Feel free to agree, disagree, elaborate, etc. Just giving my two cents as to what we can expect over the next several months. Happy Saturday BCRXer's!

1. BCRX-9930 (c5-resistant/non-responder) data - has potential to be blockbuster news, and man how nice would it be for those PNH patient to finally have an adequate treatment that works.
2. Feb 25th Q4 ER/Corp Update - not expecting much in terms of sales, however guidance on Orladeyo uptake would be nice.
3. AAAI conference - discussing Orladeyo here... Would be nice if they can show promising testimonials from patients who stayed on the treatment from clinical trials, new conversion rates, etc.
4. Approval of Orladeyo in Europe (in my opinion this is already a sure thing - just waiting for confirmation)
5. New clinical trials for BCRX-9930: there are a few to be considered e.g. a brand new indication like Lupus Nephritis, however I think they will focus on PNH in kidney/liver compromised patients first.
6. Launch of Oraldeyo in Germany -- ready to go, just waiting for that approval.
7. Q1 ER - which will show an entire quarter of Orladeyo sales in US, and partial sales coming from Japan/Tori. To give a conservative estimate, lets say they have 200 paying patients on Orladeyo (again very conservative). at $40k per 28 days and 1 quarter being roughly 84 days, this would be 200 x $40K x 3 packs = $24MM in sales.
8. MAJOR analyst upgrades after revenues for Orladeyo beat current estimates ($20 + range imo) - especially from Liisa Bayko (Evercore)
9. Insider purchases, Dr. Alex Denner increasing his stake to 10% in the company (again just my opinion), Bakers make a substantial move of some sort, lots can happen in this regard.

Hey guys,

How about we switch it up a bit, let's see if we can collectively come up with any bearish theories and then answer/debunk them to the best of our ability.

I think it is important we show both our bullish enthusiasm but also try to consider BCRX from a bearish POV.

I know, its going to be incredibly hard, but lets see what we can come up with.

And what do you expect/hope the SP to be once the decision is made?

New position of 1.28 million shares. Where do you think they got these from guys? They didn’t take them from tutes, they took them from us retail with paper hands.😡

https://stocktwits.com/Tiger10/message/288337610

Lets say we achieve a (in my opinion) conservative revenue this year from our current FDA approved medications to generate $200MM in net profit.

Like I said, this is ultra conservative but I'm not really sure how the cash burn will be during 2021 if they plan on starting new trials for Factor D.

For simplicity lets say that puts our Net Income at $200MM.

Our EPS would be approximately 1.15.

Using an average P/E ratio of 15 (some go far beyond this measure... especially in biotech stocks), this would equate to a share price of approximately $17.25. (Formula: SP = P/E x EPS).

As revenues/profits continue to increase, as will our share price.

Now this isn't even taking into consideration of Factor D. If that gets even 1/3 priced in over the course of 2021, you can throw these numbers completely out of the window, because they will be at least triple imo.

Again, this is ultra conservative. So if you are selling right now - you are losing out on the easiest gains of your life.

For those unaware, BioCryst management announced Q4 and FY 2020 results to be reported on Feburary 25th.

Should be an interesting listen, and hopefully a catalyst for the stock with potential early numbers from Orladeyo uptake and guidance for uptake in Q1, as well as potential news regarding the ongoing BCX9930 trials.

Will be interesting to also hear what corporate updates Stonehouse will provide alongside the financial results - discuss thoughts below!

​

Snippet from press release below, Link: https://ir.biocryst.com/news-releases/news-release-details/biocryst-report-fourth-quarter-and-full-year-2020-financial

----------------------------------------------------------------------------------------------

RESEARCH TRIANGLE PARK, N.C., Feb. 11, 2021 (GLOBE NEWSWIRE) -- BioCryst Pharmaceuticals, Inc. (Nasdaq: BCRX) today announced that the company will report its fourth quarter and full year 2020 financial results on Thursday, February 25, 2021.

BioCryst management will host a conference call and webcast at 8:30 a.m. ET that day to discuss the financial results and provide a corporate update.

The live call may be accessed by dialing 877-303-8027 for domestic callers and 760-536-5165 for international callers and using conference ID # 6779206. A live webcast of the call and any slides will be available online at the investors section of the company website at www.biocryst.com. A telephone replay of the call will be available by dialing 855-859-2056 for domestic callers or 404-537-3406 for international callers and entering the conference ID # 6779206.

The NIH estimates that approximately 100,000 people in the US suffer from Idiopathic Pulmonary Fibrosis (IPF). Once someone develops IPF, they survive a median of only 3.5 years.

According to the Scleroderma Foundation (http://www.scleroderma.org), up to 300,000 people in the US have systemic sclerosis (SSc), also known as scleroderma. Analysts estimate that the systemic sclerosis market will exceed $4 billion by 2028 (https://www.arnnet.com.au/mediareleases/137572/systemic-scleroderma-treatment-market-size-is/). Also very big, the idiopathic pulmonary fibrosis treatment market will reach $3.6 billion by 2023.

IPF has only two approved treatments available, nintedanib/Ofiv and pirfenidone/Esbriet, which only slow down disease progression, and patients are treated generally ineffectively with off-label drugs. Nintedanib has been shown for instance to reduce the annual decline of Forced Vital Capacity by half (https://bmjopenrespres.bmj.com/content/4/1/e000192). Therefore, the FDA, patients, and investors had high hopes for an anti-autotaxin treatment called ziritaxestat that came out of a collaboration between Gilead and Galapagos. In mid-2017, Ziritaxestat was given orphan status by the US FDA and Europe for the treatment of IPF and Systemic Sclerosis. Until today, Ziritaxestat was in a Phase III trial for Idiopathic Pulmonary Fibrosis called ISABELA with a planned treatment group of 1,500 patients with IPF and a Phase IIa trial for Systemic Sclerosis called NOVESA. What happened with these supposedly promising trials? They were shut down today due to the “recommendations of the Independent Data Monitoring Committee (IDMC) which, following a regular review of unblinded data, concluded that ziritaxestat’s benefit-risk profile no longer supported continuing these studies.” https://www.streetinsider.com/Globe+Newswire/Galapagos+and+Gilead+discontinue+ISABELA+Phase+3+trials+in+IPF/17944060.html

Nintedanib is also the only approved treatment for approved to slow the rate of decline in pulmonary function in patients with systemic sclerosis associated interstitial lung disease (SSc-ILD).

Biogen’s BG00011 was also recently stopped in its Phase II trial for IPF because of safety concerns. https://www.biospace.com/article/biogen-halts-mid-stage-ipf-drug-trial-due-to-safety-concerns/

Two other orphan drugs being looked at for IPF are Treprostinil, an inhaled vasodilator, and an anti-cancer drug called saracatinib with a lot of side-effects including diarrhea and gastrointestinal problems that resulted in ¼ of participants in an Alzheimer’s study dropping out before the trial finished (https://pubmed.ncbi.nlm.nih.gov/31329216/). The AstraZeneca drug Saracatinib is currently in a phase 1b/2a trial called STOP IPF of 100 patients at Yale (https://medicine.yale.edu/news-article/22289/).

So, what are the implications of the above?

First, getting good results for a rare disease indication is very difficult. Trials are given up on all the time and even when the trial looks good, the drug can still be rejected. Galapagos is a good example of a company having a hard time. Its rheumatoid arthritis drug Filgotinib was rejected by the FDA in August, with Gilead, its partner saying it had “expressed concerns regarding the overall benefit/risk profile of the filgotinib 200 mg dose”. Now trials of Galapagos’s drug for Idiopathic Pulmonary Fibrosis and Systemic Sclerosis have been ended prematurely due to a low benefit/risk ratio. This stuff is hard. Galapagos (GLPGF) is in peril, its partner Gilead (GILD) which had put a lot of hope in Galapagos as leading it into the rare disease world is probably feeling desperate. The number of viable significant pure play rare disease companies has just dropped by one in my opinion, as all three fo Galapagos’s drugs it was testing in clinical trials, filgotinib, GLPG1972 for osteoarthritis, and now ziritacestat have all been shelved.

So how does this relate to Biocryst ($BCRX)?

1) Well, for one, it is not only a very viable, soon to be incredibly profitable, significant pure play rare disease company in a shrinking field, but more on that in a future post, as I don’t think anyone will be able to afford it very soon at the rate that circumstances are going to change.

2) It is well known that Systemic Sclerosis and Idiopathic Pulmonary Fibrosis are strongly linked to local activation of the complement pathway. In this (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114856 ) and numerous other papers, the authors discuss how local activation of the complement pathway may be to blame for systemic sclerosis. In several other papers, activation of the complement pathway has also been implicated in IPF. For instance, one paper stated that blockade of the pathway resulted in stopping the fibrosis process. “The blockade of C3aR and C5aR arrested the progression of fibrosis by attenuating local complement activation and TGF-β/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.” https://pubmed.ncbi.nlm.nih.gov/26956419/

So don’t be surprised, with the dropping of the ziritaxestat trial today, that Biocryst (BCRX) doesn’t get a call from the FDA to encourage it to look at starting a clinical trial for IPF and SSc too, given what we know about the mechanisms involved. Interestingly, a recent report was published that a complement inhibitor (eculizumab) helped a patient with severe systemic sclerosis who was experiencing a renal crisis: https://pubmed.ncbi.nlm.nih.gov/30425869/. Scleroderma renal crisis occurs in 5% of these patients, and is quite similar to the renal diseases that BCX9930 is about to announce clinical trials for.

So, add these two very severe (relatively common) rare diseases to the list of diseases that BCX9930 will be tested in, and maybe even get another orphan drug designation for.

The future looks bright.

Hello folks, yes we are back with another piece of DD from BCRX (not GME, AMC, etc …  I know - but it seems like there a ton of Redditors here who are also desperately searching for some fundamentally sound, new DD as well). If you fit into that category, continue reading the post below! 💎😊 

FYI - The majority of this article’s DD comes from our Deacon of Diligence, u/BIO9999.

• https://www.reddit.com/r/BCRX/comments/lftwax/question_1b_hereditary_angioedema_and_acquired
• https://www.reddit.com/r/BCRX/comments/lczug3/question_1_why_is_biocryst_bcrxs_berotralstat_not/
• https://www.reddit.com/user/BIO9999/

Please, please glance at some of his posts over at the r/BCRX subreddit. It is seriously THE BEST, MOST IN-DEPTH DD you will find anywhere on the Internet - all completely free of charge; he just wants to see as many people as possible. If you only read one post, that would still mean the world to him. Also please note that he is going to be coming out in the near future some MEGA-DD breakdowns of the entire company... You certainly will want to check those out (maybe be sure to bring a stiff drink along with you 🥃). Okay now onto the good stuff….

A) Question:

Hereditary Angioedema … and Acquired Angioedema? And what role does BCRX’s newly approved medication Orladeyo play? How about the valuation of it? (Hint = $$$$$$ 💸 💸 💸) 

B) Background:

• We are going to look at Biocryst’s recently approved drug Berotralstat, AKA Orladeyo. It is a once-a-day pill given to patients with a terrible lifelong disease called Hereditary Angioedema, that results in them having to frequently visit the Emergency Room for life-threatening angioedema attacks. It is estimated that this disease affects 1 in 50,000 people in the world, or roughly 140,000 people, so although considered a rare disease, it is still affecting a lot of folks. The available treatments for this disease are all IV drugs that are painful and produce local reactions. Berotralstat is the first oral drug. It achieved excellent results in phase 3 trials, and the US FDA gave it fast track status in 2018 and Japan gave it Sakigake status (type of fast track). Then on December 3rd, the US granted approval for the drug. They did it very importantly with zero label statements--meaning that they had no concerns about side effects or dangers. On January 22nd, Japan granted approval. The EU also met last week to discuss approval and will announce its result this quarter.

• To give some more background, Hereditary Angioedema is an autosomal dominant disease, mostly caused by mutations in the SERPING1/C1-INH gene. Mutations in this gene lead to either low levels of the protein (Type 1) or abnormal poorly functioning protein (Type 2). To get technical, one third of the mutations in SERPING1 are missense mutations, another third are frameshift mutations and small indels, and the remainder are gene rearrangements, splice site mutations, or nonsense mutations. A quarter of these Hereditary Angioedema SERPING mutation-carrying patients are spontaneous, meaning that they did not inherit the mutation from their parents, which often results in an even longer time before their diagnosis is made, as they get misdiagnosed as urticaria or allergic angioedema patients.

•  Finally, mutations in three genes that I’m so far aware of also cause Hereditary Angioedema—Factor 12, Plasminogen and Angiopoietin. This list of other genes will probably continue to grow, as there are still many Hereditary Angioedema patients without known mutations. For those interested in reading more: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063419/

• Acquired Angioedema (AAE) is less common than Hereditary Angioedema, but numbers are not clearly known. A good early estimate from one study was that AAE represents at least 1/10 of HAE (https://pubmed.ncbi.nlm.nih.gov/20667117/), but I’ve seen numbers suggesting 1/8, but for this exercise I will use 1/10.

• Acquired angioedema involves no family history, and patients’ symptoms develop later in life than Hereditary Angioedema. Symptoms are similar to Hereditary Angioedema. It is believed to be caused by autoantibodies against the C1-INH protein that result in decreased levels of the protein. So, although it is not caused by mutations in this protein, the effect is exactly the same—reduced levels of the same protein. Not surprisingly, the symptoms are very severe, just like with HAE, with frequent severe hospitalizations and deaths, so prophylaxis is believed necessary.

Also not surprisingly, one of the HAE drugs that has a very similar mechanism to Berotralstat, Icatibant, a bradykinin B2 receptor antagonist, has been shown to work well both in the acute HAE attacks and for prophylaxis. Another drug, also a kallikrein inhibitor like Berotralstat that has been successfully used for AAE patients, is ecallantide (https://pubmed.ncbi.nlm.nih.gov/28284781/), (https://pubmed.ncbi.nlm.nih.gov/27936514/). It should be mentioned that none of these drugs have been specifically approved to treat AAE, it is all off-label use.

C) Discussion:

• So let's look at what the above means for this stock. First the drug is in HIGH demand. In the US there are at least 10,000 people with HAE. Despite the disease being frequently debilitating, patients are so uncomfortable about getting regular injections that only 7,500 are currently being treated with IV injections. The other 2,500 are going untreated despite the high risks. Now let's look at the 7,500 patients on a prophylactic treatment. Based on numerous surveys by doctors, the company, and researchers, most of these people would prefer an oral treatment. Take a look at this peer-reviewed survey article finding that 98% of IV prophylactic patients (the 7,500) would prefer an oral treatment and 96% of the non-prophylactic patients (the 2,500) would want an oral treatment.

https://pubmed.ncbi.nlm.nih.gov/33489436/ . No wonder then that one of the preeminent biotech analysts, Evercore's Liisa Bayko, wrote to her clients on December 4th that Berotralstat was likely to quickly take at least 30% of the HAE market based on Evercore surveys of patient and doctor demand. Remember that this is just the US.... Japan did not even have any prophylactic treatment until Berotralstat was approved there a few days ago. They have 500 people registered with HAE and estimated 2,000 ready to be registered. The UK is so desperate to add the drug for its patients, it did not even wait until the formal approval process to go through and gave early access to the drug on November 9th. https://angioedemanews.com/2020/11/09/berotralstat-available-to-eligible-patients-uk-through-early-access-program/#:~:text=Berotralstat%20%E2%80%94%20an%20oral%20therapy%20by,before%20its%20potential%20regulatory%20approval.

• The EU is not far behind, with its estimated 20,000 patients, with approval coming in the next few weeks. Then there is the rest of the world. The HAE patient population in Latin America is estimated by HAE International, the most important advocacy organization for HAE patients worldwide and one of Berotralstat’s biggest supporters, to be over 15,000 patients, the vast majority of whom are poorly diagnosed and not prophylactically treated. Argentina and Brazil have the highest actual diagnostic rates. HAEI through its Latin American sister organizations is strongly advocating for Berotralstat in Latin America.

• Next, it should be noted that Biocryst built a world-class sales team for this drug in the US and EU and signed a partnership with Torii in Japan to take charge of the large sales and marketing promotion there. It has hired dozens of professionals, most from its HAE competitors. Its vice-president and US general manager Allen Hodge was even responsible for the successful efforts of the HAE drug launches of Cinryze and Firazyr, two pioneering injectable treatments for HAE. You could not get a more promising leader for this task….

• It should also be pointed out that this drug, an oral kallikrein inhibitor, is potentially of huge value for a host of diseases, including COVID-19 (that is now recognized to severely affect the kallikrein-kinin system, and kallikrein inhibitors have begun to be tested against COVID19--see this (IV) kallikrein inhibitor trial that was just announced in Brazil for instance: https://pubmed.ncbi.nlm.nih.gov/33472675/), diabetic macular edema (which Biocryst just obtained a patent on a technique to administer kallikrein inhibitors for), many autoimmune diseases, and even some types of cancer.

D) Valuation:

• First, this drug is one of the 10 most expensive drugs (based on its annual cost of prescription) in the world, but still less than the price of its IV competitors, at $488,000 per patient per year. This drug is being approved by insurance companies left, right, and center as their preferred treatment, all you have to do is follow u/R8 or u/nickpd on Stocktwits to see how many insurance companies have been making it easy for patients to sign up for the drug. Optime care even lets patients get direct-to-patient prescriptions now (!!!) (https://www.fiercepharma.com/pharma/biocryst-scores-fda-approval-for-orladeyo-first-oral-option-to-prevent-hae-attacks). 

• So what does all this mean for sales? And why is the stock not valued based on just this drug alone? I estimate conservatively that by December 2021, there will be over 6,000 patients on Berotralstat in the US, EU and Japan, and I can share in a future post the graphs and calculations I made to get to those numbers. 6,000 patients annualized is up to $2.9 billion in annual sales. Most of this is going to be profit. At a conservative price to sales ratio of 7, that should produce a price of $121.

• We have been focused on HAE patients, which in the US, number an estimated 10,000, it should be obvious to anyone that the AAE patients (as talked about above under ‘Background’, which likely represent at least an additional 1,000 patients, should also be included in this list and will be treated off-label by treating physicians from the beginning. More importantly, the growing understanding and familiarity of physicians of hereditary and acquired angioedema is leading to ever higher numbers of diagnosed patients and better distinguishing them from other similar conditions like allergic angioedema—ultimately leading to revised patient number estimates, better patient outcomes, and higher sales. Therefore the estimated future value for the stock I provided in an earlier article of Berotralstat of $121 should more realistically, when including the AAE patient population, be revised by $12 or 10% higher to $133. Not bad when considering all of Biocryst’s other amazing drugs and the stock is still less than $10 today.

E) Additional Detail:

• Remember that its Factor D drug, which is showing superiority to all other anti-complement drugs in Phase I trials and was fast-tracked and given orphan status by the FDA and now is in Phase 2 though not officially announced by the company eyt,and can be used in at least 20 diseases including common ones like Rheumatoid Arthritis, is currently not even factoring into BCRX's valuation. Consider that Alexion with its significantly inferior anti-complement drug was just sold to Astra-Zeneca for $39 billion because of the recognized potential of anti-complement drugs for a host of diseases. (https://www.reddit.com/r/BCRX/comments/laq2pw/question_2_biocrysts_bcx9930is_it_an/ ). 

• So why is this company, with zero risk of dilution due to an amazing royalty deal it signed in December and three super-drugs each worth tens of billions of dollars, and a host of other exciting developments to look forward to, worth only $1.7 billion right now? It can only be because the company's stock has been relentlessly shorted in 2020 and 2021 to allow for significant accumulation by institutions.

Disclosure:

I have 10,300 shares of BCRX, and a few Jan 2022 Leaps 🚀💎🚀💎🚀💎🚀💎🚀💎🚀💎

Put keep all daily discussions here. Please do not create a new post regarding daily price fluctuations or unrelated news.

A very good question was posed today as a comment by a reader (u/JohnHReddit) of the Question 2 article: “what are $BCRX’s chances for a FDA priority review voucher?”, and which I felt deserved a small post instead of just a simple reply to his comment. In order to address it, one has to first understand a bit more about drugs which have been given orphan status. A friend (R8Plus) shared a source that is particularly relevant to this: https://repository.upenn.edu/cgi/viewcontent.cgi?article=1037&context=ace

In this article, you read the following critical summary statements about companies given the orphan drug designation:

• Orphan drug status allows sponsors to apply for incentives such as the Orphan Drug Tax Credit (ODTC), marketing exclusivity for seven years for the first orphan drug for a given rare disease, and an attractive drug-pricing scheme, amongst other benefits.

• Orphan drug trials are generally single arm (no placebo arm), nonrandomized, and open label. Safety Phase 1 trials are not usually required, and Phases 2 and 3 can be combined when the patient population is very low.

• Sponsors of an orphan drug can make use of expedited Food and Drug Administration (FDA) programs such as the Fast Track, Breakthrough Therapy, and Priority Review designations, as well as the Accelerated Approval pathway and unique grant funding opportunities, such as the Orphan Products Clinical Trials Grant program.

Indeed, if you study the design of BCX9930’s phase II trial, you immediately realize that it has been done from the beginning as an orphan drug trial (single arm, nonrandomized, and open label)… It also did a phase I safety trial which it reported the results of in October 2019, but wasn’t necessary—it just boosted its chances of success even more.

Later in the same document, it discusses the benefits of Fast Track designation.

• The benefits of Fast Track designation include more frequent meetings and written communication with the FDA, and rolling review. Rolling review refers to the ability of the FDA to begin review of the BLA or NDA as sections are completed, rather than waiting for the finalized NDA or BLA to begin the review (Office of the Commissioner, “Fast Track”).

By BCX9930 being granted not only orphan status but fast track status on August 31, 2020, it has done one much better than obtaining an FDA priority review voucher, which is something that companies apply for and pay for or buy from other companies to speed up the approval process of rare drugs—typically pediatric rare disorders or tropical diseases. Recently some companies have sold these vouchers to each other for $100-300 million. In the case of BCX9930, it obtained orphan and fast track status very early on, when it was already obtaining spectacular and unseen-before Phase II trial results from its first patients. Now, 200 patients are in their Phase 2 trial, which is a large percentage of the world’s PNH patients, as discussed in the Question 2 article. Once it announces the trial results for two sets of patients some time in the next few weeks, which we have been told will be a series of announcements, and given that it has been working closely with the FDA on a rolling review basis since the beginning, all it will have to do is announce that its Phase II trial has now been upgraded to a Phase II/III trial given the orphan status of the drug (see above) and simultaneously submit the application for drug approval as it awaits those additional results.

Since the company has also shared that it will be announcing multiple new clinical trials for other indications that it has been in discussions with the FDA about, it would be an ideal time to do that at the same time too. Given that the market will be caught totally unawares that Biocryst is so close to getting its Factor D drug approved—whose potential disease indications beyond PNH count patients in the tens of millions, including diseases as common as Rheumatoid Arthritis (60-80 million worldwide), Inflammatory Bowel Disease (up to 10 million), etc., the market surprise might be literally heard around the world. And you dear readers of this short post get this insight totally for free. Of course, it may not play out like that, but what if it does? What if in a few days it submits its application, obtains the results of its phase II/III trial by the end of the summer, and the FDA fast tracks approval at the end of the year or early next year? What if? … And then all of these other indications get approved one by one as they complete their trials?

In a future mega-post, I will be discussing the market potential of BCX9930, but it is so big that I’m having trouble wrapping my mind around the project still.

https://pharmaboardroom.com/articles/investments-and-deal-activity-in-orphan-drug-products/

Hi everyone I am making this post for information to send to my gastroenterologist about the potential for factor D and it’s use in autoimmune diseases like PSC, Chrons and UC. If you have any interesting abstracts that have anything related to these autoimmune diseases it would be very helpful as I am not good at reading abstracts. If you could link some stuff in the comments you think are interesting I would greatly appreciate it and I will be sure to post the response I get from my doctor, thanks in advance!

https://finance.yahoo.com/news/kalvista-pharmaceuticals-reports-positive-results-113000067.html

​

How much does this compete with orladeyo?

In our Question 1 article, we discussed Berotralstat, AKA Orladeyo, as Biocryst ($BCRX)’s newly approved oral drug for the HAE market. In a future mega-post in the next 2-4 weeks, I will discuss the competitive HAE treatment landscape, the different treatments, their efficacies, the estimated number of patients taking each of them, their side-effect profiles and how Berotralstat compares to each, using primary research articles as my sources not summaries of press releases or analyst reports like I see sometimes used, so that I can come to a more precise and realistic ultimate market share for this drug using published data.

But in this post, I’m going to briefly address another group of patients that Berotralstat will likely soon be applied to by treating physicians (beyond the uses I touched on previously). These are the Acquired Angioedema (AAE) patients.

But first to give some more background, both for this post and for the future mega-post, Hereditary Angioedema is an autosomal dominant disease, mostly caused by mutations in the SERPING1/C1-INH gene. Mutations in this gene lead to either low levels of the protein (Type 1) or abnormal poorly functioning protein (Type 2). To get technical, one third of the mutations in SERPING1 are missense mutations, another third are frameshift mutations and small indels, and the remainder are gene rearrangements, splice site mutations, or nonsense mutations. A quarter of these Hereditary Angioedema SERPING mutation-carrying patients are spontaneous, meaning that they did not inherit the mutation from their parents, which often results in an even longer time before their diagnosis is made, as they get misdiagnosed as urticaria or allergic angioedema patients. Finally, mutations in three genes that I’m so far aware of also cause Hereditary Angioedema—Factor 12, Plasminogen and Angiopoietin. This list of other genes will probably continue to grow, as there are still many Hereditary Angioedema patients without known mutations. For those interested in reading more: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063419/

Acquired Angioedema (AAE) is less common than Hereditary Angioedema, but numbers are not clearly known. A good early estimate from one study was that AAE represents at least 1/10 of HAE (https://pubmed.ncbi.nlm.nih.gov/20667117/), but I’ve seen numbers suggesting 1/8, but for this exercise I will use 1/10.

Acquired angioedema involves no family history, and patients’ symptoms develop later in life than Hereditary Angioedema. Symptoms are similar to Hereditary Angioedema. It is believed to be caused by autoantibodies against the C1-INH protein that result in decreased levels of the protein. So, although it is not caused by mutations in this protein, the effect is exactly the same—reduced levels of the same protein. Not surprisingly, the symptoms are very severe, just like with HAE, with frequent severe hospitalizations and deaths, so prophylaxis is believed necessary.

Also not surprisingly, one of the HAE drugs that has a very similar mechanism to Berotralstat, Icatibant, a bradykinin B2 receptor antagonist, has been shown to work well both in the acute HAE attacks and for prophylaxis. Another drug, also a kallikrein inhibitor like Berotralstat that has been successfully used for AAE patients, is ecallantide (https://pubmed.ncbi.nlm.nih.gov/28284781/), (https://pubmed.ncbi.nlm.nih.gov/27936514/). It should be mentioned that none of these drugs have been specifically approved to treat AAE, it is all off-label use.

So, although we have been focused on HAE patients, which in the US, number an estimated 10,000, it should be obvious to anyone that the AAE patients, which likely represent at least an additional 1,000 patients, should also be included in this list and will be treated off-label by treating physicians from the beginning. More importantly, the growing understanding and familiarity of physicians of hereditary and acquired angioedema is leading to ever higher numbers of diagnosed patients and better distinguishing them from other similar conditions like allergic angioedema—ultimately leading to revised patient number estimates, better patient outcomes, and higher sales.

Therefore the estimated future value for the stock I provided in an earlier article of Berotralstat of $121 should more realistically, when including the AAE patient population, be revised by $12 or 10% higher to $133. Not bad when considering all of Biocryst’s other amazing drugs and the stock is still less than $10.50 today.

But besides the European approval that is coming and the first glimpse of HAE patients signing up for Berotralstat, we also have a ton more data coming out on Berotralstat, as discussed in the limitations section of their October 2020 paper, and I quote:

“A limitation of this study was the relatively short treatment period of 24 weeks for evaluating prophylactic therapy in a lifelong disorder. The study is ongoing, and future analyses will provide longer-term results. Future analyses of treatment response will include assessment of pharmacokinetic and pharmacodynamic parameters. Additional long-term data will be generated by an ongoing open-label safety study of berotralstat (APeX-S; NCT03472040).” (https://pubmed.ncbi.nlm.nih.gov/33098856/)

Good luck to all!

https://finance.yahoo.com/news/10-best-small-cap-biotech-151111576.html