5 Promising MASH Therapies That Could Follow Madrigal’s Rezdiffra

 When Madrigal Pharmaceuticals’ Rezdiffra was approved last month as the first-ever treatment for metabolic dysfunction-associated steatohepatitis, experts hailed the drug as an “important first.” However, the consensus among experts is that Rezdiffra is just the beginning for a disease that has been notoriously difficult to treat.

Metabolic dysfunction-associated steatohepatitis (MASH) is inflammation of the liver caused by excess fat cells, which can lead to progressive fibrosis and cirrhosis of the liver. “[Rezdiffra] is the first oral drug that’s been demonstrated to show reversal of fibrosis in Phase III clinical studies,” said Lawrence Blatt, CEO of Aligos Therapeutics, which is also developing a candidate for MASH. “If you look at the magnitude of the impact of Madrigal’s drug, it’s good for patients,” he told BioSpace. “I don’t want to downplay what they’ve achieved . . . but there’s a lot of room for improvement.” About a quarter of patients treated with Rezdiffra have an improvement in fibrosis, he noted. “That leaves 75% of patients with the need for better therapies.”

A day before Rezdiffra’s approval, Ionis Pharmaceuticals announced that its own metabolic dysfunction-associated steatohepatitis (MASH) candidate hit the primary endpoint in a Phase II trial, showing significant improvement in steatohepatitis without worsening fibrosis, according to the company.

And this is only the tip of the iceberg. Here, BioSpace looks at five mid- to late-stage investigational MASH drugs.

Ionis’s ION224

The FDA asks MASH drug developers to show in Phase III clinical trials a one-stage improvement in fibrosis (ranked on a scale from F0, or the absence of fibrosis, to F4, full-blown cirrhosis) with no worsening of MASH, or the resolution of MASH with no worsening of fibrosis. Ionis appears to be well on its way to this metric, as 32% of people in the high dose arm of its Phase II trial of ION224 had at least a one-stage improvement in fibrosis without worsening of steatohepatitis as measured by biopsy, compared to 12.5% of patients in the placebo cohort.

The drug was safe and well-tolerated in the trial, Ionis stated, and there was a lower rate of early termination in the ION224 study arms compared to placebo.

ION224 is designed to cut production of DGAT2, an enzyme that studies have linked to fatty liver disease. The Phase II trial “is the first to demonstrate clinical evidence that the reduction of hepatic fat after DGAT2 inhibition correlates with improvements in MASH histological endpoints,” Rohit Loomba, a professor of medicine and chief of the division of gastroenterology and hepatology at the University of California San Diego, said in a company statement. 

Altimmune’s Pemvidutide

Pemvidutide, developed by Altimmune and currently entering Phase IIb trials, is a peptide-based GLP-1/glucagon dual receptor agonist. While activation of the GLP-1 receptors leads to appetite suppression, activation of glucagon increases energy expenditure, both of which are important for weight loss. Glucagon is also believed to have direct effects on hepatic fat metabolism, leading to rapid reductions in levels of liver fat and serum lipids, according to Altimmune.

Mayank Mamtani, head of healthcare research at B. Riley Securities, is bullish on therapies targeting the glucagon receptor to treat MASH. In addition to pemvidutide, he cited Eli Lilly’s retatrutide and Boehringer Ingelheim’s survodutide. “If you look at [these programs], they’re telling you that this is the drug class that’s going to win in MASH.” On top of a “profound” lowering of liver fat, he said there are other benefits with this drug class, including lowering of liver enzymes and cholesterol, “that you’re not getting from Madrigal.” Boehringer Ingelheim reported positive data from its own Phase II trial in February.

So far in clinical trials, once weekly pemvidutide has shown “compelling weight loss, robust reductions in triglycerides, LDL cholesterol, liver fat content and blood pressure,” and a clean safety profile, according to Altimmune. Topline 24-week data from the Phase II IMPACT trial is due in the first quarter of 2025.

89bio’s Pegozafermin

San Francisco–based 89bio is one of a handful of companies developing an analog of FGF21, a hormone that may address underlying metabolic issues that drive liver and cardiometabolic diseases, including MASH.

The primary unmet need in MASH is in more advanced disease, Mamtani said. “Something that works in F4 is obviously the holy grail,” he said, adding that analogs of fibroblast growth factor 21 (FGF21) could have potential here.

In November 2023, 89bio announced positive topline data from its Phase IIb trial of pegozafermin. After 48 weeks, MASH patients with stage F2 or F3 fibrosis treated with the candidate saw sustained, statistically significant improvements across liver fat and noninvasive tests of liver injury/inflammation and fibrosis.

Pegozafermin is “the first FGF21 analog candidate to demonstrate positive, sustained benefits over a 48-week period in patients with advanced NASH,” Hank Mansbach, the company’s chief medical officer, said in a statement at the time. (MASH used to be known by the name nonalcoholic steatohepatitis, or NASH.) Patients with stage F2 and F3 fibrosis are at high risk of progression to cirrhosis and increased risk of liver cancer, liver decompensation and death.

Viking Therapeutics’ VK2809

Currently in Phase IIb trials, Viking Therapeutics’ VK2809 belongs to the same thyroid hormone receptor beta (THR-β) class as Rezdiffra. William Blair analysts Andy Hsieh and Alexandra Ramsey wrote in a March 2024 note that the drug could “potentially outshine Rezdiffra’s clinical profile.”

Topline data presented in May 2023 showed VK2809 cleared the trial’s primary endpoint, significantly reducing liver fat in patients with biopsy-confirmed MASH. After 12 weeks, patients treated with 2.5 mg of Viking’s candidate saw a 45.3% decrease in liver fat content, compared to 3.7% in placebo comparators. Updated results from the Phase IIb study demonstrated “robust and comparable liver fat reductions among patients with or without type II diabetes, as well as patients with either F2 or F3 fibrosis,” Viking reported in November 2023.

Viking expects 52-week biopsy results during the first half of this year.

Aligos Therapeutics’ ALG-055009

Earlier this month, Aligos initiated dosing in the Phase IIa HERALD study of ALG-055009, also a THR-ß agonist. The placebo-controlled trial will enroll approximately 100 individuals with presumed MASH and F1–F3 fibrosis.

So far in clinical trials, Blatt said ALG-055009 is showing up to 100-fold more potency than Rezdiffra. He added that, in contrast to Rezdiffra, the drug has linear and non-variable pharmacokinetics, “so it’s very well controlled.”

With Rezdiffra, “the variation they see among these individuals is highly variable, so some people are getting the optimal dose, some people are getting underdosed [and] some people might be getting overdosed,” Blatt explained, even though they all got the same amount of the drug. He added that only about 25% of patients taking Rezdiffra had improvement in fibrosis because “you have a lot of patients who were underexposed to the drug, and they weren’t receiving the amount of drug that they needed.”

Topline safety and efficacy data from the HERALD trial are expected in Q4, 2024.

https://www.biospace.com/article/5-promising-mash-therapies-that-could-follow-madrigal-s-rezdiffra-/

Wife of ex-Harvard Medical School morgue manager pleads guilty in body part selling scheme

 The wife of a former Harvard Medical School morgue manager has pleaded guilty after shipping stolen human body parts from the motuary at the Ivy League school to buyers nationwide.

Denise Lodge, 64, pleaded guilty in the US District Court in the Middle District of Pennsylvania to a charge of interstate transportation of stolen goods on Friday, court records revealed.

Federal prosecutors said the “egregious” sprawling scheme also involved an Arkansas mortuary employee who sold body parts on Facebook for nearly $11,000 and a Massachusetts store owner who bought a human skull to create a “killer clown”-style doll she later shared on Instagram.

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Denise Lodge, left, covers her face with a printout of the indictment against her as she walks from the federal courthouse.AP

They announced the charges against Lodge, her husband Cedric Lodge and five others last year and claimed that the 64-year-old had negotiated online sales of human remains between 2018 and 2020.

Two dozen hands, two feet, nine spines, portions of skulls, five dissected human face and two dissected heads were among the items sold, PennLive.com reported.

Lodge’s attorney, Hope Lefeber, told WBUR in a February interview that her client’s husband was the mastermind and she merely “went along with it” adding that no money had been lost.

“[It’s] more a moral and ethical dilemma … than a criminal case,” Lefeber said.

Bodies donated to Harvard Medical School are used for education, teaching and research purposes before being cremated and returned to the donor’s family once used — but the morgue manager instead saw a business opportunity within the black market and sold body parts without families’ knowledge.

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Denise Lodge pleaded guilty after shipping stolen human body parts from the motuary at the Ivy League school to buyers nationwide.REUTERS

Cedric Lodge was fired on May 6, with Harvard describing his alleged actions as “an abhorrent betrayal.”

The macabre crime revealed a thriving demand for human remains in the US.

Organ and tissue donations are “heavily regulated” by the federal government, but that oversight isn’t extended to whole bodies.

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Prosecutors said the scheme involved an Arkansas mortuary employee who sold body parts on Facebook a Massachusetts store owner who bought a human skull to create a “killer clown”-style doll.David McGlynn

Just four states — New York, Virginia, Oklahoma and Florida — closely monitor whole-body donations and sales, experts told the Post in June. 

Family members of the deceased are typically approached by hospices or funeral homes who work with unregulated body brokerages in exchange for free cremation.

Meanwhile, a body broker can sell a donated corpse for roughly $5,000, although prices sometimes exceed $10,000. 

Body parts can also be resold several times by non-tissue transplant banks that often target poor or elderly clients, National Funeral Directors Association officials said.

Human heads command as much as $3,000 in a market driven primarily by medical schools, research facilities, independent collectors and cosmetic surgery firms. 

A spine can sell for $1,200, while a set of hands can fetch about $1,000, depending on condition.

An entire body can sell for up to $11,000.

https://nypost.com/2024/04/14/us-news/denise-lodge-wife-of-ex-harvard-medical-school-morgue-manager-pleads-guilty-in-body-part-selling-scheme/

You Need to Talk to Your Patients About Money

 A non-compliant patient arrives at the emergency department (ED) for evaluation of high blood pressure. Why isn't she taking her medication? It costs $300 per month, and she can't afford it. Has she talked to her doctor about a less expensive alternative? No.

Unfortunately, this type of interaction occurs far too frequently. The doctor would be happy to prescribe a cheaper alternative if requested, and the patient would love a cheaper option but doesn't want to question the doctor. It's a Catch-22 that even Heller would appreciate.

A simple conversation about the cost of treatment, the patient's insurance status, and their ability to pay would easily solve the problem. As physicians, we must learn to discuss these money matters with our patients.

Why Is It Difficult for Physicians to Talk About Money?

Everyone has a difficult time talking about money, and physicians are no different. We may worry that patients view us as "rich" and out of touch. We also don't want the patient to think we only care about money. However, the most significant barriers are ingrained in our medical education and healthcare systems.

Philosophy

Medical school and residency teach us not to think about money. In many ways, this is a good thing. We are trained to treat everyone equally regardless of race, religion, sexual orientation, or socioeconomic status. In the ED, we treat everyone regardless of their ability to pay. For years, I prided myself on not knowing my patients' insurance status. I would get slightly offended should a consultant ask me. I now know that despite coming from a good place, this perspective is naive.

Ignorance

Most of us don't know how much the medicine we prescribe or the tests we order cost. This is partly because the cost of anything in our healthcare system is opaque. Different prices exist depending on whether the patient has insurance, and each insurance company negotiates rates with individual hospitals and clinics. It's also partly because we aren't taught this in our training and haven't taken the time to learn independently.

Additionally, many providers simply don't understand how insurance and medical billing work. They don't know what the patient is being charged and probably don't know how to find out. Patients who ask what their ED bill will be are typically met with a blank stare.

The 'Best'

We generally prescribe what we think is "best" for our patients without regard to price -- the best test, medicine, or intervention. However, unless the recommendation includes a discussion about the patient's ability to afford it, the "best" is potentially useless. I would rather prescribe my patient the fourth-best blood pressure medicine that she can afford than the absolute best she cannot.

The very idea of the "best" is nebulous. What many physicians believe to be the best is simply the newest or most heavily marketed. Doctors are as susceptible to marketing as anyone else. Drug companies have a vested interest in their latest medications being perceived as the most efficacious and in doctors prescribing them. Many new medications are simply a variant of an existing one, often created when the established medication's patent expires. Even if the studies show increased efficacy at the margins or slightly fewer subjective side effects, it may not justify the increased cost.

Time and Habit

Doctors are busy. Seventy-four percent of physicians are now employees who carry that burden. We have a boss and specific metrics we must meet. Doctors are constantly pushed to do more in the same amount of time. Those in private practice feel the same pressure to keep their business financially viable. So, we all create habits and shortcuts. There are literally thousands of medications, so we develop a routine of repeatedly prescribing the same things. It's a lot easier to remember 50 medications than 500. We do the same for tests. How many of us use order sets that depend on the patient's complaint? Not every test may be necessary for every patient, but it is easier and faster just to order them together.

What Medical Providers Should Do

What can a provider do to help ease their patient's financial burden? I recommend the following three steps.

1. Educate yourselves. Do you know how much the medications you prescribe cost? Do you know your patient's insurance status? If a patient doesn't have insurance or has a high-deductible plan, they're unlikely to take the $300-per-month medicine you prescribe. Learn how insurance and medical billing work. Find out what your employer charges for every test and medication you prescribe. An intramuscular shot of penicillin G benzathine (Bicillin L-A) may be $200, while a prescription for penicillin V potassium costs $20 or less.
2. Get uncomfortable and assess your practice. Stop practicing based on habit. Review every protocol and "order set" to see if there are any unnecessary tests or those that may be applicable only under certain conditions. Reassess the medications you routinely prescribe to determine if there are cheaper alternatives that are still effective. Ask yourself the hard questions. Do I need to refer this patient to a specialist, or can I handle this with some research? Do I need to order that $700 viral panel, or can I take the time to explain that it is unnecessary?
3. Get comfortable talking about money. We talk to patients about intimate details -- drug use, sexual activity, bodily functions, etc. I ask teenagers about sexual activity in front of their parents, and grandmas about drug use. How much more difficult is it to say to a patient, "Can you afford this medication? Do you have any financial concerns about following this treatment plan? There are less expensive alternatives available." You don't have to worry about bias if you ask every patient.

Conclusion

I'm not recommending substandard care. I'm suggesting that an open dialogue about money can build trust, improve compliance, and lower patients' costs. We need more than money conversations to solve healthcare's affordability crisis, but we have to start somewhere.

Neill Slater, MD, is an emergency physician.

https://www.medpagetoday.com/opinion/kevinmd/109647

Congress Can Take Action to Prevent Older Adult Falls and Associated Opioid Use

 A common scenario we have all seen: an older person, after experiencing a fall, faces a long, hard, and frustrating road to recovery. But these individuals are not just statistics; they are our patients, parents, grandparents, and friends who deserve to live their lives without the constant fear of falling.

Physical therapy is a proven strategy for preventing falls, alleviating pain, and improving overall quality of life for aging Americans. Additionally, data show that seniors engaging in physical therapy are less likely to require emergency department visits or hospitalizationsopens in a new tab or window after a fall, and are at lower risk of long-term opioid medication useopens in a new tab or window.

The importance of such services cannot be overstated. Despite the critical role of physical therapy in preventing falls, many seniors find themselves with limited access to the preventive measures that can help save them from breaking a wrist, hip, or worse.

The primary culprit for limited access? A healthcare system that fails to prioritize prevention and obstructs seniors' access to necessary care.

The proposed Stopping Addiction and Falls for the Elderly (SAFE) Actopens in a new tab or window (H.R.7618), introduced by representatives Carol Miller (R-W.Va.) and Melanie Stansbury (D-N.M.), addresses an urgent need for better falls prevention measures for Medicare beneficiaries. The SAFE Act will allow occupational and physical therapists to administer falls risk assessments for seniors as part of their Medicare Annual Wellness benefit.

The bill will also require HHS to submit a report to Congress on the number of falls that seniors experience and the number of seniors that receive treatment each year for pain or injury related to a fall. The changes set forth in this legislation are the missing pieces that will significantly reduce the incidence of senior falls, leading to an improved quality of life for our older population and a decreased burden on the healthcare system.

The bipartisan SAFE Act is a commendable and much-needed step forward. Importantly, these assessments will be convenient and at no cost to patients. By integrating physical and occupational therapy into Medicare wellness visits, seniors can access proactive, preventive care that will help them live safely and independently.

Preventing falls among Medicare patients has become a growing public health need, and timely access to preventive care is not only beneficial -- it's imperative. Falls among older adults can lead to serious injuries, reduced quality of life, and significant healthcare costs. The CDC estimates 52 million fallsopens in a new tab or window will occur among older Americans annually by 2030, yet the current Medicare structure does not adequately cover falls risk assessments completed by true falls experts -- physical and occupational therapists.

Physical therapy won't just keep seniors on their feet and out of the hospital, it can also help them manage pain and significantly lower the need for powerful painkillers. This is important because HHS's Office of Inspector General found that approximately 52,000 Medicare beneficiariesopens in a new tab or window suffered an opioid overdose in 2022 alone. Seniors have not been spared from the overdose crisis.

While opioids will continue to play a legitimate role in recovery for some patients, they may not be appropriate for all. Some research suggests that adults who receive physical therapy may be less likely to use opioidsopens in a new tab or window for pain controlopens in a new tab or window. Just think how many older Americans could avoid the pain of falling altogether if they had a no-cost falls risk assessment.

Ultimately, the SAFE Act is a concrete step forward to addressing a problem that has been ignored for far too long. We urge lawmakers to prioritize the well-being and independence of our older adult community and recognize that preventive measures are needed to reduce costs, mitigate opioid use, and reduce fall rates.

I encourage healthcare professionals to reach out to their members of Congress to encourage them to co-sponsor the SAFE Act and support efforts to enhance access to preventive care. Doing so can help reverse the increasing number of falls and reduce opioid abuse among our older patients.

Nikesh Patel, PT,opens in a new tab or window is the executive director of the Alliance for Physical Therapy Quality and Innovation (APTQI), an organization dedicated to advocating for policies that ensure quality, accessibility, and value in the delivery of outpatient physical therapy services.

https://www.medpagetoday.com/opinion/second-opinions/109643

Reports of Unauthorized Obamacare Plan-Switching and Sign-Ups Trigger Concern

 Federal and state regulators aren't doing enough to stop the growing problem of rogue health insurance brokers making unauthorized policy switches for Affordable Care Act (ACA) policyholders, say consumers, agents, nonprofit enrollee assistance groups, and other insurance experts.

"We think it's urgent and it requires a lot more attention and resources," said Jennifer Sullivan, director of health coverage access for the Center on Budget and Policy Priorities

The CMS, which oversees the ACA, "has acknowledged the issue," said former Oklahoma insurance commissioner John Doak. "But it appears their response is inadequate."

The reactions follow a KFF Health News articleopens in a new tab or window outlining how licensed brokers' easy access to policyholder information on healthcare.gov has led unscrupulous agents to switch people's policies without express permission. Those agents can then take the commission that comes with signing a new customer. Dozens of people and insurance brokers responded to the earlier report recounting similar situations.

Some switched policyholders end up in plans that don't include their doctors or the medications they regularly take, or come with higher deductibles than their original coverage choice. If their income or eligibility for premium tax credits is misrepresented, some people end up owing back taxes.

Agents whose clients have been affected say the switches ramped up last year and are continuing into 2024, although quantifying the problem continues to be difficult. The problem seems concentrated on the federal healthcare.gov website, which is the marketplace where people in 32 states buy ACA plans, also known as Obamacare. CMS declined to provide the number of complaints that have been filed.

Even so, CMS representatives said during a December committee meeting of the National Association of Insurance Commissioners (NAIC) that they were "acutely aware" of the problem and were working on solutions.

A similar NAIC gathering was held in March. During those meetings, state regulators urged CMS officials to look for unauthorized switches, rather than reacting only to filed complaints. State regulators also want the agency to tell them sooner about agents or brokers under investigation, and to be provided with the number of affected consumers in their regions.

In an April 4 written statement to KFF Health News, Jeff Wu, acting director of CMS' Center for Consumer Information & Insurance Oversight, pointed to the agency's sharp prohibition on agents enrolling people or changing their plans without getting written or recorded consent, and said his team is "analyzing potential additional system controls to block unauthorized or fraudulent activity."

It is also working with state regulators and large broker agencies, Wu wrote, to identify "the most effective ways to root out bad actors." He also said more agents and brokers are being suspended or terminated from healthcare.gov.

Wu did not provide, however, a tally of just how many have been sanctioned.

Low-income consumers are often targeted, possibly because they qualify for zero-premium plans, meaning they might not know they've been switched or enrolled because they aren't paying a monthly bill.

Also, rules took effect in 2022 that allow low-income residents to enroll at any time of the year, not just during the annual open enrollment period. While the change was meant to help people who most need to access coverage, it has had the unintended effect of creating an opportunity for this scheme to ramp up.

"There have been bad apples out there signing people up and capturing the commissions to do so for a while, but it's exacerbated in the last couple of years, turning it from a few isolated incidents to something more common," said Sabrina Corlette, co-director of the Center on Health Insurance Reforms at Georgetown University.

Many victims don't know they've been switched until they try to use their plans -- either because agents changed the policy without talking to them or because the consumer unknowingly enrolled by responding to online advertisements promising gift cards, government subsidies, or free health insurance.

The challenge now is how federal regulators and their counterparts in the states can thwart the activity without diminishing enrollment -- a top priority for the marketplace. In fact, Obamacare's record-breaking enrollment figuresopens in a new tab or window are being touted prominently in President Joe Biden's reelection campaignopens in a new tab or window.

Thwarting the switches "really comes down to oversight and enforcement," Corlette said. "As soon as regulators identify someone who is engaged in unauthorized plan-switching or enrollment, they need to cut them off immediately."

That isn't simple.

For starters, consumers or their agents must report suspected problems to state and federal regulators before investigations are launched.

Such investigations can take weeks and states generally don't have access to complaints until federal investigators finish an inquiry, state regulators complained during the NAIC meetings.

Doak attended the December meeting, where he urged federal regulators to look for patterns that might indicate unauthorized switching -- such as policyholders' coverage being changed multiple times in a short period -- and then quickly initiate follow-up with the consumer.

"All regulators have a duty to get on top of this issue and protect the most vulnerable consumers from unknowingly having their policies moved or their information mistreated," Doak told KFF Health News. He is now executive vice president of government affairs for Insurance Care Direct, a health insurance brokerage.

Being more proactive requires funding.

Wu said the agency's administrative budget has remained nearly flat for 13 years even as enrollment has grown sharply in the ACA and the other health programs it oversees.

And the complaint process itself can be cumbersome because it can involve different state or federal agencies lacking coordination.

Even after complaints are filed, state or federal officials follow up directly with the consumer, who might have limited English proficiency, lack an email address, or simply not answer their phone -- which can stall or stop a resolution, said Katie Roders Turner, MPH, executive director of the Family Healthcare Foundation, a Tampa Bay, Florida, nonprofit that helps people enroll or deal with problems that arise with their plans.

Suggested improvements include creating a central form or portal for complaints and beefing up safeguards on the healthcare.gov site to prevent such unauthorized activity in the first place.

Currently, licensed agents need only a name, date of birth, and state of residence to access policyholder information and make changes. That information is easy to obtain.

States that run their own marketplaces -- there are 18 and the District of Columbia -- often require more information, such as a one-time passcode sent to the consumer, who then gives it to their chosen agent.

In the meantime, the frustration is increasing.

Lauren Phillips, a sales agent in Georgia, said she reached out to an agent in Florida who was switching one of her clients, asking her to stop. When it happened again to the same client, she reported it to regulators.

"Their solution was for me to just watch the policy and fix it if it happens again, which is not a viable solution, "Phillips said.

Recently, after noticing the client's policy had been switched again, she reported it and changed it back. When she checked two mornings later, the policy had been terminated.

"Now my client has no insurance at all," Phillips said. "They say they are working on solutions. But here we are in the fourth month of the year and agents and consumers are still suffering at the hands of these terrible agents."

https://www.medpagetoday.com/special-reports/features/109632