Europe likely entering another COVID-19 wave, says WHO and ECDC

 Another wave of COVID-19 infections may have begun in Europe as cases begin to tick up across the region, the World Health Organization and European Centre for Disease Prevention and Control (ECDC) said on Wednesday.

"Although we are not where we were one year ago, it is clear that the COVID-19 pandemic is still not over," WHO's Europe director, Hans Kluge, and ECDC's director, Andrea Ammon, said in a joint statement.

"We are unfortunately seeing indicators rising again in Europe, suggesting that another wave of infections has begun."

WHO's region-wise data showed that only Europe recorded a rise in COVID-19 cases in the week ended Oct. 2, clocking an increase of eight per cent from the prior week.

Public health experts have warned that vaccine fatigue and confusion over available vaccines will likely limit booster uptake in the region.

Millions of people across Europe remain unvaccinated against COVID-19, the WHO and ECDC noted.

They urged European countries to administer both flu and COVID-19 vaccines ahead of an expected surge in cases of seasonal influenza.

"There was no time to lose," the WHO and ECDC said, adding that vulnerable groups, including people over 60 years old, pregnant women and those with co-morbidities, should get vaccinated against both influenza and COVID-19.

https://www.ctvnews.ca/health/coronavirus/europe-likely-entering-another-covid-19-wave-says-who-and-ecdc-1.6105843

Brain disease startup Neumora draws more funding for ambitious research plan

 One of the most richly funded biotechnology startups to launch in recent years now has more money to add to its pot. On Tuesday, Neumora Therapeutics revealed it’s raised $112 million from a battery of pharmaceutical and venture investors to advance its pipeline of brain disease drugs.

The Watertown, Mass.-based biotech emerged from stealth one year ago with $100 million from Amgen as well as $400 million from Arch Venture Partners and more than a dozen other firms.

Neumora focuses on diseases of the brain and central nervous system, or CNS — a notoriously difficult area of research but one that’s drawn increasing investor interest in recent years. The company aims to develop therapies better targeted to specific groups of patients who, while they might share a similar diagnosis with many others, have different factors driving their disease.

New treatments are urgently needed for neurological diseases, said Neumora CEO Paul Berns. But too few have been forthcoming, in part because doctors and researchers have grouped heterogeneous conditions in broad categories.

“We thought we could ultimately break through the heterogeneity issue, which has really stifled true drug innovation in CNS medicines,” Berns said.

The company currently has two drugs in clinical trials: NMRA-140, an oral opioid receptor antagonist for depression in Phase 2 testing; and NMRA-511 for anxiety disorders in a Phase 1 study. Its pipeline is more advanced than biotech startups typically are at this stage, although the company was built from the foundation of several others.

In a statement on the newest fundraising, Neumora referenced five other drug development programs in its pipeline and Josh Pinto, the company’s chief financial officer, noted the company is looking outside its walls, too.

“We didn’t want to necessarily focus on building everything in-house and organically,” said Pinto. “From a pipeline development perspective, we’re focused on mixing both our internal discovery efforts with business development activities so we’ve been able to scale the pipeline quite quickly.”

Among the drugs in its pipeline are treatments for Parkinson’s disease and amyotrophic lateral sclerosis, or ALS. In February, the company licensed a research program from Vanderbilt University in Tennessee that it plans to develop for schizophrenia.

Pinto said Neumora expects to read out results from its Phase 2 study of NMRA-140 by the end of the year.

Neumora will use the new funding to advance its lead drug candidates into the next phases of clinical studies, and for further research on its other drugs for psychiatric and neurodegenerative disorders.

All told, Neumora has now raised more than $650 million in private investment.

“The public markets are ultimately where biotechs have to go to fund large-scale innovation, but we’re really happy that we’re in a very strong position from a balance sheet perspective,” Pinto said.

Arch, which helped build Neumora, participated in the Series B funding. Other investors include Amgen, Mubadala Capital, Polaris Partners and more than a half dozen others.

https://www.biopharmadive.com/news/neumora-series-b-brain-drugs-venture-funding/633717/

New TYK2 inhibitors: a growing race to top Bristol Myers

 When one drugmaker succeeds, many others try to do better.

That’s one reason why a protein called TYK2 has fast become one of the biotechnology industry’s top targets. At least a half dozen startups have set out to develop drugs that block it to better treat autoimmune diseases.

Conditions like psoriasis and arthritis affect millions of people. For years, they have been treated with injectable drugs like AbbVie’s Humira, which are among the sector’s most lucrative products.

Drugmakers have sought to replace them with more convenient oral medicines, but with mixed results. Pfizer, AbbVie and Eli Lilly, for example, each brought to market pills that target a family of proteins known as Janus kinases, or JAKs, which are involved in the body’s immune response. The drugs have proven effective at treating a wide range of inflammatory diseases, yet their use has been curtailed due to safety concerns.

Enter the TYK2, or tyrosine kinase 2 protein. Though part of the broader JAK family, TYK2 is viewed as a potentially safer target by scientists and drugmakers. That thinking was reinforced in September, when the Food and Drug Administration approved Bristol Myers Squibb’s Sotyktu for moderate-to-severe psoriasis without the safety warnings that have limited its JAK-blocking competitors.

Now the race is on to surpass Sotyktu. At least one startup developing a TYK2 inhibitor has launched since Sotyktu’s approval, while two other companies raised fresh funding to push their drugs further along.

Success could mean significant financial gain. Bristol Myers, which is also testing Sotyktu in psoriatic arthritis, lupus, and Crohn’s disease, forecasts yearly sales of Sotyktu could eventually reach as high as $4 billion.

Here’s where things stand.

What are TYK2 inhibitors and how do they work?

TYK2 inhibitors work by blocking the TYK2 protein and the cellular signals that run through it. Those signals can in turn activate other immune proteins and are associated with inflammation.

Disrupting that signaling by targeting TYK2 is viewed as a promising way to tamp down excessive inflammation brought on by autoimmune diseases such as psoriasis, psoriatic arthritis, Crohn’s disease and lupus.

Another part of the attraction of TYK2 inhibitors is they offer a way to target inflammation without also blocking related JAK proteins, the inhibition of which can cause serious side effects.

The first approved JAK inhibitor, known as Jakafi, was discovered by biotech company Incyte and developed for myelofibrosis and graft-versus-host disease. Since then, drugmakers have poured hundreds of millions of dollars into development of JAK blockers for autoimmune conditions, leading to Pfizer’s Xeljanz, AbbVie’s Rinvoq and Eli Lilly’s Olumiant. All three are approved for rheumatoid arthritis, as well as conditions like psoriatic arthritis that are being targeted by TYK2 developers.

But while JAK inhibitors intrigued researchers because of their ability to block multiple inflammatory cytokines, that kind of broad effect has also been their weakness.

What advantages do TYK2 inhibitors have over other treatments?

So far, TYK2 inhibitors haven’t been linked to the serious health problems that have been reported in testing of JAK inhibitors.

In clinical studies, some patients taking the JAK inhibitors developed by Pfizer, AbbVie and Eli Lilly developed infections and blood clots, meriting an FDA warning on the drug’s labeling. Additionally, a study comparing Pfizer’s Xeljanz to drugs like Humira showed a higher rate of cardiovascular complications and cancer. That finding led to the FDA to require JAK inhibitors be used only in patients who cannot take or don’t respond to those drugs.

While infections were observed in testing of Sotyktu, the majority weren’t serious and did not lead to patients discontinuing treatment. The FDA didn’t include boxed warnings of the risk of clotting, cancer or heart complications on Sotyktu’s labeling, either, despite some concerns the agency might consider anti-TYK2 drugs as similar to JAK inhibitors.

Doctors can also prescribe Sotyktu without requiring patients first try biologic drugs. In testing, Sotyktu bested Amgen’s Otezla, an oral treatment for psoriasis that works differently, indicating TYK2 blockers can be potent options for clearing skin, too.

As pills, TYK2 blockers are also more convenient than injectable drugs, such as Humira or newer medicines like Novartis’ Cosentyx, which are widely prescribed.

Which companies are developing TYK2 inhibitors?

Aside from Bristol Myers and Galapagos, another large drugmaker working on a TYK2 inhibitor, a handful of startups have cropped up to break into the field.

One of the splashiest is Priovant Therapeutics, a startup spun out of Pfizer and Roivant Sciences in June with two TYK2-targeting candidates. Pfizer holds a 25% stake in Priovant, which has not raised additional funding.

The most well-funded, Nimbus Therapeutics, has raised at least $400 million in private financing for development of its TYK2 inhibitor and other drug candidates, according to the company. Adding in partnerships and other deals, the company has to date received more than $1 billion, Nimbus company CEO Jeb Keiper recently told BioPharma Dive.

Select list of biotech startups developing TYK2 inhibitors

Company	Lead Investors	Amount Raised
Nimbus Therapeutics	RA Capital Management, BVF Partners and Atlas	At least $400 million
Alumis Therapeutics	Foresite Capital, AyurMaya	$270 million
Neuron23	Westlake Village BioPartners, Kleiner Perkins, Redmile Group, SoftBank	$213.5 million
Sudo Biosciences	Frazier Life Sciences, Velosity Capital	$37 million

SOURCE: Companies

Another company, Alumis, is working on a TYK2 inhibitor as well. Formerly known as Esker Therapeutics, the company raised a Series B round in January that brought its funding total to $270 million.

Ventyx Biosciences went public in 2021 with a $152 million initial stock offering, and in September added another $177 million in financing.

Sudo Biosciences is the latest company to launch, emerging from stealth two weeks after Sotyktu reached market.

The clean label given to Sotyktu has brightened the prospects of would-be competitors.

Furthest along in testing is Priovant, whose lead candidate, brepocitinib, blocks both TYK2 and JAK1. Unlike Bristol Myers and other startups, Priovant isn’t focusing on psoriasis. The company started a Phase 3 study in the spring testing brepocitinib for a rare skin and muscle disorder called dermatomyositis, and is evaluating the drug in lupus as well.

Alumis, meanwhile, began a Phase 2 trial of its drug in plaque psoriasis in late September and said it plans to start more mid-stage studies “in the near future.”

Galapagos has reported results from a Phase 1 trial of its TYK2 inhibitor in psoriasis, and a Phase 2 trial in dermatomyositis is expected to start by the end of 2022. A rival psoriasis drug developed by Ventyx has also read out Phase 1 results.

Other companies are nearing the clinic. Startup Neuron23 is working on a drug candidate that it expects to push into preclinical studies by early 2023, the company said.

Ventyx, Sudo and Nimbus have each claimed their drugs could be more selective and potentially more effective than Sotyktu. They have a ways to go before they can prove that claim with clinical trial data, however.

https://www.biopharmadive.com/news/tyk2-inhibitors-jak-protein-startups-biotech/633635/

Terray and Calico Strike Biotech's Latest R&D Deal Against Age-Related Diseases

 Terray Therapeutics and Calico Life Sciences struck a research and development collaboration Wednesday focused on the development of small-molecule therapeutics for age-related diseases.

The multi-target partnership will pair Terray’s tNova drug discovery and development platform with Calico’s target biology experience. The two companies intend to identify novel therapeutics for people impacted by diseases of aging, including cancer.

The potential targets will be identified by Terray’s tNova platform, an engine the company noted is capable of billions of measurements made with “massive scale and precision.” Once the targets are identified, Calico, an Alphabet company, will then undertake responsibility for clinical development and potential commercialization.

Terray launched earlier this year with $60 million. Terray’s internal programs are aimed at immunology where the company has identified a number of selective molecules. Currently, the internal programs are in the preclinical stage.

The tNova platform generates precise chemical datasets that work alongside artificial intelligence to systematically map biochemical interactions between small molecules and the causes of different diseases. Researchers are then able to rapidly assess the potential efficacy in preclinical research in order to drive them into the clinic.

Jacob Berlin, Ph.D., chief executive officer at Terray, told BioSpace the tNova platform is capable of measuring the interaction of small molecules and targets of interest in a matter of minutes. This allows the research team to refine their exploratory work for affinity and selectivity and hone in on the most promising approaches.

At its core, Berlin said the issue in drug discovery isn’t an algorithm problem, it’s a data problem. To solve that, Terray built the platform to make the tests and iterate them in unsurpassed scale and precision. The platform is designed to power computational learning and reveal new interactions as quickly as possible. It relies on libraries built on reusable chips about the size of a nickel. Each chip holds 32 million different compounds to create the world’s densest microarray technology.

“It’s not about compressing timelines but solving problems that can’t be solved with other technologies. We’ve seen the platform deliver starting points and solutions where others cannot,” he said.

In a brief statement, Jonathan W. Lewis, Calico’s chief business officer, said the collaboration will allow for the discovery of first-in-class therapeutics against age-related diseases.

The number of targets included in this collaboration was not disclosed. Berlin did note Calico is picking the targets in age-related disease and bringing them to Terray for assessment. Once the assessment is complete, Terray will then return the information to Calico, which will then begin development programs, Berlin said.

Terray’s process can shave months off the average industry timeline for optimization and delivery into animal models, Berlin noted.

Terray will receive an undisclosed upfront payment from Calico and be eligible for milestone payments, as well as royalties on any sales.

"Our combined expertise will leverage the scale, precision, and speed of our tNova platform to rapidly discover and advance therapeutics for patients. We’re tackling some really interesting age-related diseases and we have an opportunity to transform people’s health,” Berlin said.

Since its launch, California-based Calico has focused on the development of products and technologies that can extend and control one’s lifespan, as well as target age-related diseases, such as cancer and neurodegeneration.

The company has forged a number of collaborations, including one with AbbVie valued at more than $1 billion. One asset that sprang from that partnership is ABBV-CLS-7262, which is being assessed in the HEALEY ALS Platform Trial. ABBV-CLS-7262 targets eIF2B, which is a key regulator of the integrated stress response, a pathway activated in people with ALS.

https://www.biospace.com/article/terray-and-calico-strike-biotech-s-latest-r-and-d-deal-against-age-related-diseases/

World Muscle Society Congress 2022: Genentech, Fulcrum and Sarepta Present

 The World Muscle Society 2022 Congress is ongoing in Halifax, Canada, with numerous companies presenting cutting-edge research in neuromuscular diseases.

Here’s a look at presentations from Genentech, Fulcrum Therapeutics and Sarepta Therapeutics.

Genentech’s Evrysdi 2-Year Trial for SMA

Genentech, a Roche company, presented new two-year data from the JEWELFISH trial of Evrysdi (risdiplam) in patients with Type 1, 2 or 3 spinal muscular atrophy (SMA).

The results demonstrated the drug improved or maintained motor function while leading to rapid increases in SMN protein levels that were sustained after two years of receiving Evrysdi.

The trial enrolled 174 patients six months to 60 years of age. All had been previously treated with other approved or experimental SMA therapies, including Biogen’s Spinraza (nusinersen).

SMA is a genetic disorder beginning in the central nervous system that affects all the muscle in the body. It is the result of a lack of survival motor neuron (SMN) protein, which is essential for muscle development and movement.

The company notes that JEWELFISH enrolled “the broadest and most diverse patient population ever studied in an SMA trial.” In addition to the range of ages, two-thirds, or 63%, of the participants were diagnosed as having very severe disease, and 83% had scoliosis. About 44% had previously received Spinraza with olesoxime, and 8% received Novartis’ Zolgensma (onasemnogene abeparvovec) with RG7800.

Claudia Chiriboga, M.D., professor of neurology and pediatrics, department of neurology at Columbia University Medical Center, New York, stated the data “reinforces Evrysdi as a meaningful treatment option across SMA populations. The findings add to our confidence when making treatment decisions for previously treated patients in need.”

Fulcrum’s FSHD Study of Losmapimod

Fulcrum Therapeutics announced new data from the open-label extension (OLE) part of its Phase II ReDUX4 trial of losmapimod for treating FSHD, and it will also host a symposium entitled “Measuring Progression in FSHD: Implications for Clinical Trials.”

The data from the OLE support previous results showing the drug modifies FSHD disease progress, preserving or improving muscle function.

The ReDUX4 study enrolled 80 patients ages 18 to 65 with genetically confirmed FSHD1. They were randomized 1:1 to receive 15 mg losmapimod twice a day or placebo. After the initial 48-week period, all patients had the choice to enroll in the OLE segment, where all received losmapimod. Of the 77 patients who completed the 48-week segment, 99% enrolled in the OLE.

The patients who were originally in the placebo arm who crossed over to losmapimod for the OLE and stayed on the drug through 95 weeks demonstrated trends that the disease was slowing or halting progression as measured by reachable workspace (RWS). The patients who were in the drug cohort initially and stayed for the OLE continued to demonstrate slowing or stopping of disease progression and improvement in muscle function, as measured by RWS.

Bryan Stuart, CEO of Fulcrum, emphasized the importance of the data, stating, “The sustained ability to slow or halt the progression of FSHD over two years underscores the significance of our Phase III REACH trial and the potential of losmapimod to be the first approved treatment for FSHD.”

Sarepta Presents Range of Programs Across Portfolio

Sarepta Therapeutics presented new data from across its genetic medicine portfolio, including real-world evidence on eteplirsen in treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.

Sarepta also presented preclinical data from its gene therapy platform in support of the SRP-9001 (delandistrogene moxeparvovec) for treatment of DMD.

From its RNA platform, the company presented interim Phase III ESSENCE data on casimersen in DMD patients amenable to Exon 45 skipping and interim analysis of the long-term observational EVOLVE study of eteplirsen, golodirsen or casimersen in routine clinical practice.

From the company’s gene therapy programs, Sarepta presented analysis of adeno-associated virus (AAV) vector shedding after treating patients with SRP-9001. The company also presented pharmacokinetic/pharmacodynamic modeling data around AAV gene transfer therapy for DMD, as well as the pharmacology and efficacy of SRP-9001 in rat models of DMD.

Sarepta also presented Health Economic Outcomes Research (HEOR) related to DMD treatments.

https://www.biospace.com/article/genentech-fulcrum-and-sarepta-present-findings-research-at-world-muscle-society-congress/

Novartis' Zolgensma Under Fire Again as Nature Retracts 2010 Paper

 Novartis' gene therapy Zolgensma is again under a cloud of doubt after Nature Biotechnology retracted a 2010 article featuring early data on the treatment over data manipulation concerns. 

Two years after the FDA closed its Zolgensma data manipulation investigation, Nature Biotechnology retracted its 2010 article titled, "Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN," noting "issues" regarding data cited in a key figure in the report. Original source data provided earlier this year showed multiple inaccuracies in mouse models that were used to indicate the therapeutic promise.

The error was in a Kaplan–Meier curve that represented the survival of mice with spinal muscular atrophy that received either Zolgensma or a control scAAV9-GFP vector. 

The article's initial data showed that six mice survived for more than 250 days. However, earlier this year, the original data showed that only one of the treated mice lived.

In its retraction statement, Nature Biotechnology said its editorial team is "of the opinion that the extent of the inaccuracies in Fig. 1e and associated text undermines full confidence in the study."

The now-retracted paper was a foundational study that led to the SMA gene therapy treatment being greenlit for in-human studies. Those clinical studies, including the pivotal Phase III STRIVE trial, showed that Zolgensma treated SMA patients with unprecedented survival rates. 

The children dosed with the gene therapy saw improvements in motor function and durable milestone achievement, including an ability to sit up without support.

Nature Biotechnology noted that most researchers listed as authors of the article disagree with the decision to retract. One researcher never responded to the publication's repeated attempts to reach her. 

A Treatment Shrouded in Controversy

The revelation of early data manipulation concerns regarding Zolgensma's early animal studies was first realized in 2019, one year after Novartis acquired Illinois-based AveXis, the creator of the gene therapy, for $8.7 billion. 

Novartis and AveXis notified the FDA about the preclinical data manipulation concerns one month after the gene therapy was approved. When the FDA first revealed the data manipulation, the agency said it was "limited to only a small portion of the product testing data that was contained in the marketing application." 

When the FDA closed its investigation into Zolgensma, the regulatory agency acknowledged that some early data manipulation had occurred during the preclinical testing of the therapy. However, following human clinical studies, the FDA maintained that the spinal muscular atrophy gene therapyZolgensma is safe and effective as a gene therapy treatment for spinal muscular atrophy. At the time, the FDA stated that the revelation of data manipulation did not change its positive assessment of the information from the human clinical trials. 

In its support of the gene therapy, Novartis acknowledged that the assays in question were used for initial product testing but are not currently used for commercial product release. 

In the wake of the data manipulation, Novartis terminated Brian and Allan Kaspar, AveXis' chief scientific officer and head of research and development, respectively. The Kaspars are both founders of AveXis. The Swiss pharma giant placed the blame squarely on their shoulders. 

In its response to the FDA, Novartis said the two brothers "personally manipulated or instructed others to alter some of the preclinical data" that led to the approval of the gene therapy. The company acknowledged the manipulation concerned the recorded deaths of the mice used in preclinical studies, which played a key role in the now-retracted article. 

https://www.biospace.com/article/publication-retracts-2010-zolgensma-paper-for-data-manipulation/

Bayer's Vividion Bets up to $930M for Tavros Oncology Partnership

 Bayer subsidiary Vividion Therapeutics and precision oncology company Tavros Therapeutics entered into a five-year collaboration agreement, valued at up to $930 million, to discover and develop four novel oncology targets.

The deal will see Vividion hand over $17.5 million in cash upfront and commit up to $430.5 million in future payments, depending on the fulfillment of certain preclinical, clinical and commercial milestones.

The Bayer biotech will also have the option to add up to five additional targets to the collaboration, giving Tavros $482 million more in potential earnings. Tavros is also eligible for low-single-digit royalties on certain programs that will come out of the partnership.

Wednesday’s Vividion alliance follows Tavros’ 2020 deal with Zentalis Pharmaceuticals. The deal is meant to broaden the latter’s pipeline with next-generation small molecule candidates, and a 2021 collaboration with OpenBench to identify potential antagonists against an undisclosed cancer target. 

Last month, Tavros closed its second seed round of financing, where it earned $7.5 million.

Tavros CEO and co-founder Eoin McDonnell, Ph.D., told BioSpace the partnership is “an ideal pairing,” in that “it allows Tavros to tap into the ‘undruggable genome’ that otherwise would be inaccessible to us from a draggability standpoint. We see this as a great way to expand the utility of our platform and expand our reach and impact on patients.”

McDonnell added that proceeds from the deal will allow Tavros to grow the team to fulfill their obligations to the partnership and support other internal pipeline efforts.

Tavros and Vividion: 'An ideal pairing’

The collaboration will combine Tavros’ precision oncology platform with Vividion’s chemoproteomic technologies. The Durham, NC-based biotech uses high-throughput functional genomics and sophisticated computational techniques to identify unique weaknesses in tumors, which then forms the basis for more intentional drug development, leading to potentially more effective treatments.

“We harness the power of synthetic lethality and identify ways to take advantage of the genetic alterations that are enabling the tumor to grow,” McDonnell explained. “Tavros’ role will be in providing insights to Vividion on which of the thousands of potential targets that they can drug have the most de-risked and clear clinical paths with defined patient stratification biomarkers.”

Bayer’s San Diego-based subsidiary specializes in finding previously unknown functional pockets on the surface of disease-relevant proteins. Using this information, Vividion can also screen for unique small-molecule compounds that can selectively attack these pockets to therapeutic effect.

Vividion’s approach has so far spotted more than 800 novel functional pockets and has resulted in more than 100 hits with small molecule compounds. 

The potential of this platform to address previously undruggable targets, particularly in cancer and immune diseases, drove Bayer in 2021 to put forth $2 billion in an acquisition deal. At the time, Vividion had been eyeing an initial public offering. However, it decided to forego its plans in favor of the buyout.

https://www.biospace.com/article/bayer-s-vividion-puts-potential-930m-on-the-line-in-tavros-oncology-partnership/