What Is SM04554 and Does it Help with Hair Loss?

This post will introduce you to a possible new hair loss treatment, SM04554. This will include a thorough explanation of the drug’s mechanism of action, as well as an in-depth look at all the available clinical data.

It will also give you the latest updates on the status of SM04554 in the research timeline.

Note: As of 2021, Biosplice has stopped developing SM04554:

“Biosplice is not pursuing further independent development of SM04554 for androgenetic alopecia and is evaluating global out-licensing opportunities for further development and commercialization of this program.”

What Is SM04554 (Dalorsivat)?

SM04554 is an experimental drug (not approved by the FDA) that has completed clinical testing. It was developed by Samumed, a biotechnology company based in San Diego, California.

Samumed have now changed their name to Biosplice Therapeutics (1). The company also renamed SM04554 to Dalosirvat. Since most people know it as SM04554, this is what we will call it throughout this article.

How Does It Work?

SM04554 is a so-called Wnt activator. This means it modulates the Wnt pathway.

In simplest terms, the Wnt pathway is a group of protein pathways that pass signals into a cell through cell surface receptors. It is an ancient signaling pathway that goes back hundreds of millions of years in evolution.

The Wnt pathway plays a crucial role in cell growth and migration and is key for the development of embryos. It is also involved in wound healing and recovery from injuries.

What does this have to do with hair?

In the initial trial, researchers claimed three major things about Wnt signaling and its effects on hair growth.

1. Wnt signaling initiates and maintains the anagen phase of the hair cycle (2).
2. Wnt pathway activation induces endogenous dermal progenitor cells to differentiate into a hair bulge, leading to the formation of new hair follicles (3).
3. Reduction of Wnt pathway signaling is associated with hairline recession in AGA.

Let’s take a closer look at these claims.

Increases Hair Follicle Proliferation

As male-pattern baldness progresses, hair miniaturization takes place. The hair follicles progressively become smaller, to the point they can no longer produce hair. Eventually, the follicles die out completely.

According to developers of SM04554, the drug stimulates hair follicle regeneration through the modulation of the Wnt pathway. When properly manipulated, this pathway can trigger a repair-and-replenish response.

In the case of hair follicles, this would mean the repair of damaged follicles, and the replenishment of nutrients, oxygen, and blood flow. This would then trigger healthy hair regrowth.

Now that you have a better understanding of the science behind SM04554’s mechanism of action, we can more fully dig into the clinical trial data. But first, let’s outline the steps that drugs like SM04554 must take before they can enter the market.

The FDA Approval Process

Before a drug can enter the market, it must go through a rigorous approval process. This process is controlled by the Food and Drug Administration, or FDA (4).

The goal of the approval process? To ensure the safety and efficacy of prescription and over-the-counter drugs on the market.

There are three phases as part of the FDA approval process:

• Phase 1 trials are concerned with safety and dosage. They are performed on a small group of healthy participants.
• Phase 2 trials are concerned with efficacy and side effects. These trials are with individuals who suffer from the condition.
• Phase 3 trials are concerned with efficacy and long-term monitoring of adverse effects. These trials are on a larger pool of participants and for a longer period (often one to four years). They also often compare the new drug against already existing drugs.

SM04554 has now completed all three of these phases.

SM04554 Phase 1 Results

In the first study, the focus was on the safety and efficacy of the SM04554 topical treatment (5).

There were 29 male patients with AGA (ranging on the Norwood-Hamilton Classification scale from a 4 to a 7), split into four groups.

The first group received a topical application of a vehicle, while groups two, three, and four, received SM04554 in 0.05%, 0.15%, or 0.45% strengths, respectively.

In all groups, a topical application was once daily for 14 days,  followed by an additional 28 days to ensure safety.

Throughout the study, 11 (38%) of the subjects reported 15 adverse events (AEs). However, four such events were reported by those in the vehicle group.

The investigators determined that only 1 event (eye irritation) was related to SM04554, and that was in the 0.45% group. Aside from the said event, all ECGs, labs, and vital signs were unremarkable and no changes from baseline were reported.

Further, researchers assessed the scalps of participants to ensure that no adverse reactions were taking place. Again, there were no safety concerns.

SM04554 Phase 2 Results (Part 1)

This was a slightly larger study that also looked at efficacy (6). There were 49 subjects, with a score of 4 to 6 on the Norwood-Hamilton scale. They were split into three groups (0.15%, 0.25%, and vehicle). The study lasted 90 days, and subjects were followed for an additional 51 days.

Throughout the study, researchers tracked a number of parameters. These included total follicle count, vellus follicle count, terminal follicle count, and total anagen follicle count.

In terms of total follicle count, both SM04554 solutions saw significant results over the vehicle group. The group receiving 0.25% did see results more favorable than the 0.15% group at Day 91, however, the results evened out between the two treatment groups by Day 135.

While total follicle count is important, it doesn’t give us the entire picture. That’s where vellus, terminal, and anagen follicle counts come in.

Vellus hairs are shorter and lighter than terminal hair and can occur before terminal hair growth. You can see below that both treatment groups gave more vellus hair follicles over the vehicle group:

In addition to vellus hairs, however, the drug gave more terminal hairs compared to vehicle. Surprisingly, it was the lower dose solution that was superior to vehicle, not the stronger one:

Last is the number of hair follicles in the anagen phase. Those in the vehicle group saw a decrease in anagen phase hair follicles throughout the 135-day study.

However, subjects receiving both the 0.15% solution and the 0.25% solution maintained their anagen phase hair follicles. In fact, by the end of the study, both solutions were almost identical in terms of results.

While the above results are a great starting point, they don’t give the drug justice. That’s why Samumed next performed a larger-scale study to better understand the results that researchers were seeing.

SM04554 Phase 2 Results (Part 2)

This study consisted of about 300 men, ranging from a 4 to a 6 on the Norwood-Hamilton scale (7). The subjects were split into three groups (placebo, 0.15% SM04554 solution, and 0.25% SM04554 solution).

Treatment lasted 90 days total. Clinical and imaging outcomes took place at baseline, day 45, day 90, and day 135. Additionally, the researchers took scalp assessments throughout the trial.

Of course, researchers expected SM04554 to improve hair count and density better than the control treatment. And it did just that:

Surprisingly, the lower dosage (0.15%) performed better than the 0.25% solution. You can see this in the two graphs below.

These results were not very encouraging. They showed that the efficacy of the drug plateaued at relatively low strength. Also, the regrowth was not particularly impressive. Nevertheless, Samumed went on to phase 3 research. Before we get to those, let’s review the drug’s side effects and quickly compare it to the other drugs currently on the market.

Side Effects

As mentioned above, there were a few side effects experienced by subjects and they were non-serious. Almost all of them cleared up within a matter of days, and none were enough to make subjects quit the study.

In the second trial, 29 subjects experienced a total of 48 adverse effects. 18 of these occurred in the vehicle group and, therefore, are not related to the studied drug.

The most common were redness, burning, or stinging at the site of application. On a severity scale of 1-5, most were a 1 or 2.

How Does It Compare to Finasteride and Minoxidil?

As of this writing, finasteride and minoxidil are the only FDA-approved hair loss treatment drugs on the market.

How exactly do these three drugs compare, and does SM04554 stand a chance against them?

First and foremost, it’s important to point out that each of these drugs tackles hair loss differently.

• Finasteride works by inhibiting the enzyme 5-alpha-reductase and, therefore, inhibiting the conversion of testosterone to DHT (8).
• Minoxidil works by dilating the blood vessels in the scalp. This results in increased blood flow to the area (9).
• SM04554 works at the Wnt pathway.

The published results of SM04554 that we just reviewed are not very impressive. In terms of regrowth, it appears to be no better than either finasteride or minoxidil. Very likely the regrowth is weaker.

2021 Update: SM04554 Phase Three Trial Complete

On November 15, 2018, Samumed — the company behind SM04554 — began to recruit participants for its Phase 3 trial (10).

The trial consisted of 625 participants with Androgenetic Alopecia.

According to the official trial listing on ClinicalTrials.gov, the trial was completed in January 2021 (10).

Unfortunately, Biosplice Therapeutics did not publicize the results. This is generally a bad sign that suggests poor results. When the findings of a clinical trial are positive, the companies that bring them to market are generally quick to publicize them through press releases.

2021 Update: Bioscplice Stops Developing SM04554

To confirm these suspicions, in the first part of 2021 Biosplice removed Dalosirvat from their product pipeline page (11). In reply to an email inquiry from a member of the public, Biosplice reportedly sent the following reply:

“Biosplice is not pursuing further independent development of SM04554 for androgenetic alopecia and is evaluating global out-licensing opportunities for further development and commercialization of this program.”

What this means is that the Phase 3 trial was a disappointment, and there is no possibility for SM04554 to get FDA marketing approval. Biosplice will only sell the rights to another company. They will not spend any more money researching this product.

Having said that, the likelihood of another company wanting to purchase and develop the rights after the disappointing phase 3 results are close to zero. This means that we will almost certainly never see SM04554 on the market.

Closing Thoughts

SM04554 is the latest drug to join the long list of once-promising medications that failed to deliver. The Wnt pathway has been researched as a possible key to a wide range of conditions. These range from psychiatric disorders to cancer, fibrosis, and neurodegenerative conditions.

It is no surprise, then, that drug manufacturers also looked at its potential as a possible site for hair loss interventions. As history now showed, this was not to be. The unpublished phase 3 results were almost certainly a disappointment, and the company behind SM04554 has now pulled the plug on the project.

This latest development leaves clascoterone as the undisputed front-runner to gain FDA approval and become the next drug against male pattern hair loss. Aside from that, there is currently no other drug that will hit the market anytime soon.