Opinion: CMS needs to do FDA’s job, limit use of Biogen’s pricey new Alzheimer’s drug

 Now that the FDA has approved Biogen’s expensive new Alzheimer’s drug with little clinical benefit potential, but plenty of potential to speed the bankruptcy of the government’s health care program for seniors, it’ll be up to the Centers for Medicare and Medicaid Services to limit payment for it and drive the conversation on access.

While such access decisions are normally reserved for the FDA, the agency abdicated its responsibility because of the wide label and because it’s allowing Biogen to take almost a decade to figure out if aducanumab actually works.

But what CMS does now will have a massive impact on the financial health and well-being of its Medicare program, especially as Aduhelm may speed Medicare’s path to insolvency, currently set for 2026.

The financial implications of Aduhelm range from daunting to downright disturbing.

As Bernstein biotech Ronny Gal pointed out, “The total cost of Medicare part B drugs was $37B in 2019, growing at 13%. This is the budget segment President Trump called ‘out of control’. If 1M patients use Aduhelm at the current price point, total Medicare part B spending would double.”

While Biogen has said they will have the manufacturing capacity to treat 1 million Alzheimer’s patients, Gal noted that the financial implications of a more realistic scenario of just half that population “is equally mind-boggling.”

If 50% of newly diagnosed patients start Aduhelm at the current price, then the total cost to Medicare will be equal to the top five drugs in Medicare Part B combined (Merck’s Keytruda, Regeneron’s Eylea, BMS’ Opdivo, Roche’s Rituxan and Amgen’s Prolia – at $10.7B based on the Medicare dashboard), according to Gal.

“We can easily see a situation where the combination of the unrestricted label and the high price could lead in-patient facilities treating severe AD patients to [get] as many of their residents on treatment as possible,” he wrote in an investor note earlier this month.

Rep. Peter Welch (D-VT) sent a letter to Biogen’s CEO Michel Vounatsos on Tuesday, noting, “In 2019, the total amount of spending for all Part B drugs was only $37 billion, so Biogen’s price for one drug and one treatment would cost nearly $20 billion more than the entire existing Medicare Part B drug program for all beneficiaries.”

The majority of Americans suffering from Alzheimer’s— more than 6 million people—are Medicare beneficiaries, Welch added, noting, “Biogen has abused the pricing power that it holds.”

So what will CMS need to do?

The centers may be tasked with instituting what’s known as a Medicare National Coverage Determination on Aduhelm, which is usually reserved for Medicare services and not new drugs. But such a determination could protect Medicare beneficiaries from FDA’s wide label, and restrict the use of the drug to only the subgroups of seniors who might benefit and who were studied in Biogen’s failed trials.

“If CMS were to use the NCD process to restrict coverage for Aduhelm beyond the FDA’s broad label for the drug, it would set a very important precedent by delinking the FDA’s decision to approve a drug from CMS’s decision to provide reimbursement for it,” Rachel Sachs, law professor at Washington University in St. Louis, wrote recently in Health Affairs.

Biden’s newly confirmed CMS administrator Chiquita Brooks-LaSure said she’s looking into all the evidence in deciding whether to make a national coverage determination.

Others are suggesting that CMS conduct its own research on paying for Aduhelm.

Peter Bach, director of the Drug Pricing Lab at Memorial Sloan Kettering Cancer Center, and Craig Garthwaite, director of the Program on Healthcare at the Kellogg School of Management at Northwestern University, called on Medicare’s research center, the Center for Medicare and Medicaid Innovation, to evaluate whether CMS should pay for the drug and whether those payments are cost-effective.

To evaluate such payments while Biogen’s 9-year confirmatory trial is ongoing, Bach and Garthwaite called on CMS to select some counties where it would reimburse Aduhelm’s current price, and others where it would reimburse $0, and see what the differences are.

“Medicare must study aducanumab reimbursement now, and prepare to do the same whenever the FDA approves other costly, important drugs that lack evidence of effectiveness,” Bach and Garthwaite wrote. “Drug companies should know that if their medicines reach the market before the evidence is in, payment will not be automatic.”

https://endpts.com/opinion-cms-needs-to-do-fdas-job-and-limit-the-use-of-biogens-pricy-new-alzheimers-drug/

Hutchmed files for $600M+ IPO in Hong Kong as lead oncology med awaits FDA eye

 In oncology, a flush of Chinese-developed drugs has the biopharma industry rethinking the poles of power in R&D as the blossoming nation continues to make a name for itself and pick up bundles of cash in the process. Now, as its lead drug faces a pivotal FDA review, the company formerly known as Chi-Med is planting its flag on home soil with a massive public offering.

Hutchmed — recently renamed from Chi-Med, or Hutchison China MediTech — will look to raise $603 million as part of a Hong Kong IPO that serves as a homecoming of sorts for the Chinese-based oncology player, which has listed on Nasdaq since 2016.

The company plans to offer up to 104 million shares at around HK$45 per share — or roughly $5.80. Hutchmed will trade under the ticker “13” on the exchange, complementing the company’s Nasdaq ticker $HCM.

Hutchmed already has a five-firm group of cornerstone investors on board in The Carlyle Group, the Canada Pension Plan Investment Board, General Atlantic, HBM Healthcare Investments and CICC Grandeur Fund, which combined have pledged to buy up $325 million worth of shares or about 54% of the offering.

The Chinese firm is currently awaiting FDA review for its oral oncology med surufatinib for non-pancreatic neuroendrocrine tumors — which Hutchmed filed for rolling submission in May. The drug previously scored a fast track designation with the agency in April.

According to a prospectus filed with the exchange, Hutchmed intends to use 50% of the proceeds to advance late-stage trials with that drug, marketed as Sulanda in China, as well as Eli Lilly-partnered colorectal cancer drug fruquintinib, marketed as Elunate; AstraZeneca-partnered investigational MET inhibitor savolitinib; and candidates HMPL-689 and HMPL-523, which are PI3K and SYK inhibitors, respectively, for blood cancers.

The rest of the proceeds will be divvied up between BD, advancing the early pipeline, corporate strategy and internal hires, Hutchmed said.

Hutchmed was the first Chinese company to bring an in-house oncology drug to market in that country with fruquintinib, which was approved as a third-line therapy for metastatic CRC. Surafatinib hit the Chinese market in January 2021 for non-pancreatic NET and savolitinib is up for Chinese review with a potential launch expected within weeks.

With its Chinese drug discovery engine in full swing — seven other candidates are sweeping through preclinical and early human studies — Hutchmed has looked to break into the US market, where only BeiGene’s Brukinsa has earned an approval as a Chinese-developed oncology drug. Surufatinib is the furthest along in that effort, but both fruquintinib and savolitinib have started registrational studies stateside.

With a potential approval expected in the coming months, Hutchmed has already started building out a commercial team for surufatinib. The company is already at 1,300 employees spread across its global enterprise.

The rise of oncology drug development has injected a new challenger into the global marketplace and begun to shift the poles of power in R&D in that space. Companies like Samantha Du’s Zai Lab and Junshi Biosciences have earned a reputation as oncology specialists in China and have earned massive public raises to show for it.

In September, Zai Lab closed a $761 million Hong Kong IPO to drive its in-licensing business model and then followed that up with a $750 million offering in US depository shares in April. The company specializes in taking in-licensed oncology drugs to market, and recently signed a deal with Mirati to market investigational KRAS inhibitor agrositinib in the Greater China area.

Junshi, meanwhile, closed its own $450 million Hong Kong IPO back in January 2019 as part of its push to bring its own in-house PD-1 drug toripalimab to market alongside international partner Coherus. The partners read out Phase II data at this year’s ASCO showing a significant improvement in PFS for a toripalimab-chemo combo over chemo alone in patients with nasopharyngeal cancer, a disease that affects Southeast Asians at a proportionally higher rate.

That study, dubbed JUPITER-02, would be the first solely Chinese-run pivotal trial to win an FDA approval, if it crosses the finish line.

https://endpts.com/hutchmed-files-for-600m-ipo-in-hong-kong-as-lead-oncology-drug-surufatinib-awaits-fdas-good-graces/

Latest data on immune response to COVID-19 reinforces need for vaccination

 New research has found that previous infection, whether it was symptomatic or asymptomatic, does not necessarily protect you long-term from COVID-19, particularly against new Variants of Concern.

The preprint study was led by University of Oxford, in collaboration with the Universities of Liverpool, Sheffield, Newcastle and Birmingham with support from the UK Coronavirus Immunology Consortium.

The "Protective Immunity from T cells to COVID-19 in Health workers" (PITCH) study examined how the immune system responds to COVID-19 in 78 healthcare workers who had experienced either symptomatic or asymptomatic disease (66 vs 12). An additional 8 patients who experienced severe disease were included for comparison.

Blood samples were taken monthly from 1–6 months post infection to examine different elements of the immune response. This included different types of antibodies—such as Spike-specific and Nucleocapsid-specific antibodies which are produced to target different parts of the virus, alongside B cells, which manufacture antibodies and keep the body's memory of the disease, and several types of T cell.

The preprint report details a highly complex and variable immune response following COVID-19 infection. The University of Liverpool's Dr. Lance Turtle is a co-author on the study, which has been posted on Research Square.

The researchers used a new machine learning approach—nicknamed SIMON—to identify detailed patterns in the data and to see if initial disease severity and the early immune response could predict longer-term immunity.

They found an early immune signature, detectable one month post infection and linked to both cellular and antibody immunity, which predicted the strength of immune response measured at 6 months post infection. This is the first time that such a signature has been found and improves understanding of the development of lasting immunity. When serum samples (containing antibodies) obtained at 1 and 6 months post infection were tested, the majority of samples from people who produced a weak immune response signature failed to show any neutralizing antibodies against the Alpha variant, with none mounting a neutralizing antibody response against the Beta variant. This raises the possibility that the immune memory of these individuals does not provide sufficient protection to prevent reinfection by these variants.

While the majority of people who had symptomatic disease did have measurable immune responses at six months post infection, a significant minority (17/66; 26%) did not. The vast majority of people who experienced asymptomatic disease (11/12; 92%) did not exhibit a measurable immune response at six months post infection. This implies that people who have previously been infected with COVID-19 should not assume they are automatically protected against reinfection and highlights the importance of everyone getting their COVID vaccination when they are offered it.

Health Minister Lord Bethell said: "This powerful study addresses the mysteries of immunity and the lessons are crystal clear. You need two jabs to protect yourself and the ones you love. I call on anyone invited to get vaccinated to step forward and finish the job so we can all get out of this."

Key findings from the PITCH study:

• Immune memory following COVID infection is measurable at 6 months but is highly variable between people.
• Previous infection does not necessarily protect you long term from SARS-CoV-2, particularly variants of concern Alpha and Beta. Individuals who show little or no evidence of immune memory to COVID at 6 months post infection are not able to neutralize the variants of concerns.
• We can use the immune response characteristics at one month post COVID infection to predict which people will have durable immune responses at six months.
• People with COVID symptoms have variable immune responses that may decline over time and are not necessarily protected from SARS-CoV-2 variants.
• People who experienced asymptomatic infection tend to have lower immune responses across the many immune parameters we have measured.

Understanding the strength and durability of the immune response to natural COVID infection remains highly relevant as it will help us reduce reinfections, better understand immune responses to vaccination and tackle new variants of concern. Further research will continue to deepen our understanding of the immune responses over the longer term and what it means for protection against COVID-19 in the real world.

This study reinforces how important it is that everyone gets their COVID vaccination when offered. COVID-19 vaccines generate higher immune responses than natural infection, underlining the need for everyone to get vaccinated for maximum protection against this disease and in particular against Variants of Concern.

---

Explore further

Scientists find new way of predicting COVID-19 vaccine efficacy

---

More information: Adriana Tomic* et al, Divergent trajectories of antiviral memory after SARS-Cov-2 infection, medRxiv (2021). DOI: 10.21203/rs.3.rs-612205/v1

https://medicalxpress.com/news/2021-06-latest-immune-response-covid-vaccination.html

Will reduction in tau protein protect against Parkinson's, Lewy body dementias?

 A new study, published in the journal eNeuro, suggests the answer is no. If this is borne out, that result differs from Alzheimer's disease, where reducing endogenous tau levels in brain neurons is protective for multiple models of the disease—which further suggests that the role of tau in the pathogenesis of Lewy body dementias is distinct from Alzheimer's disease.

Both Parkinson's disease dementia and Lewy body dementia are characterized by intracellular aggregates of misfolded alpha-synuclein protein in brain neurons, and the two diseases together are the second most common cause of neurodegenerative dementia after Alzheimer's.

University of Alabama at Birmingham researchers, led by Laura Volpicelli-Daley, Ph.D., associate professor of neurology, used a Parkinson's disease model she developed 11 years ago. Volpicelli-Daley applies very low concentrations of altered alpha-synuclein, which has taken on a pathologic conformation, to either in vitro or in vivo neurons. The nerve cells take up some of the fibrils. Inside the cells, the altered alpha-synuclein acts as a seed to attract the soluble alpha-synuclein that is naturally present in neurons. This transforms soluble alpha-synuclein into pathological, insoluble aggregates that impair neuron function and lead to cell death. These modified alpha-synuclein inclusions share morphology with those found in the Parkinson's disease brains after death.

This disease model—termed templated alpha-synuclein inclusion formation—was used to compare neurons that produce the normal amount of tau protein, against mutant neurons that lack one or both genes for tau, and thus have less or no tau protein. If endogenous tau contributes to disease progression, the heterozygous or knockout tau mutants were expected to show protection. However, the UAB researchers found no difference from the wild-type control.

In their results, the researchers first showed that there was indeed an interaction between tau and alpha-synuclein in the cells—both proteins localized in presynaptic terminals of primary culture neurons, and in the cortex of the mouse brain, which is consistent with previous findings from preparations of human brains, and with several in vitro studies showing that the two proteins interact with each other.

However, the reduction or complete absence of tau did not prevent fibril-induced alpha-synuclein inclusion formation in primary hippocampal neurons growing in vitro. In mice, reduction or absence of tau also did not prevent fibril-induced alpha-synuclein formation in the motor control or limbic areas of the brain, including the cortex, amygdala, hippocampus and the substantia nigra pars compacta, as measured six weeks or six months after fibril injections.

Finally, while the alpha-synuclein fibrils in the mouse model caused the death of half of the wild-type neurons that produce the neurotransmitter dopamine, the dopaminergic neurons in tau-heterozygous or tau-knockout mice showed the same amount of neuron death, which meant no protection. In addition, reducing tau did not have any major impact on behavioral phenotypes of mice with fibril-induced α-synuclein inclusions.

"Here, we have shown that reduction of endogenous tau did not influence formation of templated alpha-synuclein inclusion formation or the loss of dopamine neurons," Volpicelli-Daley said. "This suggests that therapeutics directed to tau for Parkinson's disease may be more complicated than tau reduction. This is unlike Alzheimer's disease, where tau reduction has been suggested as a possible therapy."

---

Explore further

Discovery may lead to a treatment to slow Parkinson's disease

---

More information: eNeuro, DOI: 10.1523/ENEURO.0458-20.2021

https://medicalxpress.com/news/2021-06-reduction-tau-protein-parkinson-lewy.html

Biological links between red meat and colorectal cancer

 Eating less red meat is standard medical advice for preventing colorectal cancer, but the way it causes cells to mutate has remained unclear, and not all experts were convinced there was a strong link.

A new paper in the journal Cancer Discovery has now identified specific patterns of DNA damage triggered by diets rich in red meat—further implicating the food as a carcinogen while heralding the possibility of detecting the cancer early and designing new treatments.

Prior research establishing the connection was mainly epidemiologic, meaning that people who developed the condition were surveyed on their eating habits, and researchers spotted associations with colorectal cancer incidence.

But a lack of clarity around the biology meant that the case wasn't quite slam dunk, and in 2019, one team of researchers made waves when they declared they only had a "low" degree of certainty that reducing consumption would prevent cancer deaths.

"When we say red meat is carcinogenic, and that it impacts incidence of cancer, there has to be some plausible way by which it does it," Dana-Farber Cancer Institute oncologist Marios Giannakis, who led the new study, told AFP.

After all, scientists discovered long ago which chemicals in cigarette smoke are to blame for cancer, and how certain bands of UV light penetrate the skin and trigger mutations in genes that control how cells grow and divide.

To address the knowledge gap, Giannakis and his colleagues sequenced DNA data from 900 patients with colorectal cancer, who were drawn from a much larger group of 280,000 health workers participating in a years-long studies that included lifestyle surveys.

Detective work

The strength of this approach is that the people documenting their diet had no way of knowing of their future cancer diagnosis, rather than asking people to recall their eating habits after they became ill.

The analysis revealed a distinct mutational signature—a pattern that had never before been identified but was indicative of a type of DNA damage called "alkylation."

Not all cells that contain these mutations will necessarily become cancerous, and the signature was present in some healthy colon samples too.

The mutation signature was significantly associated with intake of red meat, both processed and unprocessed, prior to the patient's diagnosis of cancer, but not with the intake of poultry, fish or other lifetsyle factors that were examined.

"With red meat, there are chemicals that can cause alkylation," explained Giannakis.

The specific compounds are nitroso compounds that can be made from heme, which is plentiful in red meat, as well as nitrates, often found in processed meat.

The mutation patterns were strongly associated with the distal colon—the lower part of the bowels that leads to the anal canal, which is where past research suggested colon cancer linked to red meat mostly occurs.

What's more, among the genes that were most affected by the alkylation patterns were those that previous research has shown are among the most common drivers of colorectal cancer when they mutate.

Taken as a whole, the multiple lines of evidence build up a compelling argument, said Giannakis, likening the research to careful detective work.

Moderation urged

In this case, the suspicious mutation signature has a lot to answer for: patients whose tumors had the highest levels of alkylation damage had a 47 percent greater risk of colorectal cancer-specific death, compared to patients with lower levels of damage.

But Giannakis, also a practicing doctor, said it was important to focus on how the research can be used to help patients.

Future work might help physicians identify which patients are genetically predisposed to accumulating alkylation damage, then counsel them to limit their red meat intake.

Identifying patients who have already started to accrue the mutational signature could help identify who's at greater risk of developing cancer, or catch the disease at an earlier stage.

And because the amount of alkylation damage appears to be a biomarker of patient survival, it could possibly be used to tell patients about their prognosis.

Finally, understanding the biological pathway through which colorectal cancer occurs paves the way for medicines that interrupt or reverse the process, preventing the disease.

Giannakis stressed the takeaway message is not that people should totally abstain from red meat: "My recommendation would be that moderation and a balanced diet is key."

High levels of tumor alkylation damage were only seen among patients eating on average more than 150 grams (five ounces) a day, roughly equal to two or more servings.

---

Explore further

Red meat consumption may promote DNA damage-associated mutations in patients with colorectal cancer

---

More information: Carino Gurjao et al, Discovery and features of an alkylating signature in colorectal cancer, Cancer Discovery (2021). DOI: 10.1158/2159-8290.CD-20-1656

https://medicalxpress.com/news/2021-06-biological-links-red-meat-colorectal.html

Vaccines pivotal in war on COVID-19, but better treatments for acute COVID patients critical

 The COVID-19 pandemic has been cataclysmic for much of the planet, and the SARS-CoV-2 virus, which causes it, is far from finished with us. 

After earlier good control of the pandemic, Taiwan, Singapore and other countries are experiencing a surge, and India is facing a catastrophe, with millions of deaths counted already and the nation’s healthcare system devastated. 

In spite of the progress in suppressing the spread of COVID-19 in the U.S., U.K. and some other countries, primarily through remarkably effective vaccines and non-pharmaceutical interventions, such as masking, social distancing, and good hygiene, it seems likely that COVID-19 will not in the foreseeable future completely disappear but will become endemic, with seasonal variation, similar to influenza. 

Because people will continue to fall ill, there will be an ongoing need for treatments, which are currently in short supply. Although some moderately effective drugs are already being used, new treatments are needed to treat severe COVID-19 infections. 

The anti-viral drug remdesivir, which binds to the virus’s RNA-dependent RNA polymerase and inhibits viral replication, is currently the only drug that is approved by the FDA for the treatment of COVID-19. It is recommended for use in hospitalized patients who require supplemental oxygen.

The corticosteroid dexamethasone has been found to improve survival in hospitalized patients who require supplemental oxygen, with the greatest benefit observed in patients who are on ventilators. Adding the monoclonal antibody tocilizumab to dexamethasone therapy was found to improve survival among patients who were exhibiting rapid respiratory deterioration due to COVID-19.

In outpatients with mild to moderate COVID-19 who are at high risk for disease progression, anti-SARS-CoV-2 antibody-based therapies may have the greatest potential for a clinical benefit during the earliest stages of infection.  For these patients, a panel of NIH experts recommends administering monoclonal antibodies bamlanivimab plus etesevimab or casirivimab plus imdevimab, both of which are available through Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA).

Other analogous approaches that via various mechanisms blunt the activity of the immune response are promising. 

One of these attempts to therapeutically modulate the activity of an often-overlooked system called the lectin pathway, a part of the body’s complement system that helps the immune system respond to infection. When over-activated, as happens with severe COVID-19, it can lead to an uncontrolled cascade of inflammation, endothelial damage, dangerous blood clots, and “cytokine storm,” which can, in turn, lead to severe respiratory distress, organ failure, and death.

Once the coronavirus reaches the lungs, it soon infects the surrounding blood vessels, damaging the endothelial cells lining the vessels. This endothelial damage results in a triad of inflammation, complement activation, and excessive clotting responsible for the pathophysiology of COVID-19.

At the nexus of these three pathways sits MASP-2, the key enzyme in the lectin pathway. Endothelial injury activates MASP-2 and the lectin pathway, driving inflammation and hypercoagulation, which leads to organ-damaging thrombi or clots. In COVID-19, activation of the lectin pathway is a very early event, occurring prior to hyperinflammation and the innate antibody response. Lectin pathway activation causes further endothelial damage, initiating a positive feedback loop with further activation of systemic inflammation and clotting. 

A monoclonal antibody called narsoplimab blocks the MASP-2 enzyme and is, thus, an inhibitor of the lectin-pathway. Narsoplimab has shown impressive responses in advanced clinical trials for several illnesses marked by endothelial cell injury, and because similar pathophysiology is found in COVID-19 infections, it has been tested in a small number of infected patients, with promising results.  

The largest study, conducted in Italy in six severely ill COVID-19 patients, concluded: (1) “[n]arsoplimab down-modulates SARS-CoV-2-induced activation of the lectin pathway and endothelial cell damage”; (2) “[n]arsoplimab can reduce the thrombotic risk of Covid-19 patients”; and (3) [a]ll patients treated with narsoplimab improved and survived without any drug-related adverse events.”  This was a far better result than would have been expected, based on retrospective control groups.

Narsoplimab is only one example of the frenzy of clinical research on various treatment protocols for COVID-19, including the use of drugs, new and repurposed. This is critical, especially if new variants of SARS-CoV-2 emerge that are not effectively combated by existing vaccines.

Henry I. Miller is a physician, molecular biologist and senior fellow at the Pacific Research Institute. He was the founding director of the FDA’s Office of Biotechnology.

https://www.fiercehealthcare.com/hospitals/industry-voices-vaccines-are-pivotal-war-covid-19-but-better-treatments-for-acute-covid

Agilon Health Earns Relative Strength Rating Upgrade; Hits Key Benchmark

The Relative Strength (RS) Rating for Agilon Health (AGL) entered a new percentile Wednesday, with an increase from 77 to 82.

This unique rating tracks market leadership by using a 1 (worst) to 99 (best) score that shows how a stock's price performance over the last 52 weeks matches up against other publicly traded companies.

Decades of market research shows that the stocks that go on to make the biggest gains tend to have an RS Rating north of 80 in the early stages of their moves.

Agilon Health is now considered extended and out of buy range after clearing a 34.23 buy point in a first-stage ipo base. See if the stock forms a new pattern or follow-on buying opportunity like a three-weeks tight or pullback to the 50-day or 10-week line.

The company reported -50% earnings growth in its most recent report. Revenue increased 42%.

The company earns the No. 6 rank among its peers in the Commercial Services-Healthcare industry group. Corvel (CRVL) and Vocera Communications (VCRA) are also among the group's highest-rated stocks.

https://www.investors.com/ibd-data-stories/agilon-health-earns-relative-strength-rating-upgrade-hits-key-benchmark/