Novartis R&D heads Bradner and Tsai see hard lessons and hope in coronavirus research

Close similarity of 2003 SARS and new coronavirus underscore urgency for cross-industry collaboration

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If industry had responded to the first SARS outbreak the way it is now, we would probably have drugs on hand to treat COVID-19. That sobering conclusion was evident, said NIBR’s Jay Bradner, when the high-resolution crystal structure was published of the main protease of SARS-CoV-2, the novel coronavirus that causes the disease.

Bradner and John Tsai, CMO and global head of drug development at Novartis AG (NYSE:NVS; SIX:NOVN), believe collaborating with industry peers across the drug development continuum is the best chance now to defeat the pandemic.

In a pair of BioCentury This Week: Special Report podcast conversations, the Novartis R&D heads articulate how the galloping knowledge about the biology of the disease is informing drug development, and how behind-the-scenes collaboration among industry R&D heads is playing a pivotal role in the response.

The field has come a long way in a short time regarding the science of SARS-CoV-2, and has clearly benefited from earlier work on SARS and MERS.

“There was a blush of research that augmented our understanding of these RNA viruses, their genome organization, the way that the mRNA that ultimately yields extended proteins, is cleaved and processed,” Bradner, president of Novartis Institutes for BioMedical Research, told BioCentury.

But there is a “real gap” in the ability to study the virus in cells and animal models, and while there is a monkey model for the disease, there are no small animal models that can inform about pulmonary manifestations.

“Had we, as a community, seen it through, we would very likely have active coronavirus medicines today.”

Jay Bradner, Novartis

Still, solving that is a matter of time, said Bradner, rather than of intrinsically difficult coronavirus biology.

He said that the progress thus far has yielded the genome organization of SARS-CoV-2 at base level resolution, which predicts how many open reading frames there are, and therefore how many proteins will be expressed.

It has allowed the field to identify and characterize the RNA-dependent polymerase and the main protease (MPro, also known as 3CL), two of the best targets for antiviral drugs.

Bradner also noted, however, that the discovery that made him most surprised “and sad” was the very close similarity of the SARS-CoV-2 protease and polymerase enzymes with those of SARS-CoV-1, the virus that caused the SARS outbreak of 2003. The new protease, he said, has a root mean square deviation of less than 0.5 angstrom from the earlier one, and the active sites are virtually superimposable.

That finding was “sad,” he said, because it made clear the opportunity that had been missed after 2003 to organize around protease inhibitors and sustain the research on the SARS virus.

“Had we, as a community, seen it through, we would very likely have active coronavirus medicines today,” said Bradner. “We find this experience a real responsibility now.”

“So shame on us if we don’t organize as a community around the innovation of a SARS protease inhibitor, a SARS polymerase inhibitor, a SARS methyltransferase inhibitor,” he added.

Marriage of true minds

Bradner and Tsai each indicated that the collaborative momentum is both unusual and strong among pharma peers who are normally steeped in competition.

“It’s quite uncommon for us at Novartis to call our neighbor Takeda and ask for a stick of butter,” said Bradner. While Novartis has strengths in drug discovery, it doesn’t have a coronavirus expert in the research staff, he added.

Novartis is involved in the COVID R&D industry consortium, the COVID-19 Therapeutics Accelerator, the NIH-led ACTIV consortium and IMI (see “Pharmas Align Behind Crowdsourcing” and “Collaborating to Clobber COVID-19”).

For Bradner, the collaborations enable sharing of ideas and strategies in addition to data and resources. He credited Andy Plump, president of R&D at Takeda Pharmaceutical Co. Ltd. (Tokyo:4502; NYSE:TAK), for “just throwing his hand up and saying ‘we’ve got some protease inhibitors, you’re welcome to test them.’”

“Maybe there will be one common platform so that we can actually all advance in a common understanding and a common way.”

John Tsai, Novartis

The COVID R&D consortium, which is led by Plump and Rupert Vessey, president of R&D at Bristol Myers Squibb Co. (NYSE:BMY), has cut through many of the standard holdups involved in working with other companies, which normally labors through a series of business development meetings.

In the consortium, he said, “we just stood up a protease team right away.”

Tsai said the collaborations are serving as efficient vehicles for discussing common protocols, sharing information and designing adaptive trials to get around the problem of different endpoints being used in different trials.

“What we’re trying to achieve here is to use a common protocol so that we can understand, at what stage are these patients, and are we getting common results?” Tsai told BioCentury.

Novartis rapidly put three of its compounds into clinical trials: the antimalarial hydroxychloroquine, JAK inhibitor Jakavi ruxolitinib, and IL-1β mAb Ilaris canakinumab. Normally, it would take up to a year to get those studies started, said Tsai. “We actually got these studies up and running with agreement from the FDA within a four-week period.”

Tsai acknowledged that there’s much debate about whether hydroxychloroquine is effective against COVID-19. “Without a well-controlled, randomized clinical study, I think we won’t ever know if this hydroxychloroquine is effective in these patients,” he said.

Data sharing of results is another area where the consortia are breaking ground. The members are actively engaged in working out ways to disclose the kind of information that has traditionally been kept securely in house.

“Over the next couple of weeks, this is where there will be a meeting of the minds to ensure that we’re openly sharing, and maybe there will be one common platform so that we can actually all advance in a common understanding and a common way,” said Tsai.

Digital endpoints and remote monitoring are being test-driven out of necessity during the crisis, but will be one of the positive legacies.

Tsai said Novartis’ investment over the past two years in “infusing artificial intelligence into the conduct of clinical trials” has enabled it to maintain almost all its trials on track. Novartis uses AI in its Sense platform, a system that allows it to monitor 500 clinical trials in real time using predictive analytics.

Tsai said Novartis’ trials have included almost 10,000 remote monitoring visits over the past eight weeks. Under 1% of Novartis’ 96,000 clinical trial patients have not received their drug supply.

After the crisis, “there will be a greater acceptance of remote monitoring as well as digital means of conducting our clinical trials, and a greater acceptance from the health authorities to enable us to conduct clinical trials through these digital means,” said Tsai.

The full podcasts are available at BioCentury.com/media/podcasts.

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