FDA could reject AstraZeneca COVID vax on efficacy, manufacturing shortfalls

 It was bad enough when a study released last week concluded that AstraZeneca’s COVID-19 vaccine was largely ineffective against the aggressive B.1.351 variant that recently emerged in South Africa. Now, analysts are wondering whether inconsistent manufacturing of the vaccine for the clinical trials may have muddied the results—concerns that could give the FDA pause when considering the vaccine for emergency use.

That was the conclusion of a note SVB Leerink analysts sent to clients Wednesday, in which they laid out both the bear and bull cases for FDA authorization of AstraZeneca’s COVID vaccine. The bottom line? The bear case is worrisome, they said.

One major concern SVB Leerink cited is that AstraZeneca is manufacturing its vaccine on a “distributed” basis, meaning it’s not centralized, but spread over multiple sites and contract partners. The material used to make the vaccine for the South Africa trial came from a company in India, and it’s not clear where it was manufactured or whether the results from that trial truly reflect the properties of the vaccine that’s being developed for the U.S.

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“Changing manufacturing sites for a vaccine is problematic in the best of times, but in pandemic circumstances, without a recognized correlate of protection, or any bridging immunogenicity studies, it can be disastrous,” SVB Leerink wrote.

That uncertainty could be magnified by the fact that for earlier published trials, AstraZeneca’s vaccine was manufactured at different sites and tested at varying dosing schedules. That may not jibe with the FDA’s usually exacting standards.

“Ultimately one source, one dose, and one dose interval need to be studied and established and reviewed by regulators so the product can have a standard label for physicians and other providers to discuss with patients,” the analysts warned.

Then there’s the question of just how efficacious AstraZeneca’s COVID-19 vaccine actually is, particularly with emerging mutants of the virus spreading rapidly across the world.

Last week’s study concluded that the vaccine was just 22% effective at protecting against mild to moderate COVID symptoms and that neutralization titers against the South Africa variant were “substantially reduced” in comparison to the original virus, said researchers at Oxford University, where the vaccine was originally developed.

Oxford and AstraZeneca are now updating the vaccine so it can tackle the South Africa variant. The reformulated shot could be ready by fall. But officials in South Africa have suspended their rollout of the shot for now.

All in all, FDA officials could very well decide not to clear a sub-par vaccine, even though the demand for vaccination is far outstripping the supply of the two mRNA vaccines on the market, from Moderna and Pfizer/BioNTech. That’s especially true given the fact that the two marketed vaccines—as well as one from Johnson & Johnson that could get emergency use authorization soon—seem to be better at shielding against the novel variants, SVB Leerink said.

“Since one or more of these [mutant] strains is likely to become dominant in the US by early summer, it is hard to imagine the FDA approving a vaccine with zero efficacy against such strains, and which, if widely used, would only accelerate the spread, and perhaps the further adaptation” of the virus, they wrote.

So what’s the bull case for AstraZeneca’s product? The near-term supply of COVID-19 vaccine doses has come nowhere close to meeting the demand. By SVB Leerink’s calculations, 88% of the U.S. population has yet to start the two-dose vaccination process.

Plus, more reliable data could be on their way. A clinical trial of AstraZeneca's vaccine in the U.S. was put on hold briefly because of safety concerns last year, but it has since resumed, and results could show that manufacturing and other factors were “better controlled than in other geographies,” SVB Leerink said.

“We believe that it is possible that the overwhelming U.S. supply discrepancy with demand could weigh in on the decision to grant a U.S. AstraZeneca vaccine approval, given that data thus far implies efficacy that is above FDA COVID-19 vaccine guidelines,” the analysts wrote.

https://www.fiercepharma.com/pharma/fda-could-reject-astra-zeneca-s-covid-vaccine-efficacy-and-manufacturing-shortfalls-analyst

Safer Alzheimer's drug than Biogen aducanumab? Denali-WashU drug may show better profile

 In 2018, a research group led by David Holtzman, M.D., at Washington University in St. Louis developed an antibody drug in collaboration with Denali Therapeutics that showed promise as a potential Alzheimer’s disease therapy. Now, the team has returned with mouse data suggesting the drug prospect might be a safer option than Biogen’s much-hyped aducanumab.

The antibody, called HAE-4, targets the APOE4 gene, which is strongly associated with a high risk of late-onset Alzheimer’s disease. In a mouse model, the drug successfully reduced the toxic buildup of the beta-amyloid protein from brain tissues and blood vessels—and it did that without triggering brain bleeds, a dangerous side effect seen with anti-amyloid antibodies including aducanumab.

The findings, published in Science Translational Medicine, suggest HAE-4 could be a potentially safer amyloid-clearing drug for treating Alzheimer’s and cerebral amyloid angiopathy (CAA), the researchers said.

Many drug development efforts in Alzheimer’s focus on targeting beta-amyloid. Anti-amyloid antibodies such as aducanumab have been shown to clear the harmful protein in the brain, but their use has been linked to brain swelling and microhemorrhages, which can cause CAA, a risk factor for strokes. Almost all Alzheimer’s patients already suffer from CAA, so it would be ideal to remove beta-amyloid without worsening the condition.

“Each of the antibodies that removes amyloid plaques in clinical trials is a little different, but they all have this problem, to a greater or lesser degree,” Holtzman said in a statement.

Holtzman and colleagues previously showed that HAE-4 can recognize a particular type of human APOE that resides in the brain and influences the development of amyloid plaques. The drug reduced the plaque burden in mice by half, according to the team’s 2018 study. This time, the researchers also found this form of APOE in CAA, which is marked by amyloid buildup in the walls of brain arteries.

The scientists tested the drug in mice genetically modified with human genes for amyloid and APOE4. The animals already developed abundant amyloid plaques in brain tissues as well as robust CAA.

Both HAE-4 and aducanumab were able to clear out amyloid plaques in the brain, but only HAE-4 was able to significantly reduce beta-amyloid in brain blood vessels, the team found. The new drug also restored vascular functions such as the ability to dilate and contract.

One hypothesis is that anti-amyloid antibodies can cause an overreactive inflammatory response as they try to recruit immune cells called microglia to clear out protein debris. Holtzman’s team suspected that targeting APOE—a much smaller part of the amyloid plaque—might lessen inflammation and prevent CAA.

After two months of treatment, mice that got HAE-4 didn’t experience more bleeding episodes than did animals that were given a control antibody drug, whereas aducanumab appeared to have exacerbated microhemorrhages, the team found.

Further analysis showed that both HAE-4 and aducanumab initially elicited immune responses with increased expression of microglial genes and other pro-inflammatory genes. However, after chronic treatment and plaque removal, mice that received HAE-4 were no longer showing signs of those effects, while the response persisted in the aducanumab group.

The use of aducanumab stimulated star-shaped cells called astrocytes to cluster around beta-amyloid deposits in the blood vessels, and their activity correlated with microhemorrhage severity, the team found. “The chronic reactivity of these GFAP+ astrocytes may lose their normal functions, such as maintenance of the blood-brain barrier, and adopt a disease-associated function that leads to leaky vessels and brain hemorrhages,” the researchers explained in the study.

Overall, the study showed that targeting specific APOE—a subcomponent of both amyloid plaques and CAA—could achieve the amyloid-clearing efficacy seen with beta-amyloid antibodies while preventing CAA-related side effects in mice. Therefore, HAE-4 may represent a new disease-modifying treatment for both Alzheimer’s and CAA, the researchers said.

https://www.fiercebiotech.com/research/a-safer-alzheimer-s-drug-than-biogen-s-aducanumab-denali-washu-drug-shows-better-profile

Delay urged in Pfizer vaccine's second dose as first highly effective: NEJM

 The second dose of Pfizer Inc’s COVID-19 vaccine could be delayed in order to cover all priority groups as the first one is highly protective, two Canada-based researchers said in a letter published in the New England Journal of Medicine.

The vaccine had an efficacy of 92.6% after the first dose, Danuta Skowronski and Gaston De Serres said, based on an analysis of the documents submitted by the drugmaker to the U.S. Food and Drug Administration (FDA).

These findings were similar to the first-dose efficacy of 92.1% reported for Moderna Inc's mRNA-1273 vaccine, according to the letter here on Wednesday.

In its response, Pfizer said alternative dosing regimens of the vaccine had not been evaluated yet and that the decision resided with the health authorities.

Some countries, grappling with low supplies, are looking at dosing patterns or volumes that differ from how the vaccines were tested in clinical trials.

There are differences over the merits of such strategies, with some arguing the urgency of the pandemic requires flexibility, while others oppose abandoning data-driven approaches for the sake of expediency.

Skowronski and De Serres cautioned that there may be uncertainty about the duration of protection with a single dose, but said the administration of the second dose a month after the first provided “little added benefit in the short term”.

Skowronski works at the British Columbia Centre for Disease Control, while De Serres is from the Institut National de Santé Publique du Québec

In Britain, authorities have said that data supported its decision to move to a 12-week dosing schedule for Pfizer’s COVID vaccine. Both Pfizer and partner BioNTech have warned that they had no evidence to prove it.

Pfizer’s vaccine is authorized to be taken 21 days apart.

The U.S. FDA and the European Medicines agency have stuck by the interval tested in the trials.

https://www.reuters.com/article/us-health-coronavirus-pfizer/researchers-urge-delaying-pfizer-vaccines-second-dose-as-first-highly-effective-idUSKBN2AI0EC

Automakers, medical device firms ask Biden for U.S. chip factory subsidies

 More than a dozen business groups representing automakers, medical device makers and manufacturers sent a letter to President Joe Biden on Thursday calling on him to work with U.S. lawmakers to provide federal funding for the construction of new chip factories.

The groups, which include the U.S. Chamber of Commerce as well as industry-specific associations representing General Motors Co, Caterpillar Inc and Medtronic PLC, among others, sent the letter as a shortage of semiconductors continues to disrupt U.S. automobile factories and threatens to lower the automakers’ profits by billions of dollars.

A group of chipmakers last week sent a similar letter. Congress authorized programs last year to provide subsides for chip research and factory construction, but U.S. lawmakers still need to provide specific funding for the program.

“To be competitive and strengthen the resilience of critical supply chains, we believe the U.S. needs to incentivize the construction of new and modernized semiconductor manufacturing facilities and invest in research capabilities,” the business groups wrote in their letter on Thursday.

The majority of chip production, especially for advanced computing chips, now occurs in Asia, where major contract manufacturers such as Taiwan Semiconductor Manufacturing Co Ltd (TSMC) and Samsung Electronics Co Ltd handle production for hundreds of different chip companies. Both TSMC and Samsung are planning new U.S. chip factories in the next few years that could benefit from the program if it is funded.

In addition to funding existing programs, the business groups also called for an “investment tax credit” that could help defray the cost of semiconductor manufacturing tools, which can cost billions of dollars for new factories and typically far outstrip the cost of buildings.

American toolmakers such as Applied Materials Inc, Lam Research Corp and KLA-Tencor Corp dominate the industry, though Netherlands-based ASML Holding NV and Japan’s Tokyo Electron Ltd are also major players in some segments.

https://www.reuters.com/article/us-usa-semiconductors/automakers-medical-device-firms-ask-biden-for-u-s-chip-factory-subsidies-idUSKBN2AI153

India's Bharat Biotech pursues COVID-19 vaccine approval in over 40 countries

 India’s Bharat Biotech is in the process of filing regulatory documents for approval of its COVID-19 vaccine, COVAXIN, in more than 40 countries, the company told Reuters late on Wednesday.

“We have submitted our documentation in Brazil and other countries and await their approval. We plan to export several million doses to Brazil,” the company said in an emailed statement. “Pricing of COVAXIN for international markets will be based upon supply timelines, purchase commitments and procurement volumes,” it added.

Bharat Biotech, which last Tuesday had told Reuters it may export doses of COVAXIN to Brazil and the United Arab Emirates by the end of the week, did not name other countries and did not give exact figures on doses it expects to export.

The company has also entered into an agreement with U.S. drug developer Ocugen Inc for the commercialization of COVAXIN in the United States, which has seen the most number of infections in the world.

COVAXIN is one of the two vaccines approved for emergency use in India, though efficacy data from its late-stage trial is yet to be published.

Bharat Biotech expects results from an ongoing trial involving 25,800 participants in India only by March, though the country’s drug regulator has called the vaccine safe and effective amid criticism from some doctors and health experts.

COVAXIN is currently being used by India in its vaccination campaign, which has already covered more than 9 million health workers, and aims to cover 300 million people by August. Bharat Biotech has supplied 5.5 million doses to the government and will sell an additional 4.5 million doses.

India, with nearly 11 million coronavirus cases, has the second highest number of infections in the world, though some experts believe the worst of the disease has passed in the country.

https://www.reuters.com/article/us-health-coronavirus-india-vaccine/indias-bharat-biotech-pursues-covid-19-vaccine-approval-in-over-40-countries-idUSKBN2AI0MW

Lilly in deal with Rigel to develop autoimmune therapy for up to $960M

 Eli Lilly will gain exclusive worldwide license to Rigel Pharmaceuticals Inc’s autoimmune and inflammatory diseases treatment, including its lead candidate, R552, for potentially up to $960 million, the companies said on Thursday.

Rigel will receive an upfront cash payment of $125 million, with the potential for an additional up to $835 million in milestone payments.

R552 belongs to a class of drugs called RIPK1 inhibitors which target a critical signaling protein that regulates inflammation and cell death in tissues. It is a new approach to treat various autoimmune, inflammatory, and neurodegenerative disorders.

Under the deal, Lilly will foot the costs of global commercialization for the therapy, R552, and Rigel will have the right to co-sell the treatment in the United States.

Lilly will also lead all clinical development and commercialization of the treatment in central nervous system diseases.

Rigel’s lead therapy has completed early-stage trials and will begin mid-stage trials this year.

https://www.reuters.com/article/us-eli-lilly-rigel/eli-lilly-in-deal-with-rigel-to-develop-autoimmune-therapy-for-up-to-960-million-idUSKBN2AI1HO

Jefferies Initiates Coverage On VistaGen Therapeutics with Buy Rating

 Price target $6

https://www.benzinga.com/news/21/02/19723114/jefferies-initiates-coverage-on-vistagen-therapeutics-with-buy-rating-announces-price-target-of-6