However this begs the question, does GT20029 go systemic when applied topically? And what kind of side effects could be expected if this was to take place?

As discussed in my article about Ru58841, this discussion of topical drugs going system is a bit more complex than how it is described. 

It is extremely hard for a compound applied topically to not have any systemic absorption, because at the end of the day the way its able to work and introduce an effect is by absorbing through the skin. Its applied topically to get the most effect at a localized area (in this case the scalp) but it is basically inevitable for an amount, however small, to be absorbed systemically.

The ability for a compound to cause systemic effects is also predicated on things such as its molecular size, binding affinity, half life, and its ic50 (Half-maximal inhibitory concentration), as well as those factors for its resultant metabolites.

The first factor to discuss when questioning GT20029’s ability to go system is its molecular size. 

As discussed before, there is very limited information about GT20029 available, however looking through the patent, the liquid chromatography-mass spectrometry (LC-MS) result is listed for A46 (the initial research name for GT20029).  

The molecular size for GT20029 is notably high at 1043.2 daltons (g/mol). 

For those familiar with the 500 dalton theory of skin absorption, this may seem to mean that it would be impossible to be absorbed when applied topically. However there are a few things to consider. Firstly the 500 dalton theory isn’t widely approved as there isn’t a huge body of evidence to support its validity, instead it’s just a guideline used by cosmetic companies. Additionally there are now enhanced delivery techniques, such as better liquid and gel carriers that allow topicals to bypass the skin barrier, and even things like humidity can affect skin absorption. With all that being said, it is clear GT20029 is absorbed through the skin because it yielded statistically significant results in its phase 1 and 2 clinical trials. Its high molecular weight is actually advantageous in this regard, it acts as a barrier for excessive absorption so the remaining molecules will act on the hair AR, and be less likely to go systemic. This is similar to how Dutasteride Mesotherapy is described to work without going systemic. Keep in mind this is far from an exact science.

The second factor to consider is GT20029’s half life, ic50, and persistence systemically. 

Not a lot of information is publically available about GT20029 but fortunately the company released some data from the clinical trials. As mentioned Phase 1 clinical trials focus more on safety data, and looking at the US group it was said that the maximum drug concentration after 14 days was still very low (highest observed was less than 0.015 ng/mL). Considering the total amount of androgen receptors, this is unlikely to affect the totality of the system and androgen receptor mediated functions (muscle mass, strength, bone density, sexual function).

 

It is not clear what the half life of GT20029 is, but due to its unique mechanism of action it doesnt need to be administered daily (confirmed from the findings in phase II), and is optimal with a bi-weekly protocol. This gives time for the drug to be metabolized or broken down by the body so by the time of the next administration there is no levels present in the bloodstream, which allows for the drug to not accumulate to any significant levels in the serum, thus not affecting the totality of androgen receptor mediated functions in the body. 

This is the reason why topical finasteride treatments don’t negate side effects, because since finasteride and dutasteride have such long half lifes, when inevitably that small amount of fin/dut goes systemic when you apply it once daily, by the next day it’s still present in your blood so when you take it that day the amount increases and eventually it accumulates systemically enough to affect DHT levels in other parts of the body (prostate etc). 

Ultimately, GT20029 is extremely promising to androgenic alopecia treatment and takes a unique step forward in the battle against Androgenic Alopecia. While no topical compound can entirely avoid systemic absorption, GT20029’s high molecular weight acts as a barrier, reducing the extent of its penetration into the bloodstream. Clinical trial data indicates that even when minimal amounts do enter circulation, their levels are extremely low and unlikely to disrupt systemic androgen functions. The bi-weekly application protocol further mitigates risks by preventing accumulation in the bloodstream.