How immune cells create new types of antibodies

A team of researchers at Boston Children’s Hospital has learned more about the process of V(D)J recombination and how it makes use of chromatin looping to collect segments that are to be spliced. In their paper published in the journal Nature, the researchers outline their research and what they learned about the ways immune cells match bits of genetic code to create new types of antibodies. Ferenc Livak and André Nussenzweig with NIH have published a News & Views piece outlining the work done by the team in the same journal issue.

As the researchers note, much work has gone into learning how the human immune system works. One finding is that immune cells have a way of mixing and matching bits of genetic code to create new antibodies when new threats are discovered. But until now, this mixing and matching process has been somewhat of a mystery. In this new effort, the researchers set out to learn more about how it works.

The researchers started with the knowledge that a process called V(D)J recombination allows the immune system to generate new antibodies. They also point out that DNA strands are packaged with proteins into chromatin—and each package has multiple loops. When the body detects a new threat, the loops in the chromatin move distant DNA segments closer together.

The work by the team in Boston showed how B cells exploit loop formation to create new antibodies. They found that RAG enzymes couple with mechanisms that take part in setting off the first step of V(D)J recombination—they force the D and J to join. Next, as loops are formed, DNA moves past the RAG complexes. Meanwhile, other factors impede extrusion, which pauses the DNA movement, allowing the RAG access. This allows for presenting gene substrate segments to the RAG complex for V(D)J recombination. The team also found that a protein called cohesin is involved in running the loop extrusion/RAG process. They note also that while their work was centered on the V(D)J recombination process, they believe their findings will have implications for other processes involved in gene regulation.

More information: Xuefei Zhang et al. Fundamental roles of chromatin loop extrusion in antibody class switching, Nature (2019). DOI: 10.1038/s41586-019-1723-0

https://medicalxpress.com/news/2019-10-reveals-immune-cells-antibodies.html

Minimally-Invasive Surgery Options for Liver Cancer and Liver Tumors

VIDEO

Dr. Jin He, assistant professor of surgery, describes the minimally invasive surgical techniques available for patients with liver cancer or a liver tumor, the benefits and who is an ideal candidate.

https://clinicalconnection.hopkinsmedicine.org/videos/minimally-invasive-surgery-options-for-liver-cancer-and-liver-tumors

Google wants to give doctors web-like searches for medical records

Google made much ado of its recently created Health unit, but it didn’t offer much insight into what that division would actually… well, do. Now, however, it’s considerably clearer. Google Health lead David Feinberg and CNBC sources have outlined some of the ideas his team has, and they revolve around (surprise!) search for both you and your doctor. Feinberg envisions a search bar that would help doctors search medical records like they do the web. A doctor could search for “87” to find an 87-year-old patient instead of using the patient’s name, as an example.

An insider also claimed that Google is considering a Flights-style dedicated search experience for health. You could research conditions without wading through the regular web to find trustworthy info.

It’s not certain how close either idea is to fruition, and CNBC‘s tipster warned that it wasn’t certain the Google search team would sign off on the dedicated health search. Google might have to ditch advertising on the health page. They do indicate how Google Health and Feinberg are thinking, however, and give you a hint of what to expect in the future.

Whatever comes about, Feinberg may have been busy behind the scenes. Other CNBC sources claim he’s been “building bridges” to improve health-related searches in Google and YouTube, such as downplaying videos that push anti-vaccination myths. The team could be very busy bolstering your healthcare experiences — it just isn’t particularly apparent yet.

https://www.engadget.com/2019/11/03/google-health-doctor-search-plans/

Biotech week ahead, Nov. 4

Biotech stocks extended their gains last week amid earnings news flow and the broader market strength. Large-cap pharma stocks saw particular strength.

Here are the key catalytic event a biotech investor should keep a tab on in the unfolding week.

Conferences

• American Society of Nephrology Kidney Week – Nov. 5-10, in Washington D.C.
• Wolfe Research Healthcare Conference – Nov. 6, in New York
• Society for Immunotherapy of Cancer, or SITC, – Nov. 6-10, in National Harbor, Maryland.                                                                                                                                                                                                                                                                                      PDUFA Dates

The FDA is set to rule on Lipocine Inc LPCN 2.6%‘s NDA for Tlando, or LPCN 1021 to treat hypogonadism in adult males. The PDUFA date is set for Saturday, Nov. 9.

Clinical Trial Readouts

SITC Presentations

Alkermes Plc ALKS 0.82% – Phase 1/2 data for ALKS 4230 in solid tumors and ALKS 4230 in combination with Merck & Co., Inc. MRK 2.01%‘s Keytruda in solid tumors.

Celldex Therapeutics, Inc. CLDX 7.14% – Phase 1 data for CDX-1140 in solid tumors (Thursday, Nov. 7).

Pieris Pharmaceuticals Inc PIRS 3.63% – Phase 1/2 data for PRS-343 in HER2-positive solid tumors.

CELYAD SA/ADR CYAD 7.1% – Phase 1 data for CYAD-01 and FOLFOX in colorectal cancer (Friday, Nov. 8) and Phase 1 data for CYAD-101 in colorectal cancer (Saturday, Nov. 9).

Heat Biologics Inc HTBX 10.45% – Phase 2 data for HS-110 and Bristol-Myers Squibb Co BMY 0.35%‘s Opdivo in non-small cell lung cancer (Friday).

Oncolytics Biotech, Inc. ONCY 8% – interim Phase 1b data for Pelareorep and Roche Holdings AG Basel ADR Common Stock RHHBY 0.21%‘s Tecentriq in breast cancer (Friday).

Nektar Therapeutics NKTR 6.92% – updated Phase 1/2 data for NKTR-214 + Opdivo in multiple cancers (urothelial carcinoma, melanoma, renal cell carcinoma, and non-small cell lung cancer) (Saturday).

Mirati Therapeutics Inc MRTX 6.22% – initial Phase 2 data for sitravatinib in urothelial carcinoma (Saturday).

ASN Kidney Week Presentations

Allena Pharmaceuticals Inc ALNA 4.55% – Phase 2 data for reloxaliase, or ALLN-177, in primary hyperoxaluria and Phase 3 data for reloxaliase in enteric hyperoxaluria (Friday).

Earnings

The earnings list is not comprehensive

Monday

• Karyopharm Therapeutics Inc KPTI 7.18% (before the market open)
• Tandem Diabetes Care Inc TNDM 1.25% (after the market close)
• Myriad Genetics, Inc. MYGN 0.39% (after the market close)
• Neurocrine Biosciences, Inc. NBIX 4.19% (after the market close)
• Deciphera Pharmaceuticals Inc DCPH 2.53% (after the market close)

Tuesday

• Mylan NV MYL 2.77% (before the market open)
• Regeneron Pharmaceuticals Inc REGN 1.37% (before the market open)
• Mallinckrodt PLC MNK 7.14% (before the market open)
• Ligand Pharmaceuticals Inc. LGND 3.43% (after the market close)
• GW Pharmaceuticals PLC- ADR GWPH 1.87% (after the market close)

Wednesday

• MannKind Corporation MNKD 6.51% (before the market open)
• Elanco Animal Health Inc ELAN 1.39% (before the market open)
• Horizon Therapeutics PLC HZNP 2.13% (before the market open)
• Aimmune Therapeutics Inc AIMT 3.92% (after the market close)
• Sangamo Therapeutics Inc SGMO 4.42% (after the market close)

Thursday

• Clovis Oncology Inc CLVS 13.09% (before the market open)
• Axsome Therapeutics Inc AXSM 2.87% (before the market open)
• Viveve Medical Inc VIVE 7.91% (after the market close)
• Sarepta Therapeutics Inc SRPT 6.63% (after the market close)
• Pfenex Inc PFNX 5.31% (after the market close)

Friday

• Obalon Therapeutics Inc OBLN 4.17%
• Ocugen Inc OCGN 6.17%
• PLx Pharma Inc PLXP

IPOs

Galera Therapeutics has filed to offer 5 million shares in an IPO, with an estimated price range of $14-$16. The company has applied for listing its shares on the Nasdaq under the ticker symbol “GRTX.”

89bio, a biotech company focusing on therapies for NASH and other metabolic disorders, is planning a 4.375-million IPO at an estimated price range of $15-17. The company has applied for listing its shares on the Nasdaq under the ticker symbol “ETNB.”

Gene testing company Centogene is proposing to offer 4 million shares in an IPO, which are to be priced between $14 and $16. The company has applied to list the shares on the Nasdaq under the ticker symbol “CNTG.”

CNS Pharmaceuticals, which develops therapies for brain cancer and other CNS tumors, has filed for a 2.125-million share IPO. The shares, which are likely to be priced in the range of $4-$5, are to be listed on the Nasdaq under the ticker symbol “CNSP.”

Tela Bio, which sells soft tissue implants used in hernia repair and reconstructive surgery, is set to offer 4 million shares in an IPO, with each share to be priced between $14 and $16. The company seeks to list the shares on the Nasdaq under the ticker symbol “TELA.”

IPO Quiet Period Expiry

BioNTech SE – ADR BNTX 1.78%
Vir Biotechnology Inc VIR 6.38%

https://www.benzinga.com/general/biotech/19/11/14704372/the-week-ahead-in-biotech-smid-cap-earnings-deluge-sitc-conference-in-the-spotlight

Mastercard launches new healthcare unit on billing, data security

• Mastercard is bringing its scale and billing background to the healthcare, launching a new unit around revenue cycle management and data security.
• Previously, the financial services giant only offered flexible spending account, health savings account and health reimbursement arrangement cards for those in employer-sponsored plans.
• New products include predictive analytics built into a health system’s billing platform allowing the provider to personalize patient payment plans; artificial intelligence tech to detect suspicious claims activity and fraud; and biometrics, behavioral analytics and risk assessments to secure health data and mitigate cyberattacks.

Silicon Valley-backed startups and established tech giants alike have vied in recent years to tackle healthcare pressure points through efforts like streamlining administration functions.

However, unlike other new entrants, Mastercard does not “want to disrupt,” SVP of Mastercard Healthcare Solutions Marie Aloisi told Healthcare Dive, but “enhance the work that established stakeholders are doing today.”

The company sees the healthcare industry as “a huge opportunity,” Aloisi said. “We are not new to healthcare — this is us bringing new technology products to this space, going beyond just card.”

Mastercard contends its decades of experience protecting sensitive information against cyberattacks will serve it well in an industry that saw 32 million patient records compromised in the first half of 2019 alone, according to Protenus and IBM.

Fraud and waste are also a huge problem in the healthcare industry, costing an estimated $240 billion annually.​ Mastercard tested its new product line on reducing waste with a payer client, though Aloisi declined to share additional details.

More than 200 companies, including healthcare giants CVS Health and Walgreens, already use Mastercard’s predictive analytics to make business decisions.

Rivals Visa and American Express similarly offer HSA, FSA and HRA cards, in addition to offering healthcare-specific payment processing.

https://www.healthcaredive.com/news/mastercard-launches-new-healthcare-unit-on-billing-data-security/565758/

Research Roundup: What Are Microproteins and What Do They Do

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones.

The Role of the Mysterious Microproteins

Genes code for proteins. Prior to the Human Genome Project, the Central Dogma was that one gene coded for one protein. And since there were about 100,000 known proteins, scientists believed there were 100,000 human genes. But there weren’t, there were about 20,000 genes and proteins are created by reading those genes in various ways—from beginning to end, backwards, starting in the middle, etc. Now researchers are increasingly finding what are called microproteins, which have fewer than 100 amino acids, and are discovering that they microproteins may have more fundamental effects on cellular processes than previously thought.

Researchers with the Salk Institute published research in the journal Nature Communications on the role of 54-amino acid microprotein PIGBOS and how it mitigates cell stress.

“The study is exciting because cell stress is important in a number of different diseases, including cancer and neurodegeneration,” said Alan Saghatelian, co-corresponding author of the research. “By understanding the mechanisms behind these diseases, we think we’ll have a better shot at treating them.”

The researchers used a technique called split GFP to tag the microprotein, which was too small for the more traditional green fluorescent protein (GFP) tags. While mapping PIGBOs’ location, they found that it rests on the outer membrane of the mitochondria, which puts it in position to make contact with proteins on other organelles. They found that it interacted with another protein, CLCC1, which is part of the endoplasmic reticulum (ER) and communicates with CLCC1 to regulate stress in the ER.

“PIGBOS represents one of a limited set of microproteins that anyone has gone through the effort to characterize,” said co-corresponding author Uri Manor, director of the Waitt Advanced Biophotonics Core Facility at Salk. “And lo and behold it actually has a very important role.”

Natural Monkey Mutation Provides Model for Rare Human Blindness

Researchers identified a mutated gene in three rhesus monkeys that is associated with Bardet-Biedl Syndrome (BBS), a rare genetic disease that causes childhood-onset blindness. The science team indicates it is the first naturally occurring case of a nonhuman primate model of the syndrome and could lead to potential treatments. The BBS genes encode proteins for the function of cilia. Models of BBS have been developed from rodents, fish and roundworms, but they are not as closely related to human eyes as primate models.

Newly Found Antibody Could Be Basis of Universal Flu Vaccine

Researchers at The Scripps Research Institute, the Washington University School of Medicine in St. Louis and Icahn School of Medicine at Mount Sinai in New York identified an antibody that protects mice against a wide range of flu viruses. The antibody binds to the protein neuraminidase, which flu viruses require to replicate in the body. It is located on the surface of the virus. Tamiflu, the best-known drug to fight flu, inactivates neuraminidase. But there are numerous types of neuraminidases. This antibody could be the foundation of a universal flu vaccine.

Neural Activity and Longevity

A protein called REST has previously been shown to protect aging brains from dementia and other neurodegenerative diseases. Now researchers have identified REST as essential in a molecular cascade related to aging. The study found that excessive brain activity in humans, mice and worms is associated with shorter life spans. Suppressing that overactivity extends life. REST is part of a signaling cascade that includes the insulin and insulin-like growth factor (IGF) pathway. It’s not clear on whether or how a person’s thought, personality or behavior, within this context, affects longevity.

A Smell Test for Alzheimer’s Disease?

People who performed well on a test measuring cognitive ability and another to identify odors were linked to very low risk of Alzheimer’s disease. The tests have previously been shown to help predict the risk of developing dementia, but this study suggests the tests could help rule out people unlikely to develop Alzheimer’s. The researchers analyzed data from 749 adults with mild cognitive impairment without dementia who had completed a cognitive screening test and a 40-item smell identification test. They were then followed for four years to find whether they were later diagnosed with Alzheimer’s or other dementias. During that period, 109 people developed dementia with most diagnosed with Alzheimer’s. But the research found that 96.5% of the participants who performed well on both tests did not develop dementia during the study period.

Anti-inflammatory Drugs Can Decrease Major Depressive Symptoms

A pooled analysis found that anti-inflammatory agents like aspirin/paracetamol, statins, and antibiotics can curb symptoms of major depression. The effects are even stronger when the anti-inflammatories are given in combination with standard antidepressants. Previous studies of anti-inflammatories to treat depression were inconclusive, but this pooled analysis of 26 of 30 relevant randomized controlled trials involving 1,610 people suggested the anti-inflammatories were better than placebo and improved the effects of standard antidepressants.

Medicinal Cannabinoids Don’t Improve Mental Health

Researchers analyzed the impact of medicinal cannabinoids on six mental health disorders from 83 studies including 3,000 people. They found that the use of cannabinoids can’t be justified based on the current evidence. The conclusion was based on lack of proof of effectiveness and the known risks of cannabinoids. The medicinal cannabinoids include medical cannabis and pharmaceutical cannabinoids and their synthetic derivatives, THC and CBD. The six mental health disorders in adults were: depression, anxiety, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder (PTSD), and psychosis.

How a Key Gene Linked to Familiar Alzheimer’s Functions

A gene that is mutated in familial Alzheimer’s disease is called presenilin. Although linked to the disease, it wasn’t completely understood how this functioned. A research group found that the malfunction in this gene causes the abnormal accumulation of beta-amyloid in the brain. Presenilin is not only essential for regulating neuronal growth, but it does so through the EphaA3 receptor, a protein linked to several cancers.

https://www.biospace.com/article/research-roundup-what-are-microproteins-and-what-do-they-do-and-more/

Biopharma Q3: Pfizer, Merck, Amgen, Incyte and J&J

As the third quarter of 2019 comes to an end, most biopharma companies are reporting their earnings as they head into the final lap for the year. Here’s a look at some of the bigger companies’ reports that came out this week.

Pfizer

Pfizer reported third-quarter 2019 revenues of $12.7 billion, which is actually a 3% operational decline. It reported $13.298 billion in the third quarter of 2018. For the nine-month period, Pfizer reported $39.062 billion, down 2% from 2018’s figure of $39.670 billion.

The breakdown of the company’s three divisions were: Biopharma, $10.108 billion, up 7% from the third quarter of 2018; Upjohn, with $2.195 billion, down 28% from $3.036 billion from the same period last year; and Consumer Healthcare, $377 million, down 55% from $839 million in the 2018 third quarter.

The company has paid out $14.9 billion to shareholders in the last nine months, with $6.1 billion of dividends and $8.9 billion of share repurchases.

“We reported strong third-quarter 2019 financial results, driven by 9% volume-driven operational revenue growth in our Biopharma business, including growth from key brands such as Ibrance, Xeljanz, Eliquis, Vyndaqel and Inlyta as well as in emerging markets,” said Albert Bourla, Pfizer’s chief executive officer. “Upjohn revenues were negatively impacted primarily by the July 2019 loss of exclusivity of Lyrica in the U.S., while Consumer Healthcare revenues declined as a result of the completion of the JV transaction with GSK during the quarter.”

Merck and Co.

Merck reported third-quarter revenue had increased by 15% for the third quarter, from $10.794 billion in 2018 to $12.397 billion this year. Not surprisingly, the big driver for the company’s Pharmaceutical sales was its checkpoint inhibitor Keytruda, which brought in $3.070 billion for the quarter, up from $1.889 billion in the same period last year. This is an increase of 62%. Keytruda was followed by Gardasil/Gardasil 9, a vaccine for human papillomavirus (HPV), which brought in $1.320 billion for the quarter, up 26% from $1.048 billion in the 2018 third quarter. This was followed closely by Januvia/Janumet, for diabetes. Januvia was actually down 12% from the previous year’s third quarter, bringing in $1.311 billion compared to $1.490 from last year.

Overall, third-quarter pharmaceutical sales were $11.1 billion, up 15% from the previous year’s third quarter. Another $1.1 billion came from Animal Health, which was an increase of 10% from the third quarter in 2018.

“We achieved another quarter of strong revenue and earnings growth as we continue to realize the benefits of our sustained investment in research and development and our focus on commercial execution,” said Kenneth C. Frazier, chairman and chief executive officer of Merck. “We are confident that the investments we are making now will allow us to convert cutting-edge science into medicines and vaccines of great benefit to patients and value to shareholders.”

Amgen

Amgen reported a 3% decrease in total revenues from the third quarter of 2019 compared to the same period in 2018. Total revenues were $5.737 billion, down 3% from $5.904 billion in that period. Product sales declined globally by 1%, but certain drugs, such as Prolia, Repatha, Aimovig, Parsabiv, Kyprolis and Blincyto all grew in the double digits or better. Prolia grew 18%, Evenity, which launched in the first half of the year generated $459 million in the third quarter, Repatha sales rose 40%, Aimovig brought in $66 million, Parsabiv grew 54%, Kyprolis increased 15%, and Blincyto rose 47%.

The company also reported strong growth in its biosimilar produce line. One of the more noticeable changes is Amgen’s decision to close out its neuroscience research. David Meline, the company’s chief financial officer, indicated it was to provide financial support to other areas that will provide long-term growth. The one exception to that is its Aimovig for migraine, which it plans to continue supporting.

“Amgen continues to execute well in a dynamic environment, with many of our innovative medicines delivering double-digit, volume-driven growth, complemented by the strong performance of our recently launched biosimilar products,” said Robert A. Bradway, Amgen’s chairman and chief executive officer. “We continue to advance numerous first-in-class medicines in our pipeline, while also pursuing external opportunities that will contribute to our long-term growth, such as our pending acquisition of Otezla.”

Incyte Corporation

Incyte reported total third-quarter revenues of $551.581 million, up 23% from the same quarter last year’s figure of $449.683 million. The big driver is Jakafi, which accounted for $433.387 million of it, up 25% from $347.567 in the third quarter. In the nine-month period, Jakafi has brought in $1.2185 billion in sales, up 21% from the same period last year. Jakafi is followed by Iclusig, which for the quarter brought in $20.611 million, up 2% from $20.148 in the third quarter 2018.

“Revenue growth continues to be very strong, driven by robust demand for Jakafi (ruxolitinib) in all three approved indications and, as a result, we are raising guidance for full year Jakafi net sales,” said Herve Hoppenot, Incyte’s chief executive officer. “At the beginning of 2019, we laid out an ambitious set of development goals for our late-stage portfolio, and in the third quarter we have continued to execute against them. The recent clinical success in the REACH2 trial of ruxolitinib in steroid-refractory acute GVHD; the updated data from pemigatinib in cholangiocarcinoma and subsequent NDA submission; and the recently-presented 52-week data from the randomized Phase II trial of ruxolitinib cream in vitiligo are all illustrative of the significant progress we have made this year.”

Johnson & Johnson

Drug behemoth Johnson & Johnson reported third quarter sales of $20.729 billion, up 1.9% from the 2018 third-quarter sales of $20.348 billion. Net earnings, however, were down by 55.4%, from $3.934 billion in the third quarter of 2018 to $1.753 billion this quarter. Diluted Earnings Per Share (EPS) were down 54.2% from $1.44 to $0.66 in the same period.

U.S. sales were up 1.2% to $10.791 billion, International sales up 2.6% to $9.938 billion. In breaking out is divisions, Consumer products brought in $3.469 billion, up 1.6%, Pharmaceuticals reported $10.877 billion, up 5.1%, and Medical Devices cited $6.383 billion, down 3.1%.

The earnings exceeded Wall Street projections, despite the numerous multimillion-dollar lawsuits over talc and opioids. The company raised its full-year guidance for earnings of $8.62 to $8.67 per share, with revenue ranging from $81.8 billion to $82.3 billion. Those figures are up from full-year guidance of $8.53 to $8.63 per share on revenue of $82.4 billion to $82.3 billion.

“Our third-quarter results represent strong performance, driven by competitive underlying growth in Pharmaceuticals and Medical Devices, as well as continued optimization in our Consumer business,” said Alex Gorsky, J&J’s chairman and chief executive officer. “As we look ahead, we remain confident in the strength of our broad-based business model, which is fueled by our disciplined portfolio management, focus on transformational innovation and dedicated employees around the world who position us for success today and well into the future.”

https://www.biospace.com/article/biopharma-q3-pfizer-merck-amgen-incyte-and-j-and-j/