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Sunday, November 21, 2021

Activists urge Biden to push for intellectual property waiver for COVID-19 vaccines

 Fifteen human rights groups are urging U.S. President Joe Biden to get personally engaged in a long-running fight to enact an intellectual property waiver for COVID-19 vaccines at the World Trade Organization, calling his leadership “a moral necessity.”

Amnesty International, Human Rights Watch, Oxfam, Public Citizen and 11 other groups told Biden in a letter that an emergency waiver was urgently needed to combat the pandemic, noting that fewer than 7% of people in low-income countries had received a first COVID-19 vaccine and vaccines remained scarce.

More than 5.4 million people have died of COVID-19 around the world since the first cases were identified in China in December 2019.


Biden reversed the previous U.S. position to endorse a waiver in May, a move that caught some allies by surprise, but there has been little progress since then. The European Union, Britain and Switzerland remain opposed, arguing that issuing such waivers would undercut years of investment and research.

The White House last month called on all WTO members to support a temporary waiver and WTO Director-General Ngozi Okonjo-Iweala is pushing for a deal at the WTO ministerial conference in Geneva from Nov. 30 to Dec. 3.

In their letter, a copy of which was viewed by Reuters, the rights groups said they were “very disappointed” that the Biden administration had not done more to secure an agreement on a waiver text since Biden’s strong statement in May.


“U.S. passivity has empowered close U.S. allies – the European Union, on behalf of Germany, plus Switzerland and the United Kingdom – to block progress even as millions die or become seriously ill waiting for effective vaccines and treatments,” the groups wrote.

They urged Biden to step up his personal engagement and lead the world in reaching a meaningful agreement on the long-standing issue. Doing so would help end the pandemic and restore U.S. standing around the world, they said.

The White House had no immediate comment on the letter, which was dated Friday.

Ending the ministerial meeting without a waiver agreement would be entirely unacceptable,” the groups said. They said drugmakers were using their intellectual property rights to segment global markets instead of maximizing the scale of generic production.

They said a separate effort to issue a “declaration on trade and health” led by David Walker, the New Zealand envoy to the WTO, would “further undermine the WTO’s relevance and legitimacy” in the absence of a meaningful property rights waiver.

https://united.states.news/activists-urge-biden-to-push-for-intellectual-property-waiver-for-covid-19-vaccines/

Obseva: FDA Accepts New Drug Application for Fibroids

 Obseva SA (NASDAQ: OBSV; SIX: OBSN), a biopharmaceutical company developing and commercializing novel therapies to improve women’s reproductive health, today announced that the New Drug Application (NDA) for linzagolix for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women has been accepted for review by the United States Food and Drug Administration (FDA). The submission is based on data from the two Phase 3 PRIMROSE trials. Linzagolix has a differentiated profile and if approved, would be the first and only GnRH receptor antagonist with flexible dosing options for uterine fibroids, including a low dose option to address the needs of women who cannot or do not want to take hormones.1,4 The FDA set a target action date of September 13, 2022 for this NDA under the Prescription Drug User Fee Act (PDUFA).

https://finance.yahoo.com/news/obseva-announces-u-fda-acceptance-060500941.html

New Hope for Oral Flu Vaccine as Prime Season Descends

 A new study shows that there might be a way to protect against influenza infection without needing to stir up antibody response.

Scientists from Stanford University investigated the effectiveness of an oral tablet flu vaccine called VXA-A1.1 by Vaxart, which uses cellular correlates of protection. Results from the Phase II human influenza challenge trial showed that those who were given VXA-A1.1 were better at providing protection against viral shedding compared to the injected inactivated influenza vaccine (IIV). 

The 141 participants were divided into three groups who received either VXA-A1.1, an injected quadrivalent IIV, or a placebo and were challenged with the H1N1 flu virus 90 to 120 days post-vaccination. The researchers used mass cytometry to assess over 40 different immune cell parameters in collected blood samples. Profiling was conducted on the day before the vaccine was administered and then seven days after. 

Those who received VXA-A1.1 were found with plasmablasts and hemagglutinin (HA+)-specific cells that contributed to protection from viral shedding after 90 days. This was not seen in those who got IIV or a placebo. On day 8, those who were given the oral drug demonstrated T cell expressing markers that suggested enhanced mucosal tissue homing. 

"The data show that cellular responses are potentially more relevant for protection for an oral vaccine than circulating antibody responses," said Dr. David McIlwain, a senior research scientist from the Stanford School of Medicine and the study's lead author, in a statement. 

This is the first study to indicate that VXA-A1.1 may be viable against the influenza vaccine, providing a ray of hope to those looking for less invasive preventive solutions. 

Influenza remains a leading cause of death in the U.S. According to the Centers for Disease Control and Prevention (CDC), around 36,000 people have died from the flu over the last decade. The highest numbers were recorded from 2017 to 2018 (at 61,000). From 2019 to 2020, around 22,000 flu-related deaths were logged in the U.S. alone. Worldwide, flu deaths range from 300,000 to 600,000 per year. 

Vaxart is a clinical-stage biotechnology firm that focuses on developing oral vaccine solutions against a number of viruses, including norovirus, coronavirus, respiratory syncytial virus (RSV), seasonal flu, and the human papillomavirus (HPV). In September, the company announced a new Manufacturing and Quality Advisory Board comprised of high-profile scientists with vast drug development backgrounds as part of plans to advance the late-stage development and commercialization of its growing vaccine portfolio. In August, it formed a Scientific and Clinical Advisory Board to act as adviser to Vaxart as it develops new technology.

Details of the VXA-A1.1 study are published in Cell Host and Microbe.

https://www.biospace.com/article/oral-vaccine-against-influenza-demonstrates-greater-effectiveness-compared-to-injectables/

Weighing New Study Pointing to Wuhan Market as Likely Covid Origin

 Michael Worobey, an evolutionary biologist with the University of Arizona, has published a study in the journal Science built on medical journal studies, World Health Organization investigations, media and online accounts to weigh in on the arguments.

The two dominant theories over the origins of COVID-19 are that the virus developed naturally, probably from bats, transferred to other animals in a wet market in Wuhan, China, and was then transmitted to humans. This is the “wet market” theory. 

The other theory is a “lab leak,” which argues that although the virus probably occurred naturally in bats, the Wuhan Institute of Virology (WIV) was conducting experiments on the virus, and it escaped by way of a lab accident. These theories have a political component, with American conservatives and conspiracy-minded people leaning toward the lab leak theory. However, even a U.S. intelligence report suggested both were plausible.

Worobey was one of 18 scientists who objected to a WHO report on the disease’s origins. The WHO report, which declared it “likely to very likely” that the “wet market” theory was the origin and “extremely unlikely” for the “lab leak” theory. Worobey and his colleagues said the two theories “were not given balanced consideration” and called for “a proper investigation.” However, Worobey’s new study leans more heavily now toward the “animal spillover” explanation.

But it’s not without its critics.

David Relman, the Stanford microbiologist who organized the objection to the WHO report, said, “I don’t think this advances in a major way our collective understanding of what really happened” because Worobey’s analysis is built on “third- and fourth-hand information” and is potentially unreliable.

However, Kristian Andersen, a microbiologist with Scripps Institution, said Worobey’s research uncovered “several new key insights.”

Let’s look at Worobey’s narrative.

First, it questions the data and location of the earliest reported case of what would later be called COVID-19. The earlier reports indicated a 41-year-old accountant with no ties to the Huanan Market. Instead, Worobey’s analysis found a seafood vendor who worked there. A Chinese investigative reporter cited that the accountant’s fever was from dental surgery who would then go on to develop COVID-19 eight days later.

But 11 days before China focused on the Huanan Market, physicians at two hospitals in Wuhan had diagnosed 14 unexplained pneumonia cases. Of them, eight had spent time at the market.

Marc Suchard, a UCLA researcher whose expertise is using genetic sequences to study disease spread, said Worobey’s work shows that “most early cases occur near the market, identifying it as an early epicenter.”

In Worobey’s work, 10 of the 19 earliest cases identified were linked to the market. They were all identified before the Chinese government made any announcement. One of the supportive arguments for the lab leak theory is the percentage of early cases with no ties to the market, but Worobey notes that we now know how easily COVID-19 spreads by asymptomatic or presymptomatic individuals. Severe disease typically takes two weeks from initial infection and only about 7% of infected people become hospitalized.

Which is to say, by the time people were being hospitalized with strange pneumonia, it had been circulating for at least two weeks, and Wuhan has a population of 11 million. 

“In this city of 11 million people, half of the early cases are linked to a place that’s the size of a soccer field,” Worobey said. “It becomes very difficult to explain that pattern if the outbreak didn’t start at the market.”

Several genetic studies, including a study conducted by Worobey, suggested that the first infection occurred in about mid-November 2019. This was weeks before the fish vendor got sick. That would be consistent with other known pandemics, where the disease is circulating in a population for weeks before it breaks out in numbers enough to be recognized as something new and dangerous.

But is Worobey’s research definitive? That may never be determined beyond a shadow of a doubt, particularly if the Chinese government continues to withhold data from the WIV.

“I don’t disagree with the analysis,” Jesse Bloom, a virologist at the Fred Hutchinson Cancer Research Center told The New York Times. “But I don’t agree that any of the data are strong enough or complete enough to say anything very confidently, other than that the Huanan Seafood Market was clearly a super-spreading event.”

But Bloom added that Worobey’s study isn’t the first one to find mistakes in the WHO’s early investigation report, including problems with early patients’ potential ties to the market. That point suggests the possibility that although the market clearly was involved, the disease may not necessarily have originated there. For example, it’s not inconceivable that an infected person — potentially an employee at WIV — visited the busy and crowded market and accidentally spread the disease. 

https://www.biospace.com/article/who-was-the-first-patient-diagnosed-with-covid-19-/

Biotech week ahead, Nov. 22

 Biotech stocks showed a lack of direction in the week ending Nov. 19 before finishing modestly higher. Stocks did not have much meaningful catalysts to react to amid the winding down of the reporting season and ahead of the holiday week.

Among the major news of the week was Pfizer, Inc. (NYSE:PFE) filing an application for emergency use authorization for its oral COVID-19 pill Paxlovid. The company also bagged a $5.29 billion contract from the U.S. government to supply the investigational antiviral treatment and announced a voluntary license agreement with a U.N.-backed body to facilitate greater access to the global population.

Biogen, Inc. (NASDAQ:BIIB) was also in the news due to long-time company veteran and R&D head Alfred Sandrock, who oversaw the development of many breakthrough neurological treatments, announcing his retirement.

Connect Biopharma Holdings Limited (NASDAQ:CNTB) came under intense selling pressure after what seemed like positive topline data from the Phase 2 study of its investigational therapy CBP-201 in atopic dermatitis. Lack of efficacy details from each arm of the study irked investors, as they could not weigh in vis-à-vis existing treatments.

On the other hand, Longeveron Inc. (NASDAQ:LGVN) shares nearly doubled during the week after its Lomecel-B for hypoplastic left heart syndrome drug received a rare pediatric disease designation from the Food and Drug Administration.

Here are the key catalysts that can move stocks in the sector in the unfolding week:

Conferences

The 14th International Congress of Inborn Errors of Metabolism, or ICIEM, 2021 Meeting: Nov 21 - 24, to be held at Hilton Sydney, Sydney, New South Wales, Australia and also virtually

The Piper Sandler 33rd Annual Virtual Healthcare Conference: Prerecorded fireside chat will be made available from the week of Nov. 22, although the conference is scheduled between Nov. 30 and Dec. 2

PDUFA Dates

The FDA is scheduled to rule on Takeda Pharmaceutical Company Limited's (NYSE:TAK) new drug application for maribavir (TAK-620), which is being evaluated for the treatment of refractory cytomegalovirus infection and disease with genotypic resistance to ganciclovir, valganciclovir, foscarnet or cidofovir in transplant recipients. The PDUFA date is set for Tuesday, Nov. 23.

Aadi Bioscience, Inc. (NASDAQ:AADI) has a tryst with the FDA on Friday, Nov. 26 regarding its NDA for Fyarro. Fyarro is Aadi's lead product that is being evaluated for PEComa, which are rare tumors that form in the soft tissues of the stomach, intestines, lungs, female reproductive organs, and genitourinary organs.

The drug regulator will rule, by the PDUFA date of Nov. 27, on Fennec Pharmaceuticals Inc.'s (NASDAQ:FENC) NDA for Pedmark. Pedmark is a unique formulation of sodium thiosulfate, and is being evaluated for the prevention of ototoxicity induced by cisplatin chemotherapy in patients one month to less than 18 years of age with localized, non-metastatic, solid tumors.


Clinical Readouts/Presentations

ICIEM Meeting Presentations

  • Synlogic, Inc. (NASDAQ:SYBX): Additional Phase 2 data for bacterial therapeutic candidate SYNB1618 in patients with phenylketonuria (Tuesday, at 7:45 pm – 8:45 pm)
  • Abeona Therapeutics Inc. (NASDAQ:ABEO): interim results of Transpher A, a multicenter, single-dose, phase 1/2 clinical trial of ABO-102 gene therapy for Sanfilippo syndrome type A (mucopolysaccharidosis IIIA) (Tuesday)
  • Applied Therapeutics, Inc. (NASDAQ:APLT): new data on burden of illness for AT-007 in adults with galactosemia (Tuesday)

Earnings

  • Twist Bioscience Corporation (NASDAQ:TWST) (Monday, before the market open)
  • Adamis Pharmaceuticals Corporation (NASDAQ:ADMP) (Monday, after the close)
  • Arrowhead Pharmaceuticals, Inc. (NASDAQ:ARWR) (Monday, after the close)
  • Enanta Pharmaceuticals, Inc. (NASDAQ:ENTA) (Monday, after the close)
  • Medtronic plc (NYSE:MDT) (Tuesday, before the market open)
  • Centogene N.V. (NASDAQ:CNTG) (Wednesday, before the market open)
  • Anavex Life Sciences Corp. (NASDAQ:AVXL) (Wednesday, after the close)

IPO Quiet Period Expiry

  • Entrada Therapeutics, Inc. (NASDAQ:TRDA)
  • Biofrontera Inc. (NASDAQ:BFRI)
  • Aura Biosciences, Inc. (NASDAQ:AURA)
  • LianBio (NASDAQ:LIAN)

Link between diet, intestinal stem cells and disease discovered

 The intestine is essential for maintaining our energy balance and is a master at reacting quickly to changes in nutrition and nutrient balance. It manages to do this with the help of intestinal cells that among other things are specialized in the absorption of food components or the secretion of hormones. In adult humans, the intestinal cells regenerate every five to seven days. The ability to constantly renew and develop all types of intestinal cells from intestinal stem cells is crucial for the natural adaptability of the digestive system. However, a long-term diet high in sugar and fat disrupts this adaptation and can contribute to the development of obesity, type 2 diabetes, and gastrointestinal cancer.

The  behind this maladaptation are part of the research field of Heiko Lickert and his group at Helmholtz Munich and the Technical University of Munich. The scientists assume that  play a special role in maladaptation. Using a , the researchers investigated the effects of a high-sugar and high-fat  and compared it with a control group.

From high-calorie diet to increased risk of gastrointestinal cancer

"The first thing we noticed was that the small intestine increases greatly in size on the high-calorie diet," says study leader Anika Böttcher. "Together with Fabian Theis' team of computational biologists at Helmholtz Munich, we then profiled 27,000  from control diet and high fat/high sugar diet-fed mice. Using new machine learning techniques, we thus found that intestinal stem cells divide and differentiate significantly faster in the mice on an unhealthy diet." The researchers hypothesize that this is due to an upregulation of the relevant signaling pathways, which is associated with an acceleration of tumor growth in many cancers. "This could be an important link: Diet influences metabolic signaling, which leads to excessive growth of intestinal stem cells and ultimately to an increased risk of gastrointestinal cancer," says Böttcher.

With the help of this high-resolution technique, the researchers have also been able to study rare cell types in the intestine, for example, hormone-secreting cells. Among their findings, they were able to show that an unhealthy diet leads to a reduction in serotonin-producing cells in the intestine. This can result in intestinal inertia (typical of  mellitus) or increased appetite. Furthermore, the study showed that the absorbing  adapt to the , and their functionality increases, thus directly promoting weight gain.

Important basic research for non-invasive therapies

These and other findings from the study lead to a new understanding of disease mechanisms associated with a high-calorie diet. "What we have found out is of crucial importance for developing alternative non-invasive therapies," says study leader Heiko Lickert, in summarizing the results. To date, there is no pharmacological approach to prevent, stop or reverse obesity and diabetes. Only  causes permanent weight loss and can even lead to remission of diabetes. However, these surgeries are invasive, non-reversible and costly to the healthcare system. Novel non-invasive therapies could happen, for example, at the hormonal level through targeted regulation of serotonin levels. The research group will examine this and other approaches in subsequent studies.

About the people

Heiko Lickert and Anika Böttcher conduct research at the Helmholtz Diabetes Center of Helmholtz Munich. They specialize in the development of regenerative treatment approaches for numerous widespread diseases associated with impaired gut function. Lickert heads the Institute for Diabetes and Regeneration Research and is a professor at the Technical University of Munich (TUM). Both are scientists at the German Center for Diabetes Research (DZD).

The current study has been published as a cover story in Nature Metabolism.


Explore further

Uncovering basic mechanisms of intestinal stem cell self-renewal and differentiation

More information: Alexandra Aliluev et al, Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice, Nature Metabolism (2021). DOI: 10.1038/s42255-021-00458-9
https://medicalxpress.com/news/2021-11-link-diet-intestinal-stem-cells.html

New technique solves HIV capsid structure, could be blueprint of capsid-targeting antivirals

 A new technique using electron tomography and subtomogram averaging at Diamond's electron Bio-Imaging Centre (eBIC), has solved the structure of the HIV capsid alone and in complex with host factors. This work also led to the building of an atomistic model of the whole HIV capsid using information gained from electron tomography, which the team believes could serve as a blueprint for the development of capsid-targeting antivirals.

The , titled "High-resolution cryoET structures of native HIV-1  in complex with IP6 and CypA" is published today (19 November) in Science Advances. The work was a collaboration between scientists at the University of Oxford, eBIC—the UK's national cryo-electron microscopy facility within Diamond Light Source and the University of Delaware.

The team was led by Professor Peijun Zhang, director of the eBIC at Diamond and Professor of Structural Biology at the University of Oxford. Lead author Dr. Tao Ni, University of Oxford, says, "Despite the global efforts to combat HIV/AIDS and the achievement of antiviral treatments, there are still approximately 38 million people with HIV/AIDS with no complete cure so far."

He explains that the  (HIV) is a retrovirus; its RNA genome is encapsulated inside a conical-shaped capsid. During infection, HIV assembles and buds as immature virions with Gag polyprotein, which undergoes a maturation process, a step involving proteolysis and conformational change, which converts from an immature spherical shape to mature conical capsid. The capsid plays multiple essential roles during the early stage of HIV-1 replication, including protecting the genome from cellular innate immune responses and fostering reverse transcription, as well as regulating intracellular transport and entry into the nucleus. Many of these functions are affected by its interactions with host cell factors and .

However, because of the metastable property of HIV-1 capsid, isolating fully intact native capsids in quantities and concentrations suitable for high-resolution structural analyses has been challenging; the capsid suffers artefactual dissociation after the membrane is dissolved by detergent, a traditional method of capsid purification.

"To solve this problem, Peijun Zhang's team devised a novel approach. Instead of detergent extraction, we punctuate the membrane of HIV virus-like particles with a pore-forming toxin, which avoids the trauma associated with lysis of the virions and isolation of the cores, but also makes the capsid accessible to external cell factors and small molecules," says Dr. Ni.

Having established the experimental approach, the authors investigated the interactions between the authentic HIV capsid and a cellular factor Cyclophilin A (CypA), and a small-molecule cofactor IP6 (inositol hexakisphosphate). The team then applied electron tomography and subtomogram averaging to these samples.

Using this new technique, the team solved the structures of HIV capsid alone, and its complex with CypA and IP6 at around 5.4 Å resolution. These structures confirm the double IP6 binding site in the mature HIV capsid and provide insights into the role of IP6 and CypA in regulating HIV capsid stability.

Prof Zhang says, "In collaboration with Prof. Juan Perilla's group in the University of Delaware, using information derived from , we also built an atomistic model of the whole HIV capsid which could serve as a blueprint for the development of capsid-targeting antivirals. The perforation of the enveloped virus membrane also provides a novel approach to study host-virus interaction for other viral systems."


Explore further

Restricting HIV-1 infection

More information: Tao Ni et al, Structure of native HIV-1 cores and their interactions with IP6 and CypA, Science Advances (2021). DOI: 10.1126/sciadv.abj5715www.science.org/doi/10.1126/sciadv.abj5715
https://medicalxpress.com/news/2021-11-technique-hiv-capsid-blueprint-capsid-targeting.html