Abbott Laboratories (NYSE:ABT): Q3 Non-GAAP EPS of $0.84 in-line; GAAP EPS of $0.53 misses by $0.03.
Revenue of $8.1B (+5.7% Y/Y) in-line.
Shares +0.37% PM.
https://seekingalpha.com/news/3506054-abbott-laboratories-eps-revenue-lineWednesday, October 16, 2019
Opioid associated players up on improved settlement prospects
The spike in buying in drug distributors yesterday after the close in reaction to the news that they are closing in on a broad settlement
with states and local governments over their role in the opioid
epidemic has other companies with potential legal exposure in the green
premarket.
Teva Pharmaceutical Industries (NYSE:TEVA) (+5%), Endo International (NASDAQ:ENDP) (+3%), Mallinckrodt (NYSE:MNK) (+8%), Johnson & Johnson (NYSE:JNJ) (+1%)
https://seekingalpha.com/news/3506044-opioid-associated-players-improved-settlement-prospectsTuesday, October 15, 2019
Spoiler Alert: Medicare for All Isn’t Going to Happen
I am going to make a prediction here. No matter whom we elect in
2020, Bernie or Trump or anything in between, Medicare for All is not
going to happen in America. One can run an electrifying campaign on the
promise of Medicare for All, or be indignantly against it, but this is
pure theater on both sides. I don’t know if God can make a rock so big
and heavy that even He can’t lift it, but I do know that the government
can make corporations so big and powerful that even the government
itself can’t break them.
For decades, our government encouraged the healthcare industry to consolidate vertically, horizontally, and obliquely so it can achieve “economies of scale” and, therefore, lower consumer prices. In the last couple of decades, the government also compelled the industry to computerize its operations, because technology makes everything better and cheaper. Once the resulting monopolistic behemoths were summoned into existence, it was time to nationalize the whole lot, into one super monopoly, with super technology and super economies of scale. The only other example of such government monopoly in America is the military.
Obviously, our standing armies must be, by definition, a national monopoly, but note that the Navy is not building its own ships, and the Air Force is not building its own planes, and the Army is not manufacturing tanks. The government is contracting with private suppliers for pretty much everything, from butter to bullets. The military-industrial complex is a network of very large and utterly corrupt contractors for the government, yielding more power over foreign and fiscal policy than Congress, the president, and all citizens put together, while delivering practically nothing either on budget or on time. A powerful military is essential to America’s safety and global success, so we grind our teeth and keep paying. And medical care for hundreds of millions of people is at least as important.
I am not entirely sure how people think Medicare for All is going to work. Are you folks envisioning an angry President Bernie dragging Samuel Hazen into the Oval, wagging his finger at him, and making an offer Mr. Hazen cannot refuse? Something like, “I will pay $50 per head and not a penny more, because healthcare is a human right, and if you want to be a disgusting millionaire or billionaire, go write a bestselling book, like I did …”, at which point Mr. Hazen will be hanging his head down in shame and gratefully take the $50 deal. Upon his return to Nashville, Mr. Hazen will immediately schedule book writing workshops for all HCA department chiefs to compensate for cutting all salaries in half. Yeah … no, that’s not how this works.
Go ask Northrop Grumman or Lockheed Martin or General Dynamics or even Boeing or Booz Allen or any other “beltway bandit” how getting money from the Feds really works. There are well-greased revolving doors between the Pentagon and its contractors. There are stock options and executive positions for high-ranking federal employees. There are 535 people in Congress responsible for allocating budgets, and all 535 are for sale.
Most of this infrastructure is already in place for healthcare too, and building the HHS Heptagon shouldn’t take very long. The American president has little to no power over federal spending, and even less so when it comes to large procurement contracts, as the current occupant of the White House discovered the hard way, during the Lockheed F-35 kerfuffle.
Clearly, large health systems will survive and thrive under a Medicare for All law, but how about private health insurance? Future President Bernie says they will all be banned. Is that so? Currently, a full third of Medicare beneficiaries are insured and “managed” by a handful of large private health insurers. Medicare is paying those private contractors fixed amounts of money per head for their services. Medicaid is doing the same for most of its beneficiaries, and all military health insurance (TRICARE) is contracted out to the usual suspects.
Basically, the vast majority of people covered by public insurance are really insured by gigantic insurance corporations. Fact: Under the hood, taxpayer-funded healthcare is the bread and butter of private health insurance companies.
When future President Bernie and the hordes of uninformed supporting characters in the 2020 elections festival say that private health insurance will be banned, they are lying to you. What will be banned under a Medicare for All law is your ability or your employer’s ability to purchase health insurance directly from a private company. Instead, the government will procure contracts in bulk as it sees fit, assign people to them as it sees fit, and pay for these contracts with tax revenue as it sees fit. Just like they pay for battleships, fighter planes, bombs, tanks, and such. The U.S. military is known for lots of great things. Value-based purchasing, and cost-effectiveness in general, are not among those things.
Depending on whom you ask and what is included in the definition of healthcare, Medicare for All is projected to cost between three trillion and four trillion dollars per year, which is five times the amount we spend on the military. This number is calculated based on costs under current law, minus the waste generated by the cacophony of hundreds and thousands of different insurance plans, different healthcare facilities, and their too-many-to-count service and product vendors.
The projections do not include the effects of the inevitable massive consolidation of everything healthcare into a dozen or so federal contractors, able and willing to demand multi-billion dollar contracts for services worth a few million dollars at most on the open market. Remember the Obamacare marketplace website? Multiply that by orders of magnitude, and you have Medicare for All.
Medicare for All is as egregious a misnomer for this plan as the Affordable Care Act was. When they say Medicare for All, they mean federal government procured health insurance for all. When they say everything soup to nuts will be covered, they mean everything the heavily indebted federal government thinks should be covered, and can afford to cover, will be covered. When they say healthcare will be better, more plentiful, and much more affordable, they mean please vote for me in 2020.
Medicare for All will be built on the largely immovable foundation
our government chartered and nurtured for half a century. If you want a
glimpse into a Medicare for All future, go look at any Medicaid Managed
Care plan in any impoverished southern state, and look at the balance
sheets of the associated contractors and sub-contractors.
It doesn’t have to be this way. We don’t need to bulldoze over everything we have, and we certainly don’t need to pretend that we can, or that we must. And we need to remember that the proper role of government in a free country is not to manage the health or the care of all its citizens. Free people are not the wards of a State responsible for keeping them healthy, productive, and happy. The role of a democratic government is to keep predators, foreign and domestic, including corporate ones, at bay, while providing a sturdy safety net for the few who cannot care for themselves.
Let’s do that instead. It will be better, faster, and cheaper than the fictional construct called Medicare for All.
Margalit Gur-Arie, MSc, is founder of BizMed. She blogs at On Health Care Tech & Policy. This post originally appeared on KevinMD.
https://www.medpagetoday.com/blogs/kevinmd/82756
For decades, our government encouraged the healthcare industry to consolidate vertically, horizontally, and obliquely so it can achieve “economies of scale” and, therefore, lower consumer prices. In the last couple of decades, the government also compelled the industry to computerize its operations, because technology makes everything better and cheaper. Once the resulting monopolistic behemoths were summoned into existence, it was time to nationalize the whole lot, into one super monopoly, with super technology and super economies of scale. The only other example of such government monopoly in America is the military.
Obviously, our standing armies must be, by definition, a national monopoly, but note that the Navy is not building its own ships, and the Air Force is not building its own planes, and the Army is not manufacturing tanks. The government is contracting with private suppliers for pretty much everything, from butter to bullets. The military-industrial complex is a network of very large and utterly corrupt contractors for the government, yielding more power over foreign and fiscal policy than Congress, the president, and all citizens put together, while delivering practically nothing either on budget or on time. A powerful military is essential to America’s safety and global success, so we grind our teeth and keep paying. And medical care for hundreds of millions of people is at least as important.
I am not entirely sure how people think Medicare for All is going to work. Are you folks envisioning an angry President Bernie dragging Samuel Hazen into the Oval, wagging his finger at him, and making an offer Mr. Hazen cannot refuse? Something like, “I will pay $50 per head and not a penny more, because healthcare is a human right, and if you want to be a disgusting millionaire or billionaire, go write a bestselling book, like I did …”, at which point Mr. Hazen will be hanging his head down in shame and gratefully take the $50 deal. Upon his return to Nashville, Mr. Hazen will immediately schedule book writing workshops for all HCA department chiefs to compensate for cutting all salaries in half. Yeah … no, that’s not how this works.
Go ask Northrop Grumman or Lockheed Martin or General Dynamics or even Boeing or Booz Allen or any other “beltway bandit” how getting money from the Feds really works. There are well-greased revolving doors between the Pentagon and its contractors. There are stock options and executive positions for high-ranking federal employees. There are 535 people in Congress responsible for allocating budgets, and all 535 are for sale.
Most of this infrastructure is already in place for healthcare too, and building the HHS Heptagon shouldn’t take very long. The American president has little to no power over federal spending, and even less so when it comes to large procurement contracts, as the current occupant of the White House discovered the hard way, during the Lockheed F-35 kerfuffle.
Clearly, large health systems will survive and thrive under a Medicare for All law, but how about private health insurance? Future President Bernie says they will all be banned. Is that so? Currently, a full third of Medicare beneficiaries are insured and “managed” by a handful of large private health insurers. Medicare is paying those private contractors fixed amounts of money per head for their services. Medicaid is doing the same for most of its beneficiaries, and all military health insurance (TRICARE) is contracted out to the usual suspects.
Basically, the vast majority of people covered by public insurance are really insured by gigantic insurance corporations. Fact: Under the hood, taxpayer-funded healthcare is the bread and butter of private health insurance companies.
When future President Bernie and the hordes of uninformed supporting characters in the 2020 elections festival say that private health insurance will be banned, they are lying to you. What will be banned under a Medicare for All law is your ability or your employer’s ability to purchase health insurance directly from a private company. Instead, the government will procure contracts in bulk as it sees fit, assign people to them as it sees fit, and pay for these contracts with tax revenue as it sees fit. Just like they pay for battleships, fighter planes, bombs, tanks, and such. The U.S. military is known for lots of great things. Value-based purchasing, and cost-effectiveness in general, are not among those things.
Depending on whom you ask and what is included in the definition of healthcare, Medicare for All is projected to cost between three trillion and four trillion dollars per year, which is five times the amount we spend on the military. This number is calculated based on costs under current law, minus the waste generated by the cacophony of hundreds and thousands of different insurance plans, different healthcare facilities, and their too-many-to-count service and product vendors.
The projections do not include the effects of the inevitable massive consolidation of everything healthcare into a dozen or so federal contractors, able and willing to demand multi-billion dollar contracts for services worth a few million dollars at most on the open market. Remember the Obamacare marketplace website? Multiply that by orders of magnitude, and you have Medicare for All.
Medicare for All is as egregious a misnomer for this plan as the Affordable Care Act was. When they say Medicare for All, they mean federal government procured health insurance for all. When they say everything soup to nuts will be covered, they mean everything the heavily indebted federal government thinks should be covered, and can afford to cover, will be covered. When they say healthcare will be better, more plentiful, and much more affordable, they mean please vote for me in 2020.
It doesn’t have to be this way. We don’t need to bulldoze over everything we have, and we certainly don’t need to pretend that we can, or that we must. And we need to remember that the proper role of government in a free country is not to manage the health or the care of all its citizens. Free people are not the wards of a State responsible for keeping them healthy, productive, and happy. The role of a democratic government is to keep predators, foreign and domestic, including corporate ones, at bay, while providing a sturdy safety net for the few who cannot care for themselves.
Let’s do that instead. It will be better, faster, and cheaper than the fictional construct called Medicare for All.
Margalit Gur-Arie, MSc, is founder of BizMed. She blogs at On Health Care Tech & Policy. This post originally appeared on KevinMD.
https://www.medpagetoday.com/blogs/kevinmd/82756
Shionogi New Antibiotic for Urinary Infections Set for FDA Advisory Review
Cefiderocol, a new antibiotic, appeared effective and generally safe
for treatment of complicated urinary tract infections (cUTI) including
pyelonephritis in patients with limited treatment options, FDA staff
indicated in briefing documents ahead of an advisory committee meeting scheduled for Wednesday.
However, questions remained about its use in critically ill patients with carbapenem-resistant infections, which the FDA’s Antimicrobial Drugs Advisory Committee will be addressing. In addition to the usual safety and efficacy questions, FDA staff has asked the committee to assess “the finding of increased mortality” in one of the studies “in the overall risk benefit considerations for cefiderocol.”
Cefiderocol is a siderophore cephalosporin, described as having activity against several Gram-negative bacteria, with a proposed dose of 2 g intravenously every 8 hours, with dose adjustments for altered renal function. In 2015, the drug was granted both fast track and Qualified Infectious Disease Product designation for cUTI, hospital-acquired bacterial pneumonia (HAP), ventilator-associated bacterial pneumonia (VAP), and bacteremia, or bloodstream infections, agency staff said.
Drug maker Shionogi submitted data from three trials — the non-inferiority trial comparing cefiderocol with imipenem-cilastatin (IMP) for treatment of cUTI, with a non-inferiority margin no larger than 15%. APEKS-NP, a phase III trial comparing cefiderocol to meropenem in patients with HAP or VAP. Data from this trial was presented at the 2019 IDWeek meeting, which found mortality rates with cefiderocol to be non-inferior to meropenem in patients with nosocomial pneumonia. FDA staff noted that this trial was completed while the product was under review, and only top-line results were included.
The manufacturer also presented data from the CREDIBLE-CR trial, comparing cefiderocol to the best available therapy for infections caused by carbapenem resistant organisms “at various anatomical sites.” Results from trial datasets were submitted, agency staff said, but not the final clinical study report.
FDA staff seemed mostly satisfied with results of the non-inferiority trial, which met its non-inferiority endpoint of 15% for clinical and microbiologic success rates at test of cure visit (72.6% for cefiderocol vs 54.6% for IMP). However, they noted that “clinical response rates were similar between the treatment groups and the difference in overall response was driven primarily by the microbiologic success component of the composite endpoint.”
The most common adverse events (AEs) included diarrhea, hypertension, constipation, rash, and infusion site reactions. Agency staff also noted cephalosporin-class AEs, including hypersensitivity reactions, Clostridioides difficile colitis, seizure, and hepatobiliary adverse events. They also said there was one death in the cefiderocol arm unrelated to the study drug.
But FDA staff seemed concerned with the increased mortality in the CREDIBLE-CR study, where patients with either HAP or VAP, cUTI, and body substance isolation/sepsis due to carbapenem-resistant organisms were randomized to cefiderocol or the best available therapy (about two-thirds of which were colistin-based regimens). Not only was all-cause mortality higher in the cefiderocol group at day 14 (18.8% vs 12.2%, respectively), but also at day 28 (24.8% vs 18.4%), with the greatest mortality difference disfavoring cefiderocol in the HAP or VAP groups.
“An independent adjudication committee determined that a greater percentage of patients in the cefiderocol group than in the [best available therapy] group had infection-related death with treatment failure (15.8% vs. 8.2%), but also noted an imbalance in death due to underlying co-morbidities (9.9% vs. 4.1%),” agency staff wrote.
In addition, treatment-emergent AEs leading to death in the cefiderocol group were generally infection-related, FDA staff noted, such as septic shock, pneumonia, sepsis, and bacteremia.
They speculated on the reasons for the difference in mortality rates, noting that deaths were more common in patients with infections by organisms such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa.
“Whether this difference in mortality is a chance finding or truly reflects a deficit in the activity of cefiderocol in critically ill patients is unclear,” FDA staff wrote.
https://www.medpagetoday.com/infectiousdisease/generalinfectiousdisease/82754
However, questions remained about its use in critically ill patients with carbapenem-resistant infections, which the FDA’s Antimicrobial Drugs Advisory Committee will be addressing. In addition to the usual safety and efficacy questions, FDA staff has asked the committee to assess “the finding of increased mortality” in one of the studies “in the overall risk benefit considerations for cefiderocol.”
Cefiderocol is a siderophore cephalosporin, described as having activity against several Gram-negative bacteria, with a proposed dose of 2 g intravenously every 8 hours, with dose adjustments for altered renal function. In 2015, the drug was granted both fast track and Qualified Infectious Disease Product designation for cUTI, hospital-acquired bacterial pneumonia (HAP), ventilator-associated bacterial pneumonia (VAP), and bacteremia, or bloodstream infections, agency staff said.
Drug maker Shionogi submitted data from three trials — the non-inferiority trial comparing cefiderocol with imipenem-cilastatin (IMP) for treatment of cUTI, with a non-inferiority margin no larger than 15%. APEKS-NP, a phase III trial comparing cefiderocol to meropenem in patients with HAP or VAP. Data from this trial was presented at the 2019 IDWeek meeting, which found mortality rates with cefiderocol to be non-inferior to meropenem in patients with nosocomial pneumonia. FDA staff noted that this trial was completed while the product was under review, and only top-line results were included.
The manufacturer also presented data from the CREDIBLE-CR trial, comparing cefiderocol to the best available therapy for infections caused by carbapenem resistant organisms “at various anatomical sites.” Results from trial datasets were submitted, agency staff said, but not the final clinical study report.
FDA staff seemed mostly satisfied with results of the non-inferiority trial, which met its non-inferiority endpoint of 15% for clinical and microbiologic success rates at test of cure visit (72.6% for cefiderocol vs 54.6% for IMP). However, they noted that “clinical response rates were similar between the treatment groups and the difference in overall response was driven primarily by the microbiologic success component of the composite endpoint.”
The most common adverse events (AEs) included diarrhea, hypertension, constipation, rash, and infusion site reactions. Agency staff also noted cephalosporin-class AEs, including hypersensitivity reactions, Clostridioides difficile colitis, seizure, and hepatobiliary adverse events. They also said there was one death in the cefiderocol arm unrelated to the study drug.
But FDA staff seemed concerned with the increased mortality in the CREDIBLE-CR study, where patients with either HAP or VAP, cUTI, and body substance isolation/sepsis due to carbapenem-resistant organisms were randomized to cefiderocol or the best available therapy (about two-thirds of which were colistin-based regimens). Not only was all-cause mortality higher in the cefiderocol group at day 14 (18.8% vs 12.2%, respectively), but also at day 28 (24.8% vs 18.4%), with the greatest mortality difference disfavoring cefiderocol in the HAP or VAP groups.
“An independent adjudication committee determined that a greater percentage of patients in the cefiderocol group than in the [best available therapy] group had infection-related death with treatment failure (15.8% vs. 8.2%), but also noted an imbalance in death due to underlying co-morbidities (9.9% vs. 4.1%),” agency staff wrote.
In addition, treatment-emergent AEs leading to death in the cefiderocol group were generally infection-related, FDA staff noted, such as septic shock, pneumonia, sepsis, and bacteremia.
They speculated on the reasons for the difference in mortality rates, noting that deaths were more common in patients with infections by organisms such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa.
“Whether this difference in mortality is a chance finding or truly reflects a deficit in the activity of cefiderocol in critically ill patients is unclear,” FDA staff wrote.
https://www.medpagetoday.com/infectiousdisease/generalinfectiousdisease/82754
Joint injections: Worth the risk?
Intra-articular injections of corticosteroids for relief of the pain
of hip or knee osteoarthritis (OA) may have adverse long-term
consequences, researchers suggested.
These injections are commonly performed and have been “conditionally” recommended by the American College of Rheumatology and “should be considered,” according to the Osteoarthritis Research Society International. The American Academy of Orthopedic Surgeons, however, has advised clinicians to be on the lookout for emerging evidence for or against the use of intra-articular injections in the knee, explained Ali Guermazi, MD, PhD, of Boston University School of Medicine, and colleagues.
However, a review of the outcomes following 459 injection procedures
performed during 2018 in a single center now has identified four
potential adverse events that should raise concerns, particularly for
certain patients:
The Background
A Cochrane meta-analysis evaluated 27 trials that included more than 1,767 patients found moderate improvements in pain and slight benefits for physical function following intra-articular corticosteroid injections for knee OA. However, the review noted that the quality of evidence was low, concluding that the results were inconclusive.
“Whether there are clinically important benefits of intra-articular corticosteroids after 1 to 6 weeks remains unclear in view of the overall quality of the evidence, considerable heterogeneity between trials, and evidence of small-study effects,” the Cochrane reviewers wrote.
In an editorial accompanying the Boston University report, Richard Kijowski, MD, of the University of Wisconsin in Madison, wrote, “The use of intra-articular corticosteroid injection to treat OA remains commonplace in clinical practice despite the lack of strong evidence supporting its efficacy.”
In vitro and animal research has revealed that corticosteroids actually can have negative effects on cartilage. “The action by which corticosteroids are chondrotoxic is complex, but it seems to affect cartilage proteins (especially aggrecan, type II collagen, and proteoglycan) by mediating protein production and breakdown,” Guermazi and colleagues explained.
Moreover, the local anesthetics often combined with the steroids also have been linked with chondrolysis.
And a recent retrospective study of 70 patients with hip OA found that 44% of patients who were given injections of triamcinolone with ropivacaine had radiographic progression and 17% experienced collapse of the articular surface.
“Thus, there is a growing body of evidence to suggest that
intra-articular corticosteroid injection can accelerate the progression
of joint degeneration,” Kijowski observed.
The Events
The injection protocol used at Boston University involved 40 mg triamcinolone, 2 mL of 1% lidocaine, and 2 mL of 0.25% bupivacaine.
Accelerated OA progression, characterized by rapid loss of radiographic joint space, was first observed in trials of nerve growth inhibitors, wherein some patients required joint replacement earlier than had been expected. Some experts have suggested that a loss of joint space exceeding 2 mm within a year can be considered accelerated progression, which can be accompanied by effusions, synovitis, and local soft tissue changes.
This accelerated OA progression was seen in 26 patients, following hip injections in 21 patients and knee injections in five.
Subchondral insufficiency fractures were the second type of adverse
outcome observed, and were seen in four patients undergoing
intra-articular hip injections. This event was previously thought to
occur in elderly patients with osteopenia, but has now been reported in
younger, active patients who present with acute pain but no apparent
trauma.
The affected area often is weight-bearing and may involve loss of cartilage and meniscal tearing. Radiographic findings can be normal or subtle, while on magnetic resonance imaging (MRI) subchondral hypointensity may be detected. If the condition is identified early, before articular collapse has occurred, healing can occur, but once the articular surface has collapsed, the joint must be replaced.
Early identification of subchondral insufficiency fractures also is crucial before intra-articular injections, because the steroid may interfere with resolution of the fracture. Moreover, if an injection is performed and results in pain alleviation, the patient may increase weight-bearing and worsen the insufficiency fracture, hastening collapse.
The third type of event the researchers identified involved complications of osteonecrosis, which typically present with insidious onset of pain or can be asymptomatic. MRI is required for the diagnosis, and can help predict collapse by the extent of osteonecrosis and bone marrow edema. Once collapse has occurred, the only option is joint replacement.
The fourth adverse outcome, rapid joint destruction including bone loss (also referred to as rapidly progressive OA type 2), occurred in two patients with hip injections and one following a knee injection. Some previous authors likened this event to accelerated osteonecrosis, and others have hypothesized that the joint destruction results from undiagnosed subchondral insufficiency fractures.
The Advice
There are currently no recommendations regarding imaging before performing an intra-articular corticosteroid injection, and in some cases, findings may be subtle. “However, given the relative ease of performance and the low cost of radiography, there should be a low threshold to obtain radiographs before performing an intra-articular corticosteroid injection, as the intervention may affect the disease course (i.e., it may result in accelerated progression),” Guermazi and colleagues wrote.
Of particular concern are patients who have no apparent OA or very mild changes on radiographs who have been referred for injections because of pain. In these cases, the indication for injection should be “closely scrutinized,” as destructive or rapidly progressive joint space loss tends to develop in patients with severe pain but minimal structural change on radiographs.
“Clinicians should consider obtaining a repeat radiograph before each subsequent intra-articular injection to evaluate for progressive narrowing of the joint space and any interval changes in the articular surface that can indicate subchondral insufficiency fracture or type 1 or 2 rapidly progressive OA,” the authors advised.
“We believe that certain patient characteristics, including but not limited to acute change in pain not explained by using radiography and no or only mild OA at radiography, should lead to careful reconsideration of a planned intra-articular corticosteroid injection,” the authors concluded, adding that MRI may be helpful in these circumstances.
“Patients might be more than willing to take the small risk of an adverse joint event requiring eventual joint replacement for the possibility of at least some degree of pain relief after intra-articular corticosteroid injection,” wrote Kijowski.
“However, patients have the right to make this decision for themselves,” he stated.
These injections are commonly performed and have been “conditionally” recommended by the American College of Rheumatology and “should be considered,” according to the Osteoarthritis Research Society International. The American Academy of Orthopedic Surgeons, however, has advised clinicians to be on the lookout for emerging evidence for or against the use of intra-articular injections in the knee, explained Ali Guermazi, MD, PhD, of Boston University School of Medicine, and colleagues.
- Accelerated OA progression, reported in 6% of patients
- Subchondral insufficiency fractures, seen in 0.9%
- Complications of osteonecrosis, in 0.7%
- Rapid joint destruction including bone loss, also in 0.7% of patients
The Background
A Cochrane meta-analysis evaluated 27 trials that included more than 1,767 patients found moderate improvements in pain and slight benefits for physical function following intra-articular corticosteroid injections for knee OA. However, the review noted that the quality of evidence was low, concluding that the results were inconclusive.
“Whether there are clinically important benefits of intra-articular corticosteroids after 1 to 6 weeks remains unclear in view of the overall quality of the evidence, considerable heterogeneity between trials, and evidence of small-study effects,” the Cochrane reviewers wrote.
In an editorial accompanying the Boston University report, Richard Kijowski, MD, of the University of Wisconsin in Madison, wrote, “The use of intra-articular corticosteroid injection to treat OA remains commonplace in clinical practice despite the lack of strong evidence supporting its efficacy.”
In vitro and animal research has revealed that corticosteroids actually can have negative effects on cartilage. “The action by which corticosteroids are chondrotoxic is complex, but it seems to affect cartilage proteins (especially aggrecan, type II collagen, and proteoglycan) by mediating protein production and breakdown,” Guermazi and colleagues explained.
Moreover, the local anesthetics often combined with the steroids also have been linked with chondrolysis.
And a recent retrospective study of 70 patients with hip OA found that 44% of patients who were given injections of triamcinolone with ropivacaine had radiographic progression and 17% experienced collapse of the articular surface.
The Events
The injection protocol used at Boston University involved 40 mg triamcinolone, 2 mL of 1% lidocaine, and 2 mL of 0.25% bupivacaine.
Accelerated OA progression, characterized by rapid loss of radiographic joint space, was first observed in trials of nerve growth inhibitors, wherein some patients required joint replacement earlier than had been expected. Some experts have suggested that a loss of joint space exceeding 2 mm within a year can be considered accelerated progression, which can be accompanied by effusions, synovitis, and local soft tissue changes.
This accelerated OA progression was seen in 26 patients, following hip injections in 21 patients and knee injections in five.
The affected area often is weight-bearing and may involve loss of cartilage and meniscal tearing. Radiographic findings can be normal or subtle, while on magnetic resonance imaging (MRI) subchondral hypointensity may be detected. If the condition is identified early, before articular collapse has occurred, healing can occur, but once the articular surface has collapsed, the joint must be replaced.
Early identification of subchondral insufficiency fractures also is crucial before intra-articular injections, because the steroid may interfere with resolution of the fracture. Moreover, if an injection is performed and results in pain alleviation, the patient may increase weight-bearing and worsen the insufficiency fracture, hastening collapse.
The third type of event the researchers identified involved complications of osteonecrosis, which typically present with insidious onset of pain or can be asymptomatic. MRI is required for the diagnosis, and can help predict collapse by the extent of osteonecrosis and bone marrow edema. Once collapse has occurred, the only option is joint replacement.
The fourth adverse outcome, rapid joint destruction including bone loss (also referred to as rapidly progressive OA type 2), occurred in two patients with hip injections and one following a knee injection. Some previous authors likened this event to accelerated osteonecrosis, and others have hypothesized that the joint destruction results from undiagnosed subchondral insufficiency fractures.
There are currently no recommendations regarding imaging before performing an intra-articular corticosteroid injection, and in some cases, findings may be subtle. “However, given the relative ease of performance and the low cost of radiography, there should be a low threshold to obtain radiographs before performing an intra-articular corticosteroid injection, as the intervention may affect the disease course (i.e., it may result in accelerated progression),” Guermazi and colleagues wrote.
Of particular concern are patients who have no apparent OA or very mild changes on radiographs who have been referred for injections because of pain. In these cases, the indication for injection should be “closely scrutinized,” as destructive or rapidly progressive joint space loss tends to develop in patients with severe pain but minimal structural change on radiographs.
“Clinicians should consider obtaining a repeat radiograph before each subsequent intra-articular injection to evaluate for progressive narrowing of the joint space and any interval changes in the articular surface that can indicate subchondral insufficiency fracture or type 1 or 2 rapidly progressive OA,” the authors advised.
“We believe that certain patient characteristics, including but not limited to acute change in pain not explained by using radiography and no or only mild OA at radiography, should lead to careful reconsideration of a planned intra-articular corticosteroid injection,” the authors concluded, adding that MRI may be helpful in these circumstances.
“Patients might be more than willing to take the small risk of an adverse joint event requiring eventual joint replacement for the possibility of at least some degree of pain relief after intra-articular corticosteroid injection,” wrote Kijowski.
“However, patients have the right to make this decision for themselves,” he stated.
Guermazi reported being a shareholder of Boston Imaging Core Lab, and
having financial relationships with TissueGene, Merck Serono, Pfizer,
AstraZeneca, Galapagos, and Roche.
Kijowski reported research funding support from GE Healthcare.
Kijowski reported research funding support from GE Healthcare.
last updated
-
Primary Source
Radiology
Source Reference: Kompel A, et al “Intra-articular corticosteroid injections in the hip and knee: perhaps not as safe as we thought?” Radiology 2019;doi:10.1148/radiol.2019190341. -
Secondary Source
Radiology
Source Reference: Kijowski R “Risks and benefits of intra-articular corticosteroid injection for treatment of osteoarthritis: what radiologists and patients need to know” Radiology 2019; doi:10.1148/radiol.2019192034.
Boehringer’s VC wing backs anti-cancer virus startup
Abalos Therapeutics has raised
€12 million ($13 million) to discover and develop cancer drugs based on
an arenavirus strain. The series A round sets Abalos up to generate
anti-tumoral virus strains and take them toward testing in humans.
Germany-based Abalos is built on the work of Karl Lang and Philipp Lang, who identified viruses that preferentially infect cancer cells. The discovery led to work to develop viruses that infect cancer cells and induce cytokine response, triggering an immune response against the tumor. Unlike oncolytic viruses, these strains would not try to kill the cells directly.
Now, the work has advanced to the point that Abalos can see the clinic on the horizon. That has enabled Abalos to put a leadership team in place and reel in €12 million in a round led by Boehringer Ingelheim Venture Fund (BIVF) and Gruenderfonds Ruhr.
BIVF Director Marcus Kostka has taken up the CEO post. Kostka is
joined in the Abalos C-suite by Jörg Vollmer, a person he knows from his
time on the board of Rigontec. Vollmer was CSO of Rigontec, a cancer
immunotherapy startup, prior to its acquisition by Merck in 2017.
Vollmer now occupies the chief scientific officer position at Abalos.
At Abalos, Vollmer will get the chance to work with another twist on the idea of using the immune system to treat cancer. Abalos thinks its approach can result in long-term disease control that hits both the primary tumor and metastases.
The more commonly pursued idea of using viruses to kill cancer cells directly and trigger an immune response in the process has attracted the attention of a who’s who of drug developers. The appeal of the concept rests in part on the potential for oncolytic viruses to turn “cold” tumors “hot,” thereby rendering them vulnerable to the immune attacks launched by checkpoint inhibitors.
https://www.fiercebiotech.com/biotech/boehringer-s-vc-wing-backs-anti-cancer-virus-startup
Germany-based Abalos is built on the work of Karl Lang and Philipp Lang, who identified viruses that preferentially infect cancer cells. The discovery led to work to develop viruses that infect cancer cells and induce cytokine response, triggering an immune response against the tumor. Unlike oncolytic viruses, these strains would not try to kill the cells directly.
Now, the work has advanced to the point that Abalos can see the clinic on the horizon. That has enabled Abalos to put a leadership team in place and reel in €12 million in a round led by Boehringer Ingelheim Venture Fund (BIVF) and Gruenderfonds Ruhr.
At Abalos, Vollmer will get the chance to work with another twist on the idea of using the immune system to treat cancer. Abalos thinks its approach can result in long-term disease control that hits both the primary tumor and metastases.
The more commonly pursued idea of using viruses to kill cancer cells directly and trigger an immune response in the process has attracted the attention of a who’s who of drug developers. The appeal of the concept rests in part on the potential for oncolytic viruses to turn “cold” tumors “hot,” thereby rendering them vulnerable to the immune attacks launched by checkpoint inhibitors.
https://www.fiercebiotech.com/biotech/boehringer-s-vc-wing-backs-anti-cancer-virus-startup
AstraZeneca, past FluMist efficacy woes, now plagued by production problems
Sidelined by efficacy shortfalls for a
couple of years running, AstraZeneca’s inhaled flu vaccine FluMist
got back into regulators’ good graces last year. Now, though, the
company is dealing with an entirely different problem.
For the upcoming flu season,
manufacturing problems will severely limit U.S. supplies for the inhaled
alternative to traditional flu shots. The company has struggled with
yields in growing two of this year’s flu virus strains, so it’ll only be
able to ship three lots of FluMist to the U.S. for the coming season, a
spokeswoman told FiercePharma.
Those three lots—which comprise 758,000
doses—are one-third the number shipped last year. AZ dispatched nine
lots of FluMist for the 2018-2019 season, AZ said.
And it’s a major reduction from the
numbers FluMist has put up in some previous years; AZ shipped 40 lots in
the 2013-2014 season, 35 lots for 2014-2015, and 26 lots in 2015-2016.
After that, the numbers declined significantly, with 10 lots in
2016-2017 and three lots in 2017-2018.
“The manufacturing process for the
A/H1N1 and A/H3N2 strain recommendations made by the World Health
Organization have demonstrated lower yields, creating constraints in
bulk manufacturing,” AZ’s spokeswoman said.
The yield problem won’t affect the
quality of FluMist doses, AZ says. The company stopped taking orders
when it became aware of the problem and worked with regulators, public
health agencies and others to discuss its supply expectations.
The manufacturing setback comes after a
different type of problem for AZ in prior years. During the 2016-2017
and 2017-2018 flu seasons, the CDC recommended against FluMist due to
efficacy data from prior years, hitting AZ’s sales.
The company changed its strain
selection process and won renewed backing in February 2018 for last
year’s flu season. Still, it only distributed 2.7 million doses in the
U.S. last year.
Other flu vaccine manufacturers
Sanofi, Seqirus and GlaxoSmithKline annually distribute tens of millions
of seasonal flu vaccine doses in the U.S. This year, manufacturers
expect to distribute 162 million to 169 million flu vaccine doses, CDC
reports. The agency doesn’t expect any shortage of flu vaccine overall
this season.
AstraZeneca reported $288 million
in FluMist sales in 2015 before ACIP recommended against its
use. The drugmaker recorded $104 million in FluMist sales in 2016, $78
million in 2017 and $110 million in 2018.
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