Prime editing comes of age as FDA clears human trials

 Prime Medicine has been given the go-ahead by the FDA for the first human trial of its prime editing technology, which promises to deliver one-shot therapies for a range of severe genetic diseases.

According to the Cambridge, Massachusetts biotech, the US regulator has cleared an investigational new drug (IND) application for ex vivo use of its Prime Editor platform to correct a mutation associated with chronic granulomatous disease (CGD), which leaves patients vulnerable to recurrent life-threatening infections and severe inflammation.

The planned phase 1/2 trial will see Prime Medicine’s PM359 candidate used to modify haematopoietic stem cells (HSCs) taken from CGD patients outside the body, to edit out a mutation in the gene coding for the NADPH oxidase complex that prevents phagocytic cells of the immune system from destroying microorganisms.

At the moment, patients with CGD – which normally manifests in childhood – often have to take near-constant doses of antibiotics to protect them from infections, as well as high-dose steroids to reduce inflammation, unless they are lucky enough to have a matched donor for a bone marrow transplant.

PM359 will be tested in adults with stable disease in the phase 1 portion of the trial and, if all looks okay with safety and gene expression data, it will then enrol adults and children with active infection and/or severe inflammation.

Prime Medicine’s ‘search-and-replace’ genome editing technology – initially identified by gene-editing pioneers David Liu and Andrew Anzalone at the Broad Institute – has already been shown to work in non-human primates, and moving it into clinical trials is a major step forward for the company.

Prime editing aims to improve on the CRISPR-Cas9 gene-editing approach by allowing changes to be made to DNA without breaking the double helix or using donor DNA. It is more broadly applicable than CRISPR-Cas9, according to the biotech, which says it could be used to target more than 90% of known disease-causing mutations.

“We are thrilled to achieve this important milestone for our first product candidate, PM359, which represents the first-ever IND clearance for a Prime Editor product candidate and a significant advancement in the field of next-generation gene editing,” said Keith Gottesdiener, Prime Medicine’s chief executive.

“Based on data from our preclinical studies, we believe PM359 has the potential to sufficiently correct a prevalent disease-causing mutation of CGD, leading to amelioration of disease for these patients,” he added. Data from the study will start to emerge next year, according to the company.

The approval to start the trial comes shortly after Prime Medicine completed an upscaled $161 million public offering that will help fund the CGD trial and other candidates in its pipeline, including candidates for eye disease retinitis pigmentosa, liver diseases, and Friedreich’s ataxia. It finished 2023 with cash reserves of $135 million, down from $307 million at end-2022.

Before the end of this year, Prime Medicine is hoping to have IND-enabling activities in place for its first liver and ocular disease programmes.

https://pharmaphorum.com/news/prime-editing-comes-age-fda-clears-human-trials

''California to sell state-branded Narcan generic to cut costs'

 California has said it will start selling its own generic version of overdose reversal agent naloxone in another example of the use of government-level purchasing power to reduce drug prices in the US.

The state’s Democratic governor Gavin Newsom has reached a deal with generic drugmaker Amneal Pharma to supply a nasal spray formulation of naloxone – the active ingredient in Emergent BioSolutions’ Narcan – at a 40% discount to the brand.

Twin packs of the product costing $24 will be distributed under the CalRx brand for free to qualifying organisations, like first responders, universities, and community organisations, and will be sold to California businesses and local governments - provided they do not sell them on at a profit.

The discount means that California will be able to acquire 3.2 million twin-packs of naloxone instead of the 2 million twin-packs purchased at the previous price, helping the state manage an opioid crisis that claimed around 7,000 lives in 2022, according to a statement from the governor's office.

The latest deal comes a few months after California unveiled the CalRx project with a $50 million contract with non-profit pharma manufacturer Civica to produce affordable insulin within the state, with plans to extend that to include insulin analogues like insulin glargine, aspart, and lispro. The state also sued the ‘big three’ insulin makers – Novo Nordisk, Eli Lilly, and Sanofi – accusing them of working together to set artificially inflated prices for their products.

“California is disrupting the drug industry with CalRx, securing life-saving drugs at lower and transparent prices,” according to Newsom, who signed an executive order to introduce the programme on his first day in office. “People should not be forced to go into debt to get lifesaving prescriptions.” The naloxone product will be the first to be sold using a CalRx label.

The governor said that the drive plans to leverage California’s power as the world’s fifth-largest economy to find other ways to drive down the cost of medicines in the state. At the federal level, the US government is also drawing on purchasing power with its scheme to negotiate the prices of certain medicines reimbursed by Medicare, which is being challenged by the pharma industry.

The naloxone deal has been announced just a few days after Amneal secured FDA approval for its over-the-counter naloxone nasal spray from the FDA, a generic of Emergent’s OTC product that was launched last year at a list price of $45 per pack.

According to IQVIA, US annual commercial sales for Narcan for the 12 months ended February this year were $266 million.

https://pharmaphorum.com/news/california-sell-state-branded-narcan-generic-cut-costs

Walmart retreats from healthcare, closing clinics across US

 For the last few years, Walmart has been promising to disrupt the US healthcare sector with a national network of clinics providing low-cost care and telehealth services. Now, it is reining back on those plans.

The retail giant has said it will close all 51 of its Walmart Health clinics across the country and shut down its telehealth service, built with its acquisition of MeMD in 2021, saying “there is not a sustainable business model for us to continue.”

The company said the decision was taken on the back of “the challenging reimbursement environment and escalating operating costs” that were making it impossible to run Walmart Health as a profitable business.

The clinics – which provided medical, dental, and behavioural health services – are clustered in five states, namely Arkansas, Georgia, Florida, Illinois, and Texas.

It’s not a complete retreat, as some health services will be provided through its 4,600 pharmacies and 3,000 optician centres, a network which also underpins its recently launched clinical trials business. However, there’s no doubt it is a major reversal and comes just weeks after Walmart said it planned to open up more than 20 new clinics this year.

Other big retailers like CVS Health, Walgreens Boots Alliance, and Amazon have also tried to provide healthcare services, and so far the track record is mixed, reflecting the difficulties of bringing real change to an entrenched sector.

Walgreens has been closing dozens of its VillageMD primary care clinics and took a $5.8 billion charge in connection with the business in its last quarterly results, for example, although CVS Health has said it is committed to growing its network of Oak Street Health clinics. Amazon, meanwhile, has been adding additional sites to its One Medical service, bought for $3.9 billion in 2022, but has been slashing staff to cut costs.

The Walmart decision has raised concerns that some patients may face a gap in access to healthcare, particularly those on lower incomes and no insurance or high deductibles. The company said when it announced its first clinic in 2019 that a key objective was to provide access to people in underserved communities.

In its statement on the decision, Walmart said its “priority will be ensuring the people and communities who are impacted are treated with the utmost respect, compassion, and support throughout the transition,” adding: “In the coming days, we are focused on continuity of care for patients and providing impacted associates with respect and assistance as we begin the closing process.”

https://pharmaphorum.com/news/walmart-retreats-healthcare-closing-clinics-across-us

'Biden directs spy agencies to share more intel with private sector over China, Russia threats'

 President Biden is directing U.S. spy agencies to more proactively share intelligence with the private companies handling critical American infrastructure, to guard against risks from foreign adversaries like China and Russia, or criminal groups and hackers.

The new directive is part of a national security memorandum on Critical Infrastructure Security and Resilience that Biden issued on Tuesday. The memo serves to update guidance first introduced in 2013 during the Obama administration, identifying new security procedures for 16 critical infrastructure sectors to guard against natural disasters and man-made threats. 

“The policy is particularly relevant today, given continued disruptive ransomware attacks, cyber-attacks on US water systems by our adversaries and their frequent and repeated testimony of the FBI director and other senior administration officials who have sounded the alarm about the ways our critical infrastructure is being targeted by our adversaries,” Caitlin Durkovich, Biden’s deputy Homeland Security Advisor for Resilience and Response, said in a call with reporters previewing the memo. 

The Biden administration, drawing on lessons from its warning about Russia’s full-scale invasion of Ukraine, said they are tasking intelligence agencies to lean into declassifying information to share with the private sector, or share information with private companies with the proper clearance, to better guard against security threats. 

“I know that the IC [intelligence community] is looking to make sure that if the information can be safely declassified, then it is,” said Jen Easterly, Director of the Cybersecurity and Infrastructure Security Agency.

Easterly said that the IC declassified potential retaliatory attacks by the Russian government to share with critical infrastructure owners and operators leading up to Russia’s full-scale invasion of Ukraine in Feb. 2022. 

She said that work is becoming more urgent with “serious” threats from the People’s Republic of China. The Biden administration warned in February that Chinese cyber actors are pre-positioning themselves in U.S. critical infrastructure to launch potential cyber attacks, in an operation named Volt Typhoon.

“We have held extensive briefings at various levels of classifications with cleared sector personnel to ensure that they are aware, that we’re aware — in 2022 of the Russian threat — and are aware now of the serious Chinese threats to our critical infrastructure,” Easterly said. 

“Specifically pre-positioning to disrupt or destroy critical infrastructure in the event of a major crisis.”

The memo also tasks the Department of Homeland Security with overarching responsibility for coordination among the different federal agencies, directing DHS to submit to the president a biennial “national risk management plan” summarizing the work on mitigating risks to the nation’s critical infrastructure. 

Also, the memo seeks to codify and require minimum security and resilience requirements for critical infrastructure entities that earlier were only voluntary. 

“Voluntary approaches to enhance critical infrastructure security and resilience have meaningfully mitigated risk over the past decade, but more must be done to ensure the Nation’s critical infrastructure is secure and resilient against all threats and hazards,” the memo reads. 

“The Federal Government must focus on increasing the adoption of requirements that address sector, national, and cross-sector risks to critical infrastructure.”

The memo also reaffirms the 16 critical infrastructure sectors, identifying which government agencies should be liaising with which sectors. 

“This is part of what we refer to as our all hazards approach to the resilience of the nation,” said Durkovich.

https://thehill.com/policy/national-security/4633131-biden-directs-spy-agencies-share-china-russia-threats/

Judge rules some North Carolina abortion pill restrictions unlawful

 A judge ruled Tuesday that some of North Carolina’s restrictions on the distribution of abortion pills are unlawful, citing arguments over the drug mifepristone that bypassed federal regulators.

In her order, U.S. District Judge Catherine Eagles in Greensboro granted a partial victory to the plaintiff, a physician who sued the state over the regulations for concerns around the pill that were not addressed by the Food and Drug Administration, The Associated Press reported.

Some restrictions on the drug that have not been expressly reviewed and rejected by the FDA — such as requiring an in-person consultation 72 hours before an abortion, an in-person examination, and an ultrasound before prescribing the drug — are allowed to remain in the state, Eagles wrote.

The judge noted the state-level laws also hinder Congress from creating a federal regulation for mifepristone.

“The Court finds and concludes that to the extent North Carolina law imposes safety restrictions on the distribution of the drug that the FDA has implemented and then later affirmatively rejected and removed, those laws frustrate the congressional goal of establishing a comprehensive regulatory framework under which the FDA determines conditions for safe drug distribution that do not create unnecessary burdens on the health care system or patient access,” Eagles wrote.

The lawsuit was filed Jan. 25, 2023, by Dr. Amy Bryant, alleging it was unconstitutional for North Carolina’s government to impose regulations on medication abortion because the federal government already had through the FDA.

Following Eagles’s ruling, Bryant released a statement saying she was pleased the judge recognized the state can’t impose all restrictions on the FDA-approved medication.

Bryant said the state’s restrictions “second-guess or interfere with the FDA’s expert judgment, and that many of North Carolina’s restrictions on mifepristone are preempted — including requirements that mifepristone be prescribed, dispensed, and administered in person,” and the mandatory in-person follow-up appointments and laws that restrict nurse practitioners from prescribing the drug.

“We are carefully reviewing the ruling and the implications it has for providing care to patients in North Carolina,” she wrote.

North Carolina Attorney General Josh Stein (D), a gubernatorial candidate who has supported abortion access throughout his campaign, was named a legal party in the case. He blamed GOP legislators who enacted the law for making it “harder for women, especially in rural North Carolina, to get medication abortion,” per the AP.

The ruling is the latest in efforts to target abortion rights after Roe v. Wade was overturned by the Supreme Court in June 2022 — ending a federal right to abortion access. North Carolina’s Republican-led General Assembly enacted new laws in 2023 that moved the ban on abortions from 20 weeks of pregnancy down to 12 weeks.

Restrictions were also placed on medication abortions and violating some rules could result in criminal, civil and professional penalties, the AP noted.

The FDA approved mifepristone in 2000 as a drug that could end pregnancy, when used with a second drug, misoprostol. The FDA announced in 2021 that women would be able to get the drug via an online consultation and through the mail, but the Supreme Court heard arguments in March for advocates who want to further restrict the drug.

https://thehill.com/homenews/state-watch/4635451-north-carolina-abortion-pill-restrictions-unlawful-judge-rules/

Dems, MoveOn launch early efforts to persuade undecided voters

 Democratic groups are ramping up persuasion efforts to convince undecided voters to cast ballots for President Biden. 

In an election where enthusiasm is low and voters are lukewarm on support for both parties’ candidates, Democrats are focusing on early persuasion in battleground states to help sway so-called surge voters — the part of the electorate who sat out during the 2016 presidential race but backed Biden during the 2020 cycle. 

The Democrats say they’re seeing a need to launch these efforts earlier than usual because of the unprecedented race between Biden and former President Trump and threats from third-party candidates like Robert F. Kennedy Jr. 

This week, for example, the progressive activist group MoveOn is intensifying the persuasion phase of a $32 million election program, which will engage those much-desired voters, sources tell The Hill.

Biden lags Trump across several polls, which have strategists saying the early contact is essential.

As part of their efforts, MoveOn members will participate in house parties beginning later this week to strengthen local connections with voters. Those parties will focus on what they say is one of their marquee issues: abortion. 

Organizers at MoveOn say issues like abortion and the fight for democracy have shown to be motivating for Democratic-leaning voters. 

MoveOn’s persuasion efforts will be handled by three “personalized contacts,” the sources say, which include phone, postcards and through in-person door-knocking, the sources say.

In 2020, the group took part in get-out-the-vote efforts much later in the cycle, in August. But it didn’t focus as much on persuasion, something they say is needed during this election.

“We believe that this strategy is key to doing the important work to successfully persuade voters and supply them with the information they need to protect their progress and their freedoms from Donald Trump and MAGA,” said Britt Jacovich, a press secretary for MoveOn. 

Other Democratic groups —including Indivisible and the Renegade Collective — and even unions including AFL-CIO are also expected to engage voters early through persuasion efforts. 

One source familiar with the AFL-CIO’s efforts says there is a specific focus on the Rust Belt states and having discussions on health care, wages and other issues.

“There’s so much noise and the only way to cut through that noise is conversation,” the union source said. “People don’t want the political speak.”

The efforts come as Trump continues to lead Biden in a string of recent polls. A CNN poll released earlier this week, for example, shows Trump ahead with 49 percent support to 43 percent in a head-to-head match-up. 

And in key battleground states — Arizona, Georgia, Nevada, Michigan, North Carolina, Wisconsin and Pennsylvania — the former president has a slim advantage over Biden, according to surveys published Tuesday from Emerson College Polling/The Hill, but the difference is within the survey’s margin of error. 

The polls have added to fears among Democrats who say more work should have been done in the previous presidential elections to turn out more Democrats.

“Ask Hillary Clinton about 2016 and whether or not voter contact is important,” said Democratic strategist Jamal Simmons. “You have to do voter contact, and you have to do it early.”

“The president and his team can’t do it alone. You need the echo chamber to tell the story,” Simmons added. “You need the surround sound telling voters what the administration has done, what it wants to do and what’s at stake in this election.” 

But Republicans say Democrats won’t move the needle by talking only about certain issues like abortion. 

“They have to be able to talk about other issues, and they seem stuck,” said Republican strategist Doug Heye. “For all the attention abortion has gotten in Arizona, you might forget from a D.C. newsroom that it’s a border state.”

Heye said the persuasion is only effective if they’re talking about the issues “that voters are clamoring for solutions on,” including the economy, inflation and the border. 

But Democrats say persuasion is particularly important now that Biden is president. 

“When you’re in power and your side controls the White House, there is a tendency for your side to become complacent, and that’s where the turnout message becomes important,” said Rachel Bitecofer, a political strategist and author of the new book, “Hit ‘Em Where it Hurts: How To Save Democracy By Beating Republicans At Their Own Game.” 

“At the end of the day, the field work is important,” Bitecofer said. “A lot of these surge voters are not paying attention to the daily news … The more contacts those people have to vote and vote Democrat, the better.”

https://thehill.com/homenews/campaign/4633858-democrats-launch-persuasion-efforts-undecided-voters/

Stefanik files ethics complaint against Jack Smith

 Rep. Elise Stefanik (R-N.Y.) filed an ethics complaint against special counsel Jack Smith on Tuesday, accusing the prosecutor overseeing the federal investigations into former President Trump of trying to “unlawfully interfere with the 2024 presidential election.”

Stefanik, the House GOP conference chair and a close Trump ally, filed the complaint with the Justice Department’s Office of Professional Responsibility, arguing Smith is trying to “rush” Trump’s federal election subversion case.

“It’s obvious to any reasonable observer that Jack Smith is trying to interfere with the 2024 election and stop the American people from electing Donald Trump,” Stefanik said in a statement. “At every turn, he has sought to accelerate his illegal prosecution of President Trump for the clear (if unstated) purpose of trying him before the November election.”

Smith should be censured for violating the Justice Department’s manual, she argues, citing a section that says attorneys may “never select the timing of any action … for the purpose of affecting any election.”

“Smith’s conduct has brought disrepute to the Department of Justice and the entire federal government, and the … Office of Professional Responsibility should impose the discipline that such conduct warrants,” Stefanik said in her statement.

The New York Republican points to Smith’s actions in court to support her claims of political animus, including asking the Supreme Court to weigh Trump’s immunity claims before they had yet been weighed by an appeals court.

The complaint is unlikely to prompt any action from the Justice Department, however, as Smith’s case kicked off with an August 2023 indictment, some 15 months ahead of the presidential election.

Smith’s office declined to comment on Stefanik’s letter.

Though an unwritten policy, the Justice Department encourages prosecutors to follow the “60-day rule” — avoiding any action that might influence an election in the 60 days prior to it.

A prosecutor on Smith’s team handling Trump’s documents case in Florida recently made clear they see the “60-day rule” as applying to investigative steps or filing a case that could influence an election, as opposed to continuing efforts in an ongoing case.

Jay Bratt, the prosecutor, told the judge in that case that Smith’s team had consulted the department’s Public Integrity Section on the portion of the manual cited by Stefanik.

“That provision does not apply to cases that have already been charged, that are being litigated. It doesn’t apply to setting a trial date. We are fully in compliance,” Bratt told the court.

Trump is of course the first presidential candidate to test the limits of that rule by facing an ongoing prosecution while again running for office.

Stefanik’s complaint otherwise echoes a series of arguments already made in court by Trump’s own attorneys, saying they are being overwhelmed by the extent of evidence they must review in the case.

She also picks apart Smith’s filings to the Supreme Court. Smith at one point urged the court to leapfrog the appeals court by taking up Trump’s argument he is immune from prosecution as a former president, an unusual move that if successful would have sped resolution of the issue. 

“Aside from the upcoming election, what ‘compelling interest’ does the public have in the prompt resolution of this case?” Stefanik wrote.

She also criticized Smith for making a filing in the case after District Judge Tanya Chutkan had paused proceedings on it. While the deadlines in the case were lifted, her order did not prohibit new filings. Still, after complaints from Trump, Chutkan ordered Smith’s team to first seek permission before making any new filings.

Tuesday’s ethics complaint is the latest example of Stefanik, who is considered a potential Trump running mate, publicly demonstrating her loyalty to the former president.

In November, Stefanik filed an ethics complaint against Judge Arthur Engoron, who oversaw the former president’s civil fraud trial, accusing him of “inappropriate bias and judicial intemperance.” She called on him to resign.

Then, in December, Stefanik asked for an ethics investigation into U.S. District Judge Beryl Howell, a federal judge who oversaw cases connected to Trump and Jan. 6 rioters.

Stefanik has kept the door open to serving as Trump’s running mate, telling NBC News in a January interview “I, of course, would be honored to serve in any capacity in a Trump administration,” when asked if she would serve as his vice president.

https://thehill.com/homenews/house/4631023-stefanik-jack-smith-ethics-complaint/