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Sunday, July 26, 2020

Covid-19 vaccine battle just got interesting

A patent claim against Arbutus is thrown out, threatening parts of Moderna’s mRNA technology – including its Covid-19 vaccine.
Be careful what you wish for. Moderna had fired the first salvo against Arbutus over two years ago, seeking to assert the position of its lipid nanoparticle (LNP) technology, but in the event it has come off worse: yesterday a US court deemed that a key Arbutus patent stands, sending the tiny biotech’s stock up 120%.
Remarkably, Moderna has not issued a formal statement about the ruling, presumably not wanting to give away anything about its possible implications. The LNP tech is thought to underlie most of its mRNA work – including the high-profile Covid-19 vaccine project mRNA-1273 – but Moderna evidently does not want to spell this out.
The ruling concerns the third of three Arbutus patents Moderna had challenged through inter partes reviews; Moderna had prevailed in the first and got a mixed verdict on the second. Regarding the third, concerning US patent 8,058,069, a judge yesterday ruled that Moderna had “not shown by a preponderance of the evidence that claims 1–22 of the patent are unpatentable”.
Arbutus patents challenged by Moderna in IPR proceedings
Patent no Challenged US Patent Trial and Appeal Board verdict
9,404,127 Feb 21, 2018 All of the patent’s claims invalidated
9,364,435 Mar 5, 2018 Some patent claims upheld, others (including sole independent claim) invalidated
8,058,069 Jan 9, 2019 All of the patent’s 22 claims upheld
Of course, appeals against the last two rulings are virtually assured, though Moderna has yet to reveal its hand. It also has to be stressed that the final outcome is unlikely to see Moderna prevented from marketing an LNP-based product. At worst Moderna might have to agree to pay Arbutus a royalty.
That is, of course, as long as the LNP tech Arbutus claims is indeed implicated in most of Moderna’s mRNA work. The clinicaltrials.gov entry for Moderna’s phase I Covid-19 vaccine trial states: “mRNA-1273 is a novel LNP-encapsulated mRNA-based vaccine”.
Moreover, any infringement would depend on mRNA-1273 actually getting to market; based on clinical data generated so far the Moderna project lags Biontech/Pfizer’s mRNA rival BNT162b1 (Novavax keeps investors waiting, July 21, 2020).
But investors now have to price in extra risk, and yesterday Moderna’s stock lost 9%, equivalent to some $3bn of market cap.
It’s complicated
How the farrago came about is complicated. Markman Advisors, a New York-based patent consultancy, has pointed out that Moderna had initially licensed LNPs from Acuitas, a small Canadian firm that had itself acquired these from Arbutus.
But Acuitas’s right to sublicense became the subject of separate Arbutus litigation, which was settled in February 2018 with the effect that Acuitas was limited to four specific viral targets. Moderna thus appeared to have been frozen out, and it was then that it started challenging the validity of Arbutus’s LNP patents.
In a further twist, Acuitas is the source of the LNPs that Biontech and Pfizer use in BNT162b1. This arrangement appears to have been routed through a deal between Biontech and Genevant, a venture founded jointly in April 2018 by Arbutus and Vivek Ramaswamy’s holding company, Roivant Sciences.
The disparity of the Arbutus/Moderna David-versus-Goliath battle should not be underestimated: against Moderna’s $28bn market cap Arbutus’s valuation stands at a puny $430m, even including yesterday’s surge. And in US corporate law size and financial firepower count for a lot.
Nevertheless, this marks a sudden turnaround in Arbutus’s fortunes. The group, formerly known as Tekmira and until now best known for hepatitis B failures, could now have a stake in a second clinical-stage Covid-19 vaccine.

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Trial of Hydroxychloroquine to Prevent Covid-19 Transmission and Disease

A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease

Oriol Mitja, Maria Ubals, Marc Corbacho, Andrea Alemany, Clara Suner, Cristian Tebe, Aurelio Tobias, Judith Penafiel, Ester Ballana, Carla A Perez, Pol Admella, Nuria Riera-Marti, Pep Laporte, Jordi Mitja, Mireia Clua, Laia Bertran, Sergi Gavilan, Jordi Ara, Maria Sarquella, Josep M Argimon, Gabriel Cuatrecasas, Paz Canadas, Aleix Elizalde-Torrent, Robert Fabregat, Magi Farre, Anna Forcada, Gemma Flores-Mateo, Cristina Lopez, Esteve Muntada, Nuria Nadal, Silvia Narejos, Aroa N Gil-Ortega, Nuria Prat, Jordi Puig, Carles Quinones, Ferran Ramirez-Viaplana, Juliana Reyes-Uruena, Eva Riveira-Munoz, Lidia Ruiz, Sergi Sanz, Alexis Sentis, Alba Sierra, Cesar Velasco, Rosa Maria Vivanco-Hidalgo, Juani Zamora, Jordi Casabona, Marti Vall-Mayans, Camila G-Beiras, Bonaventura Clotet
doi: https://doi.org/10.1101/2020.07.20.20157651
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Abstract

Background Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are limited to non-pharmacological interventions. Hydroxychloroquine (HCQ) has been proposed as a postexposure therapy to prevent Coronavirus disease 2019 (Covid-19) but definitive evidence is lacking. Methods We conducted an open-label, cluster-randomized trial including asymptomatic contacts exposed to a PCR-positive Covid-19 case in Catalonia, Spain. Clusters were randomized to receive no specific therapy (control arm) or HCQ 800mg once, followed by 400mg daily for 6 days (intervention arm). The primary outcome was PCR-confirmed symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, either symptomatically compatible or a PCR-positive result regardless of symptoms. Adverse events (AEs) were assessed up to 28 days. Results The analysis included 2,314 healthy contacts of 672 Covid-19 index cases identified between Mar 17 and Apr 28, 2020. A total of 1,198 were randomly allocated to usual care and 1,116 to HCQ therapy. There was no significant difference in the primary outcome of PCR-confirmed, symptomatic Covid-19 disease (6.2% usual care vs. 5.7% HCQ; risk ratio 0.89 [95% confidence interval 0.54-1.46]), nor evidence of beneficial effects on prevention of SARS-CoV-2 transmission (17.8% usual care vs. 18.7% HCQ). The incidence of AEs was higher in the intervention arm than in the control arm (5.9% usual care vs 51.6% HCQ), but no treatment-related serious AEs were reported. Conclusions Postexposure therapy with HCQ did not prevent SARS-CoV-2 disease and infection in healthy individuals exposed to a PCR-positive case. Our findings do not support HCQ as postexposure prophylaxis for Covid-19.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT04304053

Funding Statement

Crowdfunding campaign YoMeCorono (https://www.yomecorono.com/), Laboratorios Rubio, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubio also contributed to the study with the required doses of hydroxychloroquine (Dolquine).

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Can facemasks prevent viral respiratory infections in community settings?

Facemasks for prevention of viral respiratory infections in community settings: A systematic review and meta-analysis
Nishant Aggarwal1, Vignesh Dwarakanathan2, Nitesh Gautam1, Animesh Ray3
1 Research Assistant, All India Institute of Medical Sciences, New Delhi, India
2 Senior Resident, Department of Community Medicine, All India Institute of Medical Sciences, New Delhi, India
3 Assistant Professor, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
Date of Web Publication 2-Jun-2020
Source of Support: None, Conflict of Interest: None
Abstract
Background: There is paucity of evidence on the effectiveness of facemask use in COVID-19 in community settings. Objectives: We aimed to estimate the effectiveness of facemask use alone or along with hand hygiene in community settings in reducing the transmission of viral respiratory illness. Methods: We searched PubMed and Embase for randomized controlled trials on facemask use in community settings to prevent viral respiratory illnesses published up to April 25, 2020. Two independent reviewers were involved in synthesis of data. Data extraction and risk-of-bias assessment were done in a standard format from the selected studies. Outcome data for clinically diagnosed or self-reported influenza-like illness (ILI) was recorded from individual studies. Pooled effect size was estimated by random-effects model for “facemask only versus control” and “facemask plus hand hygiene versus control.” Results: Of the 465 studies from PubMed and 437 studies from Embase identified from our search, 9 studies were included in qualitative synthesis and 8 studies in quantitative synthesis. Risk of bias was assessed as low (n = 4), medium (n = 3), or high (n = 1) risk. Interventions included using a triple-layered mask alone or in combination with hand hygiene. Publication bias was not significant. There was no significant reduction in ILI either with facemask alone (n = 5, pooled effect size: −0.17; 95% confidence interval [CI]: −0.43–0.10; P = 0.23; I2 = 10.9%) or facemask with handwash (n = 6, pooled effect size: (n=6, pooled effect size: −0.09; 95% CI: -0.58 to 0.40; P = 0.71, I2 = 69.4%). Conclusion: Existing data pooled from randomized controlled trials do not reveal a reduction in occurrence of ILI with the use of facemask alone in community settings.

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Moderna’s Covid-19 BARDA contract gets added $472M modification

Moderna (NASDAQ:MRNA) on Saturday announced that the Biomedical Advanced Research and Development Authority modified its existing contract with an added commitment of up to $472 million for the company’s Phase 3 study of the mRNA vaccine candidate (mRNA-1273) against COVID-19.
As part of discussions related to Operation Warp Speed, the co. opted to conduct a “significantly” larger study, which the added funding is designed to accommodate. The participant study will accomodate 30K participants at the 100 µg dose level in the U.S.
Combined with the prior contract, total value is $955M. The Phase 3 study will begin July 27.
“The primary endpoint will be the prevention of symptomatic COVID-19 disease. Key secondary endpoints include prevention of severe COVID-19 disease (as defined by the need for hospitalization) and prevention of infection by SARS-CoV-2.,” the co. said. 
The manufacturing of doses will function as part of the collaboration with Catalent (NYSE:CTLT) that the companies announced last month. Find out more here. 

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Biotech week ahead, July 27

Biotech stocks moved lower in the week ended July 26, as the broader market weakness and sector-specific developments pressured stocks.
Although there were promising updates from some coronavirus vaccine makers, negative headlines plagued Novavax, Inc. NVAX 4.05% and Moderna Inc MRNA 2.81%, sending their stocks lower by 4.7% and 23%, respectively, for the week.
The week saw the listing of 4 biopharma companies on the Nasdaq, which raised a combined $772.9 million.
Here are the key catalysts for the unfolding week.

Conferences:

Alzheimer’s Association International Conference, or AAIC, to be held virtually: July 27-31

PDUFA Dates

The FDA is set to rule on Ultragenyx Pharmaceutical Inc’s RARE 1.47% NDA for UX007, its investigational drug for long-chain fatty acid oxidation disorders. (Friday)
GW Pharmaceuticals PLC- ADR GWPH 2.19% has a PDUFA action date, with the FDA due to announce its verdict on the company’s sNDA for Epidiolex for the treatment of seizures associated with tuberous sclerosis complex. (Friday)

Clinical Readouts

AAIC Presentations:

Alector Inc ALEC 0.49%: preliminary data from a Phase 2 open-label study evaluating AL001 in individuals with frontotemporal dementia (Tuesday)
Eisai Co., Ltd ESALY 0.68% and Biogen Inc BIIB 2.22%: latest data of the investigational anti-amyloid beta protofibril antibody BAN2401; Biogen will also make an oral presentation of the previously publicized topline results of Phase III studies EMERGE and ENGAGE
AC Immune SA ACIU 3.6%: Key data on its alpha-synuclein-positron emission tomography tracer program along with a second oral presentation of the Phase 1b trial of the anti-Abeta vaccine ACI-24 in Down syndrome

Standalone releases:

Tcr2 Therapeutics Inc TCRR 4.1% said it plans to discuss initial data from the Phase 1 portion of the TC-210 Phase 1/2 clinical trial for patients with mesothelin-expressing solid tumors. (before the market open, Monday)
Genocea Biosciences Inc GNCA 24.44% is scheduled to present initial clinical data on the first 5 patients from Part B of the Phase 1/2 study, which is exploring the combination of GEN-009 and immune checkpoint inhibitor-based regimens in advanced solid tumors. (Friday)

Pending mid-2020 Releases:

Spectrum Pharmaceuticals, Inc. SPPI 4.28%: top-line results from Cohort 2 of the ZENITH20 trial evaluating poziotinib in previously treated HER2 non-small cell lung cancer patients
Intra-Cellular Therapies Inc ITCI 0.23%: top-line results from a Phase 3 study evaluating lumateperone as adjunctive therapy in bipolar depression.
BioXcel Therapeutics Inc BTAI 1.35%: top-line results from a Phase 1/2b trial of BXCL501 for the acute treatment of agitation associated with geriatric dementia.
Alnylam Pharmaceuticals, Inc. ALNY 0.98%: top-line results from the ILLUMINATE-B Phase 3 study of lumasiran in primary hyperoxaluria type 1 patients less than six years of age with preserved renal function.
Karuna Therapeutics Inc KRTX 6.86%: data from Phase 1b clinical trial of KarXT in experimentally induced pain
Akari Therapeutics PLC AKTX 2.5%: interim update on the Part B placebo-controlled efficacy arm of the study of nomacopan eye drops in atopic keratoconjunctivitis
Seres Therapeutics Inc MCRB 7.24%: Data from SER-109 Phase 3 study in recurrent C. difficile infection
Mesoblast MESO 1.38%: data from a Phase 3 randomized controlled trial of Revascor for advanced heart failure
Akebia Therapeutics Inc (NASDAQ: AKBA: ) top-line data from the global Phase 3 studies evaluating the safety and efficacy of vadadustat in adult patients not on dialysis with anemia due to chronic kidney disease
Anavex Life Sciences Corp AVXL 1.12%: top-line results from the Phase 2 study of ANAVEX 2-73 in Parkinson’s disease dementia Phase 2 trial
BIOLINERX LTD/S ADR BLRX 1.44%: Progression-free survival and overall survival data from the triple combination arm of the COMBAT/KEYNOTE-202 Phase 2a study of BL-8040 in combination with Merck & Co., Inc.’s MRK 1.2% Keytruda in advanced second-line pancreatic cancer
Arcus Biosciences Inc RCUS 3.95%: preliminary data from Phase 1b expansion trials involving combinations with AB928 in multiple tumor types and settings
Homology Medicines Inc FIXX 3.46%: additional data from Phase 1/2 pheNIX gene therapy trial for phenylketonuria
Vaxart Inc VXRT 11.26%: data from universal Influenza vaccine collaboration with Johnson & Johnson’s JNJ 1.02% Janssen unit
Albireo Pharma Inc ALBO 3.85%: top-line results from the Phase 3 PEDFIC 1 trial that is evaluating Odevixibat in progressive familial intrahepatic cholestasis; top-line data from the Phase 3 trial of elobixibat in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease
resTORbio, Inc. TORC 2.03%: data from the four completed cohorts of the Phase 1b/2a trial of RTB101 in combination with sirolimus in Parkinson’s disease

Earnings

Monday
Medpace Holdings Inc MEDP 4.44% (after the close)
Tuesday
Exagen Inc XGN 3.89% (before the market open)
Pfizer Inc. PFE 1.9% (before the market open)
Ironwood Pharmaceuticals, Inc. IRWD 2.96% (before the market open)
Masimo Corporation MASI 1.89% (after the close)
AtriCure Inc. ATRC 0.89% (after the close)
Amgen, Inc. AMGN 1.69% (after the close)
NeoGenomics, Inc. NEO 1.99% (after the close)
DexCom, Inc. DXCM 0.41% (after the close)
Infinity Pharmaceuticals Inc. INFI 2.35% (after the close)
Wednesday
Boston Scientific Corporation BSX 0.44% (before the market open)
United Therapeutics Corporation UTHR 1.93% (before the market open)
Hologic, Inc. HOLX 0.31% (after the close)
Alimera Sciences Inc ALIM 4.86% (after the close)
Merit Medical Systems, Inc. MMSI 1.67% (after the close)
Thursday
Lexicon Pharmaceuticals, Inc. LXRX 4.95% (before the market open)
Blueprint Medicines Corp BPMC 1.76% (before the market open)
Iradimed Corp IRMD 1.18% (before the market open)
•Alexion Pharmaceuticals, Inc. ALXN 3.15% before the market open)
Agios Pharmaceuticals Inc AGIO 2.64% (before the market open)
Eli Lilly And Co LLY 1.29% (before the market open)
Elanco Animal Health Inc ELAN 0.86% (before the market open)
Evelo Biosciences Inc EVLO 3.37% (before the market open)
BioTelemetry Inc BEAT 2.94% (after the close)
MacroGenics Inc MGNX 2.81% (after the close)
Vertex Pharmaceuticals Incorporated VRTX 2.1% (after the close)
Emergent Biosolutions Inc EBS 0.93% (after the close)
Bio-Rad Laboratories, Inc. Class A Common Stock BIO 0.96% (after the close)
Anika Therapeutics Inc ANIK 2.19% (after the close)
Gilead Sciences, Inc. GILD 2.54% (after the close)
Natus Medical Inc NTUS 1.92% (after the close)
Retrophin Inc RTRX 1.71% (after the close)
Veracyte Inc VCYT 2.03% (after the close)
Ultragenyx Pharmaceutical Inc RARE 1.47% (after the close)
Globus Medical Inc GMED 0.45% (after the close)
Quidel Corporation QDEL 0.67% (after the close)
EXACT Sciences Corporation EXAS 2.4% (after the close)
Tandem Diabetes Care Inc TNDM 3.1% (after the close)
Friday
AbbVie Inc ABBV 0.94% (before the market open)
ImmunoGen, Inc. IMGN 4.08% (before the market open)

IPOs

Cambridge, Massachusetts-based AlloVir, which develops allogenic off-the-shelf virus-specific T cell therapy candidates targeting 12 devastating viruses, proposes to offer 14.75 million shares in an IPO, with the price range estimated between $16 and $18. The company has applied for listing its shares on the Nasdaq under the ticker symbol ALVR.
Woodcliff Lake, New Jersey-based PaxMedica, Inc. has filed with the SEC to offer 2.5 million shares to be priced between $5.50 and $6.50. The company is an early clinical-stage biopharma focusing on the development of anti-purinergic therapies for the treatment of neurodevelopmental disorders, including autism spectrum disorder, and Fragile X syndrome tremor-ataxia. It has applied for listing its shares on the Nasdaq under the ticker symbol PXMD.
https://www.benzinga.com/general/biotech/20/07/16778963/the-week-ahead-in-biotech-spotlight-on-gw-pharma-ultragenyx-fda-decisions-pfizer-earnings
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Wuhan Scientist Rules Out Theories That Novel Coronavirus Originated in Lab

Shi Zhengli, the Chinese scientist who heads a group that studies bat coronaviruses at the Wuhan Institute of Virology (WIV), has for the first time spoken up on theories that the novel coronavirus (SARS-CoV-2) originated in or was leaked from her lab, flatly ruling out such possibilities and demanded an apology from US President Donald Trump.
In an e-mail interview to Science, Shi said that the virus was first detected by her lab in late 2019, in samples from patients who had a pneumonia of unknown origin. “Before that, we had never been in contact with or studied this virus, nor did we know of its existence,” she wrote, denying allegations from various quarters, including Trump, that the novel coronavirus ‘came out of a lab’ in China. With WIV located in the city where the pandemic began, the lab has been at the centre of these theories.
“US President Trump’s claim that SARS-CoV-2 was leaked from our institute totally contradicts the facts,” the scientist, who has been nicknamed ‘Bat Woman’, said. “It jeopardises and affects our academic work and personal life. He owes us an apology.”
While experts told Science that Shi’s responses would have been ‘carefully vetted’ by the Chinese government – her answers were coordinated with public information staffers at the Chinese Academy of Sciences – they nevertheless reveal ‘a lot of new facts’.
Evolutionary biologist Kristian Andersen of Scripps Research said Shi’s responses were “all logical, genuine, and stick to the science as one would have expected from a world-class scientist and one of the leading experts on coronaviruses.”
On allegations that the lab ‘grows’ viruses that could infect humans, Shi responded that over the past 15 years, the WIV has isolated only three closely-related bat coronaviruses (an isolated virus is a live virus which can grow in cultured cells in the laboratory), all of which were related to the virus that causes severe acute respiratory syndrome (SARS), which erupted in 2003.
While the lab has collected more than 2,000 samples of coronaviruses from animals, through anal swabs, oral swabs and fecal samples, none had gene sequences is similar to SARS-CoV-2, she said. Though one sample, RaTG13, is 96.2% identical to SARS-CoV-2, in genome sequences this is a “significant difference for coronaviruses”. These viruses could have shared a common ancestor decades ago and the “level of genome sequence divergence between SARS-CoV-2 and RaTG13 is equivalent to an average of 50 years (and at least 20 years) of evolutionary change”.
Shi also claimed that all the staff and students at WIV were recently tested for the viral infection and that everyone was negative. This, she said, does not support the notion that the virus could have existed in the lab and accidentally infected a worker. She also said that the lab follows strict protocol to ensure that there are no leaks or accidental infections.
While the origin of the novel coronavirus is yet unclear, Shi said that it is very likely to have originated from bats. “It may have evolved in one or more intermediate hosts, become adapted to humans, and eventually spread among humans. However, it remains unclear which animals were the intermediate hosts and how it spilled over to humans,” she said.
Asked if it is possible that a bat in Wuhan or close to the city infected someone, she said it is very unlikely that the cross-species transmission was from the natural host (bat) to humans. “When and where the earliest cross-species transmission of SARS-CoV-2 occurred from the intermediate host to humans has not been scientifically uncovered yet… Tracing the origin of a virus is a very challenging scientific task… it needs a pioneering vision, and the collective efforts of scientists all around the world, and it needs time as well,” she said.
She claimed that the lab has done bat virus surveillance in Hubei Province for many years, but have not found that bats in Wuhan or even the wider Hubei Province carry any coronaviruses that are closely related to SARS-CoV-2. “I don’t think the spillover from bats to humans occurred in Wuhan or in Hubei Province,” she claimed.
Shi also moved to clear the Huanan seafood market in Wuhan – where one of the earliest clusters of the virus was identified – as the site of human transmission from an intermediate host. “We detected SARS-CoV-2 nucleic acids in environmental samples from sources such as rolling door handles, the ground and sewage in that market, but we did not detect any SARS-CoV-2 nucleic acids in frozen animal samples. The Huanan seafood market may just be a crowded location where a cluster of early novel coronavirus patients were found,” she said.
Her team also collected samples of farmed animals and livestock from farms around Wuhan and in other places in Hubei Province and did not detect any SARS-CoV-2 nucleic acids in the samples, the scientist said.
According to Science, Shi was “particularly chagrined” about the April 24 decision by the US National Institutes of Health (NIH) to cancel a grant to the EcoHealth Alliance in New York City that included bat virus research at WIV. “We don’t understand [it] and feel it is absolutely absurd,” she said, at the axing of the grant, made at the White House’s behest.
She said the pandemic has helped her realise the importance of her lab’s work and the necessity of pursuing it. “I think if we could do more basic research and technological development on vaccines and therapeutic drugs, we would do better in this regard,” Shi said.
The risk of cross-species infection of coronaviruses is rising due to “global environmental change and the expansion of human activity”, the scientist said, which is “confirmed and supported” by her lab’s research.
Science has shared Shi’s responses in full.

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