An immunotherapy, chimeric antigen receptor T-cell (CAR-T), has revolutionized certain types of cancer treatments. The two approved CAR-T therapies are Novartis’ Kymriah (tisagenlecleucel) and Gilead Sciences’
Yescarta (Axicabtagene ciloleucel). They are essentially living
therapies. They are drawn from a patient, engineered in a lab to focus
more closely on the specific cancer, and reinfused into the patient
where the cells grow and attack the cancer cells.
New research out of the Memorial Sloan Kettering Cancer Center
suggests the genetically engineered immune cells can be used to treat
diseases of senescence, which could include fibrotic liver disease,
atherosclerosis, and diabetes.
Cellular senescence is a kind of “zombie” state related to aging,
where cells stop dividing and growing, but don’t actually die. It is
particularly associated with diseases of aging.
“Senescence is a double-edge sword,” said Scott Lowe, chair of the
Cancer Biology and Genetics Program at the Sloan Kettering Institute and
co-responding author on the study. “Cells in this state play an
important role in wound healing and cancer deterrence. But if they
linger for too long, they can cause chronic inflammation, which itself
is a cause of many diseases. Finding a way to safely eliminate these
cells would be a major therapeutic breakthrough in the treatment of
these diseases.”
The research was published in the June 17 issue of the journal Nature.
The research team compared molecules on the surface of senescent
cells to other types of cells. They identified a molecule called
urokinase plasminogen activator receptor (uPAR) that was enriched on the
senescent cells, but largely absent on other cells. They then designed
CAR-T cells that recognized uPAR.
Evaluating these newly engineered cells on mouse models of
senescence-related diseases, such as cancer and liver fibrosis, they
found that CAR-T cells successfully eliminated senescent cells from two
different mouse models of liver fibrosis. The CAR-T cells also improved
survival in lung cancer mouse models when dosed with drugs that induced
senescence in this type of cancer.
The researchers plan to continue studying uPAR-directed CAR-T cells
in other senescence-associated diseases, such as atherosclerosis,
diabetes, and osteoarthritis, with hopes of developing them for clinical
use in humans.
“This study demonstrates that T-cell engineering and CAR therapy can
be effective beyond cancer immunotherapy,” said Michel Sadelain,
director of the Center for Cell Engineering at Sloan Kettering.
Lowe added, “We think this approach has the potential to tackle a
number of senescence-related diseases for which new treatments are badly
needed.”
Senescence has been a growing field in the last few years. South San
Francisco-based Unity Biotechnology focuses on senescence to halt, slow
or reverse age-associated diseases. The company’s pipeline includes
UBX0101, which is in Phase II trials for osteoarthritis and UBX1967 and
UBX1325 for age-related macular degeneration, diabetic macular edema,
and diabetic retinopathy. Other programs are studying idiopathic
pulmonary fibrosis, liver and kidney diseases, and neurodegenerative and
cognitive disorders.
On March 31, the company announced
that it had completed enrollment in its UNITY Phase II trial of UBX0101
in moderate-to-severe osteoarthritis of the knee. It was evaluating 183
patients and expects to report results in the second half of 2020
Research
that came out of Rockefeller University last year found that,
unexpectedly, the neurons affected by Parkinson’s disease may actually
be senescent and that these “undead neurons” release molecules that shut
down neighboring brain cells that lead to common Parkinson’s symptoms.
Senescent cells occur throughout the body, but it is not usually seen
in nerve cells in the brain. Neurons halt division once fully formed.
But the research group found that dopamine neurons that regulate
motivation, memory and movement by producing dopamine can become
senescent.
Similarly, in 2018, researchers at the University of Texas Health Science Center at San Antonio found cellular senescence
was linked to tau protein tangles associated with end-stage Alzheimer’s
disease. Cellular senescence can be a survival strategy for cells under
stress, but it can also cause cells to behave abnormally and secrete
toxins that kill surrounding cells.
https://www.biospace.com/article/using-car-t-cells-in-senescent-diseases-like-diabetes-and-fibrotic-liver-disease/
Thursday, June 18, 2020
RedHill advancing study of opaganib in COVID-19 with two new trial applications
RedHill Biopharma Ltd. (RDHL -0.7%) has submitted applications in the UK and Italy for its Phase 2/3 clinical trial
evaluating Yeliva (opaganib) on top of standard-of-care treatment in
hospitalized patients with severe COVID-19 pneumonia who are receiving
supplemental oxygen.
Up to 40 sites across a range of countries will be recruited for the study.
The primary endpoint will be the proportion of
patients requiring mechanical ventilation by day 14 compared to those
receiving standard-of-care therapy alone. Preliminary data should be
available when ~100 participants have been evaluated for the primary
objective.
Last week, it filed an application in Russia for the study.
Opaganib inhibits
an enzyme called sphingosine kinase-2 (SK2) which blocks the synthesis
of a lipid-signaling molecule called sphingosine 1-phosphate (S1P) that
promotes cancer cell growth and pathological inflammation.
https://seekingalpha.com/news/3584270-redhill-advancing-study-of-opaganib-in-covidminus-19-two-new-trial-applicationsAbbVie nixes microbiome GI program collaboration with Assembly Biosciences
Assembly Biosciences (NASDAQ:ASMB) announces that it has regained global rights to all microbiome gastrointestinal (GI) programs out-licensed to AbbVie (NYSE:ABBV) unit Allergan in January 2017. Its decision was not based on efficacy or safety issues.
The transition, expected to be completed in Q4, includes Phase 1-stage ABI-M201 and preclinical-stage ABI-M301.
The company says the event will not change its projected cash runway, expected to be sufficient to fund operations into 2022.
https://seekingalpha.com/news/3584322-abbvie-nixes-microbiome-gi-program-collaboration-assembly-biosciencesAll still for play for in haemophilia gene therapy race
As durability continues to fog the future for Biomarin’s gene therapy, Pfizer and Sangamo keep up the pressure.
Biomarin is ahead of rivals with its valrox gene therapy for
haemophilia A, but in the end this might not count for much. Four-year
data released at the World Federation of Hemophilia’s annual meeting
showed treated patients’ clotting factor continuing to fade over time.
At the same conference Pfizer and Sangamo unveiled the longest-duration data seen so far for their candidate, SB-525. With a maximum of 61 weeks’ follow-up there is still much to learn about this project, but the signs are certainly encouraging, with no patients experiencing bleeding events or requiring factor VIII infusions so far.
The partners presented an update on five subjects who received a 3×1013vg/kg dose of the therapy, now generically known as giroctocogene fitelparvovec. Factor VIII activity levels, measured by chromogenic assay, were sustained at a median of 64.2%, according to a press release on the data.
It is too soon to gauge the durability of this response, although it is notable that Pfizer and Sangamo are generating this level of activity with a lower dose than Biomarin. That company’s valrox has been filed for accelerated approval at 6×1013vg/kg; a first look at results in seven patients who were given this dose four years ago was also presented at WFH this week.
This showed another decline in Factor VIII activity – dropping to a median 16.4% from 19.9% at the three-year mark (Biomarin suffers minimal bleeding on valrox readout, May 28, 2019).
At the same conference Pfizer and Sangamo unveiled the longest-duration data seen so far for their candidate, SB-525. With a maximum of 61 weeks’ follow-up there is still much to learn about this project, but the signs are certainly encouraging, with no patients experiencing bleeding events or requiring factor VIII infusions so far.
The partners presented an update on five subjects who received a 3×1013vg/kg dose of the therapy, now generically known as giroctocogene fitelparvovec. Factor VIII activity levels, measured by chromogenic assay, were sustained at a median of 64.2%, according to a press release on the data.
It is too soon to gauge the durability of this response, although it is notable that Pfizer and Sangamo are generating this level of activity with a lower dose than Biomarin. That company’s valrox has been filed for accelerated approval at 6×1013vg/kg; a first look at results in seven patients who were given this dose four years ago was also presented at WFH this week.
This showed another decline in Factor VIII activity – dropping to a median 16.4% from 19.9% at the three-year mark (Biomarin suffers minimal bleeding on valrox readout, May 28, 2019).
Biomarin presentation.
Supportive sellside analysts at Stifel noted that the rate of decline
was slowing, but it seems likely that at some point clotting factor
could drop below useful levels.
For now most patients are still benefiting. The average number of bleeds per year has dropped from 16.3 to 1.3, compared with 136 a year before the gene therapy.
It is encouraging that these measures have remained steady even as gene expression fades, and it seems highly likely that EU and US agencies will allow Biomarin to start selling the product in the next couple of months.
But questions around durability will complicate negotiations between the company and payers as a price point is negotiated, and make for a very difficult choice for patients, as they try to decide whether to wait for other gene therapies in the works that might prove more durable.
https://www.evaluate.com/vantage/articles/news/trial-results/all-still-play-haemophilia-gene-therapy-race
For now most patients are still benefiting. The average number of bleeds per year has dropped from 16.3 to 1.3, compared with 136 a year before the gene therapy.
It is encouraging that these measures have remained steady even as gene expression fades, and it seems highly likely that EU and US agencies will allow Biomarin to start selling the product in the next couple of months.
But questions around durability will complicate negotiations between the company and payers as a price point is negotiated, and make for a very difficult choice for patients, as they try to decide whether to wait for other gene therapies in the works that might prove more durable.
https://www.evaluate.com/vantage/articles/news/trial-results/all-still-play-haemophilia-gene-therapy-race
FDA gets aggressive with Covid-19 antibody tests
Chembio’s antibody test is the first to have its authorisation revoked. It might not be the last.
The US FDA’s rescinding of emergency use authorisation for Chembio’s Covid-19 antibody test on grounds of inaccuracy caused the company’s stock to plunge more than 60% yesterday. It might also have prompted the makers of other antibody tests with EUAs to wonder whether the agency’s action set a precedent.
The regulator took the action after performing its own investigation into the accuracy of the DPP Covid-19 IgM/IgG system, as Chembio’s test is called. And it is doing the same for the other assays it has authorised. Three so far have been given the all-clear, which leaves 13 authorised antibody tests still potentially vulnerable to being double-checked and found wanting.
The FDA began granting emergency market passes to antibody tests at the start of April, based on accuracy data submitted by the manufacturers; the agency checked this over but did not run separate evaluations of its own.
In mid-April the agency said it would start performing independent validations in concert with other US government agencies, including the National Cancer Institute. This has been a slow process, however, with reports on only four commercially produced antibody tests with EUAs having so far been made available. Chembio’s is the first to have run into trouble.
Crunching the numbers
The data Chembio submitted for its test claimed sensitivity of 93.5%, based on correctly identifying 29 of 31 positive samples, and specificity of 94.4%, getting 118 of 125 negative samples right. (These values are for the combined IgM and IgG antibodies; separate values were also given.) Data from an evaluation sponsored by the NCI and performed at the Frederick National Laboratory for Cancer Research found rather different numbers, summarised below.
In its revocation letter to Chembio
the FDA wrote that it was “not reasonable to believe that the test may
be effective in detecting antibodies against Sars-CoV-2”, or that its
benefits outweighed its risks, including the high rate of false results.
The FDA also stated in the letter that its current thinking on antibody tests was that they should have a minimum combined sensitivity of 90% and a minimum specificity of 95%. For tests that report specifically IgM and IgG, minimum sensitivity values of 90% and 70% for IgG and IgM respectively are called for. There are also other conditions including the number of samples on which these figures should be calculated.
So how do the other antibody tests stack up? Of the four assays that have been independently checked the most interesting is Helgen, which the FDA decided was good enough to stay on the market despite a relatively low positive predictive value – the probability that subjects with a positive test result truly have Covid-19 antibodies – of 68%.
It is important to note that the tables above and below are just
summaries – they do not include confidence intervals, for instance, or
the sizes of the samples on which accuracy values were calculated. When a
product tests separately for both IgG and IgM, combined accuracy
figures are given. The FDA’s own page on antibody test performance has a fuller picture, including accuracy data for the separate antibodies where appropriate.
As for the 13 commercial tests that have received EUA but have not yet been independently validated, all look good enough to meet the FDA’s minimum standards, though the positive predictive value of Cellex’s test is markedly low at 55%. And no matter how decent these figures look, NCI scientists might come up with different results.
https://www.evaluate.com/vantage/articles/news/policy-and-regulation/fda-gets-aggressive-covid-19-antibody-tests
The US FDA’s rescinding of emergency use authorisation for Chembio’s Covid-19 antibody test on grounds of inaccuracy caused the company’s stock to plunge more than 60% yesterday. It might also have prompted the makers of other antibody tests with EUAs to wonder whether the agency’s action set a precedent.
The regulator took the action after performing its own investigation into the accuracy of the DPP Covid-19 IgM/IgG system, as Chembio’s test is called. And it is doing the same for the other assays it has authorised. Three so far have been given the all-clear, which leaves 13 authorised antibody tests still potentially vulnerable to being double-checked and found wanting.
The FDA began granting emergency market passes to antibody tests at the start of April, based on accuracy data submitted by the manufacturers; the agency checked this over but did not run separate evaluations of its own.
In mid-April the agency said it would start performing independent validations in concert with other US government agencies, including the National Cancer Institute. This has been a slow process, however, with reports on only four commercially produced antibody tests with EUAs having so far been made available. Chembio’s is the first to have run into trouble.
Crunching the numbers
The data Chembio submitted for its test claimed sensitivity of 93.5%, based on correctly identifying 29 of 31 positive samples, and specificity of 94.4%, getting 118 of 125 negative samples right. (These values are for the combined IgM and IgG antibodies; separate values were also given.) Data from an evaluation sponsored by the NCI and performed at the Frederick National Laboratory for Cancer Research found rather different numbers, summarised below.
| Accuracy data on Chembio’s antibody test | ||
|---|---|---|
| Initially submitted by Chembio | NCI evaluation | |
| IgM sensitivity | 77.4% | 57.1% |
| IgM specificity | – | 86.2% |
| IgG sensitivity | 87.1% | 78.6% |
| IgG specificity | – | 91.2% |
| Combined sensitivity | 93.5% | 82.1% |
| Combined specificity | 94.4% | 81.2% |
| Combined PPV | 46.8% | 18.7% |
| Combined NPV | 99.6% | 98.9% |
| PPV and NPV at 5% prevalence. Source: FDA. | ||
The FDA also stated in the letter that its current thinking on antibody tests was that they should have a minimum combined sensitivity of 90% and a minimum specificity of 95%. For tests that report specifically IgM and IgG, minimum sensitivity values of 90% and 70% for IgG and IgM respectively are called for. There are also other conditions including the number of samples on which these figures should be calculated.
So how do the other antibody tests stack up? Of the four assays that have been independently checked the most interesting is Helgen, which the FDA decided was good enough to stay on the market despite a relatively low positive predictive value – the probability that subjects with a positive test result truly have Covid-19 antibodies – of 68%.
| Independently evaluated Covid-19 antibody tests with EUAs | |||||
|---|---|---|---|---|---|
| Company | Test | Sensitivity | Specificity | PPV | NPV |
| Chembio Diagnostic | DPP Covid-19 IgM/IgG | 82.1% | 81.2% | 18.7% | 98.9% |
| Euroimmun (Perkinelmer) | Anti-Sars-CoV-2 Elisa IgG | 90.0% | 100% | 100% | 99.5% |
| Hangzhou Biotest Biotech | RightSign Covid-19 IgG/IgM | 100% | 100% | 100% | 100% |
| Healgen | Covid-19 IgG/IgM | 100% | 97.5% | 67.8% | 100% |
| Commercial tests only. PPV & NPV = positive & negative predictive values. PPV and NPV calculated at 5% prevalence. Source: FDA. | |||||
As for the 13 commercial tests that have received EUA but have not yet been independently validated, all look good enough to meet the FDA’s minimum standards, though the positive predictive value of Cellex’s test is markedly low at 55%. And no matter how decent these figures look, NCI scientists might come up with different results.
| Covid-19 antibody tests with EUAs yet to be independently evaluated | |||||
|---|---|---|---|---|---|
| Company | Test | Sensitivity | Specificity | PPV | NPV |
| Abbott | Alinity i Sars-CoV-2 IgG | 100% | 99.0% | 84.0% | 100% |
| Abbott | Architect Sars-CoV-2 IgG | 100% | 99.6% | 92.9% | 100% |
| Autobio | Anti-Sars-CoV-2 | 99.0% | 99.0% | 84.4% | 99.9% |
| Bio-Rad | Platelia Sars-CoV-2 total Ab | 92.2% | 99.6% | 91.7% | 99.6% |
| Cellex | qSars-CoV-2 IgG/IgM | 93.8% | 96.0% | 55.2% | 99.7% |
| Diasorin | Liaison Sars-CoV-2 S1/S2 IgG | 97.6% | 99.3% | 88.0% | 99.9% |
| Inbios | SCoV-2 Detect IgG Elisa | 97.8% | 99.0% | 83.1% | 99.9% |
| Ortho-Clinical Diagnostics | Vitros anti-Sars-CoV-2 IgG | 90.0% | 100% | 100% | 99.5% |
| Ortho-Clinical Diagnostics | Vitros anti-Sars-CoV-2 Total | 100% | 100% | 100% | 100% |
| Roche | Elecsys anti-Sars-CoV-2 | 100% | 99.8% | 96.5% | 100% |
| Siemens Healthineers | Advia Centaur COV2T | 100% | 99.8% | 96.5% | 100% |
| Siemens Healthineers | Atellica COV2T | 100% | 99.8% | 96.7% | 100% |
| Vibrant America | Vibrant Covid-19 Ab | 98.1% | 98.6% | 78.7% | 99.9% |
| Commercial tests only. PPV & NPV = positive & negative predictive values. PPV and NPV calculated at 5% prevalence. Source: FDA. | |||||
UK ditches homegrown COVID-19 tracing app to use Google-Apple model
Britain will switch to the Apple and Google model for its COVID-19
test-and-trace app, ditching an attempt to develop an app by itself
after the homegrown system did not work well enough on Apple’s iPhone,
the government said on Thursday.
The test-and-trace programme is key to reopening the country but has
been dogged by problems. A smartphone app developed by the National
Health Service (NHS) was initially expected to be rolled out nationwide
in May but did not materialise.
Health minister Matt Hancock appeared to blame Apple in part for the pivot, adding that the decentralised Google-Apple system would benefit from work done on the abortive NHS app.
“As it stands, our app won’t work because Apple won’t change their system, but it can measure distance. And their app can’t measure distance well enough, to a standard we are satisfied with,” he said at the daily news conference.
“So we’ve agreed to join forces with Google and Apple, to bring the best bits of both systems together.”
Dido Harding, head of the test-and-trace programme has described the app as the “cherry on the cake” of the overall test-and-trace system, playing down its centrality to the programme.
But figures for the second week of England’s test-and-trace showed that while over 85,000 people who had tested positive for the new coronavirus had been reached in the first two weeks, over 25% of positive cases could not be reached.
Officials running the programme admitted that the change of tack on the app was unplanned but denied that it was a setback, emphasising that they did not want to rush out an app which fell short of standards.
But the opposition Labour party said that warnings about the homegrown app had not been heeded.
“This is unsurprising and yet another example of where the government’s response has been slow and badly managed. It’s meant precious time and money wasted,” Labour health spokesman Jon Ashworth said.
Britain’s adoption of the ‘decentralised’ approach for its app followed a growing number of European countries, including Italy, Switzerland, Germany and Austria.
But Apple and Google’s model has frustrated governments, as they undercut the technology’s usefulness by prioritising user privacy.
The pivot happened after the NHS app, which was being tested on the Isle of Wight off the southern coast of England, was found to work well on Google’s Android operating systems but not on Apple iPhones.
However, Britain wants further improvements to the Google-Apple
platform, meaning that the original hope of a launch in May is set to be
missed by months rather than weeks.
“We’re not going to put a date on it I’m afraid because I’m absolutely determined that whilst this technology can help, it’s got to be working effectively,” Hancock said.
https://www.reuters.com/article/us-health-coronavirus-britain-app/uk-ditches-homegrown-covid-19-tracing-app-to-use-google-apple-model-idUSKBN23P273
Health minister Matt Hancock appeared to blame Apple in part for the pivot, adding that the decentralised Google-Apple system would benefit from work done on the abortive NHS app.
“As it stands, our app won’t work because Apple won’t change their system, but it can measure distance. And their app can’t measure distance well enough, to a standard we are satisfied with,” he said at the daily news conference.
Dido Harding, head of the test-and-trace programme has described the app as the “cherry on the cake” of the overall test-and-trace system, playing down its centrality to the programme.
But figures for the second week of England’s test-and-trace showed that while over 85,000 people who had tested positive for the new coronavirus had been reached in the first two weeks, over 25% of positive cases could not be reached.
Officials running the programme admitted that the change of tack on the app was unplanned but denied that it was a setback, emphasising that they did not want to rush out an app which fell short of standards.
“This is unsurprising and yet another example of where the government’s response has been slow and badly managed. It’s meant precious time and money wasted,” Labour health spokesman Jon Ashworth said.
Britain’s adoption of the ‘decentralised’ approach for its app followed a growing number of European countries, including Italy, Switzerland, Germany and Austria.
But Apple and Google’s model has frustrated governments, as they undercut the technology’s usefulness by prioritising user privacy.
The pivot happened after the NHS app, which was being tested on the Isle of Wight off the southern coast of England, was found to work well on Google’s Android operating systems but not on Apple iPhones.
“We’re not going to put a date on it I’m afraid because I’m absolutely determined that whilst this technology can help, it’s got to be working effectively,” Hancock said.
https://www.reuters.com/article/us-health-coronavirus-britain-app/uk-ditches-homegrown-covid-19-tracing-app-to-use-google-apple-model-idUSKBN23P273
Fauci ‘casts doubt on football this fall’
With the United States bracing for a possible second wave of the
novel coronavirus, Anthony Fauci, director of the National Institute of
Allergy and Infectious Diseases, on Thursday cast doubt on the National
Football League playing this year.
“Unless players are essentially in a bubble — insulated from the community and they are tested nearly every day — it would be very hard to see how football is able to be played this fall,” Fauci said in an interview with CNN.
“If there is a second wave, which is certainly a possibility and which would be complicated by the predictable flu season, football may not happen this year.”
In the face of the COVID-19 pandemic, the NFL has pushed ahead with
plans to start the season as scheduled on Sept. 10, culminating with the
Super Bowl in Tampa on Feb. 7.
The outbreak has left most North American sport schedules in tatters. However the NFL, in its off-season, has been largely unaffected other than scrapping plans to hold the annual draft in Las Vegas in April and moving it online.
The league has protocols in place for the opening of team facilities and so far training camps remain scheduled to open on July 22, despite some high-profile positive tests.
Dallas Cowboys running back Ezekiel Elliott is one of several members
of his team and the Houston Texans to test positive for COVID-19, the
NFL Network reported on Monday.
NFL commissioner Roger Goodell told ESPN that the league expects some positive tests.
Fauci’s concerns also extend to U.S. college football which is scheduled to begin on Aug. 29.
https://www.reuters.com/article/us-health-coronavirus-nfl/fauci-casts-doubt-on-football-this-fall-idUSKBN23P2SL
“Unless players are essentially in a bubble — insulated from the community and they are tested nearly every day — it would be very hard to see how football is able to be played this fall,” Fauci said in an interview with CNN.
“If there is a second wave, which is certainly a possibility and which would be complicated by the predictable flu season, football may not happen this year.”
The outbreak has left most North American sport schedules in tatters. However the NFL, in its off-season, has been largely unaffected other than scrapping plans to hold the annual draft in Las Vegas in April and moving it online.
The league has protocols in place for the opening of team facilities and so far training camps remain scheduled to open on July 22, despite some high-profile positive tests.
NFL commissioner Roger Goodell told ESPN that the league expects some positive tests.
Fauci’s concerns also extend to U.S. college football which is scheduled to begin on Aug. 29.
https://www.reuters.com/article/us-health-coronavirus-nfl/fauci-casts-doubt-on-football-this-fall-idUSKBN23P2SL
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