Kintor Releases Phase 2 Trial Results for GT20029

Kintor Pharmaceuticals has announced that its proteolysis targeting chimera (PROTAC) drug GT20029 has reached its primary endpoint in its Phase 2 trial in China. GT20029 is a topical PROTAC targeted toward AGA. 

What are PROTACs?

PROTACs are a novel class of heterobifunctional molecules that can induce the degradation of target proteins by hijacking the cell’s ubiquitin-proteasome system. The key features of PROTACs are:

1. They are composed of two parts – a ligand that binds to the target protein of interest and a ligand that binds to an E3 ubiquitin ligase enzyme
2. The PROTAC brings the protein of interest and E3 ligase into proximity, allowing the ligase to ubiquitinate the protein of interest and mark it for degradation.
3. This process results in the rapid and selective depletion of the target protein rather than just inhibiting its activity like traditional small molecule drugs.

PROTACs offer several advantages over traditional approaches, including targeting “undruggable” proteins that lack well-defined binding pockets and the potential for a more durable pharmacological effect. PROTACs can be designed using either small molecule or peptide ligands to bind the protein of interest and E3 ligase, leading to different categories like bioPROTACs and hybrid PROTACs.

What is GT20029?

GT20029 is a PROTAC that targets androgen receptor (AR) proteins for degradation. The PROTAC platform used in GT20029 consists of three components: a recruiting element that binds to the AR protein, an E3 ubiquitin ligase recruiting element, and a linker that connects the two.  When these three come together, the process of ubiquitination effectively breaks down and degrades the protein. By degrading the AR, GT20029 can block the AR pathway, which may prevent hair follicle miniaturization and hair thinning. 

What Other Drugs Target Androgen Receptors?

There are a variety of other treatments out there that also target androgens but in different ways.

Anti-Androgen Treatments

• Pyrilutamide is a non-steroidal anti-androgen (NSAA) that blocks testosterone and DHT from binding to the AR. It does this by binding to AR receptors in the hair follicles, which prevents the effects of androgens on hair follicle miniaturization. 
• CB-03-01 is a steroidal anti-androgen,  that works similarly to pyrilutamide. It also binds to the AR in the skin, competing with the binding of androgens like DHT. 
• CosmeRNA utilizes short interfering RNA (siRNA). siRNA interferes with protein production from mRNA, which, in this case, is an androgen receptor. In CosmeRNA, the siRNA is called siRNA-AR 68. . Because it is a topical treatment, it is believed to interfere only with androgen receptor production in the specific area of the scalp to which it is applied, minimizing systemic effects associated with other AGA treatments.

Phase 2 Trial Results

This double-blind, placebo-controlled study was designed to determine the efficacy and safety of GT20029 for treating male androgenic alopecia (AGA) and the recommended dosage for a Phase 3 trial. 

Details and results of the completed trial are as follows (as reported through a press release):

• The study included 180 male patients with AGA.
• The patients were split into once-daily (“QD”) or twice-weekly (“BIW”) groups, each with its control (placebo) or dosing (0.5%/1%) group.
• Mean non-vellus target area hair count (TAHC) was measured at baseline and endline.
• The 0.5% “QD” GT20029 group showed an increase of 16.8 hairs/cm² (an increase of 6.69 hairs/cm² over the placebo), which was a statistically significant increase (P <0.05).
• The 1% “BIW” GT20029 group showed an increase of 11.94 hairs/cm² (an increase of 7.36 hairs/cm² over the placebo), which was a statistically significant increase (P<0.05).
• The topical treatment showed good safety and tolerability, with adverse events comparable to the placebo.
• Kintor has identified the 1% “BIW” dosage as the optimal dose for its Phase 3 trial in China.

Reflections

We have previously mentioned GT20029 here. While it is always encouraging to see novel treatments for AGA progress through trials and with statistically significant results, there are always questions to be answered:

1. How does this treatment stand up to existing treatments for AGA? While the results show statistically significant improvements over the placebo, it would be helpful to understand how GT20029 performs relative to the current standard of care.

2. What is the distribution of TAHC across participants in the groups? Although the results were positive, with an overall statistically significant outcome, we don’t know if these results are due to a small number of “hyper responders” or if average participants’ responses drove the results.

We look forward to seeing the results of this trial in a peer-reviewed journal. 

Do you think there are any other unanswered questions from this press release? Let us know in the comments.