Mysterious Lotus Casebook Score: 8.5 (Rated by 579k+)

Episodes: 40 (Duration: 45 min.) Weibo Genre: Wuxia, Investigation, Mystery Where to Watch: iQiyi, WeTV

• The filming took place in Hengdian from June to October 2022.
• Due to its immense popularity, Mysterious Lotus Casebook held a live concert and fan meeting on September 16th, 2023. Cheng Yi, Zeng Shunxi, Xiao Shunyao, Chen Duling, Wang Herun, and Chen Yihan were in attendance.
• Cheng Yi personally voiced the character of Li Lanhua, whereas Chen Zhang Tai Kang (who also voiced Tian Yao in Back From The Brink) lent his voice to Li Xiangyi.

Ripe Town Score: 8.5 (Rated by 146k+)

Episodes: 12 (Duration: 44-101 min.) Weibo Genre: Historical, Investigation, Suspense Where to Watch: WeTV, Viki

• The filming took place in Hengdian from March to June 2022.
• In a scene where the character rides a donkey, Ning Li developed a "leaning" riding technique and diligently practiced it in preparation.
• By modifying the breathing pattern, rhythm, and adjusting the pace of speech and punctuation, Ning Li elevated the naturalness of Song Chen's dialogue in the series.
• The closing theme of the series, titled "宴" is sung by Ning Li, with the harmony sections composed and performed by Ning Li's daughter.

Nothing But You Score: 8.2 (Rated by 146k+)

Episodes: 38 (Duration: 45 min.) Weibo Genre: Urban, Romance, Sports Where to Watch: WeTV, Viki, iQiyi

• The filming took place from May to September 2022.
• Because there were many scenes shot on the field, Wu Lei barely used makeup for most parts (he mentioned that it would melt due to the heat and sweat).
• Wu Lei underwent two months of training in tennis and badminton with a professional coach as part of his role preparation. He explained that since he is portraying a professional athlete, although he cannot fully replicate their professional movements and condition, he aimed to immerse himself in their mindset. Zhou Yutong also worked at the Tencent Shenzhen office to gain firsthand experience in the day-to-day responsibilities of Executive Assistants.
• Wu Lei studied Rafael Nadal's matches and playing style in his role preparation as well because he considered Nadal a resilient player, and since Song Sanchuan's transition from badminton to tennis in his athletic career was marked by numerous setbacks and comebacks, it was clear that a similar level of resilience was indispensable (according to him).

Fake It Till You Make It Score: 8.1 (Rated by 126k+)

Episodes: 14 (Duration: 1hr10min.) Weibo Genre: Urban, Romance, Workplace Where to Watch: Viki, YouTube & MGTV (warning: the sub is awful in Mango & YT)

• Filming took place in Beijing in Q4 2022.
• The original author of the novel, Liu Cuihu, is a graduate of Peking University Law School and has worked in law firms within Beijing's Red Circle. With firsthand experience in high-pressure environments at top-tier law firms in China, Liu Cuihu brings their perspective to the narrative. Additionally, director Li Mo also embarked on a diverse career path, undertaking various roles such as video editing, composing, planning, scriptwriting, working in an advertising agency, shooting commercials, producing promotional videos, and assistant directing before ascending to the role of director. For further insights, see the Director Notes.
• To capture the exaggerated mannerisms of the "Big Boss," Jiang Shimeng prepared an entire box of cups in advance, ensuring that each distinct beverage for the "Big Boss" had its specially matched cup. In Jiang Shimeng's perspective, the "Big Boss" appeared three-dimensional and complete, reflecting the complexity of human nature.
• Before filming this drama, Han Dongjun specifically consulted with friends working in investment banking around him. He discovered that they often experience significant work pressure and, in private, have hobbies to help them relax. As a result, he gave the character Xu Ziqiang a personal interest in motorcycles. (Which is also Han Dongjun's hobby)
• Unaware of the planned adjustment for a kissing scene on set, Bao Shangen had already eaten spicy snacks. Upon learning about the situation, she promptly informed Dai Yunfan and took the necessary time before shooting to thoroughly rinse her mouth and use mint candy.

Thirteen Years of Dust Score: 8.1 (Rated by 130k+)

Episodes: 24 (Duration: 45min.) Weibo Genre: Crime, Mystery, Drama Where to Watch: iQiyi

• To depict the dual timeline setting in the series and synchronize with the actual seasons, the production team deliberately chose to film scenes set in 1997 and 2010 during winter and summer, respectively.
• To accentuate the aging process over 13 years, Chen Xiao willingly requested the removal of his receding hairline and temple hair to enhance a weathered appearance.
• Veteran actor Niu Piao shed 20 kilograms within a few months to highlight character differences,
• The styling director immersed themselves in the streets of Chongqing, observing the images of ordinary locals to craft makeup and styling for each actor that captured both the mountain city's temperament and the characters' personality traits.
• To elicit authentic anger from fellow actors during scenes, Chen Jianbin, without warning, abruptly entered a room where the other actor was unprepared, allowing the actor to channel the broken anger instantly into the character, creating exceptionally authentic emotions in the scene.
• Initially brought in as a singer by the producer, Wang Xiaokun coincidentally suited the role of a rock youth in the series. Given his past acquaintance with Chen Xiao, he ended up making a guest appearance.

I Am Nobody Score: 8.1 (Rated by 98k+)

Episodes: 27 (Duration: 45min.) Weibo Genre: Comedy, Fantasy, Adventure Where to Watch: Youku

2023 Dramas that Scored 7.5~8 & Rated by <50,000

• Although delistings can sometimes hit the market all at once, like in the dotcom crash or the 2019 Chinese stock delistings, on a case-by-case basis delisting rules are applied super inconsistently.
• Despite different reasons, some stocks are delisted the day after while others for up to 2 years after first being warned. Staying under $1 a share for an extended amount of time can be a common reason for delisting across exchanges.
• CUSIPs (like the ones you see on ComputerShare letters or perhaps AST letters (?)) are basically gamer tags that can track stocks from the stock market until after their delisting, as zombie stocks in the OTC markets.
• The Sears delisting/bankruptcy had weird timing, just before the start of the Q4 retail season, big for all retailers including [video game stock].
• Apple reseller Cool Holdings had been partnered with [video game stock]. Its stock got a shit ton of FTDs around the time it was at risk for delisting. It got delisted a few months later right before it needed to pay back [video game stock], who was dealing with its own financial issues and FTDs.

1. Ulterior Motive

“Dear Chairman Cox and Commissioners,(The following text is something in between a “Comment letter” on steroids and my 5th book on naked short selling abuses; I haven’t decided which yet…
A question: in the case of the SEC’s “Delisting” process has it ever occurred to you at the SEC...the easiest way to “Bury the bodies (unaddressed FTDs) in the desert” would be to get the SEC to acquiesce to the demands of those would be “Shareholder advocates” pushing for the targeted company’s delisting purportedly “In order to prevent new investors from being defrauded by this “Scammy” management team”?
Does it not make sense that those DTCC participants pushing for delistings might have an ulterior motive for their actions that might be worthy of looking into?

2. Hodl on for Dear Life

3. Grand Opening, Grand Closing: Delisting 101

...if a security's price closed below $1.00 for 30 consecutive trading days, that exchange would initiate the delisting process. Furthermore, the major exchanges also impose requirements related to market capitalization, minimum shareholders' equity, and revenue outputs. From a bookkeeping perspective, public companies must stay current with paying exchanges their annual listing fees due, while dutifully covering the significant legal and compliance costs associated with listing on an exchange.

• Don’t stay under $1 for a long time
• File regularly
• Keep a solid market cap

4. (In)consistency is Key

• Right after being evicted, stock prices freefall but volume remains weirdly high, with their 2008 sample finding an average of 2.25 million shares traded on the 1st day of delisting (!)
• Inconsistent application of delisting rules, where some violate them but still trade for months or years later (Bethlehem Steel in violation of the 30 day rule for 157 days). Others get the ax pretty much right away (Mutual Risk Management after violating the rule for ONE FUCKING DAY)

• Bankruptcy delistings are inconsistent, with some being booted the day after (Global Crossing), others after a month (Enron) or others TWO YEARS LATER (Owens Corning)
• Even when firms are caught doing immediate fucked up shit (Enron) it’s not grounds for immediate delisting. (Surprise fucking surprise)

• Companies can sometimes stay on even with no financial statements (Fannie Mae, Freddie Mac)
• Penny stocks with high volume might prop up OTHER penny stocks that trade less frequently (the phrase they used was “Our data are consistent with a cross-subsidization effect…”)

5. Spectator Mode

6. Gamer Tags

• Outstanding 7% Notes due 2042 (CUSIP Number 812404408)
• Outstanding 7.4% Notes due 2043 (CUSIP Number 812404507)

7. Don’t Youuuuu…Forget About Meeeee….

“In the matter of SEC “Delistings” of corporations with inordinate amounts of unaddressed FTDs my concern usually falls with...What type of a regulator would “Deputize” these criminals and “Enable” these activities? Why are these “Vigilantes” not forced to cover their naked short positions on T+13 before the delisting process…shareholders would gladly take a penny on the dollar as opposed to nothing.
Yet even this token form of investor protection is dismissed….When the Wall Street community gets a whiff …how much of this selling before these actions are made public might be abusive naked short selling with no attempt whatsoever to effect a locate or a pre-borrow due to the imminent demise of the corporation?...
[This allows] fraudsters to knock out any and all bids in a rapid fire fashion in order to trip stop loss orders, induce margin calls, render securities unmarginable, trigger delistings, decrease collateralization requirements associated with “marking to market” these open positions or to just scare the average investor into panic sales is totally beyond me…

8. One More Letter: The Delisting of Sears

The first step toward delisting is a "deficiency notice" sent by the Nasdaq if a company is in violation of the index's listing standards for a period of 30 consecutive days. Once the notice is sent, the company has 90 days to get back into compliance and stay in compliance for 10 consecutive days in the 90-day period. If Sears fails to do this, the Nasdaq will then send the retailer a delisting letter that must be disclosed to the public within four business days. Once the letter is received, the company has seven days to request a hearing with the Nasdaq listing qualification panel, which postpones the delisting process until a decision is made.

“In the end, only the Sears store real estate will be left. And it remains to be seen whether Lampert or other Sears creditors will benefit the most from that.”

9. Cliffhanger

Polygon provided some context for this massive drop by framing it against some snakebitten competitors of GameStop’s. Toys R Us posted sales declines of 2.2 percent in Q3 2016 before filing for bankruptcy. Blockbuster’s sales were down 20 percent in 2010 before it went out of business. Those results don’t necessarily prove that Game. Stop is doomed to fail, but history isn’t on its side.

"I definitely think it's a melting ice cube," Wedbush analyst Michael Pachter said of GameStop's disc-based business model. "For sure it's going to go away eventually. And for sure their future will be truncated and eliminated the day that discs stop being manufactured…"They just got a seven-more-year reprieve starting in 2020," Pachter said. "GameStop's got about 10 years before that ice cube is fully melted."

10. The Dark Shadow & The Darkest Timeline

“If you listen real closely can you hear the sigh of relief or popping of champagne corks on Wall Street every time a U.S. domiciled corporation goes bankrupt or gets delisted by the SEC? When you see the displaced employees of these firms pack up their desk contents in boxes and haul them to their cars is there a sense of relief in the air?”

• Although delistings can sometimes hit the market all at once, like in the dotcom crash or the 2019 Chinese stock delistings, on a case-by-case basis delisting rules are applied super inconsistently.
• Despite different reasons, some stocks are delisted the day after while others for up to 2 years after first being warned. Staying under $1 a share for an extended amount of time can be a common reason for delisting across exchanges.
• CUSIPs (like the ones you see on ComputerShare letters) are basically gamer tags that can track stocks from the stock market until after their delisting, as zombie stocks in the OTC markets.
• The Sears delisting/bankruptcy had weird timing, just before the start of the Q4 retail season, big for all retailers including GME.
• Apple reseller Cool Holdings had been partnered with GME. Its stock got a shit ton of FTDs around the time it was at risk for delisting. It got delisted a few months later right before it needed to pay back GME, who was dealing with its own financial issues and FTDs.

We may be early, but we are not wrong.

UK pension funds have been hit with variation margin calls of as much as £100 million ($107 million) each, after sharp falls in gilts and sterling pushed mark-to-market valuations on derivatives and leveraged repo positions heavily against them. Simeon Willis, chief investment officer of consultancy XPS Pensions Group, says he knows of three different fund managers running pooled pension portfolios that have requested emergency capital from clients to keep positions open.
UK pensions hit with £100m margin calls as gilts and sterling slide (Risk.net)

🤔 Pensions trying to keep positions open? What's going on???

The Bank of England was forced to take emergency action in a desperate attempt to stabilise the UK economy to stop mass insolvencies of pension funds today, it has been claimed. Earlier today, the BoE announced it would be carrying out "temporary purchases of long-dated UK government bonds"
...
"Had they not intervened, there would have been mass insolvencies of pension funds by THIS AFTERNOON."

🐘 CITADEL SECURITIES FINANCE (UK) LIMITED

Banks: down, but never out

Australia’s central bank on Wednesday said its equity had been wiped out by losses suffered on pandemic-era bond buying, but its ability to create money meant it was not insolvent
...
Bullock noted that while this would bankrupt a normal commercial entity, the RBA’s liabilities are guaranteed by the government.
“Furthermore, since it has the ability to create money, the Bank can continue to meet its obligations as they become due and so it is not insolvent,”
...
Bullock noted other central banks around the world would be facing similar losses on their emergency stimulus programs, though many did mark their assets to market like the RBA.
CNBC: Australia’s central bank has equity wiped out by billions in bond losses (Sept 20, 2022)

Remember, Positions Are Still Open

Diving into the Definition

• This graph is a really interesting representation of the impact of orphan drugs for people with rare diseases. On the left we have the prevalence, or rate, of people with the rare disease. As you can see, the majority of people with a rare disease are those with 10k to 100k people per disease (for instance, Cystic Fibrosis affects about 30,000 people in the United State). The pie chart in the middle shows the distribution of patients currently being treated with orphan drugs. Unsurprisingly the diseases with more people represent larger sections of the pie chart because there are physically more people. However, on the right, if we average the pie chart by the size of the disease (combining the left and middle) we see that the diseases with the least amount of people have the most people being treated. Essentially, the smaller the disease the more common it would be for those people to be using an orphan drug. Kinda cool statistics for ya!
  • Less than 15% of people with a rare disease are treated by an orphan drug, why? Well there are a couple main reasons: firstly, the majority of those people are unaware that they have a disease and are just undiagnosed. Second is the generalization of non-orphan drugs to treat these rare disease—we find out that a common drug is effective in treating these rare conditions. The last is that about ¼ of the orphan drugs target populations smaller than 5,000 people.

• When we look at the drug development process, there are generally 4 major steps with many different sub-steps that have to be completed in order for the FDA to authorize progression. From conception to marketing it takes about 10 years with the clinical trials taking at least 7 years of that time. This is why the average cost of a drug is so high, about $2.8 billion.
  • The first step is the chemistry or biochemistry that enables scientists to physically create the molecule. This includes identifying the target (receptor, protein, gene, molecule, etc.) and developing the processes to determine if the drug can actually get to the target. Then the drug has to be tested in non-humans like mice, rats, or dog models (in vivo) or in lab settings on specific tissues (in vitro). Once all that safety data is generated it can then be tested in humans.

• Human testing is the most necessary step in determining if a drug can head to market. One drug named Thalidomide was marketed as an anti-nausea medication for pregnancy and was tested in rabbits, dogs, and monkeys. No significant problems were detected with Thalidomide and it was sent to market as a must have medication for severe nausea. Unfortunately Thalidomide was never tested in humans and caused severe fetal defects. Children affected by the medication were referred to as “flipper babies.” (Read our post about it here.)
  • Phase I clinical trials focus on testing the drug in healthy human volunteers. If we only tested it in patients already affected by the disease then we may never know if an adverse effect is caused by the disease interacting with the drug or the drug affecting the body independently. It’s also when pharmacokinetic data is generated—this data tells us exactly how long the drug stays in the body, how it's metabolized, and how it's eliminated.
  • By Phase II and III the drug is being studied in the intended patient population. This is when drug manufacturers test if their drug is effective and does what they say it does. This is also when a drug can fail and the billions of dollars spent to get to this point can be sent down the drain. Recently an HIV vaccine was scrapped in phase 2b/3 after proving to be ineffective in preventing new HIV infections—about $1.3 billion spent. Another example is Balovaptan which was being tested to treat autism based on the vasopressin 1a receptor. It was abandoned in phase 3 due to low efficacy.
  • If a drug can make it through clinical trials and show efficacy and safety the FDA will come in and review the process. If the FDA thinks the data is wonky they will make the drug manufacturer do another trial. If they get the coveted FDA approval then the drug can be sent to market and used in the general population. However a drug company still needs to monitor for side effects and must send that data to the FDA as part of their approval condition.

The Mad Royal Disease—Porphyria

• Some of you may remember King George III of England (1738-1820), the man who lost the American colonies sparking a new age of revolution across the globe. George was the grandson of George II and was born two months premature and was raised in isolation by his mother at Kew Palace. George’s early life was a struggle; he didn’t master reading fully until 11 years old but was determined to learn as much as he could. In 1760 George became king of Great Britain at the age of 12 and the people were excited for the first English born monarch (last was Queen Anne in 1714) in a generation who could restore English traditions.

• While hope was high George was dealt a shitty hand. While George would lose the colonies in the 1780s it was really his father’s fault for creating such a shitty situation for him to deal with. With the stress of running a country on the brink of financial ruin George’s behavior started to change. He would have periods of mania and would write letters with 400 words and only 8 verbs. He would complain incessantly of stomach pains and would be unable to sleep most nights due to the pain and convulsions that would rack his body. He was also known to hallucinate and one anecdote found him planting beef in the ground in order to grow a beef tree. These periods of madness could last up to a year and would come every few years necessitating recovery and treatment.
  • Obviously a mad king is not a good image for stability and so George was moved from Windsor Castle to his childhood home of Kew Palace during his relapses. No doctors could identify a physical illness and asked Dr. Francis Willis, the contemporary expert on mental illness, to treat the king. Willis believed the condition to be due to overexcitement and prescribed relaxation, calming activities, and complete control. If he was too manic he was placed in a straightjacket and ate soft baby foods so he wouldn’t have a fork or knife. He was also subjected to bloodletting and forced sleep and seclusion or treated with arsenic to blister the skin, castor oil to cause diarrhea, or heavy metals to induce vomiting.
  • The king had his first major attack in 1790 during the aftermath of the American Revolutionary War but recovered quickly. He would relapse in 1801 and 1804 causing a power struggle between Prime Minister William Pitt and George’s son, George IV. In 1810 George would have his last attack and would never fully recover from it. By this time his cataracts made him blind and he became permanently mad until his death in 1820.

• With the clear pattern of mania, normalcy, and depression many believed George III to be a clear case of bipolar disorder. However symptoms that were originally thought to be side effects of 18th century treatments were determined to be actually due to George’s disease. The most prominent symptom was severe and persistent abdominal pain that radiated downwards into the legs instead of diffusely into the rest of the chest. Likewise he had red urine and his… ahem… feces took on a notable purple color. This led many historians to believe that George III had porphyria, not a psychiatric illness (although this is still a theory). One key piece of evidence is that George’s direct descendent Prince William of Gloucester (1941-1972), the grandson of King George V and cousin to Queen Elizabeth II, had porphyria—a clear hereditary link.

• Alright alright so what is this mysterious disease? Porphyria is an inherited rare metabolic disorder in which a person is unable to correctly synthesize heme. Heme is the main component of hemoglobin, the protein that found in red blood cells that allows it to carry oxygen. The heme molecule is made of a large ring called the Porphyrin Ring which has 4 nitrogen atoms used to capture the Iron atom (Fe) in the middle. Its that iron that holds onto the oxygen allowing us to transfer oxygen from the lungs to every cell in your body. Kinda crazy!

• In Porphyria the body’s ability to synthesize heme is impaired due to clogging of certain enzymes involved in the biosynthesis of the heme molecule. There are three kinds of porphyria: chronic porphyrias (most common) or acute intermittent porphyria (which George likely had). While those are genetic in nature, the last is acquired porphyria which is usually caused by metal toxicity (lead, iron) or secondary to some other disordeinfection.
• Depending on the type of porphyria, it can manifest as mainly dermatological (chronic porphyria) or as GI symptoms (as in acute porphyria). Acute porphyria is known for psychiatric disturbances like hallucinations, red-purple urine, as well as nonspecific generalized pain. Both diseases have triggers that cause the symptoms to present or get worse such as iron overload, alcohol, sunlight exposure, fasting, and metabolic stress (like surgery, bloodletting!!!)
• Prior to 1983 there was no effective treatment for porphyria either due to lack of understanding of the disease or just not having the resources. Since porphyria is a disease affecting hemoglobin production many thought that giving the component parts would cure the disease. However the issue isn’t in not having the nutrients it that the enzymes making the product do not work—giving extra iron or eating meat won’t make more heme. Giving heme intravenously wreaks havoc on the blood’s ability to carry oxygen precipitating medical emergencies. That’s where Panhematin came in.

• Panhematin was the first drug released under the Orphan Drug Act and met the market in 1983. By using a special administration technique and structure, Panhematin can be administered to the patient replenishing the pool of heme in the body. Thus toxic precursors waiting for heme to be available can be used up relieving the acute porphyria attacks. The annual cost for Panhematin is about $134,800 dollars. A newer agent was just assigned its orphan drug status in 2019, Givosiran (Givlaari). Givosiran takes advantage of double stranded mRNA segments which help reduce the toxic heme precursors allowing the body to produce more heme on its own. Compared to Panhematin, this drug costs about $616,900 a year but does have greater efficacy.

Gasping for the Ability to Live—Cystic Fibrosis

• Cystic Fibrosis is caused by a defect in the CFTR gene which damages the function of the chloride channel found in cell membranes. In normal cells, chloride, sodium, and water are able to move freely between the cell and the lung airway allowing mucus thickness to be regulated. If the body needs a thicker mucus, it can remove chlorine and sodium which draws water out the mucus, thickening it or reverse the process to thin the mucus as needed. In Cystic Fibrosis, the CFTR gene mutation prevents chlorine from being regulated which prevents thinning of the mucus. The result is a very thick coating on the surface of the airways which is a great place for bacteria to grow. This process also happens in other organs like the pancreas, kidneys, and intestines which clogs their function leading to decreased function or organ failure.
  • There are 6 classes of CFTR mutations that vary in the amount of impairment on the chloride channel. Class I is a defective synthesis of the channel entirely meaning that no chlorine moves at all. Class II, a point mutation called F508del, is the most common type of CF at >90% of patients. This class has dec activity in the gene meaning chloride channels can be made but not at a rate needed. Class III is due to defective chloride channel regulation in which the channel is made but it is locked shut. Class IV has dec function of chloride flow while Class V is a reduced synthesis of the chloride channel. Finally Class VI is a normal chloride channel but it is rapidly destroyed by other processes.
• When treating Cystic Fibrosis the goals are to preserve lung function and thin the mucus allowing the person to breathe. Because of this we use lots of inhalers to help get the medication directly to the sight of action for the maximum efficacy. Bronchodilators like Albuterol are must haves because they dilate the airways and open up the lungs allowing for deeper penetration. From here there is a mixture of medications developed under the Orphan Drug Act to help accomplish the rest of the goals. In addition to drugs are non-pharmacological options like exercise and chest percussion devices to help cough up and remove the mucus.

• First up are the mucolytic agents or the drugs that will help thin the mucus sitting in the lungs. Remember that thick mucus breeds bacteria so thinning that layer for it to be coughed up helps keep patients out of the hospital with nasty respiratory infections. One of the first treatments was inhaling 7% saline solution, a concentrated fluid that has double the amount of salt as sea water (salt water is 3.5% salt). By using a highly salty solution, we are able to draw water from the cells into the lung space helping to hydrate the mucus and thin it. It’s reasonably effective but it isn’t the one-two punch that really helps patients.
  • In 1993 a new drug entered the market that revolutionized thinning mucus: Dornase alfa (Pulmozyme). Pulmozyme works by spraying an enzyme deep into the lung tissue that breaks down strands of DNA sitting in the mucus which helps the thick fluid coagulate. By breaking down this hairs of DNA, the mucus has nothing to stick to and adhere so its easier to cough up. When it was first released, a single month’s treatment could be up to $6,000 a month but luckily there are coupons and copays available through the Orphan Drug Act that can drop that price down to a few hundred dollars a month.
• So we have opened the lungs with Albuterol and thinned the mucus with mucolytics, now we have to make sure bacteria won’t cause an infection. For non-CF patients who have a respiratory infection we can use oral or IV medications to help kill the bacteria but that won’t work with Cystic Fibrosis. Instead of giving an oral agent which has to reach the lung slowly, we can give an inhaled antibiotic to get the drug directly into the lung tissue. One of the first Cystic Fibrosis specific antibiotics is Colistimethate (Colymycin) released in 1970. Although it is injection only, Colistimethate was a great first option because it has high lung penetration and is specific for the bacteria specifically found in the lung.

• Even better was two inhalers, Tobramycin (TOBI Podhaler) and Aztreonam (Cayston) released in 1997 and 2010 respectively. As inhalers, the antibiotics are able to get directly into the lung and kill bacteria directly. Both developed under the Orphan Drug Act, these drugs are must haves for Cystic Fibrosis and reduced the monthly hospitalization rate from 45% to about 20% and the monthly mortality rate from 17.4% to 3.8%. Unsurprisingly the inhalers are expensive: its about $10,000 for a months supply for the TOBI and Cayston inhalers. Luckily with insurance, manufacturer coupons, and assistance from the Orphan Drug Act, many patients pay less than $30,000 a year for treating Cystic Fibrosis with a lifetime health care cost of $300,000.
  • There is another part of Cystic Fibrosis treatment using precision medicine that targets the gene dysfunctions but i'm going to keep them a secret till we cover Cystic Fibrosis in full :P stay tuned!

Putting the ODA to the Test—HIV & AIDS

• The Human Immunodeficiency Virus (HIV) is an infection of a retrovirus part of the genus Lentivirus. There are actually two kinds of HIV viruses (1 and 2) but they both infect the immune system, specifically the T cells, macrophages, and dendritic cells. By infecting these immune cells, the virus is able to hijack the cell’s protein production to only produce viral components and assemble them making more viruses. Eventually the virus bursts the cell killing it and releasing exponentially more viruses to infect more immune cells. The result is the rapid deletion of the immune system causing the second stage of the disease: Acquired Immunodeficiency Syndrome or AIDS.

• When someone is diagnosed with AIDS their immune system is so depleted that there is nothing protecting them from even the most simple of infections. In fact, the main cause of death for AIDS patients are opportunistic infections—a group of bacterial and fungal infections that are normally easily mopped up by the immune system. These include Pneumocystis Pneumonia, Toxoplasmosis, Mycobacterium Complex, and many more. Without treatment the patient will die.

• If you hadn’t guessed, the AIDS epidemic starting in 1981 really pushed Congress to pass the Orphan Drug Act two years later to incentivize development of antiretroviral drugs. One of the first drugs to have efficacy against HIV is Zidovudine (a.k.a Azidothymidine) which was approved for use in AIDS patients in 1987 although it was initially discovered decades earlier. See, in the 1960s there was a theory that most cancers were a result of retroviruses and so research was put into developing new drugs that prevented infection from retroviruses. In 1964 Zidovudine was synthesized and was used successfully to prevent infection from several retroviruses such as the Friend leukemia virus. (Side note: if you want to learn more about viruses that cause cancer, search for oncogenic viruses!)
  • By 1983 the world was two years into an epidemic that the world was still blind too and panicking completely. By this time we knew that HIV spread through blood and swaths of national blood supplies were being destroyed in the name of protecting the greater good. Meanwhile, patients continued to die. Once a successful way of growing HIV-infected immune cells was discovered in 1983, researchers started testing every drug under the sun to find what would stick. Zidovudine would be found to be successful and was sped through the FDA approval process. It received orphan drug status for the treatment of AIDS in 1985 and eventually approved in 1987; a mere 25 months from trial to approval which is one of the shortest in history. In fact, the FDA skipped many necessary review stages for safety and efficacy in order to get the drug distributed early. While that may seem reckless, look at the choice: either you distribute a drug that potentially harms the patient or wait, do the testing, while that same patient dies of a 100% mortality rate disease. What would you do?

• Since Zidovudine in 1987, there have been several different anti-HIV medications discovered and marketed. Almost all of them have gone through the Orphan Drug Act to allow patients more options to treat their infection and to be in remission or have a viral count of undetectable. Today we have several drug classes to make dozens of combinations with all of which can turn a deadly disease into a more manageable condition with the right access and help. Take a look at the chart below at the kinds of combinations, some of them are up to 4 drugs in one pill such as Genvoya or Symtuza. Likewise, look at the mortality rate due to AIDS and correspond that to the year that drugs entered the market. You’ll notice that in 1995/6, the second drug class to treat HIV was approved which drastically improved outcomes.

Some Final Words

• The Build-up

• The Beginning

• The Dark era/Era of Dullness (2006-2009)

• India- Sri Lanka thriller aka The False Hope

• The Era of Overshadowing(2010-2015)

• The Polarizing Era/ The Era of English Batting renaissance

• 17th June 2022 & 18th June 2018 : Two days of Gruesome murder