FDA advisers reassert case against approval of Biogen Alzheimer's drug

 One of the most important decisions in the history of the Food and Drug Administration is quickly approaching. By early June, the agency should have a verdict on whether to approve aducanumab, a potentially first-of-its-kind treatment for Alzheimer's disease that became a major source of hope and controversy over the last two years.

Aducanumab is meant to the slow the cognitive decline that Alzheimer's patients experience by combating what many believe to be the root cause of disease. Such a treatment would be in high demand, given Alzheimer's care has been limited to medications that alleviate symptoms rather than change the disease's course. However, the data supporting aducanumab have come under intense scrutiny, leaving many doctors and researchers on the fence about its seeming benefit.

In November, the FDA convened a group of experts who advise the agency about brain drugs, and asked them whether there was enough positive evidence to say aducanumab works. Their answer was resoundingly negative, with all but one member voting against the drug.

While the FDA typically follows the recommendations of its advisers, it isn't required to. The agency is under immense pressure to clear more Alzheimer's treatments. And with certain high-ranking members of the FDA taking a favorable view of aducanumab, it's possible the drug may still be approved.

Perhaps that's why, on Tuesday, three of those FDA advisers rehashed their arguments against aducanumab in an editorial published in JAMA. The authors were Caleb Alexander, a professor of epidemiology and medicine at Johns Hopkins University; Aaron Kesselheim, a professor of medicine at Harvard Medical School; and Scott Emerson, a professor emeritus of biostatistics at the University of Washington.

The three were among the most vocal committee members in criticizing Biogen's case for aducanumab at the November meeting.

In their editorial, Alexander, Emerson and Kesselheim noted how the two large, near-identical clinical trials meant to prove aducanumab's merit showed very different results. One found patients who received a high dose for a long enough period of time did significantly better on a cognitive test than patients who received placebo. The other had the opposite outcome.

The authors called out the after-the-fact analyses that aducanumab's developer, Biogen, used to explain the disparate results. Namely, they took issue with how these "post hoc" analyses essentially presumed the positive study was reliable and the negative study was more a fluke, even though the consistent failure of drugs that work like aducanumab would suggest otherwise.

"In short, while post hoc analyses are useful for generating interesting hypotheses to be tested in future trials, the post hoc analyses regarding aducanumab provided limited information useful in deciding the benefit of this new drug and these post hoc analyses should not be the basis for FDA approval," they wrote.

The authors also detailed the close working relationship between the FDA and Biogen to analyze the clinical trial data. This "unusual degree of collaboration ... has been criticized as having potentially compromised the FDA's objectivity" in reviewing the drug, according to the three advisers.

While the authors acknowledged the dire need for safe and effective Alzheimer's drugs, and commended Biogen for running two large, valuable clinical trials, they ultimately see "no persuasive evidence to support approval of aducanumab at this time." FDA statisticians, ahead of the November advisory committee meeting, drew similar conclusions.

Though the arguments brought up in the JAMA article aren't new, "the decision by these authors to reiterate these points speaks to the degree to which they strongly believe that an aducanumab [rejection] is the correct decision here," wrote Brian Skorney, an analyst at Baird who's been critical of aducanumab and its approval odds.

The advisory committee members "clearly want FDA to remember what they said and not allow the long time frame between the meeting and the new [review deadline] to diminish their conclusions," Skorney added in his March 30 note to clients.

https://www.biopharmadive.com/news/aducanumab-fda-advisers-jama-alzheimers/597643/

Macron orders COVID-19 lockdown across all of France, closes schools

 President Emmanuel Macron on Wednesday ordered France into its third national lockdown and said schools would close for three weeks as he sought to push back a third wave of COVID-19 infections that threatens to overwhelm hospitals.

With the death toll nearing 100,000, intensive care units in the hardest-hit regions at breaking point and a slower-than-planned vaccine rollout, Macron was forced to abandon his goal of keeping the country open to protect the economy.

“We will lose control if we do not move now,” the president said in a televised address to the nation.

His announcement means that movement restrictions already in place for more than a week in Paris, and some northern and southern regions, will now apply to the whole country for at least a month, from Saturday.

Departing from his pledge to safeguard education from the pandemic, Macron said schools will close for three weeks after this weekend.

Macron, 43, had sought to avoid a third large-scale lockdown since the start of the year, betting that if he could steer France out of the pandemic without locking the country down again he would give the economy a chance to recover from last year’s slump.

But the former investment banker’s options narrowed as more contagious strains of the coronavirus swept across France and much of Europe.

For school-children after this weekend, learning will be done remotely for a week, after which schools go on a two-week holiday, which for most of the country will be earlier than scheduled.

Thereafter, nursery and primary pupils will return to school while middle and high school pupils continue distance learning for an extra week.

“It is the best solution to slow down the virus,” Macron said, adding that France had succeeded in keeping its schools open for longer during the pandemic than many neighbours.

FASTER VACCINATIONS

Daily new infections in France have doubled since February to average nearly 40,000. The number of COVID-19 patients in intensive care has breached 5,000, exceeding the peak hit during a six-week-long lockdown late last year.

Bed capacity in critical care units will be increased to 10,000, Macron said.

The new lockdown risks slowing the pace of France’s economic recovery from last year’s slump. It will force the temporary closure of 150,000 businesses at a cost of 11 billion euros ($12.89 billion) per month, the finance ministry said

The set-back for France, the euro zone’s second-largest economy, may also dampen Europe’s hopes of bouncing back swiftly from the pandemic, in the way that the U.S. and Chinese economies are doing.

France’s new lockdown underlines the cost of the European Union’s slow rollout of anti-COVID vaccines.

Neighbouring Britain, which finalised its divorce with the bloc on Jan. 1., has inoculated nearly half its population against the coronavirus and is re-opening its economy just as France hunkers down once again.

Macron said the vaccine campaign needed to be accelerated. Mired early on in red tape and slowed by supply shortages, it is only now finding its stride three months in, with just 12% of the population inoculated.

Bringing the calendar forward, Macron said people in their sixties would be eligible for a shot from mid-April and those in their fifties a month later. A goal of 30 million adults inoculated by mid-June remained the target, he said.

Seeking to offer hope, Macron said the April lockdown and a swifter vaccination campaign would allow the slow re-opening of the country from mid-May, starting with museums and the outdoor terraces of bars and restaurants, albeit under strict rules.

“We can see a way out of this crisis,” Macron said.

https://www.reuters.com/article/us-health-coronavirus-france-macron/macron-orders-covid-19-lockdown-across-all-of-france-closes-schools-idUSKBN2BN329

Delcath Adds Information on FOCUS Trial Power Calculation

 20.1% Lower Bound of Preliminary ORR Analysis Exceeds Required 8.3% Threshold

Delcath Systems, Inc. (NASDAQ: DCTH), an interventional oncology company focused on the treatment of primary and metastatic cancers of the liver, today provided additional information regarding the power calculation for the Phase 3 FOCUS trial of HEPZATO KIT (melphalan hydrochloride for injection/hepatic delivery system) in patients with liver dominant metastatic ocular melanoma (mOM).

In the summer of 2018, the Company amended the protocol for the FOCUS trial to a single arm design. In consultation with FDA, the FOCUS single arm trial was powered to demonstrate a superior Overall Response Rate (ORR) versus checkpoint inhibitors, one of the few mOM treatment categories with a significant amount of peer reviewed publications.

A point estimate of 21.0% ORR was calculated as the requirement to demonstrate superiority over the checkpoint inhibitors given the planned trial size and this threshold was shared with investors. The checkpoint inhibitor ORR was calculated based on a meta-analysis covering 16 different publications and 476 patients. The pooled overall response rate was 5.5% with a 95% Confidence Interval of 3.6% - 8.3%. To achieve statistical significance at a 95% Confidence Interval the lower bound of the ORR for HEPZATO needs to exceed the 8.3% upper bound of the meta-analysis. A preliminary analysis of 87% of enrolled patients analyses by the Independent Review Committee yielded an ORR of 29.2% [95% CI: 20.1, 39.8] in the Intent to Treat population, which substantially exceeds the 21.0%-point-estimate requirement. For further clarity, since the 20.1% lower bound exceeds the 8.3% upper bound of the meta-analysis the predefined success threshold was met. Further detail is available on the events and presentations section of the company website.

https://finance.yahoo.com/news/delcath-systems-inc-shares-additional-185500289.html

TG Therapeutics completes FDA filing for Roche challenger in CLL

 TG Therapeutics has completed its rolling FDA filing for its U2 combination therapy consisting of the antibody ublituximab with the oral drug Ukoniq (umbralisib) as a treatment for chronic lymphocytic leukaemia (CLL).

The US pharma is mounting a challenge to Roche, which markets an antibody therapy, Gazyvaro (obinutuzumab) in advanced CLL.

Like Gazyvaro, ublituximab targets a receptor known as CD-20 that is over-expressed on the surface of malignant B-cells that cause the disease, but adds umbralisib, an oral inhibitor of PI3K-delta and CK1-epsilon.

This adds to the potency of the medication by interfering with receptors that play an important role cell proliferation and survival, and regulate protein translation in cancer cells.

TG Therapeutics began a rolling filing with the FDA for the combination in December, following a $275 million fundraiser to bankroll late development and launch after supportive trial findings announced at the American Society of Hematology conference late last year.

The filing includes the UNITY-CLL phase 3 trial, a randomised study comparing the U2 combination therapy with an active control arm in which patients received Roche’s Gazyvaro plus chlorambucil chemotherapy in both treatment-naïve patients and those with relapsed/refractory disease.

The FDA had previously given the combination Fast Track designation, which allowed extra support to hasten development, as well as orphan drug development.

The trial met its primary endpoint of superior progression-free survival (PFS) for the U2 combination compared to the control arm to support the submission of the U2 combination in CLL.

Patients were randomly placed into four treatment arms: ublituximab single agent, UKONIQ single agent, ublituximab plus UKONIQ, and the active control arm.

A prespecified interim analysis was conducted to assess the contribution of ublituximab and UKONIQ in the U2 combination arm and allowed for the termination of the single agent arms.

The trial continued recruitment in a 1:1 ratio into the two combination arms: the investigational arm of U2 and the control arm of obinutuzumab plus chlorambucil.

About 420 subjects enrolled to the two combination arms and approximately 60% of patients were treatment-naïve and 40% were relapsed or refractory.

https://pharmaphorum.com/news/tg-therapeutics-completes-fda-filing-for-roche-challenger-in-cll/

Germany and Canada restrict AZ vaccine over blood clot fears

 Germany and Canada have both slapped restrictions on the AstraZeneca vaccine, recommending its use only in older patients, because of concerns over a link with blood clots.

The moves come after the country’s medicines regulator found 31 cases of a rare type of blood clot known as cerebral venous sinus thrombosis (CVST) in people who had received the vaccine produced by AZ.

The decision to restrict use of the shot in under-60s comes from Germany’s independent vaccine committee known as STIKO made the decision based on available data about the blood clotting events.

The decision runs counter to central guidance from the European Medicines Agency’s safety committee, which earlier this month said the AZ vaccine was safe and effective following a thorough review including incidences of CVST.

It is also a reversal of a previous position, where German authorities said that the AZ vaccine should not be used in patients in over 65, because of the smaller number of older patients in the first trials of the shot.

According to STIKO the side effect occurred four to 16 days after vaccination and was predominantly seen in people under 60 years of age.

The committee will address the issue of whether younger people who have already received a first dose of the AZ vaccine.

Germany’s Paul Ehrlich Institute said that within the 31 cases of CVST, there were 19 cases of thrombocytopenia.

Of those nine cases of thrombocytopenia, nine of the people affected died.

All but two of the 31 cases involved women aged 20 to 63 while two men affected were 36 and 57 years old, the institute said.

The decision had a knock-on effect: Canada’s National Advisory Committee on Immunization (NACI) also suspended vaccinations in those aged under-55s in updated guidance published earlier this week.

Several provinces have now suspended use of the vaccine for anyone below the age of 55 while Health Canada, the country’s central regulator, assesses the risk.

https://pharmaphorum.com/news/germany-and-canada-restrict-az-vaccine-again-over-blood-clot-fears/

Data Suggest Vaccinated Individuals Don't Carry Virus or Get Sick: CDC

 As COVID-19 cases continue to decline and vaccinations rise, people that have been fully vaccinated are wondering if they could still get the virus and if they can spread it.

“This pandemic, everything is so new, everything is constantly changing constantly evolving,” said teacher Angela Dancheva. 

The San Jose resident is fully vaccinated and not quite sure what to think about information that comes out of the Centers for Disease Control and Prevention (CDC).

“They are always changing,” said hospitality worker Yvonne Duarte. “The only thing I can say is just be informed do the best that you can.”

Their reaction comes after hearing this statement from CDC Director Dr. Rochelle Walensky.

“Our data from the CDC today suggests that vaccinated people don’t carry the virus, don’t get sick and that it’s not just in clinical trials, but it’s also in real world data,” said Walensky.

The director is referring to a new study of nearly 4,000 frontline workers, some vaccinated and some not. They tested themselves weekly for COVID-19 infections between December and March.

Among fully vaccinated people in the study, there were only three COVID-19 infections detected.

Unvaccinated participants logged 161 covid cases, scientific evidence experts say proves fully-vaccinated people are protected in two ways.

“Essentially vaccines block you from getting and giving the virus,” said UCSF Infectious Disease Specialist Dr. Monica Gandhi, adding this new information is significant.

“You can feel safe as a vaccinated person going indoor dining, going to a gym, going to the movies, going to places you did not feel safe before,” said Ghandi.

You can feel safe, she said, without being reckless.

“Now they can rewrite guidelines and say vaccinated people can be around unvaccinated people even without masks and distancing,” said Ghandi. “Not out in public because we don’t know who is vaccinated and who is not,  still going to maintain masks and distancing until everyone who wants to get a vaccine can get it.”

https://www.nbcbayarea.com/news/coronavirus/vaccinated-individuals-dont-carry-virus-or-get-sick-cdc/2506677/

Blood Clots and the AZ Vaccine, Revisited

By Derek Lowe

Once again, what’s going on with vascular events and the AZ/Oxford vaccine? I last wrote about this situation a couple of weeks ago, and it’s taken some real turns since then. At that point several EU countries had suspended dosing, but over the next week several began administering the vaccine again after the European Medicines Agency recommended it, in some cases with advisories about which age groups should be targeted.

But there’s more to the story, it seems. Here’s an excellent writeup at Science (open access) by Kai Kupferschmidt and Gretchen Vogel.   A possible concern is what’s being called vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) by Andreas Greinacher at Univ. Griefswald. This is a blood clotting syndrome that’s similar to what’s observed with the (already known) syndrome of heparin-induced thrombocytopenia. That problem, first over 40 years ago, is a paradoxical effect that occurs in a few people of administering heparin for blood clotting problems and actually making the situation worse. The mechanism for HIT is apparently the generation of antibodies to the complex of heparin bound to platelet factor 4 (PF4) protein. That binding sets off further inappropriate platelet activation, and that’s why the free platelet count drops (the “thrombocytopenia” part) as new clots form and existing blood clots become larger and more dangerous. You’d be used to someone presenting with thrombocytopenia to be at risk for bleeding disorders, not suffering from too many blood clots, but HIT is coming around from the other direction.

Greinacher’s team showed that patients who developed clotting disorders after vaccination showed the anti-heparin/PF4 antibodies, as in HIT, but it looks like these also bind to PF4 even when it’s not complexed to heparin. It’s possible that this happens (at least partially) via the adenovirus vector binding to platelets, but the details aren’t clear. There apparently is a subset of “classic” HIT cases who have shown this atypical PF4-alone antibody binding, so it’s a phenomenon that can happen without vaccination. The question, though, is whether vaccination is making it more likely, and whether there are particular populations who are more at risk.

Kupferschmidt passed on more information from Germany’s Paul-Ehrlich Institute just this morning. 2.7 million people have received the AZ/Oxford vaccine there, and 31 patients have been identified with cerebral venous thrombosis. Not all of those are HIT or VIPIT, though, because only 19 of the 31 had thrombocytopenia. There have been nine deaths, and as always, key questions are how many cases one would expect in the population that’s been dosed so far. Earlier this month, the figures were 1.7 million vaccinated and 7  cases of CVT, and the institute said that they would have expected about one case as normal background. The EMA, when they came out recommending the vaccine earlier this month, noted that figuring these background rates is not easy. But they found that if there is indeed an imbalance, it’s most noticeable in the younger age cohort and not in the older. The PEI mentioned today that of the 31 cases they have analyzed, 29 of them have been women, which certainly seems significant as well.

The UK experience with this vaccine has apparently shown no overall increase in thrombotic events – if anything, the vaccinated cohort has been slightly lower in that regard than the general population. But if there is an increased risk in people under 50, especially women, that’s actionable, as they say, even if the risk is very small (as it certainly appears to be). Other vaccines need to be available so that the doses can be aimed better. It’s also worth remembering that HIT (and presumably VIPIT, if it does turn out to be a real subset) can be treated with non-heparin anti-clotting drugs and/or by immunoglobin infusions, so the attempts by the EMA and others to raise awareness among physicians of this side effect are well worth it.

This is all happening against a background of increased infection in many European countries, of course. A worry is that some people will decide not to get vaccinated at all after hearing about these side effects, and regions where most of the available vaccine is the AZ/Oxford one may well see people deciding to wait for a different one, if that’s a possibility. If such things noticeably affect the number of people getting vaccinated, they could easily end up killing off more people in general than any of the vascular side effects will. But it’ll be in different groups – if the information we have now holds up, then younger women would be at small-but-greater-than-others risk of side effects, but the pandemic fatalities would probably be more in older men. A grim thing to be totaling up – more on this as we get more information.

https://blogs.sciencemag.org/pipeline/archives/2021/03/30/blood-clots-and-the-az-vaccine-revisited