World's Deadliest Behavioral Risk Factors

 "Smoking kills" is but one of the slogans connected to anti-tobacco advocacy groups - and it's quite true.

When looking at behavioral risks, meaning types of risk that can largely be avoided, especially in highly industrialized nations, smoking cigarettes, cigars and other tobacco products is connected to a variety of diseases responsible for 7.7 million deaths worldwide.

As Statista's Florian Zandt shows in the chart below, based on data from the 2019 Global Burden of Disease study by the Institute for Health Metrics and Evaluation at the University of Washington shows, no other behavioral risk factor comes close to the disease burden of smoking.

Coming in second on a global level as well as in terms of risk-factor-associated deaths in the United States in 2019 is alcohol use with an estimated 2.4 million global and 137,000 U.S. deaths in 2019.

Roughly 57 and 30 percent of global deaths associated with risk factors and connected to substance abuse and digestive diseases, respectively, can be traced back to alcohol use.

While a high-sodium diet is connected to almost two million deaths on a global scale and therefore ranks third worldwide, the United States have a different problem: drug abuse.

In 2019, around 105,000 people were estimated to have died from diseases connected to drug use, which constitutes a four-percent share of the overall deaths connected to behavioral risks in the country.

This is especially striking compared to the same metric globally, where the share of deaths barely reaches one percent.

The total number of deaths from risk factors in the United States amounted to 1.8 million, while the global number stood at 35 million.

While the consumption of most drugs is illegal and often carries a social stigma, alcohol and tobacco are legal drugs permeating all levels of society. The risks of both are well-known and well-documented, with the International Agency for Research on Cancer classifying both as a group 1 carcinogen, which includes agents with "sufficient evidence of carcinogenicity in humans [and] both strong evidence in exposed humans that the agent exhibits key characteristics of carcinogens and sufficient evidence of carcinogenicity in experimental animals."

https://www.zerohedge.com/medical/these-are-worlds-deadliest-behavioral-risk-factors

EMA starts review of Rocket’s Fanconi anaemia gene therapy

 Patients in the EU with Fanconi anaemia (FA) could soon have the first gene therapy option for the disorder, as the EMA starts a review of Rocket Pharma’s RP-L102 candidate.

FA is an inherited syndrome that impairs the body’s chromosomal repair systems, causing bone marrow failure, and leads to congenital malformations and a broad range of symptoms, including an increased risk of cancers. It is usually diagnosed in children under 12 but, in some cases, there are no symptoms until adulthood.

RP-L102 is based on stem cells harvested from FA patients’ peripheral blood that are modified with a lentiviral vector to contain a function copy of the FANCA gene, which codes for a protein essential for DNA repair. Around 60% to 70% of patients with FA have a FANCA mutation, causing what is known as FA complement group A or FA-A.

The hope is that the gene therapy could provide the first alternative to allogeneic haematological stem cell transplantation (HSCT), which is associated with significant toxicities due to the need for a cytotoxic conditioning regimen to clear the way for the donor cells to colonise the bone marrow. Toxicity is exacerbated in the approximately 80% of FA patients who don’t have an HLA-identical sibling donor.

Across the EU and US – where a filing is due in the next few weeks – there are estimated to be between 200 and 275 new cases of FA diagnosed per year, with somewhere between 5,500 and 7,000 patients living with the disease.

The EMA has started its review of RP-L102 based on the results of a phase 1/2 trial in patients with FA-A, which showed that the one-shot treatment was able to achieve “phenotypic correction” in eight of 12 evaluable patients with at least 12 months of follow-up, and extending out to 42 months.

That was demonstrated by increased resistance to mitomycin-C (MMC) in bone marrow (BM)-derived colony-forming cells – a biomarker for DNA repair – along with genetic correction and stabilisation in blood cell levels. There were no significant safety signals with the treatment, which unlike HSCT can be administered without any cytotoxic conditioning.

Rocket has filed RP-L102 with the EMA to prevent bone marrow failure in patients with FA, a catastrophic event that affects 80% of patients within the first decade of life. It also plans to test RP-L102 in additional forms of the disease caused by FANC C and G mutations.

Meanwhile, as the FA programme approaches the finish line, Rocket is also waiting for a decision from the FDA on Kresladi (marnetegragene autotemcel) for severe leukocyte adhesion deficiency-I (LAD-I), its lead product, which is due by 30th June after a priority review. That application has been delayed by three months by a request for more chemistry, manufacturing, and controls (CMC) data.

The company also has two phase 2 trials ongoing of gene therapies for Danon disease, an X-linked disorder leading to severe heart disease, and pyruvate kinase deficiency (PKD), a blood disorder characterised by excessive rupture of red blood cells.

https://pharmaphorum.com/news/ema-starts-review-rockets-fanconi-anaemia-gene-therapy

UK trials will put dementia blood tests through their paces

 Researchers in the UK will soon start trialling blood tests that promise to diagnose dementia at clinics across the country in the hope of having them in routine NHS use within five years.

Two teams from University College London and the University of Oxford are spearheading a pair of studies that will recruit around 5,000 volunteers at more than 50 memory clinics in the UK.

It is being funded by the Blood Biomarker Challenge, a project launched last year by the Alzheimer’s Society, Alzheimer’s Research UK, the National Institute of Health and Care Research (NIHCR), and Gates Ventures.

Only two out of three people with dementia in the UK ever receive a formal diagnosis, and the current gold standard diagnostic tests – lumbar punctures to sample cerebrospinal fluid (CSF) and PET scans – are costly and invasive.

Timely and accurate diagnosis of conditions that cause dementia, such as Alzheimer’s disease, is crucial as patients can access care and support more quickly, take part in medical research, and – potentially at least – get access to new therapies like Eisai and Biogen’s Leqembi (lecanemab), which is currently under regulatory review in the UK.

Various groups around the world are working on blood tests for Alzheimer’s, generally looking for traces in the blood of proteins like amyloid and tau, which aggregate in the brains of people with Alzheimer’s and are a hallmark of the disease.

The two new trials will use a ‘real-world’ design to get a handle on how various blood tests work in clinical settings.

The READ-OUT study led by Oxford researcher Dr Vanessa Raymont will investigate tests for a range of types of dementia – including Alzheimer’s, vascular dementia, frontotemporal dementia (FTD), and dementia with Lewy bodies – to see whether they can help detect these diseases at various stages.

The ADAPT trial led by UCL’s Professor Jonathan Schott and Dr Ashvini Keshavan is zeroing in on what they believe is the most promising test for Alzheimer’s, which measures levels of a form of phosphorylated tau known as pTau217.

Earlier this year, a pTau217 assay developed by ALZpath was found to be 96% accurate in identifying elevated levels of amyloid and up to 97% accurate in correctly identifying high levels of tau when compared with CSF testing. The UCL team will see whether levels can be used to predict Alzheimer’s in patients with early signs of dementia and mild, progressive memory loss.

According to Alzheimer’s Research UK, this dual approach will boost the chances of providing the evidence needed to allow the blood tests to be validated for use in the NHS.

“We’ve seen the enormous potential that blood tests are showing for improving the diagnostic process for people and their loved ones in other disease areas,” said Dr Sheona Scales, director of research at the charity.

“Now we need to see this same step-change in dementia, which is the greatest health challenge facing the UK,” she added. “It’s fantastic that, through collaborating with the leading experts in the dementia community, we can look to bring cutting-edge blood tests for diagnosing dementia within the NHS.”

People who are interested in volunteering for the studies can get more information here.

https://pharmaphorum.com/news/uk-trials-will-put-dementia-blood-tests-through-their-paces

Aardvark said to be planning IPO, plus other bio financings

 Our regular round-up of financings in the biotech sector is headed by rumours of a $150 to $200 million initial public offering (IPO) for Aardvark Therapeutics, an emerging player in the weight-loss category, alongside a trio of big private rounds.

San Diego, California-based Aardvark is gearing up for the IPO sometime this summer, according to a report in the Financial Times citing people familiar with the matter. The company’s lead drug, ARD-101, is a small-molecule TAS2R pan-agonist in clinical testing for obesity, as an adjunct to weight-loss surgery, and for Prader-Willi syndrome (PWS).

The company’s approach is generating excitement among investors because it works differently to the barrage of GLP-1 agonist-based therapies on or near the market, and could be less prone to their side effects, like nausea loss of lean muscle mass, said the FT. It is in phase 2 testing, with PWS, a rare genetic form of obesity, the lead indication with a possible launch date pencilled in for 2026 if all goes well.

Also in Aardvark’s clinical pipeline is an early-stage candidate for autism spectrum disorder (ASD), called ARD-501, and a drug for fibromyalgia partnered with Scilex Pharma.

Obsidian Therapeutics, a specialist in tumour-infiltrating lymphocyte (TIL) cell therapies, has raised $160.5 million in a third-round financing round that will be used to fund its clinical programmes and scale up manufacturing capacity.

Lead programme OBX-115, based on a TIL that has been genetically modified to produce a cell membrane-bound form of the cytokine IL-15, doing away with the need to co-administer IL-2, which can cause serious side effects. The therapy is in a phase 1 trial in advanced or metastatic melanoma and phase 1/2 for advanced or metastatic solid tumours including non-small cell lung cancer (NSCLC).

The Series C was led by Wellington Management, with Novo Holdings taking part along with Foresite Capital, Janus Henderson Investors, Paradigm BioCapital, RTW Investments, T. Rowe Price and Woodline Partners. Previous backers of the company include Bristol-Myers Squibb.

Cancer-focused biotech Alterome has completed a $132 million Series B led by Goldman Sachs Alternatives and backed by Canaan Partners, Driehaus Capital Management, Invus, Digitalis Ventures, Blue Owl Capital, and existing investors.

The money will be deployed to advance multiple programmes through development, including two precision oncology candidates that will start clinical trials within the next 12 months, said the San Diego, California company, which uses a structure-guided machine learning and computational chemistry platform called Kraken to generate drug candidates.

Its lead candidates are an AKT1 E17K inhibitor and a KRAS selective inhibitor, targeting two well-established cancer-causing mutations, with a pair of programmes targeting the MAPK pathway further back in preclinical development. Alterome has raised $232 million to date, completing a $99 million first round in 2022.

Finally, Diagonal Therapeutics has raised $128 million from first-round financing, co-led by BVF Partners and Atlas Venture, that will support the development of its agonist antibody candidates for the treatment of rare diseases.

The new funding should be enough to take Diagonal’s lead candidate through proof-of-concept clinical testing, said the Cambridge, Massachusetts start-up. The drug is an agonist of a receptor complex in the TGF-β superfamily that is impaired in patients with hereditary haemorrhagic telangiectasia (HHT), a genetic disorder that leads to the formation of abnormal blood vessels. Also in its pipeline are an IL-18 agonist for solid tumours and another agonist antibody for pulmonary arterial hypertension.

Lightspeed Venture Partners, RA Capital Management, Frazier Life Sciences, Viking Global Investors, Velocity Capital, and Checkpoint Capital also participated in the round

https://pharmaphorum.com/news/aardvark-said-be-planning-ipo-plus-other-bio-financings

Over 25% of cancer survivors report significant levels of disability after cancer diagnosis

 A survey of nearly 50,000 cancer survivors has found that more than a quarter had a physical disability that impaired their mobility and almost 10% had a disability affecting self-care, Dana-Farber Cancer Institute researchers report in a new study, published in the Journal of Clinical Oncology. Both rates are sharply higher than those for adults who have not had cancer.

If the findings are extended to the estimated 18.1 million cancer survivors in the U.S., they suggest that more than 5 million survivors have a mobility disability and 1.3 million have a self-care disability, according to the study authors. The impact of such disabilities falls especially heavily on members of racial and ethnic minorities, underserved groups, and individuals with unhealthy lifestyles or other medical conditions.

The study findings underscore the importance of developing ways to limit the long-term side effects of cancer treatment, and of the benefits of exercise, both during and after treatment, to preserve physical function and ward off disability, researchers say.

"The effects of cancer and its treatment can lead to a variety of physical limitations that impair people's quality of life and ability to care for themselves," says Chao Cao, Ph.D., MPH, first author of the study.

"Even as the number of cancer survivors has grown, the prevalence and patterns of physical disabilities in this group have received little scientific attention. Our study is one of the first to examine this issue."

Data for the study came from the Behavioral Risk Factor Surveillance System, a nationwide, telephone-based survey by the U.S. Centers for Disease Control and Prevention that collected data on health-related risk behaviors and chronic medical conditions among U.S. adults. Researchers focused on data from 47,768 cancer survivors and 2.4 million adults without a history of cancer who participated in the survey.

After adjusting for demographic and lifestyle factors and health conditions, the researchers found that 27.9% of cancer survivors had a mobility disability—difficulty walking or climbing stairs, for example—compared to 13.4% among non-cancer adults. And 7.4% of survivors had a disability in self-care activities such as dressing or bathing, compared to 3.8% of non-cancer adults.

Investigators also found different rates of disability within different groups of survivors. Female survivors, for example, were significantly more likely to report mobility problems than male survivors were. Mobility-related disabilities were also more common in non-Hispanic Blacks, Native Americans, and Hispanics than in non-Hispanic whites.

Low educational attainment, low family annual income, being unmarried, having obesity, current smoking, being physically inactive, and having a chronic condition, were also associated with a higher prevalence of mobility disability among cancer survivors.

"These results point to the need for prevention efforts targeted at groups more likely to experience cancer-related disability," says study senior author, Jennifer Ligibel, MD, of Dana-Farber.

More information: Chao Cao et al, Prevalence and Cancer-Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022, Journal of Clinical Oncology (2024). DOI: 10.1200/JCO.23.02536

https://medicalxpress.com/news/2024-04-cancer-survivors-significant-disability-diagnosis.html

ABOUT THAT JOBS REPORT

 Many are hailing today’s establishment and household job reports, which show 300,000, or as many as 500,000, jobs being added in March. But Steve Moore points out in his Committee to Unleash Prosperity email that the picture is far from rosy:

The new job numbers for March were strong with 300,000 jobs added in the establishment survey and 500,000 in the household survey. But those positive headline numbers camouflage a very disturbing trend in the labor market. Almost all of the new jobs on net are part-timers. That means a part-time paycheck.

Stock market advisor Stephanie Pomboy of MacroMavens has analyzed the number and reports that in the last four months, the labor market has LOST 1.8 million full-time jobs.

Here is a handy summary for the past year:

* Overall payrolls up 1.9%
* Part-time jobs up 7.5%
* Full-time jobs down -1.35%

How many of the 300,000 jobs are double counting people holding TWO jobs?

So full-time jobs are actually down over the last year. That is rather shocking. This simple chart tells the story:

Sp basically, prices have been rising rapidly, family budgets are under attack, and a lot of people are seeking to supplement their families’ earnings with part-time work. That is not something to celebrate.

UPDATE: Then there is this:

https://www.powerlineblog.com/archives/2024/04/about-that-jobs-report-2.php

Zelenskiy warns of dwindling air defence missiles

 Ukraine could run out of air defence missiles if Russia keeps up its intense long-range bombing campaign, President Volodymyr Zelenskiy warned in remarks aired on Saturday.

The Ukrainian leader's starkest warning to date of the deteriorating situation faced by his country's air defences follows weeks of Russian strikes on the energy system, towns and cities using a broad arsenal of missiles and drones.

"If they keep hitting (Ukraine) every day the way they have for the last month, we might run out of missiles, and the partners know it," he said in an interview that aired on Ukrainian television.

Zelenskiy, who has been appealing to allies for weeks to rush in more air defences, said that Ukraine had enough stockpiles to cope for the moment, but that it was already having to make difficult choices about what to protect.

He singled out in particular the need for Patriot air defence systems and said Ukraine needed 25 of them.

The sophisticated U.S. air defence system has been vital during Russian attacks with ballistic and hypersonic missiles which can hit targets within a matter of minutes.

His remarks followed a fresh spate of attacks that Ukrainian officials said killed civilians.

Two Russian missile and drone strikes, one in the early hours of Saturday and a second in the afternoon, killed eight people and wounded at least 10 more people in northeastern Kharkiv, Ukraine's second largest city.

In the eastern region of Donetsk, artillery shelling killed four people in the village of Kurakhivka including a 38-year-old woman and her 16-year-old daughter, and a 25-year-old man in the village of Krasnohorivka was killed, while in Odesa in the south, a missile strike killed one civilian.

Ukraine's largest private power company DTEK says the strikes had hit 80% of its generating capacity and the grid has introduced rolling blackouts to stabilise the system.

'WE WILL AGREE TO ANY OPTIONS'

The battlefield momentum has moved against Ukraine in recent months as Kyiv grappled with a slowdown in military assistance from the West and in particular from the United States.

"The situation is difficult, but nevertheless stabilized. The enemy does not advance: when it takes steps forward, ours repel (them), and it retreats. On the contrary, our guys are taking some steps forward," he said.

Zelenskiy said he still believed that a major aid package would be approved by Congress where it has been stuck in deliberations since late last year facing determined Republican opposition.

"I still believe that we can get a positive vote in the United States Congress," he said.

Asked by the interviewer about the possibility of Ukraine receiving the package in the form of a loan, he said: "We will agree to any options."

He added that some artillery shells were being supplied to Ukraine under foreign initiatives that he did not name and that they were being used for defensive operations.

"We don't have shells for counteroffensive actions, as for the defence - there are several initiatives, and we're receiving weapons," he said.

The interview was recorded next to a military fortification in northeastern Chernihiv region, which borders Russia.

It was not clear exactly which day the interview was recorded, but Zelenskiy met with a bipartisan group of members of Congress in the region on Friday.

https://www.yahoo.com/news/ukraine-may-run-air-defence-182702979.html