What Is SM04554 and Does it Help with Hair Loss? (2021 Update)

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What if there was a hair growth drug on the market that not only stopped hair fall, but also regenerated hair follicles and even increased the number of hair follicles in active growth?

Well, that may very well be a possibility in the next few years.

In this post, I’m going to introduce you to a possible new hair loss treatment, SM04554. This will include a thorough explanation of the drug’s mechanism for treating alopecia, as well has an in-depth look at the current research surrounding the drug.

I’ll also provide some non-chemical options that you can use instead of SM04554 to regenerate hair follicles.

What Is SM04554?

SM04554 is an experimental drug (not yet approved by the FDA) that is currently in the midst of its third phase of testing. It was developed by Samumed, a biotechnology company based in San Diego, California, and it has undergone two trials with promising results.

How Does SM04554 Work?

The developers of this “miracle molecule” claim that the drug’s positive effects are based solely on its modulation of the Wnt pathway.

In simplest terms, the Wnt pathway is a group of protein pathways that pass signals into a cell through the use of cell surface receptors.

When information needs to be passed along, a Wnt protein attaches to the Frizzled (Fz) family receptor. This signal is then passed to the Dishevelled protein within the cell.

Now, 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.

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  1. Wnt signaling initiates and maintains the anagen phase of the hair cycle.
  2. Wnt pathway activation induces endogenous dermal progenitor cells to differentiate into a hair bulge, leading to the formation of new hair follicles.
  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.

As the hair miniaturizes (changing from terminal to vellus), so too does the hair follicle.

Eventually, the follicle becomes so small that hair can no longer be produced from it, and the follicle withers away.

According to developers of SM04554, the drug stimulates the process of hair follicle regeneration through the modulation of the Wnt pathway.

As briefly described above, this pathway acts as an information delivery system.

More specifically, however, the Wnt pathway signals for the upregulation or downregulation of progenitor cells. When properly manipulated, the activation of such cells 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.

Inhibits the DKK-1 Protein

DKK-1 is a protein involved in human embryonic development, and therefore plays a role in the development and growth of stem cells.

As part of its role, DKK-1 inhibits Wnt signaling. This occurs at several points along the pathways, and it regulates Wnt’s role.

Unfortunately, this regulation can go on to cease the development of hair follicles. This is because DKK-1 protein plays a key role in cell apoptosis.

Apoptosis is a natural process that occurs when a cell has reached the end of its natural “life”.

If cells are unable to die, this can lead to a number of health issues, including tumors and lesions.

In fact, DKK-1’s role in the regulation of Wnt signaling cannot be overstated, especially as it ensures proper cranial and forelimb development in embryos.

However, for individuals with AGA, the presence of DKK-1 can mean no possibility of hair follicle stem cell proliferation.

The main mechanism stated by SM04554 developers is its activation of Wnt pathways. In order to do this in the presence of DKK-1 proteins, it must then inactive said protein and inhibit its role in Wnt signaling.

Now that you have a better understanding of the science behind SM04554’s possible mechanism, we can more fully dig into the data provided by the performed trials. But first, let’s outline the steps which 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.

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

There are four trial phases that must occur as part of the FDA approval process:

  • Phase 1 trials are concerned with safety and dosage. They’re performed on a small group of healthy participants.
  • Phase 2 trials are concerned with efficacy and side effects. These trials are performed on individuals with the condition the drug is supposed to treat.
  • Phase 3 trials are concerned with efficacy and long-term monitoring of adverse effects. These trials are performed on a larger pool of participants, and for a longer period of time (often one to four years).
  • Phase 4 trials are concerned with safety and efficacy. These trials are performed on thousands of participants with the condition, and the goal is to further understand the safety of proposed drug use, as well as how it compares to other drugs on the market.

As we’ll see below, the manufacturer of SM04554 has completed two of the four phases. As of 2020, though, they are in the midst of phase 3 trials.

SM04554 Phase 1 Results

In the first performed trial study, the focus was on safety and efficacy of the SM04554 topical treatment.

It consisted of 29 male patients with diagnosed AGA (ranging on the Norwood-Hamilton Classification scale from a 4 to a 7) who were split into four groups.

A table showing the demographics of subjects who participated in the trial one study

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% doses, respectively.

Each group received the topical application once daily for 14 days, and were then followed for an additional 28 days to ensure safety.

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

Only 1 event (eye irritation) was determined to be related to SM04554, and that was in the 0.45% group. Aside from 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. These were the findings:

The results of a trial one scalp assessment

While the focus of this study was mainly on safety, a few efficacy results were collected as well. However, these were subject-reported, so they are in no way scientifically significant.

First, subjects were asked at Day 15 and at Day 28 whether they noticed their balding patch was getting smaller:

A graph showing the percentage of subjects who felt their balding patch had gotten smaller

Next, subjects were asked how they would describe the growth of their hair since the beginning of the study. The positive responses shown below range from greatly increased to moderately increased to slightly increased:

A graph displaying the responses of subject participants when asked how they would describe their hair growth

With safety of SM04554 determined, researchers then proceeded with their second trial study.

SM04554 Phase 2 Results (Part 1)

There are a few differences between this study and the one performed previously. Aside from the studies’ focuses, there were also differences in subject group size, study duration, and number of groups.

First, 49 subjects participated in this study as opposed to 29. These new subjects ranged from a score of 4 to a score of 6 on the Norwood-Hamilton scale, and they were split into only three groups (0.15%, 0.25%, and vehicle).

Further, the study was active for 90 days, and subjects were followed for an additional 51 days.

Throughout the duration of the study, a number of results were tracked. These include total follicle count, vellus follicle count, terminal follicle count, and total anagen follicle count.

A graph and table showing the total follicle counts of subjects in the second trial study

As seen above, 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 those that are shorter and lighter than terminal hair, and can occur prior to terminal hair growth. As shown below, both treatment groups saw an increase in vellus hair follicles over the vehicle group:

Vellus follicle count comparison between placebo and both SM04554 solutions

In addition to vellus hairs, however, the number of terminal hair follicles also increased throughout the duration of the study for one solution of the SM04554. Surprisingly, it was the lower dose solution that saw positive results:

A graph comparing terminal follicle count between the placebo group and both SM04554 solution groups

Last, and perhaps one of the most significant findings, is the number of hair follicles in anagen phase.

As shown clearly below. Those in the vehicle group actually saw a decrease in anagen phase hair follicles throughout the duration of the 135-day study.

However, subjects receiving both the 0.15% solution and the 0.25% solution saw an increase in anagen phase hair follicles.

In fact, by the end of the study, both solutions were almost identical in terms of results.

Anagen follicle count comparison between placebo group and both SM04554 solutions

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. The subjects were split evenly into three groups (placebo, 0.15% SM04554 solution, and 0.25% SM04554 solution).

An image showing the timeline of the phase 2 trial

As shown above, treatment (dosing) took place for 90 days total. Clinical and imaging outcomes took place at baseline, day 45, day 90, and day 135. Additionally, scalp assessments were taken throughout the course of the trial.

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

Tables showing the hair count and hair density of subjects throughout the trial period

However, it’s surprising that the lower dosage (0.15%) performed remarkably better than the 0.25% solution. This is clearly seen depicted in the two graphs below.

A graph comparing hair count changes throughout the study
A graph comparing the hair density changes throughout the trial

What does this mean?

According to Samumed researchers, this is known as the “Goldilocks effect”. While drug developers look for something known as the drug response (more drug given = more efficacy and side effects), this isn’t always the case.

This can make it a bit more difficult for SM04554 to gain FDA approval, but it doesn’t mean the drug is a no-go.

Instead, Samumed is working to develop further Phase 2 trials to get a better understanding of dosage responses before moving forward into Phase 3.

SM04554 Side Effects

As mentioned in the above two trial results, there were a few, non-serious side effects experienced by subjects. However, the majority of these effects cleared up within a matter of days, and none were enough to make subjects quit the study.

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

A table displaying the adverse effects experienced by subjects in the second trial study

The effects determined to be related to application include: application site erythema, application site burning and/or stinging, application site pruritis, and skin exfoliation.

On a scale of 1-5, most were rated as a 1 or 2.

How Does SM04554 Compare to Finasteride and Minoxidil?

As of this writing, finasteride and minoxidil are the only FDA-approved hair loss treatment drugs on the market. However, this does not mean they are in anyway superior to SM04554, as that remains to be seen until further studies are performed on this experimental drug.

But 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.

Minoxidil works by prolonging the anagen phase of hair cells.

SM04554 works by inducing and prolonging the anagen phase, and also promotes the proliferation of new hair follicles.

By comparing mechanism alone, it seems that SM04554 already outshines its two predecessors. After all, not only does it stop hair fall, but it also claims to regenerate damaged hair follicles.

That’s something that neither finasteride or minoxidil can claim, and it may be the answer for those who are suffering from late stage male-pattern baldness.

I, personally, would like to see a comparison study performed on the three drugs. However, that’s not a possibility until SM04554 has completed its own phase 3 studies.

When Will SM04554 Be on the Market?

As studies are still currently underway (with developers looking to head into phase 3), there’s no certainty that the drug will be approved by the FDA (or even make it that far in the process).

Of course, that’s not to say that FDA approval isn’t a very real possibility. After all, the past studies have shown promising results.

I would say that expecting SM04554 to be on the market before 2020 is highly unlikely. FDA approval is a very time-consuming process. Instead, I’d say 5 years minimum is an aggressive goal for the company, but one that could be possible to meet should trials continue uninterrupted.

2020 Update: SM04554 Phase Three Trials Under Way

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

The recruitment process was completed in early 2020, and the trial is currently “active.”

This particular phase 3 trial consists of 625 participants. The participants consist of men with diagnosed Androgenetic Alopecia.

Now that Samumed has moved on to a phase 3 trial, we can expect a few things.

The first is a greater understanding of how the drug works. As this trial will typically last longer than the previous phase 2 trial, this will help scientists to determine its long-term effects and the best duration of use.

The second thing we can except is a more thorough understanding of the adverse effects. This will include a look at how the risks and benefits match up.

And finally, this trial in particular will compare drug concentrations. This will give us further insight into minimum dosage needed to see results, difference in adverse effects, etc.

So, what’s the timeline?

According to the official trial listing on ClinicalTrials.gov, the estimated date of trial completion is January 2021. This means that phase 4 trials could begin as early as 2021, though 2022 is more likely.

Closing Thoughts

Is SM04554 the AGA treatment of the future?

While studies are still underway, there’s no doubt that the results thus far are promising. However until it becomes FDA approved we really don’t know what are the long term implications, results and side effects. Minoxodil and finasteride are already FDA approved to those treatments might be the ones you choose to consider.

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