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Friday, August 28, 2020

Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity

View ORCID ProfileRobert T. Schooley, View ORCID ProfileAaron F. Carlin, View ORCID ProfileJames R. Beadle, Nadejda Valiaeva, Xing-Quan Zhang, Aaron F. Garretson, Victoria I. Smith, Joyce A. Murphy, View ORCID ProfileKarl Y. Hostetler


This article is a preprint and has not been certified by peer review [what does this mean?].


Abstract


The FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells.

Competing Interest Statement


The authors have declared no competing interest.


Versatile, Multivalent Nanobody Cocktails Efficiently Neutralize SARS-CoV-2

Yufei Xiang, Sham Nambulli, Zhengyun Xiao, Heng Liu, Zhe Sang, W. Paul Duprex, Dina Schneidman-Duhovny, Cheng Zhang, Yi Shi


This article is a preprint and has not been certified by peer review [what does this mean?].


Abstract


The outbreak of COVID-19 has severely impacted global health and the economy. Cost-effective, highly efficacious therapeutics are urgently needed. Here, we used camelid immunization and proteomics to identify a large repertoire of highly potent neutralizing nanobodies (Nbs) to the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD). We discovered multiple elite Nbs with picomolar to femtomolar affinities that inhibit viral infection at sub-ng/ml concentration, more potent than some of the best human neutralizing antibodies. We determined a crystal structure of such an elite neutralizing Nb in complex with RBD. Structural proteomics and integrative modeling revealed multiple distinct and non-overlapping epitopes and indicated an array of potential neutralization mechanisms. Structural characterization facilitated the bioengineering of novel multivalent Nb constructs into multi-epitope cocktails that achieved ultrahigh neutralization potency (IC50s as low as 0.058 ng/ml) and may prevent mutational escape. These thermostable Nbs can be rapidly produced in bulk from microbes and resist lyophilization, and aerosolization. These promising agents are readily translated into efficient, cost-effective, and convenient therapeutics to help end this once-in-a-century health crisis.

Competing Interest Statement


University of Pittsburgh has filed a provisional patent that is in connection with the manuscript


Veeva Analysts Confident In Cloud Company’s Trajectory After Q2 Beat

The pharma- and life sciences-focused cloud computing company Veeva Systems Inc VEEV 1.29% reported solid quarterly results Thursday, sending its shares higher. 

The Veeva Systems Analysts: BofA Securities analyst Brad Sills reiterated a Buy rating on Veeva Systems and upped the price target from $230 to $302.

Piper Sandler analyst Brent Bracelin has an Overweight rating and increased the price target from $220 to $310. 

Needham analyst Scott Berg maintained a Buy rating and increased the price target from $235 to $310.

Raymond James analyst Brian Peterson reiterated an Outperform rating and hiked the price target from $230 to $285.

BofA Confident In Veeva Systems’ Revenue Growth: Veeva’s key second-quarter metrics such as revenues, in both subscriptions and services, and billings beat estimates, and the company raised its fiscal year 2021 guidance, Sills said in a note.

The billings upside stemmed primarily from broad strength across both Commercial and Vault, thanks in part due to some business pulled in from the third quarter and contract duration, the analyst said.

The 10%-plus subscriber growth in commercial points to a growing value proposition in the life sciences CRM offering to manage pandemic-related sales force displacement, he said. 

“Broad Vault strength across the major clinical, regulatory and quality categories underscores the value of an end to end workflow automation offering spanning the entire drug lifecycle.” 

Sills expressed confidence in the ability of the company to sustain 20-25% growth long term, with a best-in-class 35%-plus operating margin.

Veeva Analyst Expects Sustainable Share Gains, Durable Growth: The upwardly revised price target reflects Piper Sandler’s increased confidence in the three-to-five-year opportunity for sustainable share gains and durable growth as the company modernizes the life sciences industry through cloud software, automation and data, Bracelin said.

Needham Says Veeva Can Maintain Organic Subscription Growth: Veeva’s strong sales execution and the significant billings beat suggest demand from its predominately pharma customer base has not waned during the COVID-19 pandemic, Berg said in a note. 

The key takeaway from the second-quarter results was the sales momentum, specifically from new solutions like Quality Management and CTMS, the analyst said.

“The additional sales traction and commentary with newer models along with improving usage of Crossix and Physicians World suggest the company has a strong chance to maintain its 20% organic subscription revenue growth through at least FY22.” 

Long-Term Trajectory For Shares Higher, Raymond James Says: New business highlights that included record Quality bookings, increased momentum in Clinical and another large add in OLS, which should give investors confidence in the duration of Veeva’s growth trajectory, Peterson said in a note. 

The analyst expressed confidence in the company reaching its $3-billion revenue target by calendar year 2025.

While the valuation of the shares remains inexpensive, the long-term trajectory is higher, according to RayJay. 


Abbott Labs seeking to expand FDA authorization for rapid COVID test

Abbott Labs (NYSE:ABT) has trials underway for its rapid COVID-19 test to determine whether it could effectively be used on asymptomatic people, CEO Robert Ford tells CNBC.

Abbott this week received emergency use authorization from the Food and Drug Administration for its new test, which it says will sell for $5 and can produce results in 15 minutes similar to a pregnancy test, but the FDA OK is limited in scope: It can be used only within seven days of someone showing coronavirus symptoms and in consultation with a health care provider, meaning it is not authorized to test pre-symptomatic people or those without symptoms.

“We are working on developing data for asymptomatic claims so we are running our clinical trial and we’ll eventually have data to be able to support that,” Ford says.

The U.S. government secured a ~$750M deal for 150M of Abbott’s tests, with hopes of deploying them to nursing homes, schools or other high-risk populations.


Steve Cohen constructs vehicle to invest in private biotech

The billionaire founder of Point72 Asset Management created Point72 Biotech Private Investments last month, Bloomberg reports, citing Delaware state records.

The move illustrates the continued flow of funds into closely held biotech companies.

Initially, the investment vehicle will invest on Steve Cohen’s behalf and has no plans to raise outside capital, a person familiar with the matter told Bloomberg.

The new partnership is separate from Point72 Ventures, an early stage venture capital strategy funded by Cohen and other members of the firm, the person said.

The enthusiasm for investing in biotech was expected to slow after VC funding in U.S. biopharmaceutical companies hit a record in Q1, according to Bruce Booth, a partner at Atlas Venture.

But that changed when COVID-19 emerged. VC funding of biotech is expected to exceed $6.4B in Q2, hitting another record, according to data compiled by Pitchbook.


CytoDyn to update investors on regulatory and clinical activities September 2

CytoDyn (OTCQB:CYDY) will host a conference call on Wednesday, September 2, at 4:00 pm ET to update investors on all of its regulatory and clinical initiatives including its activities related to leronlimab in COVID-19.

CEO Nader Pourhassan, Ph.D., Chairman, CMO and Head of Business Development Scott Kelly, M.D. and Chief Science Advisor Jacob Lalezari, M.D. will host.

Management will allocate ~45 minutes for Q&A.


FDA OKs emergency use of Gilead’s remdesivir for moderate COVID-19

Gilead Sciences (NASDAQ:GILD) announces the FDA emergency use nod for Veklury (remdesivir) for the treatment of hospitalized COVID-19 patients with moderate pneumonia.

It was approved for the emergency treatment of severely ill patients on May 1.

The expanded use was based on results from the Phase 3 SIMPLE study and an NIAID trial in hospitalized patients with a range of disease severity.