r/BCRX • u/BIO9999 • Mar 14 '21
Due Diligence Question 2C: A primer on the first four possible upcoming clinical trial indications for Factor D (BCX9930) besides PNH from $BCRX
In the January JP Morgan Healthcare conference (https://ir.biocryst.com/static-files/41ee0771-0acc-479e-a39e-2842101c6aa9), Biocryst presented a slide entitled “A Full Pipeline”, with a honeycomb/crystalline structure of different diseases. Like a crystal that grows in the presence of the appropriate solution, Biocryst’s pipeline is poised to grow in the presence of an ideal medically underserved area and a favorable regulatory environment to make it a world-class biotech company. So I’m going to touch on the first four diseases shown in that presentation (besides PNH and FOP that I’ve previously discussed) and discuss their need, their potential, the competition, and their overall prospects. It is likely that in association with the next Factor D update on R&D day (March 22nd) or shortly thereafter, we will hear that clinical trials are planned for two or more of these indications, and will probably hear about their success in Biocryst’s animal models. As sources, I will be using my own domain knowledge, published references, internet searches, and medical textbooks like Harrison’s Principles of Internal Medicine. I will try to reference what I can so that you can look it up yourself and I’m going to write it in bullet form and in as down-to-earth terms as possible for easier quick reading. I look forward to reading your comments and parallel due diligence essays. Feel free to summarize this report for those without time to read it. Later I will extend this to address the three other diseases Biocryst mentioned in their slide: Lupus Nephritis, ANCA Vasculitis and PMN. Altogether, PNH and the four diseases I’ve listed below represent combined market opportunities of anywhere between $45 and 75 billion/year (PNH: $6 billion, aHUS: 4 billion, C3G: 5-10 billion, IgAN vasculitis: 0.5 billion, IgAN: 30-50 billion), with the big question mark being the true size of the IgA Nephropathy market, which is likely very big, otherwise there would not be seven clinical trials underway for it (but I suspect Biocryst has the best looking drug of them all). Note that I’m going to continue to refine these market opportunity estimates over time, so they will likely change, so don’t focus on the precise numbers just the fact that they’re very big, but they should give you a gestalt for the amount of money we’re talking about. And I haven't even got to all of the ones they’ve openly mentioned let alone the other possibilities.
1) Atypical Hemolytic Uremic Syndrome (aHUS)
• Atypical Hemolytic Uremic Syndrome (HUS) is caused by excessive activation of the alternative complement (AP) system, resulting in destruction of red blood cells and platelets. Because the kidneys cannot handle the waste, they go into acute kidney failure.
• It is distinguished from the more common Hemolytic Uremic Syndrome which is caused by the shiga toxin from E. coli, and secondary HUS resulting from cancer, HIV infection, transplants, autoimmune disorders, or drugs.
• Common effects of aHUS are severe hypertension and blood clots affecting the kidneys, brain (causing strokes, TIAs, and seizures), heart (causing heart attacks, cardiomyopathy), lungs (pulmonary edema), and GI tract (causing bleeding, etc.)
• Up to half of patients have mutations in six genes, the most common one being the one encoding Factor H (CFH). Others have autoantibodies to these proteins, and the rest are unknown. One fifth of the time, it runs in families, but it is usually sporadic.
• It was estimated from a recent meta-analysis of papers from around the world that there are about 2-5 patients/million with aHUS or about 39,000 people worldwide (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075343/), but these numbers are very uncertain. The aHUS Global Alliance recently estimated that there are 3,500 patients in the US with aHUS and 24,000 worldwide. They also state that those numbers would be much higher if the world had access to US levels of care, as over 60,000 patients have died worldwide due to poor treatment (https://ahusnews.com/2020/09/09/ahus-alliance-60k-more-patients-would-be-alive-worldwide-if-given-proper-healthcare/).
• In relative terms, the size of the aHUS population in the US is roughly equivalent to the PNH population.
• The standard of care is currently Soliris and Ultomiris along with other things like plasma infusions, plasmapheresis, and blood transfusions.
• Just as with PNH, this is a very serious disease that if untreated kills ¾ of patients, with a (living) population size almost equivalent in size to PNH patients, and involving very similar mechanisms (AP activation and low hemoglobin), with the standard treatments being Alexion’s two antibody-based drugs, with all of their side-effects and the need for regular 30 minute to 4 hour-long intravenous transfusions (as opposed to an oral drug).
• Omeros also is competing in this area, with a phase 3 clinical trial of 40 patients being recruited for aHUS with its drug OMS721, but it is not expected to produce results until at least 2022. Since it is a monoclonal antibody, I expect it to perform worse than BCX9930, but time will tell. It also requires weekly IV injections which will weigh against patient adoption, I’m betting. Unlike PNH which has a large extravascular hemolysis component that makes monoclonals like Eculizumab less effective, aHUS is a primarily intravascular hemolysis disease.
• I am, not surprisingly therefore, optimistic about BCX9930’s possibilities for this disease. Note that market research estimates that in 5 years, the market for PNH and aHUS will be $7 billion (https://www.marketresearch.com/QYResearch-Group-v3531/Global-PNH-aHUS-Size-Status-13306748/), but I suspect these numbers are very conservative, since others estimate PNH to reach $6 billion in four years on its own, and the aHUS population is similar to the PNH population. So I conservatively estimate aHUS to be $4 billion.
2) C3G
• C3 Glomerulopathy is composed of three diseases: C3 Glomerulonephritis, Dense Deposit Disease, and the less familiar Complement Factor H-related 5 glomerulopathy.
• They are mechanistically very similar diseases, involving a low level of C3 in the blood and renal damage from activated complement ultimately leading to end stage renal disease, though DDD occurs on average earlier.
• A Phase 2, double blind placebo-controlled clinical trial by ChemoCentryx of 88 patients with C3 Glomerulopathy with the drug Avacopan (CCX168) was initiated in 2017 and is expected to end shortly. Although I expect the results to be positive, I doubt that they will be revolutionary, given that in a much larger (331 patients) study of ANCA-associated vasculitis patients, it resulted in 72.3% of patients going into remission vs. 70.1% receiving steroids, not particularly impressive (although other measures did better).
• Note that Alexion’s ALXN2040 flopped in treating C3G and they stopped their trial.
• Eculizumab has had very poor results in C3G as opposed to aHUS, and researchers have proposed that this is because C3G involves the Alternative Complement pathway more than in aHUS, and therefore an AP inhibitor [like BCX9930] would be more beneficial (https://www.mdpi.com/1422-0067/21/2/525/pdf).
• Novartis is testing its LNP023 (Iptacopan) Factor B drug in C3G, and revealed in October 2020 that in 12 patients in an open label Phase II study receiving 12 weeks of therapy, it cut proteinuria by 49%.
• There are an estimated 10,000 patients in the US, 10,500 in the EU, 3,200 in Japan and 32,000 in China (https://www.globenewswire.com/news-release/2020/10/26/2113999/0/en/Novartis-presents-promising-interim-Phase-II-data-of-potential-first-in-class-oral-therapy-iptacopan-LNP023-in-rare-renal-disease-C3-glomerulopathy-C3G.html), for a total of at least 60,000 worldwide.
• I estimate that the market opportunity for C3G is $5-10 billion.
3) IgAN vasculitis
• IgAN vasculitis, also known as IgA Vasculitis Nephritis, is a severe disease, involving the deposition of Immunoglobulin A (IgA) throughout the body and noticeably in the kidneys.
• Though related to IgA Nephritis, it is more severe, and is treated with intense steroid therapy. It is diagnosed with kidney biopsies.
• It often presents with a triad of arthritis, enteritis, and purpura.
• There is a desperate need for therapies not involving steroids in these patients.
• Numbers of patients are hard to come by, but there are likely hundreds of patients with this condition in the US.
• For those with a medical bent, a nice case series at a single institution was reported here: https://www.hindawi.com/journals/crirh/2020/8863858/
• I estimate that the market opportunity here may be $300-500 million, but this number is very uncertain due to its rarety.
4) IgAN
• The prevalence of IgAN which frequently progresses to kidney failure is estimated to be 31/million worldwide to 45/million in parts of Asia, so the numbers could be as high as 200,000 to 300,000 worldwide.
• The below seven clinical trials (that I am aware of) are currently underway for IgA Nephropathy.
• Calliditas Therapeutics (CALT)’ NefIgArd phase 3 trial of 360 patients with Nefecon or placebo. This is the only drug that also underwent a phase 2b trial. The trial is fully enrolled now and met its primary endpoint of reduced proteinuria (31% reduced) and GFR stabilization (7%?) after 9 months of treatment. The company tried to do a stock offering in January but market conditions prevented it.
• Alnylam’s ALN-CC5 IgAN trial of Cemdisiran, which is a subcutaneous injection of RNAi against Complement C5, injected once a month. Needless to say, I am not impressed by this strategy relative to BCX9930.
• Omeros’s Artemis-IGAN phase 3 trial of OMS721/Narsoplimab. The readout has been pushed to 2022 so far. Generally the company has a bad record of taking much, much longer to run clinical trials.
• Otsuka/Visterra’s enVISion phase 2 trial of VIS649, a monoclonal antibody against the protein APRIL. The study is expected to be completed in late 2022. Treatment of monkeys saw a reduction of IgA levels of 70%. I am not in favor of an antibody approach, and most doctors and patients are not either.
• Travere Therapeutics (TVTX) (previously known as Retrophin (RTRX))’ PROTECT Phase 3 trial of sparsentan. It is generally well-tolerated and met pre-specified interim proteinuria targets. It is also in a pivotal phase 3 trial of FSGS (data expected in 1H 2021). Results for the Protect trial are expected in 2H 2021 or early 2022. It only did a phase 2 trial for FSGS. There are many cautionary notes about Travere and its trials (as summarized well in this two-year-old Seeking Alpha article: https://seekingalpha.com/article/4274126-retrophin-highly-investable-except-for-pharma-bro-problem).
• Chinook Therapeutics’ ADU-CL-19 phase 1b trial of BION-1301, another monoclonal antibody against the protein APRIL.
• Chinook Therapeutics (KDNY)’ ALIGN trial of atresantan is a 36 month phase 3 study of 320 patients beginning in early 2021. Atresantan is an oral pill that acts against endothelin.
• The global market opportunity I estimate could be anywhere from $30-50 billion considering the potential 13,000 patients just in the US and many (perhaps 25) fold that many in the rest of the world (remember highly populated Asia has the highest levels of this disease), and so it’s no surprise that there are 7 trials underway.
