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Palforzia, the first-ever oral immunotherapy (OIT) to win FDA approval, is poised to ease peanut allergy for millions, but how widely it will be adopted remains to be seen.

Questions have been raised about whether its risks are worth the potential benefit, and some clinics already offer OIT with inexpensive peanut flour or other ingredients.

There's little doubt that oral immunotherapy works. Research has shown it can desensitize patients such that they can consume very small amounts of peanuts in a controlled manner.

And Palforzia manufacturer Aimmune -- which is also developing products for nut, egg, and milk allergies -- isn't alone in its quest to standardize peanut allergy treatment. DBV Technologies is developing an that functions through a similar desensitization mechanism.

But how Palforzia, and potentially Viaskin, will shape the peanut allergy treatment landscape is still unclear.

Peanut Immunotherapy Already in the Clinic

A few specialists have been performing peanut OIT in their clinics for decades, and prior to Palforzia's approval, that number had grown to about 200. Richard Wasserman, MD, of the Allergy Partners of North Texas in Frisco, has hosted increasingly popular for the past several years in which these physicians and others who are interested in implementing the procedure can gather to discuss advances in the field.

Some allergists who have been performing OIT for years with a tried-and-true dosing regimen don't see themselves switching over to newer products. In fact, they question the need for a standardized therapy at all.

On one hand, the relative amount of allergenic proteins in the peanut protein may be important, but OIT can be performed with many products -- shelled or unshelled peanuts (if they are roasted), peanut butter powder, or peanut flour, Wasserman told 名媛直播.

On the other hand, like any therapy, having a standardized approach can provide a way to prospectively evaluate the treatment across a variety of practices, said Thomas Casale, MD, of the University of South Florida in Tampa, and investigator on the phase III trial on which Palforzia's approval was largely based. (With Palforzia, the powdered allergen is delivered in pull-apart capsules that are sprinkled into food, and is administered in small but increasing doses. It was approved last week for children and adolescents ages 4-17 years.)

"The issue is really that what one person does in practice may not be translated into what somebody else would do, so it's very hard to judge the effectiveness of a particular treatment from an individual practice," Casale, who is also chief medical officer of Food Allergy Research and Education (FARE), a patient advocacy group backed by Aimmune, told 名媛直播.

Worth the Risk?

Though OIT has been shown to be effective in studies, determining whether the therapy is worth the risk for adverse reactions versus avoidance alone is more complex.

Palforzia's approval was primarily based on a year-long that found close to 70% of children with confirmed allergy were able to tolerate 600 mg (roughly two peanuts) by the end of the study period, compared to 4% of patients in the placebo arm.

Considering about one-third of a peanut is enough to make peanut-allergic kids sick, that means Palforzia was associated with more than ten times the protection of avoidance alone, said Edwin Kim, MD, of the University of North Carolina School of Medicine and a Palforzia trial investigator.

"What's really important ... is this is supposed to be an adjunct to avoidance," Kim told 名媛直播. "This is the treatment that will give them an extra cushion if something gets accidentally contaminated to avoid exposures."

These findings were the primary focus of an FDA advisory committee meeting Sept. 13, in which members voted 7-2 to recommend approval of Palforzia.

But critics have been quick to pull out some of the lesser-reported findings from the so-called PALISADE trial. Namely, patients in the intervention group actually had an increased rate of severe allergic reactions compared to the control group outside of the clinic (14% vs 3%).

"I think it's hard to argue that this product is safe when it increases the risk of the thing it is designed to prevent," John Kelso, MD, an allergy specialist at the Scripps Clinic in San Diego who voted no, .

Similarly, by Derek Chu, MD, PhD, of McMaster University in Ontario, Canada, found individuals on OIT had three times the risk for having anaphylaxis, were between two and three times more likely to use epinephrine, and were twice as likely to have a serious, life-threatening reaction compared to patients not on OIT. Vomiting, upset stomach, and asthma-related reactions were also linked to OIT use, as they were in the PALISADE trial.

Palforzia has been shown to increase the number of allergic reactions in the short-term to potentially decrease reactions in the future, said David Rind, MD, Chief Medical Officer for the Institute for Clinical and Economic Review (ICER). The problem is, it hasn't been proven to do that yet, he added.

"We always say we want long-term outcomes, but usually we are talking about therapies that are beneficial in the short-term," Rind told 名媛直播. "Here, we are talking about a therapy that was harmful in the short-run that we believe will be helpful in the long-run."

However, OIT specialists argue that although these reactions need to be accounted for when administering OIT, the risk is inherently part of the treatment.

"When you're getting immunotherapy, you're anticipating that risk and you instruct patients that [a reaction] may happen within one to two hours of dosing, so they're ready for it," Casale said. "That's much different than having an unanticipated allergic reaction from an accidental exposure."

Targeting the Right Providers

In the PALISADE trial, participants were required to pass double-blind, placebo-controlled "food challenges," in which they were given up to 100 mg of peanut protein orally and monitored for a reaction. However, about 40% of allergists -- and virtually no pediatricians -- perform food challenges clinically, said Wasserman. As a result, many kids who are sensitized to peanuts but not allergic, are diagnosed with peanut allergy, he added.

If more people who are not allergic take Palforzia, it may be that the drug performs even better in the real-world, once it's on the market, compared to its clinical trials, Wasserman said.

The problem with that is, less experienced providers may feel comfortable getting involved with OIT when it is not appropriate, he added.

"They may be unprepared to deal with the education necessary to keep patients safe and how to deal with reactions that occur," Wasserman said.

Implementing OIT in the clinic requires up to a 90 minute observation period after dosing and staff on hand that are prepared to answer questions from patients around the clock.

Palforzia was approved with a Risk Evaluation and Mitigation Strategy (REMS) in which providers are required to undergo specific training. The initial dose escalation phase and first dose of each increasing dose must also be administered in specially certified healthcare settings as well, according to the FDA.

In addition, providers administering the therapy must counsel families on the need to continue avoiding the allergen, carrying injectable epinephrine, and recognizing signs of anaphylaxis, the agency stated.

Allergists who already administer allergy shots -- which is the majority -- likely have all of the protocols in place to begin administering Palforzia, said Aimmune chief commercial officer Andrew Oxtoby during an earnings conference call on Nov. 6.

In an the most commonly reported reasons for not starting OIT were the lack of an approved therapy and safety concerns.

This makes sense considering the therapy itself is inherently risky -- carrying a high risk for anaphylaxis or other adverse events, Kim said.

"What you're seeing is these early adopters, the super motivated providers and patients, are doing it now, but most are not," Kim said. "One of the reasons is, they are [cautious]. They want to see if this works and that's where the FDA stamp of approval will make a big difference."

David Stukus, MD, of Nationwide Children's Hospital in Boston, said OIT is not something provided at the large academic center where he works, but the FDA stamp of approval may help convince the administration to dedicate the staff and resources required to provide the new therapy.

"The biggest fear is that a lot of primary care providers or other physicians with no real experience or training in this starts offering it," Stukus told 名媛直播. "Someone could get really hurt that way."

'Show Me the Data'

Questions remain about when patients should begin OIT and for how long they should be treated.

The PALISADE trial followed patients for 1 year, but other trials have shown the effects of OIT are not permanent. That is, Palforzia would likely be an indefinite and possibly lifelong treatment, with some data suggesting starting therapy in childhood is more effective than starting it as an adult. (In the PALISADE trial, no treatment effect was observed among adult patients.)

An underreported outcome with OIT is the effect peanut allergy treatment has on quality of life. In this regard, Palforzia could improve the anxiety burdening patients and families, who sometimes avoid taking family trips or going out to eat, or isolate children with peanut allergies for fear of accidental exposures.

"There has been inadequate attention paid to the enormous burden patients with food allergy experience and the freedom and liberation they experience when they have become desensitized and can feel more comfortable about going to a restaurant," Wasserman said.

But data on Palforzia and quality of life are lacking. Chu's meta-analysis found no meaningful differences reported between OIT and standard care groups, and the PALISADE trial did not report quality-of-life outcomes.

"The bottom line is: Show me the data," Chu said. "Everyone is enthusiastic at the idea of having a new treatment for peanut allergy [approved] ... and it's monumental we've gotten so far, but we also need to temper our expectations and make sure we do something right rather than doing something rushed."

Cost & Patient Access

Evidence suggests that children from lower socioeconomic households and African-American children have historically had for food allergies. If Palforzia's arrival on the market allows more centers to offer OIT, it could bridge some of these disparities in food allergy maintenance and treatment.

On the other hand, this will depend on how it is reimbursed by insurance -- on the Nov. 6 conference call, Aimmune said the drug would indeed be covered by insurance.

Recent reports suggest the of Palforzia will reach $890, for an annual total surpassing $10,000.

In an ICER analysis released last summer before pricing was known, the cost-effectiveness watchdog estimated that at a cost of $4,200 per year, just 41% of eligible patients could be treated without exceeding ICER's budget impact threshold.

Aimmune said it will provide . But what it takes to qualify for these resources is not yet clear.

Alternatively, individualized OIT protocols are relatively inexpensive, although since they are not FDA-approved, patients may be required to pay out-of-pocket.

For example, Wasserman's clinic uses a pound of peanut flour -- purchased at the grocery store for roughly $6 -- to treat multiple patients. They also charge a one-time fee of $180 to start therapy to cover the cost of storage, supplies, and administration.

Regardless of some aspects of the product, most allergens agree that Palforzia is a monumental step in the field of food allergy treatment.

"I can't think of any other disease where you have almost 32 million Americans affected with food allergies and not one FDA-approved treatment," Casale said. "Is this the best treatment in the world? No, but it's a first step, and I think a critical first step for patients and their families to have access to something other than just avoidance."

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