Peanut Immunotherapy

Number: 0968

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

1. Prescriber Specialties

   The requested drug is being prescribed by, or in consultation with an allergist or immunologist.

   Note: The Initial Dose Escalation and first dose of each Up-Dosing level must only be administered in a healthcare setting equipped to monitor members, and to identify and manage anaphylaxis.

2. Criteria for Initial Approval

   Aetna considers peanut (Arachis hypogaea) allergen powder-dnfp (Palforzia) for oral administration medically necessary for the mitigation of allergic reactions, including anaphylaxis, in a member with a confirmed diagnosis of peanut allergy when all of the following criteria are met:

   1. Diagnosis of peanut allergy has been confirmed by a serum IgE levels or skin prick testing; and
   2. Palforzia is being used in conjunction with a peanut-avoidant diet; and
   3. Member meets either criteria:
      1. Member is 4 to 17 years of age for initial dose escalation; or
      2. Member is 4 years of age or older for up-dosing or the maintenance phase of treatment; and
   4. The member does not have uncontrolled asthma, a history of eosinophilic esophagitis, or other eosinophilic gastrointestinal disease.
      

      Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

3. Continuation of Therapy

   See Dosage and Administration section.

4. Related Policies

   • CPB 0038 - Allergy and Hypersensitivity

Dosage and Administration

Palforzia [peanut (Arachis hypogaea) allergen powder-dnfp] is available for oral administration supplied in 0.5 mg, 1 mg, 10 mg, 20 mg, and 100 mg capsules or 300 mg sachets. 

Treatment with Palforzia is administered in 3 sequential phases: Initial Dose Escalation, Up-Dosing, and Maintenance. Healthcare supervision in a health care setting with the ability to manage potentially severe allergic reactions, including anaphylaxisis, is required for initial dose escalation and the first dose of each new up-dosing level. 

Initial Dose Escalation:

Administered in sequential order on a single day, beginning at dose level A, with a total of 5 levels (0.5 mg, 1 mg, 1.5 mg, 3 mg, and 6 mg), and each dose should be separated by an observation period of 20-30 minutes. No dose level should be omitted. Individuals must be observed after the last dose for at least 60 minutes until suitable for discharge. Individuals who tolerate at least the 3 mg single dose (Level D) of Palforzia during Initial Dose Escalation must return to the health care setting for initiation of Up-Dosing. If possible, begin Up-Dosing the day after Initial Dose Escalation. Repeat Initial Dose Escalation in a health care setting if the patient is unable to begin Up-Dosing within 4 days.

Initial Dose Escalation is supplied as a single card consisting of 5 blisters containing a total of 13 capsules.

Table 1: Dosing Configuration for Initial Dose Escalation (Single Day Dose Escalation)

Dose Level	Total Dose	Dose Configuration
A	0.5 mg	One 0.5 mg capsule
B	1 mg	One 1 mg capsule
C	1.5 mg	One 0.5 mg capsule; One 1 mg capsule
D	3 mg	Three 1 mg capsules
E	6 mg	Six 1 mg capsules

Up-Dosing:

Initiated at a 3 mg dose and consists of 11 dose levels, administered in sequential order at 2 week intervals; no dose level should be omitted. No more than 1 dose should be consumed per day. Individuals are to be instructed to not to consume a dose at home on the same day as a dose consumed in the clinic.

Table 2: Daily Dosing Configuration for Up-Dosing

Dose Level	Total Daily Dose	Daily Dose Configuration	Dose Duration (weeks)
1	3 mg	Three 1 mg capsules	2
2	6 mg	Six 1 mg capsules	2
3	12 mg	Two 1 mg capsules; One 10 mg capsule	2
4	20 mg	One 20 mg capsule	2
5	40 mg	Two 20 mg capsules	2
6	80 mg	Four 20 mg capsules	2
7	120 mg	One 20 mg capsule; One 100 mg capsule	2
8	160 mg	Three 20 mg capsules; One 100 mg capsule	2
9	200 mg	Two 100 mg capsules	2
10	240 mg	Two 20 mg capsules; Two 100 mg capsules	2
11	300 mg	One 300 mg sachet	2

Maintenance: 

All levels of Up-Dosing should be completed before starting Maintenance at 300 mg daily; daily maintenance is required to maintain the effect of Palforzia and the individual should be assessed for adverse reactions at regular intervals.

Table 3: Daily Dosing Configuration for Maintenance

Dose Level	Total Daily Dose	Daily Dose Configuration
11	300 mg	One 300 mg sachet

See the Full Prescribing Information (Aimmune Therapeutics, 2020) for full details on dose modification schedule, missed doses and discontinuation of Palforzia therapy.

Source: Aimmune Therapeutics, 2020

Experimental and Investigational

Aetna considers co-administration of Palforzia with a monoclonal antibody (e.g. omalizumab) experimental/Investigational due to lack of clinical evidence.

Aetna considers Palforzia experimental and investigational for the emergency treatment of allergic reactions, including anaphylaxis.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
0165U	Peanut allergen-specific IgE and quantitative assessment of 64 epitopes using enzyme-linked immunosorbent assay (ELISA), blood, individual epitope result and interpretation
90473	Immunization administration by intranasal or oral route; 1 vaccine (single or combination vaccine/toxoid)
+90474	each additional vaccine (single or combination vaccine/toxoid) (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
Palforzia (peanut [Arachis hypogaea] allergen powder-dnfp) powder - no specific code
Other HCPCS codes related to the CPB:
H0033	Oral medication administration, direct observation
J2357	Injection, omalizumab, 5 mg
ICD-10 codes covered if selection criteria are met:
Z91.010	Allergy to peanuts
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
T78.01xA - T78.01xS	Anaphylactic reaction due to peanuts

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Background

Peanut allergy can be severe or life-threatening and is one of the most common causes of food-related anaphylaxis. According to the American College of Allergy, Asthma, and Immunology (ACAAI), a 2017 study reported that peanut allergy in children had increased 21 percent since 2010, and that nearly 2.5 percent of U.S. children may have an allergy to peanuts. Symptoms of a peanut allergy may include wheezing, repetitive cough, hoarse voice, hives, and gastrointestinal symptoms (e.g., vomiting, stomach cramps, and diarrhea). The most severe allergic reaction to peanuts is anaphylaxis — a life-threatening whole-body response to an allergen. Symptoms may include impaired breathing, swelling in the tongue, lips or throat, a sudden drop in blood pressure, pale skin or blue lips, fainting and dizziness. Anaphylaxis should be treated immediately with epinephrine (adrenaline), typically administered in an auto-injector. There are no approved treatment options for peanut allergy. The cornerstone of food allergy management has traditionally consisted of careful, targeted elimination of the allergy-provoking food, and timely, severity-driven treatment in the case of accidental ingestion. The concept of desensitization to peanut has arisen in the past 10-15 years with the hope of effecting more of a cure, however, desensitization is not without complications and does not necessarily equate to tolerance development, so is an area of ongoing research and controversy (Gray 2020).

Kim et al (2020) state peanut allergy has continued to increase in prevalence and despite efforts to prevent the allergy with early peanut introduction, treatments for those already with the allergy have been lacking. While the physical effects of peanut allergy have been well known, what has more recently begun to be discussed are the broad psychosocial and financial implications that are also related to the allergy. Oral (OIT), epicutaneous (EPIT), and sublingual (SLIT) immunotherapy have been developed as potential treatments for peanut allergy. The authors reviewed pivotal clinical trials in OIT, EPIT, and SLIT from the past 10 years. Peanut OIT has been shown to induce strong desensitization; however, side effects and safety of the treatment have remained a concern. Peanut EPIT has demonstrated a reassuring safety profile but with a more modest protective effect. Peanut SLIT has remained behind in development but recent studies have suggested a balance of desensitization, safety, and convenience. The authors conclude that there are no perfect treatments for peanut allergy and OIT, EPIT, and SLIT each has its unique pros and cons. Shared decision-making between patients and providers will be essential to achieve optimal care for patients with peanut allergy (Kim 2020).

U.S. Food and Drug Administration (FDA)-Approved Indications for Palforzia

• Palforzia is an oral immunotherapy indicated for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut. Palforzia is approved for use in patients with a confirmed diagnosis of peanut allergy. Initial Dose Escalation may be administered to patients aged 4 through 17 years. Up-Dosing and Maintenance may be continued in patients 4 years of age and older. 
  
  Palforzia is to be used in conjunction with a peanut-avoidant diet. 
  
  Limitation of Use: Not indicated for the emergency treatment of allergic reactions, including anaphylaxis.

On January 31, 2020, the FDA approved the Biologic License Application (BLA) for Palforzia [peanut (Arachis hypogaea) allergen powder-dnfp] (Aimmune Therapeutics, Inc.). Palforzia is an oral immunotherapy indicated for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut. Palforzia is manufactured from defatted peanut flour and is available in capsules containing 0.5 mg, 1 mg, 10 mg, 20 mg, and 100 mg peanut protein, and a sachet containing 300 mg peanut protein. Initiation of Palforzia is approved in patients aged 4 through 17 years with a confirmed diagnosis of peanut allergy. Palforzia may be continued in patients 18 years of age and older. Palforzia is to be used in conjunction with a peanut-avoidant diet.

The efficacy of Palforzia for the mitigation of allergic reactions, including anaphylaxis, in patients with peanut allergy was investigated in Study 1 (NCT02635776). In a phase 3 trial, the authors screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive Palforzia (AR101; a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. Of the 551 participants who received Palforzia or placebo, 496 were 4 to 17 years of age (372 in the Palforzia group; 124 in the placebo group). The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. Results showed that 67.2% of the Palforzia group, as compared with 4.0% of the placebo group, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; p<0.0001). Other secondary endpoints included 76.6% of the Palforzia group as compared with 8.1% of the placebo group, were able to ingest a dose of 300 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 68.5 percentage points; 95% confidence interval, 58.6 to 78.5; p<0.001). Also, 50.3% of the Palforzia group as compared with 2.4% of the placebo group, were able to ingest a dose of 1000 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 47.8 percentage points; 95% confidence interval, 38.0 to 57.7; p<0.001). The completer population consisted of all subjects aged 4 through 17 years in the ITT population who stayed on treatment and had an evaluable exit DBPCFC (296 Palforzia, 116 placebo). In the completer population, the proportion of subjects who tolerated single highest doses of 300 mg, 600 mg, and 1000 mg with no more than mild symptoms at the exit DBPCFC were 96.3%, 84.5%, and 63.2%, respectively for Palforzia-treated subjects compared with 8.6%, 4.3%, and 2.6% for placebo-treated subjects. Efficacy was not shown in the participants 18 years of age or older. The authors concluded that in this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with Palforzia resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. There are no data available on the efficacy of Palforzia in individuals who did not progress onto Maintenance therapy. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. During the exit food challenge, the maximum severity of symptoms was moderate in 25.3% of the participants in the active-drug group and 58.9% of those in the placebo group and severe in 5.1% and 10.5%, respectively. The incidence of mild-to-moderate adverse events was high in both the active and placebo groups, but serious adverse events were significantly higher in the active group. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. The most common adverse reactions reported in subjects treated with Palforzia (incidence ≥ 5% and at least 5 percentage points greater than that reported in subjects treated with placebo) are abdominal pain, vomiting, nausea, oral pruritus, oral paresthesia, throat irritation, cough, rhinorrhea, sneezing, throat tightness, wheezing, dyspnea, pruritus, urticaria, anaphylactic reaction, and ear pruritus (Vickery 2018).

The first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product, was a randomized, double-blind, placebo-controlled trial conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms. Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both p < 0.0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs. The authors concluded that, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults (Bird 2018) .

While peanut oral immunotherapy (POIT) represents a promising treatment for peanut allergies in children, safety concerns remain a common barrier to widespread adoption. The authors aimed to systematically assess available evidence to determine the risk and frequency of adverse events occurring during POIT, and examine study-level characteristics associated with their occurrence and severity. A systematic search of MEDLINE, EMBASE, and Web of Science was conducted through April 2019. Controlled and non-controlled studies evaluating POIT were eligible. Twenty-seven studies, involving 1488 subjects, were included. Adverse events to POIT were common and led to treatment discontinuation in 6.6% of children (95% CI 4.4-9.0; 27 studies, I2 = 48.7%). Adverse events requiring treatment with epinephrine occurred among 7.6% (4.5-11.4; 26 studies, I2 = 75.5%) of participants, at a rate of 2.0 per 10,000 doses (0.8-3.7; 15 studies, I2 = 64.4). Use of a rush treatment phase and targeting a higher maintenance dose were associated with a higher risk and frequency of epinephrine use, while using co-treatments in addition to POIT was associated with a lower risk of treatment discontinuation due to adverse events. While adverse events to POIT are common, this study provides promising explorative evidence that certain modifications to existing treatment protocols could significantly improve treatment outcomes (Grzeskowiak 2020).

Palforzia carries a black box warning for risk of anaphylaxis. Anaphylaxis has been reported during all phases of Paliforzia dosing, including Maintenance and in subjects who have undergone recommended Up-Dosing and dose modification procedures. Other warnings and precautions include risk of asthma, eosinophilic esophagitis, and chronic or recurrent local gastrointestinal allergic symptoms. The most common adverse reactions reported in subjects treated with Palforzia (incidence 5% or more and at least 5 percentage points greater than that reported in subjects treated with placebo) includes abdominal pain, vomiting, nausea, oral pruritus, oral paresthesia, throat irritation, cough, rhinorrhea, sneezing, throat tightness, wheezing, dyspnea, pruritus, urticaria, anaphylactic reaction, and ear pruritus (Aimmune Therapeutics, 2020).

Palforzia use is contraindicated for uncontrolled asthma, history of eosinophilic esophagitis or other eosinophilic gastrointestinal disease.

The FDA requires enrollment in the Risk Evaluation and Mitigation Strategy (REMS) program called the Palforzia REMS Program. Requirements include the following:

• Health care providers who prescribe Palforzia must be certified with the program by enrolling.
• Health care settings must be certified in the program, have on-site access to equipment and personnel trained to manage anaphylaxis, and establish policies and procedures to verify that patients are monitored during and after the Initial Dose Escalation and first dose of each Up-Dosing level.
• Patients must be enrolled in the program prior to initiation of Palforzia treatment and must be informed of the need to have injectable epinephrine available for immediate use at all times, the need for monitoring with the Initial Dose Escalation and first dose of each Up-Dosing level, the need for continued dietary peanut avoidance, and how to recognize the signs and symptoms of anaphylaxis.
• Pharmacies must be certified with the program and must only dispense Palforzia to health care settings that are certified or to patients who are enrolled depending on the treatment phase.

Jones et al (2022) noted that for young children with peanut allergy, dietary avoidance is the current standard of care (SOC).  In a randomized, double-blind, placebo-controlled study, these investigators examined if peanut oral immunotherapy (OIT) could induce desensitization (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness following discontinuation of immunotherapy) in this population.  This trial was carried out in 5 U.S. academic medical centers.  Eligible participants were children aged 12 years to younger than 48 months who were reactive to 500-mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC).  Participants were randomly assigned in a 2:1 allocation ratio, to receive peanut OIT or placebo for 134 weeks (2,000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment.  The primary outcome was desensitization at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5,000 mg in the intention-to-treat population.  Safety and immunological parameters were evaluated in the same population.  Between August 13, 2013 and October 1, 2015, a total of 146 children (median age of 39.3 months; inter-quartile range [IQR] of 30.8 to 44.7), were randomly assigned to receive peanut OIT (96 participants) or placebo (50 participants).  At week 134, 68 (71 %, 95 % CI: 61 to 80) of 96 participants who received peanut OIT compared with 1 (2 %, 0.05 to 11) of 50 who received placebo met the primary outcome of desensitization (risk difference [RD] 69 %, 95 % CI: 59 to 79; p < 0.0001).  The median cumulative tolerated dose during the week 134 DBPCFC was 5,005 mg (IQR 3,755 to 5,005) for peanut OIT versus 5 mg (0 to 105) for placebo (p < 0.0001).  After avoidance, 20 (21 %, 95 % CI: 13 to 30) of 96 participants receiving peanut OIT compared with 1 (2 %, 0.05 to 11) of 50 receiving placebo met remission criteria (RD 19 %, 95 % CI: 10 to 28; p = 0.0021).  The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0 to 2,755) for peanut OIT and 0 mg (0 to 55) for placebo (p < 0.0001).  A significant proportion of participants receiving peanut OIT who passed the 5,000 mg DBPCFC at week 134 could no longer tolerate 5,000 mg at week 160 (p < 0.001).  The participant receiving placebo who was desensitized at week 134 also achieved remission at week 160.  Compared with placebo, peanut OIT decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160.  By use of multi-variable regression analysis of participants receiving peanut OIT, younger age and lower baseline peanut-specific IgE were predictive of remission.  Most participants (98 % with peanut OIT versus 80 % with placebo) had at least 1 OIT dosing reaction, predominantly mild-to-moderate and occurring more frequently in participants receiving peanut OIT.  A total of 35 OIT dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut OIT.  The authors concluded that in children with a peanut allergy, initiation of peanut OIT before age 4 years was associated with an increase in both desensitization and remission.  Development of remission correlated with immunological biomarkers.  These findings suggested a window of opportunity at a young age for intervention to induce remission of peanut allergy.

Casale and Irani (2023) stated that peanut allergy could result in severe, sometimes fatal hypersensitivity reactions that place a considerable burden on the lives of patients.  These investigators reviewed the 1st FDA-approved immunotherapy for the mitigation of allergic reactions following accidental peanut exposure, peanut (Arachis hypogaea) allergen powder-dnfp (PTAH).  They highlighted the unmet need for patients with peanut allergy, described the therapeutic landscape, and reviewed the development of and clinical data for PTAH.  The authors concluded that PTAH offers a standardized preparation of peanut allergen, with a tolerability and efficacy profile clearly defined via its robust clinical development and trial program.  In children 4 to 17 years of age, PTAH provides a standardized, approved product that many clinicians sought before initiating oral immunotherapy.  PTAH reduced the likelihood of more severe reactions following exposure to peanut protein; although peanut avoidance remains essential, PTAH will enable more individuals with peanut allergy to participate in activities of daily life (ADL) with less anxiety.

Portnoy et al (2023) noted that PTAH is the 1st oral immunotherapy indicated for children aged 4 to 17 years with peanut allergy.  There are limited real-world data on patients treated with PTAH.  These investigators characterized pediatric patients treated with PTAH and associated treatment patterns in U.S. clinical practice.  U.S.-based physicians with allergy/immunology training treating patients with peanut allergy aged 4 to 17 years with PTAH were recruited from an existing physician panel and completed an online case report form (October 2021 to December 2021) with data abstracted from patient medical charts.  Physician practice circumstances, patient characteristics, and PTAH treatment patterns were reported.  Time to reach the 300-mg dose and treatment persistence were examined using Kaplan-Meier analysis.  A geographically balanced sample of 43 physicians contributed data for 118 demographically diverse pediatric patients.  Patients had heterogeneous diagnostic test results, with a wide range of peanut-specific IgE levels; 6.8 % received an oral food challenge.  During the up-dosing phase, there were no temporary interruptions and 5.1 % of patients required down-dosing.  Patients reached the 300-mg dose at a median of 21.3 weeks post-initiation.  The rate of PTAH persistence at 24 weeks was 93.4 %.  Only 1 patient discontinued treatment due to treatment-related systemic allergic symptoms and the remaining discontinuations were for reasons other than treatment-related symptoms.  Prophylactic anti-histamines were used by 33.9 % of patients to prevent PTAH side effects.  The authors concluded that PTAH was prescribed in demographically diverse patients with a wide range of peanut-specific IgE levels.  Treatment persistence with PTAH was high in this study population, with a small number of patients experiencing treatment modification.

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References