Some people taking GLP-1 agonist-based weight-loss drugs have spectacular results, while others do less well and are affected badly by side effects – and a new study has started to explain why that is so.
An analysis carried out by the non-profit research arm of genetic testing company 23andMe on the genomes of almost 28,000 GLP-1 users has identified variations in two genes that are targeted by the drugs, such as Novo Nordisk's Wegovy (semaglutide) and Eli Lilly's Zepbound (tirzepatide), that can affect patient reactions to them.
Specifically, the researchers identified a missense variant in the GLP1R gene that seems to be associated with greater weight loss, along with multiple variants in the GIPR gene that appear to make patients more susceptible to side effects like nausea and vomiting when taking Zepbound, which also acts as a GIP agonist. They have published their findings in the journal Nature.
Hypothetically, the findings suggest that people who are eligible for weight-loss treatment using GLP-1-based therapies could be tested to see which therapy would deliver the best outcome for them, in efficacy and safety terms, as part of a precision medicine approach.
The 23andMe Research Institute said that some people lose less than 5% with GLP-1 drugs, while others can lose 20% or more, and the risk of gastrointestinal side effects with Zepbound ranges from 5% to 78%.
"The market is crowded with weight loss support and medications, but the approach to weight management is typically one of trial and error. This can lead people to leap into treatment with a high degree of uncertainty and unrealistic expectations about efficacy and possible side effects," said Dr Noura Abul-Husn, chief medical officer at the 23andMe Research Institute.
"We believe these reports are a step forwards in meeting an unmet need for a more informed and personalised approach to weight management."
One commentator on the findings, Dr Marie Spreckley of the University of Cambridge, said that "genetics is only one part of a much more complex picture."
The magnitude of the genetic effects is small in clinical terms, she contends, pointing out that in clinical trials typical weight loss with these medications is often in the range of around 10%-15%. That means that the difference in weight loss associated with the genetic variants – 0.76 kg additional loss per allele – is pretty modest.
"Importantly, non-genetic factors such as sex, drug type, dose, and duration appear to explain a substantially larger proportion of variability," added Spreckley. "The authors’ model suggests that most of the explained variance comes from these factors, with genetics adding only a modest incremental contribution."
That said, she said the study "is an important step towards understanding variability and the potential for future precision approaches."
AbbVie has opened a new front in the pharma industry's battle to change the 340B drug discounting programme for safety net hospitals in the US, after an early attempt was blocked in the courts.
For some time, the industry has been trying to change the 340B programme's use of upfront discounts on medicines to hospitals and clinics serving under-insured and low-income patients to one where rebates are paid to hospitals only after medicines have been purchased at normal commercial prices.
That change was due to be tested in a pilot programme proposed by the US government, but was recently knocked back by a federal judge, who ruled it would be unlawful and could hamstring healthcare systems serving some of the most vulnerable people in the US.
In its new lawsuit, AbbVie says it is attempting to "close loopholes and strengthen accountability" in the 340B programme, which it claims is open to abuse because of "an outdated and overly broad definition of a 340B patient."
The current definition, which dates back to 1996, allows hospitals and clinics to claim drug discounts for patients with "minimal or unrelated patient contact thousands of miles away, or even for the same prescription multiple times."
The result is that savings are being diverted elsewhere, which AbbVie maintains leads to higher healthcare costs for employers, taxpayers, and patients.
"Congress designed the 340B programme as a means of assisting a narrow class of safety-net providers in giving their low-income and vulnerable patients access to lower-cost prescription drugs and more-comprehensive healthcare services," according to the complaint.
"But in the years since its enactment, sophisticated participants have developed ways to exploit the programme for profit, causing it to grow exponentially. The volume of discounts accessed under the programme has similarly exploded – from approximately $6.6 billion in 2010 to $43.9 billion in 2021."
Abuse of the 340B system is a familiar complaint of the pharma industry, which has previously contended that recipients of the discounted medicines charge both uninsured patients and insurance companies higher prices, pocketing the difference. It is particularly unhappy about the proliferation of for-profit contract pharmacies, rather than in-house dispensers, using the programme.
Pharma companies were excluded from the federal government's defence of the rebate pilot in the December ruling, on the grounds that they had not been able to argue effectively that the government was capable of representing their interests in the dispute.
AbbVie's lawsuit takes a new tack, seeking changes to the definition of an eligible patient that include, for example, that prescriptions must be connected to care at the facility treating them and not from a different doctor or for an unrelated medical reason.
It also wants evidence of recent "real and substantive care" – via a visit that was sufficiently thorough to properly diagnose and treat the condition for which the drug is prescribed – and also that the provider is directly managing the care, not passing along a referral.
"As a longtime, proud participant in the 340B programme, AbbVie has seen firsthand how a nebulous interpretation of 'patient' can undermine – and ultimately destroy – [its] altruistic goals," said AbbVie in a statement.
"Our filing seeks to establish a clear, sensible patient definition to realign 340B with its original intent – serving vulnerable individuals and true safety net providers, not padding revenue streams that increase overall healthcare costs."
The lawsuit (1:26-cv-01190), which names HHS Secretary Robert F Kennedy Jr and HRSA Administrator Thomas Engels as defendants, has been filed in the US District Court for the District of Columbia.
Another bidder, which remains unidentified, dropped out of the bidding process. Analysts at William Blair now think it unlikely that another suitor could offer a counter-proposal to Merck’s outstanding $6.7 billion acquisition offer.
When Merck unveiled its $6.7 billion buyout bid for Terns Pharmaceuticals last month, analysts called the deal a bargain for the pharma. William Blair even suggested that the price undervalued Terns and that a rival suitor could emerge. Now, new disclosures about the drug at the center of the acquisition have dampened that enthusiasm and revealed that Merck had once offered roughly $1 billion more.
“The emergence of a higher bidder is unlikely,” William Blair told investors in a note on Tuesday, walking back its previous assessment of the acquisition. “We now believe that the Merck acquisition will be completed later this quarter.” Merck initiated its tender offer for Terns on the same day.
The pharma had initially proposed to purchase Terns’ shares for $61 a pop, according to an SEC filing posted on Tuesday, resulting in a total offer of around $7.7 billion. This was in early February, at which point Terns was also fielding an acquisition offer from an unnamed “large pharmaceutical company,” which had proposed a per-share price of $58—an offer that it later raised to $61.
Days after Merck’s initial proposal, Terns provided both of its suitors with updated clinical data from the Phase 1 CARDINAL study of TERN-701, an oral tyrosine kinase inhibitor being tested for chronic myeloid leukemia and the biotech’s lead asset.
Tuesday’s SEC document did not detail what these updated findings were, revealing only that “the MMR [major molecular response] achievement rate was lower” than the 64% rate at 24 weeks that had previously been disclosed in a December 2025 presentation. MMR is a common bellwether for how effective a leukemia therapy is.
Merck seemed underwhelmed by these new disclosures and lowered its proposed purchase price to $50 per share. “Merck believed that the MMR achievement rate for TERN-701 would likely be at the low end of the range discussed by Terns management,” the biotech reported in its securities filing.
The unnamed bidder was similarly unimpressed with the updated CARDINAL data and withdrew its offer. The company “did not view TERN-701 as sufficiently differentiated or sufficiently de-risked to proceed,” according to Terns’ filing.
Despite the downward adjustment in the purchase proposal, Merck nevertheless believed that TERN-701’s data were still “compelling,” Terns claimed on Tuesday. The biotech negotiated upward, and ultimately the parties settled on the final per-share price of $53, or $6.7 billion as announced last month.
Leerink Partners agreed with Merck’s assessment. “We continue to think that the deal price underestimates the potential for TERN-701 in chronic myeloid leukemia,” the firm wrote to investors on Tuesday evening, projecting sales to reach “blockbuster levels” by 2032. At its peak, TERN-701 could hit global revenues of around $6.2 billion by 2040.
When the transaction closes—which Leerink expects will happen in early May—Merck will gain a potential challenger to Novartis’ Scemblix, a kinase inhibitor approved in October 2021 for Philadelphia chromosome-positive chronic myeloid leukemia. The drug has already broken blockbuster status, bringing in more than $1.28 billion last year.
The Terns deal also plays into Merck’s strategy of enriching its pipeline in preparation for the loss of exclusivity of mega-blockbuster cancer drug Keytruda. Market protections for the PD-1 inhibitor are set to expire in 2028, after which the pharma expects biosimilars to eat away at its market share.
Aside from the Terns takeover, Merck in November 2025 absorbed Cidara Therapeutics for $9.2 billion, winning over a late-stage antiviral drug, and acquired Verona Pharma for $10 billion in July that year for an FDA-approved chronic obstructive pulmonary disease drug Ohtuvayre.
Roche is jumping into degrader-antibody conjugates, a modality that in recent years has attracted investments from Merck KGaA and Bristol Myers Squibb.
Roche is fronting $20 million to ink another deal with long-time partner C4 Therapeutics and join its fellow Big Pharma players in advancing a novel type of targeted protein degradation therapy.
Under the terms of the new agreement, announced Thursday morning, the pharma’s upfront payment will provide access to two degrader-antibody conjugate (DAC) programs, as well as the opportunity to add a third target. If Roche exercises this option, C4 Therapeutics (C4T) will be entitled to an additional payment, though the specific amount was not disclosed.
On top of the upfront commitments, Roche has also put more than $1 billion on the line in discovery, regulatory and commercial milestones. C4T will also be eligible for tiered royalties on future sales, if any products from the partnership reach the market.
The partners did not disclose what specific indications they will go after, revealing only that their DACs will be designed against “undisclosed oncology targets.”
C4T will design the degrader payload while Roche will be in charge of creating the antibody. The pharma will also assume responsibility for taking the resulting construct through preclinical and clinical development, as well as handling regulatory and commercialization activities.
Roche first became a C4T partner in January 2016, when the biotech launched with $73 million in series A funds. Aside from supporting the financing round, the pharma at the time signed a deal with C4T to develop targeted protein degraders, with a potential contract value over $750 million.
Structurally, DACs resemble antibody-drug conjugates (ADCs), also using antibodies to seek out certain proteins found on target malignant cells. Unlike ADCs, which carry cancer-killing chemicals, DACs instead carry molecular glue degraders, which are compounds that force the interaction between two typically unrelated molecules, ultimately leading to the destruction of a disease-causing protein.
Such an approach presents “a new way to treat cancer,” according to the companies’ news release on Thursday, “that leverages both the specificity and catalytic efficiency of degraders with the delivery capabilities of ADCs.”
Several pharma companies have bought into the promise of DACs—a couple of them through partnerships with C4T. Merck in December 2023, for instance, paid the biotech $10 million, though the pharma axed the agreement last November. In March 2024, Merck KGaA—a similarly named but completely separate entity headquartered in Germany—also linked up with C4, putting out $16 million upfront and promising up to $740 million in milestones.
Meanwhile, Bristol Myers Squibb in November 2025 acquired Orum Therapeutics’ ORM-6151 for acute myeloid leukemia or high-risk myelodysplastic syndromes. The pharma paid $100 million for the DAC and promised up to $180 million in milestones.
Asia One journalist Anas Mallick writes that "To my understanding, By tomorrow, first break of light, is when both delegations of US and Iran will be in Islamabad to hold talks."
There's some optimism regarding the US-Iran ceasefire holding, as it's been relatively quiet in the Middle East overnight into Thursday, despite Israel getting some final shots on Lebanon in. On this, Iran's president has made clear Tehran's position that Israel's renewed incursion into Lebanon and against Hezbollah violates the ceasefire, warning that these actions could make talks moot before they even begin.
Reuters observes, "Even as the U.S. and Iran seek to cement a ceasefire, Israel is seizing more territory from its neighbors in preparation for a long, drawn-out conflict across the Middle East. Israel's creation of 'buffer zones' in Gaza, Syria and now Lebanon reflects a strategic shift after the attacks of October 7, 2023, one that puts the country in a semi-permanent state of war."
Still, Gulf countries like the UAE have stated that no air threats have been detected or are inbound in the past hours, which is a rare positive development. There has been a decline in Iranian attacks across Arab states in the Persian Gulf region. Also, Israeli society has begun to return to normalcy, with emergency and shelter in place measures lifted across most parts of the country, and Ben Gurion airport in Tel Aviv having resumed operations as of midnight.
The reality of who actually controls the Hormuz Strait, told in one awkward WH press exchange:
Q: As of today, who controls the Strait of Hormuz?
LEAVITT: We expect that the strait will be opened immediately
But the reality remains that on Wednesday - the first day of the fragile ceasefire - a mere few tankers were allowed passage through the Strait of Hormuz before Iran shut down traffic again, citing the heavy Israeli attacks on Lebanon, which were the largest and deadliest of the war to date.
Sky News reports that at least 254 people were killed by the Israeli strikes across Lebanon on Wednesday, citing government health authorities. In Beirut alone, at least 91 people were killed, amid ongoing rescue efforts and treatment of the wounded in area hospitals. Over 1,000 Lebanese were wounded and injured. The Lebanese government has declared a day of mourning.
Trump To Renew Attacks if Tehran Fails in 'Real' Ceasefire Deal, Oil Rises
Meanwhile President Trump in a Truth Social message issued overnight says that "all US ships, aircraft, and military personnel" will remain in place around Iran until the "real agreement" on a ceasefire "is fully complied with" - warning of more US military action to come if not.
The renewed threats have pushed WTI back above $100...
Here's president Trump's full Truth Social statement wherein he warns that the shooting can start again "bigger, better, and stronger than anyone has ever seen before":
Iran's leadership has meanwhile been insistent on Lebanon being part of the Iran ceasefire, and has on this basis accused Washington of already violating at least three clauses of the ten point plan. It too has serious cards to play - especially while still de facto controlling Hormuz, and with the ability to renew attacks on energy sites in Gulf states.
— محمدباقر قالیباف | MB Ghalibaf (@mb_ghalibaf) April 9, 2026
Iran on Lebanon Violations: 'Choose War or Ceasefire, You Can't Have Both'
Iran's deputy foreign minister Saeed Khatibzadeh has told CBS News Israel's attacks on Lebanon Wednesday were "a grave violation" of the ceasefire agreement, and emphasized the US must choose "between war and ceasefire - you cannot have it both at the same time."
"You cannot ask for a ceasefire and then accept terms and conditions, accept areas the ceasefire is applied to, and name Lebanon, exactly Lebanon in that, and then your ally just start a massacre," Khatibzadeh said.
Netanyahu's message has remained that Israel can strike Hezbollah whenever and "wherever" it chooses. "In Beirut, we eliminated Ali Youssef Kharshi, the personal secretary of Hezbollah terror organization Secretary-General Naim Qassem and one of the people closest to him. At the same time, overnight, the IDF struck a series of terror infrastructures in southern Lebanon: crossings used to transfer thousands of weapons, rockets, and launchers, as well as weapons depots, launchers, and Hezbollah headquarters," Netanyahu said.
"Our message is clear: Whoever acts against Israeli civilians will be struck. We will continue to strike Hezbollah wherever required, until we restore full security to the residents of the north."
Meanwhile, Israeli Foreign Minister Saar: "In the last 40 days, Hezbollah has fired approximately 6,500 missiles, rockets, and drones at Israel."
Pakistan Welcomes Vance Heading up US Delegation
WH Press Secretary Karoline Leavitt made clear Wednesday that Vice President JD Vance will head up talks for the US side in Pakistan, leading Jared Kushner and Steve Witkoff. Tehran had previously expressed its disdain for the latter two, accusing them of lying and being deceptive the first go-round before Iran suffered surprise US-Israeli attack. The pair are also accused of lacking technical know-how when it comes to talking about the nuclear issue.
Al Jazeera also freshly reports that the choice of Vance heading the US delegation is "being viewed very positively in Pakistan." Pakistan’s former Ambassador to the UN Maleeha Lodhi says, "Politicians know the art of the possible, and therefore I think it’s a good decision by the Trump administration to have Vance lead the talks."
Vance has stressed that Trump is "impatient to make progress" with Iran and warned that if Iranian officials don't engage in good faith "they're going to find out that President Trump is not one to mess around with." The US has clamed Iran 'begged' for ceasefire while Tehran insists it was the other way around.
More Geopolitical Headlines
via Newsquawk...
US President Donald Trump posted: "All U.S. Ships, Aircraft, and Military Personnel....will remain in place in, and around, Iran, until such time as the REAL AGREEMENT reached is fully complied with".
US President Donald Trump posted: "NATO WASN’T THERE WHEN WE NEEDED THEM, AND THEY WON’T BE THERE IF WE NEED THEM AGAIN. REMEMBER GREENLAND, THAT BIG, POORLY RUN, PIECE OF ICE!!!".
The Trump administration is considering a plan to penalize NATO members viewed as unhelpful during the Iran war by relocating US troops to more supportive countries, with potential base closures in Europe, including in Spain or Germany, according to WSJ.
NATO Secretary-General Mark Rutte told President Trump that most European nations provided support.
US officials stated they do not rule out resuming fighting in Iran and confirmed Trump will not offer major concessions to reopen the Strait of Hormuz, warning Iran’s demands could trigger renewed conflict.
Iran’s deputy foreign minister stated that the speaker of parliament will lead Iran’s delegation in upcoming talks, with communication continuing through Pakistan, according to Al Jazeera.
Iran’s ambassador to Pakistan stated the delegation will arrive in Islamabad on Thursday night for “serious talks” based on Iran’s 10-point proposal.
The IRGC Navy announced alternative shipping routes to bypass potential sea mines, according to ISNA.
The IRGC stated that shipping through the Strait of Hormuz slowed sharply and then stopped following what it described as an Israeli ceasefire violation in Lebanon, according to CNN.
Iranian lawmaker Ibrahim Azizi stated: "Once again, you have proven that you do not know the meaning of a ceasefire" and "Only fire will discipline you...so wait for it".
Saudi Arabia and Iran discussed de-escalation during a call, according to SPA.
A Pakistani Foreign Ministry source indicated the US has backed away from including Lebanon in the ceasefire with Iran, according to Al Arabiya.
Israeli Prime Minister Benjamin Netanyahu stated Israel will continue striking Hezbollah, with the IDF targeting infrastructure in southern Lebanon overnight.
Israel’s Ministry of Energy ordered the resumption of operations at the Karish gas platform after a shutdown during the war, according to Channel 12.
Hezbollah stated its attacks on Israel will continue until aggression stops and launched rockets citing ceasefire violations, according to Fars News Agency.
A missile was fired from Lebanon into northern Israel, according to Fars News Agency.
Israeli strikes in Lebanon continued despite the ceasefire with Iran, according to Anadolu Agency.
French President Emmanuel Macron spoke with Iran’s President Masoud Pezeshkian and US President Donald Trump, stating their decision to accept the ceasefire was the best course of action.
Russia launched 119 drones at Ukraine overnight, according to Ukrainian media.
Valero Energy (VLO) is dealing with significant operational challenges following a March 23 explosion and fire at its 380,000 bbl/day Port Arthur, Texas, refinery. The incident destroyed a diesel hydrotreater and the control room managing several hydrotreating units. Although no injuries were reported, the company is establishing a temporary control room to restart the 45,000 bbl/day Unit 245 gasoline Gulfiner hydrotreater. Repairing the control room will take weeks, and the timeline for rebuilding the diesel hydrotreater remains uncertain. The refinery plays a crucial role, contributing 3.7% of the Gulf Coast's refining capacity.
OpenAI(OPENAI)plans to reserve a portion of shares for individual investors in what’s expected to be a blockbuster initial public offering, CFO Sarah Friar toldCNBC, adding that the San Francisco-based AI giant started testing the waters with retail in its latest funding round and saw “really strong demand” from individuals.
OpenAI will “for sure” hold a slice for retail when it goes public, Friar said on Wednesday.
“AI needs to garner trust in everything that we do. That is part of why retail particularly speaks to me,” Friar said. “It has to be that everyone partakes, that it isn’t just that a very small group, and everyone else gets left behind.”
She pointed to her time as CFO of Square, now known as Block, where the fintech company offered a direct selling program to small business owners and sellers in its IPO. She also highlighted OpenAI cofounder Elon Musk’s model with Tesla (TSLA) and SpaceX (SPACE).
SpaceX is expected to go public as soon as June and is said to be holding almost 30% of its shares for retail buyers.
“Everybody wants to own part of a rocket company — I hope everyone wants to own part of ChatGPT. It helps when you’re a consumer brand,” Friar added.
