In this video, I discuss the details of the advisory committee that recently occurred regarding Aimmune Therapeutics’ peanut allergy treatment, Palforzia (formerly AR101). The committee voted in support of approval and should pave the way for a positive PDUFA decision.
On this episode, I talk about results from the Gilead Phase 3 NASH trial that announced no improvement in patients treated with Selonsertib (ASK1 inhibitor). I also talk about the DBVT BLA resubmission and a hot hot Q319 trading idea on CBIO.
Hey everybody, I hope you’ve all been enjoying the holidays. I talk about 3 things in this video:
1. The federal reserve and chairman Powell’s comments on their guidance and the economy.
2. DBVT pulling their BLA and my opinion on both them and AIMT.
3. CRISPR/Cas9 and the companies commercializing the tech.
*This is only my opinion and should not be considered financial advice*
The bad: DBVT failed to achieve their primary endpoint. They saw a 21.7% improved response rate with a p-value < 0.00001 but their 95% confidence interval (CI) was 12.4%-29.8%. They needed to reach 15% on the lower bound of the confidence interval, and they were just below that. CIs provide information about the population mean at a specified time. So if repeated samples were taken and the 95% confidence interval was computed for each sample, 95% of the intervals would contain the population mean. The important takeaway for us is that they technically failed, but saw a significant improvement in their Viaskin EPIT product compared to controls.
Following initial conversations with the FDA on these topline efficacy and safety results, DBV will continue ongoing discussions with the agency, and plans to proceed with the BLA preparation process.
Suggesting they are hoping the FDA will still let them submit a Biologics License Application (BLA) despite this CI miss. It will all be up to the agency, but at the point, the market is currently not impressed with this announcement.
The good: In my AIMT post, I wrote that I expected this PEPITES trial to be a success and that both DBVT and AIMT would react positively to the news. The rationale being that if this EPIT product succeeds with only 250μg of peanut protein being exposed to patients, it is more likely that children exposed to 300mg of peanut protein daily will succeed in the DBPCFC.
This failure has led to a ~60% drop in DBVT and ~50% gain in AIMT in anticipation of AIMT getting all the peanut allergic patient market share, if PALISADE is a success.
We’re left with some decisions to make and the next few months WILL be volatile.
For the conservative trader: Sell your AIMT and enjoy the gains. I have a feeling that between now and Jan, 2018 there will be opportunities to buy back in. Any news from the FDA that they are considering approval of the Viaskin Peanut product will send AIMT back to the $25 price level.
For the aggressive trader: Sell a portion of your AIMT and keep some to enjoy any upside regarding announcement of the PALISADE results. The next couple months will be volatile, so I don’t think it’s prudent to leave all your money in the game when a jump this big has just happened.
I’m going to reduce my position and keep a comfortable number of AIMT shares. I plan on buying any dips that are near the $25 price because I am still confident that PALISADE will report positive results We will have to wait and see how regular hours trading goes this upcoming Monday to see how much upside is left in AIMT.
Peanut allergy is reported to affect ~3 million Americans and there are approximately 210,000 emergency department visits attributed to food anaphylaxis in the USA per year (Sicherer SH, 2010, Clark S, 2013). Given that the only treatment for accidental ingestion of allergens is intramuscular epinephrine, companies have sought other ways to help patients with peanut allergies. One of these companies is Aimmune Therapeutics and their AR101 characterized oral desensitization immunotherapy (CODIT).
Oral immunotherapy (OIT) has been suggested as a treatment for allergies for decades, but the research has finally started to catch up and successful protocols now exist to treat patients. Peanut allergic reactions are an Immunoglobulin E (IgE)-mediated type I hypersensitivity reaction. The priming of an allergic person happens often childhood, whereby there is a failure of oral tolerance of an antigen (i.e. certain food proteins). Instead, cell-cell interactions involving T-cells and Dendritic Cells leads to a T-helper-2 cell response, which prompts B-cells to produce allergen-specific IgE. This abnormal IgE presence floods high-affinity FcεRI receptors in cells of allergic-responsive organs including the lungs, skin, gut and blood vessels. Then, in response to an allergen, IgE-FcεRI complexes cross link when IgE binds to the allergen, leading to a cascade of feed-forward events, which can include deadly anaphylaxis (Gould HJ and Sutton BJ, 2008).
Rather than developing a drug to try and disturb the molecular dysfunctions associated with food allergies, OIT accomplishes this by changing the patient’s T cell profile and reducing peanut-specific IgE levels (Moran TP, 2013). The literature demonstrates a variety of studies illustrating that OIT works to reduce sensitivity to food allergies but not cause complete oral tolerance (Moran TP, 2013, Norwak-Wegrzyn A, 2011). The general protocol of OIT involves giving incrementally larger doses of daily peanut protein capsules, starting at 3mg, for 6 months, then daily maintenance doses of 300mg peanut protein for another 6 months (Fig. 1. Adopted from the Aimmune presentation at the BofA Healthcare Conference, 2017). Epicutaneous IT (EPIT) and sublingual IT (SLIT) have also been used to reduce the immunogenicity of peanuts in allergic patients. EPIT and SLIT have the advantage of reducing gastro-related side effects and SLIT has uniquely showed sustained desensitization of peanuts after discontinuing treatment (Yang L, 2017). AIMT’s competitor, DBV technologies, uses their Viaskin product to epicutaneously administer peanut to patients (EPIT), and they will be announcing their Phase III trial results soon. DBV’s Phase II trial (VIPES, NCT01675882) showed a significant response rate in patients (especially children) that used their Viaskin 250μg product compared to placebo.
Figure 1. Aimmune’s AR101 treatment regiment.
Aimmune’s Phase III trial, PALISADE, has two primary endpoints. Peanut allergy desensitization after 12 months in subjects ages 4-17 years who tolerate the highest dose of at least:
600mg (1043mg cumulative, North America)
1000mg (2043mg cumulative, Europe)
of peanut protein with no more than mild symptoms at the exit Double-Blind Placebo-Controlled Food Challenge (DBPCFC). The DBPCFC is carried out by giving gradually higher doses of peanut protein (or placebo) every 20 minutes or so and waiting to observe symptoms of allergy. The final dose in the end points of this study is 600mg and 1000mg, but because the patients will have been given a series of smaller doses before, the total amount they will receive by the end of the test is 1043mg and 2043mg, respectively. They have enrolled ~500 patients, and randomized them 3:1 to receive the proprietary AR101 or placebo.
Here are the important positive points regarding this trial:
The only patients that will be included in the data are those who undergo the DBPCFC, and thus must have completed the entire 12 month regimen. This point is critical because it leads to a self-selected group that is likely to respond to treatment. These patients will have been taking a daily dose of 300mg peanut protein for 6 months (as well as the 6 month up-dosing) before undergoing the 600mg peanut DBPCFC, which showed success in the Phase II trial in 90% of patients compared to placebo. Patients that drop out will not be considered for the final DBPCFC but will reviewed with respect to adverse events or issues with compliance.
Patients in the placebo group nearly all had moderate/severe symptoms at the 600mg peanut DBPCFC (Fig 2. Adopted from the Aimmune presentation at the BofA Healthcare Conference, 2017). Aimmune’s Phase II data shows that all of their placebo patients had moderate/severe reactions at the DBPCFC, which is a clear 0% pass rate. The PALISADE trial has ~500 patients randomized 3:1. This means that ~125 patients will be given placebo and ~375 will be given AR101. If we assume a generous 8% patient success in the Placebo group in PALISADE, the AR101 group needs to only be ~15% to achieve statistical significance (Fig. 3). Since the data is pass/fail, statistics that are likely to be used is Fisher’s or Barnard’s Exact test. Phase II data showed 90% success in the AR101 group, so there is a very good chance they will achieve significance, even if there is much less efficacy.
Figure 2. Aimmune’s Phase II data demonstrates that the AR101 group had 90% of patients succeed in the 600mg DBPCFC, whereas the placebo group had 0% success.
Figure 3. Mock data analysis for the Phase III PALISADE clinical trial.
OIT reduced IgE levels, increased IgG4 and reduced peanut-specific Th2 cells. I bring this up only to mention that Aimmune observes a correlation between successful peanut tolerance and a reduction in markers of peanut-specific hypersensitivity in subjects treated with AR101. If this wasn’t the case, we could be suspicious of their data, given that the scientific literature on food allergy specifically mentions IgE, IgG4 and T-helper-2 cells.
The only point of contention I have in this trial:
The 1000mg peanut DBPCFC was only successful in 60% of patients. One of the two primary endpoints is success in the 1000mg peanut DBPCFC, and the AR101 group had substantially less efficacy compared to the 600mg test. In Aimmune’s corporate presentation, August 15, 2017, the company refers to this endpoint as a secondary endpoint, but it is clearly listed in the primary outcome measure on the clinicaltrials.gov site (NCT: NCT02635776). This is slightly concerning because if they were to fail, it would be at this dose DBPCFC. The clinical trial page mention that the group undergoing the 1000mg exit test is only for the European study, but it is not clear why. I don’t think we should be completely deterred by this because we can assume that zero placebo patients will pass the 1000mg DBPCFC, which still leaves a lot of room for variable efficacy in the AR101 group and achieve success in this endpoint.
Like every clinical trial, the prior chance of success is 1:1. Based on past clinical trial success rates, allergy Phase III clinical trials move on to submit a New Drug Application (NDA) to the FDA 71.4% of the time, which is much higher than the average (58.1%). The points listed above increase my opinion on the likelihood of success to 90% and I see this as the start of a new market in drug-treatment for food allergies.
There are two catalysts for a move in Aimmune:
Release of DBV Technology’s Phase III data
Release of the PALISADE Phase III data
I believe that DBVT’s Phase III trial will succeed, and if so, will be a great sign for AIMT in terms of the likelihood that they will achieve success too. If you want to be conservative, I would recommend buying AIMT equity after DBVT releases their results, especially if DBVT announces positive results. If you want to take on more risk, I would buy AIMT today and hold until they release the PALISADE data (Jan/Feb, 2018). The bid-ask spread in the options chain is too wide for my liking, so I have opened a straight equity position. I may increase it between now and Jan, 2017, depending on news from their earnings report (Nov, 2018) or upcoming conferences they have planned. I’m expecting about a 30% move by Q1, 2018. I’ll make an updated post if anything interesting comes to light.
Aimmune Therapeutics at Bank of America Merrill Lynch Global Healthcare Conference. Sept, 2017
Clark S, Espinola J, Rudders SA, Banerji, A, Camargo CA. Favorable trends in the frequency of U.S. emergency department visits for food allergy, 2001-2009. Allergy Asthma Proc. 2013
Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008
Moran TP, Vickery BP, Burks AW. Oral and sublingual immunotherapy for food allergy: current progress and future directions. Curr Opin Immunol. 2013
Nowak-Węgrzyn A, Sampson HA. Future therapies for food allergies. J Allergy Clin Immunol. 2011
Sicherer SH, Muñoz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol. 2010
Yang L, Steele PH, Hamilton D, Bennick S, Herlihy L, Pitkin E, Burks AW, Kim E. Sustained Unresponsiveness After Sublingual Immunotherapy for Peanut-allergic Children (Abstract). J Allergy Clin Immunol. 2017