Blog – Page 35 – shiqiv.com

CAR-T Therapies: 2+ Years Into Commercialization (1)

Approvals and Acquisition

Back in 2017, when Kymriah by Novartis was first approved by FDA, it marked the beginning of commercializing CAR-T cell therapies in the US.

CAR-T therapies have shown superior effects in treating blood cancers. Kymriah’s initial approved indication is B-cell precursor ALL that is refractory or in second or later relapse for patients up to 25 years of age. There are approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year; 15-20 percent of pediatric B cell precursor ALL patients relapse after their initial remission.

On Aug 28, 11 days after Kymriah’s approval, another CAR-T cell therapy company Kite Pharma was acquired by Gilead for $11.9 billion. The $180.00 per share acquisition price represents a 29% premium to Kite’s closing on Friday, August 25, and a 50% premium to the company’s 30-day volume weighted average stock price.

At the time of acquisition, Kite’s lead candidate was under FDA’s priority review and had submitted the first CAR-T therapy application in Europe for the treatment of relapsed/refractory DLBCL, TFL and PMBCL with the European Medicines Agency (EMA).

On Oct 18, FDA approved Kite’s Yescarta for use in adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. DLBCL is the most common type of NHL in adults, with 24,000 new cases diagnosed each year in the US (1/3 of newly diagnosed NHL).

Concurrently, in Gilead’s press release, it estimated that in the US each year there are approximately 7,500 patients with refractory DLBCL who are eligible for CAR T therapy.

In May 2018, FDA expanded Kymriah’s approval for adults with relapsed or refractory large B-cell lymphoma as well.

In August 2018, Yescarta received European Marketing Authorization for adult patients with relapsed or refractory DLBCL and PMBCL, after two or more lines of systemic therapy; Kymriah was approved in EU for the treatment of pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse; and for the treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

In March 2019, Japan’s Ministry of Health, Labor and Welfare (MHLW) has approved Kymriah (tisagenlecleucel) for the treatment of two distinct indications – CD19-positive relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) and CD19-positive r/r diffuse large B-cell lymphoma (DLBCL).

Clinical Trails and Data

r/r ALL

Kymriah was first approved by FDA based on 82.5% overall remission rate (ORR) reported at 3 months, of which all were MRD– (n=52/63).

lower limit of the 95% confidence interval for ORR is 70.9%, which is above the pre-set null hypothesis rate of 20%
40 subjects (63.5%) had the best response of CR within the first 3 months after infusion
12 subjects (19.0%) had the best response of CRi.
Among the 52 responders, the median duration of response (DOR) was not yet reached (range: 1.2 to 14.1+ months) with the median follow-up of 4.8 months.
84% (n=57) experienced Grade 3 or higher events
Cytokine release syndrome (CRS) occurred in 79% of patients; CRS Grade 3 or higher occurred in 49% of patients

On ASH 2018, Novartis presented an updated ORR rate of 82.3% (n=65/79); relapse-free survival was 62% at 24 months.

ORR and MRD Remission

r/r DLBCL

Yescarta was approved in 2017 based on an ORR of 72% (n=73/101), with a CR rate of 51%. SAEs Grade 3 or higher occurred in 48 (44%) patients. CRS occurred in 94% of patients; CRS Grade 3 or higher occurred in 13% of patients.

On ASH 2019, Gilead provided updates on ZUMA-1 that median overall survival (OS) was 25.8 months.

When Kymriah was approved for r/r DLBCL in 2018, the overall response rate (ORR) was 50% at 3 months (n=34/68). On ASH 2019, in the 24-month analysis of the JULIET trial, ORR was 52% (N=115).

Youtube’s First Official Financial Result

It has been more than 13 years since Youtube was acquired for $1.65 billion by Google back in October 2006.

Founded in February 2005, with $11.5 million total venture funding and 65 employees at that time, Youtube commanded 46% of visits to U.S. online-video sites in September. That compared with a 21% share for the video activities of News Corp.’s MySpace site and 11% for Google Video. Youtube had close to 20 million monthly visitors in August 2006.

A year and half before Youtube’s acquisition, MySpace’s parent company Intermix Media Inc. was acquired by News Corp. for $580 million.

Back then, Google reported total revenues of $6.14 billion in 2005 and $10.60 billion in 2006, and had a market value of $132 billion. Its net income was $3 billion in 2006 with $3.6 billion cash flow from operations and more than $11 billion cash balance.

On Monday Feb 3, 2020, Alphabet first provided the breakdown for some of its non-Google-search businesses, including Youtube.

Year Ended December 31,
	2017		2018		2019
Google Search & other	$	69,811	$	85,296	$	98,115
YouTube ads⁽¹⁾	8,150		11,155		15,149

(1) YouTube non-advertising revenues are included in Google other revenues.

Youtube ads generated $4,717 million revenue in 2019 Q4 – a ~$19 billion run rate.

Using a multiple of 5.0x, Youtube could be valued at ~$100 billion – a 60 times return for google acquisition or an IRR of 37% for 13 years.

I guess the success formula is: with the right synergies, acquire early & provide support to grow it.

Alphabet 2019 10-K

2019 Q4 Earnings Call Transcript

「News of the Week」Coronavirus

WSJ – What to Know About the New Coronavirus

Dots to connect: Gilead’s drug Remdesivir for Ebola, Abbvie’s Kaletra (Lopinavir/Ritonavir), Roche’s Tamiflu, Oseltamivir generic versions, JNJ’s Prezista, restaurant/coffee chains Yum China, Luckin Coffee, Starbuck, airline industry, drop in demand for oil and oil prices, other travel related industries such as Trip.com and Huazhu, second-order effects on internet-based services & healthcare services investments, etc.

「Video of the Week」Ebola Virus And How Our Understanding Of Life Sciences Evolved

Suntory And Whisky (2)

Current Availability

Suntory’s whiskies, especially Yamazaki, has been in shortage in the past few years; the prices have been increasing constantly.

This week, Suntory unveiled a limited edition 55-year-old Yamazaki single malt whisky, which it will sell for 3 million yen ($27,347.31) a bottle. Only 100 bottles will be sold from June 30, and buyers will be chosen by lottery. Blended from whisky matured in mizunara and white oak casks, the edition will be the oldest version of Yamazaki.

The company in 2005 sold a limited edition of a 50-year-old Yamazaki for 1 million yen. One of them auctioned by Bonhams in Hong Kong in 2018 fetched HK$2.695 million.

In May 2018, it was reported that sales of Hakushu 12 Year and Hibiki 17 Year to be suspended in Jun 2018. Suntory said the demand was far outstripping supply and distillers were not being able to produce enough of it.

Before that, the demand for the Hibiki 12 year has become unsustainable and in 2015 Suntory announced it would be discontinuing the expression.

Currently the most commonly seen versions for Yamazaki are 12yr, 18yr, 30yr and Distiller’s Reserve (no age).

The Distiller’s Reserve version was launched in 2014, containing a range of liquid aged from around eight to 20 years. Blended by Suntory chief blender Shinji Fukuyo, the Yamazaki Distiller’s Reserve is a vatting of whisky matured in French oak Bordeaux wine casks, Sherry casks, mizunara casks (Japanese oak) and American oak casks, with some peated malt added. [thespiritsbusiness]

Awards (Whisky Bible: WORLD WHISKIES OF THE YEAR)

2016: Suntory Yamazaki Mizunara (Bot.2014) (ranked 5th our of 5 picks)
2015: The Yamazaki Single Malt Sherry 2013 (ranked 1st out of 3 picks)

Awards (World Whiskies Awards)

2019 WORLD’S BEST BLENDED WHISKY – Hibiki 21 Years Old
2018 WORLD’S BEST SINGLE MALT – Hakushu 25 Years Old
2017 WORLD’S BEST BLENDED – Hibiki 21 Years Old
2016 WORLD’S BEST BLENDED – Hibiki 21 Years Old

Awards (International Spirits Challenge, Gold)

Yamazaki

2007 – The YAMAZAKI Single Malt Whisky 18 years old
2009 – Yamazaki 1984
2010 – The YAMAZAKI single malt whisky 12YO
2010 – The YAMAZAKI single malt whisky 18YO
2011 – The Yamazaki Single Malt Whisky 1984
2012 – The Yamazaki Single Malt Whisky Aged 18 Years
2013 – The Yamazaki single malt whisky Puncheon 2012
2013 – The Yamazaki single malt whisky Mizunara 2012
2013 – The Yamazaki single malt whisky 18 Years Old
2014 – THE YAMAZAKI SINGLE MALT WHISKY MIZUNARA 2013
2014 – THE YAMAZAKI SINGLE MALT WHISKY BOURBON BARREL 2013
2014 – THE YAMAZAKI SINGLE MALT WHISKY 18 YEARS OLD
2015 – THE YAMAZAKI SINGLE MALT WHISKY MIZUNARA 2014
2017 – The Yamazaki Single Malt Whisky Limited Edition 2016
2018 – THE YAMAZAKI SINGLE MALT WHISKY 12 YEARS OLD
2018 – THE YAMAZAKI SINGLE MALT WHISKY 18 YEARS OLD
2019 – THE YAMAZAKI SINGLE MALT WHISKY MIZUNARA 2017 EDITION

Hakushu

2008 – Single Malt Whisky “Hakushu” aged 25 years
2009 – Hakushu 18 y.o.
2010 – The HAKUSHU single malt whisky 25YO
2010 -The HAKUSHU single malt whisky HEAVILY PEATED
2011 – The Hakushu Single Malt Whisky Bourbon Barrel
2012 – The Hakushu Single Malt Whisky Aged 25 Years
2012 -The Hakushu Single Malt Whisky Aged 12 Years
2012 – The Hakushu Single Malt Whisky Sherry Cask (12 years old and under)
2013 – The Hakushu single malt whisky Heavily Peated 2012
2013 – The Hakushu single malt whisky 25 Years Old
2013 – The Hakushu single malt whisky 18 Years Old
2014 – THE HAKUSHU SINGLE MALT WHISKY SHERRY CASK 2014
2014 – THE HAKUSHU SINGLE MALT WHISKY 25 YEARS OLD
2014 – THE HAKUSHU SINGLE MALT WHISKY 18 YEARS OLD
2015 – THE HAKUSHU SINGLE MALT WHISKY 25 YEARS OLD
2016 – The Hakushu Single Malt Whisky 25 Years Old
2016 – The Hakushu Single Malt Whisky 18 Years Old
2017 – The Hakushu Single Malt Whisky 25 Years Old
2017 – The Hakushu Single Malt Whisky 18 Years Old
2019 – THE HAKUSHU SINGLE MALT WHISKY 25 YEARS OLD
2019 – THE HAKUSHU SINGLE MALT WHISKY 18 YEARS OLD

Hibiki

2009 – Hibiki 17 y.o.
2010 – SUNTORY Whisky HIBIKI 12YO
2010 – SUNTORY Whisky HIBIKI 21YO
2012 – Hibiki Japanese Blended Whisky Aged 21 Years
2012 – Hibiki Japanese Blended Whisky Aged 17 Years
2013 – Hibiki Japanese Blended Whisky aged 17 years
2013 – Hibiki Japanese Blended Whisky aged 12 years
2014 – HIBIKI JAPANESE BLENDED WHISKY DEEP HARMONY
2014 – HIBIKI JAPANESE BLENDED MELLOW HARMONY
2015 – HIBIKI JAPANESE BLENDED WHISKY AGED 12 YEARS
2016 – Suntory Whisky Hibiki 17 Years Old
2016 – Suntory Whisky Hibiki Mellow Harmony
2017 – Suntory Whisky Hibiki Japanese Harmony Master’s Select
2019 – SUNTORY WHISKY HIBIKI JAPANESE HARMONY Master’s Select

Chita

2017 – Suntory Single Grain Whisky Chita Distillery

Suntory And Whisky (1)

A History of Suntory’s Three Whisky Distilleries

The founder of Suntory, Shinjirō Torii (born in 1879), started with selling imported wine in Osaka in 1899.

Incorporation – the store became the Kotobukiya company in 1921.

In 1923, the Yamazaki Distillery was constructed – Japan’s first malt whisky distillery. It was built in the town called Yamazaki 山崎町 (now in Shisō 宍粟市, Hyōgo 兵库县), on the periphery of Kyoto. This region was formerly referred to as “Minaseno”, where one of the purest waters of Japan originates. Yamazaki Distillery is where the Katsura, Uji and Kizu rivers converge, providing a unique misty climate and one of Japan’s softest waters. The diversity of this region’s temperature and humidity creates ideal conditions for cask aging, known as the signature “Suntory Maturation”.

Production began in 1924 and five years later it launched Japan’s first single-malt whisky Suntory Whisky Shirofuda (white label) in 1929.

Keizo Saji (Torii’s son) becomes 2nd president in 1961 (at age of 42); Shinjirō Torii passed away in 1962.

In 1963, Kotobukiya changed its name to “Suntory” from “Torysan”, taken from the name of the whisky it produces.

In the same year, Musashino Beer Factory (in Fuchū 府中市, Tokyo 东京都) began its production of the Suntory Beer.

In 1972, Keizo built Chita Distillery on the shores of Chita Peninsula (Chita 知多市, Aichi 爱知县).

In 1973, Hakushu Distillery was established, in the Toribara locality of the former town of Hakushū 白州町 (now part of Hokuto 北杜市 in Yamanashi 山梨县), It is located in the foothills of Mt. Kaikomagatake.

1980s – Distilleries Becoming Brands

Until the 1980s, whisky made at Yamazaki was bottled as Suntory blends. It began to market their distilleries in the way the Scottish market theirs, by branding the whisky for the distillery at which it is made. [Japanese Whisky Handbook by Gary Clark]

Saji pioneered the distillery’s move into single malt whisky in 1984, with the launch of Suntory Single Malt Whisky Yamazaki – the first time Yamazaki is used as the brand name. This was followed by Yamazaki 18 Years Old in 1992. [thespiritsbusiness]

In 1989, the 90th anniversary of the company’s founding, Suntory Hibiki was released. It is a blended whisky using whiskies from the three distilleries Yamazaki, Hakushu, and Chita.

Shinichiro Torii becomes the 3rd president in 1990.

In 1994, Hakushu Single Malt Whisky is launched.

In 2003, the Yamazaki 12 Years single malt whisky became the first Japanese whisky to win the gold medal at the International Spirits Challenge, the most authoritative liquor competition in the world.

Online Higher Education (6): 2U’s Graduate Programs

Charting for 2U : 1) insignificant growth for fee-for-degree programs since 2019; 2) more diversified with expensive fee-for-certificate programs.

Online Higher Education (5) – Education Company Stocks

A Python Generated Graph On Airlines’ Load Factors

Major airlines usually would post their monthly operation results on IR websites. While United Airlines and Southwest Airlines among other stopped reporting in 2019, Alaska and Delta are still doing so.

Load factor is a measure of the use of aircraft capacity that compares Revenue Passenger-Miles as a proportion of Available Seat-Miles.

Below is a three-part project that automatically downloads, summarizes and creates chart for 4 airlines’ load factor.

Download

Given certain years, the program will go through pre-defined links to search for monthly report urls and scrap relevant data based on the page structure. BeautifulSoup is used here.

Summary

The program uses file reading and writing to put four airlines’ data together while adjusting for missing data (aligning based on month)

Charting

The program converts csv to excel and draws the chart based on data. pandas and xlsxwriter are used here.

With some adjustments, the program should be able to scrape and virtualize other web-based standard reports.

Germline Genetic Testing: BRCA

Genetic testings have different significances and it seems that BRCA is currently the only gene of hard demand (CDx) in cancer treatments among germline testings.

Myriad and AstraZeneca

Back in Dec 2014, AstraZeneca received FDA approval for the first PARP inhibitor LYNPARZA, as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

Concurrent with the approval of LYNPARZA, FDA has approved the BRACAnalysis CDx (Myriad Genetics) for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes.

Myriad is a pioneer in genetic testing, especially for BRCA. BRACAnalysis CDx is blood-based, using PCR and Sanger sequencing to gauge single nucleotide variants and small indels, and multiplex PCR to assess large deletions and duplications.

Foundation Medicine and Clovis Oncology

In Dec 2016, Foundation Medicine’s FoundationFocus CDxBRCA was approved by FDA as the first NGS-based companion diagnostic, for Clovis Oncology’s PARP inhibitor Rubraca (rucaparib), for patients with deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies.

Myriad and Clovis

In April 2017, Myriad and Clovis Oncology announced the CDx collaboration on Rubraca. “The companion diagnostic test approved with Rubraca does not discriminate between germline and somatic mutations. Knowledge of germline status is important to provide patients appropriate counseling.”

Myriad and Pfizer

In Oct 2018, the Myriad’s BRCA test was also approved as CDx for Pfizer’s PARP inhibitor Talzenna, for patients with HER2-negative metastatic breast cancer (mBC) who have a germline BRCA mutation.

Expanded PARP usage

In Jan 2018, AstraZeneca’s LYNPARZA received approval for expanded usage in breast cancer, for patients with germline breast cancer susceptibility gene (BRCA) mutated, HER2-negative metastatic breast cancer, who have been previously treated with chemotherapy. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior hormonal (endocrine) therapy or be considered inappropriate for endocrine treatment.

FDA also expanded the approval of the BRACAnalysis CDx, an approved companion diagnostic to Lynparza, to include the detection of BRCA mutations in blood samples from patients with breast cancer.

In Dec 2019, Lynparza was approved in the US as a 1st-line maintenance treatment of germline BRCA-mutated metastatic pancreatic cancer, for patients whose disease has not progressed on at least 16 weeks of a 1st-line platinum-based chemotherapy regimen. Myriad’s CDx usage was also expanded.

While the market expanded, more players are coming to this field. Since 2013, there is a growing number of labs providing BRCA testings – mostly are not for CDx.

Prices are very different for example.

Image result for brca testing price

But overtime, the ASP is definitely coming down.

Image result for brca testing price 2018

Meanwhile, FDA approved 23andMe’s DTC BRCA genetic testing in March 2018 (again, not for CDx) – testing for 3 BRCA1 or BRCA2 mutations to identify women at increased lifetime risk of breast cancer.