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Friday, May 6, 2022

PBMs Under Fire at Senate Hearing

 The role of pharmacy benefit managers (PBMs) in the drug supply chain and whether "anti-competitive" practices are driving up healthcare costs was scrutinized by the Senate on Thursday.

PBMs are just one player in a "broken supply chain" explained Richard Blumenthal (D-Conn.), during a Thursday hearing of the Senate Subcommittee for the Committee on Commerce, Science, and Transportation.

As middlemen, PBMs are hired by health plans to manage prescription drug benefits and, in theory, to keep costs to the health plan low by negotiating rebates with drug companies, he said.

"The problem is that patients rarely see or feel the benefits," said Blumenthal, chair of the subcommittee. "Drug prices continue to rise. Insurance costs continue to eat into incomes, and more and more often, drugs patients need are not covered by their healthcare plan at all."

One reason patients may not be reaping the benefits of PBM negotiations is that PBMs are incentivized to keep "list prices" -- the initial price of a drug set by the manufacturer -- high. PBMs receive their rebates based on the list price and get to keep a portion of those rebates; therefore the higher a drug's initial price, the more PBMs profit, Blumenthal said.

Robin Feldman, JD, professor and researcher at UC Hastings College of the Law in San Francisco and a witness at the hearing, likened PBM practices to a store that raises the price of a jacket before later putting it back on sale at the original price. A customer walking into the store may see the markdown as a bargain, but it isn't.

But that's not the worst part, she said. "Imagine if the price jump is higher than the sale discount. That's what's happening with medicine. Prices are rising faster than the rebates," she said, noting that Medicare prices for pharmaceuticals after rebates rose 313% on average from 2010 to 2017.

"We are buying the same jacket, but it's costing us more and more," Feldman said, "and a significant portion of that increase is going to the PBMs."

Another reason these high list prices matter, even though most consumers do not pay them, is that most commercial insurers and the Medicare program base patients' out-of pocket payments on the list price itself, not the price after rebates, Blumenthal said.

PBMs may argue that those rebates are funnelled through to insurers and ultimately lower patients' healthcare costs, but "we have no idea whether this is accurate, because PBMs shroud this information in secrecy," he added.

PBMs are "probably one of the least regulated areas of the drug supply chain," said David Balto, JD, an antitrust attorney for David A. Balto Law Offices and a witness at the hearing, citing a lack of enforcement, particularly from the Federal Trade Commission (FTC).

This lack of enforcement has allowed PBMs to form a "tight oligopoly" in which three firms "dominate the market" giving them the opportunity to act anti-competitively, he said. For instance, by forcing pharmacies to "reimburse below cost" or denying a generic drug access to a health plan's formulary because the manufacturer isn't offering the kinds of rebates that brand name drugs provide. He compared the PBMs' process of determining a formulary to "an auction for shelf space in which ... the highest-cost products to the consumer is going to win the auction."

Blumenthal noted that "hundreds of drugs" have been excluded by the largest PBMs every year -- ranging from certain types of insulin, to cancer drugs, to medications for other chronic conditions.

"The PBM industry is the only stakeholder in the chain dedicated to seeking lower costs, and we are proud to play that role," said J.C. Scott, president and CEO of the Pharmaceutical Care Management Association. "PBMs do that work for the employer, union health plan, and government clients who hire them and most importantly, the patients for whom those plans provide coverage."

He argued that PBMs return $10 in savings for every $1 dollar spent on their services and "will lower the cost of health care by $1 trillion this year alone."

One witness, Craig Garthwaite, professor and director of the Program on Healthcare for the Kellogg School of Management at Northwestern University in Chicago, also defended PBMs by arguing that in the past they offered contracts to health plans that would pass rebates to consumers at the point-of-sale. But such contracts were "routinely ignored," he said, "in favor of capturing high rebates."

He acknowledged that PBMs "do appear to be exploiting a lack of transparency" in the market. However, he stressed that there are ways to improve transparency and that "if we are worried about high list prices leading to high cost-sharing, we should attack that directly through congressional action."

Ranking Member Marsha Blackburn (R-Tenn.) introduced a bill, the Pharmacy Benefit Managers Accountability Study Act alongside Sen. Mike Braun (R-Ind.) that would require the Government Accountability Office to produce a report for both HHS and Congress focused on PBMs' role in the drug supply chain and encouraged her colleagues to support the bill.

Blackburn, Blumenthal, and the full Senate Commerce Committee Chair Maria Cantwell (D-Wash.) also sponsored a bill last year directing the FTC to report to Congress on anti-competitive practices in the supply chain.

In response to questions from Blumenthal regarding the bill, Scott said on behalf of his group representing PBMs that if the FTC were required to examine the drug supply chain, "we would not be opposed to that study."

https://www.medpagetoday.com/washington-watch/washington-watch/98574

Atypical Antipsychotics Linked to Lower Odds of COVID

 Second-generation antipsychotics appeared to curb COVID-19 infection in those with serious mental illness, a retrospective study showed.

Looking at adults hospitalized long-term in the New York psychiatric system in 2020, those taking any agent in the class of second-generation antipsychotic medications, also known as atypical antipsychotics, had a 38% lower chance of infection (OR 0.62, 95% CI 0.45-0.86), reported Donald C. Goff, MD, of the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, and colleagues in JAMA Network Open.

After adjusting for age and sex, lower odds of infection were seen in association with use of:

  • Clozapine: OR 0.79 (95% CI 0.64-0.98)
  • Paliperidone: OR 0.59 (95% CI 0.42-0.81)
  • Risperidone (Risperdal): OR 0.67 (95% CI 0.53-0.86)
  • Olanzapine (Zyprexa): OR 0.70 (95% CI 0.58-0.86)

After full adjustment for sociodemographic factors, use of paliperidone remained associated with a lower chance of infection (OR 0.59, 95% CI 0.41-0.84).

In an accompanying commentary, Benedetta Vai, PhD, of IRCCS San Raffaele Scientific Institute, and Mario Gennaro Mazza, MD, of Università Vita-Salute San Raffaele in Milan, noted that atypical antipsychotics "appear to be a safe and good treatment option" for those with serious mental illnesses.

These findings are particularly encouraging for clozapine, as there have been concerns about this agent acting as a risk factor for pneumonia and having other potential toxic effects during acute infection, Goff and team noted.

"Clozapine is unique among antipsychotics in its ability to enhance the T helper cell type 1 response that supports antiviral immune response and is blunted in schizophrenia," they explained, adding that additional research is needed to determine if clozapine may actually offer protection against severe COVID infection.

However, the study also showed that mood stabilizers were associated with increased odds of COVID infection (OR 1.23, 95% CI 1.03-1.47). Among the moods stabilizers studied -- valproic acid, lithium, and lamotrigine -- valproic acid appeared to drive this increased risk (OR 1.39, 95% CI 1.10-1.76).

As for the first-generation (or "typical") antipsychotics, haloperidol, fluphenazine, and chlorpromazine, only chlorpromazine was associated with decreased infection after adjusting for age and sex (OR 0.59, 95% CI 0.40-0.86).

No agents in any class were linked with COVID-related mortality. However, Goff and colleagues pointed out that this may have been due to an insufficient sample size. COVID-related mortality appeared to be lower among patients on an antidepressant, including sertraline, citalopram, and escitalopram, although this link wasn't statistically significant.

"The potential harms and benefits associated with several psychotropic medications have been explored in preclinical and clinical studies since the start of the COVID-19 pandemic, but, to our knowledge, this is the largest study to systematically assess associations between the use of individual medications and the risk of COVID-19 infection among inpatients with serious mental illness," the authors wrote.

This population is particularly vulnerable, as nearly half of the patients in this cohort contracted laboratory-confirmed COVID -- 969 of 1,958 patients. Furthermore, infection-related mortality was more than four times higher than the general New York population during this same time period, Goff and team highlighted.

They noted that it's important to bear in mind that this study time frame took place during the first pandemic peak in New York, and as such, interventions to curb transmission weren't yet implemented.

The patients included in the analysis were continuous inpatients at 18 New York State Office of Mental Health psychiatric hospitals from March 8 to July 1, 2020. Of the 969 inpatients with confirmed infections, 3.9% died. Mean age was 51.4, and 74% were men.

Among all inpatients, 46.5% had an affective psychotic disorder, including schizoaffective disorder, bipolar I disorder, or major depressive disorder with psychotic features. The rest of the cohort had schizophrenia, delusional disorder, or schizotypal disorder.

Most patients were taking multiple psychotropic medications at the time. Of the total cohort, 61.2% were on a first-generation antipsychotic, 91.6% were on a second-generation antipsychotic, 53.3% were on a mood stabilizer, 51.9% were on benzodiazepines, and 27.9% were on antidepressants.

One limitation to the study was that medication adherence wasn't directly measured, although it was likely high due to the fact that all individuals were inpatients.

Because this study only looked at those in an inpatient setting, commentators Vai and Mazza said future research should focus on patients with serious mental illness in outpatient settings, as these patients may face higher risks since they aren't under close constant medical supervision.


Disclosures

Goff reported no disclosures. Co-author Lindenmayer reported relationships with Roche, Takeda, Lundbeck, Avanir, GW/Jazz, Neurocrine, and the National Institute of Mental Health, and has a patent for the Structured Clinical Interview for the Positive and Negative Syndrome Scale.

Vai reported grants from the Italian Ministry of Health.

What Do We Know About Paxlovid Rebound?

 It's not yet clear exactly how often it happens, but doctors are confident they're observing relapses after 5-day courses of nirmatrelvir/ritonavir (Paxlovid) for COVID-19.

Paul Sax, MD, clinical director of infectious diseases at Brigham and Women's Hospital in Boston, said most rebound cases he's seen have been mild, "but some, anecdotally, have been severe."

And even though COVID-19 has been associated with biphasic illness since the beginning of the pandemic, rebound with nirmatrelvir/ritonavir looks different, he said.

"I do think, though, that in these rebound cases, they have such a striking diminution in their symptoms, accompanied by clearance on home antigen tests, that at least part of the explanation for their biphasic illness must be nirmatrelvir acting as an antiviral," Sax told MedPage Today.

Despite widespread clinical observation, there have been less hard data on the phenomenon. Although it wasn't reported in the New England Journal of Medicine publication of nirmatrelvir/ritonavir data from the EPIC-HR trial, data submitted by Pfizer to the FDA (see pages 22-23) showed that "several subjects appeared to have a rebound in SARS-CoV-2 RNA levels around Day 10 or Day 14."

Pfizer also told NBC News that about 2% of participants in that trial experienced a rebound, compared with about 1.5% of those on placebo.

There's also a preprint case report from clinicians at the Boston VA involving a 71-year-old vaccinated and boosted patient who had a rapid and complete resolution of symptoms within two days of taking nirmatrelvir/ritonavir -- only to have a rebound a week later. Rebound symptoms were lesser, and resolved after two days, but the patient had clear peaks in viral load on day 1 and day 9, and no other respiratory pathogens were detected, Michael Charness, MD, and colleagues reported.

Fortunately, sequencing didn't reveal any treatment-emergent mutations, nor was there infection with a different subvariant, they reported. That's consistent with Pfizer data showing no evidence of resistance in rebound cases in preliminary analyses from EPIC-HR, according to the documents submitted to FDA.

But Sax warned that "we know in general with anti-infective treatments that are not completely effective at eradicating infection -- I'm thinking of our immunocompromised hosts -- there is potential to develop resistance, so that's something that will need to be carefully monitored."

There are many plausible explanations as to why rebound can occur. Antiviral treatment may blunt a helpful immune response, Sax said. It could also be that some people may be prone to prolonged viral replication and thus destined to rebound after 5 days, and those ideas aren't mutually exclusive, he said. It's also unknown if rebound has anything to do with not completing the full course of therapy.

Better monitoring is needed, and fast, Sax said. Prospective observational trials can be organized relatively quickly, and large health systems like Geisinger, Kaiser, or the VA can examine their existing data. There may also be a need for randomized controlled trials to figure out how best to treat patients who relapse, he said.

In an email to MedPage Today, a Pfizer spokesperson said the company "continue[s] to monitor data from our ongoing clinical studies and post-authorization safety surveillance," but did not provide additional details on those assessments.

When asked about treatment duration, the Pfizer spokesperson said the 5-day course was "based on observations from the treatment of acute respiratory viral infections (e.g., [Xofluza] for influenza, remdesivir for hospitalized SARS-CoV-2, etc.) that showed a 5-day treatment duration to be adequate, with little evidence suggesting increased benefit of longer treatment durations."

"Based on these prior observations, the decision was made to evaluate a 5-day treatment course in EPIC-HR," the spokesperson stated, noting that results from the trial indicate the 5-day course was sufficient for the majority of patients. "There may be some patient populations who may benefit from longer durations of treatment, and we are considering additional studies to evaluate this in some populations."

In the meantime, clinicians are getting conflicting advice on how to proceed if a patient has a rebound. Pfizer CEO Albert Bourla told Bloomberg that patients who relapse can take another course of the antiviral.

The FDA, however, said earlier this week in a statement from John Farley, MD, MPH, director of the Office of Infectious Diseases at the Center for Drug Evaluation and Research, that there's no evidence of benefit for repeating a treatment course in people who relapse.

Sax said he would limit re-treatment with a second course to the most immunocompromised and vulnerable patients, because "without data, we don't know if we're doing good or if we're doing harm."

Patients who relapse and have symptoms and a positive antigen test need to behave as if they're contagious and can transmit the virus to others, he added.

Sax also said he's added a disclosure when he prescribes nirmatrelvir/ritonavir, telling patients they may experience a relapse after their treatment course.

"I prescribed Paxlovid this morning and part of my counseling now is that this can happen," he said. "I think it's important that clinicians remember to tell people this can happen."

https://www.medpagetoday.com/special-reports/exclusives/98584

Medicare Beneficiaries 'Need More Help Navigating the Program'

 More needs to be done to help Medicare beneficiaries -- especially low-income beneficiaries -- navigate their participation in the program, several experts said Friday.

"Low-income Medicare beneficiaries navigate complex and fragmented sources of insurance coverage ... not just within Medicare, between the choice of a Medicare Advantage plan or traditional Medicare, but also from the patchwork of programs that supplement Medicare and help to lower out-of-pocket costs for low-income individuals," which include Medicaid, said Eric Roberts, PhD, of the University of Pittsburgh School of Public Health.

"The additional eligibility rules for these programs are restricted, and they exclude many people with low to moderate incomes from assistance," Roberts explained during a webinar presented by the Alliance for Health Policy and sponsored by the Commonwealth Fund and Arnold Ventures.

One big problem for low-income beneficiaries is that there are no limits in the program for out-of-pocket costs, said Tricia Neuman, executive director of the Program on Medicare Policy at the Kaiser Family Foundation.

For example, "Medicare doesn't have an out-of-pocket cap on Part D prescription drugs," she said. "That's something that has been talked about a lot in the past couple of years, and it's something that was included in the Balanced Budget Act that has passed the House and is now stalled in the Senate."

Neuman pointed out that this raises "serious concerns," particularly for those prescribed very high-cost specialty drugs. Plus, she added that Medicare generally doesn't cover costly long-term services and supports.

"Dental services are not generally covered, and hearing and routine eye exams are not covered -- all of which have been subject to some policy discussion, but none of which have made it across the finish line," she said.

As a result of all the coverage gaps, the average Medicare beneficiary pays $6,150 annually out-of-pocket on premiums and services. For those 85 and older, that amount nearly doubles to $12,063 annually.

More and more Medicare beneficiaries are enrolling in Medicare Advantage, for several reasons, noted Neuman. For instance, these plans often offer extra benefits that traditional Medicare doesn't cover, such as eye exams or fitness programs. Also, "you get all [the benefits] in one, and you don't need a supplemental plan [or] a separate Part D [drug] plan," she said, and added that these plans also tend to have low payments.

However, there are tradeoffs to Medicare Advantage that beneficiaries often are not aware of, such as a restricted provider network. There may also be prior authorization restrictions which don't apply to traditional Medicare. "There is also cost-sharing for services that may or may not matter to people when they're healthy, but could be an issue for people when they're sick," she said.

Finally, if people leave Medicare Advantage and go back to traditional Medicare, they frequently can't buy a Medigap policy -- also known as Medicare Supplement Insurance -- because they have a preexisting condition. "The 'guaranteed issue' protections that people know a lot about thanks to the Affordable Care Act do not apply to Medigap, so people with preexisting conditions in almost all states can be denied a plan," Neuman explained.

And despite lower premiums for some plans, a higher percentage of Medicare Advantage enrollees -- 19% -- reported cost-related problems compared with only 15% of enrollees in traditional Medicare. The lower percentage for the latter group was likely due to their supplemental coverage; in fact, 30% of traditional Medicare enrollees who didn't have a supplemental plan reported cost-related problems. "These are trends that we are watching and they are important because as Medicare spending continues to rise, out-of-pocket costs will continue to be a serious concern," she said.

On a more positive note, there is evidence that Medicare can shrink racial and ethnic gaps in access to care, said Loren Saulsberry, PhD, of the University of Chicago Department of Public Health Sciences. She cited a 2021 JAMA Internal Medicine study led by Jacob Wallace, PhD, of the Yale School of Public Health, which found that eligibility for Medicare at age 65 years was associated with reductions in racial and ethnic disparities in insurance coverage, access to care, and self-reported health.

However, Saulsberry explained that while Medicare may improve these outcomes in some ways, "it's not quite bringing all populations to parity."

Procedural issues also cause problems for Medicare beneficiaries, according to Lindsey Copeland, JD, director of federal policy at the Medicare Rights Center. Although people who start taking Social Security at age 65 are notified of their eligibility for Medicare, those who take Social Security later -- which includes an increasing number of beneficiaries -- are not notified.

"As a result, many people bear the full burden of navigating Medicare's complex enrollment process alone, often to disastrous effect," due to Medicare's late enrollment penalty, she said.

For example, if someone waited until 7 years after they first became eligible for Medicare to sign up, "they must pay 70% more every month for as long as they have Medicare, amounting to a lifetime penalty," said Copeland. "An example for 2022 would be since the base Part B premium this year is $170.10, their monthly premium with a penalty would be $289.17."

Currently, an estimated 776,2000 people are paying a late enrollment penalty, she said.

"Financial challenges, along with rising healthcare costs including prescription drug costs, antiquated program rules, and burdensome administrative requirements can make it difficult for many beneficiaries to obtain the care they need," Copeland concluded. "It's really critical that policymakers step in to help reduce these barriers to care."

https://www.medpagetoday.com/practicemanagement/reimbursement/98603

CDC still unsure on cause of child hep, issues new adenovirus test guides

 The Centers for Disease Control and Prevention (CDC) is issuing new guidance to clinicians on testing for adenovirus in children as the cause behind the recent cases of pediatric hepatitis around the world remains uncertain.

During a press briefing on Friday, CDC Deputy Director for Infectious Diseases Jay Butler shared an update on the hepatitis cases that have been found in children in the U.S. According to the most recent data, 109 children across 25 states and territories have been found to have hepatitis due to an unknown cause.

Ninety percent of the children were hospitalized, 14 have had to have liver transplants and five have died. The CDC was unable to share in which states the deaths had occurred.

The 25 U.S. states and territories that have reported cases are: Alabama, Arizona, California, Colorado, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Michigan, Minnesota, Missouri, North Carolina, North Dakota, Nebraska, New York, Ohio, Pennsylvania, Puerto Rico, Tennessee, Texas, Washington and Wisconsin.

Symptoms of hepatitis include vomiting, dark urine, light-colored stool and jaundice, which is a yellowing of the skin.

The CDC officials on Friday said it remained to be seen if the COVID-19 virus was connected to the hepatitis cases, as most of the children are not believed to have had documented cases of coronavirus.

The median age for the patients is 2, meaning most are ineligible to receive the COVID-19 vaccine, ruling out the possibility that these cases are tied to side-effects from coronavirus immunization.

As the CDC has previously stated, none of the children are believed to have had underlying conditions.

One CDC official noted that it is unclear whether these cases are a regular occurrence that the agency is picking up on due to expanded testing or if they are in fact an unusual phenomenon.

Adenovirus has been found in some of the hepatitis cases, leading officials to investigate a possible link between the liver inflammation that the children are experiencing and the virus. According to Butler, more than half of the 109 patients in the U.S. were found to have adenovirus.

“Following input and collaboration with laboratories around the country, CDC is issuing new guidance for clinicians related to adenovirus testing and reporting the possible cases of pediatric hepatitis of unknown cause,” Butler said.

Adenovirus normally does not cause damage to the liver. The usual symptoms of the pathogen are flu-like and include inflammation of the stomach and lungs. The virus is typically spread through microdroplets from coughs and sneezes, but it can also be transmitted when someone touches a surface and then touches their mouth, nose or eyes.

The CDC reiterated that hand-washing, covering coughs and sneezes and avoiding people who are sick are all methods that could help prevent adenovirus infection, though its connection with the hepatitis cases is still uncertain.

https://thehill.com/policy/healthcare/3479894-cdc-still-unsure-on-cause-of-hepatitis-cases-in-children-issues-new-guidance-for-adenovirus-testing/

Asco 2022 – Affimed suffers withdrawal symptoms

 After becoming the first company to see an NK cell engager, AFM13, score clinical validation, courtesy of an MD Anderson trial splashed at AACR in April, Affimed was priming investors for more at next month’s Asco conference. Not any more, it seems: MD Anderson’s abstract 7505, which yesterday was still listed for oral presentation on June 3, no longer appears in the meeting programme. At the time of going to press neither Asco nor Affimed had responded to questions seeking to clarify the situation. And Affimed has not issued a public statement about it – something that presumably will need to be rectified soon, given that the planned presentation was press released on April 27. Assuming that this is not a technical glitch, one reason for the presentation’s removal might be that the results have been deemed old, with nothing new versus the AACR dataset. There is precedent: at the 2016 Asco meeting, for instance, the organisers removed from a press briefing a late-breaking presentation by Dr James Kochenderfer that had already been disclosed in an EHA abstract, and kicked Immunomedics out entirely for revealing embargoed data at investor meetings. Affimed is off 10% today, still with no explanation.

Update: after market close Affimed issued a statement confirming the abstract's withdrawal, citing non-compliance with Asco's embargo policies given that the data had been presented at AACR.

Anthos goes pivotal as Novartis and Pfizer look on

 In about 18 months' time Novartis will find out whether it made a mistake to give up on the blood-thinning project abelacimab. The MAb, spun out into the Blackstone-backed Anthos Therapeutics in 2019, yesterday became the first factor XI inhibitor to begin phase 3 patient enrolment. Two pivotal studies, Aster and Magnolia, are now under way, both with primary completion dates of September 2023. The mechanism (abelacimab also hits factor XIa) is an unusual area of research, featuring a small handful of big players, with Bayer and Bristol Myers Squibb working on several distinct assets. Both have franchises to defend: the former’s Xarelto loses US patent protection in 2024, while the latter’s Eliquis will likely go two years later. Unusually, Bristol’s Eliquis partner Pfizer is not active in factor XI, and was asked about this on its first-quarter call. It said: "We really want to see a similar step-up in breakthrough potential as we saw with Eliquis. And we haven't yet been convinced about that step-up, but we are carefully monitoring." The Aster study compares abelacimab head to head against Eliquis, so the answer – for Novartis and Pfizer alike – will come soon enough.

Selected inhibitors of factor XI or XIa
ProjectCompanyMechanismStudy design/status
Phase 3
Abelacimab (MAA868)Anthos (ex Novartis)Anti-factor XI & XIa MAbAster vs Eliquis
Magnolia vs LMW heparin
Phase 2
Osocimab (BAY1831865)BayerAnti-factor XIa MAbConvert, in dialysis, ended Dec 2021
Fesomersen (IONIS-FXI-LRx/ ISIS 416858/ BAY2306001)Bayer/ IonisFactor XI ligand conjugated antisenseEmerald, in dialysis, ended Dec 2019
Asundexian (BAY 2433334)BayerOral factor XIa inhibitorPacific-AMI ended Feb 2022
Pacific-Stroke ended Feb 2022
Milvexian (JNJ-70033093/ BMS-986177)Bristol Myers Squibb/J&JOral factor XIa inhibitorAxiomatic-SSP ended Apr 2022
AB023AronoraAnti-factor XI MAbNCT03612856, in dialysis, ended 2019
Phase 1
ONO-7684Ono PharmaceuticalOral factor XIa inhibitorNCT03919890 ended 2019
BMS-986209Bristol Myers SquibbOral factor XIa inhibitorNCT04154800 ended Aug 2021
BMS-262084 OralBristol Myers SquibbNon-peptide factor XIa inhibitorUnclear
Source: Evaluate Pharma & clinicaltrials.gov.

https://www.evaluate.com/vantage/articles/news/snippets/anthos-goes-pivotal-novartis-and-pfizer-look