PERTH, Australia – Melbourne-based Aravax Pty Ltd. is progressing its peanut allergy immunotherapy to phase II trials after reporting positive phase I data for lead candidate PVX-108.

Aravax is developing PVX-108 as a simple monthly intradermal injection to induce tolerance to peanuts and reduce the risk of severe allergic reactions from accidental exposure. 

"Our product is unlike other approaches that are in later stages of development, and those products generally use natural extracts from peanuts to treat peanut allergy sufferers. Aravax is developing a peptide-immunotherapy approach because it precisely targets the underlying cause of disease to induce tolerance, which can be long-lived, not just short-term desensitization," Aravax CEO Pascal Hickey told BioWorld.

Aravax reported positive phase I results of PVX-108, which showed a favorable safety profile, even in patients with severe peanut allergies.

Comprising two phases, the trial assessed single, ascending doses of PVX-108 and enrolled eight cohorts of six subjects each in the first phase. Subjects of each cohort were randomized to receive PVX-108 or placebo. Cohorts were enrolled one at a time, starting with a single injection, and the dose was escalated for each successive cohort, with the eighth cohort receiving the highest dose. In the second phase, 18 additional subjects were randomized to receive six injections of the highest dose over a 16-week period.

There were no serious adverse reactions in patients receiving PVX-108. Adverse events considered possibly related to treatment were mild or moderate, with the majority being transient, mild injection site reactions. None of the adverse events were deemed of clinical concern by the study safety review committee.

"The real problem is not those mild and moderate reactions; it's the fact that somebody can experience those for a number of years and then one day have a very serious reaction for no good reason. A serious reaction can lead to anaphylaxis, which can be fatal," Hickey said.

"And, peanut allergy is not just about the risk of having a severe reaction; it's about the psychological aspects that it has on the sufferer, as well as the families and immediate friendship circles because everybody is nervous about what foods can be eaten."

The phase II trial program will recruit children, which is the population of patients where the disease carries the greatest impact.

Peanut allergy is prevalent in about 1% to 3% of the global population, with most sufferers experiencing mild reactions such as swelling of the lips or a tingling of the tongue or a moderate rash.

Competitive landscape

There is no approved treatment for peanut allergy; however, there are two products in late-stage development, including Aimmune Therapeutics Inc.'s Palforzia (AR-101), an oral immunotherapy that recently won a positive recommendation from the FDA's Allergenic Products Advisory Committee. (See BioWorld, Sept. 16, 2019.)

Aimmune has taken the natural extract of peanuts and developed a fine-tuned dose-escalation protocol and a product in capsule form that gradually reintroduces peanut flour into the diet of patients with peanut allergies.

"This relies on the practice of whole-allergen immunotherapy, which has been around for 100 years, and it's hardly changed," Hickey said.

"That approach is still being used by allergists around the world today for things like hay fever, house dust mites and a number of other allergies. But for peanut allergy, it's never been taken up widely because it's just too dangerous. In fact, people have died when this approach has been tried."

Earlier this year Aimmune released its phase III trial results, which met the primary endpoint for efficacy, "but they certainly did so at a cost of adverse events that we believe will mean the product isn't for everybody."

In the PALISADE (Peanut ALlergy oral Immunotherapy Study of AR-101 for DEsensitization in children and adults) trial, one-fifth of patients discontinued treatment, and then 14% of the population experienced systemic adverse events. (See BioWorld, Feb. 21, 2018.)

At the other end of the spectrum is DBV Technologies SA, which submitted a BLA to the FDA in October 2018 for its Viaskin Peanut, a whole-allergen immunotherapy that uses an extract of peanut and is a transdermal patch formulation. Unlike Aimmune's phase III trial, DBV's phase III failed to meet the primary efficacy endpoint. (See BioWorld, Oct. 24, 2017.)

DBV's product is "very safe, but it hasn't achieved the efficacy that they hoped for," Hickey said.

"The expectation is that both products will reach the market, and while they will deliver benefits to patients, neither of those two products really deliver everything that people want, which is an immunotherapy that's safe, disease-modifying, and appropriate for everybody with a peanut allergy. And that's what we're aiming for with Aravax.

"The challenge with immunotherapy is to have reprogrammed the immune system so that the allergen is seen as non-pathogenic, and to achieve this, the allergen must be seen by the immune system in a non-inflammatory context," he explained. "That's difficult with most approaches currently available or being developed, and that's the approach that the two market leaders are taking, because the presence of the whole allergen in the product actually triggers inflammatory signals, so you're trying to convince your immune system to tolerate the protein, but when you administer the protein, that's driving inflammation.

"Aravax's solution is to understand the science more from the ground up and identify the key fragments of the allergens that are critical for immune recognition and memory. Lead compound PVX-108 is a mixture of synthetic peptides that represent those critical fragments from those allergens.

"Once we've identified the short sequences that those T cells recognize, we're able to engineer peptides that represent those sequences. More importantly, we can engineer them to make sure they don't drive the acute allergic responses that are really driving the problem, because the inflammation is caused when the whole peanut protein cross-links the IgE on the surface mast cells and basophils, causing them to degranulate and produce a range of inflammatory mediators like histamines.

"Only large proteins are generally capable of doing that," he added. "PVX-108 mimics the presentation of the allergen to the specific T cells in your body, but it does so in a non-inflammatory context because those peptides are not producing acute inflammation."

The product was designed as an intradermal injection because the skin is probably the most important barrier the body has against the invasion from pathogens, so it's "natural to expect that the skin has a high concentration of immune cells, particularly the antigen-presenting cells we're seeking to target. By delivering the dosing to the skin, we target a high concentration of the antigen-presenting cells that will present the peptides to the T cells."

The technology underpinning PVX-108 was developed by Robyn O'Hehir, Jennifer Rolland and Sara Prickett at Alfred Health and Monash University in Melbourne. As co-inventors, they played a significant role in the foundation of Aravax. Prickett is the company's chief scientific officer, O'Hehir is the chief medical officer, and Rolland is semi-retired.

Aravax was incorporated in 2015. The private company has a single major investor, Australia's Medical Research Commercialization Fund (MRCF), which is administered by Brandon Capital.

"Roughly AU$8 million (US$5.3 million) has gone into Aravax, and we've been able to achieve a lot with that amount of money through taking advantage of the Australian R&D tax incentive system," Hickey said.

The company also received a $5 million grant from the Benaroya Research Institute, which was an NIH grant application that was submitted in collaboration with Benaroya and Stanford University.

The company plans a series B fundraising round toward the middle of the year to fund the company through the phase II program. It plans to start the phase II trial by the end of this year.

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