Tall midwit
Iron
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DENIFANSTAT
Acne has four main causes, or pathogenic factors: increased sebum production, abnormal skin shedding, bacterial activity, and inflammation. Increased sebum production is often considered one of the earliest and most important contributors to acne.
Historically, most acne treatments have focused on skin shedding, inflammation, or bacteria. The problem has always been that sebum production is one of the most important parts of acne pathogenesis, yet most medications do not directly target it. This is why Accutane has remained the ultimate acne weapon, as it is essentially the only acne medication that dramatically reduces sebum production. Now, a new drug is emerging as a promising potential alternative to Accutane, particularly given Accutane’s side effects and limited accessibility for many patients.
Historically, most acne treatments have focused on skin shedding, inflammation, or bacteria. The problem has always been that sebum production is one of the most important parts of acne pathogenesis, yet most medications do not directly target it. This is why Accutane has remained the ultimate acne weapon, as it is essentially the only acne medication that dramatically reduces sebum production. Now, a new drug is emerging as a promising potential alternative to Accutane, particularly given Accutane’s side effects and limited accessibility for many patients.
Denifanstat, also known as ASC40 in China, is an experimental once-daily oral drug originally developed by Sagimet Biosciences and licensed to Ascletis Pharma for development in Greater China. It treats acne through a completely different mechanism. Now what's interesting is that it's not a retinoid but works through a different mechanism as it decreases sebum production by inhibiting fatty acid synthase, or FASN.
The sebaceous glands, the structures responsible for oil production contain cells called sebocytes, which manufacture sebum, the oily substance found on the skin. These cells do not obtain all their fatty acids directly from food or the bloodstream. Instead, they manufacture new fatty acids through a process called de novo lipogenesis.
This process uses an enzyme called fatty acid synthase, or FASN, which converts smaller molecules into fatty acids. Denifanstat selectively inhibits FASN. By slowing this internal fat-production system, it decreases the production of sebum lipids and may also suppress inflammatory signaling within sebocytes, thereby reducing acne.
The sebaceous glands, the structures responsible for oil production contain cells called sebocytes, which manufacture sebum, the oily substance found on the skin. These cells do not obtain all their fatty acids directly from food or the bloodstream. Instead, they manufacture new fatty acids through a process called de novo lipogenesis.
This process uses an enzyme called fatty acid synthase, or FASN, which converts smaller molecules into fatty acids. Denifanstat selectively inhibits FASN. By slowing this internal fat-production system, it decreases the production of sebum lipids and may also suppress inflammatory signaling within sebocytes, thereby reducing acne.
How does this differ from isotretinoin, or Accutane?
Isotretinoin is a retinoid derived from vitamin A. It broadly changes gene activity within the sebaceous glands, substantially reduces their size and activity, and also targets the other components of acne pathogenesis, including abnormal skin shedding, inflammation, and bacteria, although its antibacterial effects are indirect.
What we can take from this is that the low relapse rate associated with isotretinoin most be likely won't occur with denifanstat, given its different mechanism of action.
Isotretinoin is a retinoid derived from vitamin A. It broadly changes gene activity within the sebaceous glands, substantially reduces their size and activity, and also targets the other components of acne pathogenesis, including abnormal skin shedding, inflammation, and bacteria, although its antibacterial effects are indirect.
What we can take from this is that the low relapse rate associated with isotretinoin most be likely won't occur with denifanstat, given its different mechanism of action.
I predict that many dermatologists may eventually prescribe a combination of topical tretinoin and denifanstat. Hypothetically, combining denifanstat with a topical retinoid could target all four major components of acne pathogenesis and potentially provide effectiveness approaching that of isotretinoin, but with fewer side effects and given Accutanes demonization in dermatology and the reluctance of most derms to prescribe it this might eventually make this the new standard.
Clinical-trial results
In a Chinese Phase III trial, 480 people with moderate-to-severe acne received either 50 mg of denifanstat or a placebo once daily for 12 weeks.
By week 12:
In a Chinese Phase III trial, 480 people with moderate-to-severe acne received either 50 mg of denifanstat or a placebo once daily for 12 weeks.
By week 12:
- 33.2% of patients receiving denifanstat were rated clear or almost clear, with at least a two-grade improvement, compared with 14.6% of those receiving placebo.
- Total lesion counts decreased by 57.4%, compared with 35.4% in the placebo group.
- Inflammatory lesion counts decreased by 63.5%, compared with 43.2% in the placebo group.
- Non-inflammatory lesion counts decreased by 51.9%, compared with 28.9% in the placebo group.
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