Search This Blog

Friday, May 3, 2019

Denosumab in Rheumatoid Arthritis: Protecting the Bone

Combining denosumab (Prolia) with a conventional disease-modifying antirheumatic drug (DMARD) such as methotrexate showed promise for slowing radiographic damage in rheumatoid arthritis (RA), a manufacturer-sponsored phase III trial called DESIRABLEfound.
At 1 year, patients who were randomized to placebo had a change from baseline in their total Sharp score of 1.49 (95% CI 0.99-1.99), while those who received subcutaneous denosumab, 60 mg every 6 months, had a change of 0.99 (95% CI 0.49-1.49, P=0.0235) and those given that dose of denosumab every 3 months had a change of 0.72 (95% CI 0.41-1.03, P=0.0055), according to Tsutomu Takeuchi, MD, PhD, of Keio University School of Medicine in Tokyo, Japan, and colleagues.
In addition, the proportions of patients with no radiographic changes at 12 months were 64.2% in the placebo group, 75.6% in the 6-month group (P=0.0097), and 78.1% in the 3-month group (P=0.0014), the researchers reported online in Annals of the Rheumatic Diseases.
Denosumab is a monoclonal antibody that inhibits the receptor activator of nuclear factor ΚB ligand (RANKL) that is used for the treatment of osteoporosis. Binding of RANKL suppresses bone resorption and may help slow the progression of bone erosions.
“The concept of using osteoporosis drugs in RA to reduce erosions has previously been studied with bisphosphonates, but with very little benefit,” commented John J. “Jack” Cush, MD, of Baylor Research Institute in Dallas, who was not involved in the study.
“The use of denosumab makes a lot more sense given that RA inflammation drives RANK ligand and osteoclast activity to promote local damage and systemic bone loss,” Cush told MedPage Today.
Earlier phase II trials of denosumab demonstrated significant inhibition of bone erosions in patients with RA also given methotrexate, so Takeuchi and colleagues enrolled 654 patients from 2013 to 2015. Mean age was 57, disease duration was slightly over 2 years, and three-quarters were women. Mean total Sharp score at baseline was 14.75.
All patients were taking methotrexate or other conventional DMARDs, but previous treatment with biologics was not permitted. Radiographs of the hands and feet were obtained at baseline, 6 months, and 1 year.
Changes in erosion scores from baseline to 1 year were smaller in the two denosumab groups, but there were no differences in joint space narrowing scores.
The proportion of patients with rapid radiographic progression, defined as annual progression of 5 or more points on the total Sharp score, were 10.6% in the placebo group, 6.9% in the 6-month group (P=0.1785), and 5% in the 3-month group (P=0.0310).
Percent changes in bone mineral density at the lumbar spine were -1.03%, 3.99%, and 4.88%, respectively (P<0.0001 for both denosumab groups). The increases seen in the denosumab groups occurred regardless of whether the patients were taking glucocorticoids.
Patients receiving denosumab also had significant declines in the bone metabolism marker CTX-I, but had no changes on the marker of cartilage turnover COMP.
There were no differences on efficacy outcomes such as the 20%, 50%, and 70% improvement criteria of the American College of Rheumatology (ACR20, 50, and 70) or Disease Activity Scores in 28 joints (DAS28). This lack of effect on inflammatory activity was expected, the researchers noted.
“These data are impressive. But the results say that RANKL inhibition can be adjunctive therapy to protect bone, but would not be a replacement for existing anti-inflammatory, disease-modifying, or biologic therapy, primarily because denosumab has no effect on ACR20/50/70 or DAS28 scores,” Cush noted.
Adverse events were similar across the groups, with rates of hypocalcemia and fracture being comparable. Serious adverse events were reported in 5.8% of the placebo group and 8.6% of both denosumab groups, although stomatitis occurred more often in the denosumab groups. One patient in the 3-month group died of interstitial lung disease, which was considered drug related although the patient also had rheumatic interstitial pneumonia.
“We believe that this drug is a novel treatment option for patients with RA who do not respond well to conventional synthetic DMARDs, are unable to adjust or start other DMARDs due to safety concerns or costs, or require treatment for osteoporosis,” Takeuchi and colleagues concluded.
A limitation of the study was its short duration.
The trial was sponsored by Daiichi Sankyo.
The authors reported financial relationships with multiple companies including Amgen, Daiichi Sankyo, AbbVie, Asahi Kasei, Astellas, Chugai, Eisai, Mitsubishi Tanabe, Novartis, Pfizer, Takeda, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Sanofi, UCB, Merck Sharp & Dohme, Teijin, Boehringer Ingelheim, Celgene, and Nippon Shinyaku.
Posted by at No comments:

CAR T-Cell Therapy Emerges in Multiple Myeloma

A novel chimeric antigen receptor (CAR) T-cell therapy induced complete and durable responses in a phase I trial involving patients with heavily pretreated multiple myeloma.
Of 33 patients treated with bb2121, a B-cell maturation antigen (BCMA)-directed product, 85% achieved an objective response, reported James N. Kochenderfer, of the National Cancer Institute in Bethesda, Maryland, and colleagues.
And the agent induced complete and stringent complete responses in 9% and 36%, respectively, they wrote in the New England Journal of Medicine.
“The exciting thing with what was reported with bb2121 is that patients truly are having deep responses,” Sarah Holstein, MD, PhD, of the University of Nebraska Medical Center in Omaha, told MedPage Today. “For many of these patients these responses lasted an average of about a year.”
Median duration of response was 10.9 months in the study, progression-free survival (PFS) was 11.8 months, and all responders who could be evaluated for minimal residual disease (MRD) reached MRD negativity.
Holstein, who was not involved in the research, said the study provides the “first benchmark” for CAR T-cell therapy in multiple myeloma. “From now on, all future CAR T-cell studies are going to refer to this.”
And she noted that other trials of active agents in patients with heavily pretreated disease have yielded response durations “best measured in the 3- to 6-month range,” and with responses not typically as deep as those in the present study.
To that point, the authors highlighted a study of single-agent daratumumab(Darzalex) with a response rate of 29% and median PFS of 3.7 months, as well as a study on pomalidomide (Pomalyst) plus dexamethasone that showed a response rate of 31% and median PFS of 4 months. Similarly, the FDA recently convened an advisory committee to review whether selinexor, an agent that combined with dexamethasone elicited responses in roughly 26% of pretreated myeloma patients, should receive regulatory approval.
Holstein said the next step will be to see if CAR T-cell therapies in earlier lines of myeloma therapy will result in even better responses for patients than current approaches (studies in these settings are ongoing with bb2121 and another BCMA-targeting CAR T-cell agent).
“The million dollar question — or perhaps more, given the cost of these drugs — is really the durability of these responses,” she said. “At this point it’s too early to say that patients are being cured, but even if we can get patients several years’ worth of treatment-free time, that would be an incredible thing for this field.”
Study Details
From 2016 to 2018, the open-label phase I study enrolled 36 patients with relapsed or refractory multiple myeloma at centers across the U.S. who then underwent leukapheresis. Eligible patients had to have been treated with a minimum of three previous lines of therapy, including an immunomodulatory agent and a proteasome inhibitor, but most were far more heavily pretreated than that — median of 7 prior therapies in the dose-escalation group and 8 in an expansion cohort. All patients had been exposed to bortezomib (Velcade) and lenalidomide (Revlimid), and 91%, 94%, and 92% had exposure to carfilzomib (Kyprolis), pomalidomide, and daratumumab, respectively.
The CAR T-cell therapy was successfully manufactured in all patients, but three experienced disease progression prior to the infusion and were unable to receive bb2121.
“Sometimes the problem with CAR T-cell therapy is the amount of time that it takes between collecting the patients’ cells and then finally re-infusing them, and sometimes the myeloma can’t be controlled and patients get too sick to then receive the product,” said Holstein. “Overall, the majority of patients who enrolled in the study in fact received CAR-T therapy, which is a really important point.”
Grade 3/4 adverse events (AEs) were mostly hematologic in nature and included neutropenia (85%), leukopenia (58%), thrombocytopenia (45%), and anemia (45%). Cytokine release syndrome occurred in 76% of patients but were mostly grade 1/2 (70%). Two grade 3 cases (the remaining 6%) resolved within 24 hours. Grade 1/2 neurologic toxicity occurred in 39% of patients, and one reversible grade 4 neurologic event was reported in a patient 11 days post-infusion.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the authors wrote.
“There really were no alarming off-target toxicities that were seen — that’s always a concern because the cellular therapy is so effective,” said Holstein. “Even though BCMA is expressed on plasma cells, there’s always the concern that very low expression in other tissues could be affected by the CAR-Ts, but certainly there’s no indication of that here.”
Prior to the single CAR-T infusion, patients underwent lymphodepletion with fludarabine and cyclophosphamide. During the dose-escalation phase of the study, patients were given CAR T-cell doses ranging from 50×106 to 800×106. During the expansion portion of the trial, doses ranged from 150×106 to 450×106. In all, most patients received the 450×106 dose (n=19). Complete responses were seen in all doses of 150×106 and above. At data cutoff, six of the 15 complete responders had relapsed.
Tumor BCMA expression did not appear to have an impact on treatment response, the authors noted. At the 450×106 dose, response rates were similar among patients with tumor BCMA expression levels below 50% and in those with expression levels of 50% and above.
BCMA “is a member of the tumor necrosis factor superfamily of proteins that is primarily expressed by malignant and normal plasma cells and some mature B cells, making it a potential target for multiple myeloma,” Kochenderfer’s team explained.
Holstein said that since BCMA has been identified as a target in multiple myeloma, the CAR T-cell therapy field has moved along quickly. Current FDA-approved CAR T-cell therapies — such as those for diffuse large b-cell lymphoma and acute myeloid leukemia — target CD19, but myeloma cells really don’t express CD19, she said.
The study was funded by Bluebird Bio and Celgene.
Kochenderfer reported relationships with Celgene, Kite/Gilead, and disclosed patents related to BCMA targeting CAR T-cell therapy. Co-authors disclosed relationships with other industry entities and several are employed by either Bluebird Bio or Celgene.
Posted by at No comments:

Nanofiber-hydrogel composite allows soft tissue to regenerate

 Nanofiber-hydrogel composite allows soft tissue to regenerate


Electron microscope images comparing native fat tissue in rats (B) to the nanofiber-hydrogel composite material (C). Credit: X. Li et al., Science Translational Medicine (2019)
A team of researchers at Johns Hopkins School of Medicine has developed a gel that, when injected into test animals, allowed new soft tissue to grow—replacing lost tissue. In their paper published in the journal Science Translational Medicine, the group describes their work developing the gel and how well it worked in test rats and rabbits.
When a person loses a chunk of soft due to an accident, infection or , surgeons have very few options available to induce the body to regenerate the missing tissue, leaving patients with disfiguring reminders of their loss. In this new effort, the researchers have developed a new gel that shows promise as a soft-tissue regenerative tool.
To make the gel, the team created nanofibers using a polymer that was known to biodegrade easily. It has been used for several years in real medical applications. Next, the nanofibers were treated to allow some of them to bind with —it, too, has been used in real medical applications—in this case, to create gels that promote infiltration by macrophages, which leads the body to create blood vessels. The result was an easily injectable gel that could serve as a scaffolding that also promotes regeneration of lost soft tissue. The researchers note that the gel was very close in feel to real tissue, both resilient and soft.
The researchers tested their gel by removing tissue from lab rats and rabbits and then filling the cavities with the gel. They report that the gel very easily conformed to the shape of the cavity before it firmed up. But more importantly, macrophages appeared and began infiltrating the gel and sending out signals that induced the body to create new cells and blood vessels inside the gel as it biodegraded. The end result was regeneration of lost tissue. The researchers note that the gel assisted in regenerating missing soft tissue up to 10 cubic centimeters, which, they further note, is about the size of a human finger. Clinical trials to test the new gel in humans could come very quickly, as all of the ingredients are already used in other medical applications.



Explore further
More information: Xiaowei Li et al. Nanofiber-hydrogel composite–mediated angiogenesis for soft tissue reconstruction, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aau6210
Posted by at No comments:

10 most, least expensive cities for prescription drugs

Relative to nationwide averages for the cost of the 500 most commonly prescribed medications, Atlanta is the least expensive city to purchase those drugs, according  according to GoodRx’s inaugural quarterly report, an in-depth analysis of drug prices and fill rates in the U.S.
For its report, GoodRx analyzed the cash prices of the 500 most commonly prescribed medications in 30 of the most populated cities in the U.S. for the last year. The pricing data includes costs from pharmacies and insurers.
The 10 most expensive cities and percent above the national average:
1. New York City (+16.9 percent)
2. San Francisco (+14 percent)
3. Los Angeles (+9.9 percent)
4. Philadelphia (+6.4 percent)
5. San Diego (+6.2 percent)
6. Milwaukee (+4.5 percent)
7. Birmingham, Ala. (+3.3 percent)
8. Sacramento, Calif. (+3.2 percent)
9. Seattle (+3.1 percent)
10. Little Rock, Ark. (+2.8 percent)
The 10 most expensive cities and percent below the national average:
1. Atlanta (-20.4 percent)
2. Houston(-19.3 percent)
3. Dallas (-17.5 percent)
4. Denver (-17.4 percent
5. Cincinnati (-12.7 percent)
6. Tampa, Fla. (-10.7 percent)
7. Indianapolis (-10.6 percent)
8. Salt Lake City (-8.6 percent)
9. Chicago (-7.6 percent)
10. Detroit (-5.7 percent)
Posted by at No comments:

1st cancer-targeting CRISPR clinical trial in US seeks FDA approval

A study that will deliver CRISPR gene editing technology directly into cancer cells in patients’ bodies is preparing to seek regulatory approval from the FDA, STAT reports.
The study, proposed by Newark, Del.-based Christiana Care Health System’s gene editing institute, would be the first of its kind in the U.S. Other clinical trials using CRISPR to treat cancer use the technology to modify immune cells that have been removed from the body, then infuse the cells back into the patient.
If approved, Christiana Care is reportedly planning on recruiting six to 10 patients with late-stage, non-small-cell lung cancer. Researchers would target the patients’ NRF2 genes by either injecting CRISPR directly into tumors or packaging it within adeno-associated viruses infused into the blood. Previous studies have shown that disabling NRF2 genes can slow down tumor cell proliferation and increase chemotherapy’s effectiveness.
Researchers told STAT the study’s goals will be “modest”: The treatment will hopefully add a few more months to the lives of stage 3 and 4 cancer patients who have been told they only have about six months to live.
Posted by at No comments:

Weight Watchers Gains, But These Analysts Remain Wary

Weight Watchers International, Inc. NASDAQWW surged more than 18 percent Friday after reporting a first-quarter bottom-line beat. The company’s 16-cent loss per share far exceeded analyst expectations for a 27-cent loss. The $363 million sales figures was just under analysts estimates.

What Weight Watchers Achieved

Bank of America Merrill Lynch attributed the beat to favorable operating margins, which came in at 6 percent against estimates of 3.2 percent. The firm also notched 0.9-percent subscriber growth against expectations for a decline. Growth in digital app engagement helped.
But that was the extent of Weight Watchers’ celebrated metrics.
“Gross margin was +110bps as weakness was disproportionately driven by the lower-margin studio (meetings) business; high marketing and SG&A were anticipated,” Bank of America analysts wrote in a note.
Meanwhile, product sales fell 30 percent year over year — an issue Bank of America attributed to recruitment problems and KeyBanc attributed to poor studio attendance. Recruitment challenges remain from rebranding issues and pressure from diet competitors.
“The Studios business was challenged, but remains a critical component of the Business,” KeyBanc wrote. “[…] The Studios part of the business is a key competitive advantage as it allows for deeper engagement with members through interaction with coaches and other members to build a wellness community.”

Weight Watchers’ Target Weight

Bank of America suspects Weight Watchers may be conservative on 2019 bottom-line projections, but it sees little room for sales expansion. It expects promotional campaigns to drive recruitment during seasonal lulls and product sales declines to level off with the consumables relaunch. However, soft sales may stunt near-term recovery.
With slightly more optimism, KeyBanc anticipates retention gains from the WellnessWins loyalty program and app engagement.
“Improving retention will be critical for WW this year after a soft start to recruitment trends since about 40% of annual recruits join in 1Q,” KeyBanc wrote.

The Ratings

KeyBanc Capital Markets maintained a Sector Weight rating, while Bank of America Merrill Lynch maintained an Underperform rating with a $21 price target.
“While we expect shares to rally off of very low expectations, in our view, questions remain as to WW’s ability to return to a sustainable, consistent growth trajectory,” Bank of America wrote.
Posted by at No comments:

FDA to end program that hid millions of reports on faulty medical devices

The Food and Drug Administration announced it is shutting down its controversial “alternative summary reporting” program and ending its decades-long practice of allowing medical device makers to conceal millions of reports of harm and malfunctions from the general public.
The agency said it will open past records to the public within weeks.
A Kaiser Health News investigation in March revealed that the obscure program was vast, collecting 1.1 million reports since 2016. The program, which began about 20 years ago, was so little-known that forensic medical device experts and even a recent FDA commissioner were unaware of its existence.
Former FDA official S. Lori Brown said ending the program now is a “victory for patients and consumers.”
“The No. 1 job of the FDA — it shouldn’t be ‘buyer beware’ — is to have the information available to people so they can have information about the devices they are going to put in their body,” Brown said.
FDA principal deputy commissioner Dr. Amy Abernethy and its device center director, Dr. Jeff Shuren, announced the decision to terminate the program in a statement on increasing transparency about the safety of breast implants.
Makers of breast implants for years were allowed to report hundreds of thousands of injuries and malfunctions out of the public eye, federal records show.
“We believe these steps for more transparent medical device reports will contribute to greater public awareness of breast implant adverse events,” Abernethy and Shuren said in a Thursday statement. “This is part of a larger effort to end the alternative summary reporting program for all medical devices.”
FDA spokeswoman Angela Stark said the agency will also end “alternative summary reporting” exemptions still in place for makers of implantable cardiac defibrillators, pacemakers and tooth implants. The FDA has said the program was originally designed to allow for more efficient internal review of well-known risks.
The agency said it began winding down the program in mid-2017, revoking many reporting exemptions, including those for saline breast implants and for balloon pumps used inside patients’ blood vessels.
At that point, the agency required device makers with ongoing exemptions to file quarterly reports in its public device-harm database known as MAUDE, short for the Manufacturer and User Facility Device Experience.
Still, FDA data provided to KHN shows that during the first nine months of 2018 the FDA continued to accept more than 190,000 injury reports and 45,000 malfunction reports under the hidden “alternative summary reporting” program.
Ronni Solomon, vice president and chief policy officer of the ECRI Institute, which studies device safety, said the staff uses the FDA’s open data on a daily basis to look for signals that might show heightened risks with a particular device.
“We think it’s really vital for the sake of transparency, for the sake of policy, for sake of science,” she said. “We’re really glad to see this, the sooner the better.”
The agency said its forthcoming data release will be for the alternative summary reports filed before mid-2017. The FDA for years reached agreements with makers of about 100 devices, allowing them to cease public reports of certain types of problems. The agency previously said the agreements and resulting records were available only by filing a Freedom of Information Act request, a process that can take months or even years.
Going forward, device makers will be required to file individual reports describing each case of patient harm related to a medical device.
The FDA has not said it will stop allowing device makers to file other types of device-harm exemption reports that are withheld from the public, such as when there is mass litigation over a device or when a company is submitting reports from an independent device-tracking registry. Nor has a plan been announced to open those records, which contain reports of harm related to pelvic mesh and surgical robots and reports of deaths related to several cardiac devices.
The FDA had granted Covidien, now a division of Medtronic, a long-standing “alternative summary reporting” exemption for its surgical staplers, a device used to cut tissues and vessels and quickly seal them during a variety of surgeries.
In 2016, when just 84 reports of stapler-related harm were disclosed in the FDA’s MAUDE database, almost 10,000 more malfunction reports were sent directly to the FDA’s in-house database, the agency acknowledged.
The device has been subject to numerous lawsuits over patient deaths and grave harm.
Matt Baretich, a Denver-area biomedical engineer who advises health systems on device safety, is eager to examine the hidden reports as they’re released by the FDA.
“I’m really interested to see what information has been hidden so I can go back,” Baretich said. “I may have been looking for that information and not found anything and thought there was not a problem.”
Posted by at No comments:
Subscribe to: Comments (Atom)