From $18; reiterates Buy.
Tuesday, March 16, 2021
Optimism on Lilly Novel Anti-Amyloid Slowing Cognitive Decline in Phase II Alzheimer Trial
Donanemab, an investigational agent targeting N-terminal pyroglutamate beta amyloid {pyroglutamate-3), slowed decline in patients with early symptoms of Alzheimer's disease in the phase II TRAILBLAZER-ALZ trial, now published in a major journal.
In a study of 257 early symptomatic Alzheimer's patients -- 131 assigned to donanemab and 126 to placebo -- the intravenous drug met the primary endpoint of a composite measure of cognition and daily function known as the Integrated Alzheimer's Disease Rating Scale (iADRS), slowing decline relative to placebo.
Baseline iADRS score was 106 in both groups. Change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo, a difference of 3.20 (95% CI 0.12-6.27; P=0.04), reported Mark Mintun, MD, of drug maker Eli Lilly in Indianapolis, and co-authors, in New England Journal of Medicine. The findings were presented simultaneously at the International Conference on Alzheimer's and Parkinson's Diseases (AD/PD 2021).
Secondary endpoints also showed differences in the trial, though many were unsubstantial. On the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score, the difference in change between groups was −0.36 (95% CI −0.83 to 0.12). On the 13-item cognitive subscale of ADAS-Cog (ADAS-Cog13), it was −1.86 (95% CI −3.63 to −0.09); on ADCS-iADL, it was 1.21 (95% CI −0.77 to 3.20); and on the Mini–Mental State Examination (MMSE), it was 0.64 (95% CI −0.40 to 1.67).
Lilly had released topline results in January that lacked most of the numerical findings now published. A second phase II trial with 500 patients, TRAILBLAZER-ALZ 2, is underway.
The iADRS, a measurement developed by Lilly, combines scores from the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL). Together, these measures are better suited for detecting changes early in the Alzheimer's disease process, co-author John Sims, MD, Lilly's senior medical director for neurodegeneration research, told MedPage Today. Scores range from 0 to 144, with lower scores indicating greater cognitive and functional impairment.
What's unique about donanemab is its target, noted Cynthia Lemere, PhD, a basic and translational scientist at Brigham & Women's Hospital and Harvard Medical School in Boston, who wasn't involved with the trial. "The big difference is that this particular form of beta amyloid, called pyroglutamate-3 beta amyloid, is a pathogenic form," she said.
"Pyroglutamate-3 beta amyloid is not really hugely abundant in the brain in Alzheimer's; there's relatively small amounts compared to regular beta amyloid," Lemere told MedPage Today. "But the difference is that pyroglutamate-3 resists degradation. It's been shown to be very toxic to neurons in vitro. It aggregates not just amongst itself, but it can actually help regular beta amyloid aggregate and form plaques."
"In my own hands, when we've looked at unfixed human brain sections from Alzheimer's patients, we see pyroglutamate-3 in every single plaque, every single one," Lemere added. "We think it's an integral part of the plaque pathogenesis, the actual initial deposition and the continuous deposition of plaques in the brain."
Pyroglutamate-3 beta-amyloid is normally not detected in blood or cerebrospinal fluid. In TRAILBLAZER-ALZ, overall reductions in amyloid plaque levels and global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo at 76 weeks. Patients stopped taking donanemab and switched to placebo once their plaque level was below 25 centiloids for two consecutive measures or below 11 centiloids at any one measure, Sims said.
"The antibody dropped the amyloid levels rather dramatically, rather quickly," noted Ronald Petersen, MD, PhD, of Mayo Clinic in Rochester, Minnesota, who wasn't involved with the study. "Then they stopped treating, and the effect persisted."
What this may mean is that, with certain drugs, "you might not have to treat Alzheimer's patients monthly for the rest of their lives," he told MedPage Today. "If this finding is replicated in other studies, it may be possible that you could drop the amyloid level to a baseline, then stop treating them."
TRAILBLAZER-ALZ randomly assigned participants to receive donanemab {700 mg for the first three doses and 1400 mg after) or placebo for up to 72 weeks. The dosing regimen aimed to achieve rapid amyloid plaque removal, Mintun said at the AD/PD meeting. Starting amyloid plaque levels were 107.6 and 101.1 centiloids for the donanemab and placebo groups, respectively.
Demographics, including age and sex, were balanced in the two arms. Mean baseline MMSE was 23.5, which "represents more advanced patients in this study than others in the field," Mintun pointed out. Almost three-quarters of participants carried APOE4.
All participants had positive PET scans for both amyloid and tau at baseline, but patients with the highest levels of tau, whose disease may be more resistant to anti-amyloid treatments, were excluded.
"We believe that it's important that all future Alzheimer's trials and Alzheimer's therapies should be based on the pathological stage of the patient, as it's done in oncology," Mintun noted. "As a field, it now seems obvious that Alzheimer's disease trials should have knowledge of the participants' amyloid status. I think it's going to be interesting to know if this will soon be true for tau as well."
Amyloid-related cerebral edema or effusions occurred in approximately one in four participants in the donanemab group, mostly asymptomatic. Overall, 6% of participants had symptomatic amyloid-related imaging abnormalities with edema (ARIA-E). This was more common in APOE4 carriers. There was no significant difference in the incidence of death or serious adverse events in the study groups.
The study had several limitations: its sample size was small and it mostly included white participants. The donanemab group had a higher incidence of discontinuing due to adverse events, which may have introduced survivor bias.
ARIA-E may have led to unblinding, but an analysis showed iADRS scores were similar in participants with and without ARIA-E, Mintun said. The minimal clinically important difference on the iADRS has not been established.
Disclosures
This study was funded by Eli Lilly.
Mintun and Sims are employees of Eli Lilly. Other researchers reported relationships with Eli Lilly, Biogen, Eisai, Genentech, and Roche.
Primary Source
New England Journal of Medicine
Source Reference: Mintun M, et al "Donanemab in Early Alzheimer's Disease" New England Journal of Medicine 2021; DOI: 10.1056/NEJMoa2100708.
https://www.medpagetoday.com/neurology/alzheimersdisease/91625
AstraZeneca Vaccine Unfairly Under Fire Over Clot Risk?
Thromboembolic and bleeding risk has been cited by a number of countries in halting use of AstraZeneca's COVID-19 vaccine, but the company and health agencies argued against a causal link.
Denmark and Norway were first to stop administering AstraZeneca's vaccine last week over isolated cases of bleeding, blood clots, and low platelet count. Others followed.
Germany and France on Monday became the latest to announce a pause in administration. Germany cited seven cases of cerebral vein thrombosis among patients getting one of the 1.6 million AstraZeneca shots given there so far. German Health Minister Jens Spahn call this a "very low risk" but above average if confirmed to be linked to the vaccine.
Norwegian public health officials over the weekend reported three more cases of blood clots or brain hemorrhages in 30- to 40-year-olds after vaccination, which spurred Ireland to join in. The Netherlands jumped in over the weekend, pointing to its own 10 cases of serious events, including possible thrombosis or embolism but no thrombocytopenia.
Italy and Austria have banned certain batches of the vaccine after isolated sudden deaths and thrombotic events in recently-inoculated people.
In a statement released Sunday, AstraZeneca said it has seen no evidence of increased risk of pulmonary embolism, deep vein thrombosis, or thrombocytopenia either overall or for specific age groups, genders, batches, or particular countries.
It said there had been 15 deep vein thrombosis (DVT) events and 22 pulmonary embolism (PE) cases reported among the some 17 million recipients of its vaccine in the European Union and U.K. as of March 8.
"This is much lower than would be expected to occur naturally in a general population of this size and is similar across other licensed COVID-19 vaccines," it said.
AstraZeneca also pointed to the clinical trials in which, "even though the number of thrombotic events was small, these were lower in the vaccinated group. There has also been no evidence of increased bleeding in over 60,000 participants enrolled."
The European Medicines Agency (EMA) reemphasized that there is no indication the vaccine has caused these events.
It too pointed to no apparent bump in rates compared with the general population. As of March 10, it has received a report of 30 cases of thromboembolic events among close to 5 million people who got the AstraZeneca shot in the European Economic Area.
In fact, the lower rate than in the general population may even suggest that the vaccine protects against thrombosis, and certainly reducing the disease reduces thrombosis from it, tweeted Mary Cushman, MD, medical director of the University of Vermont Medical Center Thrombosis and Hemostasis Program in Burlington.
Even so, there are concerns that slowing down vaccination -- AstraZeneca's vaccine has accounted for around a third of inoculations in Europe -- will cost lives and could contribute to hesitancy.
"I do worry that some people will not be able to differentiate between an unrelated or coincidental VTE [venous thromboembolism] occurrence (due to DVT/PE being so common in the general population) and a causative relationship," Stephan Moll, MD, of the division of hematology at the University of North Carolina at Chapel Hill, told MedPage Today.
Soumya Swaminathan, MD, WHO chief scientist, noted that it has happened before: Norway early on raised concerns about deaths among the elderly getting vaccinated, but then clarified it was only the expected rate of death.
Of the some 300 million doses of all COVID vaccines administered globally, not a single death has been documented to have been caused by vaccination, she pointed out. "We do not want people to panic. We would for the time being recommend that countries continue vaccinating with AstraZeneca."
Canada has said it continues to back AstraZeneca's vaccine. The company is expected to apply for emergency use authorization in the U.S. in the coming weeks, once its U.S. phase III trial results become available.
The EMA has an ongoing review of clotting risk with the AstraZeneca shot that is expected to yield more information when it meets Tuesday, with its monthly safety report coming out this week too. WHO's advisory committee on vaccine safety has been monitoring the data in close contact with the EMA and also will meet Tuesday.
"This does not necessarily mean these events are linked to vaccination, but it's routine practice to investigate them," WHO Director-General Tedros Adhanom Ghebreyesus, PhD, said at a press briefing Monday. "It shows that the surveillance system works and effective controls are in place."
https://www.medpagetoday.com/infectiousdisease/covid19/91641
MedPAC Again Backs No Pay Raise for Docs Treating Medicare Patients
Should doctors who treat Medicare patients get a pay raise for 2022? No, says the Medicare Payment Advisory Commission (MedPAC).
"Our indicators are positive" when it comes to physician payment rates in Medicare, said Jim Mathews, MedPAC's executive director, in a briefing announcing the release of MedPAC's annual March report to Congress. "We do see through the course of our Medicare beneficiary survey fielded in 2019 that Medicare beneficiaries have access to clinician services at least as good as -- if not better than -- their privately insured counterparts aged 55 to 64. They have better rates of finding a physician when they need one and better rates of not foregoing needed care relative to the commercially insured population -- although, consistent with longstanding trends, we do see that Medicare beneficiaries do have more difficulty finding a primary care physician when they're looking for one relative to finding a specialist."
Although 2019 was the latest information available on those data points, MedPAC also fields its own beneficiary access survey each year, he continued. "This year we did field that survey in late summer/early fall 2020, and even at that point in time, Medicare beneficiaries were not experiencing substantial increases in foregone care or an increase in difficulty in finding new physicians if they were looking for one," he said. Mathews admitted that even though "we do not have robust quality-of-care information and don't have information on physician costs in providing care," the indicators that are available led the commission to agree with current federal law, which mandates no payment increase in 2022 for clinicians.
In response to a question from MedPage Today, Mathews said the commission was "cognizant of the fact that clinicians, like the rest of us, do experience year-over-year inflation in the cost of living, which does involve the cost of running a practice -- it's always a consideration when we are contemplating the adequacy of Medicare payments."
However, "we don't have cost information to calculate a profit margin ... where we can say Medicare is paying way too much relative to cost, or Medicare is not paying enough," he continued. "We have to rely more on direct or indirect measures of adequacy of Medicare payments" such as survey data, the numbers of clinicians who take assignment from Medicare, and changes in utilization of services by Medicare beneficiaries. "And when we look at all those indicators, we see all of them indicating that Medicare payments are sufficient to ensure beneficiary access to physician services, at least this year," Mathews said.
The lack of a pay increase, however, "is something many commissioners have been concerned about, and they have made a passing mention in public meetings," he added. "Should any of these indicators start to change, at that point we would reconsider ... but at the moment, all indicators are positive enough that the commission has not moved away from the current-law 0% update for physicians."
This is not the first time MedPAC has recommended a 0% update for the physician sector. Commissioners made the same recommendation for 2021, and for both 2020 and for 2019 they endorsed a 0.5% increase, as recommended under the budget rules at the time.
Physicians did fare better this year than inpatient rehabilitation facilities (IRFs), for whom MedPAC recommended a 5% decrease in reimbursement. "Our analysis of IRF supply and volume of services provided suggests that capacity remains adequate to meet demand," the commission noted in its report. "Moreover, the marginal profit, an indicator of whether IRFs with excess capacity have an incentive to treat more Medicare beneficiaries, was robust for both freestanding and hospital-based IRFs, providing a very positive indicator of patient access." MedPAC recommended the same decrease for home health agency payments.
On the other hand, the commission recommended a 2% reimbursement increase for acute care hospitals, who continue to lose money on Medicare patients. Despite that fact, "we see very robust participation in Medicare by hospitals," Mathews said. "We see slight declines in inpatient utilization and small increases in outpatient utilization consistent with longstanding trends."
"When we look at financial performance over the last couple of years, we have seen increases in profit margins for hospitals participating in the Medicare program; for 2019 we are calculating a -8.7% Medicare margin, and projecting that to increase to -6.o% in 2021," he added. "On the basis of these indicators, we are recommending a 2% increase in the rates for inpatient and outpatient services," as well as asking that Medicare revise its quality improvement programs for hospitals. Combining those recommendations "result in net increases in hospitals' Medicare revenues in 2022."
On the issue of telehealth, "we think Congress and CMS did the right thing by the expansions that were implemented to address potentially tremendous access-to-care issues created by the pandemic, but now we're starting to think about what the landscape should look like once we're free and clear of the public health emergency," Mathews said.
MedPAC is not making a formal recommendation in this area yet, but the commissioners agree that "the expansions that have been implemented should be allowed to continue for some period of time after the public health emergency, but definitely not permanent yet," he said. "Once the public health emergency ends, we believe that Medicare should revert back to the lower facility rate that it paid for telehealth prior to the public health emergency; that would reduce payments for telehealth services and the program could use data collected over 1 or 2 years after the end of the public health emergency to fine-tune those payment rates."
https://www.medpagetoday.com/practicemanagement/reimbursement/91640
Enzo 2FQ 2021 Results, Leadership and Corporate Updates
Total second quarter revenue of $31.5 million increased 62% year-over-year on continued recovery and expansion from impact of COVID-19 pandemic
Second quarter clinical laboratory revenue of $24.0 million increased 92% on significant volume and pricing growth due to improved product mix
Consolidated quarterly gross margin of 50% improved 2000 basis points year-over-year
Achieved adjusted EBITDA at $4.3 million for the quarter with increases in sequential and YOY profitability
EPS of $0.05 for the quarter vs. EPS loss of ($0.16) in Q2 2020
Dr. Elazar Rabbani, Founder and CEO, to step down as CEO and transition to a scientific role with the Company once a qualified successor is identified and hired by the Board
Executive search firm Korn Ferry engaged to identify CEO candidates
Gary M. Huff, former LabCorp Diagnostics CEO, named Strategic Consultant to Board
Enzo retains Cain Brothers to help identify, evaluate, and execute strategic initiatives
Ampio: Early Positive Results for Inhaled Ampion in COVID Respiratory Distress
Ampio Pharmaceuticals (NYSE American: AMPE), a biopharmaceutical company focused on the advancement of immunology-based therapies for prevalent inflammatory conditions, recently revealed preliminary positive results in its AP-014 Phase I clinical trial utilizing inhaled Ampion in treating respiratory distress in patients as a result of COVID-19. The Company also outlined its progress toward initiating a Phase I clinical trial using inhaled Ampion for treating those suffering lingering respiratory effects after COVID-19 infection, the so-called COVID-19 "long haulers," as well as its continued research focusing on the use of Ampion in kidney and pediatric diseases.
Preliminary results from the AP-014 Phase I trial of inhaled Ampion indicate:
Ampion demonstrated an improvement in all-cause mortality in COVID-19 patients compared to standard of care (SOC). A lower all-cause mortality rate of 8% is observed for the Ampion treatment group, compared to 21% in standard of care alone.
Patients who received Ampion required less hospitalization time. The average hospital length of stay was 7 days for the Ampion group compared to 11 days for standard of care patients.
Patients who received Ampion required less oxygen than standard of care alone, and 86% of Ampion patients were stable or had improvement compared to 75% of SOC patients.
More patients who received Ampion were stable or had improvement on a scale of clinical improvement compared to standard of care alone. By day 5, 86% of patients who received Ampion were stable or had improvement compared to 75% of standard of care patients. This trend in improvement with Ampion treatment is noted as early as day 2 and continues to day 5.
Adverse events were the same between Ampion and standard of care, and no drug-related serious adverse events have been reported.
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