Aimmune Beats DBV Technologies In Multi-Billion Dollar Market To Treat Peanut Allergies

Summary

• The FDA recently approved AIMT's Palforzia as first ever treatment for peanut allergies, but for now, DBVT's Viaskin might only be months behind.
• It is difficult to make an apples-to-apples comparison between the efficacy of Palforzia v. Viaskin, but I explain how to do so using a new, easy-to-compare APPLE #.
• The apples-to-apples comparison reveals AIMT's Palforzia is dramatically more effective than DBVT's Viaskin in treating peanut allergies.
• AIMT's Palforzia passed the phase 3 trial with impressive results.  DBVT's Viaskin failed its phase 3 trial.
• Extension studies reveal that continued use of AIMT's Palforzia provides greater benefits in far less time than continued use of DBVT's Viaskin.

5/12/20 Update: Based on a May 11 comment from "micro", I added updates in paragraphs that starts with "***Update 5/12/20." In summary, my original article did not explain that about 17% of participants in DBVT's PEPITE trial were in a "low-eliciting dose subgroup" and they were considered to have met the primary endpoint by reaching a lower posttreatment dose than I originally indicated. AIMT's PALISADE trial did not create an easier-to-reach endpoint for any subgroup. Based on that, DBVT's results might be even less favorable compared to AIMT's results than I originally presented.

Purpose of this Article

For those who have followed AIMT or DBVT closely, this article does not change what should be well known: Palforzia soundly beats Viaskin. But despite following this story for years, I've often been confused about how to compare study results as presented by the different companies, which use different terms. In this article, I provide a new system to make an apples-to-apples comparison of the study results by assigning an APPLE # to the different results. It turns out that in food allergy studies, there is a limited number of possible results and it is thus relatively easy to describe results with just a few different APPLE # labels. I also give some quick bullet points of my understanding of the key results of the companies' major studies.

COVID-19 Is Distracting Investors from an Amazing Market Opportunity

While the world remains hyper-focused on COVID-19 as the biggest healthcare challenge of the past century, it is perhaps easy to overlook progress being made to treat more mundane (yet far more durable) medical problems. A prime example is food allergies and the multi-billion dollar opportunity that exists for treating such conditions. Long after treatments and vaccines have relegated COVID-19 to the history books, society will continue to deal with the ever-growing scourge of food allergies.

Peanut allergies (PA) are among the most common and dangerous types of food allergies. For those who suffer from it, exposure to the tiniest amounts can cause anaphylaxis (an allergic response which often involves swelling, hives, low blood pressure and in severe cases, shock). If not treated quickly, it can be fatal. Unlike many other allergies, most people do not outgrow PA, and for unknown reasons, the prevalence of PA continues to increase at a staggering rate. According to the American College of Allergy, Asthma and Immunology, the incidence of PA increased by 21% between 2010 and 2017.

It is estimated that in the U.S. alone, there are currently 1.6 million children between the ages of 4-17 with PA, of which about 1.25 million have been diagnosed. Europe likely has a similar population of PA patients. And because this counts only children, it is an ever-replenishing population. Any given year, about 100,000 children in the U.S. with PA have their fourth birthday and enter the treatable age population.

And lest anyone think PA is an easy to manage condition, accidental peanut exposures send about 25% of this population to the emergency room each year. That’s about 400,000 ER visits per year in the U.S. alone. This takes an enormous emotional and financial toll for children, parents, medical providers and the insurance companies that pay for most such treatments. PA results in about $4 billion in direct medical expenses each year in the U.S. alone. In short, there is a massive unmet medical need.

Finally, an FDA-Approved Treatment

It has been long known that allergies can be treated with immunotherapy, where a patient is desensitized by exposing them to tiny amounts of an allergen and then increasing the dosage as the body builds up tolerance. For many years, some allergists offices have prepared their own “homemade” regimen of peanut protein to administer patients. But the vast majority of allergists have not dared incur the liability and risks associated with giving some homebrew remedy to their patients, and they have waited for an FDA-approved treatment.

During the past decade, two companies raced to develop an effective, FDA-approved treatment for PA: the French company DBV Technologies (NASDAQ:DBVT) (OTC:DBVTF) and the California company Aimmune Therapeutics (NASDAQ:AIMT). DBVT is pursuing a treatment called Viaskin, a band-aid type patch with peanut protein that is applied daily to children’s skin. AIMT developed a treatment called Palforzia (previously called AR101), a daily pill containing peanut protein that is opened and the powder is sprinkled onto food eaten by children. Neither treatment requires shots or pills to swallow that children might consider traumatic.

In January 2020, the FDA approved Palforzia for the treatment of PA in children aged 4-17. Meanwhile, DBVT’s FDA application for Viaskin is pending, with a decision currently scheduled to be made by August 5, 2020, although there is some uncertainty about whether that date will need to move based on DBVT's need to address certain questions recently raised by the FDA about Viaskin's efficacy and patch adhesion.

Although Palforzia won the race to be the first to get FDA approval, the COVID-19 restrictions on non-essential medical treatments have hindered AIMT’s launch, and the first-mover advantage might not mean as much if DBVT also obtains FDA approval in the near future. And for future patients and allergists, the most important consideration is unlikely to be whose drug was approved first, but instead which drug works better: Palforzia or Viaskin?

It Is Difficult to Make Apples-to-Apples Comparison of Palforzia and Viaskin Results

AIMT and DBVT present results about their drugs' studies using different terminology, making it difficult to compare the drugs' efficacy on an apples-to-apples basis. But such a comparison is possible, and it's definitely important, although it does require getting deep into the weeds of how such studies work. If you're not interested in these weeds, you can skip to the next section which states it can all be reduced to an APPLE # shown on Table 3.

AIMT presents study results about Palforzia using the term “tolerated dose” while DBVT presents study results about Viaskin using the term “eliciting dose.” (The industry sometimes refers to “eliciting dose” as the “reactive dose.”) Any apples-to-apples comparison of the products requires an understanding of how the tolerated dose compares to the eliciting dose. But even then, both companies discuss study results in terms of either the largest single dose or the cumulative of all administered doses.

To understand these terms, one must understand how a food allergy study works. As explained in The Journal of Allergy and Clinical Immunology, the standard measurement in a food allergy trial is to perform a double-blind, placebo-controlled food challenge (DBPCFC). In other words, trial participants are given a double-blind food challenge at the beginning of a trial, and another double-blind food challenge at the end of the trial, and results are compared.

During these food challenges, participants are given increasing amounts of an allergen. First, they receive a truly tiny amount of the allergen, 3 mg. (A typical peanut has about 300 mg of the allergen, so this is about 1/100^th of a peanut.) The participant is observed, and if there is no allergic symptom within about 20 minutes, they are given a 10 mg dose. The participant is observed, and if there is no allergic symptom within about 20 minutes, they are given a 30 mg dose. And so on. The process continues as follows:

TABLE 1.

Dose number	New dose amount	Cumulative administered	Peanut equivalent
1	3 mg	3 mg	0.01 (1/100th)
2	10 mg	13 mg	0.04 (1/23rd)
3	30 mg	43 mg	0.14 (1/7th)
4	100 mg	143 mg	0.5 (1/2)
5	300 mg	443 mg	1.5
6	600 mg	1043 mg	3.5
7	1000 mg	2043 mg	6.8
8	2000 mg	4043 mg	13.5

Click to enlarge

When an allergic symptom is observed, the food challenge stops. For example, if a participant is given dose #4 and no allergic symptom is observed, then dose #5 will be given 20 minutes later. If an allergic symptom is observed after dose #5, the challenge stops and the participant does not get dose #6.

Under this scenario, dose #4 is the “tolerated dose” because the participant could tolerate that amount without symptoms. Dose #5 is the “eliciting dose” because that is the dose that elicited an allergic response, meaning it caused symptoms. Regardless of the terms used, in this example the study stopped after the participant was given dose #5. The result can be presented on a table like this:

TABLE 2.

Dose number	New dose amount	Cumulative administered	Terminology
4	100 mg	143 mg	Tolerated dose
5	300 mg	443 mg	Eliciting dose

Click to enlarge

In the example, the “tolerated dose” was 100 mg, the tolerated cumulative dose was 144mg; the “eliciting dose” was 300 mg and the eliciting cumulative dose was 444mg.

One thing quickly becomes apparent: the reported “eliciting dose” is always greater than the corresponding “tolerated dose.” Because each new dose is usually 2x to 3x greater than the prior dose, the eliciting dose is usually 2x to 3x greater than the tolerated dose. As a result, “eliciting dose” figures sound more impressive than the corresponding “tolerated dose.” For example, would you rather have a "tolerated dose" of 143 mg or an "eliciting dose" of 443mg? The bigger number might sound better, but it’s the exact same result.

Palforzia and Viaskin results can be easily compared using a new APPLE # system

I believe both Palforzia and Viaskin studies used the same DBPCFC dosing regimen. With that information, and the details from the section above, it becomes relatively easy to adjust the terms to make an apples-to-apples comparison of the trial results for AIMT and DBVT, as shown in the table that follows. The value of Table 3 is in column e (on the far right) that assigns an "APPLE #" to different results, regardless of how the terms and numbers used by the companies in presenting study results.

***Update 5/12/20: Here's another way to think of this, with a food allergy challenge, there are only 9 possible ending points, or 9 possible scores. Whatever labels the companies use, they describe one of these 9 possible results, which I call APPLE #. My Table 3 only shows APPLE 1 to 8, so why do I say 9? That's because in some food challenges (like PEPITE) the first dose is even smaller, 1 mg, which could be shown on Table 3 as Dose 0 and APPLE 0. But instead of re-writing this whole article with different labels (which probably doesn't help too many readers) I'll just leave it with this note and add some italics placeholders in Table 3. This article is not intended to substitute for scientific journals.

TABLE 3.

	a	b	c	d	e
Dose	AIMT Tolerated Dose	AIMT Cumulative Tolerated Dose	DBVTEliciting Dose	DBVT Cumulative Eliciting Dose	Apples-to-Apples Term
0	1 mg		3 mg	3 mg	APPLE 0
1	3 mg	3 mg	10 mg	13 mg	APPLE 1
2	10 mg	13 mg	30 mg	43 mg	APPLE 2
3	30 mg	43 mg	100 mg	143 mg	APPLE 3
4	100 mg	143 mg	300 mg	443 mg	APPLE 4
5	300 mg	443 mg	600 mg	1043 mg	APPLE 5
6	600 mg	1043 mg	1000 mg	2043 mg	APPLE 6
7	1000 mg	2043 mg	2000 mg	4043 mg	APPLE 7
8	2000 mg	4043 mg			APPLE 8

Click to enlarge

All that said, there are at least four ways data can be presented: (a) latest tolerated dose; (b) latest eliciting dose; (c) cumulative tolerated dose; and (d) cumulative eliciting dose. Using Table 3, the easiest way to tell which of the four is being used is as follows: AIMT uses the word “tolerated” so it will be either column (a) or (b); DBVT uses the word “eliciting” so it will be either column (c) or (d); if the number ends in “0” it probably refers to the latest dose, or column (a) or (c); if the numbers end in “3” it probably refers to the cumulative dose in columns (b) or (d).

But forget about all those other columns. The "APPLE #" term in column (e) is my own creation, which I use to quickly compare results from different studies.

Comparing Phase 3 results for Palforzia and Viaskin

With the complex terminology hopefully out of the way, it becomes easier to compare Palforzia and Viaskin, a comparison that highlights Palforzia's dramatic outperformance of Viaskin.

AIMT’s Palforzia Phase 3 Trial: ARC003/PALISADE

The phase 3 trial for Palforzia was known as both ARC003 and PALISADE. As explained in the FDA Advisory Committee materials provided by AIMT, it had 496 participants aged 4-17 who at the beginning had a “tolerated dose” of 144mg or less (APPLE 4), meaning participants had an allergic reaction after getting dose #5 and had to stop before receiving dose #6. Qualifying participants were split into active:placebo groups in a 3:1 ratio, meaning 372 (75%) participants received active Palforzia.

The primary endpoint was the proportion of patients aged 4-17 years who tolerated a single highest dose of at least 600 mg peanut protein (APPLE 6) with no more than mild symptoms at the Exit DBPCFC.

Results showed that 67.2% of those who took Palforzia had a tolerated dose of 1043 mg or greater (APPLE 6) compared to only 4.0% of those who took the placebo. The confidence interval between Palforzia and placebo was a stunning 56.7%, where the FDA's primary endpoint for success was anything greater than 15%.

In short, there was no dispute that Palforzia worked exceptionally well for more than two-thirds of trial participants and the placebo group had very little response.

DBVT's Viaskin Phase 3 Trial: PEPITES

The phase 3 trial for Viaskin is known as PEPITES, explained in this DBVT press release. It enrolled 356 participants aged 4-11 who at the beginning had an “eliciting dose” of 300 mg or less (APPLE 4). Qualifying participants were split into active:placebo groups in a 2:1 ratio, meaning 238 (67%) participants received active Viaskin.

***Update 5/12/20: The PEPITE trial actually had two subgroups. As explained in JAMA, of the 356 participants, there were 295 in a "high-eliciting dose subgroup" who at the beginning had an "eliciting dose" of APPLE 4 and 61 in a "low-eliciting dose subgroup" who at the beginning had an "eliciting dose" of APPLE 2. As shown in JAMA Table 1, of the 61 in the low-ED subgroup, 41 were assigned to the Viaskin arm and 20 the placebo arm. The subgroups had different primary endpoints, described as follows:

Participants with baseline eliciting dose of 10 mg or less [APPLE 2 or less] were responders if the posttreatment eliciting dose was 300 mg or more [APPLE 4 or more] ; participants with baseline eliciting dose greater than 10 to 300 mg [APPLE 3 OR APPLE 4] were responders if the posttreatment eliciting dose was 1000 mg or more [APPLE 6 or more]

The primary endpoint was the proportion of patients aged 4-11 years with an eliciting dose of at least 1000 mg peanut protein (APPLE 6) with no more than mild symptoms at the Exit DBPCFC.

In other words, for the 83% of participants in DBVT's PEPITE high-ED subgroup, both the enrollment criteria (APPLE 4) and the primary endpoint (APPLE 6) were the same as for everyone in AIMT’s PALISADE study.

Results showed that 35.3% of those who took Viaskin met the primary endpoint, but so did 13.6% of those who took the placebo. The low end of the confidence interval (12.4%) missed the agreed upon endpoint of no less than 15%.

In short, Viaskin only helped about 1/3^rd of trial participants get to the APPLE 6 primary endpoint, but in PEPITES, even the placebo helped about 1/8^th of the participants get to that same endpoint.

***Update 5/12/20: In fact, because 61/365 (16.7%) of the PEPITE participants were in the low-ED group, it is possible that around 17% of PEPITE's successful participants had an eliciting dose of only APPLE 4 or APPLE 5.

Palforzia’s Efficacy Dramatically Outperformed Viaskin's

In summary, Palforzia’s PALISADE study compares to Viaskin’s PEPITE study as follows:

TABLE 4.

Company	AIMT	DBVT	Comparison
Underlying Study	PALIDADE	PEPITES
Participants completing study	496	356	72%
Participants in active treatment	372	238	64%
Participants receiving placebo	124	118	95%
Active participants who met primary endpoint (tolerated dose of 600 mg+ after treatment (APPLE 6))	67.2%	35.3%*	53%
Placebo participants who met primary endpoint (tolerated dose of 600 mg+ after treatment (APPLE 6))	4.0%	13.6%*	340%
Difference active – placebo	63.2%	21.7%
Confidence interval (all numbers must be at least 15%)	53.0% to 73.3% PASS	12.4% to 29.8% FAIL

Click to enlarge

* ***Update 5/12/20: Because 61/365 (16.7%) of the PEPITE participants were in the low-ED group, it is possible that around 17% of PEPITE's successful participants had an eliciting dose of only APPLE 4 or APPLE 5.

• The Palforzia phase 3 study had about 39% more total participants than the Viaskin study.
• The Palforzia phase 3 study had about 56% more participants who received the active drug than the Viaskin study.
• For those taking the active drug, nearly twice as many Palforzia trial participants (67%) met the primary endpoint compared to Viaskin trial participants (35%).
• The placebo effect was 340% greater in the Viaskin trial compared to the Palforzia trial.
• In the Palforzia trial, the confidence interval (53% to 73.3%) comfortably exceeded the FDA’s 15% primary endpoint.
• In the Viaskin trial, with a much smaller difference in results between those getting Viaskin and those getting placebo, the lower end of the confidence interval (12.4%) failed the FDA’s 15% confidence interval primary endpoint.
• Palforzia definitely works for most participants; Viaskin maybe works for about one-third of participants, but it’s hard to know because even the placebo effect for those taking Viaskin was also quite high.

Extension studies confirm that Palforzia continues to outperform Viaskin even with prolonged use

After completion of the PALISADE and PEPITE studies, both companies conducted extension studies during which participants who had received the active drug were given the opportunity to continue taking the drug to determine if it provided additional therapeutic benefit with prolonged use. Nobody from the underlying placebo arms participated in the extension studies, and everyone in the extension studies was given the active drug, meaning the results of the extension studies cannot be compared to a placebo.

The extension of AIMT’s PALISADE trial was called ARC004. The extension of DBVT’s PEPITE study was called PEOPLE.

In AIMT’s underlying phase 3 PALISADE study, participants were given Palforzia for 12 months. In AIMT’s ARC004 extension, Palforzia was given for an additional 28 weeks to 104 PALISADE participants and for an additional 56 weeks to a separate group of 32 PALISADE participants. Participants showed substantial additional improvement the longer they continued using Palforzia. For example, whereas about 65% of ARC004 participants could tolerate a cumulative dose of 2043 mg of peanut protein at the end of PALISADE (APPLE 7), the number increased to 80% after 28 additional weeks of Palforzia use, and to 96% after 56 additional weeks. In fact, more than 80% of ARC0004 participants could tolerate 4043 mg (APPLE 8) after 56 weeks. In real world terms, after two years of taking Palforzia, more than 80% of participants could tolerate eating more than 13 peanuts without an allergic response. The company would likely never encourage it, but that’s probably getting close to peanut butter and jelly sandwich levels!

In DBVT’s underlying PEPITE study, participants were given Viaskin for 12 months. In DBVT’s PEOPLE extension, Viaskin was given for an additional 2 years to 141 PEPITE participants. After three years of using Viaskin, 52% of participants had an eliciting dose of at least 1,000 mg (APPLE 6) and about 13% of participants “completed the food challenge without meeting stopping criteria” at “cumulative dose of 5,444 mg” (APPLE 8).

The numbers in the extension studies do not line up perfectly, but again, it can be summarized roughly as follows:

• After 1.0 year of Palforzia, 67% of participants at APPLE 6.
• After 1.5 years of Palforzia, 80% of participants at APPLE 7.
• After 2.0 years of Palforzia, 96% of participants at APPLE 7.
• After 2.0 years of Palforzia, 80% of participants at APPLE 8.
• After 1.0 years of Viaskin, 35% of participants at APPLE 6.
• After 3.0 years of Viaskin, 52% of participants at APPLE 6.
• After 3.0 years of Viaskin, 13% of participants at APPLE 8.

***Update 5/12/20: Again, because 61/365 (16.7%) of the PEPITE participants were in the low-ED group, it is possible that about 17% of PEPITE's successful participants had an eliciting dose of only APPLE 4 or APPLE 5, not APPLE 6.

Conclusion

It's often difficult to make sense of drug trial results put out by any single company. It's much more difficult to compare results put out by different companies that use different terms for the same treatment target. And for me, it’s even more challenging because I’m neither a scientist, nor doctor, nor any type of expert in this field. I might have messed up some of the analysis above. If you notice a mistake, let me know and I’ll try to post a correction, either in the article or comments below.

The results show Palforzia is the undisputed winner in the race to develop a treatment for peanut allergies. Not only does it already have an FDA-approved drug in Palforzia while DBVT waits for what will happen to Viaskin, but Palforzia’s trial was larger and the results were dramatically better. Because DBVT presents its results using the term “eliciting dose,” its results sound like they compare well to AIMT’s results, but in a fair apples-to-apples comparison, DBVT’s results are not nearly as impressive.

As things stand, with AIMT trading at $16.54 (market cap of $1.07 billion) and having an FDA-approved treatment in Palforzia, compared to DBVT at $5.96 (market cap of $655 million) with no FDA-approved drug, AIMT appears to offer a dramatically better risk-reward proposition for investors.

FOOTNOTE TO TABLE 3. Things get a bit fuzzy about how much is administered after dose #7. The The Journal of Allergy and Clinical Immunology only provides explanations up to dose #7 and the companies’ press releases do not provide detailed explanations. An AIMT poster suggests dose #8 was 2000 mg, but DBVT press release suggested its cumulative eliciting dose for APPLE 8 was 5043 mg, meaning after dose #7 it gave doses in increments of 1000 mg.

Analyst’s Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

I have a long position in AIMT. I have no position in DBVT. Please don't based your investment decision on my recommendations; do your own study.