Cyclerion effectively fails in their Phase 2 Sickle Cell Disease trial but shows mixed CNS data. I go through the positive aspects of the data and discuss the potential for the company (and my position). In the latter part of the video, I do a follow up to the Hepion interview I did with the CEO, Dr. Robert Foster. I also talk about how I plan to play the stock given the upcoming catalysts.
I also touch on Amgen and their AMG510 Phase 2 data that was released in early Oct/2020.
Disclaimer: All opinions expressed by Matt in this podcast are solely his opinions. You should not treat any opinion expressed by Matt in this podcast as a specific inducement to make a particular investment or follow a particular strategy, but only as an expression of his opinion. Matt’s opinions are based upon information he considers reliable, but Matt cannot warrant its completeness or accuracy, and it should not be relied upon as such. Matt is not under any obligation to update or correct any information provided in this podcast. Past performance is not indicative of future results. Matt does not guarantee any specific outcome or profit. You should be aware of the real risk of loss in following any strategy or investment discussed in this podcast. #biotech
Hey everybody, hope you’re all doing well! In this video, I talk about Pfizer’s DMD gene therapy update that indicates continued Sarepta hegemony in the space. I also talk about ContraVir and their NASH drug, CRV431.
I must have drank too much coffee before recording because I made more than a couple errors this time around. So, if you’re an audio-only listener and hear something that doesn’t sound right, double check the video version, which corrects the mistakes via captions or has it written properly even though I say it wrong (i.e. I say 3E16 when 3E13 is clearly written on the slide).
Thanks to everyone for listening and do your own due diligence if you are considering investing, this is not a substitute for investment advice.
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.
Viking Therapeutics reports their latest phase 2 data with their candidate thyroid hormone receptor β agonist. I compare both the madrigal and viking drug and discuss their potential in the NASH/NAFLD space.
-Gilead loses 3 executives in the last 6 months, but that’s not why I sold!
-New research suggests that closed-loop insulin delivery-glucose monitoring keeps type 2 diabetics in range better than conventional therapy
– Today I look at Madrigal’s Phase 2 results and talk about competitors in the NASH space.
– I also talk about Tandem and how we can use competitors to compare value
– Follow me on twitter @matthewlepoire
*This is not investment advice. I am not liable for any trading decisions you have made.*
The pathophysiology of NASH involves a number of co-morbidities such as:
Type 2 diabetes
Cardiovascular and microvascular dysfunction
Therefore, any ideal drug candidate will, at worst, not aggravate these diseases, and at best, eliminate them along with NASH. In my last post, I ruled out ICPT as a good buy because their drug, OCA, increases patient risk for coronary heart disease and type 2 diabetes. Madrigal Pharmaceuticals and Genfit, on the other hand, have drug candidates that show improvement in NASH-related co-morbidities. In this post, I’m going to focus on Madrigal’s MGL-3196 drug, and a follow-up post will look at Genfit’s Elafibranor.
In December 2017, Madrigal announced their drug, MGL-3196 achieved the primary endpoint in their phase 2 NASH study. The important statistically significant takeaways were:
Decreased liver fat (steatosis)
Decreased LDL-C, triglycerides and lipoprotein a
Decreased liver enzymes
This news doubled the stock, increasing its market cap to ~$1.2 billion and rightfully so.
MGL-3196 is a selective beta-thyroid hormone receptor (βTHR) agonist. When βTHR is activated in the liver, it increases metabolic rate and cholesterol metabolism in rodents and primates (Grover GJ et al. 2003). The phase I study conducted by MDGL showed that MGL-3196 was well-tolerated in humans with potent effects to lower blood LDL-C and triglycerides (Taub R et al. 2013). Animal studies showed that βTHR agonism had insulin sensitizing effects similar to rosiglitazone (very strong insulin sensitizer) along with beneficial effects on liver steatosis and blood cholesterol and triglycerides (Taub R et al. 2009). MDGL presented a poster at the AASLD Liver Meeting in Washington, DC in late 2017, which showed that MGL-3196 had a very profound effect on high-fat diet-fed mice, including a variety of beneficial gene expression changes, and normalization of hyperinsulinemia (MDGL press releases, October, 2017).
The final data of their phase 2 study is expected in April, 2018, which will include more formal biopsy data to confirm the MRI techniques they used for the interim analysis.
MGL-3196 and Familial Hypercholesterolemia
MDGL also has a phase 2 trial using MGL-3196 to treat familial hypercholesterolemia (FH, NCT03038022). This disease causes elevated blood cholesterol as a result of a gene mutation and puts patients at an increased risk for atherosclerosis. Heterozygous FH occurs in approximately 1:500 people, and has been traditionally treated by statins (Rader DJ et al. 2003). However, normalizing cholesterol levels in FH patients has proven challenging with the standard of care. If MGL-3196 can show efficacy in FH patients treated with statins, it would provide them another indication and revenue stream.
In 2012, there were about 834 500 American adults with FH (Ferranti SD et al. 2016). The annual cost of nongeneric simvastatin, for example, was $1428 per year (Jick H, et al. 2012). This would generate $1.19 billion for MDGL per year. This estimate is in line with reported revenue of nongeneric statins, such as Zocor, which generated $2.8 billion in sales in 2006 (Merck annual report, 2008), or the combination statin Vytorin (ezetimibe/simvastatin), which generated $1.14 billion in 2016 sales (Merck annual report, 2017).
The data from MDGL’s phase 1 study on LDL-C changes are below (Fig. 1).
Figure 1. Adapted from Taub R, et al. 2013. Red box shows effect of MGL-3196 on LDL-C.
At the highest dose, MGL-3196 reduces LDL-C 30% from baseline. This is similar to most market cholesterol lowering drugs according to MDGL’s corporate presentation data (Fig. 2). However, combinations of statins and other drugs are now often prescribed, which are able to reduce LDL-C from baseline by about 50% (Bohula EA, et al. 2015) or 54.2% (Foody M, et al. 2010). Despite these large decreases, LDL-C recommendations of <70mg/dl are only achieved by about 40-60% of patients in these studies. Therefore, MDGL has an opportunity in this arena, but it depends if their drug can be used in combination to significantly lower LDL-C more than what is currently available.
Figure 2. Various drug treatment effects on LDL-C in FH patients.
With all of this in mind, here is my play.
I am going to wait until the phase 2 study data on FH is released before buying anything. Predicting the effectiveness of a combination therapy is very difficult in my experience. If the effect is as strong as already established combination drugs, i.e. Vytorin, it might lead to a ‘sell the news’ event. So I’m going to buy after this data is released, especially if there is a significant drop in the stock. I’m holding out for the end of the NASH phase 3 data, which will not be for 3-5 years. Release of the final NASH phase 2 data will occur around April, 2018, and I will likely pick up more stock then.
In my next post, I’m going to go through Genfit’s Elafibranor, which showed some skeptical phase 2 data in NASH.
Grover GJ, Mellström K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R, Vennström B, Mookhtiar K, Horvath R, Speelman J, Egan D and Baxter JD. Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. PNAS. 2003.
Taub R, Chiang E, Chabot-Blanchet M, Kelly MJ, Reeves RA, Guertin MC and Tardif JC. Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-β agonist. Atherosclerosis. 2013.
Taub R, Grimsby J, Laringan JD, Pietranico S, Dvorozniak M and Conde-Knape K. VIA-3196, a Liver-directed Thyroid Beta Agonist for Treating Cardiometabolic Disease. (Abstract) Circulation. 2009.
Rader DJ, Cohen J and Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J. Clin. Invest. 2003.
Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK and Sheldrick RC. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation. 2016.
Jick H, Wilson A, Wiggins P and Chamberlin DP. Comparison of prescription drug costs in the United States and the United Kingdom, Part 1: statins. Pharmacotherapy. 2012.
Bohula EA, Giugliano RP, Cannon CP, Zhou J, Murphy SA, White JA, Tershakovec AM, Blazing MA, Braunwald E. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015.
Foody JM, Brown WV, Zieve F, Adewale AJ, Flaim D, Lowe RS, Jones-Burton C, Tershakovec AM. Safety and efficacy of ezetimibe/simvastatin combination versus atorvastatin alone in adults ≥65 years of age with hypercholesterolemia and with or at moderately high/high risk for coronary heart disease (the VYTELD study). Am J Cardiol. 2010.
Non-viral liver disease is affecting western nations at an unprecedented rate. Much of this is attributable to poor diet, but given that lifestyle intervention doesn’t really fix the problem, there is a gigantic market opportunity. Non-alcoholic steato-hepatitis (NASH) affects ~5% of the population and the market in 2016 is estimated at around $800 million (Cassidy S and Syed BA. 2016). NASH is associated with high liver fat, inflammation and fibrosis (Fig. 1). The NASH liver can either progress to cirrhosis and hepatocellular carcinoma (requires liver transplant), or can resolve towards non-alcoholic fatty liver disease (NAFLD)/healthy liver depending on the intervention. Many doctors currently use FDA-approved drugs off-label to treat NASH, since there are none approved for the disease. As such, many pharmaceutical companies are trying to develop good drugs to push NASH towards resolution (NAFLD/healthy liver). Here, I’m going to look deeper into Intercept Pharma, which has the exclusive rights to Ocaliva (obeticholic acid, OCA), a potent farnesoid X receptor (FXR) agonist.
Figure 1. Depiction of progressive non-viral human liver disease.
The FXR is a receptor for bile acids, which are produced by the liver, and recycled through the gut. They play an important role in lipid and nutrient absorption, and can also transmit signals that affect metabolic, inflammatory and immune pathways in many organs. FXR is expressed on numerous cell types, and is reduced in the livers of patients with NAFLD (Yang ZX et al. 2010). In rodent models of NASH/NAFLD, increasing FXR expression or stimulation of FXR reduces hepatic steatosis, bile acids, lipids, glucose and fibrosis (Adorini L et al. 2012). Therefore, it’s possible that this target could be viable for humans with NASH.
Intercept Pharmaceuticals (ICPT) currently has OCA approved for Primary Biliary Cholangitis (PBC) and has generated $20.6M in Q1-2017 sales. OCA has shown efficacy in NASH, but I’m going to go through why I do not think ICPT is a good buy.
OCA and NASH
Many rodent studies have shown that FXR agonism may improve NASH (see the reviews above). We care much more about the human studies since rodents aren’t people. One study looked at the effect of the bile acid ursodeoxycholic acid (UDCA) in NASH patients and showed no benefit, despite being non-specific to FXR (Lindor KD, et al. 2004). ICPT sponsored a phase 2 clinical trial to see if OCA is able to reduce NASH in 141 patients (Neuschwander-Tetri BA et al. 2014). The primary outcome was a decrease in NAFLD activity score, without worsening of fibrosis evaluated by histology from a liver biopsy.
When ICPT released their results from this trial (Jan, 2014), its stock rose from ~$60 to $500, before settling down to around $250 after issuing more stock. This Phase 2b trial was stopped early after their planned interim analyses showed positive results in consultation with the Data Safety Monitoring Board. Two things happened here,
1) They saw a significant effect of OCA in their primary endpoint (Fig. 2) and
Figure 2. OCA improves NASH on multiple metrics.
2) There were significant persistent changes in cholesterol concentrations in OCA-treated patients recommending treatment discontinuation (Fig. 3, Neuschwander-Tetri BA et al. 2014).
Figure 3. Total cholesterol and LDL cholesterol are significantly elevated in OCA-treated patients.
This study showed that OCA treatment nearly doubled the number of patients that saw an improvement in fibrosis, NAFLD activity score, hepatocellular ballooning, steatosis and inflammation. However, the FXR seems to play a role in mobilizing cholesterol/triglycerides, which may be its primary mechanism of action in the liver. OCA appears to be reducing hepatocyte fat, and moving it to the bloodstream leading to increased serum cholesterol and LDL with reduced HDL. A primary concern with this drug, if approved, is that it will likely be restricted to patients who are not at risk for coronary heart disease. ICPT has shown that co-treatement of OCA with a statin significantly improves the cholesterol profile in OCA-treated patients, but this is definitely less than ideal (ICPT press release, July 31, 2017).
Lipid profile aside, this trial also showed that OCA patients had significantly increased serum insulin and significantly worse insulin resistance despite weight loss. This result is interesting because FXR stimulation has previously been shown to improve insulin sensitivity in rodents and man (Fang, S. et al. 2015; Mudaliar, S. et al. 2013). The authors of the Phase 2 study speculate that long-term FXR agonism reverses any short-term changes in insulin resistance through adaptive mechanisms. This certainly appears possible, and does not bode well for NASH patients that are already type 2 diabetic. ICPT may need to exclude these patients for treatment, or encourage co-treatment with established type 2 diabetes drugs.
GENERATE Phase 3 Trial
After seeing a positive effect in their Phase 2 study, ICPT went on to start Phase 3 studies for OCA in treating NASH. They have 2 primary outcomes of which they only need to achieve one (slightly easier metrics to achieve compared to other NASH trials), as per their February 10, 2017 conference call:
A. Evaluate the effect of OCA on liver histology:
1. Improvement of at least 1 stage of liver fibrosis
2. Number of treated patients achieving NASH resolution
GENERATE started in September, 2015, where they aimed on enrolling ~2000 patients, split evenly into 3 arms with an interim analysis of 1400 patients in mid-2019. Things appear to have changed since their Feb 10, 2017 conference call, where ICPT representatives said there would only be 750 patients for the interim analyses. This may be related to patient recruitment issues from the uncomfortable pruritus side effects of OCA. On top of that, the FDA recently issued a warning to patients taking OCA that they need to be very careful with dosing of the drug based on their liver function. The company’s conference call a few days later reiterated that patients with late stage liver disease need less frequent OCA doses since their livers cannot process the drug as well as patient’s with normal liver function (Sept, 2017 conference call). Though apparently unrelated to OCA, ICPT has seen some deaths in their trials that may not have sat very well with prospective patients.
Given all of this, I have concerns. Above all, I am convinced that OCA helps with NASH at a high enough dose. Their phase 2 study showed good efficacy, and it looks like with a larger population, they will get good data on their primary endpoint. However, if approved, this drug will not come close to reaching a substantial part of the NASH market. It will likely be restricted to patients that are not at risk for cardiovascular disease nor diabetes. This may leave only 10% of the NASH market, since these diseases go together very often (Bang, KB and Cho, YK. 2015). Co-treatment with statins or anti-type 2 diabetic drugs will open the market more, but I’m not so sure patients will find the treatment proposition very enticing.
I am not taking a position on the company and I don’t recommend it. Any news between now and the interim analysis will send the stock in either direction. The tremendous NASH market opportunity has brought in a lot of interesting drug companies, so this environment will get competitive quickly. I need to do more research, but a couple drugs I’m looking into are MGL-3196 from Madrigal Pharmaceuticals, and Elafibranor from Genfit. Both of these drugs seem to improve NASH without negative side effects. If anyone has a good NASH drug recommendation, let me know in the comments below. I will be making another NASH related post soon.
Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discovery Today. 2012
Bang KB and Cho YK. Comorbidities and Metabolic Derangement of NAFLD. J Lifestyle Med. 2015
Cassidy S and Syed, BA. Nonalcoholic steatohepatitis (NASH) drugs market. Nat Rev Drug Discov. 2016
Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, Atkins AR, Khvat A, Schnabl B, Yu RT, Brenner DA, Coulter S, Liddle C, Schoonjans K, Olefsky JM, Saltiel AR, Downes M, Evans RM. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015
Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004
Mudaliar S, Henry R, Sanyal AJ, Morrow L, Marschall HU, Kipness M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D. Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Gastroenterology. 2013
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Mae Diehl A, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicenter, randomized placebo-controlled trial. Lancet. 2014
Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int. 2010