US FDA AdComm Win For Aimmune’s Palforzia Bodes Well For DBV’s Peanut Allergy Patch
Executive Summary
Aimmune’s oral immunotherapy seems destined to come to market with a strict REMS, though analysts do not expect this will impact adoption. DBV is awaiting word on whether the FDA will review its second attempt at a BLA submission for Viaskin Peanut.
A US Food and Drug Administration panel’s positive review of Aimmune Therapeutics Inc.’s peanut allergy oral immunotherapy Palforzia would seem to bode well for DBV Technologies SA’s epicutaneous immunotherapy Viaskin Peanut, assuming the latter’s resubmitted application is up to snuff on manufacturing and the firm is prepared with a Risk Evaluation and Mitigation Strategy.
Although some analysts see the DBV patch product as having a more attractive safety profile than Aimmune’s Palforzia, the recent advisory committee review’s focus on a restrictive Risk Evaluation and Mitigation Strategy (REMS) for the oral immunotherapy may be an indication DBV should be prepared on the REMS front as well.
In the case of Palforzia, however, analysts do not expect the REMS requirements will be a rate-limiting factor to adoption in a potential $1bn market that currently lacks an approved, standardized treatment for peanut allergy.
On 13 September, the Allergenic Products Advisory Committee endorsed the efficacy and safety of Palforzia (peanut, Arachis hypogaea, allergen powder for oral administration) by votes of 7-2 and 8-1, respectively. (See sidebar.)
Aimmune is seeking approval to reduce the incidence and severity of allergic reactions, including anaphylaxis, after accidental exposure to peanut in patients ages 4-17 years with a confirmed diagnosis of peanut allergy.
Given the advisory committee’s nod, the agency appears on track to approve Palforzia by the end of January.
That timeline will give the FDA and Aimmune four months to reach agreement on the specifics of a REMS that the agency has deemed necessary to mitigate the risk of systemic allergic reactions, including anaphylaxis.
In Pursuit Of A Standardized Treatment
Peanut allergy is the most common food allergy in the US, affecting approximately 2% of children.
The current standard of care is strict peanut avoidance and management of symptoms with antihistamines or epinephrine following accidental exposure. However, avoidance is difficult, and accidental exposures resulting in allergic reactions are common.
Although some allergists offer oral immunotherapy, these unregulated products are typically formulated in physicians’ offices using commercial food product, and they vary by dosage and treatment protocol.
“We need a defined therapy so patients and physicians know what to expect in terms of outcomes and side effects” from oral immunotherapy, Aimmune consultant James Baker, director of the food allergy center at the University of Michigan, told the advisory committee.
“We need a defined therapy so patients and physicians know what to expect in terms of outcomes and side effects” from oral immunotherapy. – University of Michigan’s James Baker
In the pivotal Phase III PALISADE trial, Palforzia (also known as AR101) met the prespecified success criterion on the primary endpoint – the proportion of patients ages four to 17 years in the intent-to-treat population who tolerated a dose of at least 600mg of peanut protein, with no more than mild symptoms, at the double-blind, placebo-controlled food challenge at the end of the maintenance period. The treatment difference between Palforzia and placebo was 63.2%. (Also see "Aimmune Accelerates Commercial Planning For Peanut Allergy Drug " - Scrip, 20 Feb, 2018.)
However, in controlled trials, Palforzia was associated with a higher rate of systemic allergic reactions and rescue epinephrine use compared with placebo.
The drug is proposed to be given in three dosing phases: initial dose escalation from 0.5mg to 6mg in a single day; up-dosing every two weeks for 24 weeks; and maintenance dosing of 300mg a day. In the clinical trial, the initial dose escalation and each new step-up in dosing were administered in the clinic under observation.
In the controlled safety population, 9.4% of subjects taking Palforzia reported systemic allergic reactions during initial dose escalation and up-dosing combined, compared to 3.8% of subjects in the placebo group. During the maintenance dosing phase, 8.7% and 1.7% of Palforzia and placebo subjects, respectively, reported systemic allergic reactions.
In the controlled safety population, epinephrine use to treat systemic allergic reactions was reported by 6.1% of Palforzia recipients and 3.1% of placebo recipients during initial dose escalation and up-dosing combined. During the maintenance phase, epinephrine use to treat systemic allergic reactions was reported by 6.1% and 1.7% of Palforzia and placebo subjects, respectively.
Aimmune and its experts said some allergic reactions are expected with daily dosing of an oral immunotherapy. However, the risks of Palforzia are well characterized, and frequency of allergic reactions declined the longer that subjects were on the therapy, the company said. (Also see "Aimmune’s Peanut Allergy Immunotherapy Brings Safety Concerns To US FDA Panel" - Pink Sheet, 11 Sep, 2019.)
Voluntary Vs. Required Risk Management Measures
Aimmune proposed a voluntary risk management plan that included the following:
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- Initial dose escalation and the first dose of each up-dosing level be administered in a facility equipped to treat systemic allergic reactions;
- Patients have a valid prescription for injectable epinephrine prior to initiation of Palforzia;
- Drug distribution limited to specialty pharmacies; and
- Packaging designed so that patients only receive their appropriate dose.
However, the agency appears to have deemed the voluntary plan insufficient. In framing the voting question on safety, the agency said it would require a REMS with the following elements to assure safe use:
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Documentation that any patient prescribed Palforzia has a valid prescription for injectable epinephrine;
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Caregiver/patient attestation to carry injectable epinephrine while on Palforzia; and
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A requirement that initial dose escalation and the first dose of each up-dosing level be administered in a certified facility capable of treating system allergic reactions.
Some committee members did not think the agency’s REMS proposal went far enough and pushed for additional measures. These included: informed consent; documentation that patients and their families understand they are to continue to avoid eating peanut-containing products; and guidance on missed doses.
Panelists also discussed the need to clearly spell out when epinephrine should be administered, as well as the recommendation that patients avoid certain activities, such as exercising or taking a hot shower, shortly after dosing to reduce the risk of experiencing an allergic reaction.
FDA officials said the REMS was still under discussion with the company. However, labeling would include a boxed warning on the risk of systemic allergic reactions as well as a patient Medication Guide.
In a statement after the meeting, Aimmune said it proposed a boxed label warning consistent with immunotherapies to treat allergic conditions.
“Patient safety has been central to us since the beginning of the Palforzia development program. We are gratified to be aligned with FDA in our focus on patient safety,” Aimmune president and CEO Jayson Dallas said in the statement. “We look forward to working with the agency to finalize our proposals, which we believe will support the safe and appropriate use of Palforzia.”
Panel Outcome As Expected
In the analyst community there appeared to be little surprise at the outcome of the advisory committee.
In a 13 September note, Credit Suisse analyst Evan Seigerman said the REMS requirements being discussed were “reasonable.”
“Panelists generally agreed that education of patients, caregivers and providers is a necessary component for approval, and discussed ways to incorporate this and other safeguards into a potential REMS strategy to minimize risk,” he said.
“We do not see a rigorous REMS as a major gating factor going forward.” – JMP Analysts
In a 16 September note, JMP Securities analysts said they were not surprised that Aimmune and the FDA will further define the REMS plan to incorporate some of the committee's feedback on optimal conditions for use and symptoms warranting rescue epinephrine.
“AIMT has already made strides in this area with a field team in place to provide allergist support for optimal Palforzia administration, and combined with the strong motivation for a therapy in the peanut allergy community, we do not see a rigorous REMS as a major gating factor going forward,” the JMP analysts said.
Rather, “the key debate now in our minds is the size of the commercial opportunity” which “could be in the $1bn range, mostly coming from the US, driven by the significant size of the food allergy market, with 6m kids affected in the US alone,” the analysts said.
Seeing Viaskin In The Rear View Mirror
Aimmune may have the market to itself only for a short period of time before another competitor launches.
DBV’s Viaskin Peanut is an electrostatic patch containing solubilized antigen in a condensation chamber, where it can be captured by Langerhans cells in the upper epidermis. Like Palforzia, Viaskin Peanut holds both fast track and breakthrough therapy designation.
DBV submitted the biologics license application (BLA) on 6 August after withdrawing the original submission in December due to the need to provide additional information on manufacturing procedures and controls. (Also see "Keeping Track: Amarin And Nektar Signal Delays, DBV Returns, And Provention Notches A BTD" - Pink Sheet, 11 Aug, 2019.) The company told Scrip it expects to hear around 5 October whether the BLA is accepted for review.
The BLA seeks approval for treatment of peanut-allergic children ages four to 11 years old. However, Viaskin Peanut missed the primary endpoint in the Phase III PEPITES trial.
Although a statistically significant greater proportion of patients treated with Viaskin Peanut had an increase in the amount of peanut protein required to elicit an allergic reaction during the food challenge compared with placebo (treatment difference = 21.7%), the primary endpoint, which evaluated the 95% confidence interval in the difference in response rates between the active and placebo arms, did not reach the prespecified 15% lower bound threshold.
Yet, some analysts believe Viaskin may bring a better safety profile.
The Palforzia panel “maintained an intense focus on safety, an area in which Viaskin Peanut has been differentiated.” – Morgan Stanley analysts
The company reported a low rate of treatment-related epinephrine use (2.9% treatment group vs. 0.8% placebo group) in PEPITES. There were 10 cases in eight Viaskin Peanut patients (3.4%) of possibly or probably treatment-related anaphylaxis.
When asked whether it submitted a REMS with its BLA, the company said it was not able to discuss the contents of its application.
In a 15 September note, Morgan Stanley analysts saw three key positives from the Palforzia advisory committee for Viaskin Peanut's prospects.
“We think there was a clear consensus that peanut allergy presents a true unmet need that providers & patients would like to address with a safe & effective therapy,” analysts Vikram Purohit and Matthew Harrison said.
“We found that the panel maintained an intense focus on safety, an area in which Viaskin Peanut has been differentiated,” the analysts said. In addition, approval of Palforzia “would help define a regulatory pathway for future peanut allergy treatments including Viaskin Peanut.”
While the panel was overall a positive for DBV, the agency’s decision to accept or reject the Viaskin Peanut resubmission remains a key overhang, the Morgan Stanley analysts said.
In a 13 September note, SVB Leerink analysts said the panel’s acceptance of the Palforzia pivotal trial’s use of an oral food challenge endpoint bodes well for DBT because this was the primary efficacy endpoint in the PEPITES trial.
“Given the robust efficacy data of Palforzia, however, the read through to DBVT is somewhat less clear as Viaskin Peanut ... did not meet the pre-specified criterion for a positive trial result,” the analysts said.
Nevertheless, given that DBV’s epicutaneous immunotherapy leverages a different modality with a potentially better safety profile and added convenience, “we remain optimistic that with the resubmitted BLA, panelists and regulators will be receptive to Viaskin Peanut.”