Senate passes bill to rework animal testing requirements for drug developers

 The US Senate passed via unanimous consent on Thursday afternoon a bipartisan bill that would alter a federal mandate for animal testing on new drugs, but stops short of removing animal testing entirely.

Touted as a much-needed modernization of FDA’s rules, co-sponsor Sens. Rand Paul (R-KY) and Cory Booker (D-NJ) have said the bill will stop lots of needless suffering of animals.

But the FDA has made clear that although drug companies seek to use as few animals as possible and to ensure their humane and proper care, animal testing is still crucial for drug development and for determining the toxicity of experimental compounds.

“Two or more species are typically tested because a drug may affect one differently from another. Such tests show whether a potential drug has toxic side effects and what its safety is at different doses. The results point the way for human testing and, much later, product labeling,” the FDA explains.

NIH also notes that researchers try to perform toxicology tests using biochemical or cell-based (in vitro) systems instead of with animals such as mice. But “the development of in vitro tests that can reliably identify chemical hazards resulting in cancer or birth defects is more difficult because of the complexity of the biological processes involved.”

The text of this bill shows it would replace the term “animal” in several key sections of the FDCA, and add the term “nonclinical test,” defined as in vitro, in silico, in chemico, and other nonhuman in vivo testing that may include animal tests.

The Senate-passed bill, which comes amid monkey shortages for researchers, also includes language from another bill sponsored by Sen. Ben Ray Luján (D-NM) to amend the Public Health Service Act to remove the animal testing requirement for biosimilars too.

On the House side, the chamber previously passed its user fee reauthorization as part of a package that also included these animal-related reforms.

https://endpts.com/senate-passes-bill-to-rework-animal-testing-requirements-for-drug-developers/

New inflation-linked drug rebates go into effect on Saturday

 Beginning October 1, biopharma companies can be charged rebates for any new drug price increases rising faster than the rate of inflation.

The new rebates are part of the newly signed Inflation Reduction Act, which introduces this new requirement that manufacturers pay rebates to Medicare for Part D drugs whose price increases exceed inflation, and in January 2023, the same will occur with Part B drugs.

The rebate system “was designed to reduce the frequency and size of drug price increases,” HHS says. The IRA also includes a provision that allows CMS to negotiate and/or cap the prices of 10 of the most expensive drugs.

While those negotiations will be limited, the rebates paid by the industry may be significant. HHS released a new report on Friday outlining what the IRA could do as more than 1,200 drug price increases from July 2021 to July 2022 exceeded the inflation rate of 8.5% for that time period. The report notes:

Most price increases occur at the beginning of January, with more than 3000 drugs experiencing a price increase in 2022, up from 2650 in 2016. The number of July price increases trended downward from 613 NDCs in 2016 to 203 in 2021, but in July of 2022, the number of increases rose to a level similar to that observed in 2016, with 601 increases.

HHS on Friday also released another report that “found a steady increase in prescription drug spending from $520 billion in 2016 to $603 billion in 2021. This increase was driven by increases in spending per prescription, and less so by increases in the number of prescriptions.”

And while the inflation-linked rebates will hit all pharma companies, HHS notes that drug spending “is heavily driven by a relatively small number of high-cost products. The cost of specialty drugs has continued to grow, totaling $301 billion in 2021, an increase of 43% since 2016.”

https://endpts.com/new-inflation-linked-drug-rebates-go-into-effect-on-saturday/

Main target of SARS-CoV-2 in brain and effects of virus on nervous system IDd

 A Brazilian study published in the journal PNAS describes some of the effects infection by SARS-CoV-2 can have on the central nervous system. A preliminary version (not yet peer-reviewed) posted in 2020 was one of the first to show that the virus that causes COVID-19 can infect brain cells, especially astrocytes. It also broke new ground by describing alterations in the structure of the cortex, the most neuron-rich brain region, even in cases of mild COVID-19.

The cerebral cortex is the outer layer of gray matter over the hemispheres. It is the largest site of neural integration in the central nervous system and plays a key role in complex functions such as memory, attention, consciousness, and language.

The investigation was conducted by several groups at the State University of Campinas (UNICAMP) and the University of São Paulo (USP). Researchers at the Brazilian Biosciences National Laboratory (LNBio), D'Or Institute (IDOR) and the Federal University of Rio de Janeiro (UFRJ) also contributed to the study.

"Two previous studies detected the presence of the novel coronavirus in the brain, but no one knew for sure if it was in the bloodstream, endothelial cells [lining the blood vessels] or nerve cells. We showed for the first time that it does indeed infect and replicate in astrocytes, and that this can reduce neuron viability," Daniel Martins-de-Souza, one of the leaders of the study, told Agência FAPESP. Martins-de-Souza is a professor at UNICAMP's Biology Institute and a researcher affiliated with IDOR.

Astrocytes are the most abundant central nervous system cells. Their functions include providing biochemical support and nutrients for neurons; regulating levels of neurotransmitters and other substances that may interfere with neuronal functioning, such as potassium; maintaining the blood-brain barrier that protects the brain from pathogens and toxins; and helping to maintain brain homeostasis.

Infection of astrocytes was confirmed by experiments using brain tissue from 26 patients who died of COVID-19. The tissue samples were collected during autopsies conducted using minimally invasive procedures by Alexandre Fabro, a pathologist and professor at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP). The analysis was coordinated by Thiago Cunha, also a professor in FMRP-USP and a member of the Center for Research on Inflammatory Diseases (CRID).

The researchers used a technique known as immunohistochemistry, a staining process in which antibodies act as markers of viral antigens or other components of the tissue analyzed. "For example, we can insert one antibody into the sample to turn the astrocytes red on binding to them, another to mark the SARS-CoV-2 spike protein by making it green, and a third to highlight the virus's double-stranded RNA, which only appears during replication, by turning it magenta," Martins-de-Souza explained. "When the images produced during the experiment were overlaid, all three colors appeared simultaneously only in astrocytes."

According to Cunha, the presence of the virus was confirmed in five of the 26 samples analyzed. Alterations suggesting possible damage to the central nervous system were also found in these five samples.

"We observed signs of necrosis and inflammation, such as edema [swelling caused by a buildup of fluid], neuronal lesions and inflammatory cell infiltrates," he said.

The capacity of SARS-CoV-2 to infect brain tissue and its preference for astrocytes were confirmed by Adriano Sebolella and his group at FMRP-USP using the method of brain-derived slice cultures, an experimental model in which human brain tissue obtained during surgery to treat neurological diseases such as drug-refractory epilepsy, for example, is cultured in vitro and infected with the virus.

Persistent symptoms

In another part of the research, conducted in UNICAMP's School of Medical Sciences (FCM), 81 volunteers who had recovered from mild COVID-19 were submitted to magnetic resonance imaging (MRI) scans of their brains. These scans were performed 60 days after diagnostic testing on average. A third of the participants still had neurological or neuropsychiatric symptoms at the time. They complained mostly of headache (40%), fatigue (40%), memory alterations (30%), anxiety (28%), loss of smell (28%), depression (20%), daytime drowsiness (25%), loss of taste (16%) and low libido (14%).

"We posted a link for people interested in participating in the trial to register, and were surprised to get more than 200 volunteers in only a few days. Many were polysymptomatic, with widely varying complaints. In addition to the neuroimaging exam, they're being evaluated neurologically and taking standardized tests to measure performance in cognitive functions such as memory, attention and mental flexibility. In the article we present the initial results," said Clarissa Yasuda, a professor and member of the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN).

Only volunteers diagnosed with COVID-19 by RT-PCR and not hospitalized were included in the study. The assessments were carried out after the end of the acute phase, and the results were compared with data for 145 healthy uninfected subjects.

The MRI scans showed that some volunteers had decreased cortical thickness in some brain regions compared with the average for controls.

"We observed atrophy in areas associated, for example with anxiety, one of the most frequent symptoms in the study group," Yasuda said. "Considering that the prevalence of anxiety disorders in the Brazilian population is 9%, the 28% we found is an alarmingly high number. We didn't expect these results in patients who had had the mild form of the disease."

In neuropsychological tests designed to evaluate cognitive functioning, the volunteers also underperformed in some tasks compared with the national average. The results were adjusted for age, sex and educational attainment, as well as the degree of fatigue reported by each participant.

"The question we're left with is this: Are these symptoms temporary or permanent? So far, we've found that some subjects improve, but unfortunately many continue to experience alterations," Yasuda said. "What's surprising is that many people have been reinfected by novel variants, and some report worse symptoms than they had since the first infection. In view of the novel virus, we see longitudinal follow-up as crucial to understand the evolution of the neuropsychiatric alterations over time and for this understanding to serve as a basis for the development of targeted therapies."

Energy metabolism affected

In IB-UNICAMP's Neuroproteomics Laboratory, which is headed by Martins-de-Souza, experiments were performed on brain tissue cells from people who died of COVID-19 and astrocytes cultured in vitro to find out how infection by SARS-CoV-2 affects nervous system cells from the biochemical standpoint.

The autopsy samples were obtained via collaboration with the group led by Paulo Saldiva, a professor at the University of São Paulo's Medical School (FM-USP). The proteome (all proteins present in the tissue) was mapped using mass spectrometry, a technique employed to identify different substances in biological samples according to their molecular mass.

"When the results were compared with those of uninfected subjects, several proteins with altered expression were found to be abundant in astrocytes, which validated the findings obtained by immunohistochemistry," Martins-de-Souza said. "We observed alterations in various biochemical pathways in the astrocytes, especially pathways associated with energy metabolism."

The next step was to repeat the proteomic analysis in cultured astrocytes infected in the laboratory. The astrocytes were obtained from induced pluripotent stem cells (iPSCs). The method consists of reprogramming adult cells (derived from skin or other easily accessible tissues) to assume a stage of pluripotency similar to that of embryo stem cells. This first part was conducted in the IDOR laboratory of Stevens Rehen, a professor at UFRJ. Martins-de-Souza's team then used chemical stimuli to make the iPSCs differentiate into neural stem cells and eventually into astrocytes.

"The results were similar to those of the analysis of tissue samples obtained by autopsy in that they showed energy metabolism dysfunction," Martins-de-Souza said. "We then performed a metabolomic analysis [focusing on the metabolites produced by the cultured astrocytes], which evidenced glucose metabolism alterations. For some reason, infected astrocytes consume more glucose than usual, and yet cellular levels of pyruvate and lactate, the main energy substrates, decreased significantly."

Lactate is one of the products of glucose metabolism, and astrocytes export this metabolite to neurons, which use it as an energy source. The researchers' in vitro analysis showed that lactate levels in the cell culture medium were normal but decreased inside the cells. "Astrocytes appear to strive to maintain the energy supply to neurons even if this effort weakens their own functioning," Martins-de-Souza said.

As an outcome of this process, the functioning of the astrocytes' mitochondria (energy-producing organelles) was indeed altered, potentially influencing cerebral levels of such neurotransmitters as glutamate, which excites neurons and is associated with memory and learning, or gamma-aminobutyric acid (GABA), which inhibits excessive firing of neurons and can promote feelings of calm and relaxation.

"In another experiment, we attempted to culture neurons in the medium where the infected astrocytes had grown previously and measured a higher-than-expected cell death rate. In other words, this culture medium 'conditioned by infected astrocytes' weakened neuron viability," Martins-de-Souza said.

The findings described in the article confirm those of several previously published studies pointing to possible neurological and neuropsychiatric manifestations of COVID-19.

Results of experiments on hamsters conducted at the Institute of Biosciences (IB-USP), for example, reinforce the hypothesis that infection by SARS-CoV-2 accelerates astrocyte metabolism and increases the consumption of molecules used to generate energy, such as glucose and the amino acid glutamine. The results obtained by the group led by Jean Pierre Peron indicate that this metabolic alteration impairs the synthesis of a neurotransmitter that plays a key role in communication among neurons.

Unanswered questions

According to Martins-de-Souza, there is no consensus in the scientific literature on how SARS-CoV-2 reaches the brain. "Some animal experiments suggest the virus can cross the blood-brain barrier. There's also a suspicion that it infects the olfactory nerve and from there invades the central nervous system. But these are hypotheses for now," he said.

One of the discoveries revealed by the PNAS article is that the virus does not use the protein ACE-2 to invade central nervous system cells, as it does in the lungs. "Astrocytes don't have the protein in their membranes. Research by Flávio Veras [FMRP-USP] and his group shows that SARS-CoV-2 binds to the protein neuropilin in this case, illustrating its versatility in infecting different tissues," Martins-de-Souza said.

At UNICAMP's Neuroproteomics Laboratory, Martins-de-Souza analyzed nerve cells and others affected by COVID-19, such as adipocytes, immune system cells and gastrointestinal cells, to see how the infection altered the proteome.

"We're now compiling the data to look for peculiarities and differences in the alterations caused by the virus in these different tissues. Thousands of proteins and hundreds of biochemical pathways can be altered, with variations in each case. This knowledge will help guide the search for specific therapies for each system impaired by COVID-19," he said.

"We're also comparing the proteomic differences observed in brain tissue from patients who died of COVID-19 with proteomic differences we've found over the years in patients with schizophrenia. The symptoms of both conditions are quite similar. Psychosis, the most classic sign of schizophrenia, also occurs in people with COVID-19."

The aim of the study is to find out whether infection by SARS-CoV-2 can lead to degeneration of the white matter in the brain, made up mainly of glial cells (astrocytes and microglia) and axons (extensions of neurons). "We've observed a significant correspondence [in the pattern of proteomic alterations] associated with the energy metabolism and glial proteins that appear important in both COVID-19 and schizophrenia. These findings may perhaps provide a shortcut to treatments for the psychiatric symptoms of COVID-19," Martins-de-Souza pondered.

Marcelo Mori, a professor at IB-UNICAMP and a member of the Obesity and Comorbidities Research Center (OCRC), the study was only possible thanks to the collaboration of researchers with varied and complementary backgrounds and expertise. "It demonstrates that first-class competitive science is always interdisciplinary," he said. "It's hard to compete internationally if you stay inside your own lab, confining yourself to the techniques with which you're familiar and the equipment to which you have access."

More information: Fernanda Crunfli et al, Morphological, cellular, and molecular basis of brain infection in COVID-19 patients, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2200960119

https://medicalxpress.com/news/2022-09-reveals-main-sars-cov-brain-effects.html

Some officials now say monkeypox elimination unlikely in US

 Some U.S. health officials are conceding that monkeypox is probably not going away anytime soon.

The disease’s spread is slowing but the virus is so widespread that elimination is unlikely, the Centers for Disease Control and Prevention said. That conclusion was in a recent CDC report, and echoed Friday by Marc Lipsitch, director of science in the agency’s disease-forecasting center.

Lipsitch hesitated to say monkeypox is permanently here to stay, but he said it stands to be a continuing threat for the next few years.

“It’s in many geographic locations within the country” as well as in other countries, Lipsitch told The Associated Press. “There’s no clear path in our mind to complete elimination domestically.”

The virus has mainly spread among gay and bisexual men, though health officials continue to stress that anyone can be infected. It’s important that people at risk take steps to prevent spread and that vaccination efforts continue, Lipsitch said.

The CDC report contained some good news: The U.S. outbreak seems to have peaked in early August. The average number of daily cases being reported — fewer than 150 — is about a third what it was reported in the middle of the summer, and officials expect the decline will continue for at least the next several weeks.

Lipsitch attributed the good news to increasing vaccinations, cautious behavior by people at risk and infection-derived immunity in the highest risk populations.

Dr. Tom Inglesby, director of the Johns Hopkins Center for Health Security, agreed that it’s unlikely that spread of monkeypox will stop in the U.S. anytime soon, but he said it’s still possible in the long term.

If domestic transmission were stopped, infections may still continue if people catch the virus while traveling internationally, he said. But the declining cases makes it seem like “we’ve turned a real corner.”

“The efforts underway are succeeding, and should be continued, if not intensified,” he said.

With case numbers going down, this is a good time for local health departments to take a new stab at doing intensive contact tracing to try to stop chains of transmission, he said.

Monkeypox is endemic in parts of Africa, where people have been infected through bites from rodents or small animals, but it wasn’t considered a disease that spreads easily among people until May, when infections emerged in Europe and the U.S.

There have been more than 67,000 cases reported in countries that have not historically seen monkeypox. The U.S. has the most infections of any country — more than 25,600. One U.S. death has been attributed to monkeypox.

More than 97% of U.S. cases are men. The vast majority have been men who reported recent sexual contact with other men.

Though cases have been declining, the proportion of new cases that have information about recent sexual contact is also down, officials said. That’s causing a growing blind spot about how the virus may be spreading, Lipsitch noted.

https://apnews.com/article/monkeypox-science-health-centers-for-disease-control-and-prevention-9f23d14764f886288138fe607157150e

Opthalmology Space Gains Clarity with Partnerships & Acquisitions by Outlook & Visus

 A cloudy ophthalmic space got a little clearer Wednesday with the announcements of two collaborations by Visus Therapeutics and Outlook Therapeutics, now preparing for FDA approval.

Outlook Therapeutics also tapped AmerisourceBergen to distribute ONS-5010. ONS-5010 is the monoclonal antibody bevacizumab to treat wet age-related macular degeneration, commonly referred to as wet AMD and other eye diseases.

Bevacizumab is one of the oldest monoclonal antibodies on the market, developed by Roche’s Genentech and previously approved to treat several cancers. Its best known under the brand name Avastin.

Outlook submitted a biologics license application to treat eye disease in March, but the FDA required the company to submit more data over the summer.

Analysts expect approval of the eye drug candidate, brand named Lytenava, sometime in 2023.

Outlook previously partnered with FUJIFILM Diosynth Biotechnologies and Ajinomoto Bio-pharma Services for material sourcing and manufacturing assistance in anticipation of a commercial launch.

“Following our recent Biologics License Application submission, entering a relationship with AmerisourceBergen for ONS-5010 is a critical step in the next phase of our pre-commercial strategy execution,” said Outlook Pres. and CEO C. Russell Trenary, III in a statement.

If ONS-5010 is approved, AmerisourceBergen’s Besse Medical will handle distribution. AmerisourceBergen’s Innomar Strategies will handle medical information and pharmacovigilance, or the monitoring, detection and prevention of adverse events.

Outlook and AmerisourceBergen are also discussing a distribution agreement for outside the U.S.

Meanwhile, Visus Therapeutics on Wednesday announced it's expanding its ophthalmic pipeline by acquiring the patents and assets of ViewPoint Therapeutics.

ViewPoint is developing an alpha-crystallin aggregation inhibitor as a non-surgical treatment for protein misfolding in the eye.

Misfolding causes cataracts and presbyopia, age-related near-sightedness. Presbyopia and cataracts are the leading causes of vision disability.

Alpha-crystallin aggregation inhibitors aim to restore lens clarity and have the potential to reverse near-sightedness and cataracts without surgery. Some 128 million U.S. adults have presbyopia. Most people treat age-related near-sightedness with reading glasses. More than half of U.S. adults older than 80 have cataracts.

Visus is currently conducting Phase III trials of its eye drops, Brimochol, for the treatment of presbyopia. Brimochol is a combination of carbachol and brimonidine tartrate. Carbachol is a miotic agent that constricts pupils.

“More than a third of the world’s population have presbyopia or cataracts, and this will only increase as the population ages,” said Dr. Eric Donnenfeld of Ophthalmic Consultants of New York and NYU. “A non-surgical approach to treating and possibly preventing cataracts and presbyopia could improve the quality of life of millions of people, globally, and would be a disruptive addition to the management of our patients.”

https://www.biospace.com/article/opthamology-space-gains-clarity/

Adverum: Improvements After Single IVT Injection of Ixo-vec (ADVM-022) in Wet AMD Study

  New data highlight that a single intravitreal injection of Ixo-vec can lead to stable and persistent aflibercept expression through three years resulting in fluid control supporting favorable vision outcomes, as well as decreasing treatment burden by an 81-98% reduction in mean annualized anti-VEGF injections

- The 2x10^11 vg/eye (2E11) dose meaningfully reduced fluid volume, including a 93% reduction in intraretinal (IRF) and 55% reduction in subretinal fluid (SRF) from baseline to week 48

- The Phase 2 LUNA trial of Ixo-vec is underway, evaluating the 2E11 and 6x10^10 vg/eye (6E10) dose with enhanced prophylactic steroid regimens for the treatment of wet AMD subjects

https://finance.yahoo.com/news/adverum-biotechnologies-presents-anatomical-improvements-204500690.html

Apellis: Phase 3 Post Hoc Results Showing Treatment Led to Preservation of Function in Retina in Geographic Atrophy

 

• New analyses of microperimetry data showed positive trends with both monthly and every-other-month pegcetacoplan treatment near the GA lesion border compared to sham
  
  

• These analyses provide further evidence that slowing GA lesion growth with pegcetacoplan has the potential to preserve visual function
  
  

• Data were presented during an oral presentation at the American Academy of Ophthalmology Annual Meeting

https://finance.yahoo.com/news/apellis-announces-24-month-phase-213000053.html