Biden to visit Michigan's autoworkers amid planned protests over Gaza

 U.S. President Joe Biden will visit autoworkers in Michigan on Thursday, where he is likely to face protests over his handling of the war in Gaza, after several leaders of the state's Arab-American community declined to meet his campaign team last week.

Biden's travel to the election battleground state was intended as a celebration after the United Auto Workers (UAW) union recently endorsed his reelection bid. But his trip may be overshadowed by opposition from the state's Arab-American and Muslim population, which is upset the president has not called for a ceasefire in the Israel-Gaza conflict.

The Biden campaign has kept details of the president's visit private in the face of expected protests. Across the Detroit area, hundreds of protesters were standing by in cars and vans armed with blue and white "Abandon Biden" signs and Palestinian flags to rush to whichever UAW local Biden will visit.

"We're ready to go. I have my megaphone in the car," said Farah Khan, a Pakistani-American who voted for Biden in 2020 but now supports the Abandon Biden campaign in Michigan, told Reuters. "We have 92 Abandon Biden chapters across the country. This is bigger than just Michigan."

Before heading to Michigan, Biden attended the National Prayer Breakfast in Washington. He said he was working to resolve the Israel-Hamas conflict, including a two-state solution for Palestinians and bringing home the hostages still held following Hamas's Oct. 7 attack on southern Israel.

"We are actively working for peace," he said at the breakfast.

UNION BACKING

In the Detroit area, Biden will meet with UAW President Shawn Fain, who last week gave a full-throated endorsement of the Democratic incumbent and a sharp rebuke of Republican frontrunner Donald Trump.

https://finance.yahoo.com/news/1-biden-visit-michigans-autoworkers-134857656.html

Biden imposes sanctions on Israeli settlers accused of West Bank violence

  President Joe Biden on Thursday issued an executive order that targets Israeli settlers in the West Bank who have been accused of attacking Palestinians and Israeli peace activists in the occupied territory, imposing financial sanctions and visa bans in an initial round against four individuals.

Those settlers were involved in acts of violence, as well as threats and attempts to destroy or seize Palestinian property, according to the order. The penalties aim to block the four from using the U.S. financial system and bar American citizens from dealing with them. U.S. officials said they were evaluating whether to punish others involved in attacks that have intensified during the Israel-Hamas war.

Biden's order is a rare step against America’s closest ally in the Mideast who, Biden says, has the right to defend itself. But the Democratic president has pressed Israeli Prime Minister Benjamin Netanyahu’s government to show greater restraint in its military operations aimed at rooting out Hamas. Netanyahu denounced the U.S. penalties.

Palestinian authorities say some Palestinians have been killed, and rights groups say settlers have torched cars and attacked several small Bedouin communities, forcing evacuations.

“This violence poses a grave threat to peace, security, and stability in the West Bank, Israel, and the Middle East region, and threatens the national security and foreign policy interests of the United States,” White House national security adviser Jake Sullivan said in a statement.

Biden is facing growing criticism for his administration's strong support of Israel as casualties mount in the conflict, which began when Hamas, the militant group that rules Gaza, attacked Israel on Oct. 7.

The order notes that the violence by settlers undermines U.S. foreign policy objectives, “including the viability of a two-state solution and ensuring Israelis and Palestinians can attain equal measures of security, prosperity, and freedom.”

Biden has reinvigorated calls for an independent Palestinian state that would exist alongside Israel, a goal that has eluded American presidents and Middle East diplomats for decades. Biden has said that finding a way to achieve Palestinian sovereignty once the Israel-Hamas war ends is essential to building a durable peace.

Netanyahu has rejected such an idea throughout his political career and has told U.S. officials he remains opposed to any postwar plan that includes establishment of a Palestinian state.

The Israeli leader quickly denounced the sanctions. “The vast majority of settlers,” he said in a statement, ”are law-abiding citizens, many of them these days are fighting as conscripts and reservists for the defense of Israel." He said his country "takes action against law-breakers in every place, and therefore there is no place for exceptional steps on this measure.”

The State Department, in a statement, identified the four settlers and described the accusations against them:

https://news.yahoo.com/biden-issue-executive-order-targeting-150947920.html

Novartis calls time on Tim3 drug sabatolimab in MDS

 Novartis’ position as the frontrunner in the race to bring a Tim3-targeting drug to market has been lost after it pulled a phase 3 trial of its sabatolimab candidate.

The STIMULUS-MDS2 trial was testing sabatolimab (MBG453) in combination with azacitidine in previously untreated adult subjects with intermediate, high, or very high-risk myelodysplastic syndromes (MDS) who were not eligible for intensive chemotherapy or a haematopoietic stem cell transplantation (HSCT).

In its fourth-quarter results update, Novartis revealed that the programme was being discontinued to prioritise other programmes in its portfolio because STIMULUS-MDS2 had not met its primary endpoint.

The study’s main objective was to show an improvement in overall survival for the combination compared to azacitidine plus placebo. It started in 2020 and had been due to follow up patients for five years, with a main readout due in 2027.

Sabatolimab also missed the mark in the phase 2 STIMULUS-MDS1 study, which also looked at the combination of the drug with azacitidine in previously untreated higher-risk MDS and was published in The Lancet Haematology journal earlier this month.

Novartis has also been developing sabatolimab in combination with Gilead Sciences’ CD47-targeted antibody magrolimab – another drug struggling to show efficacy – in a phase 2 trial involving patients with acute myeloid leukaemia (AML) unfit for treatment with intensive chemotherapy, but the future of the programme now looks increasingly in doubt.

The company had been nominally out in front among developers of Tim3-targeted drugs, slightly ahead of GSK and partner AnaptysBio with cobolimab, which is being tested alongside GSK’s PD-1 inhibitor Jemperli (dostarlimab) and docetaxel in the phase 3 COSTAR trial in advanced non-small cell lung cancer (NSCLC) patients who have progressed after prior anti-PD-1/PD-L1 therapy.

Plenty of other companies, meanwhile, have been interested in the target, but a number of projects have fallen by the wayside, including Roche’s Tim3/PD-1 inhibitor bispecific antibody RO7121661 - which had reached phase 2, but no longer appears in its pipeline listing.

Bristol-Myers Squibb was also testing its candidate BMS-986258 as a monotherapy and in combination with its PD-1 inhibitor Opdivo (nivolumab) in solid tumours, but that also no longer appears in its R&D portfolio and, according to the clinicaltrials.gov register, was terminated due to changed “business objectives”.

Meanwhile, Incyte and partner Agenus’ verzistobart (INCAGN2390) remains in phase 2 for endometrial cancer and squamous cell carcinoma of the head and neck (SCCHN), and relapsed/refractory melanoma, while Servier/Symphogen have S95018 in a phase 1/2 combination study in NSCLC, and BeiGene’s surzebiclimab (BGB-A425) is in phase 1/2 studies with tislelizumab in solid tumours, including NSCLC.

Novartis also revealed in its fourth-quarter report that its BTK inhibitor remibrutinib would not be developed in the autoimmune disorder Sjogren’s syndrome, where it had reached phase 2, but is still in testing for other indications, including chronic spontaneous urticaria (CSU) and multiple sclerosis (MS).

https://pharmaphorum.com/news/novartis-calls-time-tim3-drug-sabatolimab-mds

Lundbeck study knocks confidence in alpha-syn as CNS target

 A phase 2 trial of Lundbeck’s alpha-synuclein-targeting drug Lu AF82422 has failed to reach statistical significance in patients with multiple system atrophy (MSA), although the company says there are encouraging “signals of efficacy” in the data.

The AMULET trial is comparing the anti-alpha-syn antibody to placebo in 61 patients with MSA, a rapidly progressing and rare condition that causes damage to nerve cells in the brain, to see if it can slow down the deterioration caused by the disease.

The primary endpoint is the change from baseline in the Unified Multiple System Atrophy Rating Scale (UMSARS) Part I and Part II Total Score after 48 to 72 weeks from the start of treatment, and Lu AF82422 was unable to show a statistical separation from placebo on this measure.

Only the top-line finding is available so far, with full data due to be reported later, but Lundbeck says that there was a trend towards improvement in patients in the Lu AF82422 group on the UMSARS scale – as well as unspecified clinical and biomarker endpoints, which gives it hope that the drug may still have a role to play in MSA therapy.

Alpha-syn is a protein that tends to get misfolded and accumulates into clumps in the brains of patients with MSA and other diseases including Parkinson’s, and is somewhat analogous to amyloid and tau proteins in Alzheimer’s disease.

“The outcome of the trial is encouraging, despite not reaching statistical significance,” insisted Johan Luthman, head of R&D at the Denmark-headquartered group. “We will now finalise the analysis of the data and plan the next step for progressing the Lu AF82422 MSA programme in dialogue with health authorities,” he added.

Despite the encouraging words, this isn’t the first time that an alpha-syn-directed therapy has missed the mark in a clinical trial, although others have generally targeted Parkinson’s.

Biogen’s cinpanemab was abandoned in 2021 after it failed a phase 2 study, while Roche/Prothena’s prasinezumab flunked one phase 2 trial, but is still in the phase 2b PADOVA trial in early-stage Parkinson’s patients.

AbbVie, meanwhile, had an antibody called ABBV-0805 in development with BioArctic, which cleared phase 1, but was side-lined for strategic reasons, and also abandoned an alpha-syn gene therapy candidate it had previously licensed from Voyager Therapeutics.

That track record hasn’t reduced the appetite for the development of alpha-syn therapeutics, however, and once again there is an analogy with amyloid in Alzheimer’s that has now led to an approved treatment (Eisai/Biogen’s Leqembi), despite dozens of earlier failed trials with amyloid-targeting drugs.

In 2021, Novartis licensed rights to an alpha-syn antibody from UCB – codenamed DLX313/UCB0599 – for $150 million upfront in a deal that could be worth up to $1.5 billion. Phase 2 results from that programme are due around the middle of this year. Sanofi stumped up $75 million upfront for a preclinical-stage bispecific antibody from South Korea’s ABL Bio in a $1 billion deal two years ago.

Other drug candidates in clinical development include Annovis Bio’s oral alpha-syn, tau, and amyloid-targeting buntanetap – which has completed phase 3, but with a data readout delayed for “data cleaning” – as well as Enterin’s ENT-01, which met its objectives in a phase 2b Parkinson’s study, and Takeda’s TAK-431 in mid-stage testing for MSA.

AstraZeneca, meanwhile, started phase 2 trials of MEDI341, an anti-alpha-syn antibody in development for both MSA and Parkinson’s, towards the end of 2022.

https://pharmaphorum.com/news/lundbeck-study-knocks-confidence-alpha-syn-cns-target

Intellia’s CRISPR drug could offer one-shot angioedema treatment

 A single dose of a gene-editing drug being developed by Intellia Therapeutics almost eliminated attacks in patients with hereditary angioedema (HAE) in a clinical trial, pointing to the potential of CRISPR-based drugs delivered in vivo to treat diseases.

The results of the phase 1 study of NTLA-2002 – which inactivates the gene encoding kallikrein B1 (KLKB1) – have been published in the New England Journal of Medicine, revealing that it led to 95% average reduction in monthly HAE attack rate, with nine out of 10 patients completely attack-free after at least 16 weeks of follow-up, even if they stopped taking preventative therapies.

Currently, patients have to have lifelong treatment with C1 esterase, bradykinin B2 receptor, or plasma kallikrein inhibitor drugs as prophylaxis against attacks.

While still early, the results back up the potential of NTLA-2002 to provide “lifelong control of angioedema attacks after a single dose,” according to the trial investigators. The subjects in the study will be followed for up to 15 years in order to gauge the durability of the treatment.

HAE is a rare genetic disorder estimated to affect about one in 10,000 to one in 50,000 people worldwide. It can result in unpredictable and potentially life-threatening recurring attacks of debilitating and painful swelling in various parts of the body, which can last for several days and lead to asphyxiation if affecting the airways.

The trial result comes shortly after the first-ever CRISPR-based therapy was approved for market - Vertex Pharma and CRISPR Therapeutics’ Casgevy (exagamglogene autotemcel) for sickle cell disease beta thalassaemia – although, that is an ex vivo application of the gene-editing technology, as it involves editing of bone marrow cells outside the body, rather than systemic dosing of the CRISPR agent.

“Despite currently available treatments, people living with hereditary angioedema continue to face frequent anxiety about their next swelling attack,” commented Intellia’s president and chief executive, John Leonard. “We are highly encouraged by [this] data and look forward to presenting extended follow-up from the phase 1 and results from the phase 2 portion [of the trial] later this year.”

Intellia is also planning to move NTLA-2002 quickly into a pivotal clinical trial programme, targeting a start before the end of the year if it can get regulatory approvals for the study.

The company – co-founded by Nobel Prize winner Jennifer Doudna – was the first to generate clinical data with an in vivo CRISPR drug back in 2021 with NTLA-2001, a Regeneron-partnered drug now in late-stage clinical testing for rare disease ATTR amyloidosis.

https://pharmaphorum.com/news/intellias-crispr-drug-could-offer-one-shot-hae-treatment

LifeStance Health Shares Tumble After Short-Seller Hindenburg’s Report

  LifeStance Health Group Inc. is tumbling after Nate Anderson’s Hindenburg Research released a report saying it’s betting against the provider of mental-health services.

Shares of the Arizona-based firm fell as much as 21% on Thursday before paring some of the loss to trade about 8% lower. The stock has declined nearly 30% this year.

The company, which has a market capitalization around $2.1 billion, has been under pressure over metrics including its clinician retention rate. On Tuesday, a judge in the US District Court for the Southern District of New York approved a deal that states LifeStance will pay $50 million to end a lawsuit that alleged it misled investors about its clinician retention rates ahead of its June 2021 initial public offering. The stock fell about 7% Tuesday.

Payment to settle litigation is a reason Hindenburg notes in its Thursday report assessing that LifeStance will need to raise cash imminently.

“Overall, we think LifeStance is a classic example of what happens when private equity meets a ‘hot’ healthcare sector: Massive debt fueling a grinding, metric-focused corporate culture resulting in worse quality of care for patients, a worse environment for clinicians and long-term losses for the average investor,” Hindenburg wrote in the report.

LifeStance didn’t immediately respond to requests for comment via email and phone.

The company has 4 buys, 4 holds and 1 sell rating with an average 12-month price target of $7.71, roughly 40% above where shares currently trade, according to data compiled by Bloomberg. The shares were down almost 70% since its public offering as of Wednesday’s close.

https://finance.yahoo.com/news/lifestance-health-shares-tumble-short-153906977.html

Cigna upped to Buy from Hold by Deutsche Bank

 Target to $370 from $355

https://finviz.com/quote.ashx?t=CI&p=d