Search This Blog

Tuesday, October 15, 2019

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:
  • 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
These findings were published in Radiology.
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.
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.
last updated

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

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.

State laws trying to force drug price transparency come up short

Transparency in drug pricing sounds like a great idea, but a new study from the University of Southern California (USC) found almost none of the laws passed in an attempt to force transparency will do much good.
In fact, fewer than 5% of the drug pricing laws passed by states in the past few years would result in new information about drug pricing, according to the study by Neeraj Sood and Martha Ryan at USC’s Shaeffer Center for Health Policy & Economics, published in JAMA.
The problem is, the laws don’t go far enough in shedding light on the current opaque drug supply chain, Sood said. That is, while some of the laws require list price or some transaction pricing data, none require true transaction information at the drug level and none require it from every participant in the drug chain. The study identified pharma manufacturers, insurers, pharmacy benefit managers (PBMs), wholesalers and pharmacies as the five participants.

“These laws are really not truly making the system more transparent. They’re really not helping us tell whose story is right—are the pharma companies right or are the wholesalers right or are the PBMs right? Look, it’s good that there’s some activity going on, but we haven’t solved the problem even with all these laws,” he said.
Sood and Ryan reviewed 166 drug pricing laws passed between 2015 and 2018 and found that 35 bills in 22 states included transparency mandates. Only seven of the laws were deemed informative, such as Maine’s law requiring drugmakers to report net prices and Oregon and Nevada laws forcing pharma to report profits.

Of the less-effective laws, one key problem was compelling list-price disclosures. As Sood pointed out, not only is that information already readily available, list price is pretty disconnected from the real price patients pay, and it doesn’t reveal who’s making the profits and where.
That’s an opinion shared by drugmakers, who in recent years have pointed the finger at PBMs and accused them of pocketing the discounts drug companies offer on their products. With the drug-pricing debate sparking ire from the public, many drugmakers have made a point to demonstrate that their net prices are actually falling.
Federal regulations that cover all states would be one way to address the disparate transparency, Sood said. However, those kinds of efforts to date have languished in committee on Capitol Hill or been rebuffed by lawmakers. Even the drug list price regulation for TV ads mandated by the Department of Health and Human Services (HHS) earlier this year has been shut down, blocked by a lawsuit and federal court ruling that the HHS did not have the authority to issue it. HHS is currently appealing that ruling.
https://www.fiercepharma.com/pharma/state-laws-trying-to-force-drug-price-transparency-come-up-short-study-says

J&J bridging its $2B patent cliff gap, with help from Stelara, Darzalex

Johnson & Johnson is dealing with a multibillion-dollar hit this year as generics and biosimilars eat away at sales. That’s the bad news. The good? Its newer meds continue to deliver enough oomph to push up its top line.
The company’s immunology unit grew 10% in the third quarter, trailed by 9% growth for oncology and 8% for neuroscience. Altogether, J&J’s pharma group turned in 6.4% operational growth to $10.9 billion for the quarter, easily outpacing its other business units.
The performances come as J&J deals with copycat versions of prostate cancer med Zytiga and rheumatoid arthritis blockbuster Remicade, along with other recent patent losses. Previously, the company said generics and biosimilars would erode sales by $3 billion to $3.5 billion in 2019. But now, J&J expects the hit to be $2 billion, pharma chairman Jennifer Taubert said on a Tuesday conference call. The copies will keep digging into sales next year, she said.
On the flip side, 10 J&J drugs posted double-digit sales growth in the third quarter. Executives highlighted operational sales jumps of 31% for Stelara, 57% for Darzalex, 33% for Imbruvica, 70% for Tremfya and 95% for Erleada.
And there’s more ahead for Darzalex, Taubert said. The drug is already competing in second-line and later uses in multiple myeloma, but J&J now has an opportunity to move into frontline use. The med won approval for previously untreated patients ineligible for stem-cell transplant in June and in transplant-eligible patients in September.

J&J recently filed a subcutaneous version of Darzalex, which would take the dosing procedure from a multiple-hour infusion to a five-minute injection process. She said the more convenient formula would be an “important catalyst for growth,” especially in the outpatient setting.
On Xarelto, J&J execs said they were “pleased” to see the med hold its own during the third quarter after previous declines. The company has been working to get past sales hits from the Medicare donut hole and payer rebates, execs said. Plus, the drug on Monday scored its eighth approval, this time to help prevent blood clots in acutely ill patients without a high risk of bleeding, both during and after hospitalization.
With the third-quarter performance, J&J raised its 2019 sales guidance to $83.7 billion to $84.2 billion, up from a previous range of $82.4 billion to $83.2 billion. The new forecast translates to top-line growth of 2.5% to 3%. J&J’s shares were up 2% Tuesday morning after the company released earnings.
Also on Tuesday’s call, J&J CFO Joe Wolk addressed recent legal setbacks the company has faced. J&J expects an “egregious” $8 billion Risperdal verdict, leveled last week, to be reduced in appeals, Wolk said.
As for its load of opioid litigation, Wolk said J&J couldn’t reach a “reasonable” settlement in Oklahoma, and it will now appeal the $572 million verdict. In Ohio, by contrast, J&J was able to strike a deal Wolk called reasonable and the company was “particularly pleased” the money was set to benefit opioid addiction victims.
And on the thousands of talc lawsuits J&J’s facing, the CFO said it’s “probably the poster child for how big a business plaintiffs attorneys” have made suing life sciences companies such as J&J.
Overall, 50% of product liability cases are over life sciences products at a time when “products have never been safer,” he said. Wolk insists the science supports J&J and that plaintiffs attorneys are spending hundreds of millions of dollars on TV advertising to create a $36 billion litigation industry.

Pfizer scrambles to fill void as Teva stops making chemo drug often given children

Pfizer is playing a new role in the dramas that often surround drug shortages. While manufacturing issues at its Hospira unit have sometimes been responsible for hospital drug shortages, Pfizer is now trying to fill a serious shortfall after Teva Pharmaceutical discontinued production of a chemo drug used to cure children of serious cancers.
It is ramping up production of vincristine—often used with other drugs to treat leukemia, brain tumors and lymphomas—after Teva in July notified the FDA that it had made the “business decision” to discontinue production. Its move has left pediatric oncologists scrambling to find supplies.
“Due to a competitor’s outage, we are expediting additional shipments of this critical product over the next few weeks to support three to four times our typical production output. Pfizer is committed to providing this important medicine to patients,” Pfizer said today in an email.
The New York Times reports that vincristine is so widely used that the shortage is affecting clinical trials as well as treatments.
“Vincristine is our water. It’s our bread and butter. I can’t think of a disease in childhood cancer that doesn’t use vincristine,” Yoram Unguru, M.D., a pediatric oncologist at the Herman and Walter Samuelson Children’s Hospital at Sinai in Baltimore, tells the NYT.
Teva did not respond to the newspaper about its decision to discontinue vincristine, a drug that has been on and off the FDA shortage list for years. With margins on generics having gotten very thin in recent years, many drugmakers have given up production of products where they are not dominant in the marketplace. There are currently 202 drug discontinuations listed on the FDA Drug Shortages website.
Teva also has been closing many plants as part of its attempt to cut $3 billion in annual costs in an effort to return to financial stability after the company found itself in dire economic straits several years ago. Often with a plant closure, it can been easier to give up certain drugs than move production to another facility.
Playing the hero in a drug shortage is a turnabout for Pfizer, which has been under pressure to upgrade several plants after manufacturing issues left certain drugs in very short supply. Problems at a Hospira plant in Kansas led to shortages at hospitals of some injected pain meds. Issues at another Pfizer facility that makes injectors resulted in shortages of Mylan’s popular EpiPen for treating anaphylactic shock.
https://www.fiercepharma.com/manufacturing/pfizer-scrambles-to-fill-void-after-teva-stops-making-chemo-drug-often-children

Johnson & Johnson $110M talc verdict overturned

An appeals court in Missouri has overturned a $110M verdict against Johnson & Johnson (NYSE:JNJ) over whether its talc caused ovarian cancer.
That reverses a 2017 decision in favor of a Virginia woman who says she developed the cancer after decades of using the talc for feminine hygiene.
The appeals court cited a state supreme court ruling limiting out-of-state plaintiffs’ ability to sue in the state.
The company still faces several other lawsuits in St. Louis, including the one that brought a record $4.69B talc verdict against it.
https://seekingalpha.com/news/3505990-johnson-and-johnson-sees-110m-talc-verdict-overturned