Aimmune Therapeutics Inc. is navigating a host of new challenges as it launches Palforzia, the first peanut allergy immunotherapy to be approved by the US Food and Drug Administration. Most notably, it must get physician practices and individual allergists certified to administer the treatment.
Aimmune (NASDAQ: AIMT) president and CEO Jayson Dallas talked to our sister publication the Pink Sheet about the certification process, part of the company’s Risk Evaluation and Mitigation Strategy (REMS), in an interview in New York last month. He also discussed the complexities involved in manufacturing the food-derived treatment.
Some analysts have speculated that the restriction on administration might slow the uptake of Palforzia and limit its use, but Dallas does not see it as a significant hurdle. He said clinics must go online and certify via a box check-off that they have the experience and staff to do immunotherapy and have access to the emergency allergic reaction treatment EpiPen (epinephrine injection) at all times. The certification process is similar for physicians, who are not required to go through training.
The US Food and Drug Administration approved Palforzia [peanut, (Arachis hypogaea) Allergan Powder-dnfp] on 31 January to mitigate allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut in patients ages four to 17 years.
Palforzia was associated with a higher rate of systemic allergic reactions and epinephrine use in clinical trials, and to mitigate this risk the agency required Aimmune to implement a REMS.
SETTING PATIENT EXPECTATIONS
Members of FDA’s advisory committee had requested that additional measures be included in the REMS beyond those suggested by the agency, including informed consent and documentation that patients and their families understand they are to continue to avoid eating peanut-containing products.
The final REMS incorporates the panel’s recommendations. Patients must certify that they understand how Palforzia works and will always carry an EpiPen and return to the practice to get new EpiPen prescriptions when they run out or expire.
“They have to understand that for the first couple months they may have allergic reactions to treatment that will go away over time as efficacy gets better,” he said. “This is where setting expectations up front is critical.”
Patients check-off the certification form online in the physician’s office. The patient data goes to a third-party REMS administrator, which submits a report to FDA every six months. Dallas said it is almost exactly the kind of consent that allergy practices require from children undergoing immunotherapy for grass and pollen allergies.
Once the patient is cleared to receive the product, the powder in the capsules, which consists of peanut flour, is emptied onto semisolid food, such as applesauce, yogurt or pudding. Patients are given increasing doses in three sequential phases to desensitize them. They receive the initial single day dose escalation in the doctor’s office and then receive a 14-day supply from one of three specialty pharmacies that are certified to distribute it, AllianceRx Walgreens, CVS Specialty, and Optum Specialty Pharmacy. They return to the doctor’s office in two weeks to receive the second dose and then are put on a maintenance dose of 300 mg daily.
Aimmune’s 80-person field team began meeting with allergists on 4 February to encourage them to incorporate Palforzia into their practice. And the company announced on 16 March that the first patients in the US are being treated with Palforzia.
The company launched a REMS website which lists the prescribers and healthcare settings that are certified to administer Palforzia capsules.
MANUFACTURING ADVANTAGES AND CHALLENGES
The nature of the product also involves novel manufacturing considerations. Dallas said that he had received a lot of questions about how the company was faring with the chemistry, manufacturing and control (CMC) processes, as they pose hurdles for many biotech companies in the final stages of FDA review.
Dallas said most manufacturing challenges arise during the production of the active pharmaceutical ingredient (API), which has to be made at the same quality and scaled up for commercial marketing.
“Our process in a way is fortunate because our API is roasted, defatted ground peanut flour. So we don’t have a whole lot of complexity and challenge on the API production side or on the ability to scale up or scale down API supplies,” Dallas said.
He noted that the biggest challenge is getting the API accepted as a good manufacturing process drug substance. “We have to do the allergen expression analytic and measure so that every piece of every batch has exactly the right allergenic expression on it,” he said. “That analytic that turns it into drug substance is the most complicated part of the process.”
The product then goes through a sterile manufacturing process and a comprehensive individual dose measuring process at Aimmune’s plant. The entire process is based in the US. The peanuts are grown in Georgia, the manufacturing is done in Clearwater, FL, and the packaging is done in Illinois.
“It has not been without complexity but we have not run into any issues,” Dallas said. “We had an FDA inspection and did very well.”
During a 16 March call with analysts, Dallas acknowledged the impact that the coronavirus will likely have on the launch of Palforzia, but he said manufacturing operations remain fully operational and the company has sufficient Palforzia finished product on hand to meet demand for the foreseeable future and expects to remain in a position to continue to produce new product as necessary.
“We don’t have an end date here, but we are able to meet demand for quite some time,” he stated.
RIVAL STUMBLES AGAIN
DBV Technologies (NASDAQ: DBVT), which is looking to be the second entry into the peanut allergy treatment space, is facing another delay with review of its Viaskin Peanut patch. On 16 March, DBV announced that FDA had informed the company that during its ongoing review of the BLA it “identified questions regarding efficacy, including the impact of patch-site-adhesion.”
Therefore, the Allergenic Products Advisory Committee that had been slated for 15 May will not take place as scheduled.
DBV said it may submit additional information on patch-site adhesion from its clinical program as well as long-term efficacy results from the three-year open-label extension study, PEOPLE, to answer FDA’s questions. DBV said to its knowledge the target action date of 5 August remains unchanged, but noted that if it submits additional information to FDA, that may constitute a major amendment to the BLA and could extend the target action date.
It’s the second significant review setback for Viaskin Peanut. The company withdrew its BLA in December 2018 after FDA requested additional data on manufacturing procedures and quality controls. The application was resubmitted on 6 August and DBV announced in October that FDA had accepted the BLA with a user fee action date of 5 August.
Dallas expressed skepticism that Viaskin Peanut would clear the agency. “It’s a very long reach to believe it is going to be approved,” he said. “None of their data is statistically significant.”
Even if Viaskin Peanut does get approved, Dallas predicted that the patch won’t work in eight of 10 kids who use it. He said the patch includes a miniscule dose and requires proteins to be dissolved in sweat and absorbed. “So the concept of that getting into the body and generating immunity is tricky,” he said. “It’s a problem for all patches.”
CHANGING MEDICAL PRACTICE
Dallas has been involved in many high-profile launches over the past 25 years. Prior to joining Aimmune in June 2018, he served as chief commercial officer at Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), overseeing the launches of its first two products, Mepsevii (vestronidase alfa-vjbk) and Crysvita (burosumab).
He also served as general manager of Roche in the UK and head of global commercial strategy groups focused on oncology, immunology, and ophthalmology at Genentech Inc., and headed the specialty medicines operating unit for Novartis (NYSE: NVS) in the US.
The launch of Palforzia differs from his previous work as it breaks totally new ground. “To actually get something approved that is going to rewrite medical textbooks and change medical practice all over the world is just phenomenal,” he said.
Aimmune, previously called Allergen Research Corporation, was established in 2011 with seed funding from the nonprofit group Food Allergy Research & Education. The group held a research retreat earlier that year with members of the food allergy community to reach a consensus on the future of food allergy research. Aimmune said the participants, which included members of the pharmaceutical industry and representatives of the FDA and the National Institutes of Health, decided to focus on oral immunotherapy, the practice of giving a small amount of the allergen protein with a gradual increase in dose to desensitize a patient.
On 16 March, Aimmune announced its analysis of ARC004, the open-label follow-on trial to the 52-week pivotal PALISADE trial. The data had been scheduled to be presented at the American Academy of Allergy, Asthma & Immunology’s annual meeting in Dallas, which was cancelled due to the COVID-19 pandemic. The company said the analysis showed that patients tolerated more peanut protein, experienced fewer adverse events and continued immunomodulation as evidenced by reductions in peanut-specific immunoglobuin (IgE) blood levels after an additional 56 weeks of daily treatment with Palforzia.
Aimmune has a Phase 3 study underway to expand the indication for use in children aged 1 to less than four years. Last month it licensed AIMab7195, an investigational anti-IgE monoclonal antibody with three mechanisms of action, from Xencor (NASDAQ: XNCR). The company’s goal is to see if a larger proportion of patients can achieve remission from their food allergy more quickly with concomitant therapy with AIMaB7195 than on immunotherapy alone.
GAINING REGULATORY CONFIDENCE
Dallas said getting the first food-derived medicine through the FDA’s robust review process “gives us a lot of comfort that our concept and the platform of characterized oral immunotherapy actually works and we can show it works and we can persuade regulators that it is a valuable therapeutic option for people with food allergies.”
The company has two additional products in the pipeline, AR201 in Phase 2 for treatment of egg allergy, and a single therapy for treatment of allergies to five tree nuts (walnuts, hazelnuts, cashews, pistachios and pecans) in pre-IND development. Dallas said this is a new challenge in terms of how you make a multitherapeutic in a single product and deal with regulators. But he said doing a development program for five nuts would take too long and be too complicated and be clinically quite challenging for individuals to desensitize five different times to five different things.
“We think it’s much more elegant to do it in one,” he said.
The experience gained in getting Palforzia through regulatory authorities, past payers and convincing physicians to give it to patients will provide the company important lessons that will help it with the additional programs.
Next up, though, is the expected approval of Palforzia in Europe at the end of the first quarter. Dallas said the company will launch in Germany first, as other countries require a product to obtain reimbursement prior to marketing.