Homology Publishes on System for Delivery of Genetic Medicines to Brain, Heart and Muscle

  Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines company, announced today the peer-reviewed publication of data showing that AAVHSC16, one of the capsids in its family of 15 naturally occurring AAVHSCs, demonstrated low levels of tropism to the liver while maintaining robust distribution to the central nervous system (CNS) and peripheral organs following a single I.V. administration in preclinical models. The Company believes that its unique properties, with high levels of tropism to the brain, heart and muscle, and no elevations in liver enzymes, could make AAVHSC16 an attractive capsid for new disease indications with Homology’s genetic medicines platform.

“Our ongoing efforts to fully characterize our family of 15 naturally occurring AAVHSCs as it relates to biodistribution, tissue tropism and the role different features of the capsids play, continues to reveal their unique profiles that allow us to best select capsids for different diseases,” said Albert Seymour, Ph.D., President and Chief Scientific Officer of Homology Medicines. “In the case of AAVHSC16 with its ability to reach key tissues without targeting the liver in preclinical models, we can potentially expand into additional disease areas where we want to deliver to the CNS, cardiac tissue, or muscle while avoiding exposure in the liver. By continuing to publish our discoveries about the unique structure and function of our AAVHSCs, we believe we can contribute to the field’s greater understanding and development of AAV-based therapies that will ultimately benefit more patients.”

Homology’s AAVHSC capsids differ from each other by one to four amino acids, resulting in differences in biodistribution and transduction efficiencies. As described in the manuscript, AAVHSC16 has two unique amino acids, 501I and 706C, in addition to 505R that is shared across six AAVHSC serotypes. A series of experiments demonstrated that these amino acids contribute to AAVHSC16’s unique properties, which include significantly reduced liver tropism compared to other AAVs, no liver enzyme elevations, and high tissue tropism to the CNS and other peripheral organs. Specifically, these data demonstrated:

https://www.biospace.com/article/releases/homology-medicines-announces-peer-reviewed-publication-on-novel-discovery-of-aavhsc-with-robust-distribution-to-the-central-nervous-system-and-peripheral-organs-with-low-affinity-for-the-liver/

AstraZeneca to buy biotech firm TeneoTwo for up to $1.27 bln

 AstraZeneca agreed to acquire biotechnology firm TeneoTwo Inc in a deal worth up to $1.27 billion on Tuesday, in a move to bolster its roster of therapies to treat blood cancers.

At the heart of the deal is the U.S.-based company's early stage experimental treatment for a form of Non-Hodgkin's lymphoma, a type of cancer that involves the growth of abnormal white blood cells that can lead to the emergence of tumours.

The Anglo-Swedish drugmaker - whose key blood cancer drug Calquence generated sales of more than $1.2 billion last year - plans to acquire all outstanding equity of TeneoTwo for an upfront payment of $100 million, with additional milestone-related payments of up to $1.17 billion.

TeneoTwo's experimental drug, TNB-486, belongs to a class of bispecific antibodies that are engineered to redirect the immune system to recognise and kill cancer cells.

It is currently in a phase 1 trial in patients with B-cell non-Hodgkin's lymphoma, who have received 2 or more previous lines of therapy.

The transaction is likely to close in the third quarter of this year and is not expected to impact AstraZeneca's 2022 outlook, the London-listed company said.

TeneoTwo Inc was spun off from Teneobio, which was bought by U.S. biotechnology company Amgen last year.

https://finance.yahoo.com/news/1-astrazeneca-buy-biotech-firm-064117732.html

Queen Elizabeth’s job duties rolled back after ‘alarming’ health concerns

 In recent months, the Queen has been sitting out important events due to ongoing mobility issues. But now her job has officially been scaled back amid those health concerns.

The monarchy’s annual report, which was released last week, revealed that Queen Elizabeth II’s role as head of state has been tweaked from 13 bulleted points to a less specific description. And the duties the 96-year-old “must fulfill” have also been reduced, according to the Sunday Telegraph. (The Post has reached out to the Queen’s press office for comment.)

It’s the first time in more than a decade that there have been formal changes made to her job description. And it’s an acknowledgement of the long-reigning monarch’s health issues.

For months, the Queen, who lost her husband Prince Philip last April, has been sitting out of high-profile events and ceding some commitments to her family. In May, Prince Charles formally opened Britain’s Parliament. It was the first time in nearly 60 years that his mother did not attend the ceremony.

The Queen accessorizes her lavender outfit with a cane at the annual Holyrood week in Scotland last week.

AFP via Getty Images

Last month, the Queen also missed the first day of Royal Ascot because of mobility issues, and during her Platinum Jubilee celebration she was absent from a church service due to “discomfort.” She then appeared in the closing parade via hologram. The proud royal also used a cane for an official portrait during the Order of the Garter service at St. George’s Chapel in Windsor Castle in June.

Last month, royal expert Daniela Elser penned an op-ed for Australian outlet News.com.AU, saying images of the queen greeting New South Wales Governor Margaret Beazley in the UK were “nothing short of alarming.”

Queen Elizabeth II with her son, Prince Charles, who has been taking on more of her duties.

Jane Barlow-PA/POOL supplied by

The 96-year-old Queen last week in Scotland.

Getty Images\
Elser compared the photos to those taken nearly a year ago.

“The difference is truly startling,” Elser wrote. “In the intervening 12 months, Her Majesty would appear to have become markedly more stooped, much thinner and overall appears to have shrunk.”

However, last week, she visited Scotland for her annual Holyrood week, which celebrates the nation’s culture, in an eye-catching monochromatic lavender ensemble.

https://nypost.com/2022/07/04/queen-elizabeths-job-duties-rolled-back-after-health-concerns/

Wuxi Biologics takes step to getting off US 'unverified' trade list

 Wuxi Biologics, a Chinese company that makes ingredients for AstraZeneca's COVID-19 vaccine, may be a step closer to being taken off a U.S. trade list that it landed on five months ago, wiping HK$77 billion($9.9 billion) off its market value.

Chinese authorities allowed a U.S. export control officer to conduct inspections of at least one company in the city of Wuxi last week, a U.S. Commerce Department official said.

The official declined to identify the company or companies involved, but a person familiar with the matter told Reuters a check was conducted last week at Wuxi Biologics.

If the U.S. deems the check favorable, it could be removed from the list.

The company did not respond to requests for comment.

Wuxi Biologics units in Wuxi and Shanghai were among 33 entities added to the U.S. Commerce Department's "Unverified List" in February. The company was one of only two added to the list with addresses in Wuxi.

The United States placed the entities on the list because it could not conduct on-site inspections to verify information related to them and U.S. items shipped to them.

The resumption of inspections is seen by the United States as a positive development amid increased tensions with China over a range of issues, including the U.S. blocking of imports linked to forced labor in China and the possible delisting of Chinese companies that don't meet audit requirements.

Last week, there also were renewed threats to shut down SMIC, China's top chipmaker, if it is found to be supplying Russia in violation of U.S. export controls.

"I do have some good news," the Commerce Department official, who could not be identified publicly, told a conference on export controls in Washington on Thursday.

"We were able to get some end-use check movement this week in Wuxi."

The official added that hopefully a U.S. export control officer would be able to go into another province, Anhui, in the coming weeks, though that could be delayed by fresh COVID-19 outbreaks.

U.S. inspections of Chinese companies require approval and scheduling by China's commerce ministry, the U.S. official said.

China's zero tolerance COVID-19 protocols account for most of the delay over the last couple of years, though there were some opportunities to have conducted checks, the official said.

"Covid aside, it's really dependent on them to agree to schedule the pending end-use checks that we have," the official said.

China's commerce ministry did not respond to a request for comment.

In February, U.S. Assistant Commerce Secretary Matthew Axelod said the additions to the list "signal to the PRC government the importance of their cooperation in scheduling end-use checks."

But China's Ministry of Commerce slammed the development and said Washington should correct its "wrongdoings," return to the track of cooperation and contribute more to the global economic recovery.

During an investor day on June 16, Wuxi Biologics said that it hoped to see the "unverified list" issue resolved for at least one of its units by September, and for the other by the end of the year.

The company said it had initially expected an inspection in April, which was disrupted by COVID-19. It said it had not seen a significant impact on actual operations from being added to the list.

U.S. exporters can engage with parties on the unverified list, but are required to conduct additional due diligence before they can ship goods to them, and may need to apply for more licenses.

https://www.channelnewsasia.com/business/exclusive-wuxi-biologics-takes-step-getting-us-unverified-trade-list-2789576

Sarepta Pipeline No One is Talking About

 Few drug developers are more ambitious than Sarepta Therapeutics  (SRPT) - Get Sarepta Therapeutics Inc. Report. The company boasts 34 pipeline programs spread across gene therapy, gene editing, and tools based on RNA. Although the company is primarily focused on muscle disorders such as Duchenne muscular dystrophy (DMD), it has recently branched out into diseases impacted by genes in the liver and brain. If its three approved drug products continue to ramp revenue, then the business could reach profitability near the middle of the decade.

Despite the breadth of the pipeline and portfolio, Wall Street analysts have trained investors to focus their attention on a single program: a gene therapy for DMD named SRP-9001. On the one hand, the program is financially important. Sarepta Therapeutics licensed international development rights to Roche  (RHHBY)  for $1.15 billion in upfront cash. It could also earn up to $1.7 billion in milestone payments, plus royalties on future sales.

On the other hand, biotech stocks that become too attached to a single pipeline program expose investors to significant volatility. That's become a headache in recent years, as preliminary clinical data for SRP-9001 have underwhelmed at worst and been mixed at best.

Investors have no control over stock volatility. However, those who can keep their emotions in check might be able to see another major opportunity hiding in plain sight.

A Next-Generation Approach to Proven Tech

Sarepta Therapeutics is developing a next-generation version of the tool that led to its three drug approvals from the U.S. Food and Drug Administration (FDA). Preliminary clinical data suggest the first program could be 18x more effective than an existing drug on a key metric.

• Prior-generation tool: The company's three FDA-approved products are based on RNA tools called morpholinos. If we take the nerdy chemical name of the molecules, then they earn the abbreviation PMOs.
• Next-generation tool: A part of the company's RNA pipeline is based on next-generation morpholinos. These molecules earn the abbreviation PPMOs.

Both PMOs and PPMOs work by blocking cells from reading instructions to make proteins. If the disrupted reading instructions code a mutation, then the cell might be able to create functional protein. That could have therapeutic potential in diseases caused by simple, short mutations resulting in faulty proteins that don't do their job.

For example, DMD is caused by mutations in the dystrophin gene. Dystrophin is a protein that helps muscles function properly. Individuals with DMD have one of several mutations that result in dysfunctional dystrophin protein, which results in progressively worse muscle, heart, and lung function.

Sarepta Therapeutics designed PMO drugs to skip over instructions for making mutated dystrophin in three separate mutations. Although each led to increases in production of working dystrophin proteins, the results were controversial. Patients receiving Exondys 51 achieved dystrophin levels that were 1% of normal.

Despite debate in the scientific community, the company earned multiple approvals. The three drugs earned combined product revenue of $612 million in 2021, which is expected to exceed $1 billion in 2023.

That's what makes the emerging PPMO platform so exciting. The next-generation tools make chemical modifications to a traditional morpholino that increase potency and reduce side effects. The lead drug candidate, SRP-5051, has delivered impressive results in clinical trials to date.

• Patients receiving the highest dose of SRP-5051 block an average of 10.5% of the mutated instructions after 12 weeks of treatment. That represented an 18x increase compared to 24 weeks of treatment with Exondys 51.
• Patients receiving the highest dose of SRP-5051 achieved an average dystrophin production that was 6.5% of normal after 12 weeks of treatment. That represented an 8x increase compared to 24 weeks of treatment with Exondys 51.
• Patients receive SRP-5051 through an intravenous (IV) infusion once every four weeks, compared to a weekly IV infusion for Exondys 51.

Sarepta Therapeutics thinks SRP-5051 can achieve even better outcomes over longer periods of time. Simulations from the company suggest the PPMO compound could achieve dystrophin levels that are 14% of normal after 96 weeks of treatment. That compares to just over 1% for Exondys 51.

It's important to acknowledge two things. First, the PPMO portfolio's success would come at the expense of currently-approved drug products. There would likely be some cannibalization of revenue, but the increased effectiveness and reduced dosing schedule could also lead to greater patient access and faster growth. In other words, PPMOs could have much higher peak annual revenue than their predecessors.

Second, there's one worrisome side effect from SRP-5051. Patients receiving the highest dose tested in ongoing clinical trials have developed hypomagnesemia, or low levels of magnesium in the blood. This should be relatively easy to treat with monitoring and magnesium supplementation, but the FDA did recently place a clinical trial on hold to gather more data and potentially recommend a change in the study design. 

The worst-case scenario is that hypomagnesemia is caused by kidney damage. The kidneys process and clear PPMOs from the body, but their unique chemical modifications -- the very engineering decisions that make them a next-generation morpholino to begin with -- could also cause them to clump together inside these essential organs. So far, other key measurements of kidney function appear normal in patients, but it's something for investors to keep an eye on nonetheless.

Keep an Eye on PPMOs at Sarepta Therapeutics

Investors have been trained to focus on the gene therapy program known as SRP-9001, but the PPMO platform represents a significant economic opportunity. The emerging tools apply important upgrades to a proven, FDA-approved therapeutic modality. The result could be a portfolio of safer, more effective, and more convenient treatment options for individuals with DMD. Importantly, commercializing PPMOs could maintain Sarepta Therapeutics' lead in DMD treatment, especially if gene therapies and gene editors from the company's own pipeline or the competitive landscape prove less effective in upcoming clinical trials.

https://www.thestreet.com/investing/sarepta-therapeutics-ppmo-platform

Cruise Line Drops Pre-Cruise Covid Testing Rule

 The major cruise lines walk a delicate line. They need to take the actual steps required to keep their passengers safe and they also need to be aware of how things look to the outside public. It's a mix of practical covid policy balanced with covid theater.

You have to do the right thing -- and Royal Caribbean International (RCL) - Get Royal Caribbean Group Report, Carnival Cruise Lines (CCL) - Get Carnival Corporation Report, and Norwegian Cruise Lines (NCLH) - Get Norwegian Cruise Line Holdings Ltd. Report have been doing that with very meticulous protocols-- but you also have to show the general public you're taking the pandemic seriously. The cruise industry has been under the microscope of both public perception and the Centers for Disease Control (CDC) since covid first appeared.

That's not because you're likely to get infected on a cruise ship than at a concert, sporting event, theme park, restaurant, or any other crowded space. It's because when you get sick at one of those locations nobody can pinpoint the source of your infection

Cruises last from 3 days to 7 days or even longer and that means that some people will get covid onboard and that will be blamed on the cruise industry. To mitigate that Carnival, Royal Caribbean, and Norwegian have rigid protocols in place that require passengers 12 and over to be vaccinated as well as pre-cruise covid tests taken no more than two days before your cruise leaves.

Once cruise line has dropped that testing requirement (at least on a few sailings) and that could lead Royal Caribbean, Carnival, and Norwegian to follow. 

Sina Schuldt/picture alliance via Getty

Holland America Drops Some Covid Testing

As the largest cruise lines sailing from the U.S., Royal Caribbean, Carnival, and Norwegian don't want to be the first to make major covid policy changes. They acted more or less in tandem when it came to loosening, then dropping mask rules and have generally followed the lead of the CDC, even when that agency's rules became optional.

Now, Holland America cruise line has dropped pre-cruise covid testing on a handful of cruises. It's a minor move, but it does provide cover and precedent for Royal Caribbean, Carnival, and Norwegian to eventually do the same.

"Holland America Line becomes the first US-based cruise line to remove testing for select cruises. Unfortunately for those taking a cruise from the United States, the new protocols are only in place for certain cruises onboard the company’s latest ship, the Rotterdam, in Europe," Cruisehive reported.

https://www.thestreet.com/investing/cruise-line-drops-pre-cruise-covid-testing-rule

Cancer drug delays muscular dystrophy progression in mice

 A new surprise discovery could hold big implications for muscular dystrophy patients, with researchers finding that an existing cancer drug may delay progression of the hard-to-treat disease.     

Scientists at the University of British Columbia’s (UBC's) School of Biomedical Engineering found that suppressing a colony-stimulating factor 1 receptor (CSF1R)—a drug class already used in clinical trials to treat rare forms of cancer—increased muscle resilience and helped slow the progress of Duchenne muscular dystrophy (DMD) in a mouse model.

The new findings, published June 29 in Science Translational Medicine, caught the Canadian research team by surprise. The scientists initially set out to study the role of resident macrophages—a type of white blood cells—in muscle regeneration.

A model from mice with DMD revealed that CSF1R inhibitors, which deplete resident macrophages, made muscle fibers more resistant to the kind of tissue damage characteristic of muscular dystrophy. After the inhibitor drug was administered, fast-twitch muscle fibers sensitive to damage (type IIB fibers) started to transition to a slower-twitch type more resistant to damage caused by muscle contractions (IIA/IIX fibers).

“The results were actually quite dramatic,” Farshad Babaeijandaghi, M.D., a postdoctoral fellow at UBC and first author on the study, said June 29. “The improvement in muscle resiliency was profound.”  

Within a few months, the mice receiving treatment were able to perform physical tasks such as moderate running on a treadmill with less muscle damage than the mice without treatment.   

Further studies are needed to understand whether CSF1R is effective and safe in humans with DMD, but the authors expressed hope that a new treatment is soon on the horizon, especially when considering the multiple short-term clinical studies that have already shown the class of drug is safe for people.

“While this is not a cure, it could significantly delay disease progression, helping people stay mobile and out of wheelchairs for longer,” said senior author Fabio Rossi, M.D., professor at UBC’s school of biomedical engineering and department of medical genetics. “It could be used in conjunction with other treatments and emerging gene therapy approaches aimed at the genetic defect.”

The scientists aren’t the first to test CSF1R inhibitor in hard-to-treat diseases beyond cancer. Biotech Elixiron Immunotherapeutics aims to test out its lead asset, EI-1071, for patients with Alzheimer’s. The drug aims to leverage the CSF1R inhibition’s anti-macrophage ability to treat neuroinflammation.

https://www.fiercebiotech.com/research/dramatic-surprise-discovery-finds-cancer-drug-delays-muscular-dystrophy-progression-mice