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Sometimes You Get Lucky In Biotech

|Includes: BioLineRx Ltd. (BLRX), MDGL, VKTX

Many years ago I started a position in Synta (Ganetespib).

Over the years they had one failure after another.

The Last straw was the P-III failure of Gane in Lung Ca in 2016.

I was devastated by my losses in Synta, which were in the 10sof Thousands.I had been wrong before, but this one was so hard to explain.The Science and the People were the best I seen.The drug was doing well in P-I and than P-2, it seemed like I had fallen onto another SLAM DUNK, but than early 2016 and was TOAST!

But out of the ASHES called Synta came a merger with Madrigal a private BT working in NASH. All of a sudden my penny stock had life, the Madrigal Drug was well thought of and so too its Inventors at Madrigal and soon they would control my LOSING SYNTA shares.But why SYNTA, was it Dr Paul Friedman the CEO who would become the new Leader.Was it the cash on hand, was it a SHELL CO w/ a NADAQ symbol easy to get a hold onto...probably a little of all these things but I cared NOT because I was saved. The GURUS said to hold onto your mergerd MDGL shs that they would move up quickly and they did.I sold at about $65 when I needed $80 to get to BE but I was in shock that it went so HIGH so FAST I decided to take the Bird in the hand not the two in the Bush and now I want to share with all why that was stupid!

Who is MADRIGAL and what are they working on that is so REVOLUTIONARY?

Madrigal NASH/Lipid/HeFH/HoFH Science 2017

Paul Friedman, M.D. -Chairman and CEO • Former CEO of Incyte Pharmaceuticals; former President of DuPont Pharmaceuticals Research R & D • Rebecca Taub, M.D. -Chief Medical Officer, Executive Vice President, R&D • Founder of Madrigal • Led teams that discovered Eliquis and MGL-3196, Madrigal’s lead compound • Recognized expert in liver regeneration and diseases of the liver • Marc Schneebaum -Chief Financial Officer, Senior Vice President • SVP, CFO of Synta since 2014 • Over 20 years of executive operational experience in the biotechnology and health care sector

The THR-β receptor mediates the beneficial effects of thyroid hormone in the liver, on LDL-cholesterol and triglycerides, fatty liver and insulin sensitivity • Lipid benefits of liver THR-β established by decades of clinical experience • The liver is hypothyroid in NASH: treatment with MGL-3196 should normalize hepatic thyroid function • Hypothyroidism at the level of the thyroid gland is at least twice as common in individuals with NASH as in the general population* and increases the risk of of nonalcoholic fatty liver disease** (*Clinical Gastroenterology,2003;37(4):340-343; **J ClinEndocrinolMetab.2016; 101(8:3204-3211) • Liver-specific hypothyroidism, present in human NASH, is caused by degradation of thyroid hormone (increased deiodinase(DIO) 3 produced by stellate cells) in the NASH liver (Endocrinology. 2014;155(11):4591-4601) • MGL-3196 has pleiotropic effects characteristic of an “ideal” NASH drug, with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooned, pre-apoptotic hepatocytes, fibrosis (both directly and indirectly) • NASH patients with advanced fibrosis have increased CV risk and primarily die of CV (not liver) disease (Hepatology. 2015;61:1547-54, Gastroenterology, 2015;149:389-97 ) • MGL-3196 lowers LDL-cholesterol and may provide CV benefit to NASH patients • Treating NASH, rather than fibrosis, is key to addressing the disease • Resolution of NASH, without reducing fibrosis, is an approvable endpoint • Recognition that liver fibrosis will decrease with time after NASH resolves (similar to reduction of fibrosis as the liver regenerates after cure of HCV)

We believe MGL-3196 is the first bona fide THR-β selective molecule with key advantages over previous companies’ analogues • Discovery of MGL-3196 and backups at Roche utilized a novel functional assay that went beyond what previous companies had done (simple receptor binding assay) • Earlier compounds from other companies, purported to be THR-β selective, show no functional selectivity in this assay and, like thyroid hormone, activate the THR-α receptor equally well as the β receptor • in vivodata confirm MGL-3196’s high liver uptake and preclinical safety: no heart, bone/cartilage, or brain uptake; safe in long-term animal toxicology studies • Avoids activity at the systemic THR-α receptor (increased heart rate, osteoporosis) • Unlike other company’s earlier thyroid receptor agonists, no cartilage findings in chronic toxicology or liver enzyme increases in human studies

Fat deposition, lipotoxicity and resultant local inflammation are seen in NASH

• Hepatocyte dysregulation and damage ensue up to and including apoptosis. These perturbations lead to a profibrotic environment through: • Ongoing inflammation; • Production by the dysregulated/ damaged / dying hepatocytes of profibrotic factors, with TGF-β among the most important

• Thyroid hormone receptor agonism has been shown to dampen inflammation in vivo and to inhibit TGF-β signaling in cell culture and in vivo

• In animal models of liver fibrosis, the extent of fibrosis is decreased by thyroid hormone administration and increased if thyroid hormone receptors are knocked out (PNAS 113: 3451, 2016)

• THR-β is the operative receptor in hepatocytes

Completed Single Ascending Dose (SAD) study

• Multiple Ascending Dose (MAD) study • Six dose cohorts, 36 total HV dosed daily with MGL-3196 (5, 20, 50, 80, 100, or 200 mg) and 12 with placebo for 14 days • Healthy volunteers with slightly elevated LDL cholesterol (> 110 mg/dL) • Well-tolerated, appeared safe at all doses tested • No effect on vital signs, heart rate, central thyroid axis, or liver enzymes

• Phase 1 studies dosing MGL-3196 with statins • Series of GLP toxicology and CMC studies support all indications • Manufacturing and product formulation • Chronic toxicology package • Phase 2-enabling

Excellent correlation between decline in fat content on MRI-PDFF and NAS score, steatosis and ballooning on biopsy (Ther. Adv. Gastroenterol. 2016; 9:692-701)

• Rapid liver fat changes detectable with MRI-PDFF after caloric restriction and weight loss: easily detectable and near maximal by 6 weeks (PLoSOne.2016; 11(4):E0153595)

• Two regularly scheduled DSMB meetings held May 2017 and September 2017 to review data from the Madrigal NASH Phase 2 trial • DSMB recommended to continue the trial with no changes to the protocol

We believe that the impressive preclinical NASH animal and human lipid lowering effects coupled with the excellent safety profile point to a high probability of success..

MGL-3196: Unique and Complementary Lipid Lowering Profile

• Thyroid pathway clinically validated and differentiated in FH

• Both LDL receptor-dependent and –independent cholesterol lowering: • Stimulates cholesterol breakdown and elimination • Lowers Apo Band Lp(A) • Decreases levels of PCSK9 (human data) and angiopoietin-like protein 3 ANGPTL3 (gene expression) • MGL-3196 lowers LDL in concert with statins in clinical & preclinical studies • Thyroid agonists lower cholesterol in LDL receptor knockout mice* • In Phase 3 trials in HeFH, an earlier THR agonist lowered LDL cholesterol and Lp(A)** • MGL-3196 acts through a mechanism that potentially lowers Lp(A), a severely atherogenic particle that is elevated in FH

** Lancet Diabetes Endocrinol2014; 2: 455–63 * Endocrinology 2012 Nov;153(11):5143-9

In FH, we believe MGL-3196 will deliver additional LDL-C and Lp(A) lowering on top of conventional treatment

Potential Near and Longer-term Value Drivers

Clinical trial initiated: • Ph2 in NASH: 12 week MRI-PDFF with 36-week liver biopsy

Potential Data Readouts: • Ongoing safety assessment, Phase 2 trials • Ph2 topline results in HeFH • Ph2 topline results in NASH (12 weeks)

Completed Previously: • MGL-3196 long-term toxicology studies • MGL-3196 dosed with statins in Ph1 studies (20152Q2016)

Clinical trial initiation: • Ph2 in HeFH: 12-week clinical trial (initiated)

Potential Data Readouts: • Ph2 topline results in NASH (liver

Phase 2 once-daily oral, liver-directed thyroid hormone receptor-βagonist (THR-β); efficacy and safety profile validated by preclinical and clinical data

Large & Underserved Markets in NASH & Genetic Lipid Disorders

Expected Funding to Key Inflection Points

• Experienced management team with proven track record in drug discovery, development and commercialization; expertise in liver diseases

• Cash resources sufficient past key clinical inflection points in NASH and HeFHand into 2019 (~$67M at 6/30/2017, incl. $35M June financing)

• Phase 2 NASH & HeFH trials initiated; enrollment completed for NASH and HeFH trials. HoFH pilot study planned.

• Initial indications are NASH and familial hypercholesterolemia; possibility to expand indications with either MGL-3196 or pre-clinical follow-on MGL-3745

Second DSMB review includes data from both Phase 2 studies in NASH and HeFH --

-- Top-line results from NASH expected late 2017 and HeFH early 2018 --

CONSHOHOCKEN, Pa., September 19, 2017 -- Madrigal Pharmaceuticals, Inc. (Nasdaq:MDGL) today announced that the Company’s independent Data Safety Monitoring Board (DSMB) held its second prespecified meeting to evaluate both the heterozygous familial hypercholesterolemia (HeFH) and non-alcoholic steatohepatitis (NASH) Phase 2 clinical trials and recommended that both studies continue without protocol modifications. Madrigal also announced that the Phase 2 study of MGL-3196 for the treatment of HeFH, a severe genetic dyslipidemia that causes early onset cardiovascular disease, has enrolled 113 patients, thereby exceeding the target patient enrollment of 105 patients, and will continue enrollment for the next several days. Topline results from the study are expected in early 2018.

“Individuals with HeFH suffer from a life-long burden of cholesterol buildup and are at high risk of early coronary artery disease. While treatable with LDL-C lowering strategies, we estimate that more than one-third of HeFH patients do not achieve their cholesterol reduction goals,” said John J. P. Kastelein, MD, Ph.D., FESC, Professor of Medicine in the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam and the principal investigator of the study. “We are hopeful that results from this Phase 2 study will support further development of MGL-3196 as a much needed additional oral agent to treat people with HeFH.”

MGL-3196 is a first-in-class, oral, once-daily, liver-directed, thyroid hormone receptor (THR) β-selective agonist medication that has demonstrated significant LDL lowering in both clinical and preclinical studies. MGL-3196 is also in a fully enrolled Phase 2 clinical trial for the treatment of NASH.

“We are encouraged by the recommendation of our DSMB to continue both the NASH and HeFH clinical trials with no modifications to either protocol. In the HeFH study, we have exceeded target enrollment of patients who have not met treatment goals despite high intensity statin therapy, including up to 40 mg of rosuvastatin and 80 mg of atorvastatin , thus, providing opportunity for additional LDL cholesterol lowering in HeFH,” stated Rebecca Taub, M.D., CMO and Executive VP, Research & Development, and founding scientist of Madrigal.

“We anticipate that the data from both the HeFH and NASH Phase 2 studies will confirm the potential therapeutic value of MGL-3196,” stated Paul A. Friedman, M.D., Chairman and CEO of Madrigal. “We look forward to the potentially exciting opportunities for Madrigal as we advance through clinical development of this drug.”

MY POA on MDGL is to allow the stock to run for awhile as it releases new info late 2017 into 2018 it could reach TARGET SP $65 given by Evicore and possibly move past..I need roughly $81/sh to BE but would start selling it at $65-70 range all 221 shares…the GOAL for now is to get most of my MONEY back from SYNTA loss!

Its possible that I could re enter the stock down the road once I BE!


Well its now the year 2019, I have never re entered MDGL which climbed from $81 to a High=$325 on 6/6/18 on that day I was in SHOCK loss in SYNTA was maybe $20K and I had erased that loss by maybe $15K by SELLING my SAVIOR  Madrigal because I was FEARFUL of losing it all over again!

75% back on a DOA loss was great,right...?

Today the shorts have entered, the stock trades way down from the high to about $115-125 range so what would YOU have done in this example. I gave you all my notes above on MDGL and their Science which is pristine. I keep notes on all my BT plays..I simply CUT and PASTE to a word.doc all I can find...

Now let me tell you what I did next..I learned ALL I COULD ON NASH, who are the players and who has the best meds, best people!

MDGL was Top dog but did I need the Top Dog in a $35B projected NASH Market? Whats wrong w/ number 2 or 3 or 4 or even 10? Big Markets like this will need multiple players like the Statins in Cholesterol.

I think I found a very good Surrogate called Viking(VKTX) and I bought a ton and sold a Ton and now I hold only 4K shs at $.47/share when it trades at about $8.25! I put all the MDGL money I had into VKTX which was about $14-15,000 to play the spread over time and I sucked out all the extra cash as profit to go elsewhere.I actually became fond of a second player who had NASH as a back up called BLRX...more of a Cancer play partnered w/ MRK>

Will VKTX ever achieve greatne$$ in the NASH markets of the future, who really knows for sure. I have 4K shares that say it will and I have another $12K+ invested in other BT plays like BLRX and it all came from my FAILURE in Synta who merged to became MDGL.

This was a once in a lifetime event..I have never seen it before and likely will not see it again but Happy New Year to my Followers. If you have MDGL I would hold tight, if you have VKTX do the same, and if you are not in NASH get invested NOW before the NASH wave crashes.

Happy BT Investing in 2019!


Disclosure: I am/we are long VKTX and BLRX.