By Henry Ehrlich
Ready for prime time or not, a pharmaceutical version of peanut oral immunotherapy (OIT) may be coming to a drugstore near you in a couple of years. At the beginning of the summer, Aimmune Therapeutics, Inc., a privately held biopharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) had granted Breakthrough Therapy Designation status to AR101 for oral immunotherapy for peanut-allergic children and adolescents 4-17 years of age. Fast-tracking is getting a lot of play these days, between this and the “female Viagra.” Perceived medical necessity trumps caution.
According to the press release, Breakthrough Therapy Designation, is “intended to facilitate and expedite development and review of new drugs and biologics for the treatment of a serious or life-threatening condition, requires preliminary clinical evidence that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints.” Much to the chagrin of the doctors around the country who are already offering oral immunotherapy using peanut flour and other allergens, no doubt.
A couple of weeks ago, there appeared briefly on YouTube an investor presentation by Aimmune’s CEO, Stephen Dilly, which I watched a couple of times and found highly revealing, although not necessarily flattering to the company. Their advisors must have had thoughts similar to mine since it received the Snapchat treatment, and disappeared. (If I get any of what follows wrong, I apologize; I would love to check it against the actual video, but I can’t.)
Among my concerns, it had an elementary mistake about anaphylaxis. Contrary to what the CEO said, when you have anaphylaxis, your blood pressure falls drastically and the pulse weakens. Higher blood pressure is the solution, not the problem, thanks to epinephrine. (Note: anaphylaxis doesn’t always involve catastrophic loss of blood pressure, and epinephrine is the recommended first line therapy in the event of a reaction.)
Second, the peanut-in-a-pill only contains three of the four storage proteins associated with anaphylaxis, Arah 1, 2, and 6, but not 3, and neither the birch pollen analogue Arah 8 nor the lipid transfer protein Arah 9, which are in the whole package you get from Planters. This was done because otherwise one of the world’s most ubiquitous foodstuffs wouldn’t be patentable. The three-component combo is now locked up, like snap, crackle, and pop. If it works as described, many patients will be “bite proof” (able to tolerate a trace exposure) but not all. Maybe the firm intends to create another pill with the missing components, as they prepare to roll out one allergen after another.
This was an investor forum and the big swinging checkbooks in the audience naturally wanted to hear how they were going to make money. Economies of scale make a good story for investors, but the example used for making this point was gratuitous, as if the speaker needed a straw man to drive his point home. He twice referred to a major research institution and asserted it has full time employees grinding up whole peanuts. The story was highly misleading, at best. The institution in question only does research and procures its supplies according to protocol. It has no need to crank the stuff out. Aimmune’s idea of a refined product using peanuts sourced from a single grower is well suited to meet pharmaceutical standards and the marketplace, but it is not competitive with a research institution that has no patients in treatment outside of clinical trials.
The most interesting section concerned the incentives for physicians. Apparently the doctor visits and up-dosing of allergen can be coded as “slow-graded challenges” or words to that effect, which I gather is the case with ordinary private practice OIT. Mr. Dilly spoke of 11 biweekly office visits at a reimbursement rate of about $250, with net payment to the doctor in the range of $2500-3000. I can’t recall his words verbatim, but they were something like, “Allergists will finally have something they can prescribe and get paid for.” Admittedly, many allergists are frustrated that they can’t do more for their food allergy patients, although I’m not sure this wording will jibe with their vision of themselves as healers.
I have nothing against this form of therapy, but I do worry how it will proliferate. The history of allergy treatment is that when mass-market remedies arrive, they are taken up with great enthusiasm, but their limitations are revealed with time and wider use. This was certainly the case with Singulair, the asthma pill, as my cousin Dr. Ehrlich recounted in our book, when many primary care physicians decided to treat asthma without referral to specialists. The same happened with combination inhalers Advair and Symbicort; millions of prescriptions are written for patients who aren’t even helped by the steroid component and they are renewed on autopilot without regular evaluation.
As for food allergies, many current patients are avoiding foods that they aren’t even allergic to on the basis of broad panels of blood tests that aren’t diagnostic, not to mention being prescribed epinephrine at a cost of hundreds of dollars a year. Aimmune’s tiny and promising trials begin with food challenges to make sure the subjects are allergic, but once there is a pharmaceutical treatment, I have a feeling lots of non-allergic patients will beat a path to the drugstore with their prescriptions on the basis of modest blood antibody levels and no reaction history. Some patients will have gastric reactions, as about 20% of Aimmune’s test subjects did, and have to drop out. But others will not experience adverse reactions because they aren’t really allergic.
One favorable outcome could be that instead of approving every prescription, insurance companies will require more definitive diagnosis.
A further concern is what will happen to patients after they have reached maintenance. Will they have to continue taking only their three-component designer drug, will they be able to shift to generic peanuts, or will they be able to eat Thai food a few times a week? What will happen when they exceed the bite-proof threshold achieved with ARA101? Will they have anaphylaxis? Will their mouths itch because the drug has done nothing for the components other than 1, 2, and 6?
I hope this therapy will one day be part of a repertoire of treatments for the peanut epidemic. Maybe Aimmune will make its case better in the future as it addresses patients. I have written enough investor presentations in my time to know that the human need behind any product or service, no matter how compelling, comes out sounding like a cash cow.
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“…the peanut-in-a-pill only contains three of the four storage proteins associated with anaphylaxis, Arah 1, 2, and 6, but not 3, and neither the birch pollen analogue Arah 8 nor the lipid transfer protein Arah 9, which are in the whole package you get from Planters.”
This is a huge problem considering reactions to any of the proteins can result in a severe anaphylactic incident.
As always, great thoughtful analysis. I also want to point out that we may not have even identified all of the possible allergenic components of the peanut. There is an article published a few months back in JACI, identifying novel peanut components – Peanut defensins: Novel allergens isolated from lipophilic peanut extract (http://www.jacionline.org/article/S0091-6749(15)00570-9/abstract). I would hate to have my son go through such an involved treatment only to find out he’s still sensitized to other portions of the peanut that aren’t included in this pill.