Genetic structure of SARS‐CoV‐2 does not rule out laboratory origin

Rossana Segreto

Yuri Deigin

First published: 17 November 2020

https://doi.org/10.1002/bies.202000240

No external funding was received for this work.

PDF: https://onlinelibrary.wiley.com/doi/epdf/10.1002/bies.202000240

Abstract

Severe acute respiratory syndrome‐coronavirus (SARS‐CoV)‐2′s origin is still controversial. Genomic analyses show SARS‐CoV‐2 likely to be chimeric, most of its sequence closest to bat CoV RaTG13, whereas its receptor binding domain (RBD) is almost identical to that of a pangolin CoV. Chimeric viruses can arise via natural recombination or human intervention. The furin cleavage site in the spike protein of SARS‐CoV‐2 confers to the virus the ability to cross species and tissue barriers, but was previously unseen in other SARS‐like CoVs. Might genetic manipulations have been performed in order to evaluate pangolins as possible intermediate hosts for bat‐derived CoVs that were originally unable to bind to human receptors? Both cleavage site and specific RBD could result from site‐directed mutagenesis, a procedure that does not leave a trace. Considering the devastating impact of SARS‐CoV‐2 and importance of preventing future pandemics, researchers have a responsibility to carry out a thorough analysis of all possible SARS‐CoV‐2 origins.

https://onlinelibrary.wiley.com/doi/10.1002/bies.202000240

Inovio Analyst: COVID-19 Competition Could Be Too Great

Inovio Pharmaceuticals Inc INO 8.81% reported Monday the lifting of the FDA-imposed partial clinical hold on the start of the Phase 2 study of INO-4800, its DNA coronavirus vaccine candidate. 

The Inovio Analyst: Roth Capital Partners analyst Jonathan Aschoff downgraded Inovio from Neutral to Sell and maintained an $8 price target. 

The Inovio Thesis: The Phase 3 portion of the INO-4800 program remains on partial clinical hold until Inovio satisfactorily resolves the FDA's remaining questions related to the CELLECTRA 2000 vaccine delivery device, Aschoff said in a Tuesday note.

Even if Inovio resolves all issues to help advance INO-4800 swiftly into Phase 3 trial, the amount of competition will be too great to allow INO-4800, if approved, to garner much, if any, market share, the analyst said.

Additionally, Inovio has appreciated about 50% since Roth's upgrade of the shares to Neutral on Nov. 9, he said. 

Despite the favorable storage requirements Inovio is touting for its vaccine candidate, the lead time for frontrunners Pfizer Inc. PFE 3.49%, Moderna Inc MRNA 4.9%, Johnson & Johnson JNJ 1.06% and AstraZeneca plc AZN 2.36% — and the sheer size of three of the contenders — raises serious questions regarding Inovio's ability to compete, Aschoff said. 

The analyst said he does not favor the requirement for the CELLECTRA device for a product requiring such a large-scale launch.

"When it comes to an enormous commercial rollout and slugging it our with big pharma, we are not optimistic for INO-4800," he said. 

https://www.benzinga.com/analyst-ratings/analyst-color/20/11/18410239/inovio-analyst-covid-19-competition-could-be-too-great

CureVac hiking capacity to 300 million COVID-19 doses in 2021

German biotech firm CureVac 5CV.DE is building a network with partners to allow it to ramp up manufacturing of its experimental COVID-19 vaccine so it can produce up to 300 million doses in 2021 and up to 600 million in 2022.

The company said in a statement on Tuesday that it wants to build a broad European vaccine manufacturing network using expertise and capacity in Germany, France, the Netherlands, Belgium, Spain and Austria, plus potentially Sweden, Poland, Italy and Ireland.

CureVac said it expects to announce partnerships with vaccine developers and manufacturers in the coming weeks.

“It is our goal to ramp up the production capacity of our vaccine candidate within a short period of time to ensure a stable supply,” said Florian von der Muelbe, Chief Production Officer of CureVac.

CureVac said last week its vaccine candidate has been shown to remain stable at 5 degrees Celsius (41 F) for at least three months, making it potentially easier to distribute than some rivals’ compounds.

https://www.reuters.com/article/us-health-coronavirus-curevac/curevac-hiking-capacity-to-300-million-covid-19-doses-in-2021-idUSKBN27X1L9

Boston deadheads its Lotus

All device developers run into snags with their hardware, and only some of these issues can be resolved. Boston Scientific has admitted defeat in the case of its Lotus Edge catheter-mounted aortic valve prosthesis, saying today that it was ceasing production of the device and recalling those as yet unused.

Lotus Edge was forecast to be the third biggest-selling transcatheter aortic valve in 2026, and Boston says it will take a hit of up to $300m as a result of canning the programme. In the aortic space Boston is now entirely reliant on Acurate Neo2, recently launched in Europe. But this is not expected to reach the US until 2024, and Boston’s stock is down 10% in early trade.

“We have struggled with the Lotus platform for a number of years,” said Mike Mahoney, Boston’s chief executive officer, on a conference call today, and this was no overstatement: the system used to deliver Lotus Edge has been bedevilled by problems. On the eve of the product’s US launch the group was forced to recall it from the European market, having discovered a fault in the delivery mechanism (No Lotus élan for Boston, February 24, 2017). It was eventually released in the US two years later.

And despite trouncing Medtronic’s aortic valve, CoreValve, in its pivotal study, Lotus failed to set the market on fire. When it was approved in the US in spring 2019, sellside consensus forecast 2024 sales of $1.1bn for Boston’s aortic valve technologies, according to EvaluateMedTech, with Lotus accounting for much of this. Yesterday this figure sat at less than $600m.

Now even those relatively low numbers cannot be realised by Boston. Convinced that developing a better version of the delivery system would not be worth the time and effort, Boston is to “retire” the entire Lotus platform immediately. Because the problem is not with the valve itself, people who have already had one implanted are perfectly fine, but Boston is recalling all unused Lotuses. 

Head to head

So that’s that. Now Boston must turn to its other transcatheter aortic implant, Acurate Neo2, the next-generation version of the Acurate Neo valve Boston obtained through the acquisition of Symetis in 2017, just as the problems with Lotus were becoming apparent. 

Unfortunately this product has disappointed too. In the Scope II trial which reported last month, the primary endpoint of death or stroke at one year occurred in 16% of patients treated with the first-gen Acurate Neo and 14% of those given Medtronic’s CoreValve Evolut. It thus missed the benchmark for noninferiority with a p value of 0.0549.

This delayed the expected US launch of Acurate Neo2 from next year to 2024, though the EU launch had already got under way. Neo2 is currently in a 600-patient US clinical trial, Acurate IDE, comparing it with both CoreValve and Edwards Lifesciences’ market-leading Sapien. Results could emerge next year.

Boston said on today’s call that shuttering Lotus might enable it to reallocate resources to the Acurate Neo2 programme, potentially speeding the approval timeline up; however, there is always a risk that Covid-19 could negatively affect enrolment, negating any gains. 

The Acurate franchise is, it turns out, already outpacing Lotus. “Truth be told … in calendar year 2020 we will sell more Acurate and Acurate Neo2 in Europe than we did Lotus globally,” Mr Mahoney said. This is in contrast to most analysts’ forecasts, which had seen Acurate Neo2 coming second to Lotus for the next few years at least. 

Perhaps Neo2 can rescue Boston’s status as a transcalther aortic valve player. But it will need to score a convincing hit in Acurate IDE. Going head-to-head with both CoreValve and Sapien – the latter is widely considered the best and safest device of its kind on the market – will be a tough test. 

https://www.evaluate.com/vantage/articles/news/corporate-strategy/boston-deadheads-its-lotus

Delay piles more doubt on Celgene payout

The payout of a contingent value right linked to the acquisition of Celgene by Bristol Myers Squibb was already looking like a long shot. Now the chances of it bearing fruit look even slimmer, after the Pdufa date for liso-cel came and went yesterday without approval from the FDA. It could have been worse: liso-cel did not receive a complete response letter, so optimistic investors can cling to the hope that the asset might still get the go-ahead by December 31 – the date needed to meet the conditions of the CVR. The FDA delayed making a decision because its staff have been unable to inspect a Texas manufacturing facility, due to Covid-19 travel restrictions – a situation that seems unlikely to improve any time soon. Bristol gave no indication of whether an inspection has been scheduled, in a press release. Even if liso-cel does get the nod by the end of the year, another Car-T project, ide-cel, must also be approved by March 31, 2021, just four days after its Pdufa date – not leaving much room for manoeuvre. The tradable CVR, which could be worth $9 if all three milestones are met, plunged as much as 25% this morning to $1.05.

The Bristol Myers Squibb/Celgene CVR
Project	CVR-triggering event*	Status
Ozanimod	Approval by 31 Dec 2020	Approved
Liso-cel	Approval by 31 Dec 2020	BLA filed; Pdufa date initially 17 Aug, new date of 16 Nov missed
Ide-cel	Approval by 31 Mar 2021	BLA filed, RTF letter; refiled 22 Sep 2020; Pdufa date 27 Mar 2021
*Each CVR pays out $9 only if all three events are met. https://www.evaluate.com/vantage/articles/news/snippets/delay-piles-more-doubt-celgene-payout

FDA declines to approve Alkermes' schizophrenia treatment

Drugmaker Alkermes said on Tuesday the U.S. Food and Drug Administration declined to approve its treatment for schizophrenia and bipolar disorder, citing concerns related to a tablet coating process at its manufacturing site.

The company, which has FDA-approved antipsychotic and alcohol dependence treatments in the market, is preparing to resubmit data and plans to work with the agency to resolve the issue.

Alkermes Chief Executive Officer Richard Pops said on an investor conference call the company was preparing in anticipation of the drug's launch in the first quarter. "We want to be ready for that."

The company said the FDA's observations were specific to certain batches of the treatment, ALKS 3831, and that the issue has been resolved, with sufficient data available to address the agency's concerns.

The health regulator has not asked for any new clinical trials to support approval, Alkermes said.

"Given that no issues were raised with the clinical studies, we believe that ALKS 3831 will ultimately be approved," Cantor Fitzgerald analyst Brandon Folkes said.

Folkes, however, believes that the FDA's decision does provide additional uncertainty for investors and expects some weakness in the company's stock until there's further clarity on the approval pathway.

ALKS 3831 is expected to generate sales of more than $600 million in 2030 and will probably be approved by the first half of 2021, Mizuho analyst Vamil Divan said.

The FDA has designated the resubmission as a complete, class 1 response, which typically means that the agency will review the drug within a 60-day period.

https://www.marketscreener.com/quote/stock/ALKERMES-PLC-13323547/news/Alkermes-U-S-FDA-declines-to-approve-Alkermes-schizophrenia-treatment-31801501/