Moderna’s Upcoming Clinical Trials

 By Derek Lowe 

One of the ways in which this pandemic will be looked back on as a pivot point will (almost certainly) be in the use of mRNA vaccines. It seems clear at this point that these have come through spectacularly against the coronavirus: every new study of their effects in the broad population just adds to the efficacy story, and safety concerns have been minimal. We are extremely fortunate that this is the case – never forget that. The huge amount of work that’s gone into this platform over the years paid off at just the right time for us to quickly get such therapies into human trials, and what’s more, they worked when they got there. That’s not always the case – never forget that, either. Vaccines for infectious disease have a historic two-out-of-three failure rate in the clinic (which is nonetheless the lowest such failure rate by far compared to all other drug development areas!) We had a substantial leg up on the current virus because of all the work that went into SARS and MERS, but even so we’ve seen coronavirus vaccine failures from large, well-resourced, extremely competent outfits like Merck, Sanofi, and GSK. There is a timeline in which this happened to everybody, and I’m glad I’m not living in it.

Now that we’ve seen this, though, there is naturally going to be a big push for the mRNA platform as a whole. Moderna and BioNTech are of course good companies to watch for such developments. The first of these will surely be continued targeting in immunology. That’s because systemic mRNA dosing is still a real problem – you get far more effect if you can use the technology to leverage the power of the immune system, which is just what a vaccine does, rather than try to soak the whole body in it as a therapy all its own. I wrote here about some recent BioNTech work directed at multiple sclerosis, so today let’s see what Moderna is up to.

The weeds are not growing up around them, that seems clear. This press release updates several long-running efforts of theirs, and you can see the effect of a big infusion of money, capacity, and clinical confidence. Their first update is on mRNA-1345, a vaccine candidate for RSV (respiratory syncytial virus). That one is of special concern in infants and also in the elderly, and there is as yet no vaccine. That’s not really for lack of trying – people have been working on such candidates for many years, but it’s a challenge. This 2020 review estimates that there are 38 candidate vaccines in development (!), and it is clear that (a) not all of these are going to work in the first place, or surely not to the same degree, and (b) the market will end up dominated by whichever of these many candidates can truly stand out in efficacy, ease of administration, and safety.

Moderna is obviously betting that theirs can. They’ve had previous swings at this target (mRNA-1777), but the Phase I data they’re presenting now indicate that the 1345 vaccine leads to much higher levels of neutralizing antibodies, with no safety concerns yet. The fifty-microgram dose seems just as good as the 100-microgram one, so far. This is just a first look in a small number of young adult patients, and there are many more groups being tested, but so far, so good. As with all vaccines and all drug candidates, Phase II is where the bat will make contact with the ball (or not!), and that efficacy data is still some time in the future. There will likely be other RSV candidates before various regulatory authorities (or even approved) by the time Moderna is ready to make its case, and the story will also be how well their candidate compares.

The release also updates data on their cytomegalovirus vaccine (mRNA-1647). CMV is quite common – over half of adults in the US have already been infected, most of them without much incident. The big concerns are pregnant women and immunocompromised adults (especially organ transplant recipients) for which the infection can mean real trouble. This is another area where vaccine work has been going on for a long time, and there are some significant challenges. CMV is a huge virus, and codes for over two hundred proteins, a ridiculously large number by viral standards. Which of those are the best candidates as vaccine antigens, and how are you sure about that? Right.

Moderna’s candidate actually was the first mRNA vaccine candidate to go into a human Phase II – it made it in just as the pandemic was gathering earlier last year. The interim data show a strong neutralizing antibody response, and the company is moving on with one of the doses (100 micrograms) to a Phase III study in women 18-40. That one will produce preventative data, obviously the key for the whole effort.

The company also has a longrunning flu vaccine program, and that’s a tough place to work in. The existing vaccines hover around 50% efficacy – far better than nothing, but plenty of room for improvement – and the influenza viruses themselves are notoriously good at rearranging their surface proteins season by season. As an aside, we should be very, very happy that the coronavirus does not have these abilities (and no, it’s not going to acquire them suddenly – they’re built differently from the start). One real advantage of the mRNA platform would be shorter lead times for vaccine production. If the damn flu is going to change every time around, which it is, we’d be better off tracking the strains in closer to real time to match vaccine antigens. The Moderna press release says that they heading into Phase I with “multiple candidates”, and they they hope to come up with combination vaccines against flu, SARS-CoV-2, RSV and human metapneumovirus (hMPV) all at once. This is a very worthy goal, but it’s obviously going to take a while.

Finally, Moderna has also had a longtime interest in the HIV vaccine field, and if you want to pick a tough area to work in, that’s the place to be. As the world knows, decades of work have yet to yield a useful vaccine in this area. But over the past thirty years, a great deal of effort has identified several broadly-neutralizing antibody types, featuring rare but powerful binding modes that remain active across many different viral strains. Moderna is going into a range of Phase I trials around their candidate mRNA-1644, partnered with the International AIDS Vaccine Initiative (IAVI) and the Gates Foundation. IAVI and Scripps recently saw good results with the induction of such broadly-neutralizing antibodies, and the hope is that mRNA-1644 can be optimized even past that. This is going to also take a while, but overall the bNAb approach is the most promising HIV vaccine news around. Moderna has another approach being developed with the NIH, mRNA-1574, a multiple-antigen vaccine that will also be moving into Phase I this year.

That’s a lot of trials! I’m glad to see the company moving so quickly and aggressively. They’re clearly putting the money and momentum from the coronavirus vaccine work to good use. And remember, this is just the clinical trial end of things, the tip of the spear, and there is surely a good deal going on preclinically that we’re not hearing about. I wish them, BioNTech, and all the other mRNA immunology developers every success. The acceleration of work in this area is one of the few real silver linings of the pandemic.

https://blogs.sciencemag.org/pipeline/archives/2021/04/21/modernas-upcoming-clinical-trials

State warned Conn. CVS was vaccinating out-of-staters

 More New York residents than Connecticut residents had been vaccinated at a CVS by the time state officials visited the location in February, according to a published report.

Health officials had been warned days earlier that New York residents were lining up at the CVS in Waterford to get vaccinated, according to documents and emails obtained by the New Haven Register under freedom of information laws.

By the time officials visited the store, 318 people with New York addresses had been vaccinated there, compared to 301 Connecticut residents who had received shots, according to records reviewed by the newspaper. Residents from 10 other states also had received vaccines.

Many of the New York residents had taken advantage of a computer glitch to get appointments, and had typed in Long Island zip codes and were directed to the Waterford site.

On the day health officials visited the store, they found 10 people from Long Island in line to get vaccinated. None of them were eligible under state guidelines at the time, which restricted vaccinations to first responders and people over 75, according to the newspaper.

Police were called when some of the New Yorkers refused to leave the line, but no arrests were made.

More than two weeks after the visit, state health officials instructed CVS not to honor second vaccine appointments for people who had been vaccinated in error at the Waterford site, but instead to find them doses in their state of residence, according to emails reviewed by the newspaper.

A CVS spokesperson told the newspaper the company has since changed its website to make sure vaccine recipients meet eligibility requirements, and worked directly with patients who had received their first shot at the Waterford store to make sure they received their second shots in their home states under applicable guidelines.

https://apnews.com/article/ny-state-wire-health-business-coronavirus-4a2732525e2ae72ebb43347d08284000

Biotech start­up looks to end the moral de­bate over cell lines once and for all

 For millions of Catholics around the world, the development of new vaccines to combat Covid-19 has sparked a moral dilemma. All the approved vaccines in use relied — in some fashion — on cell lines that were derived from aborted fetal tissue.

While church leaders accepted the vaccines and recommended their use to end the pandemic, a number also highlighted their preference for the mRNA vaccines from Pfizer/BioNTech and Moderna over the J&J and AstraZeneca shots, which they noted were more heavily dependent on cell lines that they found morally objectionable.

That intense debate over cell lines that large numbers of people object to on moral grounds, widely used in therapeutic development programs, has now spawned a newly created upstart biotech which is absolutely determined to replace cell lines like the commonly used HEK293 — used to manufacture the AstraZeneca Covid-19 vaccine — and PER.C6, a cell line based on human embryonic retina tissue used to manufacture the J&J jab. And they plan to use new gene editing tools to do an even better job at creating cell lines that no one could object to.

The company — Agathos — is tiny right now as it steps out on the biotech stage, but it’s being founded by a trio of experienced execs who have built up Aldevron, one of the world’s top manufacturers of plasmid DNA, mRNA, CRISPR/Cas9, vectors and more, serving the burgeoning world of gene therapy developers around the world.

The 3 are James Brown, Michael Chambers and John Ballantyne. Brown recently left Aldevron in Fargo, ND to join a small band of biotech entrepreneurs that have been quietly building a thriving little hub of their own in the environs around the CMO, which has specialized in cell and gene therapy. And he’s invested in the company alongside Chambers and Ballantyne, the two men who founded the company in the late ’90s and now find themselves in the midst of one of the biggest booms in biotech.

Their new company has 3 main focuses, says Brown:

Biomanufacturing and cell line development.

Payload delivery, whether it’s proteins or nucleic acids how they’re delivered.

And then the in-house development of cell and gene therapies.

“We’re just getting started,” Brown tells me in a Zoom interview from newly leased space. He’s building the initial team now that will create a platform they plan to use themselves, and make available to others.

“This isn’t the case where we have a technology that’s looking to solve a problem,” Brown says. “We have a problem and we’re looking to solve it with technology.”

They’re not looking for a debate and have vowed to remain politically agnostic. But they think they can do a better job and offer new cell lines that would be preferable — if only because mass numbers of people shun pharma products that don’t square with their conscience.

“Our goals are to take advantage of the advances in cell and gene therapy, biomanufacturing and genetic payload delivery. We look at how drugs are manufactured, especially in cell and gene therapy, and think there are opportunities to do better,” says Brown.

“In particular one of the challenges that I think the field faces with some of these manufacturing processes and the materials that are used is that they are very good at what they do but they come from ethically problematic sources,” he adds. “We can use the tools that are available to develop these drugs and manufacture them without using morally compromised cell lines and avoid that choice that people have to make in following their conscience.

“If we had something that was just as good and a company looked at it and said: ‘I have something just as good, so why wouldn’t I choose that one because more people are going to buy my product?’”

I asked Michael Chambers via email why he was co-founding the biotech. His reply:

There are a few reasons we are investing in Agathos. James is a talented scientist and CEO, and he is putting a world-class team together. We are primarily interested because Agathos meets an unmet need for millions of people from different faiths and backgrounds — the desire for technologically superior biomanufacturing cell lines and products without ethical concerns

Just starting out, they’re focused on various mammalian cell lines that could offer a better alternative. Or, they might develop cell lines from scratch.

“Michael jokes, he’s like, ‘Go out and kill a jackrabbit and put it in a blender and create cell lines from scratch and develop them,” Brown says. “Because we have so many more tools with CRISPR and gene editing and whatnot, that we can manipulate these things. We want to use these tools to do new and innovative things and address some of the shortcomings.”

By the end of this year, says Brown, he expects the team will grow to 5 to 10 people. After that, he says, “the sky’s the limit.”

https://endpts.com/aldevron-founders-back-a-biotech-startup-thats-looking-to-end-the-moral-debate-over-cell-lines-once-and-for-all/

After Inovio, are oth­er fed-backed Covid hope­fuls in trou­ble?

 Inovio received some harsh news from the Pentagon on Friday regarding its Covid-19 vaccine program, and it could prove foreboding to other mid-stage players in the space.

The US Department of Defense has scuttled funding for Inovio’s Phase III Covid-19 vaccine trial, Inovio said in a press release, but will continue to fund the study’s Phase II segment. Friday’s move comes as a result of a growing availability of authorized vaccines in the US, Inovio said the department communicated to them. Endpoints News has reached out to DoD for comment.

“The decision results from the changing environment of COVID-19 with the rapid deployment of vaccines,” DoD said, per Inovio. “This decision is not a reflection of the awardee or product, rather a fast-moving environment associated with the former Operation Warp Speed on decisions related to future products.”

Inovio hustled to reassure investors that the funding withdrawal did not stem from their vaccine candidate itself, dubbed INO-4800, saying in its statement that the decision was unrelated to the program’s data or partial clinical hold that’s been in place since last September. Furthermore, the company’s release led with the seemingly innocuous note on how they’re planning for a Phase III trial to take place predominantly outside the US.

But most didn’t seem to be assuaged, as Inovio $INO shares were crushed early Friday. The stock was down more than 30% at points in pre-market trading, and opened down 25%.

Inovio’s support had come from the department’s Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense. The office’s point over vaccine availability could prove as a warning sign for other government-backed Covid-19 projects that haven’t yet hit the market. According to the latest CDC numbers, more than 135 million Americans have received at least one vaccine dose, accounting for 52% of the population over 18.

Those figures come largely as a result of the Pfizer/BioNTech and Moderna vaccines, which were the first two to receive EUAs in the US after their Phase III data read out last November. Of the nearly 219 million doses administered so far, about 114 million have come from Pfizer/BioNTech and 95 million from Moderna.

An additional 8 million doses of the one-shot J&J vaccine have also been given, and that shot’s rollout hold is expected to be lifted as early as Friday. And Novavax has previously said it expects its own EUA to come as soon as next month, further complicating matters for Inovio and other Covid-19 shots from small players in late-stage development.

INO-4800 is a DNA-based vaccine candidate composed of an optimized DNA plasmid, Inovio says. The approach differs from the major vaccine players’ strategy of using mRNA (Pfizer and Moderna), adenoviruses (J&J and AstraZeneca) and protein-based delivery (Novavax). Inovio had released some early-stage data on their candidate just last week, saying T cell responses were “fully maintained” against the coronavirus variants that emerged in the UK, South Africa and Brazil when compared to responses to the original Wuhan, China strain. They noted that the samples were collected from varying timepoints from when their Phase I trial participants were immunized.

It’s been a troubled few months for Inovio, which has seen its Covid-19 vaccine program stuck in neutral ever since the FDA slapped a partial hold on its Phase III trial in late September. Regulators had raised questions over the program’s device used to inject the vaccine into the skin, and Inovio said in March that it is planning to respond to the agency next month.

In a 10-K filing at the time, Inovio admitted its vaccine efforts may end up being fruitless, writing, “We do not know whether our planned Phase 3 clinical trial will begin on time or be completed on schedule, if at all.”

https://endpts.com/inovios-covid-19-vaccine-studies-just-hit-a-brick-wall-at-the-pentagon-are-other-hopefuls-in-trouble/

Preclinical oncology biotech TScan Therapeutics files for a $100 million IPO

 TScan Therapeutics, a preclinical biotech developing engineered T cell cancer therapies, filed on Friday with the SEC to raise up to $100 million in an initial public offering.

TScan Therapeutics is developing a pipeline of T cell receptor-engineered T cell, or TCR-T, therapies for the treatment of hematological and solid tumors. The company uses one of its propriety technology platforms, TargetScan, to analyze the T cells of cancer patients who have shown excellent responses to immunotherapy to inform the design of their TCR-T therapies. The company plans to submit INDs for its lead two liquid tumor candidates in the 4Q21 and at least three of its four solid tumor candidates in the 2H22. 

The Waltham, MA-based company was founded in 2018 and plans to list on the Nasdaq under the symbol TCRX. TScan Therapeutics filed confidentially on March 19, 2021. Morgan Stanley, Jefferies, Cowen and Barclays are the joint bookrunners on the deal. No pricing terms were disclosed.

Relevant Profile: TCRX

https://www.renaissancecapital.com/IPO-Center/News/81122/Preclinical-oncology-biotech-TScan-Therapeutics-files-for-a-$100-million-IP

J&J Covid-19 Shot Set to be Given Again at Vaccination Sites

 Health officials around the country are preparing to resume offering Johnson & Johnson's Covid-19 vaccine as soon as this weekend after getting a green light from federal regulators on Friday.

The U.S. Food and Drug Administration and U.S. Centers for Disease Control and Prevention lifted their recommendation to pause the shots after investigating reports of rare but potentially dangerous blood clotting in certain recipients. On Friday, FDA and CDC officials said inoculations could continue because their benefits outweigh their risks.

Vaccinations can begin as soon as Saturday morning, said FDA's vaccines chief Peter Marks on a conference call with reporters Friday. The FDA issued updated informational guides that inform vaccine recipients and doctors of the risk of a blood-clotting side effect that has primarily affected adult women under 50. The overall risk is about 1.9 cases per million people, though the risk is about 3.5 times higher for women ages 18 to 49, officials said.

Doctors and public-health officials said it could take a few days to schedule appointments but welcomed the return of J&J's vaccine after last week's pause sent states scrambling to reschedule thousands of appointments.

"It does have some advantages over the other vaccines in particular populations where it may be difficult to give them a second shot," said Onisis Stefas, chief pharmacy officer at Northwell Health. "We really need to have multiple options out there to have people comfortable to get vaccinated so we can get to herd immunity."

Pharmacy chains Walgreens Boots Alliance Inc. and CVS Health Corp. said they would restart vaccinations with the J&J shot next week.

Arizona's health department said it had advised healthcare providers in the state to resume offering the J&J shot, of which the state has nearly 105,000 doses. The Minnesota Department of Health said the state had distributed 9,600 doses of the vaccine to healthcare providers that it expects to be available to the public in the coming days.

J&J's shot achieves immunity with one shot rather than two as required for Pfizer Inc.'s and Moderna Inc.'s vaccines. J&J's shot is easier to keep refrigerated and for longer periods.

States and hospitals are taking advantage of the simpler dosing to vaccinate people who are less likely or able to return for a second shot, such as the homeless, people who travel frequently for business, and older people confined to their homes.

J&J's vaccine supplies aren't as plentiful as its rivals because of manufacturing bottlenecks, but millions of distributed doses have yet to be administered, according to CDC data, and are a key tool to help speed the U.S.'s inoculation campaign.

Northwell will likely resume offering the J&J shot next week once it updates the informational materials it provides to patients to include a warning about blood clots and once it educates its doctors and nurses on how to communicate the risk to patients, particularly women under 50 years old, Dr. Stefas said.

Northwell, based in New Hyde Park, N.Y., had been using J&J's shot primarily for people discharged from the hospital and for nursing-home residents and plans to resume doing so next week, Dr. Stefas said. The hospital will assess how much demand there is from the general public before deciding whether to offer the shot at its public vaccination sites, he said.

"Just because we offer it doesn't mean people are going to take it," Dr. Stefas said. "We'll educate them on the risk, why the pause occurred and see if people are comfortable with taking the vaccine."

Yale New Haven Hospital in Connecticut hopes to restart offering shots to patients being discharged from the hospital or who visit the emergency room for conditions unrelated to Covid-19, said Chief Clinical Officer Thomas Balcezak.

The hospital runs several mass-vaccination sites around the state that are already booked next week with appointments to receive the Pfizer and Moderna vaccines, Dr. Balcezak said. Public-appointment slots for J&J's shot will likely be made available in the first week of May, he said.

Despite the blood-clot warning, J&J's shot will remain a preferred choice for some people, said Dr. Balcezak. Informal polling of patients and hospital staff after the past week's pause showed that some people are more comfortable with the vaccine because it doesn't use the relatively new messenger RNA technology used by Pfizer and Moderna, Dr. Balcezak said.

"Some of our employees say, 'I just want to have the J&J shot and be one and done,' or 'I like the idea that the technology is not mRNA," Dr. Balcezak said. "There's a lot of hesitancy regardless of the technology, so I don't know if this [pause] is going to add to it or not."

Washington state could restart J&J vaccinations as soon as this weekend pending a review of the latest FDA-CDC guidance by an independent committee of experts, said Umair Shah, the state's secretary of health. J&J's shots represented about 6% of all vaccine shots administered in the state when shots were paused last week; the state expects to receive an additional 8,600 doses over the first two weeks of May, he said.

Dr. Shah said he doesn't expect demand for the vaccine to be significantly less because the pause was short and the finding was that the blood-clot risk is extremely rare. Some pharmacies have reported receiving calls from patients requesting to be placed on a wait list to receive the J&J shot once the pause was lifted, he said.

"In general, this has not shaken confidence in the vaccine by many in the community," Dr. Shah said. "And every bit is going to help us, even a few thousand is helpful. People want it because it's one shot and they're not as concerned about the safety piece."

https://www.marketscreener.com/quote/stock/JOHNSON-JOHNSON-4832/news/Johnson-Johnson-s-Covid-19-Shot-Set-to-be-Given-Again-at-Vaccination-Sites-Update-33061896/

The Origin of COVID-19 and Why It Matters

 David M. Morens,1,2* Joel G. Breman,3 Charles H. Calisher,4 Peter C. Doherty,5 Beatrice H. Hahn,6,7 Gerald T. Keusch,8,9,10 Laura D. Kramer,11,12 James W. LeDuc,13 Thomas P. Monath,3,14 and Jeffery K. Taubenberger15

Abstract. The COVID-19 pandemic is among the deadliest infectious diseases to have emerged in recent history. As with all past pandemics, the specific mechanism of its emergence in humans remains unknown. Nevertheless, a large body of virologic, epidemiologic, veterinary, and ecologic data establishes that the new virus, SARS-CoV-2, evolved directly or indirectly from a β-coronavirus in the sarbecovirus (SARS-like virus) group that naturally infect bats and pangolins in Asia and Southeast Asia. Scientists have warned for decades that such sarbecoviruses are poised to emerge again and again, identified risk factors, and argued for enhanced pandemic prevention and control efforts. Unfortunately, few such preventive actions were taken resulting in the latest coronavirus emergence detected in late 2019 which quickly spread pandemically. The risk of similar coronavirus outbreaks in the future remains high. In addition to controlling the COVID-19 pandemic, we must undertake vigorous scientific, public health, and societal actions, including significantly increased funding for basic and applied research addressing disease emergence, to prevent this tragic history from repeating itself.

https://www.ajtmh.org/downloadpdf/journals/tpmd/103/3/article-p955.pdf