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Saturday, July 10, 2021

Key Biopharma Catalysts To Keep An Eye On In Q3

 Biopharma stocks underperformed in the first half of 2021, and several of these stocks could be in for a rebound in the coming months.

Needham analyst Serge Belanger highlighted companies in the firm's coverage universe that have key catalysts in the third quarter.

PDUFA Events: PDUFA goal dates are key binary events that can make or break stocks. The date denotes the end of the review period for the regulatory application filed with the Food and Drug Administration.

A standard review takes 10 months from the date of filing of the application, while a priority review takes up to six months.

Revance Therapeutics, Inc. (NASDAQ:RVNC): Daxi, or daxibotulinumtoxin A, for glabellar lines will likely clear the FDA hurdle by the middle of the third quarter, 

Verrica Pharmaceuticals Inc. (NASDAQ:VRCA): Ycanth, or VP-102, for molluscum contagiosum has a PDUFA date of Sept. 23.

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Clinical Trial Readouts: Another stock-moving catalyst for biopharma stocks is clinical readouts. A drug goes through several stages of testing, starting with preclinical testing, before its efficacy and safety can be established.

Xenon Pharmaceuticals Inc. (NASDAQ:XENE): Data from the Phase 2b study, dubbed 2b X-TOLE, of XEN-101 in adult focal epilepsy is due mostly in the late third quarter.

Aerie Pharmaceuticals, Inc. (NASDAQ:AERI): Results from a phase 2b trial of AR-15512 in dry eye patients.

Revance: results from the open-label safety trial of daxi in cervical dystonia patients are expected in the second half.

Clearside Biomedical, Inc.'s (NASDAQ:CLSD) collaboration partner REGENXBIO Inc. (NASDAQ:RGNX): Data from the first cohort of a Phase 2 AAVIATE study evaluating suprochoroidally-injected RGX-314 in wet age-related macular degeneration patients.


Regulatory Filings: Filing a new drug application or a biologic license approval is considered a major milestone in the drug approval process.

Zogenix, Inc. (NASDAQ:ZGNX): The biopharma is due to complete an sNDA filing for Fintepla, seeking a label expansion to include Lennox-Gastaut Syndrome patients.

Acer Therapeutics Inc. (NASDAQ:ACER): The company plans to file an NDA for ACER-001 as a treatment for urea cycle disorder in the third quarter.

Regulatory Development Updates: Among Needham's coverage universe, KalVista Pharmaceuticals, Inc. (NASDAQ:KALV) and Zynerba Pharmaceuticals, Inc. (NASDAQ:ZYNE) are due to meet with the FDA to gain clarity on advancing their programs to the next development step.

Belanger also looks ahead to Amphastar Pharmaceuticals, Inc. (NASDAQ:AMPH), Heron Therapeutics, Inc. (NASDAQ:HRTX) and Zogenix to provide development updates, including potential filing and approval timelines, on their late-stage programs. The intellectual property rights proceedings that could impact Liquidia Corporation's (NASDAQ:LQDA) LIQ861 for pulmonary arterial hypertension could also be important, he added.

Launch Progression Updates: The main product launch updates that investors are likely to keep an eye on, include BioCryst Pharmaceuticals, Inc.'s (NASDAQ:BCRX) Orladeyo for hereditary angioedema, Revance's RHA filler and HintMD platform, and Zogenix's Fintepla for Dravet Syndrome, Belanger said. The next launch of significant interest is Heron's Zynrelef, which became commercially available on July 1, he added.

https://www.benzinga.com/analyst-ratings/analyst-color/21/07/21882595/18-key-biopharma-catalysts-to-keep-an-eye-on-in-q3

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Brain mapping method illuminates targets for treating neuropsychiatric symptoms

 Researchers have made significant advancements in correlating aberrations in specific brain circuits with neuropsychiatric conditions like depression. However, it remains difficult to prove that damage to these circuits causes the symptoms themselves and that targeting them with therapeutics could help patients. By integrating brain lesion datasets with data on how two treatments -- deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) -- influence neuropsychiatric disorders, researchers from Brigham and Women's Hospital and collaborators developed a new brain mapping approach that may help clarify the cause of a variety of neuropsychiatric conditions and identify promising stimulation sites to target therapeutically. Findings are published in Nature Human Behavior.

"This is a new technique that uses existing data on patients with brain damage to develop new treatment targets for real-world patients with similar symptoms," said the paper's corresponding author, Shan Siddiqi, MD, of the Center for Brain Circuit Therapeutics at the Brigham. "In principle, this should open the floodgates for researchers to study any stroke- or brain-injury-associated symptom to find a new treatment target for people who developed the same symptom without brain damage."

The researchers developed their approach using data on depression and Parkinson's disease, both of which are already associated with well-defined brain lesions and are commonly treated with DBS and TMS. They combined the location and connectivity of 461 brain lesions, 101 DBS sites, and 151 TMS sites, and compared patients who developed depression, patients who had improvement in depression, and patients who had no change in mood. Using this approach, they identified a brain circuit that is an effective therapeutic target for both invasive and noninvasive brain stimulation treatments. The study also indicates that brain stimulation outcomes vary not according to the technique used -- DBS versus TMS -- but according to the circuit that is targeted.

The researchers subsequently used their approach with Parkinson's disease data. Combining data on 29 lesions and 95 stimulation sites for tremors and rigidity, they showed that lesions associated with the motor symptoms of Parkinson's disease are connected to the same circuits as the stimulation sites that that relieve those symptoms.

The researchers are now working to refine circuit maps for other neuropsychiatric conditions such as anxiety disorders, post-traumatic stress disorder, mania, hallucinations, and movement disorders. Clinical trials are still necessary to determine whether physicians can relieve patient symptoms by targeting the brain circuits identified through the new approach. The authors of the study are currently conducting a trial to confirm the distinct TMS targets that they recently identified for depression and anxiety.

"Now that we have concrete evidence that lesions map to treatment targets, we can design more clinical trials to generate new treatments," Siddiqi said. "This approach gives us highly rigorous hypotheses about treatment targets. When we don't know much about the brain circuitry of a particular disorder, our study shows how to find the answer to that question and turn it into new treatment targets."

Story Source:

Materials provided by Brigham and Women's Hospital. Note: Content may be edited for style and length.

Journal Reference:

  1. Shan H. Siddiqi, Frederic L. W. V. J. Schaper, Andreas Horn, Joey Hsu, Jaya L. Padmanabhan, Amy Brodtmann, Robin F. H. Cash, Maurizio Corbetta, Ki Sueng Choi, Darin D. Dougherty, Natalia Egorova, Paul B. Fitzgerald, Mark S. George, Sophia A. Gozzi, Frederike Irmen, Andrea A. Kuhn, Kevin A. Johnson, Andrew M. Naidech, Alvaro Pascual-Leone, Thanh G. Phan, Rob P. W. Rouhl, Stephan F. Taylor, Joel L. Voss, Andrew Zalesky, Jordan H. Grafman, Helen S. Mayberg, Michael D. Fox. Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease. Nature Human Behaviour, 2021; DOI: 10.1038/s41562-021-01161-1

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Anti-tumor agent from the intestine

 It is believed to be involved in the development of chronic inflammatory intestinal diseases, to trigger diabetes, to be responsible for obesity, even neurological diseases such as multiple sclerosis and Parkinson's could have their causes here -- not to mention depressions and autistic disorders. We are talking about the microbiome -- the vast collection of bacteria in the human gut. It is estimated that each person carries around 100 trillion bacterial cells in their digestive tract, belonging to several thousand species.

The microbiome has been the focus of research for 20 years -- ever since a new technique made it possible to analyse these bacteria quickly and precisely: high-throughput sequencing. Since then, there has been an increasing body of findings that the microbiome, which is sometimes also referred to as the second human genome, is not only of central importance for digestion, but also influences, if not controls, at least a large number of body functions. The immune system is mentioned particularly frequently.

The microbiome influences the immune system

Scientists at the Universities of Würzburg and Marburg have now succeeded for the first time in experimentally demonstrating that bacterial metabolites are able to increase the cytotoxic activity of certain immune cells and thus positively influence the efficiency of tumour therapies. Ideally, the composition of the bacterial species in the microbiome could be used to control its influence on the success of the therapy.

The research team published the results of its study in the journal Nature Communications. Dr. Maik Luu, postdoc in the laboratory of Professor Michael Hudecek at the Medical Clinic and Polyclinic II of the University Hospital of Würzburg, was responsible for the finding. Another participant was Professor Alexander Visekruna from the Institute of Medical Microbiology and Hygiene at the Philipps University in Marburg, where Luu did research before moving to Würzburg.

Fatty acids increase the activity of killer cells

"We were able to show that the short-chain fatty acids butyrate and, in particular, pentanoate are able to increase the cytotoxic activity of CD8 T cells," Maik Luu describes the central result of the now published study. CD8 T cells are sometimes also called killer cells. As part of the immune system, it is their task to specifically kill cells that are harmful to the organism.

Short-chain fatty acids, in turn, belong to the most dominant class of metabolites of the gut microbiome. On the one hand, they can boost the metabolism of T cells by inducing central regulators of energy metabolism. On the other hand, they can inhibit specific enzymes that regulate the accessibility to the genetic material and thus the gene expression in the T cells. In doing so, they induce epigenetic changes.

Solid tumor models are combated more effectively

"When short-chain fatty acids reprogram CD8 T cells, one of the results is increased production of pro-inflammatory and cytotoxic molecules," Luu explains. In the experiment, treatment with the fatty acid pentanoate increased the ability of tumor-specific T cells to fight solid tumor models. "We were able to observe the same effect when fighting tumor cells with so-called CAR-T cells," says the scientist.

CAR-T cells are written out as "chimeric antigen receptor T cells." While normal T cells are largely "blind" to tumor cells, CAR T cells are able to recognize specific target antigens on the tumor surface and destroy the cancer cells thanks to a genetic modification. Michael Hudecek is one of the leading experts in the field of CAR-T cell research.

Targeted control via the composition of the microbiome

"The results are an example of how metabolites of intestinal bacteria can change the metabolism and gene regulation of our cells and thus positively influence the efficiency of tumor therapies," says Maik Luu. In particular, the use of CAR-T cells against solid tumors could benefit from this.

In these cases, therapy with genetically modified cells has so far been much less effective than the treatment of haematological tumours such as leukaemia. This could change if the CAR-T cells were treated with pentanoate or other short-chain fatty acids before being used in patients, the scientists hope.

This effect might specifically be exploited via the composition of the bacterial intestinal colonisation -- especially since Luu and the others involved in the study were also able to identify the essential pentanoate producer of the intestinal flora: the bacterium Megasphaera massiliensis.

A long way to clinical applications

However, there is still a long way to go before the new findings will lead to new therapies for cancer patients. In a next step, the research team will initially expand the spectrum of tumour diseases investigated and, in addition to other solid tumours, also look at haematological tumour diseases such as multiple myeloma. In addition, it wants to investigate the functioning of short-chain fatty acids more intensively in order to identify starting points for targeted genetic modifications.

Story Source:

Materials provided by University of Würzburg. Original written by Gunnar Bartsch. Note: Content may be edited for style and length.

Journal Reference:

  1. Maik Luu, Zeno Riester, Adrian Baldrich, Nicole Reichardt, Samantha Yuille, Alessandro Busetti, Matthias Klein, Anne Wempe, Hanna Leister, Hartmann Raifer, Felix Picard, Khalid Muhammad, Kim Ohl, Rossana Romero, Florence Fischer, Christian A. Bauer, Magdalena Huber, Thomas M. Gress, Matthias Lauth, Sophia Danhof, Tobias Bopp, Thomas Nerreter, Imke E. Mulder, Ulrich Steinhoff, Michael Hudecek, Alexander Visekruna. Microbial short-chain fatty acids modulate CD8 T cell responses and improve adoptive immunotherapy for cancer. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-24331-1

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Engineered cells successfully treat cardiovascular and pulmonary disease

 Scientists at UC San Francisco have shown that gene-edited cellular therapeutics can be used to successfully treat cardiovascular and pulmonary diseases, potentially paving the way for developing less expensive cellular therapies to treat diseases for which there are currently few viable options.

The study, in mice, is the first in the emerging field of regenerative cell therapy to show that products from specially engineered induced pluripotent stem cells called "HIP" cells can successfully be employed to treat major diseases while evading the immune system. The findings subvert the immune response that is a major cause of transplant failure and poses a barrier to using engineered cells as therapy.

"We showed that immune-engineered HIP cells reliably evade immune rejection in mice with different tissue types, a situation similar to the transplantation between unrelated human individuals. This immune evasion was maintained in diseased tissue and tissue with poor blood supply without the use of any immunosuppressive drugs." said Tobias Deuse, MD, the Julien I.E. Hoffman, M.D. Endowed Chair in Cardiac Surgery and a first author of the study.

Deuse's research is an example of "living therapeutics," an emerging pillar of medicine in which treatments are broadly defined as living human and microbial cells that are selected, modified, or engineered to treat or cure disease.

The study appears in PNAS (Proceedings of the National Academy of Science).

"Universal Stem Cells" Avoid Immune Detection

The prospects of generating specialized cells in a dish that can be transplanted into patients to treat various diseases are encouraging, the scientists report. However, the immune system would immediately recognize cells that were recovered from another individual and would reject the cells. Hence, some scientists believe that custom cell therapeutics need to be generated from scratch using a blood sample from every individual patient as starting material.

The research group at UCSF followed a different approach, using gene editing to create 'universal stem cells' (named HIP cells) that are not recognized by the immune system and can be used to make "universal cell therapeutics."

The team tested the ability of these cells to treat three major diseases affecting different organ systems: Peripheral artery disease; chronic obstructive pulmonary disease from alpha1-antitrypsin deficiency; and heart failure, increasingly a global epidemic with more than 5.7 million patients in the United States alone and some 870,000 new cases annually.

The scientists transplanted specialized, immune-engineered HIP cells into mice with each of these conditions and were able to show that the cell therapeutics could alleviate peripheral artery disease in hindlimbs, prevent the development of lung disease in mice with alpha1-antitrypsin deficiency, and alleviate heart failure in mice after myocardial infarction.

To enhance the translational aspect of this proof-of-concept study, the researchers assessed the treatment's efficacy using standard parameters for human clinical trials focusing on outcome and organ function.

The Promise of an Affordable Option

Deuse, who is also surgical director of the Transcatheter Valve Program and directs Minimally Invasive Cardiac Surgery, plans to explore the potential of these universal stems cells for treating other endocrine and cardiovascular conditions. He noted that, because of the novelty of the approach, a careful and measured introduction into clinical trials will be crucial. Once more is known about human safety, he said, it will be easier to estimate when treatments using HIP cells might be approved and available for patients.

One of the great benefits of this approach, said Deuse, is that the strategy of immune engineering comes with a reasonable price tag. It would make the manufacturing of universal, high-quality cell therapeutics more cost effective, could allow future treatment of larger patient populations, and facilitate access for patients from underserved communities.

"In order for a therapeutic to have a broad impact, it needs to be affordable," said Deuse. "That's why we focus so much on immune-engineering and the development of universal cells. Once the costs come down, the access for all patients in need increases."

Story Source:

Materials provided by University of California - San Francisco. Note: Content may be edited for style and length.

Journal Reference:

  1. Tobias Deuse, Grigol Tediashvili, Xiaomeng Hu, Alessia Gravina, Annika Tamenang, Dong Wang, Andrew Connolly, Christian Mueller, Beñat Mallavia, Mark R. Looney, Malik Alawi, Lewis L. Lanier, Sonja Schrepfer. Hypoimmune induced pluripotent stem cell–derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice. Proceedings of the National Academy of Sciences, 2021; 118 (28): e2022091118 DOI: 10.1073/pnas.2022091118

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As Delta Cases Surge, FDA Pressured to Fully Approve COVID Vaccines

 More and more experts are urging the FDA to grant full approval to the Pfizer and Moderna COVID-19 vaccines because it might jump-start the stalled national vaccination program and slow down the surge of the Delta variant infection.

The FDA granted emergency use authorization in December to those two vaccines, which are based on mRNA technology. Both companies have applied for full approval but it's unclear when the FDA will act. 

Eric Topol, a professor of molecular medicine at Scripps Research, and editor-in-chief of WebMD's sister site, Medscape, is one scientist urging full approval soon.

In a guest essay in The New York Times, he wrote that people taking a wait-and-see attitude toward the vaccine might get a shot if the FDA granted full approval. Also, people might take the step if required by their employers. 

"Some people who understand that the 'E' in 'EUA' stands for 'emergency' are waiting for full FDA approval before they receive a shot," Topol wrote. "Others may not get immunized unless their employers require it, and many organizations — including, reportedly, the military — are waiting for the vaccines to be fully approved before instituting such mandates."

Topol said the rapid spread of the Delta variant is one reason for the FDA to move more quickly.

"The agency should make full approval its number one priority, and its leadership should communicate its plans to the public," he wrote.

The CDC says 183 million doses of the Pfizer vaccine and 135 million doses of the Modern vaccine have been administered in the United States since December. Infections, hospitalizations, and deaths have dropped sharply since.

"That's as good as it gets when it comes to having data on safety and efficacy," said Céline Gounder, MD, an epidemiologist at New York's Bellevue Hospital, according to Politico.  "We have it in real life — what more can people ask for?"

But vaccine hesitancy remains. The CDC says only 55.2% of the total U.S. population has gotten at least one dose and 47.7% is fully vaccinated. The Delta variant has been recognized as the dominant strain in the United States.

In a comment to Politico, FDA spokesperson Abby Capobianco declined to offer a timeline for when the agency might grant full approval of the Pfizer and Moderna vaccines.

"Although an authorization is not an FDA approval, the FDA conducted a thorough scientific evaluation of each of the authorized vaccines and can assure the public and medical community that the vaccines meet FDA's rigorous standards for safety, effectiveness, and manufacturing quality," she said.

Politico said Pfizer and Moderna requested priority review, meaning the agency's goal would be to make a decision within 6 months of receiving the application.

Some scientists want the FDA to go slow. A group of them lodged a "Citizen Petition" with the FDA asking the agency to delay full approval, according to a blog on the website of the BMJ, formerly known as the British Medical Journal.

"The message of our petition is 'slow down and get the science right — there is no legitimate reason to hurry to grant a license to a coronavirus vaccine.' We believe the existing evidence base — both pre- and post-authorization — is simply not mature enough at this point to adequately judge whether clinical benefits outweigh the risks in all populations," the BMJ reported.

The one-shot Johnson & Johnson vaccine received emergency authorization in February, but the company has not applied for full approval yet. That vaccine does not use mRNA technology.

Delta Variant Grows Quickly Inside People, Study Says

Meanwhile, two studies showed the dangers the Delta variant poses.

Researchers at the Guangdong Provincial Center for Disease Control and Prevention in China say the Delta variant is not just highly transmissible. It also grows faster inside an infected person than other strains, according to NPR.

The scientists determined that "people infected with the Delta variant had about 1,000 times more copies of the virus in their respiratory tracts than those infected with the original strain of the coronavirus," NPR said.

The Delta variant also makes a person sicker faster, taking around 4 days to reach detectable levels inside a person, compared to 6 days with the original COVID-19 strain, NPR said.

A second study, out of France, highlighted the importance of getting two shots of two-dose vaccines like Moderna and Pfizer.

The study said one dose "barely inhibited" infection by the Delta variant, whereas two doses provided a 95% neutralizing response. The study, published in Nature, echoes previous research about how much protection vaccines offer against the Delta variant.

LA County COVID Cases Jump 165% in a Week

COVID-19 is making a comeback in Los Angeles County, also because of the Delta variant.

Los Angeles County Public Health said in a news release that there were 839 new COVID-19 cases this week, a 165% increase over last week.

The daily average case rate is now 3.5 cases per 100,000 people, compared to 1.74 cases a week ago. The daily test positivity rate on Thursday was 2.5%, up from 1.2% last week.

"Overall COVID-19 trends are going in the wrong direction for everyone, and are particularly concerning given the proliferation of the Delta variant," said Barbara Ferrer, director of public health.

The department said the Delta variant has been the most commonly sequenced variant in L.A. County since the beginning of June and "now accounts for the majority of variants of concern identified by labs."

Sources

The New York Times: "It's Time for the F.D.A. to Fully Approve the mRNA Vaccines."

Politico: "Calls mount on FDA to formally endorse Covid vaccines as Delta surges."

BMJ. "Why we petitioned the FDA to refrain from fully approving any covid-19 vaccine this year."

Virological: "Viral infection and transmission in a large well-traced outbreak caused by the Delta SARS-CoV-2 variant."

NPR: "The Delta Variant Isn't Just Hyper-Contagious. It Also Grows More Rapidly Inside You."

Nature: "Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization"

L.A. County Department of Public Health: "L.A. County Sees Increased Spread of COVID-19 and Delta Variant Cases; Fully Vaccinated People Remain Well Protected - 11 New Deaths and 839 New Confirmed Cases of COVID-19 in Los Angeles County."

https://www.medscape.com/viewarticle/954554

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