Biotech week ahead, Nov. 30

 Biotech stocks had a rather uneventful week, as the sector was seen mostly flatlining amid light trading volume ahead of the Thanksgiving holiday.

The week kickstarted with lukewarm news on the coronavirus vaccine front, as AstraZeneca plc AZN 0.02% reported late-stage interim efficacy data that did not match up to data from rival vaccine makers Pfizer Inc. PFE 2%/BioNTech SE – ADR BNTX 4.79% and Moderna Inc MRNA 16.35%.

U.S. Food and Drug Administration decisions for the week panned out mostly negative for other companies. Liquidia Corp LQDA 3.06% received a complete response letter from the FDA, turning down the NDA (new drug application) for a pulmonary arterial hypertension drug. Revance Therapeutics Inc RVNC 1.14% said the FDA will defer a review of the license application for DaxibotulinumtoxinA, an investigational neuromodulator product for treating glabellar lines, also known as frown lines. The FDA was unable to conduct on-site inspection of a Revance facility, the company said.

However, Christmas came early for Alnylam Pharmaceuticals, Inc. ALNY 3.52% as the FDA greenlighted its Oxlumo product as the first treatment for primary hyperoxaluria type 1, a rare genetic disorder.

Merck & Co., Inc. MRK 0.25% went shopping this week by agreeing to buy privately-held OncoImmune, a company that has a late-stage COVID-19 treatment candidate, for $425 million in cash.

Here are the key catalysts for the coming week.

Conferences

Piper Sandler 32nd Annual Virtual Healthcare Conference: Nov. 30-Dec. 3
3rd Annual Evercore ISI 2020 Virtual HealthCONx Conference: Dec. 1-2
American Epilepsy Society, or AES, Annual Meeting (virtual event): Dec. 4-8
62nd American Society of Hematology, or ASH, Annual Meeting and Exposition (virtual event): Dec. 5-8

PDUFA Dates

The FDA is scheduled to rule on Y-mAbs Therapeutics, Inc's YMAB 10.15% BLA for naxitamab, which is being evaluated for
relapsed/refractory high-risk neuroblastoma. The NDA has a PDUFA action date of Nov. 30.

The regulatory agency will also decide by Dec. 1 Vanda Pharmaceuticals Inc.'s VNDA 2.48% sNDA for Hetlioz capsules and its NDA for the liquid formulation of Hetlioz for the treatment of Smith-Magenis Syndrome.

BioCryst Pharmaceuticals, Inc. BCRX 7.77% awaits an FDA nod for the NDA for oral, once-daily berotralstat for the prevention of hereditary angioedema attack, with the application having a PDUFA action date of Dec. 3.

Related Link: Odds Of Vertex's Pipeline Success Aren't Dismal As Some Fear, Bernstein Says

Clinical Readouts

Standalone Releases

Imv Inc IMV 4.06% is scheduled to hold a KOL (key opinion leader) event at 8 a.m. on Dec. 3, wherein it will provide an update on the Phase 2 trial of its T cell therapy in patients with advanced ovarian cancer.

Sutro Biopharma Inc STRO 3.64% will provide at a KOL meeting scheduled for 5 p.m. , Dec. 3, a clinical update from the dose escalation Phase 1 study of STRO-002, an antibody-drug conjugate, for patients with ovarian cancer. The data will be based on a new data cut-off date of Oct. 30.

AES Meeting Presentations:

Xenon Pharmaceuticals Inc XENE 0.53%: interim data from the Phase 2 proof-of-concept study evaluating XEN007 as an adjunctive treatment in pediatric patients diagnosed with treatment-resistant childhood absence epilepsy

Ovid Therapeutics Inc OVID 5.01% and Takeda Pharmaceutical Co Ltd TAK 1.35%: abstracts from the TAK-935/OV935 clinical development program in Dravet syndrome or Lennox-Gastaut syndrome and Phase 2 data from the OV101 clinical development program in Angelman syndrome

ASH Meeting Presentations (Dec. 5)

Syros Pharmaceuticals Inc SYRS 2.9%: new clinical data from the Phase 2 trial of SY-1425 in acute myeloid leukemia, or AML, and Myelodysplastic Syndrome, MDS

Celyad ADR Representing Ord Shs CYAD 3.32%: results from the Phase I study of CYAD-01 in relapsed or refractory AML and MDS patients; first results from the dose escalation segment of the Phase 1 study of CYAD-02 in relapsed or refractory AML and MDS patients (Saturday, 10 a.m. to 6:30 a.m.)

Trillium Therapeutics Inc TRIL 13.11%: update from the first-in-human dose escalation study of TTI-622 in patients with advanced relapsed or refractory lymphoma (Saturday from 10 a.m. onwards)

Allogene Therapeutics Inc ALLO 0.91%: initial data from the Phase 1 UNIVERSAL trial of ALLO-715 in relapsed/refractory multiple myeloma patients

Legend Biotech Corp LEGN 0.31%: latest data from the Phase 1b/2 CARTITUDE-1 study of ciltacabtagene autoleucel, that is being studied for the treatment of patients with relapsed or refractory multiple myeloma

Actinium Pharmaceuticals Inc ATNM 2.8%: Phase 3 data for antibody Radiation Conjugate Iomab-B in AML

Beyondspring Inc BYSI 2.75%: data from the confirmatory trial to demonstrate superiority of the Plinabulin+Pegfilgrastim combo versus standard-of-care Pegfilgrastim for the prevention of chemotherapy-induced neutropenia in breast cancer patients

Gamida Cell Ltd GMDA 0.76%: updated data from the Phase 1 study of GDA-201, an investigational, natural killer cell-based cancer immunotherapy, for the treatment of patients with non-Hodgkin lymphoma; new data from the ongoing Phase 1/2 study of omidubicel in patients with severe aplastic anemia

Cellectis SA CLLS 7.98%: Preliminary results from the Phase 1 study of of BALLI-01 in adult patients with relapsed or refractory CD22+ B-cell Acute Lymphoblastic Leukemia; Phase 1 study of AMELI-01 in AML

Autolus Therapeutics PLC AUTL 9.17%: Updated Phase 1 data for AUTO1 in acute lymphoblastic leukemia; updated Phase 2 data for AUTO3 in relapsed or refractory diffuse large B-cell lymphoma

ImmunoGen, Inc. IMGN 4.15%: oral presentation of updated data from the IMGN632 monotherapy blastic plasmacytoid dendritic cell neoplasm expansion cohort and a trial-in-progress poster on the AML monotherapy and combination cohorts
Aptose Biosciences Inc APTO 2.45%: data from the Phase 1a/b dose escalation study of Apto-253 in patients with relapsed or refractory AML or High-Risk MDS

Corvus Pharmaceuticals Inc CRVS 3.33%: Updated Phase 1 data for CPI-818 in patients with advanced peripheral T cell lymphoma

Constellation Pharmaceuticals Inc CNST 1.34%: clinical and translational data from MANIFEST Phase 2 study of CPI-0610, including 24-week data from 50 – 60 first-line and 90 –100 second-line myelofibrosis patients

Fortress Biotech FBIO 6.13% and Mustang Bio Inc MBIO 1.76%: interim Phase 1/2 data on MB-106, a CD20-targeted, autologous CAR T cell therapy for patients with relapsed or refractory B-cell non-Hodgkin lymphoma

Agios Pharmaceuticals Inc AGIO 2.17%: Phase 2 data for AG-348 in sickle cell disease

Pluristem Therapeutics Inc. PSTI 2.9%: first clinical results from the Phase I study evaluating PLX-R18 as a treatment for incomplete hematopoietic recovery following hematopoietic cell transplantation

Kura Oncology Inc KURA 2.28%: Preliminary data on a Phase 1/2a study of KO-539 in patients with relapsed or refractory AML

IGM Biosciences Inc IGMS 4.93%: Results of the Phase 1 dose escalation study of bispecific antibody IGM-2323 in patients with advanced B-cell malignancies

Hutchison China MediTech ADR Representing 5 Ord Shs HCM 2.03%: Results from a Phase 1 dose escalation study of HMPL-689 in Chinese patients with relapsed/refractory lymphoma

Beigene Ltd BGNE 8.23%: efficacy and safety of zanubrutinib in patients with treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma with del(17p)

Keros Therapeutics Inc KROS 0.62%: Phase 1 data for KER-047 in anemia

https://www.benzinga.com/general/biotech/20/11/18538051/the-week-ahead-in-biotech-hematology-conference-gets-underway-vanda-and-biocryst-await-fda-decisi

Home-Made Covid Vaccine Appeared to Work, but Questions Remain

 Josiah Zayner’s plan was simple: replicate a Covid-19 vaccine that had worked in monkeys, test it on himself and then livestream the experiment online over a period of months. Now, that improbable bid is over.

Around the world, dozens of Covid-19 vaccines are in human clinical trials involving tens of thousands of people. While vaccines typically take years to develop, U.S. scientists are racing to produce one in months through Operation Warp Speed. But Zayner, a one-time NASA researcher who left the scientific establishment in favor of engaging in do-it-yourself experiments, bet that by working outside regulatory structures, he could test a vaccine even more quickly and certainly more cheaply by giving it to himself.

Instead, Zayner discovered, testing a vaccine is far more complicated than he had imagined. 

Even though his experiment yielded a promising result, Zayner found too many unanswered questions to say that it worked. For one, it wasn’t clear whether antibodies he found in his own body in extremely tiny measures before the experiment began made a difference. Zayner has long-believed that biohackers such as himself have the potential to make science move faster. In June, he told Bloomberg News that Covid-19 presented "the perfect opportunity" to show just what biohackers can do. 

Now, his message is decidedly different: “Human beings — their biology is so complex,” he said in a recent interview. “The results are going to be messy. The experiments are going to be messy. So you test 30,000 people so that the messiness kind of averages out.”


As the U.S. rushes to bring a vaccine to market far faster than has ever been done, Zayner said he has discovered why the long, slow process of clinical trials shouldn’t be rushed. A promising early stage result is just that: promising. It’s a message that’s resonating nationwide in the U.S. as the timeline for a development of a safe and effective vaccine has become a touchpoint in the presidential election, with President Donald Trump saying we could see an outcome before the Nov. 3 vote, Democrats worrying that he is putting a thumb on the scale,  and scientists saying it will probably arrive close to the end of the year, even in January.

Zayner is infamous for attention-grabbing experiments in which he uses himself as a guinea pig. He self- injected the gene-editing tool Crispr while giving a talk at a San Francisco biotech conference, and performed his own fecal matter transplant. Such stunts have made him an informal figurehead for a growing movement of do-it-yourself scientists emboldened by advancements in technology that have made such feats as engineering biology increasingly simple. Zayner believes such cutting-edge science should be accessible to anyone, and that democratizing science could help curb exorbitant drug prices and speed science along.

Initially, Zayner assumed that the experiment he named Project McAfee, after the antiviral software, would be relatively straightforward. The vaccine selected had  triggered protective immunity against the virus in rhesus macaque monkeys in a paper published in May. Zayner was able to order the same spike protein sequence from the DNA-synthesis company the researchers had used. The plan: He and two fellow biohackers — Daria Dantseva in Ukraine and David Ishee in Mississippi — would themselves test the concoction they ordered online. They would then livestream the entire process online over several months, with the first showing to occur in June.

But early on in the experiment, complications arose. Before starting, Zayner took a test at Lab Corp Inc. that told him he didn’t already have antibodies to the virus. But when he performed a similar test on himself shortly afterward, he found that he did have some antibodies, just not enough to produce a positive result on Lab Corp’s test. While those antibodies didn’t appear to be the neutralizing type, he wondered whether the result came because the vaccine was picking up signals from antibodies to a different virus — or how this faint antibody signal might affect things. 

“I’m very suspicious of my own data,” he said.

He’s not alone. Hank Greely, a bioethicist at Stanford University, said Zayner’s experiment pointed out an underappreciated reality of vaccine development. “Actually making the vaccine isn’t that hard,” he said. “It’s testing it and knowing that it’s safe — and knowing that it’s effective.”

Greely said that while Zayner’s DIY experiment probably presented more risks than potential benefits, there  is value in demonstrating to people that vaccine development isn’t “magic.”

For his part, Zayner said his turn at vaccine testing has tempered his appetite for DIY human experimentation. He still believes such experiments have a role to play, especially for those with fatal illnesses that lack approved treatments. But for now, he's taking a break from experimenting on himself.  His next project will focus on showing people how to grow chicken cells to make their own fake meat. 

With vaccines,  Zayner concluded, “Large scale clinical trials are probably required, because it is so messy.”

https://www.bloomberg.com/news/articles/2020-10-10/home-made-covid-vaccine-appeared-to-work-but-questions-remained

Ketogenesis restrains aging-induced exacerbation of COVID in mouse model

 Seungjin Ryu, Irina Shchukina, Yun-Hee Youm, Hua Qing, Brandon K. Hilliard, Tamara Dlugos, Xinbo Zhang, Yuki Yasumoto, Carmen J. Booth, Carlos Fernández-Hernando, Yajaira Suárez, Kamal M. Khanna, Tamas L. Horvath, Marcelo O. Dietrich, Maxim N. Artyomov, Andrew Wang, Vishwa Deep Dixit

doi: https://doi.org/10.1101/2020.09.11.294363

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2020.09.11.294363v1.full.pdf

SUMMARY

Increasing age is the strongest predictor of risk of COVID-19 severity. Unregulated cytokine storm together with impaired immunometabolic response leads to highest mortality in elderly infected with SARS-CoV-2. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain MHV-A59 (mCoV-A59) that recapitulated majority of clinical hallmarks of COVID-19. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective γδ T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against COVID-19 in the elderly.

• - Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly.

• - Aged infected mice have systemic inflammation and inflammasome activation

• - Murine beta coronavirus (mCoV) infection results in loss of pulmonary γδ T cells.

• - Ketones protect aged mice from infection by reducing inflammation.

eTOC Blurb Elderly have the greatest risk of death from COVID-19. Here, Ryu et al report an aging mouse model of coronavirus infection that recapitulates clinical hallmarks of COVID-19 seen in elderly. The increased severity of infection in aged animals involved increased inflammasome activation and loss of γδ T cells that was corrected by ketogenic diet.

Competing Interest Statement

The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2020.09.11.294363v1

Dangers of COVID-19 lockdown: Inactivity can take toll on health in just 2 weeks

 As the world digs in for the second wave of COVID-19, flu season and winter, people also face a serious risk from reduced physical activity — especially older adults. Developing a plan to be physically active now will help you to stay strong and healthy through the long winter ahead.

While most people are aware of the benefits of physical activity — increased muscle and strength, reduced risk of disease, better quality of life and a lower risk of death — we tend to be less aware of how damaging and expensive reduced physical activity can be.

The loss of muscle and strength as you get older (known as sarcopenia) is something with which we are all familiar. We have all heard older family members say, “I’m just not as strong as I used to be,” or “I just can’t do that anymore.” But did you know that inactivity can make muscle loss a whole lot worse?

Health effects of inactivity

Physical inactivity can be forced on a person by an acute event such as a broken arm or leg or becoming bed-bound due to illness. However, reduced physical activity, such as step reduction, is a long-term choice that brings about multiple negative health consequences.

Insulin resistance (a warning sign for the development of type 2 diabetes), reduced muscle mass, increased body fat and poor sleep quality are just some of the health concerns caused by physical inactivity. Physical inactivity is also a major contributor to poor mental health and social isolation, which can be particularly problematic for older adults.

The health effects of inactivity start piling up within days.

McMaster University researchers have shown that reducing daily steps to fewer than 1,500 — similar to the activity level of people who are housebound during this pandemic — for just two weeks can reduce an older person’s insulin sensitivity by as much as one-third. The same period of inactivity also led to individuals over age 65 losing as much as four per cent of their leg muscle.

To make matters worse, once an older individual loses muscle, it is much more difficult to restore. Even when the research subjects returned to their normal daily routines, they did not regain their lost muscle. Effectively, older individuals simply don’t possess the same ability to bounce back that younger people do.

Regaining muscle requires deliberate effort. So, it truly is a case of use it or lose it.

Resistance is not futile

As a muscle physiologist with a keen interest in healthy aging, I’m pleased to report it’s not all doom and gloom. There are some things you can do — resistance exercise and eating your protein — to keep and even build muscle, get stronger and maintain your health for this winter and beyond.

The most effective way to maintain the muscle you have is strength training, or resistance exercise, which, put simply, means performing work against an additional load. And it doesn’t have to be complicated. If you have access to a gym to use free-weights and guided-motion machines, that’s great. However, there are many valuable alternatives you can easily do at home. Body-weight exercises such as push-ups, squats and lunges, elastic-band exercises and stair-climbing are just a few options that will help you to meet the World Health Organization’s latest physical activity guidelines.

The good news for those who may be put off by the sound of resistance exercise is that doing any exercise with a high degree of effort will help you to get stronger and prevent (at least some) muscle loss. If, for any reason, performing resistance exercise isn’t possible, simply adding a walk, a bike ride or some lower-intensity strength exercises such as yoga or Pilates to your daily routine can have significant physical and mental health benefits.

Protein and muscle

Of course, a healthy diet and avoiding overeating are also critical to staying healthy. Protein-rich foods are particularly important, since they make you feel fuller for longer and provide building blocks for your muscles.

It is generally agreed that older adults need more protein than current guidelines suggest.

A good, easily achievable, target would be to eat 25 to 40 grams of protein with each meal (about one or two palm-sized portions). This equates to approximately 1.2 to 1.6 grams of protein per kilogram of body mass each day. Also, getting your protein from both animal (dairy, meat, fish, and eggs) and plant-based (beans, nuts, seeds, and lentils) sources may be beneficial.

Given how quickly inactivity and poor nutrition can sap your strength and your health, doing something now is the best way to power through the cold, dark winter and beyond.

https://theconversation.com/dangers-of-a-sedentary-covid-19-lockdown-inactivity-can-take-a-toll-on-health-in-just-two-weeks-149666