Will Oral Weight-Loss Drugs Break Open an Already Lucrative Market?

 Sales of Eli Lilly and Novo Nordisk’s injectable GLP-1 drugs have soared in weight-loss indications, with Lilly’s Zepbound overtaking Novo’s Wegovy in new U.S. prescriptions for the first time last month. Obesity is a major global health crisis, and the allure of a market that could exceed $100 billion has companies throwing their R&D dollars into treating it. The next big move for the space—an easy-to-pop pill—is already well underway.  

Along with Novo and Lilly, Pfizer, Roche and a handful of smaller biotechs are racing to create an oral GLP-1 option with efficacy rivaling that of the currently approved injectable drugs. A pill could be the ticket to truly cracking open the massive market, Graig Suvannavejh, a senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas told BioSpace in an email. 

“Oral [GLP-1s] hold huge potential in lowering prices and broadening access for patients,” he said, adding that it could potentially bring them to a more global population.

Lilly Leads a Crowded Pipeline

Now in Phase III with its small molecule orforglipron, Lilly is leading the oral GLP-1 race. The company is already ramping up manufacturing capacities as it advances the pill into late-stage development.

In June 2023, the company shared Phase II data that showed weight loss of between 9.4% and 14.7% after 36 weeks on the drug compared to 2.3% for the placebo group. Lilly expects Phase III results in 2025, according to a company spokesperson. The results were comparable to the Zepbound injection, which led to weight loss of up to 15.7% after 72 weeks of treatment in the SURMOUNT-2 trial versus 3.3% for those on placebo.

Not to be left behind, Novo last month touted data from its Phase I trial of amycretin, a next-generation co-agonist of both the GLP-1 and amylin receptors. After 12 weeks, patients taking the drug saw 13.1% weight loss.

In December 2023, Roche bought its way into the obesity game with the $2.7 billion acquisition of Carmot Therapeutics. The deal gave Roche access to the biotech’s two dual agonists targeting GLP-1 and GIP receptors (a similar mechanism to Zepbound), as well as a once-daily oral GLP-1 drug currently in Phase I. At the time, Levi Garraway, the company’s chief medical officer and head of global product development, said the portfolio offered “different routes of administration and opportunities to develop combination therapies.”

Pfizer is working on an oral formulation of its oral GLP-1 receptor agonist of danuglipron. Last year, the pharma company chose to focus on a once-daily formulation and drop the twice-daily version of danuglipron due to smaller weight reductions than the competition and high rates of side effects and patient dropouts, STAT News reported. The pill is currently in a Phase I trial comparing pharmacokinetics between immediate and modified-release formulations.

On the biotech side, Viking Therapeutics is working on both a subcutaneous and oral formulation of its dual GLP-1/GIP receptor agonist. Viking unveiled promising Phase I data in March demonstrating dose-dependent decreases in mean body weight. Participants treated with the highest dose level of the drug saw a 3.3% drop in mean body weight relative to placebo.

Meanwhile, San Francisco–based Structure Therapeutics believes the successful Phase II trial of its oral small molecule GLP-1 asset proves its best-in-class potential. Interim results at eight weeks showed a mean weight drop of 5.5%. The company expects to initiate a Phase IIb obesity study in the second half of 2024, according to the announcement.

“Safe and effective oral small molecule GLP-1 receptor agonists would be a significant advance in that they could expand access for many patients for whom this is not now possible,” Structure CEO Raymond Stevens said in a statement.

Improved Accessibility

Despite their exploding popularity, the current GLP-1 injections face accessibility issues due to cost and limited insurance coverage, challenges oral versions may be able to address to some extent.

Weight loss medications currently aren’t covered by Medicare for obesity, and Medicaid coverage varies by state.

Commercial insurers can cover the drugs if the employer opts in, but many plans require prior authorization, a restriction that wasn’t an issue before GLP-1’s use for weight loss became common, said Michael Glickman, an obesity medicine physician and CEO of Revolution Medicine. An October 2023 survey found that only about a quarter of corporate health insurance plans cover GLP-1 drugs for weight loss, though another 13% were considering adding it as of February 2024.

“The majority of Americans still don’t have access to GLP-1s,” Glickman told BioSpace.

He hopes the approval of oral drugs will alleviate some of the pricing burden, as more medications on the market will drive competition. Suvannavejh concurred, saying he believes the arrival of oral GLP-1 drugs on the market will drive the cost down for consumers and perhaps also lead to better coverage from insurers. 

Glickman also pointed out that a small percentage of the population is needle averse enough to not want to inject themselves. Pfizer believes the factor plays a role why the current obesity injections are underutilized, a representative told BioSpace in an email. The spokesperson added that Pfizer expects a small molecule oral GLP-1 could be “well-reimbursed.”

A Lower Manufacturing Burden

Drug shortages of GLP-1s have been consistently frustrating for patients, Glickman said, adding that his practice receives multiple calls each week from patients having trouble refilling their obesity medications. In January, the World Health Organization issued a warning to patients regarding falsified versions of the drugs as shortages continue to limit GLP-1 drug access.

“It’s very challenging to keep patients on track when you can’t maintain medication consistency,” Glickman said.

Creating and packaging injectable peptides is a complex process. If successful, the arrival of oral formulations to the market should ease the current bottleneck, he added. “The complexity of producing an oral medication is going to be a lot simpler than producing a sterile subcutaneous product.” Additionally, having multiple options on the market would allow patients to pivot from one brand to another in the face of a supply chain issue, Glickman said.

With the current global focus on obesity, large companies with ample production capacity simply have to tap into the opportunity, while small companies are betting on “building a better mousetrap,” or formulation, in order to compete in the crowded space, Suvennevejh said. If these drugs do eventually make it to market, “there’s plenty of room to go around.”

https://www.biospace.com/article/will-oral-weight-loss-drugs-break-open-an-already-lucrative-market-/

FDA Action Alert: Vanda, Basilea and J&J/Legend

 After a hectic month, the FDA’s calendar appears to be easing up a bit. In the next two weeks, the regulator is facing just three major target action dates, including one potential CAR-T therapy approval that could push the class into earlier lines of treatment for multiple myeloma.

Read below for more.

Vanda Seeks Expansion of Fanapt into Bipolar Disorder

Vanda Pharmaceuticals is proposing its atypical antipsychotic Fanapt (iloperidone) as a treatment for bipolar I disorder. The FDA’s verdict is due on April 2.

In January, the Washington, D.C.-based biotech published Phase III data for iloperidone in the Journal of Clinical Psychiatry. The randomized, double-blinded and placebo-controlled study enrolled 414 adults with bipolar mania and demonstrated that iloperidone could induce significant symptom improvement within four weeks of treatment.

For instance, scores on the Young Mania Rating Scale, an 11-point clinical interview scale, were significantly better in the iloperidone group. The antipsychotic treatment likewise led to better scores on the Severity and Change subscores of the Clinical Global Impressions scale.

As for safety, treatment-emergent adverse events were more common in the iloperidone arm, though most were mild or moderate. Eighteen patients in the iloperidone group dropped out due to side effects, as opposed to 11 in the placebo arm. There were no deaths resulting from treatment toxicities.

Iloperidone is an atypical antipsychotic whose exact mechanism of action is still unknown, according to its label. Nevertheless, Vanda proposes that iloperidone exerts its effects by inhibiting the dopamine type 2 and serotonin type 2 pathways.

Iloperidone was approved in 2009 for the treatment of schizophrenia in adults. It comes with a boxed warning for a heightened risk of death in elderly patients suffering from dementia-related psychosis.

Basilea Awaits Approval for Antibiotic

By April 3, the FDA is expected to release its decision on Basilea Pharmaceutica’s New Drug Application (NDA) for its investigational antibiotic ceftobiprole for Staphylococcus aureus bacteremia (SAB), acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

Designed to be administered intravenously, ceftobiprole is the active portion of the prodrug ceftobiprole medocaril. The drug candidate is a cephalosporin antibiotic that has shown rapid bacteria-killing properties with proven activity against the Gram-positive S. aureus, including methicillin-resistant strains, according to Basilea. Ceftobiprole has also shown potency against Gram-negative bacteria.

Basilea supported its NDA, which the FDA accepted in October 2023, with three Phase III studies. The first, dubbed ERADICATE, tested ceftobiprole in SAB patients.

Basilea published data from ERADICATE in September 2023, demonstrating that ceftobiprole was non-inferior to daptomycin in terms of the study’s primary endpoint of treatment success, which was a composite of survival, symptom improvement, bacteremia clearance, no new infection-related complications and no need for other antibiotics.

The NDA also included data from the Phase III TARGET study, which focused on ABSSSI, and another late-stage trial in CABP.

J&J, Legend Look to Push Carvykti into Earlier Lines of Multiple Myeloma Treatment

The FDA’s biggest decision in the coming week is for the CAR-T therapy Carvykti (ciltacabtagene autoleucel, cilta-cel), which its manufacturers Johnson & Johnson and Legend Biotech are proposing for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who have received at least one previous line of therapy.

The regulator’s decision is due on April 5, 2024.

Carvykti works by reprogramming a patient’s own T-cells, inducing the expression of a receptor that allows these immune cells to seek out and destroy cancer cells expressing the BCMA protein. Currently, Carvykti is indicated for patients who have undergone at least four prior lines of therapy, according to its label.

J&J and Legend are seeking an earlier-line approval for Carvykti on the back of their Phase III CARTITUDE-4 trial, which compared the CAR-T treatment to standard chemotherapy regimens, including pomalidomide-bortezomib-dexamethasone and daratumumab-pomalidomide-dexamethasone. The study showed that Carvykti reduced the risk of disease progression or death by 74% versus standard of care.

Earlier this month, the FDA’s Oncologic Drugs Advisory Committee voted 11–0 to back Carvykti’s approval as an earlier-line therapy. The unanimous support came despite what the FDA’s internal reviewers flagged as a “higher rate of early deaths” in patients treated with Carvykti.

The FDA has been erring on the side of caution when it comes to CAR-T therapies. In November 2023, the regulator launched a probe into the drug class, particularly regarding reports of secondary T-cell malignancies in treated patients. In January 2024, the FDA called for a class-wide boxed warning to alert prescribers and patients to such risks.

https://www.biospace.com/article/fda-action-alert-vanda-basilea-and-j-and-j-legend/

Sanofi and Regeneron's Dupixent set for large gains with likely COPD approval

 Dupixent from Sanofi and Regeneron Pharmaceuticals is expected to gain approval for COPD, which would significantly increase its sales

https://seekingalpha.com/news/4085383-sanofi-regeneron-dupixent-set-large-gains-likely-copd-approval

In Easter Ruling, Judge Orders Release Of 'Border Riot' Migrants Who Overwhelmed National Guard

 A group of migrants involved in a riot at the southern US border have been ordered to be released by an El Paso magistrate judge.

The swarm of migrants overwhelmed Texas National Guard soldiers who were trying to organize them into groups to be taken into custody by Customs and Border Protection (CBP). At one point, a migrant attempted to grab a soldier's firearm, one National Guard source told the NY Post.

Following the riot, authorities confiscated knives and shanks from some of the migrants.

"These people were willing to assault military," said the Post's source. "They were willing to assault law enforcement. They have complete disregard for our laws."

In an Easter Sunday decision, presiding Magistrate Judge Humberto Acosta ordered the rioters released after accusing the El Paso DA's Office of being unprepared to proceed with detention hearings for each defendant, so they should be released, the El Paso Times reports.

"It is the ruling of the court is that all the rioting participation cases will be released on their own recognizance," Acosta ordered, noting that they will only remain jailed if there's a federal immigration hold blocking their release.

The arrests were made by the Texas Department of Public Safety in connection with a March 21 stampede of asylum-seeking migrants — mostly men from Venezuela — who torn down razor wire along the Rio Grande and rushed the border fence at Border Safety Initiative Marker No. 36 in the Riverside area of El Paso's Lower Valley.

Some migrants face charges of assault of a public servant for knocking down National Guard troops before order was regained. The migrants had sought to surrender themselves to U.S. Border Patrol in bids for asylum.

It was unclear if Acosta's decision applied only to the "riot participation" charge, or the assault and criminal mischief charges related to the border incident.

It is unknown how many migrants were booked on the charge of "riot participation," a Class B misdemeanor - though Acosta referred to "hundreds of arrestees," who he says are entitled to individual detention hearings within 48 hours.

The DA's office requested a continuance to have the hearings at a later date, however Acosta rejected the request.

"So if the DA’s office is telling me that they are not ready to go, what we’re going to do is we’re going to release all these individuals on their own recognizance," Acosta said at the hearing.

Meanwhile on Sunday, two other migrants - including a Colombian man, had separate hearings on criminal mischief charges for allegedly cutting border fencing. After being jailed with a $2,000 bond each, Magistrate Judge Antonio Aun also released them on personal recognizance bonds, however both men have immigration holds.

Last week, Texas sent 700 National Guard soldiers to El Paso, including 200 with the Texas Tactical Border Force, to reinforce the border.

As the El Paso Times notes further, 'Operation Lone Star video shows troops boarding a transport plane and on the border with riot shields moving migrants back so crews could replace rolls of damaged razor wire along the banks of the Rio Grande.'

https://www.zerohedge.com/political/judge-orders-release-border-riot-migrants-who-overwhelmed-national-guard

House office promoting diversity shuttered

 The House Office of Diversity and Inclusion (ODI) was disbanded this week as part of a government spending bill passed earlier this month, the office’s president, Sesha Joi Moon, told CNN. It’s the latest blow to the DEI movement, which has come under mounting criticism from Republicans over the past several years.

“The elimination of the House Office of Diversity and Inclusion is a tremendous loss, not only for the U.S. House of Representatives, but for the advancement of equity and opportunity in America overall,” Rep. Joyce Beatty (D-Ohio) said in a statement to The Hill.

Beatty, the first-ever chair of the Financial Services Committee’s Subcommittee on Diversity and Inclusion, has been a strong proponent of DEI practices as limitations on the programs have spread throughout the country.

Janet Stovall, Global Head of Diversity, Equity and Inclusion at NeuroLeadership Institute, said focus on these programs picked up in 2020 following the murder of George Floyd, an event that led to wider discussions involving representation in the workforce, among other issues.

But the effort to promote DEI programs also sparked backlash, especially from the right, members of whom argue that they push a divisive left-wing agenda under the guise of advocating for inclusion.

Rep. Alex Mooney (R-W.Va.) last year introduced a bill to abolish ODI, saying it promoted “cultural Marxism” in the workplace.

“These offices start with the premise that white people are inheritably racist and oppressive,” he said at the time. “The House of Representatives does not need bureaucrats promoting this divisive ideology.”

High-profile Republicans across the country have similarly criticized DEI programs, turning it into a political weapon for the second straight election cycle in a row.

The dissolution of the office comes as Republican lawmakers in more than 30 states have introduced or passed more than 100 bills this legislative session to either restrict or regulate DEI initiatives, according to an NBC News analysis.

Last May, Florida Gov. Ron DeSantis (R) signed a bill into law banning the state’s public colleges and universities from spending money on DEI programs.

“If you look at the way this has actually been implemented across the country, DEI is better viewed as standing for discrimination, exclusion and indoctrination,” DeSantis said at the time.

And, after the Supreme Court’s 2023 decision to overturn affirmative action, 13 Republican attorneys general sent a letter to Fortune 100 corporations warning them to refrain from using racial preferences in hiring and promotion decisions.

Meanwhile, in December, Utah Gov. Spencer Cox (R) garnered scrutiny when he said that the signing of diversity statements as part of the hiring process were “bordering on evil” and that his state would no longer have “diversity statements that you have to sign to get hired.”

Cox later said his comments were taken out of context by the media and stressed that he supported diversity.

https://thehill.com/homenews/race-politics/4564129-dei-advocates-sound-alarm-house-office-diversity/

China's SAIC aims to slash jobs at GM, VW ventures and EV unit, sources say

 China's SAIC Motor aims to cut thousands of jobs this year at its joint ventures with General Motors and Volkswagen and at an electric-car unit, two people with knowledge of the matter told Reuters.

The state-owned automaker hopes to cut 30% of employees at SAIC-GM, 10% at SAIC Volkswagen and more than half at its Rising Auto EV subsidiary, the people said.

Large-scale workforce reductions are rare at state-owned Chinese firms and come amid a cut-throat automotive price war as the nation's economy falters. The cutbacks also reflect the explosion of electric vehicles in China, a sector where SAIC and its foreign partners have rapidly lost market share to Tesla and privately owned Chinese automakers led by BYD.

The staff reductions won't happen all at once in mass layoffs but are targeted for 2024, the sources said. A large portion will come through implementing stricter performance standards and offering payouts to lower-rated employees who resign, they said.

A SAIC spokesperson said Reuters' "speculation" about staff downsizing is "not true" and that the company would not set targets for worker dismissals. SAIC did not respond to questions about efforts to get low-performers to resign or other staff-reduction strategies.

The company added that it had recruited 2,000 employees in the first two months of 2024 who will focus on software and new-energy vehicles.

A GM spokesperson in China said it would be "inaccurate" to say SAIC-GM is "reducing its workforce by 30%" but declined to elaborate. A VW China Group spokesperson said it did not plan “layoffs” and that it was “incorrect” to say SAIC-VW plans to cut 10% of its workforce.

The VW spokesperson declined to comment on whether the company had changed its employee performance reviews but called them a “long-term mechanism” and said SAIC-VW provides counseling and resources aiming to ensure “every employee can be qualified for their job requirements.” FALLING SALES SAIC has been China’s biggest automaker for nearly two decades but saw its sales fall by 16% during the first two months of 2024 from a year earlier, according to an SAIC filing. It employed 207,000 people at its parent company and major subsidiaries at the end of 2023, according to SAIC’s annual report.

https://finance.yahoo.com/news/exclusive-chinas-saic-aims-slash-234308964.html

Needham sees orthopedics market slowing; favors Enovis, Paragon 28

 Needham says it expects growth in the orthopedic device market to slow later this year, but sees Enovis (ENOV) and Paragon 28 (FNA) as above average performers.

https://seekingalpha.com/news/4071389-needham-sees-orthopedics-market-slowing-favors-enovis-paragon-28