Structural basis for SARS-CoV-2 inhibition by Remdesivir uncovered

A team of Chinese scientists have reported the high-resolution cryo-EM structure of Remdesivir-bound RNA replicase complex from SARS-CoV-2, the infective virus of COVID-19.

The research, published online in Science on May 1, was conducted by Prof. Xu Huaqiang and Prof. Xu Yechun from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), Prof. Zhang Yan from the Zhejiang University School of Medicine, Prof. Zhang Shuyang from Peking Union Medical College and Chinese Academy of Medical Sciences, and their collaborators.
COVID-19 has spread rapidly around the world and is an ongoing humanitarian crisis. Many countries are now facing tremendous challenges in the fight against SARS-CoV-2. Finding an effective treatment is a very urgent matter.
SARS-CoV-2 is a positive-strand RNA virus that mainly infects human cells through the mucosal system. The massive replication of the virus requires the rapid synthesis of its genetic RNA. This process is mediated by a multi-subunit replication transcription complex composed of multiple non-structural proteins (nsp) of the virus. The core element is the replicase complex, which is the core component of coronavirus replication. Numerous nucleoside drugs targeting replicase are currently under clinical testing, including Remdesivir.
After 46 days of hard work, the scientists were able to elaborate the replicase-targeting mechanism underlying the antiviral efficacy of these nucleoside drugs. Their study reports the cryo-EM structure of the SARS-CoV-2 replicase both in the apo form at 2.8 Å resolution and in complex with a template-primer RNA and Remdesivir at 2.5 Å resolution. The overall conformation of the complex structure is very similar to that of the apo form, with the identical structures at the core catalytic active site. Comprehensive analysis of the structures showed that the SARS-CoV-2 replicase complex is a very efficient enzyme. During RNA extension, conformational change is small, which also explains the highly contagious nature of SARS-CoV-2.
The replicase complex recognizes RNA—but not DNA—through a sequence-independent binding way. The structure of the complex explains how Remdesivir enters the replication active site and covalently links with the viral genome, thereby inhibiting virus replication.
The residues involved in RNA binding as well as those comprising the catalytic active site are highly conserved among most RNA viruses. This shows the conservative mechanism of the replicase complex during gene replication and suggests it may be possible to develop broad spectrum antiviral inhibitors.
The structures described in this study reveal potential binding patterns that offer theoretical support for the design of more powerful, efficient and specific anti-SARS-CoV-2 drugs. In this way, they provide a basis for the design of the antiviral drugs, which are so urgently needed to fight the COVID-19 crisis.

---

Explore further

Structure-based design of antiviral drug candidates targets SARS-CoV-2 main protease

---

More information: Wanchao Yin et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science  01 May 2020: DOI: 10.1126/science.abc1560

https://medicalxpress.com/news/2020-05-scientists-uncover-basis-sars-cov-inhibition.html

Can germ-zapping robot kill coronavirus?

As doctors continue to debate how the fast-spreading coronavirus rose to pandemic levels, a Texas medical engineering company claims their $125,000 “germ-zapping” robot may be our best hope on the front lines against the invisible enemy.
San Antonio-based Xenex developed a robot that tracks, disinfects and collects data on hospital-acquired infections. Now, the company hopes its LightStrike robot, a “full germicidal spectrum” UV light smart cleaning device, will be used to combat COVID-19.
The autonomous tech is already being used in some of the world’s best hospitals, including health-care facilities for the Department of Defense. And this week, the independent Texas Biomedical Research Institute announced that Xenex’s latest bot can deactivate 99.99% of SARS-CoV-2 in just two minutes.
In 2015, the lab shared similar praise, claiming the LightStrike killed Ebola in just 60 seconds.
“Our robots have been adopted as the environmental standard of care by many of the world’s leading hospitals because they work — and they work very quickly,” said Dr. Mark Stibich, chief scientific officer and co-founder of Xenex in a statement.
“We wanted our current and future customers to know with certainty that their pulsed xenon UV robots could stop COVID-19,” Stibich said.
Xenex was founded by two former Johns Hopkins epidemiologists in 2009, Stibich and Julie Stachowiak. Unlike similar infection-blasting bots, their innovation was proven to reduce certain infection rates by up to 100 percent, based on studies published in journals including the American Journal of Infection Control.
Whereas similar companies use pulsed mercury UV devices, Xenex touts their unique pulsed xenon UV technology, which is more efficient and environmentally friendly than the former method, the company’s CEO Morris Miller told Crunchbase News last month.
Since the coronavirus outbreak, Miller said they received “hundreds” of requests for their costly robot, namely from Italy as well as countries in Asia.
“We’ve been working seven days a week for the last three to four weeks,” Miller said. “In addition, we’ve seen an increase in orders from existing hospitals for robots for their emergency rooms.”
Xenex is now looking to fulfill bulk orders “in the thousands,” he added, and projects growth in 2020 to be somewhere between 400 and 600 percent.
Despite sticker shock, the company estimates that the $125,000 price tag breaks down to just $2 to $8 per room. And the cost wasn’t too much for a number of big name hospitals, including the University of Texas MD Anderson Cancer Center, the Mayo Clinic Health System, Stanford University, 55 Veterans Affairs (VA) facilities and 10 DOD health-care buildings, according to Xenex. The company reports that the LightStrike was also sent to countries on almost every continent.
Earlier this year, the spike in sales — thanks to the pandemic — prompted the company’s VP of sales Irene Hahn to email a somber memo to her colleagues, according to Forbes.
“At any other time, we celebrate these wins,” she said. “However, in light of what is happening, this one is different … we are absolutely humbled.”
https://nypost.com/2020/05/01/can-this-germ-zapping-robot-really-kill-the-coronavirus/

U.S. needs to make more CPAP machines. Our supply chain is blocking that

I don’t want to be intubated.
That was my main thought a few weeks ago as I lay in bed at home, having trouble breathing and watching my pulse oximeter show that my blood oxygen was under 93% when it should have been over 95%.
I had just tested positive for Covid-19 and wanted to stay out of the hospital completely, or at least for as long as I could. Being short of breath meant I could develop hypoxia — too little oxygen in my bloodstream — which would mean I’d need to go to the hospital, something I wanted to avoid because it would increase my chances of being intubated and put on a ventilator.

The thought of being put on a ventilator frightened me, since nearly 90% of Covid-19 patients in the New York City area who were put on ventilators died.

Because I had been short of breath, exhausted, and feeling a tightness in my chest before testing positive for Covid-19, my father sent me a continuous positive airway pressure machine, also known as a CPAP, to help me breathe. This device is commonly used to treat obstructive sleep apnea.

Using CPAP requires wearing a mask that covers the nose and mouth. It is connected to a blower that pushes air through a hose and into the mask. Computer logic in the blower sends puffs of air into the mask timed to the user’s breathing patterns. The extra air pressure in the mask keeps the airway open and allows the user to breathe. It’s different in that way from a ventilator, which breathes for you.
I put on the mask, turned on the machine, and watched as my blood oxygen level rose to a manageable level, and helped keep it there over the next few days. I was able to work every day with intermittent use of the CPAP machine, and within a week was back on my feet.
I’m not alone in thinking that CPAP machines can play roles in fighting Covid-19. Emergency physicians I’ve spoken with directly, and others I have seen in the news, such as Colleen Smith from Elmhurst Hospital in Queens, N.Y., say that CPAP machines can be used for some patients in place of ventilators, providing all of the breathing support that’s needed and freeing up scarce ventilators for sicker people. For others, they could act as a bridge before crossing over to a ventilator. For patients coming off ventilators, CPAP machines could initially help regulate their breathing.
One drawback to using CPAP machines or their cousins, bilevel positive airway pressure (BiPAP) machines, at home or in the hospital is the cost of these devices. ResMed, the leading manufacturer of CPAP and BiPAP machines, charges approximately $1,500 for them. While that’s less than the cost of a ventilator, it is too much for individuals, much less for medical systems in crisis.
My father, an inventor and inveterate tinkerer, predicted the value of CPAP in treating patients with Covid-19 weeks before sending me one. With some experimentation, he came up with the prototype below, which could be built for approximately $200 apiece.

But what we found when we began to procure the most basic parts needed for production was that, due to outsourcing, none of the components were currently being made in the U.S., including basic items such as hoses, masks, and blowers. Outsourcing to China had led China to outsource to Vietnam, and so on. Despite the free-trade mantra that outsourcing to lower-wage countries leads to lower-cost products, there has been a persistent creep in the availability and cost of almost everything that Americans need to manufacture our own products.

This wasn’t always the case. Growing up in Cuyahoga Falls, Ohio, my father worked for a company he started in his early 20s called Polymerics, for which he invented PolyGel, a common component in rubber compounds. Polymerics sold to U.S. companies different types of rubber and plastic that were needed to build anything ranging from windshield wipers to medical devices and engine mounts. While the company still exists and is still family-owned, the supply chain it depends on has become so much more complex that today we cannot find a single plastic made in the U.S. that we could use to build a low-cost CPAP device.
This dearth applies to the CPAP mask and blower. The mask involves run-of-the-mill injection molding with either additive manufacturing (3D printing) or craftsmanship machining. The blower is the heart of the CPAP. It inflates and deflates as the patient inhales and exhales. Its parts are similar to a computer fan, and those parts should be in the American arsenal to battle against pathogens. Yet they almost exclusively are made in China.
The upshot is that many individuals and hospitals in need of alternatives to highly invasive and potentially harmful ventilators facing a supply chain that makes it impossible to quickly produce them in this time of need.
What is at the root of this supply chain crisis? It could be our complacency, or unnecessary complexity, or a depletion of our greatest natural resource — expertise. The inability to get parts to make the products that we need in a timely fashion is felt across industries, but it is most relevant now to the medical industry.
My call to action is not to speed up shipments of the parts needed to build medical equipment like CPAP machines from China and Vietnam and beyond. It is to create businesses in the U.S. with the capabilities to quickly and easily build the parts we need to improve the health of Americans.
Matthew Putman, Ph.D., is the cofounder and CEO of Nanotronics, a science technology company that creates AI platforms and advanced inspection tools for manufacturing.

The U.S. needs to make more CPAP machines. Our supply chain is blocking that

Crucial trials Medtronic had to pause

Covid-19 could mean Medtronic loses out to Abbott, its rival in the mitral valve space.

Geoff Martha has taken over as chief executive of Medtronic in less than ideal circumstances. The world’s largest medtech has been hit hard by patients delaying elective surgical procedures so as to stay out of hospital while the Covid-19 pandemic rages on. Last week Medtronic said its weekly US sales for the past few weeks had declined around 60% year over year.
This is bad enough. But the group also said it would pause enrolment into its clinical trials currently recruiting patients, “to allow hospital clinical resources to focus on fighting Covid-19”. This could have a longer-term effect, delaying the launch of some of its important new products, most notably Intrepid, its transcatheter mitral valve.
The pivotal US trial of Intrepid is – or was – still in its recruitment phase. The Apollo study aimed to sign up 1,600 patients with moderate or severe symptomatic mitral regurgitation and compare the minimally invasive valve with surgical valve implantation. Results were expected in the third quarter of 2021.
This is now in doubt, which is a concern since Abbott Laboratories is hot on Medtronic’s heels. Abbott’s US pivotal of its own mitral valve, Tendyne, is scheduled to conclude in spring 2022, and the group has said nothing about halting recruitment into this or any other study. If Abbott can keep its trial on track, Medtronic’s first mover advantage could shrink or disappear entirely.

The mitral race: Medtronic and Abbott’s US pivotal studies
Company	Device	Trial name	N	PCD	Trial ID
Abbott Laboratories	Tendyne	Summit	958	Jun 2022	NCT03433274
Medtronic	Intrepid	Apollo	1600	Oct 2021	NCT03242642
PCD = primary completion date. Source: Clinicaltrials.gov & company communications.

Another transcatheter valve trial will also be affected by the trial halt. A small study of the Harmony pulmonary valve had been expected to read out in the coming months but according to clinicaltrials.gov is still recruiting patients. This could slow Medtronic’s plans to add a second pulmonary valve to its offering – its Melody device has been on sale in Europe since 2006 and in the US since 2010.
Lastly, a trial investigating the application of Medtronic’s Visualase laser ablation system to temporal lobe epilepsy could be delayed beyond 2022. The device is used under MRI guidance, and is approved as a surgical device for many different applications; this trial specifically examines its use in patients with drug-resistant epilepsy, a significant unmet need.
Of these trials, Apollo is by far the most important to Medtronic’s ambitions. The table below shows EvaluateMedTech’s consensus sales forecasts for the top five medtechs in 2026, and while Medtronic is still forecast to be at the top Abbott is set to climb the rankings. If Apollo is halted for six months or so and Summit continues as scheduled, the valves could be launched in the US at roughly the same time, giving Abbott a better chance than it might otherwise have had.

Top 5 medtech companies in 2026
	Total medtech sales 2019 ($bn)	Total medtech sales 2026e ($bn)	CAGR	Market share 2019	Market share 2026e
Medtronic	30.8	42.4	+5%	6.8%	5.9%
Johnson & Johnson	26.0	33.1	+4%	5.7%	4.6%
Abbott Laboratories	19.9	30.7	+6%	4.4%	4.3%
Stryker	14.9	22.1	+6%	3.3%	3.1%
Siemens Healthineers	16.3	22.1	+4%	3.6%	3.1%
Source: EvaluateMedTech.

Medtronic will report its full-year results for fiscal 2020 next month, and has already cautioned that it expects further pressure from the pandemic, stating that its results will reflect an additional month of impact compared with many other companies that operate on a calendar-based fiscal year.
It also set out where it expects to see the most dramatic effects. The products used in more urgent procedures such as pacemakers and its Solitaire device, used to treat ischaemic stroke, are likely to continue selling; its cryoablation catheters, used in atrial fibrillation, and attempts to move diabetes patients onto its insulin pumps, might be less resilient.

Medtronic’s therapies – urgent vs elective
More urgent	Moderately elective	More elective
Cardiac and vascular
Pacing	Implanted defibrillators	Atrial fibrillation
Aortic	TAVR/structural heart	Endovenous
Coronary	Peripheral	Diagnostics
Cardiac surgery
Minimally invasive therapies
Surgery: appendectomy, bowel obstruction, trauma	Surgery: CABG, oncology	Surgery: bariatric, hysterectomy, hernia
Respiratory and patient monitoring		Gastrointestinal
Renal Care
Restorative therapies
Spine trauma	Brain modulation	Other spine
Neurovascular: ischaemic stroke	Neurovascular: haemorrhagic stroke	Pain therapies
		Pelvic health
		Ear, nose and throat
Diabetes
Diabetes supplies		New insulin pump starts
TAVR = transcatheter aortic valve replacement. CABG = coronary artery bypass graft.Source: adapted from Medtronic release.

https://www.evaluate.com/vantage/articles/news/corporate-strategy/crucial-trials-medtronic-has-had-pause

Go or no go? Oncology dominates upcoming decisions

Astrazeneca’s Lynparza is due US approval decisions in prostate and ovarian cancers, while Bristol’s Opdivo’s fate will be determined in lung cancer.

Approval decisions for oncology drugs feature heavily in May and the coming months. Two Parp inhibitors will take the spotlight in prostate cancer, with Clovis’s Rubraca due a decision in patients with BRCA1/2 mutations by May 15, and Astrazeneca’s Lynparza, which has been filed in the broader setting of homologous recombination repair gene mutations, and has a second quarter date.
Last week the latest cut of Lynparza’s Profound study found a survival benefit in patients with BRCA1/2 or ATM gene mutations, but no efficacy data were released from carriers of other mutation types. The question will be how broad a label the FDA might give the drug.
Lynparza is filed in the earlier second-line setting, versus Rubraca’s third, and there is little evidence to support retreating patients with a Parp inhibitor. Sales by indication data from EvaluatePharma gives Astra’s therapy the lead in prostate cancer with $1.3bn Lynparza sales forecast for 2026, versus Rubraca’s $347m.
Another decision for Lynparza, also due in the second quarter, is in ovarian cancer, based on the results of the Paola-1 study. The investigator-sponsored study tested the anti-VEGF antibody Avastin plus Lynparza, and recruited patients regardless of mutation status.
Data released at last year’s Esmo showed that progression-free survival was significantly extended, although the result was clearly driven by patients with homologous recombinant deficiency (HRD) – in the subgroup of those without evidence of HRD the hazard ratio dropped to an unimpressive 0.92.
The big question is whether Paola-1 will allow Lynparza to gain approval to treat all front-line ovarian cancer, regardless of HRD status, though presumably any label would restrict its use to Avastin combination therapy.
Astrazeneca will now have to contend with GSK’s own parp, Zejula, which as a single agent gained US approval just a few days ago in ovarian cancer regardless of biomarker status. Zejula’s decision was based on the Prima study, in a group described as “HRD-proficient”, essentially negative, in which the hazard ratio was 0.68, or a 32% reduction in the risk of progression.
Meanwhile Bristol Myers Squibb will find out whether Opdivo plus Yervoy will get the green light in first-line lung cancer. The latest filing is based on a pooled result of part one of the Checkmate-227 trial. Bristol had earlier controversially claimed a progression-free survival benefit in patients with high tumour mutation burden after abandoning its original statistical analysis plan and creating a whole new cohort of patients, but this filing plan was abandoned.
Bristol is doubling its chances in first-line NSCLC with a Pdufa set for August based on the Checkmate-9LA study, this time concerning Opdivo plus Yervoy and chemotherapy. Merck’s Keytruda is already on the market first line in combination with chemotherapy, and according to consensus from EvaluatePharma Keytruda forecasts sit at $4.4bn by 2026 versus Opdivo’s $3.7bn.

Supplementary and other notable approval decisions in May
Product	Company	Indication (clinical trial)	Date
Rubraca	Clovis	BRCA1/2-mutant recurrent mCRPC (Triton3)	May 15
Opdivo + Yervoy	Bristol Myers Squibb	1L NSCLC without chemo (Checkmate-227)	May 15
Dupixent	Sanofi	Atopic dermatitis in children aged 6 to 11 years	May 26
Subcutaneous Darzalex	J&J	Multiple myeloma (Columba)	Q2
Farxiga	Astrazeneca	Reduce the risk of CV death or the worsening of heart failure in adults with HFrEF with and without type 2 diabetes (Dapa-HF)	Q2
Lynparza + Avastin	Astrazeneca	Advanced ovarian cancer maintenance with Avastin (Paola-1)	Q2
Lynparza	Astrazeneca	mCRPC and germline or somatic HRR mutations (Profound)	Q2
Source: EvaluatePharma & company releases.

Oncology aside, Astrazeneca’s SGLT2 inhibitor Farxiga, already marketed for type 2 diabetes, looks set to be approved for heart failure based on the Dapa-HF trial.
Overall, patients receiving Farxiga plus standard of care had a 26% reduction in the primary endpoint – cardiovascular death, hospitalisation for heart failure, or an urgent heart failure visit – versus those receiving standard of care alone. The difference was highly statistically significant, with a p value of less than 0.001.
Astra has a chance to get a head start against the competition − Lilly and Boehringer’s SGLT2 inhibitor Jardiance is the biggest threat. Jardiance’s Emperor-Reduced study, analogous to Dapa-HF, has a primary completion date in June.
Jardiance is set to be the biggest in the class in 2026, according to EvaluatePharma sellside consensus, with forecast sales that year of $4.2bn versus Farxiga’s $3.2bn. Neither of these estimates includes heart failure, so presumably there could be a big upside if the drugs can make a mark here.
Lastly Abbvie’s Orilissa, already on the market for the management of pain associated with endometriosis, has a decision due in uterine fibroids. If approved the GnRH antagonist would be ahead of competition from Myovant and Obseva, and cross trial comparisons of the three puts Abbvie’s product out on top in terms of placebo-adjusted response rate.

Notable first-time US approval decisions due in May
Project	Company	PDUFA date	2026e sales ($m)	Evaluate Vantage note/story link
Naloxone Nasal Spray	Insys Therapeutics	Est May	–	–
Ayvakit	Blueprint Medicines	May 14	1,119*	Supporting Voyager trial in 4L GIST failed so approval very unlikely.
Dasotraline/SEP-225289	Sumitomo Dainippon Pharma	May 14	124	Filed in binge eating disorder, received a CRL in ADHD.
Apomorphine sublingual film (APL-130277)	Sunovion/Aquestive Therapeutics	May 21 (resubmission)	155	Received CRL last year, filed to treat off episodes in Parkinson’s disease.
Phexxi (Amphora vaginal pH regulator)	Evofem biosciences	May 25 (resubmission)	541	Previous CRL.
Adstiladrin/nadofaragene firadenovec	Ferring/Fergene	Est May 29	–	Filed in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC); Merck’s Keytruda received approval in this setting in January.
Aximris XR (oxycodone extended-release tablets)	Intellipharmaceutics International	Q2 (resubmission)	43	Negative adcom in January, 24 to 2 voted against approval.
Orilissa	Abbvie/Neurocrine	Q2	1,143 (538 in uterine fibroids)	See text.
Travivo	Fabre-Kramer Pharmaceuticals	Q2	–	–
*Forecasts made before Voyager failure. Source: EvaluatePharma & company releases.

https://www.evaluate.com/vantage/articles/events/upcoming-events/go-or-no-go-oncology-dominates-upcoming-decisions

NYPD adding forces to target social distancing offenders this weekend

Cops in all ranks will be out in full force over the weekend — with gorgeous weather in the forecast — as part of the NYPD’s all-out blitz on social distancing offenders, The Post has learned.
The department will increase its presence in city parks, adding a number of cops ready to make arrests or issue summonses, police sources said.
Commanding officers in each of the department’s precincts are also being forced to work during the day on Saturday and Sunday, with their second-in-charge working overnight to supervise the crackdown, according to police sources.
Sources said that City Hall was concerned about social distancing enforcement appearing anti-Semitic after a heavy police presence a Hasidic Jewish neighborhood in Brooklyn for the second time this week.
News of the increased presence comes a day after City Hall assigned 1,000 workers to break up any unlawful gatherings through the Big Apple.
https://nypost.com/2020/05/01/nypd-up-numbers-for-social-distancing-offenders-this-weekend/

Remdesivir cleared for use for COVID-19

As expected, the FDA has approved the emergency use of Gilead Sciences’ (NASDAQ:GILD) remdesivir for the treatment of COVID-19 infection.

President Trump made the announcement at a White House event with company CEO Dan O’Day.

More details: Vice-President Pence says 1M vials of the drug will begin to be distributed to hospitals on Monday. CEO O’Day says some patients benefit from as few as five doses.

Approval was a foregone conclusion after two studies showed that it shortened recovery time in severely ill patients, the first drug to demonstrate a clear treatment benefit.

Shares have pared earlier losses, now down 4.5%.

Approval letter from FDA

FDA fact sheet

https://seekingalpha.com/news/3567792-remdesivir-cleared-for-use-for-covidminus-19