Acceleron sotatercept: positive action in mid-stage pulmonary arterial hypertension studies

• Acceleron Pharma (XLRN -1.8%) announces new data from two Phase 2 clinical trials, SPECTRA and PULSAR, evaluating sotatercept in patients with pulmonary arterial hypertension (PAH).
• Preliminary results from 10 participants in SPECTRA showed that treated patients experienced substantial improvements in a range of hemodynamic measures and exercise tolerance/capacity. Of note was almost a 36% drop in pulmonary vascular resistance, a metric for resistance against blood flow from the pulmonary artery to the heart's left atrium.
• New cardiac and pulmonary function data from PULSAR showed improvements in right ventricular-pulmonary arterial (RV-PA) coupling, which represents the match between the output of the right ventricle (RV) and the resistance of the pulmonary vasculature, and RV function. In January, the company announced that the study met the primary endpoint.
• A 284-subject Phase 3 trial, STELLAR, should launch next month. The primary endpoint will be the change from baseline to week 24 in the 6-minute walk test.
• Sotatercept is a fusion protein that acts as a ligand trap for proteins involved in fibrosis and late-stage erythropoiesis (red blood cell production). The company says it can potentially restore vascular homeostasis (stable equilibrium).
• PAH-related tickers: Moderna (MRNA +0.6%), United Therapeutics (UTHR +0.6%), VIVUS (VVUS),  Bellerophon Therapeutics (BLPH +2.6%), Liquidia Technologies (LQDA -5.7%), PhaseBio Pharmaceuticals (PHAS -1.1%), Johnson & Johnson (JNJ +1.0%), Gilead Sciences (GILD +1.4%), Tenax Therapeutics (TENX +0.8%)
• https://seekingalpha.com/news/3636208-accelerons-sotatercept-shows-positive-action-in-mid-stage-pulmonary-arterial-hypertension
  

Silverback tees up $100M IPO to push ADCs for cancer, Hep B

Silverback Therapeutics is on a roll. After banking more than $160 million in venture capital this year, the immuno-oncology biotech filed on Tuesday to raise up to $100 million in its Wall Street debut. The funds will bankroll early-phase trials for its lead antibody-drug conjugate and preclinical work for its other programs.

The lead program, SBT6050, targets TLR8 in solid tumors that express the HER2 gene. The antibody makes sure the payload is delivered only to the HER2-expressing cancer cells, while the TLR8 agonist activates immune cells called myeloid cells to attack the tumor and “reprogram” the tumor microenvironment.

It’s an improvement on previous efforts with TLR8 agonists, which must be given systemically and cause side effects that can limit the amount of drug a patient can take, Valerie Odegard, Ph.D., Silverback president and chief scientific officer, in a previous interview.

Silverback plans to fund the ongoing phase 1 study with the IPO proceeds, including an expansion into specific tumors and a phase 1b study in combination with a PD-1 inhibitor.

The funds will also push a second program toward an IND filing in the fourth quarter of 2021 and into phase 1, according to a securities filing. The treatment, SBT6290, also targets TLR8, but in solid tumors expressing Nectin4 rather than HER2.

Finally, the IPO will fuel a third TLR8-targeting program, but not in oncology. The ADC combines the payload with a monoclonal antibody targeting ASGR1 for the treatment of chronic hepatitis B infection. It hopes to file an IND for the program, SBT8230, in the second half of 2022, according to the filing.

Beyond Hep B, Silverback is also working on treatments that “localize therapies to modulate important pathways in additional oncology and fibrosis indications,” the company said in the filing.

Silverback's work is based on its ImmunoTAC platform, which attaches antibodies to small molecules that adjust the immune system, instead of cytotoxic, or cell-killing, drugs. This approach allows Silverback to target pathways that have previously been out of reach for small molecules because of their side effects.

The IPO comes six months after biopharma veteran Laura Shawver, Ph.D. took the company’s helm and joins an ever-growing list of biotech companies who have gone public, or sought to do so, during the COVID-19 pandemic.

https://www.fiercebiotech.com/biotech/silverback-tees-up-100m-ipo-to-push-adcs-for-cancer-hep-b

Cleveland Clinic team draws link between COVID-19 protection, sleep aid melatonin

The idea of repurposing existing medicines as a fast approach to containing COVID-19 is still popular, even as vaccines and antibodies designed to combat the disease are starting to gain steam. Scientists at the Cleveland Clinic are among those examining existing compounds as possible treatments for the coronavirus, and now they're suggesting that the popular over-the-counter sleep aid melatonin may be a possible option in treating the disease.

The researchers used an artificial intelligence tool to analyze data from 26,779 individuals in the Cleveland Clinic’s COVID-19 registry, of whom 8,274 tested positive for SARS-CoV-2, the novel coronavirus that causes COVID-19.

They found that people who were taking melatonin were 28% less likely to test positive for SARS-CoV-2, after adjusting for factors such as age, sex and underlying diseases, according to results published in the journal PLOS Biology.

The melatonin effect was more pronounced in African Americans, with a reduction of 52%. In White Americans, the number was 23%.

Melatonin is a hormone released by the body that regulates the sleep-wake cycle. As a dietary supplement, it’s commonly used to help manage insomnia and jet lag.

Besides melatonin, the Cleveland Clinic team also found that the beta-blocker carvedilol, sold under the brand Coreg for high blood pressure and other heart diseases, was associated with a 26% reduction in a person’s chance of testing positive for SARS-CoV-2.

Some members of the same Cleveland Clinic team previously pinpointed melatonin among a group of drugs they suggested might work for COVID. They showed that melatonin and mercaptopurine might work as a good combo for COVID. Those findings came from a pharmacology-based platform that used a technique called “network proximity analysis.” It was based on the idea that some proteins involved in other diseases might hold “proximity” to a virus’ interaction with the host.

The researchers applied the same method in the current study to shed a light on clinical manifestations and pathologies common between COVID-19 and 64 other diseases. Closer proximity would mean a higher likelihood of pathological associations between the diseases.

They found that proteins involved in respiratory distress syndrome and sepsis were highly connected with SARS-CoV-2. That wasn’t a surprise given that the two disorders can also cause death in patients with severe COVID-19.

“This signals to us that a drug already approved to treat these respiratory conditions may have some utility in also treating COVID-19 by acting on those shared biological targets,” Feixiong Cheng, Ph.D., the study’s senior author, said in a statement.

Overall, they identified close network proximity to SARS-CoV-2 proteins from inflammatory bowel disease, attention deficit hyperactivity disorder, as well as pulmonary diseases such as COPD. Using a computational model, they identified 34 drugs that were significantly proximal to two or more SARS-CoV-2 host protein sets.

A team at Columbia University has also linked melatonin with increased likelihood of clinical improvement among critically ill COVID-19 patients on intubation or mechanical ventilation.

The sleep-promoting supplement was also reportedly used by President Donald Trump during his COVID-19 infection, though it’s not clear if he was taking it specifically to treat the disease or as part of his daily nutrition routine.

Despite melatonin emerging as a top pick from the Cleveland Clinic registry, Cheng cautioned that larger, randomized control trials would be needed before the supplement could be widely adopted in the treatment of COVID-19.

Cheng added that AI-based approaches to analyzing COVID-19 patient registries should be embraced in the effort to find effective treatments for the disease. “Recent studies suggest that COVID-19 is a systematic disease impacting multiple cell types, tissues and organs, so knowledge of the complex interplays between the virus and other diseases is key to understanding COVID-19-related complications and identifying repurposable drugs,” Cheng said. “Our study provides a powerful, integrative network medicine strategy to predict disease manifestations associated with COVID-19 and facilitate the search for an effective treatment.”

https://www.fiercebiotech.com/research/does-sleep-aid-melatonin-work-as-a-covid-19-treatment

Janssen combines Darzalex with COVID-19 drug in new multiple myeloma submission

Janssen has submitted a new combination regimen for its blockbuster multiple myeloma drug Darzalex for approval with the FDA and EMA, hoping to give the treatment another edge over emerging competitors.

Specifically, the combination utilises the subcutaneous formulation of the drug, Darzalex Faspro (daratumumab/hyaluronidase) with Celgene’s multiple myeloma drug Imnovid (pomalidomide) and dexamethasone – which has gained new fame this year as one of the few treatments available for COVID-19.

Darzalex Faspro was approved earlier this year and cuts the drug’s dosing time to just a few minutes from hours.

Janssen is seeking approval for use in the treatment of patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. 

The submission is supported by data from the phase 3 APOLLO study, which showed significantly longer progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma who received the combination compared with pomalidomide and dexamethasone alone. 

Analysts think the shorter treatment of Darzalex Faspro time could become a particularly important advantage over the established formulation during the coronavirus pandemic, when getting access to healthcare has become more difficult under lockdown, and this combination could further boost the drug’s profile.

In September Janssen also submitted the formulation for approval in the rare and potentially fatal disease light chain amyloidosis.

The original IV version of Darzalex has been a big earner for J&J ever since it was first approved in 2015 as a fourth-line myeloma therapy, growing rapidly on the back of successive approvals in earlier lines of therapy – including most recently in newly-diagnosed patients.

The product brought in almost $3 billion in sales last year, and shows no signs of slowing down, growing another 49% to reach $937 million in the first three months of 2020. J&J licensed the drug from Danish biotech Genmab in 2012 in a deal valued at $1.1 billion.

Last month however saw the approval of its first direct competitor – Sanofi’s anti-CD38 antibody Sarclisa (isatuximab) – which was given the nod by the FDA as a third-line therapy for myeloma.

Sanofi’s drug is delivered intravenously and – according to Sanofi – has simpler, two-hour dosing that improves on the current Darzalex formulation, although analysts think the availability of J&J’s new subcutaneous version will likely cancel out that advantage.

Last year, J&J licensed a follow-up to Darzalex from Genmab, HexaBody-CD38, that it says could be used in Darzalex-resistant patients as well as in other cancer indications beyond myeloma, in the hope of extending its anti-CD38 franchise.

https://pharmaphorum.com/news/janssen-combines-darzalex-with-covid-drug-in-new-multiple-myeloma-submission/

Heron Therapeutics resubmits US application for HTX-011 in postop pain

• Based on outcome and final minutes of a Type A End- of-Review meeting with FDA in September, Heron Therapeutics (NASDAQ:HRTX) has refiled marketing application with the FDA seeking approval for HTX-011 for management of postoperative pain.
• The submission is classified as a Class 2 resubmission, which means that the FDA can take up to 6 months to review the new information.
• Earlier in June this year, the FDA rejected the application citing need for additional non-clinical information. There are four non-clinical issues, three relate to confirming exposure of excipients in preclinical reproductive toxicology studies and the fourth relates to changing the manufacturing release specification of the allowable level of an impurity.
• Heron generated data showing that peak plasma levels of excipients in reproductive toxicology studies are >50- to >200-fold higher than the levels observed in patients receiving the highest dose of HTX-011. The FDA also agreed with the change to the manufacturing specification proposed by Heron to address the concern.
• https://seekingalpha.com/news/3636147-heron-therapeutics-resubmits-us-application-for-htxminus-011-in-postop-pain
  

Musk questions accuracy of rapid coronavirus antigen tests

• "Something extremely bogus is going on. Was tested for covid four times today. Two tests came back negative, two came back positive. Same machine, same test, same nurse. Rapid antigen test from BD," Elon Musk wrote on Twitter, likely referring to Becton Dickinson's (NYSE:BDX) rapid antigen test.
• Back in September, Becton Dickinson said it was investigating reports from U.S. nursing homes that its rapid coronavirus testing equipment was producing false-positive results, but did not respond to a request for comment following the latest news.
• The FDA has also issued a letter to alert clinical laboratory staff and health care providers that false positive results can occur with antigen tests.
• "For example, a test with 98% specificity would have a positive predictive value (true positives) of just over 80% in a population with 10% prevalence, meaning 20 out of 100 positive results would be false positives."
• "The same test would only have a PPV of approximately 30% in a population with 1% prevalence, meaning 70 out of 100 positive results would be false positives. This means that, in a population with 1% prevalence, only 30% of individuals with positive test results actually have the disease."
• "At 0.1% prevalence, the PPV would only be 4%, meaning that 96 out of 100 positive results would be false positives."
• https://seekingalpha.com/news/3635981-musk-questions-accuracy-of-rapid-coronavirus-antigen-tests
  

Welltower cut to In Line after recent outperformance: Evecore ISI

• Evercore ISI analyst Steve Sakwa downgrades Welltower (NYSE:WELL) to In Line from Outperform after the stock rallied almost 16% on the positive news on Pfizer/BioNTech's COVID-19 vaccine candidate and the emergency use authorization of Eli Lily's antibody treatment for the virus.
• "While we do expect senior housing to rebound off depressed levels, particularly given the demographic wave of baby boomers turning 80 beginning to take hold and new supply shut down, we are moving to the sidelines on WELL for the immediate term after this significant outperformance," Sakwa writes.
• He expects near-term market volatility due to the increasing COVID cases and near-term economic uncertainty.
• Still, he'd look for an opportunity to be more constructive on the stock on a potential pullback.
• Lifts price target to $64 from $60.
• His recommendations on three other healthcare REITs — Community Healthcare Trust (NYSE:CHCT), Healthpeak Properties (NYSE:PEAK), and Ventas (NYSE:VTR) remain at In Line; boosts price targets on CHCT to $52 from $51, PEAK to $31 from $30, and VTR to $45 from $43.
• https://seekingalpha.com/news/3636080-welltower-downgraded-to-in-line-after-recent-outperformance-evecore-isi