Novavax tumbles 30% as waning COVID-19 vaccine demand hits outlook

 Shares of U.S. vaccine maker Novavax fell about 30% on Tuesday after it cut its annual revenue forecast by half over falling demand for its COVID-19 shot from low- and middle-income nations.

Demand for its vaccine is also waning in the United States, where it was authorized for use among adults last month and was expected to be preferred by the skeptics of messenger RNA-based shots from Moderna Inc and Pfizer Inc.

But only 7,381 Novavax vaccine doses have been administered so far in the country and Chief Executive Stanley Erck said that its late launch could have hampered demand.

The company now expects 2022 revenue between $2 billion and $2.3 billion, compared with its prior forecast of $4 billion to $5 billion when it was hoping to benefit from the demand for its shots as part of the COVAX vaccine sharing program.

https://www.marketscreener.com/quote/stock/NOVAVAX-INC-58256108/news/Novavax-tumbles-30-as-waning-COVID-19-vaccine-demand-hits-outlook-41258319/

Circadian clocks play a key role in fat cell growth

 Disruption of the circadian clocks that keep the body and its cells entrained to the 24-hour day-night cycle plays a critical role in weight gain, according to a pair of studies by Weill Cornell Medicine investigators.

One study, published June 27, in Cell Reports revealed that stress caused by chronically administering glucocorticoid stress hormones and disturbing the normal daily cycle of release triggers a temporary protective mechanism in mice. This mechanism boosts fat cell growth and insulin production while reducing excess blood sugar and fat levels in the bloodstream and liver. The second study, published Aug. 8 in the Proceedings of the National Academies of Sciences, shows that fat cell precursors commit to becoming fat cells during the rest period of mice. The studies suggest that stress and other factors that throw the body's "clocks" out of rhythm may contribute to weight gain and suggest new treatment approaches for obesity.

"A lot of forces are working against a healthy metabolism when we are out of circadian rhythm," explained the senior author of both studies Dr. Mary Teruel, associate professor of biochemistry and a member of the Gale and Ira Drukier Institute for Children's Health at Weill Cornell Medicine. "The more we understand, the more likely we will be able to do something about it."

In the first study, Dr. Teruel and colleagues mimicked the disruptive effects conditions like Cushing's disease or chronic stress have on the usual daily fluctuations in glucocorticoids, a class of stress-linked hormones. To do this, they implanted pellets that released glucocorticoids at a constant rate over 21 days under the skin of mice and compared them with normal mice who have normal daily fluctuations. The amount of brown and white fat in the mice with the glucocorticoid pellets doubled within 21 days, and insulin levels in their bodies skyrocketed even though the mice still ate the same healthy diet as the normal mice.

"If you stress the animals at the wrong time, it has a dramatic effect," Dr. Teruel said. "The mice aren't eating differently, but a big shift in metabolism causes weight gain."

Surprisingly, these metabolic disruptions seemed to have a "protective effect" by keeping blood sugar levels low and preventing fat from accumulating in the blood or liver. When they removed the pellets, the metabolic changes quickly reversed.

"It shows the animals can cope with chronic stress for a while," she said.

In the second study, Dr. Teruel and her colleagues attached a red fluorescent protein to protein that controls the expression of important circadian clock genes and a yellow fluorescent protein to peroxisome proliferator activated receptor gamma (PPARG), a protein that regulates fat cell production. They used these two fluorescent markers to monitor the daily fluctuations of PPARG and circadian gene expression in mouse fat cell precursors. During the rest period of the day, they found a circadian protein called CCAAT enhancer binding protein alpha (CEBPA) causes a rapid increase in the production of PPARG. Once PPARG levels reach a certain threshold, the precursor cells commit to becoming fat cells, a process that takes a few days to complete.

"The decision to become a fat cell happens rapidly over 4 hours. It is like a switch," she said. "It only happens at a certain time of day."

Dr. Teruel and her colleagues are now working to understand why disturbing the daily rhythms of glucocorticoids triggers temporary protective metabolic changes. They also want to learn whether prolonged stress or a high-fat diet makes these changes permanent. The results of these studies could help determine how long it is safe to treat individuals with glucocorticoid drugs for conditions like asthma.

The research might also lead to the development of drugs that help reset circadian rhythms in people with obesity as an alternative to more invasive treatments like bariatric surgery. Another possibility might be therapies targeting the 4-hour window when fat cell precursors commit to becoming fat cells to prevent excess fat accumulation.

Dr. Teruel and her colleagues also believe learning how to synchronize the body's cellular and master circadian clocks will be essential.

"Every cell in our body has an intrinsic cell clock, just like the fat cells, and we have a master clock in our brain, which controls hormone secretion," she said. "We are trying to understand how they work together and how we can coordinate them."

---

Story Source:

Materials provided by Weill Cornell Medicine. Note: Content may be edited for style and length.

---

Journal References:

1. Stefan Tholen, Roma Patel, Agnieszka Agas, Kyle M. Kovary, Atefeh Rabiee, Hayley T. Nicholls, Ewa Bielczyk-Maczyńska, Wenting Yang, Fredric B. Kraemer, Mary N. Teruel. Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy. Cell Reports, 2022; 39 (13): 111018 DOI: 10.1016/j.celrep.2022.111018
2. Zhi-Bo Zhang, Joydeb Sinha, Zahra Bahrami-Nejad, Mary N. Teruel. The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell-differentiation commitment. Proceedings of the National Academy of Sciences, 2022; 119 (33) DOI: 10.1073/pnas.2204470119

https://www.sciencedaily.com/releases/2022/08/220808211750.htm

FDA Authorizes Bavarian Nordic's Jynneos for Emergency Use Against Monkeypox

 The U.S. Food and Drug Administration on Tuesday authorized Bavarian Nordic Jynneos vaccine for emergency use via intradermal injection in individuals aged 18 years and older who are determined to be at high risk for monkeypox infection.

The authorization will increase the total number of doses available for use by up to five-fold and also allows for use of the vaccine in individuals younger than 18 years of age determined to be at high risk of monkeypox infection by subcutaneous injection.

"In recent weeks the monkeypox virus has continued to spread at a rate that has made it clear our current vaccine supply will not meet the current demand,” said FDA Commissioner Robert M. Califf. (https://bit.ly/3p7C9Ao)

https://www.usnews.com/news/top-news/articles/2022-08-09/u-s-fda-authorizes-bavarian-nordics-jynneos-for-emergency-use-against-monkeypox

Halozyme Financial Report and Business Update

 Closed Antares Pharma Acquisition, Accelerating High Growth Drug Delivery Leadership and Projected to be Accretive to Revenue for Full Year 2022

Second Quarter Revenue Increased 12% YOY to $152.4 million, with GAAP Diluted Earnings per Share of $0.16 and Non-GAAP Diluted Earnings per Share of $0.53

Record Second Quarter Royalty Revenue Increased 86% YOY to $85.3 million

Raising 2022 Revenue Guidance to $655 Million to $685 Million, up from $530 Million to $560 Million, Representing 48%-55% Growth over Reported 2021 Revenue     

https://finance.yahoo.com/news/halozyme-reports-second-quarter-2022-200100443.html

Amphastar Crashed As Runaway Syndax Hit Profit-Taking Zone

 Amphastar Pharmaceuticals (AMPH) crashed Tuesday after the company received its second Food and Drug Administration rejection since June.

FDA officials declined to approve Amphastar's AMP-002. The company is developing the injectable drug as a generic, but hasn't disclosed what it treats. Amphastar hopes to respond to the FDA's concerns in the third quarter and, potentially, secure a new review date in the first quarter of 2023.

This is the second setback for a prominent generic from Amphastar since June, Needham analyst Serge Belanger said in a report to clients. Earlier, the FDA rejected Amphastar's AMP-015, a hormone to help increase bone mineral density and strength.

"While new products recently launched, additional and more notable product approvals are unlikely until 2023," he said.

In morning trades on today's stock market, the biotech stock tumbled 16.8% near 31.40.

The FDA rejection overshadowed a strong second-quarter report.

During the June quarter, Amphastar earned 39 cents per share, excluding certain items, on $123.5 million in sales. Earnings climbed 86% while sales jumped 21%. Both measures easily beat biotech stock analysts' projection for earnings of 35 cents a share and $118.1 million in sales.

The quarter was driven by strength from lidocaine and epinephrine. Lidocaine is a pain blocker and epinephrine is an injection for unexpected allergic reactions. Sales of both offset seasonal weakness for Amphastar's asthma inhaler, Primatene Mist.

"Based on these trends, and the seasonality around Primatene Mist, we expect sales growth to be flattish in the fourth quarter," Needham's Belanger said. He reiterated his hold rating on the biotech stock, noting its epinephrine is still benefiting from competitors' market shortages.

Amphastar stock is consolidating with a buy point at 42.41, according to MarketSmith.com.

Also late Monday, runaway biotech stock Syndax Pharmaceuticals (SNDX) reported a net loss of 62 cents per share, crushing analysts' call for a 64-cent per-share loss. Syndax doesn't yet have a commercial product.

https://www.investors.com/news/technology/biotech-stocks-amphastar-earnings-syndax-earnings-q2-2022/

CRISPR cut to Equal Weight from Overweight by Barclays

 Target to $88 from $99

https://finviz.com/quote.ashx?t=CRSP&ty=c&ta=1&p=d

Sanofi pauses enrolment in ex-US tolebrutinib trials

 Sanofi has paused recruitment in its international phase 3 trials of BTK inhibitor tolebrutinib for multiple sclerosis, although it says studies aimed at getting US approval are on track to complete on schedule.

The decision to pause recruitment outside the US comes after the FDA’s decision to order a partial clinical hold on phase 3 trials of the drug – one of the main assets of Sanofi’s $3.7 billion buyout of Principia Biopharma – while a safety signal is investigated.

Sanofi said the GEMINI 1 and 2 trials of tolebrutinib in relapsing forms of MS are fully enrolled and  should read out in time to meet its plan of filing for regulatory approval in the US in 2024.

The French pharma group said that while regulators outside the US were happy for other trials in MS and myasthenia gravis to continue after it implemented measures to reduce recruitment of people with pre-existing liver risk factors, it had decided to pause enrolment globally on the advice of its data monitoring committee.

It stressed that the decision was not due to any additional safety findings, and that all patients already in studies will continue to be treated with the drug. It also anticipates providing further information on the safety signal to the FDA by the end of September.

The pause affects the HERCULES trial in non-relapsing secondary progressive MS, the PERSEUS study in primary progressive MS, and URSA in myasthenia gravis

“Patient safety remains our top priority as we continue to investigate the impact of tolebrutinib on liver function during this recruitment pause,” said Sanofi’s head of R&D John Reed in a statement.

“We remain confident in the future of tolebrutinib as a potentially transformative oral treatment option for people living with MS and are working closely with regulatory authorities in order to resume active recruitment within the fourth quarter of 2022,” he added.

Tolebrutinib is one of three clinical-stage BTK inhibitor candidates that Sanofi acquired with the Principia takeover in 2020, and the second to suffer a setback after rilzabrutinib failed a trial involving patients with rare autoimmune skin disorder pemphigus in September 2021.

Sanofi will be anxious not to delay progress with the drug too much, as it is competing with other BTK inhibitors to be first to market for MS.

Among its rivals is Merck KGaA, whose evobrutinib has shown promise in a phase 2 trial in relapsing MS, with 2.5-year efficacy and safety data reported at the American Academy of Neurology (AAN) annual meeting in April.

Phase 3 trials are ongoing, with recruitment recently re-opened as a result of the Russian invasion of Ukraine, which prompted Merck to add extra patients outside these countries. It also amended the trial protocol to be event-driven.

Meanwhile, Roche”s fenebrutinib and Biogen’s orelabrutinib are two other BTK inhibitors in mid-stage testing for MS.

All the BTK inhibitors are designed to be able to cross the blood brain barrier and enter the central nervous system, dampening down the autoimmune response that leads to neuronal damage in MS.

https://pharmaphorum.com/news/sanofi-pauses-enrolment-in-ex-us-tolebrutinib-trials/