Neuromodulators

Botox Cosmetic (Onabotulinumtoxin A)

Botox Cosmetic (onabotulinumtoxin A) has been the “gold standard” and has changed the way the world thinks about nonsurgical treatments. It is hugely popular and reliable, and the reason is because it works! It has been and will always be viewed as the product to match or beat. It was the first botulinum neurotoxin A to be approved in the United States. This accolade is tempered because it is also one of the last injectables to be developed “first” in the United States. Botox Cosmetic has been the undisputed champion in the NT world because it is safe, predictable, and relatively easy to use. It has a high patient satisfaction, and no other NM has been so vigorously studied. Until recently, it has had no “real” competition. As with all medications, there are a lot of “hate groups” (the same with vaccinations) trying to say Botox Cosmetic is dangerous, but every time they make an argument, another use becomes approved.

Many of the older NTs entering the market made missteps in marketing. Some companies gave reasons why they were better than Botox. Other companies claimed their products were the same and they had noninferiority clinical studies backing this up. Some of these companies relied on unproven or unsubstantiated claims to show how they worked. Healthcare providers (HCPs) experienced holes in some of these concepts with personal use. Market research, at times, was also skewed to fit a particular narrative that was not helpful. Examples of this is the failure to grow the market with the exhaustion of huge marketing resources to particular group subsets, such as what was perceived as underpenetrance to the male market, which still remains the substantial minority. Despite attempts by some competitors to improve their market penetration, time and provider experience in the past has ensured that the market leader continues to be Botox Cosmetic.

Dysport (Abobotulinumtoxin A)

Dysport (abobotulinumtoxin A) was the second drug to market with FDA approval. Dysport is also a very good drug, but it is not the same as Botox. Experienced injectors can obtain similar effects, and this rings true with the other NMs discussed in this introduction. The company marketed this drug the same as Botox, saying the onset was faster and lasted longer. Despite our experiences confirming that Dysport is not the same as Botox Cosmetic and is a very different drug with a unique clinical profile, excellent clinical results can be obtained when used appropriately.The safety and effectiveness of Dysport has earned them second place in the NT market, with while Botox still leads market share.

Xeomin (Incobotulinumtoxin A)

Xeomin (incobotulinumtoxin A) was the third FDA-approved NM in the United States. The maker, Merz Aesthetics ( www.merz.com ) hung its hat on their unique and state-of-the-art manufacturing process. Their statement was as follows:

“Xeomin is made through a unique precision manufacturing process that isolates the therapeutic component of the molecule and removes the accessory proteins that don’t play an active role in treatment. Xeomin is a highly purified NT and studies have not been performed to determine whether the presence or absence of accessory proteins has a long-term effect on safety or efficacy.”

The problem was their scientific assumption (a main tenet of their competitive marketing approach) that removing the protein coat and having a bare 150-kD molecule would be superior. They felt that the accessory proteins were unnecessary and in part were cause for immunologic resistance, tachyphylaxis, and other “allergic” issues. The company felt that the excipient proteins had no beneficial role, and removing the accessory proteins would yield a more precise, potent, and consistent formulation. They felt that this would result in a longer-lasting and more predictable result and that the results should be better than Botox Cosmetic. Frankly, their presumption, although logical, was primarily based on unproven theory. Historically, this has not come to fruition; however, Xeomin is also a very good drug, and the results are quite similar to Botox Cosmetic when used appropriately and when the provider better understands the unique differences. The drug is less expensive, so some HCPs prefer it. Some clinicians complain that it does not last as long, and others claim that they can make it last longer by increasing the dosing, which in the end can negate the cost savings. Requiring a larger dose to last longer begs the unanswered and reasonable question if the accessory proteins might actually be important for successful NTs as the protein coat protects the toxin from your body trying to destroy it. This has been an evolutionary benefit for millions of years for the self-preservation and survival of the toxin within the Clostridium bacterium.

For a solid decade, Botox Cosmetic has remained the leader in this industry. Regarding the new NMs entering the market, what will their company’s strategy be to be competitive? HCPs and patients have different motivations.

So in the microcosm, what are HCPs asking when considering a new product? The foremost question is, “Is the new product safe and predictable?” Another question is, “Is the new product the same as Botox Cosmetic (or competitors) or better? If not, how is it different?” For sure, HCPs will want to know how much a new product costs and its relation to profit. Other relevant considerations of busy practitioners include if the new product requires refrigeration or freezing for storage or must be reconstituted, and how long it can be used once reconstituted. Although Botox Cosmetic is still “king,” there are numerous perceived associated drawbacks on which new products can capitalize.

Industry, on the other hand, states “ours lasts longer, is better, is just as good, is cheaper, is more predictable, works better in certain areas, spreads less, spreads more, and does not require refrigeration.” Industry will also be quick to point out that only 5% of the population get NT treatments, which shows an obviously wide-open market. This research is fascinating and garnered through considerers . Considerers are the demographic with the ability and wherewithal to afford to pay for such medications as NMs. In other words, because they can afford it, they would consider treatment. The considerers state to the companies that only 5%–7% of the population uses injectables because of fear of the procedure. This, however, is untrue, and it has much more to do with economics and pricing. NMs are very expensive treatments for the average person. Although fear may be on the list of reasons why people do not use such an available treatment, cost is above all the biggest hurdle. It may not be a great business plan for a company to be the “cheapest,” but in reality, this would drive popularity.

On the other side of the coin, what are patients asking? Of course they want to know if it is safe, if it will hurt, and will they look natural. They also want to know how it is different from the “Botox” they are already using. Other considerations include how long it will last, how many times per year they will need to return, and, of course, how much it will cost. The need for reconstitution, the need for cold storage, and having to use one’s own syringes and needles are also difficulties for the injector, and improving these issues would be innovative.

Industry will spin the narrative to market their products, and it is up to the injector and the end user to decide which is science and which is hype. What is important is that all NTs are manufactured differently, and manufacturing definitely affects, in fact dictates , performance, so this is a relevant factor.

Jeuveau (Prabotulinumtoxin A)

Evolus ( www.evolus.com ) introduced Jeuveau (prabotulinumtoxin A) in May 2019. Jeuveau is unique because it is also a 900-kD molecule, which would “theoretically” suggest that it should be identical to the market leader (remembering that the other available NTs in the United States are not 900-kD). Jeuveau is manufactured in one of the most modern plants in South Korea and is vacuum-dried instead of freeze-dried, which may be gentler (during the manufacturing process to preserve integrity) to the sensitive toxin ( Fig. 9.3 ). The company claims that other steps in the manufacturing process, including enhanced filtration and unique polarization steps, add to product integrity and potency. Clinical studies, which are commonly for first approval of NTs limited to the glabella with a five-point injection pattern, showed efficacy and a safety profile similar to other NTs. A paired, double-blind simultaneously coordinated US study against a placebo showed excellent efficacy. A Canadian/European study compared with Botox Cosmetic showed excellent comparatives that led to FDA approval. Most injectors will say, in general and in most patients, that Jeuveau is very similar to Botox Cosmetic in most areas.

Evolus is the only NT company with a purely aesthetic product with no therapeutic indications. This allows them more leeway to market and price their drug because they are less regulated. There are no therapeutic indications, and the product is only cosmetic. Therefore the cost to HCPs is not regulated under Pharma guidelines, and Evolus can charge less, which can be a huge motivator to HCPs in the marketplace.

Daxibotulinumtoxin A

(“Daxi”) Revance Therapeutics

During the production of this edition, daxibotulinumtoxin A will be released and is making big waves in NT circles, primarily because of its reported extended effect of action ( Fig. 9.4 ). What is unique about daxibotulinumtoxin A and how did Revance Therapeutics ( www.revance.com ) get there?

Of interest, it started by the Revance Company exploring a means to get topically injected macromolecules into/through the skin (e.g., insulin and others) via topic application. Their goal was topical delivery of a NM that did not need to be injected. This process used a small “peptide” that was capable of cell penetration. Although this would have been a medical breakthrough, the topical studies under FDA application did not sufficiently reach the high bar, and the FDA strongly suggested that the study material should not be used topically, but rather injected! This led to an animal pilot study to explore this suggestion, which showed surprising results that led to a pilot human study in Mexico. The disappointment of the FDA denial led to the successful propagation of this new and promising NT with a potentially extended effect compared with the market leader.

This newest NM is different in multiple ways that relate to, and as always, include a unique and proprietary manufacturing process. The formulation contains the 150-kD core NT type A molecule and a proprietary stabilizing peptide that is unique to this product ( Fig. 9.5 ). The proprietary peptide seems to prevent the 150-kD NT from sticking to itself and to the glass of the vial and allows for elimination of human serum albumin (which is used for the same purpose by other companies) from the formulation. The elimination of human and animal products from all medications currently seems to be a desirable situation for manufacturers, injectors, and consumers.

The stabilizing peptide has a molecular weight of ~5 kD and a highly positively charged amino acid sequence that forms an electrostatic (noncovalent) interaction with the negatively charged 150-kD NT. This prevents adsorption of the botulinum toxin A molecules to container surfaces and also prevents the molecules from aggregating (sticking to themselves). Presumably, when the molecules aggregate, there are fewer active molecules to contact motor end plates. This would be the difference between shooting a single bullet versus a shooting shotgun with many pellets; more targets can be hit. Again, this was previously done by adding human serum albumin. Combining this with a stabilizer and a buffer produces the uniqueness of daxibotulinumtoxin A.

The peptide seems to be the main driver in the formulation that mitigates thermally induced aggregation in the manufacturing process. In addition, keeping each 150-kD molecule separated (not stuck together) ensures that the maximum number of motor end plates are affected, thereby increasing the odds that the finite amount of NT in each 50-unit vial will have its maximal chemodenervation effect. Another practical consequence of the stability imparted by the peptide/botulinum toxin molecule electrostatic interaction is that daxibotulinumtoxin A is anticipated to have at least 2 years of room temperature stability. Preliminary experience suggests that daxibotulinumtoxin A has a larger field of spread than other available products. This will also be discussed later in this chapter.

So, what does this type of manufacturing process mean to injectors and consumers? It has the potential to last significantly longer than existing NMs, which means that patients may amend their treatment appointments from three to four per year to two per year. The potential advantage of lasting twice as long will obviously be appreciated by the consumer. This could be an issue as the usual patient annuity of having patients return three times per year can be reduced to bi-annual visits for “Daxi,” so HCPs will likely charge more for products that last longer. Also, will the companies charge more for products that last longer, as we have seen with fillers? Our experiences suggest that for some patients this change will be worth it. Such issues will need to find balance between science and clinical practice. It is manufacturing processes and science that will drive future generations of NMs.

QM1114: The “Unnamed Neurotoxin”

Dilutions, Devices, and Caveats

I routinely use all of the FDA-approved NMs in my practice. Having said this, probably 90% of my injections are Botox Cosmetic. The scope of this textbook does not allow me to discuss the finite manipulations of every preparation, so I will focus on Botox as it has remained the gold standard. It is important for injectors to understand that all toxins are not the same: they are different in how they are made, how they work, their spread of effect, onset of action, longevity, and dilution. My advice to the novice injector is to start with a single toxin and study and learn the effects of this before moving on.

Botox Cosmetic is sold in 50- and 100-unit vials. The undiluted product is visible as a small precipitate on the vial floor. Because the vials are considered single use, we mix one at a time and draw this up in multiple syringes for use throughout the day. At no time do we ever reenter a vile as this could result in cross-contamination. The package insert that accompanies all brands of NMs provides dilution directions. The Botox Cosmetic insert shows dilution values from 1 mL to 10 mL ( Figs. 9.8–9.10 ). I prefer 2.5 mL of preserved saline mixed with a 100-unit vial. Inadvertent waste can occur when mixing, and spilling several drops of a 2.5-mL dilution is less expensive than spilling the same amount of a 1-mL dilution. This provides 0.4 Botox Cosmetic units per each 0.1 mL of reconstituted product. I find this dilution useful because the math is easy, and we draw up five 0.5-mL syringes from the vial. That means each syringe will be 20 units, which is the recommended dosage for treatment initiation in most areas of the upper face. It is important to note that the final syringe may contain less than 20 units as a result of product loss within needles, hubs, and vial walls. After reconstitution, the syringes are stored in a medical refrigerator with a temperature graph and power backup. In the event of power loss, the product can be ruined. Unopened vials are also stored in a similar refrigeration unit.

The diluent is injected into the vial with an 18-gauge needle, and the vial is gently rotated end on end to adequately mix the NT. I use a bottle opener to remove the vial cap, and the first syringes are drawn from the vial into the 1-mL injection syringe using the same 18-gauge needle. The final syringe is drawn from the vial with a 32-gauge needle. Using this small needle and tilting the vial will capture “every last drop” of the expensive toxin. I have done studies that showed an average of 4–5 units of waste left in discarded NM vials. I did the math, and losing a residual of 4 to 5 units per vial in 1 year translated into a $15,000 waste of unavailable product. A welcome improvement will be companies shipping their product in an already reconstituted form. Daxibotulinumtoxin A from Revance is one of these companies. This will save time and money for the injector. If the bottle top is not removed, it is important not to pierce the rubber stopper with the same small needles that will be used for injection as they dull very quickly.

Different products may have different dilution schemes. For instance, Dysport comes in a 300-unit vial. I personally dilute Dysport with 3 mL of preserved saline (see Fig. 9.9 ). This yields six syringes of 0.5 mL with each syringe containing 60 Dysport units. Again, this math works well for me because 60 units is the average dose that I use to treat common areas in the upper face. Because many offices will offer NMs that do and do not need mixing, it is important to have a laminated guide in the area where the vials are reconstituted. This guide should have a picture of the product and succinct instructions on how to prepare it.

As an early adapter of Botox Cosmetic for cosmetic treatments, I have seen many changes over the past two decades. In the early treatment days, patients would present and demand total paralysis and sometimes ask for a refund if they had even the slightest amount of movement left after treatment. Today’s patients are much more refined and do not want the frozen or paralyzed look. They are also very astute, and most regular users are familiar with what they want and what works best for them because these treatments have been around for decades. It is not unusual for somebody to come in and request 5 units in the frontalis, 6 units on one side of the lateral canthus and 4 units on the other side of the lateral canthus or similar precision patterns. I feel that patient-directed treatment is a good thing, and we always document on the chart that the patient requested this specific regimen. Although my usual amount of Botox Cosmetic in the glabella is 25 units, some patients may request 10 units. We remind them at the time of injection that this is less than one-half of a dose, so they should not expect the same efficacy or longevity. In general, with all of the currently available FDA-approved NMs, we tell patients that they will usually see some effect in the first 48 hours and a total effect at 2 weeks. The average time between treatments is approximately 90 days; however, this is a variable situation and is never promised. Some patients may call 3 to 4 days after treatment and complain that their Botox was ineffective, and I will generally advise them wait a minimum of 7 to 10 days before touch-up injections because the results can take longer to fully appear in some individuals.

Numerous types of syringes and needles are available for the injection of NMs. I prefer the syringes with the plunger extension as they deliver residual syringe product compared with standard syringes ( Fig. 9.11 ). I also prefer a 32-gauge needle. I think the pain difference between a 30-gauge needle and a 32-gauge needle is significant, and for the extra pennies, a painless reputation is worth the investment.

Some injectors prefer a more precise dilution and delivery that favors 1 mL of preserved saline mixed with the 100-unit Botox vial. When this dilution is transferred to a standard 0.3-mL insulin syringe, a single hash mark on the syringe represents 1 Botox unit ( Fig. 9.12 ). This can be useful when an area requires precision delivery of a small number of units.

Pain Control

One of the big fears that prevent people from seeking NM treatment is fear of needles. It is still somewhat hard to believe that after getting to the moon we cannot figure out an easier way to deliver these products. Some injectors use a topical anesthetic. Although I have not found this necessary, I have used small vibratory devices for years and I am completely sold on their benefit ( Fig. 9.13 ). Small, rechargeable personal massage devices and the back of an electric toothbrush are also effective. Whether one believes in the gate theory of pain control or views these devices as simple diversions, patients report a better experience with them. Once I inject with a vibratory device, the patient will usually remind me that they desire it at future sessions. “Where is the buzzer?” is a common question if they do not see it in your hand.

Another device that is useful with cosmetic injectables is the Accuvein vein finder ( Fig. 9.14 ). This device uses laser technology to display a vein map on the skin in real time. This can identify veins up to 10 mm deep, and it is useful for the injector and intriguing for the patient. There is a saying with cosmetic injectables “If you bruise them, you’ll lose them.” This certainly can be true, and bruising can be a big problem when a new patient presents to your office to look better and leaves with a large bruise. Devices like the Accuvein will not guarantee prevention of bruising, but they show the patient that the injector has the technology and the interest in avoiding bruising. These devices are great practice builders, especially in patients who are presenting for the first time and have had problems with bruising at other offices.