European Commission Raids AstraZeneca’s Belgian Vaccine Plant

 The European Commission’s (EC) fight with AstraZeneca heated up Wednesday when it sent Belgium regulators to the manufacturer’s COVID-19 vaccine production site near Brussels. Regulators removed samples and records from the plant, which are being examined by experts from Belgium, the Netherlands, Italy and Spain. A report, and a possible second visit, is expected within days.

The raid was triggered by production problems at the facility run by AstraZeneca’s partner, Novasep, a European leader in the production of viral vectors. Those problems resulted in AstraZeneca reducing the doses it can supply to the European Union (EU) this quarter by 60% (down from 56.2 million doses to only 31 million) and also called the number of doses anticipated for Q2 2021 into question.

In a letter to AstraZeneca, EC Commissioner Stella Kyriakides seemed to suggest that doses may have been diverted from EU member states to other nations. As she said, “The European Union wants to know exactly which doses have been produced by AstraZeneca and where exactly so far, and if or to whom they have been delivered. The answers of the company have not been satisfactory so far.”

The inspection of AstraZeneca’s Seneffe production site, south of Brussels, was conducted to ensure “that the delivery delay is indeed due to a production problem on the Belgian site,” according to a spokesperson for the Belgium health ministry, speaking to The Guardian.

Assurances by the World Health Organization’s Special Envoy on COVID-19, Dr. David Nabarro, that shortfalls result from efforts to improve the quality of production and they are just a part of reality, weren’t sufficient for the EC.

On Thursday, in another salve aimed at the company, Germany’s Federal Ministry of Health advised that AstraZeneca’s vaccine not be used for people older than 65, Reuters reported. AstraZeneca refuted those claims, but South Korea also is assessing the vaccine’s efficacy among the elderly. So far, the vaccine’s efficacy data for elderly populations remains limited.

The European Medicines Agency (EMA) meets Friday, January 29^th, to vote on approving the AstraZeneca vaccine. While side-stepping AstraZeneca’s debacle with the EC, EMA Executive Director Emer Cooke said the company still was providing data early in the week and that emergency use authorization was up to the EU member states rather than her agency, Ireland’s national public radio, RTE, reported.

Speaking at the World Economic Forum held virtually this week (rather than at its usual Davos, Switzerland venue), EC President Ursula von der Leyen pledged to form a “vaccine export transparency mechanism” to monitor vaccine exports from Europe. As she pointed out, "Europe invested billions to help develop the world's first Covid-19 vaccines to create a truly global common good. Now, the companies must deliver. They must honor their obligations. Europe means business.”

That determination was expressed by Kyriakides, too, noting, “all companies producing vaccines against COVID-19 in the EU will have to provide early notification whenever they want to export vaccines to third countries.”

Humanitarian shipments were excluded.

This includes doses leaving the EU for the U.K.

The day of the raid in Belgium, Kyriakides suggested that the AstraZeneca vaccines that were made in the U.K. should be distributed within the EU. Although the U.K. signed a contract three months before the EU, Kyriakides maintained that “first-come, first served works in a butcher’s shop, but not in contracts and not in our advanced purchase agreements.”

Causing the U.K. to rely upon vaccine produced on its shores could delay the time to reach herd immunity (defined as 75% vaccination) by two months, according to the analytics firm Airfinity and reported by MSN.

Thursday, U.K. Cabinet Office minister Michael Gove agreed to help the EU with its shortage, but only if it had spare vials. “But the really important thing is to make sure our own vaccination program proceeds precisely as planned,” he said in The Guardian newspaper.

There’s no denying that Europe is suffering. Hospitals in Paris and two other regions (Burgundy and Hauts-de-France) plan to suspend COVID-19 vaccinations next week because of vaccine shortfalls. Germany says its shortages will continue into April. Portugal says it will have only half its expected doses by March.

None-the-less, AstraZeneca pointed out that its supply chains were established to meet the needs of specific contracts. Consequently, any production problem in one region affects only that region.

With manufacturing issues slowing production, EC officials are threatening to make AstraZeneca’s contract public, the British newspaper The Telegraph reported. If that happens, the public will learn that AstraZeneca, unlike other large vaccine manufacturers, is making the vaccine available at cost.

Since Tuesday, AstraZeneca’s share prices have fallen 5.5% and its reputation risks being tarnished. In light of this and an ongoing row with the EC, some speculate the company may revisit its at-cost pricing decision.

https://www.biospace.com/article/european-commission-raids-astra-zeneca-s-belgian-vaccine-plant/

AIM ImmunoTech in Pact for Intranasal Safety Study of Ampligen

 AIM ImmunoTech Inc. (NYSE American: AIM) today announced that it has entered into a sponsorship agreement with the Centre for Human Drug Research (CHDR) for the proposed AMP-COV-100 (CHDR2049) clinical study on the safety of AIM’s drug Ampligen as an intranasal therapy, a critical step in the company’s ongoing efforts to develop Ampligen as a COVID-19 treatment.

CHDR, an independent institute located in Leiden in the Netherlands, will conduct and manage the proposed clinical study, titled “A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Activity of Repeated Intranasal Administration of Ampligen (Poly I:Poly C₁₂U) in Healthy Subjects.”

Current study plans call for the enrollment of eight healthy subjects in each of four Ampligen treatment groups and one placebo group, for a total of 40 healthy subjects. They will receive intranasal dosing every other day for 13 days, for a total of seven doses each.

AIM is funding the clinical study. The company is working to finalize the study protocol and will announce new information as it becomes available.

https://www.biospace.com/article/releases/aim-immunotech-enters-into-agreement-for-proposed-intranasal-safety-study-of-ampligenaim-is-working-to-develop-an-effective-covid-19-intranasal-therapy/

Pandemic mutations prompt antibody collaborations

 Several new variants of the pandemic virus are causing alarm around the world, in case existing vaccines, monoclonal antibodies and natural immunity become less protective. Drug developers are racing to stay ahead of these mutations, and a collaboration announced yesterday between Lilly, Glaxo and Vir was the latest example of these efforts.

The groups will test a new combination of Lilly’s bamlanivimab plus Vir’s VIR-7831; however, staying ahead of variants is only one of the problems that these antibody developers face. Usage has also failed to take off as expected, and it is not inconceivable that the virus could render some of these MAbs ineffective before they can become entrenched.

Lilly’s existing combination – bamlanivimab plus etesevimab – seems to be particularly vulnerable, if academic research released this week holds up to scrutiny. The MAbs’ effectiveness was found to be markedly reduced against the so-called South African variant (B1351), which is causing the most concern for its potential for increased transmissibility and ability to cause more severe disease.

The researchers also tested Regeneron’s antibody cocktail, casirivimab and imdevimab, and found this did manage to knock down the B1351 variant, although the latter antibody was responsible for the knockdown. Both MAb combinations held up well against the UK variant (B117).

It should be remembered that this paper, from Columbia University, is only available as a pre-print. There are also questions around the extent to which results obtained via lab assays translate to the real world.

It is also far from clear whether the South African variant will become widespread and present a problem; however, some believe that the results do not bode well for Lilly. Leerink analysts went as far as to say that it will be hard to justify continued use of bamlanivimab once other antibodies are available, and that monotherapy with this antibody should be phased out.

Leading anti-Covid-19 antibodies
Product (company)	Authorisation setting	Ongoing or confirmatory trials
Casirivimab + imdevimab (Regn-COV2; Regeneron)	Patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation	Subcutaneous formulation; prevention; confirmatory in mild to moderate; hospitalised.
Bamlanivimab (LY-CoV555; Lilly)	Patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation	Prevention study (Blaze-2); + etesevimab mild to moderate (Blaze-1)
Bamlanivimab + etesevimab (LY-CoV016; Lilly)	Filed for patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation	Prevention study (Blaze-2); mild to moderate (Blaze-1)
Source: Company statements.

It seems likely that Lilly had already anticipated bamlanivimab’s weaknesses, and indeed this week the company said that the monotherapy product will be phased out as the combination with etesevimab comes on line. The company anticipates emergency use authorisation for the combo on the back of new data from the Blaze-1 trial, reported this week, which showed a remarkable 70% reduction in the risk of death among non-hospitalised high-risk patients.

On a call this week, Lilly executives insisted that the bamla + ete combo could knock down variants being found in the US right now. A novel project thought to be highly potent against the South African variant is “moving towards human trials” in case that becomes widespread, said Dan Skovronsky, the group's chief scientific officer.

Guarding against future variants is also no doubt the aim of the Vir collaboration. The company's antibody, which is being developed in partnership with Glaxo, will be tested in combination with bamla in a new arm of Blaze-1.

Lilly has several other preclinical projects in the wings, Mr Skovronsky said. “We may need antibodies that are more variant specific in the future. We might need cocktails of three or more antibodies.” 

This is one reason why Lilly is trying to drive dosages down, he said: the successful data from Blaze-1 was derived from two huge 2,800mg doses each of bamla and ete, which require infusion times of over an hour.

Logistics

The logistical problems associated with long infusion times, on top of the novelty of such a therapy to treat an infectious disease, have been major brakes on uptake of these antibody therapies. Lack of data was another barrier, according to the Lilly execs, but the Blaze-1 results should change things.

“We’ve removed that obstacle and we think uptake should improve dramatically based on this dataset,” Mr Skovronksy said.

Lilly has forecast sales of $1-2bn this year from its Covid-19 products, most of which will be from antibodies, an estimate that seems extremely bullish considering the limited use so far. Success in accelerating infusion times is surely going to be needed for these numbers to be met.

Lowering dosages could help for another reason: more people can be dosed with the same amount of raw product. Global antibody manufacturing capacity is finite, Mr Skovronksy pointed out, and developers for now only have leverage on dose.

Mr Skovronksy also said that the lead time for identifying and manufacturing a new antibody is five or six months, at a minimum. Of course MAbs have yet to win a place at the forefront of the fight against this virus, despite data suggesting they should be used more widely. But that time lag should probably be considered another hurdle for these therapies against this incredibly fast-changing virus.

 Bamlanivimab: 102

https://www.evaluate.com/vantage/articles/news/pandemic-mutations-prompt-antibody-collaborations

NY nursing home COVID deaths more than 12K: Cuomo health chief

 A damning attorney general’s report that showed Gov. Andrew Cuomo and other officials downplayed the deadly impact of COVID-19 on New York’s nursing homes finally led the state’s embattled health commissioner on Thursday to reveal the total number of resident fatalities.

In a defensive, nearly 1,700-word statement, Dr. Howard Zucker released figures that put the tally of confirmed and presumed deaths in both nursing homes and hospitals at 12,743 as of Jan. 19.

The staggering number is only slightly less than the 13,000-plus suggested by the report issued earlier in the day by Attorney General Letitia James.

That report said data from 62 nursing homes showed the death toll of residents was 56 percent higher than publicly acknowledged by by the Department of Health.

“The New York State Office of the Attorney General report is clear that there was no undercount of the total death toll from this once-in-a-century pandemic,” Zucker claimed.

“The word ‘undercount’ implies there are more total fatalities than have been reported; this is factually wrong.”

Prior to Zucker’s grudging announcement, the official DOH count of nursing home deaths from COVID-19 included only residents who actually died in nursing homes — and not anyone who died at a hospital while undergoing treatment.

Earlier Thursday, the DOH website put that figure at 8,740, citing data current as of a day earlier.

“DOH data audited to date shows that from March 1, 2020 to January 19, 2021 9,786 confirmed fatalities have been associated with Skilled Nursing Facility residents, including 5,957 fatalities within nursing facilities, and 3,829 within a hospital,” Zucker said.

“When 2,957 presumed COVID nursing home fatalities – those fatalities that occurred when testing was scarce and lack confirmed evidence the deceased had COVID – are included, the state’s share of fatalities of individuals that died in nursing homes or in hospitals after transfer is 29.8% of the total number of confirmed and presumed deaths in New York State listed by CDC.”

Zucker’s statement doesn’t actually include the total of those various death counts.

The DOH had been facing calls to release the total number of deaths from The Post, lawmakers on both sides of the aisle and the Empire Center for Public Policy, which filed suit under the state Freedom of Information Law in September.

On Monday, state Senate Investigations Committee Chairman James Skoufis (D-Newburgh) even threatened to issue a subpoena, calling it “downright insulting…that, six months later, DOH is continuing to stonewall us on basic questions.”

Zucker also said that James’ report “found no evidence” that a controversial, March 25 DOH directive for nursing homes to admit coronavirus patients had “resulted in additional fatalities in nursing homes.”

However, one of the findings listed in James’ report says in full, “Government guidance requiring the admission of COVID-19 patients into nursing homes may have put residents at increased risk of harm in some facilities and may have obscured the data available to assess that risk.”

More than 6,300 “COVID-positive residents” were admitted to nursing homes before Cuomo rescinded the policy in May, according to a DOH report from July that blamed the spread of the coronavirus on infected, but asymptomatic, workers.

https://nypost.com/2021/01/28/ny-nursing-home-covid-deaths-more-than-12k-cuomo-health-chief/

Fauci: Biden push to reopen schools in 100 days ‘may not happen’

 Dr. Anthony Fauci warned in a new interview that President Joe Biden’s push to reopen most schools within 100 days “may not happen” amid the coronavirus pandemic.

Among a flurry of executive orders, Biden has issued an order requiring the Departments of Education and Health and Human Services to provide federal guidance on reopening, “with the goal of getting a majority of K-8 schools safely open in 100 days.”

“The president is taking very seriously the issue … both from the student standpoint and from the teacher standpoint,” Fauci said during a virtual event sponsored by the American Federation of Teachers and National Education Association, according to Education Week.

“He really wants to and believes that the schools need to reopen in the next 100 days, essentially all the K to 8 schools, within 100 days. That’s the goal,” continued Fauci, 80, the director of the National Institute of Allergy and Infectious Diseases and the president’s chief medical adviser.

“That may not happen because there may be mitigating circumstances, but what he really wants to do is everything within his power to help get to that,” he added.

The top doc noted that there is “some light at the end of the tunnel” regarding the availability of effective COVID-19 vaccines and that reopening schools is a critical part of the White Houses’ response to controlling the pandemic.

“We’re not going to get back to normal until we get children back into school, both for the good of the children, for the good of the parents, and for the good of the community,” he said.

 “We want to make sure we do that by giving the teachers and the teams associated with teachers the resources that they need to do that. The idea of, ‘Go do it on your own’ — that doesn’t work,” Fauci added.

https://nypost.com/2021/01/29/fauci-joe-bidens-push-to-reopen-schools-may-not-happen/

WCLC: Takeda kinase inhibitor curbs 78% of lung cancers with rare EGFR mutation

 EGFR inhibitors like AstraZeneca’s Tagrisso and Genentech’s Tarceva have been on the market for years to treat patients with lung cancer. But those drugs are designed to treat patients with specific mutations, and one patient group with a rare type of EGFR mutation has fallen through the cracks. With promising phase 1/2 data, Takeda is one step closer to providing those patients with a targeted treatment.

The company’s tyrosine kinase inhibitor (TKI) curbed tumor growth in 78% of 114 patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions. It shrank tumors in 28% of the patients and staved off cancer progression for a median of seven months. Patients responded to the treatment for a median of 17.5 months.

The study tested the drug, mobocertinib, in patients whose cancer had gotten worse despite undergoing platinum chemotherapy. The data come from patients who had received a 160-mg dose of mobocertinib each day. These include those in the dose-escalation and initial expansion portions of the study—in which multiple doses were tested—as well as from the pivotal phase 2 extension group, in which 96 patients received the same 160=mg dose.

“This patient population is so desperately in need of a treatment that can specifically address that oncodriver mutation responsible for the metastatic non-small cell lung cancer,” Chris Arendt, Ph.D., Takeda’s oncology therapeutic area head, said. Patients with this type of mutation have one or more nucleotide bases—or letters—inserted in a segment of DNA called exon 20.

“It affects about 10% of patients who present with EGFR mutations, while other exons—18, 19, 21—cause different subtypes of disease,” Arendt said, adding that exon 20 insertions affect about 2% of NSCLC patients globally.

Because there is no targeted treatment for this specific mutation, patients with this type of lung cancer are treated with platinum chemotherapy.

“Some patients have been placed, historically, on other EGFR inhibitors, or in some cases, on checkpoint inhibitors, but across the board, responses to these are limited,” Arendt said.

“These are relapsed, refractory patients with essentially very little left in terms of options and we now see a majority of patients—almost 80%—getting a meaningful clinical benefit from mobocertinib,” he said.

There were no surprises in the drug’s safety profile, which mirrors what is typically seen with TKIs. As of the May data cutoff, the most common side effect was diarrhea, afflicting 90% of patients, followed by rash, affecting 45% of patients. Most side effects were mild to moderate and managed with supportive care, Arendt said.

Nineteen patients (17%) quit the study because of side effects, most commonly diarrhea (4%) and nausea (4%). Takeda has worked with investigators on a plan to manage side effects over the course of the study that went into effect toward the tail end of the phase 2 extension study.

“The good news is we have a plan going forward and also now something we can include in the prescribing information,” Arendt said. “It’s fairly simple and patient-friendly and aims to allow patients and their practitioners to be as prepared as possible to treat gastrointenstinal adverse events … as early as possible in the course of treatment.”

Takeda is not the only company working to treat patients with this particular EGFR mutation. Johnson & Johnson filed its bispecific antibody, amivantamab, for FDA approval just last month. Though J&J may snag the first approval for this patient population, its drug is given through intravenous infusion, which could give mobocertinib, an oral drug, an advantage on the convenience side.

“It can’t be understated what this can mean for the quality of life of patients. It’s easy to forget that patients live all over the map and not everyone lives close to a cancer center,” Arendt said. Oral medicines that can be delivered to patients’ homes have become even more important during a pandemic where patients may want to avoid coming into hospitals or clinics.

https://www.fiercebiotech.com/biotech/wclc-takeda-s-new-kinase-inhibitor-curbs-78-lung-cancers-rare-egfr-mutation

1-dose COVID-19 vaccine candidate storable at room temp prompts immunity in animals

 Among the logistical challenges facing public health agencies that are struggling to vaccinate the masses against COVID-19 is that the two mRNA shots on the market, from Moderna and Pfizer, need to be stored at ultra-cold temperatures. Now, an alternative technology for shielding patients from the novel coronavirus—one that doesn’t pose that storage challenge—is showing early promise.

Two vaccine candidates built from gene-therapy technology and developed by Mass General Brigham scientists elicited strong immune responses in mouse and nonhuman primate models, the researchers reported on the journal preprint site bioRxiv. The team received a grant of up to $2.1 million from the Bill & Melinda Gates Foundation to further develop the vaccine technology, called AAVCOVID.

The vaccines, which remain stable when stored at room temperature, use an adeno-associated virus (AAV) vector to deliver genetic sequences of SARS-CoV-2, the virus that causes COVID-19. That generates antigens of the virus’s signature spike protein, in turn prompting an immune response.

A single injection of either of the AAVCOVID vaccine candidates induced neutralizing antibodies in one mouse model of obesity and another of aging—two conditions that have been linked with poor COVID-19 outcomes. The response lasted for at least three months, according to the study. In the monkey models, the immune response lasted for five months.

All animals also showed memory T-cell responses, which are believed to be critical for maintaining long-term immunity to COVID-19.

Although the demand for the mRNA vaccines from Pfizer and Moderna is strong, the shots present some hurdles. The need for cold storage will make distributing the vaccines in developing countries difficult. And both vaccines require two doses to confer full immunity, which only adds to the logistical challenges—and the cost—the Mass Gen researchers argued in their study.

Because AAVs are already widely used to deliver gene therapies like Novartis’ Zolgensma for spinal muscular atrophy, the Mass Gen team was able to ramp up its preclinical studies quickly. To accelerate the effort, the researchers formed early partnerships with gene therapy specialists at the University of Pennsylvania and with Novartis, which agreed to manufacture the AAVCOVID vaccines for clinical trials.

“The fact that there’s an established industry out there around AAV made it easy for us to step into the existing [manufacturing] capacity, rather than having to build it,” said lead investigator Luk Vandenberghe, Ph.D., an associate professor at Harvard Medical School and director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear, in an interview with Fierce Biotech last year.

Vandenberghe’s team is now planning to start clinical trials of the vaccines overseas.

The researchers acknowledged in the study that several other vaccine candidates are nearing approval. But they believe the AAVCOVID shots will prove valuable because of other attributes that “will likely be critical to achieving the desired long-lasting herd immunity at a global population scale,” they wrote. “Many of these considerations are logistical in nature and seek to reduce the cost, time, and complexity of vaccine distribution using available infrastructure around the world.”

https://www.fiercebiotech.com/research/one-dose-covid-vaccine-candidate-can-be-stored-at-room-temperature-prompts-immunity