NTSB board releases initial report on East Palestine derailment

 The National Transportation Security Board (NTSB) on Thursday issued its preliminary report on the derailment of a train carrying hazardous chemicals in East Palestine, Ohio, earlier this month, tentatively corroborating reports that a wheel bearing severely overheated ahead of the accident.

In its preliminary report, NTSB said investigators have examined the first car to derail, the 23rd overall, as well as local surveillance cameras and signal data. A nearby residence’s surveillance footage seemingly shows a wheel bearing in late-stage overheat failure immediately ahead of the accident, according to the preliminary report.

At the time of the accident, the report states, the train had passed through several hot bearing detectors (HBDs), which repeatedly tested as hotter than average and, by the third HBD, was 253 degrees above average, which meets Norfolk Southern’s criteria for “critical.” The train applied brakes at that point, but was unable to stop, according to the preliminary report.

The train, operated by Norfolk Southern Railway, derailed on Feb. 3. The 38 derailed cars included several cars containing vinyl chloride, a hazardous substance used in the production of plastics. Federal and state officials have both said drinking water in the area is safe, but both Gov. Mike DeWine (R) and Environmental Protection Agency Administrator Michael Regan have recommended residents drink bottled water.

NTSB investigators have taken possession of the wheel bearing in question as well as the affected wheel mechanism, according to the preliminary report. The investigation is ongoing and will further examine the design of the vinyl chloride tank cars and the derailment damage. It will also analyze the immediate response, in which first responders burned the five vinyl chloride tank cars to prevent a possible explosion.

In the report, NTSB emphasizes that potential environmental hazards are the purview of the EPA, which announced earlier this week that it would take over the cleanup effort and require Norfolk Southern to assume responsibility.

https://thehill.com/policy/energy-environment/3870923-preliminary-ntsb-board-report-on-east-palestine-derailment-confirms-bearing-overheated/

Putin says he’ll strengthen nuclear forces after suspending Russian participation in treaty

 Russian President Vladimir Putin on Thursday said he would strengthen Moscow’s nuclear forces after he moved to suspend Russia’s participation in its major nuclear arms treaty with the U.S.

Putin said Moscow will “put our focus on strengthening the nuclear triad” of land, air and sea weapons, according to a transcript from the Kremlin. His remarks came one day before the one-year anniversary of Russia’s invasion of Ukraine.

“This year, the first Sarmat missile system launchers with the new heavy missile will be put on combat duty. We will continue full production of the Kinzhal air-launched hypersonic systems and begin mass deployment of Tsirkon sea-launched hypersonic missiles,” Putin said. 

“With the Borei-A nuclear-powered submarine Emperor Alexander III becoming operational in the Navy, the share of modern weapons and equipment in the naval strategic nuclear forces will reach 100 percent. In the coming years, three more cruisers from this project will be delivered to the Navy.”

Putin announced he was suspending Russia’s participation in the New START nuclear arms treaty in a speech hours before President Biden gave remarks in Warsaw, Poland, to highlight U.S. support for Ukraine and vow that “Putin’s craven lust for land and power will fail.”

The U.S. president a day earlier had visited embattled Kyiv, Ukraine, to meet with Ukrainian President Volodymyr Zelensky. It was his first trip to the country since the start of the war.

Biden called Russia’s suspension of the arms treaty a “big mistake” but later said the U.S. has no indication Moscow is moving to actually use the weapons. 

“It’s a big mistake to do that. Not very responsible. And — but I don’t read into that that he’s thinking of using nuclear weapons or anything like that,” Biden told ABC News.

Putin has long provoked international concern over the possible use of nuclear weapons in his war on Ukraine, or of a potential nuclear accident as the Zaporizhzhia nuclear power plant is destabilized by the conflict.

https://thehill.com/policy/defense/3870962-putin-says-hell-strengthen-nuclear-forces-after-suspending-russian-participation-in-treaty/

Sickle cell pipeline gets edited down

 The pipeline for gene-edited ex vivo projects for sickle cell disease, once full to bursting, now looks a lot less crowded. Three contenders have dropped out of the race in the past two days: Intellia/Novartis’s OTQ923, Graphite’s nula-cel and Sangamo’s BIVV003. The writing was already on the wall for OTQ923 and nula-cel following disappointing data at Ash 2022 and a clinical hold respectively. Intellia is now focused on an in vivo editing approach in sickle cell, which is in preclinical development. Sangamo produced decent data with SAR445136; Sanofi handed back its rights to the project around 12 months ago after deciding to refocus on allogeneic approaches. Sangamo is now looking for a new partner, but the project might be too far behind Crispr/Vertex’s exa-cel to draw much interest. Attention now turns to Editas, which expects to give a mid-year update on the Ruby study of EDIT-301.

Selected ex vivo gene-edited sickle cell projects in development
Project	Company	Description	Status/trial details
CTX001	Crispr/Vertex	Crispr/Cas9 gene-edited cell therapy targeting BCL11a	Filed in EU and UK Dec 2022; US submission expected to conclude by the end of Q1 2023
EDIT-301	Editas	Crispr/Cas12a gene-edited cell therapy targeting beta-globin to increase foetal haemoglobin	Update from Ph1/2 Ruby trial expected mid-2023
BEAM-101	Beam Therapeutics	Base-edited cell therapy promoting foetal haemoglobin	Ph1/2 Beacon trial could report 2025
SAR445136 (BIVV003)	Sangamo	Zinc finger nuclease gene-edited cell therapy targeting BCL11a	Ph1/2 Precizn-1 trial will be completed, but no further investment will be made; company seeking a partner for Ph3 trials
GPH101	Graphite Bio	Homology-directed repair gene-edited cell therapy targeting underlying beta-globin mutation	Discontinued following case of pancytopenia in Ph1/2 Cedar trial
OTQ923 & HIX763	Intellia/Novartis	Crispr/Cas9 gene-edited cell therapy targeting BCL11a	Discontinued following poor Ph1/2 data
BEAM-102	Beam Therapeutics	Base-edited cell therapy recreating HbG Makassar variant	Deprioritised in favour of BEAM-101 and other technologies
Source: Evaluate Pharma & clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/corporate-strategy-snippets/sickle-cell-pipeline-gets-edited-down

Astra buys itself a second shot at the Claudin18.2 goal

 While Astellas’s Spotlight study of zolbetuximab stole most of the thunder for assets targeting Claudin18.2 at the recent Asco-GI meeting, Astrazeneca was apparently taken by a more low-key project, Keymed’s CMG901. A phase 1 trial of the latter elicited a 75% remission rate among just eight patients, the meeting heard, and this was enough for the UK company to license it for $63m up front this morning. The trial actually enrolled 27 subjects, and the eight highlighted represent only patients with Claudin18.2-positive gastric/gastroesophageal junction cancer. Claudin18.2 has become a hot area, and Astrazeneca is notable for having struck two deals now in the space of a year; as well as CMG901, an antibody-drug conjugate (ADC), last April Astra licensed in Harbour Biomed’s HBM7022, a T-cell engaging MAb. It appears that Astra wants to have multiple shots on goal, and if the price does not break the bank this seems wise. Innovent is another group targeting Claudin18.2 with multiple modalities – having an ADC as well as a Car-T therapy in clinical development. Perhaps Astra’s next move here, given its recent interest in cell therapy, will involve an anti-Claudin18.2 Car-T project.

Claudin18.2-targeting projects excluding simple antibodies*
Project	Company	Approach	Status	Claudin18.2 positivity required?
SKB315	Merck & Co (ex Kelun)	MAb-drug conjugate	Ph1 solid tumours	Yes
TPX-4589/ LM-302	Bristol Myers Squibb (ex Turning Point/Lanova)	MAb-drug conjugate	Ph1/2 solid tumours	Yes
CMG901	Astrazeneca (ex Keymed)	MAb-drug conjugate	Ph1 gastric, pancreatic, GEJ	Only in dose expansion
EO-3021/ SYSA1801	Elevation Oncology (ex CSPC)	MAb-drug conjugate	Ph1 gastric, pancreatic, GEJ	Yes
SOT102	Sotio/ Boehringer Ingelheim (ex NBE-Therapeutics)	MAb-drug conjugate	Ph1/2 gastric, pancreatic, GEJ	Only in dose expansion
SHR-A1904	Jiangsu Hengrui	MAb-drug conjugate	Ph1/2 solid tumours	Yes
TORL-2-307-ADC	Torl Biotherapeutics	MAb-drug conjugate	Ph1 gastric, pancreatic, GEJ	No
RC118	Remegen/ Biocytogen	MAb-drug conjugate	Ph1 solid tumours	Yes
JS107	Shanghai Junshi	MAb-drug conjugate	Ph1 +/- toripalimab	No
IBI343	Innovent Biologics	MAb-drug conjugate	Ph1 solid tumours	Only in dose expansion
IBI345	Innovent Biologics	Car-T	Ph1 solid tumours	Only in dose expansion
CT041	Carsgen Therapeutics	Car-T	Ph1/2 gastric, pancreatic	Yes
LB1908	Legend Biotech	Car-T	Ph1 gastric, pancreatic, oesophageal, GEJ	Yes
KD-496	Kaedi Biotech	Car-T**	Ph1 gastric, pancreatic	Yes***
Notes: *only clinical-stage assets, excluding naked MAbs or T-cell engagers; **bispecific Car that also hits NKG2DL; ***also requires NKG2DL positivity. Source: clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/snippets/astra-buys-itself-second-shot-claudin182-goal

Bankman-Fried Charged With Conspiracy To Make Unlawful Political Donations, Defraud FEC

 Disgraced FTX founder Sam Bankman-Fried was charged on Thursday with 12 new counts, including illegally making over 300 political contributions to the tune of tens of millions of dollars through straw donors and using corporate funds.

"Bankman-Fried's use of straw donors allowed him to evade contribution limits on individual donations to candidates to whom he had already donated," reads the indictment, which adds that the "fraudulent conduct" impaired the FEC's functioning.

"In dozens of instances, BANKMAN-FRIED's use of straw donors allowed him to evade contribution limits on individual donations to candidates to whom he had already donated."

"As a result of this fraudulent conduct," SBF and his co-conspirators caused false information to be reported by campaigns and PACs to the FEC."

SBF had previously only faced charges of conspiracy to commit wire fraud on customers and lenders, as well as commodities fraud, securities fraud, money laundering, conspiracy to defraud the United States, and violating campaign finance laws.

According to the new indictment, Bankman-Fried and others, while attempting to open a bank account, "falsely represented to a financial institution that the account would be used for trading and market making," when in fact it was used to receive and transmit customer funds.

SBF and co-conspirators "agreed to and did make corporate contributions to candidates and committees in the Southern District of New York that were reported in the name of another person," the indictment continues.

FTX's former CEO wanted to give at least $1 million to a pro-LGBTQ political action group, but couldn’t find anyone bisexual or gay at the company whom he trusted, the document said. One unnamed executive, believed to be Nishad Singh, was urged to make the donation, while another right-wing executive, apparently Ryan Salame, did so for Republican causes, the document said. -Coindesk

Bankman-Fried was the second largest individual donor during the 2022 US midterm elections, contributing $39 million to various Democrat causes.

It wasn't just Bankman-Fried that made donations to politicians with $72 million overall donated by FTX execs...

Here is the full list of politicians who received donations from FTX executives...

https://www.zerohedge.com/political/sam-bankman-fried-charged-conspiracy-make-unlawful-political-donations-defraud-federal

Denali: New Interim Data From Early-Stage Hunter Syndrome Study

 

• Denali Therapeutics Inc 
  DNLI-3.39%+ Free Alerts
   announced new interim results from the ongoing open-label, single-arm Phase 1/2 study of DNL310 in children with MPS II (Hunter syndrome), including data from additional participants and up to 104 weeks of treatment. 
• Over 49 weeks of DNL310 treatment in the Phase 1/2 study, positive changes across measures of exploratory clinical outcomes, including VABS-II (adaptive behavior) and BSID-III (cognitive capabilities) scores and global impression scales, were observed.
• Interim Phase 1/2 data also suggest that DNL310 improves hearing.
• The data demonstrate that DNL310 enables rapid and sustained normalization of heparan sulfate in cerebrospinal fluid (CSF) with mean reductions from baseline of 91% and 90% at weeks 24 and 49, respectively.
• Normalization of CSF heparan sulfate was observed even in participants with high levels of preexisting anti-iduronate-2-sulfatase antibodies.
• A sustained reduction of lysosomal lipid biomarkers in CSF was also observed, consistent with improved lysosomal function.
•  At week 24, the mean decline in gangliosides GM2, GM3, and glucosylsphingosine lipids were 64%, 54%, and 57%, respectively, sustained at week 49 (63%, 49%, and 48%, respectively).
• After switching from idursulfase to DNL310, a mean decline from baseline of 85% and 89% was observed for heparan sulfate and dermatan sulfate biomarkers in the urine, respectively, at week 49, suggesting DNL310 has added peripheral activity over approved enzyme replacement therapy.

https://www.benzinga.com/general/biotech/23/02/31025815/denali-therapeutics-reveals-new-interim-data-from-early-stage-hunter-syndrome-study