Biotech week ahead, Oct. 4

Biotech stocks came under pressure in the week ending Oct. 1, dragged by broader market weakness and the selling of vaccine stocks.

Positive tidings from Merck & Co., Inc. 

MRK +8.44%

 (Get Free Alerts for MRK) regarding its COVID-19 treatment candidate sent vaccine stocks tumbling Friday. Data from a late-stage study showed that molnupiravir, which Merck co-develops with Ridgeback Biotherapeutics, reduces hospitalization risk or death by approximately 50% in at-risk, non-hospitalized adult patients with mild-to-moderate COVID-19.

Merck was also in the headlines this week after it confirmed speculation regarding its acquisition of Acceleron Pharma Inc. 

XLRN +1.31%

 (Get Free Alerts for XLRN) for $11.5 billion, as it strives to cushion any downside from a potential slowdown in the sales of its blockbuster cancer immunotherapy Keytruda.

Omeros Corporation 

OMER +38.07%

 was among the biggest decliners of the week after the company disclosed that the FDA identified deficiencies in its biologic license application for narsoplimab in the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Here are the key catalysts that could move stocks in the unfolding week:

Conferences

American Society for Bone and Mineral Research, or ASBMR, 2021 Annual Meeting (hybrid): Oct. 1-4 (San Diego, California)

2021 Annual Northeast Amyotrophic Lateral Sclerosis, or NEALS, Meeting (virtual): Oct. 6-7

Chardan's 5th Annual Genetic Medicines Conference (virtual): Oct. 5-6

Goldman Sachs Small/Mid-Cap Healthcare Day (virtual): Oct. 7

AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics: Oct. 7-10

American Society of Retina Specialists, or ASRS, 2021 Annual Meeting: Oct. 8-12 (San Antonio, Texas)

PDUFA Dates

The Food and Drug Administration is scheduled to rule on ChemoCentryx, Inc. 

CCXI +7.49%

's new drug application for avacopan as a treatment for ANCA-associated vasculitis. After a split Adcom verdict, the FDA had extended the review period by three months, thereby pushing forward the PDUFA date.

ANCA-associated vasculitis is a systemic disease in which over-activation of the complement pathway further activates neutrophils, leading to inflammation and destruction of small blood vessels. This leads to organ damage and failure, mainly the kidney, and is fatal if not treated.

Adcom Calendar

FDA's Antimicrobial Drugs Advisory Committee will discuss Takeda Pharmaceutical Company Limited 

TAK +0.12%

's NDA for maribavir oral tablets for the treatment of adults with post-transplant cytomegalovirus infection and/or disease, including infections resistant. The meeting is scheduled to be held Thursday, Oct. 7, between 9 a.m. and 5 p.m.

Clinical Readouts

ASBMR Presentation

Ascendis Pharma A/S 

ASND +1.79%

: Phase 2, week 58 data from the PaTH Forward trial of TransConPTH, an investigational hormone replacement therapy for adult patients with hypoparathyroidism (Monday, 2:30 pm to 3:45 pm)

NEALS Meeting Presentation

Denali Therapeutics Inc. 

DNLI +1.05%

: data from the Phase 2, study, followed by an open-label long-term extension, to evaluate the efficacy and aafety of SAR443820 in adult participants with amyotrophic lateral sclerosis (Wednesday, 4 pm to 5 pm)

AACR-NCI-EORTC Conference Presentations

Prelude Therapeutics Incorporated 

PRLD +1.57%

: data from the dose escalation portion of the Phase 1 trial of PRT543 in unselected solid tumor patient populations; data from the dose escalation portion of the Phase 1 trial of PRT811 in solid tumors and high-grade gliomas

Turning Point Therapeutics, Inc. 

TPTX +1.35%

: Update from the Phase 2 registrational trial of repotrectinib in TKI-pretreated patients with ROS1+ advanced non-small cell lung cancer and with NTRK+ advanced solid tumors (Thursday, 9 am)

Bicycle Therapeutics plc 

BCYC +7.04%

: data from Phase 1/2 study of BT5528 in patients with advanced malignancies associated with EphA2 expression (Thursday, 12:50 pm)

Turning Point & Zai Lab Limited 

ZLAB +2.54%

: Preliminary interim Phase 1 data of elzovantinib (TPX-0022) in patients with advanced solid tumors harboring genetic alterations in MET (Thursday, 9 am)

Forma Therapeutics Holdings, Inc. 

FMTX +3.84%

: initial results from the Phase 1 trial of FT-7051 in men with metastatic castration-resistant prostate cancer

ORIC Pharmaceuticals, Inc. 

ORIC +2.92%

: initial results from the Phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with Pfizer, Inc. 

PFE +0.26%

's Xtandi in patients with metastatic prostate cancer (Thursday, 9 am)

Relay Therapeutics, Inc. 

RLAY +5.61%

: initial results of RLY-4008 in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors (Friday, 10:25 am)

Repare Therapeutics Inc. 

RPTX +0.15%

: data from the Phase I TRESR trial of RP-3500 in patients with advanced solid tumors harboring synthetic lethal genomic alterations (Friday, 3:15 pm)

ASRS Meeting Presentations

Adverum Biotechnologies, Inc. 

ADVM +0.46%

: Phase 2 data for intravitreal gene therapy for diabetic macular edema with ADVM-022 (Saturday, 11:28 am)

REGENXBIO Inc. 

RGNX +3.91%

 & Clearside Biomedical, Inc. 

CLSD +5%

: initial data from the Phase 2 AAVIATE trial of RGX-314 for the treatment of wet age-related macular degeneration (Saturday)

Earnings

Enzo Biochem, Inc. 

ENZ +3.39%

 (Tuesday, before the market open)
Theratechnologies Inc. 

THTX +0.27%

 (Wednesday, before the market open)

IPOs

IPO Pricing

Branford, Connecticut-based IsoPlexis Corporation NASDAQISO has filed a preliminary prospectus with the SEC for offering 8.333 million shares in an initial public offering. The company expects to price the offering between $14 and $16 and list the shares on the Nasdaq under the ticker symbol "ISO."

The company's single cell proteomics platform has been adopted by the top global biopharmaceutical companies and comprehensive cancer centers in the U.S. to help develop more durable therapeutics, overcome therapeutic resistance, and predict patient responses for advanced immunotherapies, cell therapies, gene therapies, vaccines, and regenerative medicines.

Cingulate Inc NASDAQCING, a clinical stage biopharma using its proprietary "Precision Timed Release" drug delivery platform technology, has filed for offering 4.55 million shares in an IPO at an estimated price range of $10-$12. The Kansas-based company has applied for listing its shares on the Nasdaq under the ticker symbol "CING."

Theseus Pharmaceuticals, Inc. NASDAQTHRX proposes to offer in an IPO, 8.3335 million shares of its common stock, which it expects to price between $14 and $16. The Cambridge, Massachusetts-based biopharma is engaged in the development of targeted cancer therapies. It has applied for listing its shares on the Nasdaq under the ticker symbol "THRX."

https://www.benzinga.com/general/biotech/21/10/23209669/the-week-ahead-in-biotech-oct-3-9-chemocentryx-fda-decision-conference-presentations-ipos-and-mor

Keep your kids safe from COVID while playing sports

 COVID-19 shouldn't keep budding athletes on the sidelines. But it's critical to keep them safe from the coronavirus while playing sports.

The National Athletic Trainers' Association has some timely tips.

COVID vaccines for those 12 and older have been a game changer for many families. Being fully vaccinated can make returning to sports safer, the association said.

But for kids too young to get the vaccine yet, it's important to take steps that lower the risk of spreading the virus.

Remember, too, that kids have who been less active during the pandemic are at risk for injury. Plus, any child or teen who has recently had COVID-19 should have a heart evaluation before returning to physical activity.

Before the sports season starts:

• Understand the safety rules and expectations and talk about them with your child.
• Make sure your children have a face mask, hand sanitizer, towel, water bottle and tissues labeled with their names
• See your doctor if your child needs a pre-participation physical exam.
• If your kids haven't been active during COVID-19, start easing into exercise. For sports with a lot of running, consider a beginner conditioning program before the season.

Before practice or games:

• Keep your children home from practice or games if they feel sick or have any symptoms of COVID-19.
• Have your children wash their hands before arriving, or use hand sanitizer if soap and water aren't available.
• Bring labeled personal sports equipment, water bottle, towel, tissues, hand sanitizer and face mask.
• For children not fully vaccinated, wear face masks when arriving or leaving the playing field. Encourage your child to wear a mask in crowded indoor spaces.
• During play, kids should tell a coach if they're not feeling well and leave practice or game with a parent or caregiver.

Returning to physical activity after COVID-19 infection:

• If your child has a positive COVID-19 test, notify your pediatrician.
• Have children with no symptoms or mild symptoms of COVID-19 screened for heart symptoms. Those with moderate symptoms should not exercise until their symptoms are gone and have had cardiac screening.
• Children who were very sick from COVID-19 must be treated as though they have an inflamed heart muscle (myocarditis). They should not exercise or compete for three to six months. A pediatric cardiologist should examine these children before they are allowed to return to exercise or competition.
• If the sport is outdoors and your child is not fully vaccinated against COVID-19, they should wear face masks when on the sidelines, in the dugout and during team chats.
• Anyone not fully vaccinated should wear a face mask for all indoor sports.

Masks should not be worn during:

• Water sports.
• Gymnastics, cheer stunts and tumbling, and wrestling.
• Exceptions to masks might be appropriate when the risk of heat-related illness is high.
• Unless fully vaccinated, coaches, officials, spectators and volunteers should wear masks. In addition, anyone over 2 who has had close contact with someone who has COVID-19 should wear a mask.

To help protect unvaccinated children, try to avoid:

• Huddles, high-fives, fist bumps and handshakes.
• Sharing food or drink.
• Cheering, chanting, or singing when closer than 6 to 8 feet from others.
• Spitting or blowing nose without a tissue.
• Storing personal equipment less than 6 to 8 feet away from other equipment.
• Sharing equipment as much as possible. (Remember to sanitize hands before and after using balls, bats, sticks and other equipment that must be shared).

After sports practice or games:

• Sanitize or wash hands.
• Wash or replace face masks, towels and practice clothes or uniforms.
• Clean personal equipment and water bottles.

https://medicalxpress.com/news/2021-09-kids-safe-covid-sports.html

NY system gives sign-on bonuses, on-the-spot job offers amid staffing shortage

 Amid intensified staffing strain fueled by the latest COVID-19 wave, Ellis Medicine is making on-the-spot job offers and offering sign-on bonuses of up to $20,000 for nurses, up to $25,000 for medical technologists and up to $15,000 for respiratory therapists, the Schenectady, N.Y.-based system confirmed to Becker's. 

Samuel Pierre, director of talent acquisition and human resources operations at Ellis Medicine, said the aim is to attract healthcare professionals as organizations across the U.S. are competing for talent. 

"We understand most, if not all, hospitals are competing for the same talent out there, so our hope is that the bonus does attract" people, he said.  

Ellis Medicine, a nonprofit, 438-bed community and teaching system, is also holding on-the-spot interviews during weekly events known as "Walk-in Wednesdays."

Each Wednesday, candidates for nursing-related positions, including registered nurses and licensed practical nurses, can come to the system's Ellis Hospital for an on-the-spot interview with nursing leadership, according to the system website. 

The goal, said Mr. Pierre, is to get offers out to candidates while they're at the hospital interviewing. 

Ellis Medicine's hiring efforts come as the system has about 500 job openings across various areas, including environmental services, compared to the 300 job openings the system typically sees.

Mr. Pierre attributed the increase in openings primarily to a high number of retirements, as well as people leaving the profession, rather than losing workers because of New York's vaccine mandate. 

The state's mandate took effect Sept. 27.

https://www.beckershospitalreview.com/workforce/new-york-system-gives-sign-on-bonuses-on-the-spot-job-offers-amid-staffing-shortage.html

Fauci: 'False narrative' to see COVID vaccine not needed if Merck drug OKd

 President Biden’s top medical adviser, Anthony Fauci, said on Sunday that it is a “false narrative” to think that the COVID-19 vaccine would not be needed if an antiviral COVID-19 treatment from Merck is federally approved.

“This Week” co-anchor Jonathan Karl asked Fauci on ABC if the approval of the antiviral treatment could make taking the COVID-19 vaccine unnecessary.

“Oh, absolutely not. That's such a false narrative that someone says, ‘Well now you have a drug.’ Remember, the easiest way to stay out of the hospital, and not die, is don't get infected,” Fauci told Karl. 

“I mean this idea about ‘We have a drug, don't get vaccinated,’ just doesn't make any sense,” Fauci added.

Fauci’s comments come as the United States surpassed the grim milestone of 700,000 COVID-19 deaths.

He also said that many of those deaths could have been avoidable had they taken the COVID-19 vaccine, explaining “if you look at the people who get hospitalized, and the people who die, it is overwhelmingly weighted towards the people who are unvaccinated.”

Merck said last week that its antiviral COVID-19 treatment, molnupiravir, was effective against COVID-19. The pharmaceutical giant said that in phase three trials, only 7.3 percent of those who received the medication were hospitalized for COVID-19 within 29 days while 14.1 percent of those who received the placebo either ended up in the hospital or died.

Merck also said that none of the people who received molnupiravir died during the trial, but eight people who received the placebo did.

Merck said that it would be applying for emergency authorization of the drug.

https://thehill.com/homenews/sunday-talk-shows/575061-fauci-says-its-a-false-narrative-to-think-covid-19-vaccine-not

U.S. Judge upholds COVID-19 vaccine requirement for those with 'natural immunity'

 A U.S. judge upheld the University of California's COVID-19 vaccine requirement against a challenge by a professor who alleged he had immunity due to a prior coronavirus infection, in what appears to be the first ruling on the issue.

U.S. District Court Judge James Selna in Santa Ana, California, said the university system acted rationally to protect public health by mandating the vaccine and not exempting individuals with some level of immunity from an infection.

More than 43 million Americans have had confirmed cases of COVID-19 and some opponents of vaccinations have argued that immunity from an infection negates the need for an inoculation.

The U.S. Centers for Disease Control and Prevention (CDC) said on Aug. 6 that a study showed vaccines offer better protection than natural immunity gained from prior infection, which wanes over time.

On Wednesday, a group of physicians who are Republican members of Congress wrote to the CDC to urge the agency to acknowledge natural immunity.

The lawmakers said if the growing number of vaccine mandates ignore natural immunity it could lead to labor shortages as people are fired for failing to get a shot. Their letter said such mandates could even trigger a security crisis because up to 20% of the military faces "separation" and many of them "likely have natural immunity."

Selna's ruling denied a motion for a preliminary injunction by Aaron Kheriaty. And while Selna said the professor at the University of California, Irvine School of Medicine did not show a likelihood of success, Kheriaty said he plans to continue the litigation.

He told Reuters he plans to use the discovery process to determine how the policy was formulated and to question the university's expert witnesses about their reasoning for rejecting his arguments on natural immunity.

https://www.reuters.com/world/us/us-judge-upholds-covid-19-vaccine-requirement-those-with-natural-immunity-2021-09-30/

Rethinking Obesity

BY DEREK LOWE 

Like many people, I have a shelf that has several of my old high school and college yearbooks on it. The faces and scenes they depict are receding farther back in time, damn it all, and as they do they take on interesting aspects that you couldn't have predicted at the time. In my case, the high school ones are from the late 1970s and the college ones are correspondingly from the early 1980s. The hairstyles and the clothing therein have over the years cycled in and out of looking (alternately) odd and old-fashioned or weirdly contemporary, as these things do. Just about any electronic device looks bizarre, of course, and more bizarre by the year - it's the same feeling of watching someone in an old sitcom episode pick up a portable telephone the size of an uncut loaf of bread. 

But you know what looks strange, to the point of being unable to not notice it once you've seen it? How thin almost everyone is. I don't (necessarily) mean by comparison to their later selves, but just in general. And it's not just because these are pictures of high school and college students, because (1) people of those ages definitely aren't as thin as that now and (2) the same observation applies to the photos of the faculty and staff. Looking at these pictures, you inescapably have to admit that people have gotten bulkier over the years, in every category. The numbers bear this out, of course. Sixty years ago, the estimate is that just under 15% of the US population had a BMI over 30, and now it's more like 40%. A lot of those gains have come since the early 1980s, and one rather startling statistic is that the least obese state now (Colorado) would have been the most obese state with those same numbers in 1980, and by a wide margin. Similar trends are obvious in many other countries around the world.

Opinions on how and why this has happened are easily obtained. But I wanted to highlight what is sure to be a controversial proposal that's just come out recently. If there's one thing that people can agree on about weight gain, it's that it happens when people consume more calories than they expend. But as Gary Taubes notes in that commentary, that's not a very useful explanation. You wouldn't get very far if you applied that same level of reductionism to personal finance: the way to get rich is obviously to spend less money than you take in, but there are some key details lacking in that approach. Getting rich is better approached by studying the many ways that one can accumulate excess money, rather than looking at "money imbalance" by itself, and obesity may well be better approached by thinking of it as a disorder of fat accumulation, rather than just as an illustration of calorie imbalance.

Coming at the problem from this direction feels strange at first, because we've all been used to thinking in energy-balance terms for decades - and frankly, we've all been used to thinking of this as largely a behavioral problem as well (willpower, depression, and all that). But as Taubes details, this used to be a very prominent view in the field decades ago, and it was not abandoned because it was disproven. Indeed, a close look at what we now know about human obesity and animal models of it suggests that this is still a valuable approach. Fat mobilization, patterns of fat deposition, the metabolic effects of fat deposits once they accumulate (it's far from a passive store) - all of these point to a "fat storage disorder".

Here's a new review (open access) of the proposed mechanism. In short, eating a high-glycemic-load diet (rich in easily metabolized carbohydrates) deranges the insulin signaling axis towards glucose uptake, lipogenesis, and fat storage. It's not just the calorie content; there are consequences to the fat storage that get worse over time. Instead of a positive calorie balance gradually increasing fat deposition, this is more the opposite: fat deposition (caused by high glycemic foods) drives a positive energy balance. The solution would be to avoid diet rich in high glycemic foods, favoring one whose calories come more from proteins and oils.

This has been a longstanding argument in human nutrition, and one good thing about that review is that it lists the evidence for and against this idea, along with the various attempts to prove or disprove it in human studies and animal models. In the end, the authors say that dogmatic statements about which approach to human obesity have been proven simply cannot be supported by the evidence: we need more data, and better-designed studies, and we definitely need to stop assuming that we already know what the answer is. That's not going to be easy. You see this in any field - people get invested in a given framework and are not happy about having to treat it as it were back to being a matter for speculation again. That investment is partly psychological, partly in career capital and reputation, and partly literal investment as in money and assets. The authors:

The field of obesity should embrace paradigm clash as an essential step forward. Toward this end, investigators should, first, refrain from hyperbolic claims to have disproven (or proven) alternative explanations of the obesity pandemic; second, clarify the Energy Balance Model, specifying contrasting causal and testable hypotheses; third, form collaborations among scientists with diverse viewpoints to test predictions in rigorous and unbiased research; and fourth, to facilitate these aims, depersonalize the debate, scrupulously avoiding ad hominem argument. Rigorous research using complementary designs will be needed to resolve the debate, clarify a middle ground, or point the way to new explanatory models that better encompass the evidence.

Hard to argue with that. We clearly are getting something wrong - and as evidence, I present the Harrisburg High School 1979 yearbook.

https://www.science.org/content/blog-post/rethinking-obesity

mRNA's History- And Its Future

 BY DEREK LOWE

This is a really good article on the history of mRNA vaccines, and I recommend it. I and many others have been emphasizing that we've been very fortunate that so much work had already gone into this area before the pandemic hit - that and the experience we gained during the previous SARS and MERS outbreaks have been absolutely crucial to vaccine development (the latter not just for the mRNA vaccines), and without them we would be in far, far worse shape now. 

That Nature piece will also give non-scientists a realistic picture of what development of a new technology is like in this field. Everyone builds on everyone else's work, and when a big discovery is finally clear to everyone, you'll find that you can leaf back through the history, turning over page after page until you get to experiments from years (decades) before that in hindsight were the earliest signs of the Big Thing. You might wonder how come no one noticed these at the time, or put more resources behind them, but the truth is that at any given time there are a lot of experiments and ideas floating around that have the potential to turn into something big, some day. Looking back from the ones that finally worked out brings massive amounts of survivorship bias into your thinking. Most big things don't work out - every experienced scientist can look back and wonder at all the time they spent on various things that (in retrospect) bore no fruit and were (in retrospect!) never going to. But you don't see that at the time. When the first experiments were run that showed that mRNA could indeed be induced to enter cells and set off a bit of protein synthesis, it was clear that this could eventually be a therapeutic pathway. Emphasis on "could", because there were also a thousand issues that would have to be addressed along the way, and most any of them could (on closer inspection) turn out to sink the idea.

You'll also see that the earliest mRNA work was not directed at the idea of vaccines at all. It was going to be a laboratory tool to make cells produce whatever protein you coded the mRNA for, to run all sorts of experiments in what we would perhaps now call synthetic biology or chemical biology, or perhaps it was going to be a direct therapeutic to make people produce such proteins in their own bodies. The first attempts to use this technique to produce a protein antigen as a vaccine in the early 1990s were hard to reproduce, and the whole idea was still too expensive for the amount of risk it contained. As the article says, "In the 1990s and for most of the 2000s, nearly every vaccine company that considered working on mRNA opted to invest its resources elsewhere." RNA was considered too hard to work with, too unstable, and the whole idea too full of fresh problems that would have to be worked out along the way, compared to other options for the time and money.

And plenty of time and money did get spent in the intervening years. The RNA constructs did turn out to be too unstable in many cases - they fell apart in the blood, or they just landed in the liver on the first pass and were never seen again. Or they didn't get into cells very well, or didn't get translated into much protein when they did. A lot of the early attempts set off a general inflammatory response as well, because the body's innate immune system picked up on the sudden presence of foreign RNA and reacted as if this were a viral attack in itself. So there were a lot of stops and starts, with each failure leading to more refinement. This technique, like so many others, stands before you after spending years in the scientific equivalent of an expensive finishing school.

But now that many of the problems have been laboriously uncovered and dealt with, we do indeed have what looks like a really useful platform for vaccines (and for other uses as well). Here's where I break out the hose and turn it on some of the rowdier parts of the crowd, though. It's good to remember that the vaccine application is really the most straightforward of them all: for starters, you're depending on the huge amplification of the adaptive immune system working for you, so you don't need much of an mRNA dose. Your targets can (in the best cases) be pretty  clear: the earlier work on SARS strongly suggested that the Spike protein was the antigen of choice, and we have similar ideas for infectious diseases like RSV. Honestly, the development pathway for mRNA coronavirus vaccines was about as good as it can get.

There are plenty of other things in the works, and many of them are getting headlines. Keep in mind, though, that some of these have been in the works for years already; they're not just sudden turbocharged programs that have zipped into prominence since Covid-19. Moderna, for example, has been working on mRNA flu and RSV vaccines for years now - the recent headlines about their work on a combination of these two with their coronavirus vaccine (or booster) is good to hear, but it's not a gigantic leap from a standing start.

Similarly, talk of mRNA cancer vaccines takes you into an area that has had many, many years of effort put into it already (and so far, without much to show for it in human therapy). BioNTech had this as their story when they launched in 2008, for example. That Nature history link mentions a number of earlier attempts (and earlier companies) from the 1990s as well. The whole cancer vaccine idea was one of the first waves of immuno-oncology, and it is nowhere near as straightforward as coming up with a vaccine against a respiratory virus.

That's not to say it can't work - it's just going to be a longer time down a hard road before we can say that it does, though. mRNA is not magic. Using it does not address the biggest obstacle to the cancer vaccine idea, which is figuring out what to aim your neat technology at in the first place. What protein on a cancer cell should you be raising an immune response to? You need one that is going to set off a robust attack on those cells, for sure, but at the same time one that will not set off a similarly robust attack on the linings of your kidneys or the valves of your heart. This is a far, far easier problem when you have some completely non-human viral protein to aim at, as you can appreciate. And as we've seen with viral vaccine side effects (Guillain-Barré, myocarditis), the human population varies enough that in small numbers of people you're going to see misfires even when you target a virus.

I like mRNA therapeutics and vaccines, and I'm really glad that they're getting the chance to prove their worth. We're going to get a lot of useful things out of this platform. But the platform itself does not guarantee success, especially in those areas where the problems that it can fix are not the ones holding things back.

https://www.science.org/content/blog-post/mrna-s-history--and-its-future