Category Archives: Molecular Medicine

Antibody-drug conjugates (ADCs) illustrate the continued evolution of treatment options across HER2-positive breast cancer, hormone receptor (HR)positive, HER2-negative breast cancer, and triple-negative breast cancer (TNBC). Following the success of fam-trastuzumab deruxtecan-nxki (Enhertu) in the phase 3 DESTINY-Breast03 trial (NCT03529110), other ADCs are likely to enter the treatment fold in the future, according to William J. Gradishar, MD.

What we will likely have in the coming years is a series of ADCs that we can use that will extend the duration of therapy and options for patients, Gradishar said in an interview with OncLive following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

In the interview, Gradishar spoke about the expansion of ADCs across subsets of breast cancer, along with emerging treatment options within each space. Gradishar is the Betsy Bramsen professor of Breast Oncology, a professor of medicine (hematology and oncology) at the Feinberg School of Medicine, and chief of Hematology and Oncology in the Department of Medicine at Northwestern Medicine.

Gradishar: In the HER2-positive space, there have been major advances in the past many years. It seems like every year we get new drugs, and thats a great thing for [clinicians] and patients [because] its improving patient outcomes. I focused on the evolving landscape in metastatic HER2-positive breast cancer and the emergence of ADCs. [This includes] not only ado-trastuzumab emtansine [T-DM1; Kadcyla] but also the emergence of trastuzumab deruxtecan, as well as the results from other trials and new drugs that are still in development.

What this is showing us is that we have a series of drugs to try. Even when a patient develops disease progression on one [treatment], theres the probability that not only will we have [another agent] to offer [patients] but we have the high probability that theyll benefit from it.

The DESTINY-Breast03 trial showed that trastuzumab deruxtecan is an excellent drug that can be used after patients progress on a [pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel] regimen, so T-DM1 will likely get moved back [in treatment sequencing].

I covered other ADCs that are in development, including the results of the phase 3 TULIP trial [NCT03262935] with vic-trastuzumab duocarmazine, which looked better than alternative options that were used for standard of care.

The other area that I talked about was new TKIs, focusing on the phase 2 HER2CLIMB trial [NCT02614794] with tucatinib [Tukysa]. [I discussed] the results of the overall trial, which showed a superior outcome for patients getting [tucatinib, trastuzumab, and capecitabine (Xeloda)] compared with trastuzumab and capecitabine [with placebo]. [I specifically addressed] the enhanced benefits seen in patients with brain metastases. This is the first trial that focused on that subset of patients, where its shown that including tucatinib had a marked effect on central nervous system [CNS] progression-free survival [PFS] and overall survival [OS] in those patients.

There are anecdotes with other HER2-directed therapies for CNS brain metastases, but [tucatinib] is one of the most compelling stories so far. Trastuzumab deruxtecan is starting to develop some data [in patients with brain metastases], but [data] are clearly the most robust for tucatinib in this setting.

The final thing I talked about was subcutaneous trastuzumab/pertuzumab, which is an option for patients who are getting [intravenous] trastuzumab/pertuzumab. [These 2 treatment administrations] are equally effective [with] no new toxicities. [The subcutaneous administration adds] an element of convenience, both in terms of time in the chair and [length] of infusion. That is a good option for patients.

One [area I discussed] was ADCs, in this case, sacituzumab govitecan-hziy [Trodelvy], which is an ADC that targets TROP2. [Previous] data from the phase 3 ASCENT trial [NCT02574455] demonstrated that sacituzumab govitecan was superior to alternative chemotherapy options. The effect was seen regardless of [low, medium, or high] TROP2 expression. Patients who received sacituzumab govitecan had a better outcome, regardless of whether they harbored a BRCA mutation.

Where we must consider our decision making is in patients who are PD-L1 positive. In patients who are PD-L1 positive, we would consider immunotherapy. There are data showing that pembrolizumab [Keytruda] added to chemotherapy improves overall outcomes for patients with a combined positive score greater than 10. Most [clinicians] would proceed with immunotherapy first for a patient with metastatic TNBC. Until it stops working, [immunotherapy] would continue. However, when it does [stop working], a drug such as sacituzumab govitecan could be considered for lines of therapy beyond immunotherapy.

In patients with early disease, the phase 3 KEYNOTE-522 trial [NCT03036488] demonstrated that neoadjuvant chemotherapy plus pembrolizumab vs chemotherapy alone enhanced not only the pathological complete response rate, but, with long follow-up, event-free survival [EFS]. In the preoperative setting, patients do not need to be PD-L1 positive. Pembrolizumab can be used [regardless of PD-L1 status]. For most patients who fit the criteria for KEYNOTE-522, we would now use a pembrolizumab-based regimen with chemotherapy preoperatively. [Patients with] node-positive tumors bigger than 2 cm are those who we would consider for preoperative therapy.

There are things well have to think about for those patients who have still have residual disease after surgery who get preoperative pembrolizumab. Do you simply give them [adjuvant] pembrolizumab alone, or pembrolizumab with capecitabine? If patients harbor a BRCA mutation, would you add a PARP inhibitor? These are all questions that we dont have clear answers on, but those are expanding options for patients who remain at risk for disease recurrence.

Dr Rao gave us an overview of the role of CDK4/6 inhibitors in the metastatic setting and [shared] emerging data in the adjuvant setting. In the metastatic setting, she covered some of the updates, particularly with ribociclib [Kisqali] and fulvestrant [Faslodex], which clearly demonstrates an OS benefit. All the CDK4/6 inhibitor trials with palbociclib [Ibrance],abemaciclib [Verzenio], or ribociclib, as first- or second-line therapy, all showed an improvement in PFS.

We are starting to see the emergence of an OS benefit, particularly with ribociclib and abemaciclib, and more recently with palbociclib to a smaller degree. There is a consistency in the data. Some might argue that the data with ribociclib are the most compelling, particularly when combined with fulvestrant in the second-line setting, but the general idea is that patients should be getting a CD4/6 inhibitor. Theyre all associated with improvements in outcome, and all have manageable [adverse] effect [AE] profiles.

In the adjuvant setting, weve had data with palbociclib that did not show an advantage to adding it to [treatment for] high-risk patients, either in those with residual disease or as an adjuvant therapy. We still have data that has not reported from the phase 3 NATALEE trial [NCT03701334] with ribociclib.

The one data set that we have positive data from is the phase 3 monarchE trial [NCT03155997] with abemaciclib, which [examined] patients who are at higher risk. They could have had more than 3 positive nodes, or if they had fewer than 4 positive nodes, then they had to have other [high-risk] features, [regarding] tumor size or proliferation, that would have conferred a greater risk of recurrence. What was demonstrated in that trial, with short follow-up, was that there was a clear benefit with abemaciclib. When the trial data were first presented, a minority of patients had gone through the entire duration of abemaciclib therapy of 2 years. Now with longer follow-up, more of the total pool of patients have completed their abemaciclib therapy. The data still favor the use of abemaciclib. Weve started using [abemaciclib with endocrine therapy] in patients who fit the criteria for the monarchE trial. Its been included in the ASCO guidelines and the NCCN guidelines as an option for patients.

Dr Kalinsky, who was the presenter of the phase 3 RxPONDER trial [NCT01272037] when it first was presented, gave an overview of the molecular tools we have to decide prognosis and determine the benefit from chemotherapy. He briefly covered the phase 3 TAILORx trial [NCT00310180], which was conducted in node-negative patients and served as the basis for the RxPONDER trial, which was conducted in higher-risk patients with 1 to 3 positive nodes.

From [RxPONDER], we were able to identify a subset of patients with node-positive disease where we would have almost universally recommended chemotherapy in the past. There is a subset of patients, based not only on their recurrence score but also clinical features and menopausal status, where we can defer chemotherapy and not compromise their overall outcome. Dr Kalinsky discussed the RxPONDER trial and its nuances, particularly as it relates to premenopausal vs postmenopausal women and where we might draw the line on who must get chemotherapy and who would not benefit from it.

That [assay] has been a practice-changing tool that we now employ daily in our practice, just as we did with the TAILORx data for node-negative patients. Dr. Kalinsky put into perspective all the data and nicely reviewed how clinicians would employ this data to make treatment decisions in this setting.

The TAILORx trial is an older data set at this point. Based on that data, we can identify patients at very low risk of recurrence who dont require chemotherapy. [As with] RxPONDER, there are many patients with node-negative disease who would have universally gotten chemotherapy [in the past]. Now, because of long-term data from the TAILORx trial, we can feel comfortable avoiding chemotherapy in a significant fraction of patients who would have likely gotten chemotherapy in the past because it does not compromise their outcomes.

The IPC webinar and discussions by both myself and my colleagues reflect that weve made progress in almost every silo of breast cancer and every strategy we use to reduce risk and to identify patients who can avoid or need specific therapies. [Clinicians] sometimes have to have a longer perspective to understand where we started from, and its one of the benefits of being around for a while. Seeing what we were doing 20 years ago was, by some measure, somewhat crude. We have come a long way in terms of dividing breast cancer into subsets, developing therapies for each subset, using molecular tools to identify patients at risk, and [learning] how we can mitigate their risk.

That is different from the landscape I had when I was training, and I suspect in 20 years, what were doing now will be viewed as crude. Well have something new that makes everything we do today look [antiquated]. Nonetheless, what we heard about in the four talks reflects all the progress that has been made to benefit patients.

Read the original here:
Antibody-Drug Conjugates Are Carving Out Expanded Roles Throughout Breast Cancer - OncLive

Olivia Rissland, DPhil, compares RNA to photocopies of pages of books at a library.

RNA is to DNA what photocopies are to precious books in library stacks: An abridged reproduction with a temporary existence, explains Rissland, a scientist with the University of Colorados RNA Bioscience Initiative.

You can read just a few photocopies, and only for a limited time. Understanding those copies depends on where and when you read them. Even then, you get a just a few clues about whats in the book; you dont get the whole story. Those pages wont easily yield the librarys secrets.

What is really cool about RNA is what happens to those photocopies once they leave the library is different for each photocopy, Rissland says.

Figuring out which photocopy to read and how to interpret what its saying before it disappears is a challenging task at best. It becomes a staggering enterprise when considering the numbers.

There are some 20,000 genes in the human genome. In humans, genes vary from a few hundred DNA base pairs to more than 2 million bases. Messenger RNA the temporary photocopy provides a picture of a piece of the DNA, a snippet of the story.

But ask Rissland about the challenge of studying those photocopies and you discover that its more than a practical question for framing a particular study. Its a philosophy.

I think about what research is, Rissland says. Research exists at the boundary of known and unknown. And so, what were always looking for are mysteries and things that dont make sense. We are trying to understand what it is that were missing, that explains what we see.

Rissland, an assistant professor of biochemistry and molecular genetics, joined the CU School of Medicine in 2017 when the school boosted investment into RNA research, thanks to a gift from The Anschutz Foundation and other supporters. Those funds allowed Dean John Reilly, Jr., MD, to target strategic growth opportunities, which is how the RNA Bioscience Initiative, or RBI, was born.

The goal with these investments is to bring together teams of scientists to work on some of the most challenging questions in human health.

I think were very lucky in the RBI, Rissland says. Its easy for us to foster collaborations. There were five of us who were hired in the same search. Were all close enough in our work that we can have a conversation with points of common interest. But were not so close that therell be competition. For me, that is probably the starting point for all the collaborations. We are bouncing ideas with others in the offices right here and then building out from there.

Risslands lab studies what happens to messenger RNA, or mRNA, after its made. Specifically, she and her lab team are trying to understand how the mechanics of protein production and of mRNA destruction connect with one another. Why do some mRNAs get destroyed quickly and others slowly?

The processes are connected, but how remains a multifaceted mystery and a source of endless fascination for Rissland and the team of scientists in her laboratory. Understanding what happens during that interaction could yield insights into genetic factors causing of human disease.

Although all cells have the same collection of genes, cells differ in which genes are turned on and which are turned off. When that process goes awry, adverse health conditions can result, such as cancer, neurodegeneration, or developmental defects.

One area of inquiry for Risslands lab is the impact of translation elongation speeds on how fast mRNAs are destroyed. Translation occurs when the ribosome in the cell reads the sequence on the mRNA and turns that into a sequence of amino acids, thus building proteins.

You have these machines theyre called ribosomes that are the actual interpreters that go between the different languages and make the protein, Rissland says. The speed at which the ribosome moves matters. A way to think about this is like on a freeway.

You accelerate as you get on the freeway, but your speed can vary once youre on the road. That time span between destinations is elongation. Your speed depends on weather, it depends on traffic, and sometimes you slow down or speed up depending on the conditions. In a cell, a traffic jam is a signal that theres a problem, that theres something a little bit wrong about the RNA, then the cell takes action to deal with that, Rissland says.

There are ample opportunities for traffic jams in a cell because the average cell produces 2 million protein molecules every minute. For a researcher, that means there are ample opportunities to explore.

Thats when you sit down and try to come up with what question to ask, she says. You read the literature and you say, Well, what things are here that dont make sense? What things surprise me? Or what is an implication of something that we know if this is true, then that would imply this is true?

Questions shape the experiments, and the experiments provide answers.

The majority of the time it doesnt work the way you think its going to, Rissland says. You think it could be answer A or it could be answer B. And its always answer C.

Surprise endings are nothing new in literature or life.

Rissland had planned to go to medical school after completing her undergraduate degree in Biology, Mathematics, and Classics (Latin) at Brown University in 2004. She was awarded a Rhodes Scholarship and went to University of Oxford where she earned a DPhil in molecular biology.

The plan actually was to come back to the States and go do my MD, Rissland says. Then Id be an MD, PhD, and drive off into the sunset.

Well, plans change, and the sun also rises. In Risslands case, the light on the horizon was the opportunity to become an independent investigator running a research laboratory.

When I came of age as a scientist was right when we started having all of these methods that allow us to ask questions about RNA and answer them. Five or 10 years earlier, this just wasnt possible, Rissland says. For me it was not only that there were all these questions that I wanted to answer, but we also had these tools to answer them. It was just this huge technological revolution. I mean, its like being a kid in a candy store. How could you say no to that?

The advent of high-throughput sequencing technology has allowed scientists to look widely and deeply into the full spectrum of genetic variations and other factors affecting biological change that were impossibly laborious to study for previous generations of investigators.

Classically, we were able to look at gene A or gene B and we looked at them one by one, she says. What high-throughput sequencing allowed us to do is to not look at things one-by-one, but to look at every single gene at the same time and that gives you just so much more power.

Its the power to think about the themes and larger plot of the story rather than paying attention to one or two characters in a book.

I am most interested in general principles, Rissland says. Specific examples dont provide general insight. They are fine, but theyre not what really get me out of bed in the morning. And to know if something is general you need to be able to look at many things. High throughput sequencing, then, is a really good match for the types of questions I like to ask.

After completing her doctorate, Rissland did postdoctoral work at the Whitehead Institute, an independent biomedical research institute in Cambridge, Mass., and then launched her laboratory at The Hospital for Sick Children, which is affiliated with the University of Toronto, in 2014.

Since starting her career as an independent investigator, her laboratory has trained more than 20 young scientists, nurturing their research, preparing them for their own careers, and encouraging them to ask questions.

I think success looks like someone who has taken real intellectual ownership of their project, who pushes back against my ideas, who tells me that Im wrong. I think when they do that, thats the best part. It means that they have the skills so that they can put those ideas into practice.

Its like reading a book that never ends.

Continue reading here:
Reading a Book That Never Ends - University of Colorado Anschutz Medical Campus

In the age of Big Data and Digital Everything, computers, specialised software, and the Internet have become essential tools in every researchers toolkit to accelerate and assist in their research initiatives. In molecular biology, bioinformatics is the driving force behind the researchers endeavours to continue unravelling the secrets behind the genetic code, together with the forces and factors underlying a living organism.

So what is bioinformatics? Bioinformatics is an interdisciplinary field which typically combines computer science along with statistical analysis to predict, treat and solve biological problems. The origin of bioinformatics dates back to the early 1960s, when Margaret Dayhoff and Robert Ledley published a paper describing a computer program called COMPROTEIN, coded in Fortran on punch cards for the IBM 7090 Mainframes, to aid in protein-structure determination.

Advancements in high-throughput sequencing technology, coupled with reduced costs and turnaround time, has seen an exponential increase in the generation and availability of genomic data. Yet, this was also accompanied by computational and data storage challenges. Aided with the widespread availability of the Internet, bioinformatics has created advanced ways to store, organise, explore, extract, annotate and visualise complex data, while requiring constant updating to standardise new resources to ensure their sustainability and ease of use.

Bioinformatics featured heavily in the COVID-19 pandemic, both in the detection and treatment of different SARS-CoV-2 variants. Lung fluid samples were taken from patients with severe respiratory symptoms. The samples DNA was sequenced, followed by bioinformatics processing that helped to filter out known human and microbial DNA, and to assemble the then unknown SARS-CoV-2 genomic sequence. The whole process took 10 days to complete and the newly assembled sequence was compared to other known sequences and was classified as a coronavirus closely related to a strain found in bats.

The applications of bioinformatics also extend to the identification of disease-causing genetic defects, prognosis and drug discovery, among others. If the disease is genetic in nature, it is first connected to the causative genetic alteration. The next step would be to identify a drug target (usually a protein) which would restore normal cellular function or eliminate the malfunctioning cells. The drug would then have to be filtered from a list of all possibilities based on the drug target.

The importance of bioinformatics in this day and age must be accompanied by skilled bioinformaticians to keep up with this fast-paced field. The Masters in Bioinformatics offered by the Centre for Molecular Medicine and Biobanking at the University of Malta is an interdisciplinary program that combines the application of computer technologies to the handling and analysis of biological data. The course provides the essential knowledge to develop new algorithms and apply the latest technologies in order to process biological data generated from experiments. This program is particularly suited to those with a biology or medical science background seeking to acquire computer programming skills, or vice versa.

Tristan Camilleri, Donald Friggieri, and Matthew Pace are enrolled in the MSc in Bioinformatics programme at the University of Malta.

Sound Bites

The largest-ever genetic study of schizophrenia has identified large numbers of specific genes that could play important roles in the psychiatric disorder. A group of hundreds of researchers across 45 countries analysed DNA from 76,755 people with schizophrenia and 243,649 without it to better understand the genes and biological processes underpinning the condition. The new study found a much larger number of genetic links to schizophrenia than ever before, in 287 different regions of the genome, the human bodys DNA blueprint.

Scientists have published the first complete, gapless sequence of a human genome, two decades after the Human Genome Project produced the first draft human genome sequence. According to researchers, having a complete, gap-free sequence of the roughly three billion bases (or letters) in our DNA is critical for understanding the full spectrum of human genomic variation and for understanding the genetic contributions to certain diseases.

For more soundbites, listen to Radio Mocha every Saturday at 7.30pm on Radju Malta and the following Monday at 9pm on Radju Malta 2 https://www.fb. com/RadioMochaMalta/.

DIDYOU KNOW?

In the early years of the BBC, there was a framed warning near the microphone in the radio studio that read: If you sneeze or rustle papers you will DEAFEN THOUSANDS!!!

Venereal diseases are named after Venus, the Roman

goddess of love. Greeks call them aphrodisiac diseases ( ) after Aphrodite, the Greek goddess of love.

Caesars Palace in Las Vegas was built with such a large car park that it used to host Formula One races.

The first Met Office weather forecast took six weeks to come up with and only predicted the following six hours.

For more trivia, see: http://www.um.edu.mt/think.

Independent journalism costs money. Support Times of Malta for the price of a coffee.

See more here:
Understanding bioinformatics, the key to unlocking our genetic secrets - Times of Malta

Total New Medical Entities by Pharma Company 1999-2018. Modified from "R&D efficiency of leading ... [+] pharmaceutical companies A 20-year analysis"

Last week I published an article on the three academic and industry groups that perform detailed analysis of the pharmaceutical industry, evaluate R&D productivity, and look for best practices. In order to improve, we do need to understand where we are and where we are going. If I am making a claim that I can discover a novel target for a broad disease, design a novel molecule, complete Phase 0 human clinical trial, and go into Phase I in under 30 months - how much impact am I making and how does it compare to the traditional approaches in terms of the probability of getting there, speed and cost? How do you compare to the peers? And are you doing the right thing? To answer these questions we do need to have specialist industry observers, and to set the stage I got to talk to Prof. Alexander Schuhmacher and Prof. Oliver Gassmann of the Competence Network for Life Science Innovation at the Institute of Technology Management at University of St. Gallen about their recent papers covering pharma R&D productivity. What comes next is a more detailed analytical piece that many of the pharmaceutical companies will not exactly like.

During the COVID-19 Pandemic we got to observe how the various pharmaceutical companies utilized their R&D, partnering, and market access capabilities to develop and market vaccines, and drugs. It was very surprising to see the established vaccine and anti-viral drug vendors like GlaxoSmithKline (GSK) fail to deliver either vaccine or a drug, while the other giants with smaller vaccine and antiviral franchises performed spectacularly well.

Top pharmaceutical companies by anti-viral revenue in 2017

For example, Pfizer was not even on the list of Statistas top 10 anti-viral pharmaceutical companies but due to the heroic efforts and actions of their CEO, Dr. Albert Bourla, Pfizer made history in both categories by partnering on BioNTech vaccine and developing PAXLOVID, a small molecule viral 3CL protease inhibitor, where they had a starting point since the original SARS scare. His bold actions quickly propelled Pfizer to the top of the anti-viral Olympus.

But COVID-19 is just one example. Many companies just did not want to pivot from their current R&D programs. When the COVID-19 pandemic just stated many companies with significant capabilities decided not to pivot to or allocate substantial resources to the COVID-19 programs. When it just emerged, many proposals to the board of directors were met with This will be another SARS. You will spend the money but it will go away. I am sure that many companies did not pursue anti-COVID-19 programs for this reason and at some companies, including ours these projects got substantially delayed.

Screenshot of the Amazon.com website for the bestseller by Dr. Albert Bourla, "Moonshot"

From what I hear from the market is that Dr. Bourla let go the strategy advisors that were recommending against going after COVID and mobilized all internal R&D resources to get PAXLOVID on the market setting many industry records and saving millions of lives - a heroic achievement worthy of a Nobel Peace Prize. So we can clearly see that in the face of adversity, the pharmaceutical companies can mobilize and deliver spectacular results. Fortunately, we can read the public side of the story in Dr. Albert Bourlas new book, Moonshot.

As pharmaceutical companies begin to rely on internal data science and AI, how do they decide the amount of expenditure required for efficient use of R&D resources? A comprehensive analysis of the productivity in the pharmaceutical industry will help streamline the industry into cutting waste and developing meaningful new molecular entities (NMEs).

The August 2021 edition of Drug Discovery Today contained an article titled R&D efficiency of leading pharmaceutical companies A 20-year analysis that was written by heavy-hitting academics and industry experts: Alexander Schuhmacher, Oliver Gassmann, and Lucas Wilisch of University of St Gallen, Michael Kuss of PricewaterhouseCoopers, Andreas Kandelbauer of Reutlingen University, and Markus Hinder of Novartis Institute of BioMedical Research.

Screenshot of the article "R&D efficiency of leading pharmaceutical companies - A 20-year analysis" ... [+] in Drug Discovery Today, April 9, 2022

In this study, the group took 20 years-worth of data from 1999 to 2018 comprised of financial, drug output and bibliographic data, to conduct a qualitative and quantitative comparative analysis of 14 leading pharmaceutical companies to identify success factors for R&D efficiency.

NMEs per Year 1999-2018. Modified from "R&D efficiency of leading pharmaceutical companies A ... [+] 20-year analysis"

The group also compared the new molecular entities (NMEs) going through the pipelines of leading companies segmented into one of three ways: through internal R&D, through M&A, and through licensing.

Pfizer came in as a clear leader in total R&D productivity over 20 years followed by MSD (Merck US), and Novartis.

Total New Molecular Entities 1999-2018 by Big Pharma Company. Modified from Schuhmacher and ... [+] Gassmann, "R&D efficiency of leading pharmaceutical companies A 20-year analysis"

Despite delivering the highest total number of drug approvals, most of the NMEs developed and approved by Pfizer came through M&A - 29 in total. Only 8 NMEs came through internal R&D. When it comes to the internally-developed drugs, the clear leader was Novartis with 20 NMEs followed by GSK with 13, and then by a tie between MSD and Bristol Myers Squibb (BMS) with 10 each.

Total NMEs by Big Pharma through Internal R&D 1999-2018. Modified from "R&D efficiency of leading ... [+] pharmaceutical companies A 20-year analysis"

Unsurprisingly, most of the approved NMEs in pharma pipelines come through mergers and acquisitions. For example, in 2009 Pfizer acquired another pharmaceutical giant founded in 1860, Wyeth bringing in a large portfolio of drugs. 2009 was a big year for M&A. Same year, Roche acquired Genentech, which had a celebrated portfolio of NMEs several of which came through Genentechs strong internal biology capabilities. So naturally, the top three leaders in M&A over the past two decades were Pfizer, MSD and Roche.

Total NMEs by Pharma through M&A 1999-2018. Modified from "R&D efficiency of leading pharmaceutical ... [+] companies A 20-year analysis"

Another way to advance internal R&D is through licensing. Many pharmaceutical companies in-license the molecules from biotechnology companies. Recognizing promising assets in early stages also requires strong internal capabilities in business development, chemistry, and biology. Here, we have a tie between GSK and MSD with 7 successfully-developed NMEs each, closely followed by Novartis and Sanofi.

Total NMEs by Pharma through Licensing 1999-2018. Modified from "R&D efficiency of leading ... [+] pharmaceutical companies A 20-year analysis"

One finding of this study that surprised me the most was surprisingly average performance by AstraZeneca. Over the past decade, we saw the many celebrated papers by their R&D leadership explaining the internal R&D best practices. We even attempted to replicate the popular 5R Approach by developing 5R-compatible AI pipelines. However, it scored 7th out of 14 in internally-developed NMEs, 5th in NMEs through M&A, and 11th in licensing.

I also noticed that the recent announcements of AI-partnership achievements are not very impressive either. 2+ years from April 2019 announcement of a target discovery partnership to lead identification in December 2021 that generated a lot of hype in social networks, seems to be closer to industry average using traditional approaches. This does not mean AstraZenecas 5R approach or partnership practices do not work or are overhyped. However, looking at the numbers from the Schuhmacher and Gassmann paper, and the AstraZeneca numbers seem to be surprisingly average as they have a perception of being the most productive. In fact, in my popular 2020 article, which was abundantly shared by AstraZeneca itself, it did look like AstraZeneca held the leading position in AI-powered drug discovery and development.

Furthermore, the study compared the leading pharmaceutical companies by the number of scientific publications during this period and showed the leadership of Pfizer (24,564), followed by GlaxoSmithKline (GSK) and Merck & Co. (22,727 and 15,556 respectively).

Total publications by Big Pharma 1999-2018. Modified from "R&D efficiency of leading pharmaceutical ... [+] companies A 20-year analysis"

In terms of cumulative impact factor (CIF), GlaxoSmithKline topped the chart with 104,047, with Pfizer coming in second place with a CIF of 101,825. Roche came in third place with a CIF of 95,603. But I guess that the average impact factor is a more important metric and here Gilead and Amgen, that have the lower total number of papers, are clearly in the lead.

Average impact factor by big pharma 1999-2018. Modified from "R&D efficiency of leading ... [+] pharmaceutical companies A 20-year analysis"

The analysts found that between 1999 and 2018, the R&D investments of the 14 leading pharmaceutical companies increased from US$49.2 billion in 1999 to US$ 87.1 billion in 2018, and that they launched 270 of the 602 NMEs approved throughout the industry.

The study also revealed that the more a company invested in R&D in the past 20 years, the higher was their output (expressed as approved NMEs or as cumulative impact factor). In brief, this paper proves that higher R&D investments are associated with higher R&D output.

To learn more about the study, I reached out to two members of the group - Alexander and Oliver and asked them about the study and their take on how to build up an R&D ecosystem.

What are some of the key findings that are important in this paper?

Alexander: Really surprising for us is the finding the bigger the company [its R&D organization] was, the higher the R&D output was. This is what we described as economies of scale in pharmaceutical R&D in the paper - if you think about it, it makes sense because pharma R&D can leverage from size (resources, competencies, technologies).

Oliver: Yes, and for those companies whose R&D organization is not big enough to profit from economies of scale, its all about building an R&D ecosystem that can mimic the difference in size. In consequence, for some pharmaceutical companies it is advantageous to pursuit of size with M&A, while other should focus stronger on collaborations and strategic alliances with peers in terms of sharing data, competencies, and technologies in open innovation manner.

In this context, the future threat for pharmaceutical companies is not just within the industry itself, but also coming from outside the pharmaceutical sector. In one of our recent publications we described that large parts of the value creation will be captured by new players (new pharma entrants) all in front the Tech Giants. For example, we recently saw Apple getting a first FDA approved smart healthcare device a disruptive technology coming from the outside (see hereto Clayton Christensen's innovator's dilemma). Google/Verify and other tech companies are also entering the pharma/healthcare market. Already today and even more in the future, value creation will come from data and business models will be more data-driven - the only solution for pharma is: Build partnerships with peers to profit from economies of scale and collaborate with tech companies to leverage from economies of scope.

Would it be true to suggest that the larger you are as a company, the more acquisitive you are too?

Alexander: Neither yes nor no. We see both models in the industry one based on knowledge creation and the other on acquisition. Just to name to examples: Novartis has built a very strong and successful R&D organization that leverages from its internal competencies, while Pfizer was very successful with acquiring R&D portfolios (e.g. Wyeth, Warner Lambert, Pharmacia). So, the important question is, how can you leverage from the resources you have and which R&D models suits best to the resources at hand? There is not a simple answer to this complex question.

Looking at individual companies and how they ranked in the paper, were there any surprises when you put this data together and you compared that to the analyst ratings of those companies and what people perceive?

Alexander: As scientists, we are always surprised about the outcomes of our research. Indeed, it looks like that some companies use their R&D resources more efficient than others or have built R&D models that enable them to perform more efficiently.

As we have used data from 20 years, our results are meaningful. For example, a simple calculation is to take the cumulative R&D expenditures of a pharma company over the 20 years and divide it by the number of drugs it launched in that period. Youll see that top 20 pharma companies have (clearly) different R&D efficiencies.

With respect to ratings and ratings companies; this is not our home turf. We are scientists interested in analyzing and understanding specific settings or type of setting as well as generalizing from it. We do not give any company-specific analysis or even investment recommendations. For example, one of our foci is on R&D efficiency, as it is an industry-specific type of challenge. And we analyze and try to understand this complex field and aim at drawing conclusions that are generalizable for the whole industry.

Do you think that findings in this paper should incentivize people to merge, to acquire, to become even bigger? Because if this statement holds true that the bigger you are, the more efficient you are, it probably kind of postulates the mergers and acquisitions pathway for pretty much any pharma company.

Oliver: In very general terms, yes this paper is a template for M&As. But M&As are not new to the industry. Over the past years, we saw several big M&A transactions and countless acquisitions of small biotechs. What might be new to the industry is the acquisition of tech start-up companies that bring along the highly needed digital competencies for a data-driven R&D. Or it is the thinking in R&D ecosystems that include traditional biotech and pharma players but also new partners from other industries. In consequence, we foresee pharma going away from the more traditional path of open innovation with research collaborations and licensing to a new network-based model that is more agile, more smart and may provide better R&D efficiency.

In consequence, those companies who like to address and build up an R&D ecosystem in a more modern way have to think of what I call a win-win-win formula, which means you need to get a win for the users, for the partners, and for your own company. At the end, it's really a question of to whom do you create value for? Its not only that you have to think the great value for the patient or for your customers and for yourself, but also thinking actually stronger for what could you do to be more attractive for your partners in the ecosystem?

Professor Alexander Schuhmacher

Prof. Dr. Alexander Schuhmacher graduated in biology at the University of Konstanz (Germany), in pharmaceutical medicine at the University of Witten/Herdecke (Germany) and made its PhD in molecular biology at the University of Konstanz; he is also a graduate of the Executive MBA program at the University of St. Gallen (Switzerland). Alexander holds a full professorship in life science management at the Technische Hochschule Ingolstadt (Germany). His research focus is on biopharmaceutical innovation management with a specialization on R&D efficiency, artificial intelligence and open innovation. Prior to that, Alexander worked 9 years as professor at Reutlingen University (Germany) and 14 years in various R&D positions in the pharmaceutical industry.

Professor Oliver Gassmann

Prof. Dr. Oliver Gassmann is a professor for technology and innovation management at the University of St.Gallen, one of Europes leading business schools. He is managing director of the Institute of Technology Management. Until 2002 he worked for Schindler and led its Corporate Research as VP Technology Management. He is co-founder of the BMI-Lab which focusses on business model innovation. His research lead to a revolutionary method of how to design new business models: The Business Model Navigator. Oliver has published over 300 publications and several books on management of innovation. His book The Business Model Navigator by Hanser and Financial Times Publishing has been called as a sensation by the leading German newspaper F.A.Z. and became rapidly a bestseller. He is one of the most cited innovation researchers, the most published author in R&D Management.

Excerpt from:
What Are The Most Productive Pharmaceutical Companies?Pharmaceutical R&D Efficiency Review 1999-2018 - Forbes

Would you like to contribute your creativity to an international team of scientists from various disciplines focusing on basic research in the area of molecular life sciences?

The European Molecular Biology Laboratory (EMBL) invites you to apply for PhD positions in Heidelberg, Barcelona, Grenoble, Hamburg, Hinxton (near Cambridge) and Rome. We welcome candidates with diverse backgrounds, such as in Biology, Chemistry, Physics, Mathematics, Computer Science, Engineering and Molecular Medicine.

EMBL provides PhD students with a starting platform for a successful career in science by fostering early independence and interdisciplinary research. The enriching encounter of different nationalities, the friendly and collaborative atmosphere, and the passion for science is what unites EMBL s diverse staff and provides an ideal setting to forge long-lasting connections and make studying at EMBL a formative experience. Our PhD positions are fully funded and offer broad health care and pension benefits.

Full details on how to submit your online application are available here: https://www.embl.org/about/info/embl-international-phd-programme/applica...

The deadline for submitting the application is 19 April 2022.

Recruited candidates would start their work at EMBL latest by mid of October 2022.

For further information, please visit our web page or contact the EMBL Graduate Office (graduate-office@embl.org).

View post:
Exciting PhD positions at the European Molecular Biology Laboratory (EMBL) job with EUROPEAN MOLECULAR BIOLOGY LABORATORY (EMBL) | 288637 - Times...

Basel, April 6, 2022 Novartis today announced that the U.S. Food and Drug Administration (FDA) granted accelerated approval to Vijoice (alpelisib) for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy.1 Vijoice is the first FDA-approved treatment for PROS, a spectrum of rare conditions characterized by overgrowths and blood vessel anomalies impacting an estimated 14 people per million.2,3 In accordance with the Accelerated Approval Program, continued approval may be contingent upon verification and description of clinical benefit from confirmatory evidence.

Todays approval of the first treatment for PROS offers hope for a better quality of life to patients and families affected by these rare conditions, said Kristen Davis, Executive Director of CLOVES Syndrome Community. PROS conditions can be debilitating and disabling and can result in disruptions to everyday activities. Until today, often the only treatment options for patients were surgical or interventional radiology procedures.

PROS conditions can affect quality of life and pose a range of physical, emotional and social challenges for patients and their families, ranging from functional impacts and developmental delays to chronic pain, mobility issues, and feelings of isolation.3-6 PROS management can be challenging, requiring collaboration from a multidisciplinary team, and patients and physicians have only had access to interventions focused on symptom management.6,7

I am proud of this outstanding achievement for the PROS community. The EPIK-P1 study results build on our earlier pre-clinical findings and demonstrate the efficacy of Vijoice for select PROS conditions, effectively reducing PROS growths, said Guillaume Canaud, MD, PhD, Necker-Enfants Malades Hospital AP-HP, the Paris Descartes University, Inserm (INEM Institute Necker Enfants Malades Centre for Molecular Medicine). This is a significant advancement in therapy for PROS with the potential to positively change the treatment trajectory and outcomes for patients.

FDA approval was based on real-world evidence from EPIK-P1, a retrospective chart review study that showed patients treated with Vijoice experienced reduced target lesion volume and improvement in PROS-related symptoms and manifestations. The primary endpoint analysis conducted at week 24 showed 27% of patients (10/37) achieved a confirmed response to treatment, defined as 20% or greater reduction in the sum of PROS target lesion volume. Nearly three in four patients with imaging at baseline and week 24 (74%, 23/31) showed some reduction in target lesion volume, with a mean reduction of 13.7%, and no patients experienced disease progression at time of primary analysis. Additionally, at week 24, investigators observed patient improvements in pain (90%, 20/22), fatigue (76%, 32/42), vascular malformation (79%, 30/38), limb asymmetry (69%, 20/29), and disseminated intravascular coagulation (55%, 16/29). These improvements were observed in subsets of patients across the study population (n=57) who reported symptoms at baseline and at week 24.1,2

The approval of Vijoice marks a turning point for patients who, until now, have not had an approved therapy to specifically address their disease, said Victor Bulto, President, Novartis Innovative Medicines US. We are grateful to the physicians, patients and families who participated in the EPIK-P1 trial. We are continuing to invest in studies to advance the scientific understanding of PROS conditions and to understand the full potential of Vijoice.

In EPIK-P1, the most common adverse events (AEs) of any grade were diarrhea (16%), stomatitis (16%), and hyperglycemia (12%). The most common grade 3/4 AE was cellulitis (4%); one adult case was considered treatment-related.1

Novartis is committed to providing patients with access to medicines, as well as resources and support to address a range of needs. The Novartis Oncology Patient Support Program is available to help guide eligible patients through the various aspects of getting started on treatment, from providing educational information to helping them understand their insurance coverage and identify potential financial assistance options. Patients or providers can call 800-282-7630 or visit Patient.NovartisOncology.com or HCP.Novartis.com/Access to learn more about eligibility and to enroll.

About PIK3CA-Related Overgrowth Spectrum (PROS)The PROS classification was proposed by researchers and parent representatives of patient-family support and advocacy organizations at a National Institutes of Health workshop in 2013 to unite a group of rare overgrowth conditions caused by PIK3CA mutations.4,6Specific conditions associated with PROS include KTS, CLOVES syndrome, ILM, MCAP/MCM, HME, HHML, FIL, FAVA, macrodactyly, muscular HH, FAO, CLAPO syndrome and epidermal nevus, benign lichenoid keratosis, or seborrheic keratosis.4,6The estimated prevalence of PROS conditions is approximately 14 people per million.3

About VijoiceVijoice (alpelisib) is a kinase inhibitor that treats rare overgrowth conditions caused by the effects of PIK3CA mutations in adults and children with PIK3CA-Related Overgrowth Spectrum (PROS). Vijoice works by inhibiting the PI3K pathway, predominantly the PI3K-alpha isoform.1 Vijoice is the first FDA-approved treatment for PROS conditions. Vijoice is not approved for use outside the United States.

FDA approval of Vijoice is based primarily on real-world evidence from the EPIK-P1 study. To further understand the long-term efficacy and safety of alpelisib in PROS, Novartis is conducting additional clinical trials. EPIK-P2 is a prospective Phase II multi-center study with a randomized, double-blind, upfront 16-week placebo-controlled period, and extension period to evaluate the safety, the efficacy and pharmacokinetics of alpelisib to treat pediatrics and adults with PROS. EPIK-P3 is a Phase II study to assess long-term safety and efficacy of alpelisib in people with PROS who participated in EPIK-P1.

DisclaimerThis press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as potential, can, will, plan, may, could, would, expect, anticipate, seek, look forward, believe, committed, investigational, pipeline, launch, or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AGs current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About NovartisNovartis is reimagining medicine to improve and extend peoples lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the worlds top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 108,000 people of more than 140 nationalities work at Novartis around the world. Find out more at https://www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis at https://twitter.com/novartisnewsFor Novartis multimedia content, please visit https://www.novartis.com/news/media-libraryFor questions about the site or required registration, please contact media.relations@novartis.com

References

# # #

Novartis Media RelationsE-mail: media.relations@novartis.com

Novartis Investor RelationsCentral investor relations line: +41 61 324 7944E-mail: investor.relations@novartis.com

Follow this link:
FDA approves Novartis Vijoice (alpelisib) as first and only treatment for select patients with PIK3CA-Related Overgrowth Spectrum (PROS) -...

SAN ANTONIO (April 5, 2022) In a breakthrough discovery, scientists from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) today reported that inhibiting a liver enzyme in obese mice decreased the rodents appetite, increased energy expenditure in adipose (fat) tissues and resulted in weight loss.

The finding, published in Cell Metabolism, provides a potentially desirable drug target to treat metabolic issues such as obesity and diabetes, the authors said.

We first needed to discover this mechanism and, now that we have, we can develop drugs to improve metabolic syndrome, said senior author Masahiro Morita, PhD, assistant professor of molecular medicine in UT Health San Antonios Sam and Ann Barshop Institute for Longevity and Aging Studies.

We have an enzyme inhibitor that we want to make more specific to increase its effects, said first author Sakie Katsumura, DDS, PhD, postdoctoral fellow in the Morita laboratory.

The liver enzyme, called CNOT6L deadenylase, turns off messenger ribonucleic acids (mRNAs) that ordinarily carry genetic instructions from the nucleus to sites in the cell where two liver proteins are made.

One of the proteins, growth differentiation factor 15 (GDF15), sends signals to two regions of the hindbrain to control food intake. The other, fibroblast growth factor 21(FGF21), sends signals to brown and white adipose tissues to increase energy expenditure. CNOT6L deadenylase impedes mRNA code-carrying for both GDF15 and FGF21, which reduces these benefits.

The researchers first-in-class CNOT6L inhibitor, dubbed iD1, stabilized liver GDF15 and FGF21 mRNAs in obese mice, increasing levels of the two proteins in the blood. After 12 weeks, treated rodents ate 30% less food and exhibited 30% reduced body weight. Energy expenditures in the adipose tissues increased by about 15%. Liver fat decreased 30%.

Mice treated with iD1 showed improved insulin sensitivity and lower blood glucose levels.

In the treatment of metabolic disease, targeting mRNA is a fairly novel concept, said coauthor Nicolas Musi, MD, professor of medicine at UT Health San Antonio and director of the Sam and Ann Barshop Institute. It is a new platform for thinking about how to treat this group of diseases.

In Texas and the U.S., obesity, type 2 diabetes, fatty liver disease and related metabolic disorders are at epidemic proportions.

According to the U.S. Centers for Disease Control and Prevention (CDC), more than 37 million Americans have diabetes. Type 2 diabetes represents at least 90% of the cases. In Texas, approximately 2.7 million people have diagnosed diabetes, and an additional 600,000 people in Texas have diabetes but dont know it. Another 7 million people in Texas have prediabetes.

Obesity prevalence in the U.S. is more than 40% and is climbing, according to the CDC. Obesity-related diseases include heart attack, stroke, type 2 diabetes and some cancers.

These are very serious problems, and any intervention, including drugs, that can treat them are necessary, Dr. Musi said. Dr. Morita and Dr. Katsumura have made a groundbreaking discovery by delineating this mechanism and the proof of concept that a drug that targets this pathway improves all these parameters including glucose levels, glucose tolerance and insulin resistance caused by a high-fat diet and fatty liver.

Their next step, Dr. Katsumura reiterated, is to refine this mechanism and identify new drugs that may be more specific and more potent.

I want to congratulate Dr. Morita and Dr. Katsumura for this fantastic work, Dr. Musi said. It is comprehensive, thorough and paradigm-changing.

The Sam and Ann Barshop Institute, one of the worlds premier centers of aging research, is among more than a dozen institutes, schools and departments that collectively make The University of Texas Health Science Center at San Antonio the preeminent research institution and primary engine of innovation in South Texas.

Dr. Masahiro Moritas work was supported by The University of Texas System Rising STARs Award, Cancer Prevention and Research Institute of Texas (CPRIT) Award (RP220267), Helen F. Kerr Foundation Grant, Shelby Tengg Foundation Grant, Cancer Center Support Grant (P30 CA054174), Grant-in-Aid for Scientific Research (18K07237 and 21K07102), and JST FOREST Program (JPMJFR216D). Dr. Sakie Katsumura was supported by the American Heart Association Postdoctoral Fellowship, JSPS Overseas Research Fellowship and Uehara Memorial Foundation Postdoctoral Fellowship. Dr. Nicolas Musi was supported by the San Antonio Claude D. Pepper Older Americans Independence Center (P30 AG044271) and the San Antonio Nathan Shock Center of Excellence on the Biology of Aging (P30 AG021890), and by grants from the National Institute on Aging (R01-DK80157 and R01-DK089229) and the American Diabetes Association.

Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure

Sakie Katsumura, Nadeem Siddiqui, Michael Rock Goldsmith, Jaime H. Cheah, Teppei Fujikawa, Genki Minegishi, Atsushi Yamagata, Yukako Yabuki, Kaoru Kobayashi, Mikako Shirouzu, Takeshi Inagaki, Tim H.-M. Huang, Nicolas Musi, Ivan Topisirovic, Ola Larsson, Masahiro Morita

First published: April 5, 2022, Cell Metabolism

https://doi.org/10.1016/j.cmet.2022.03.005

The University of Texas Health Science Center at San Antonio(UT Health San Antonio)is the chief catalyst of San Antonios $42.4 billion health care and biosciences sector, the citys largest economic generator. UT Health San Antonio is the largest research university in South Texaswith a research portfolio of approximately $350 million. With its five professional schools, a diverse workforce of 7,200, an annual operating budget of $1 billion and a clinical practice with annual revenues of more than $540 million, UT Health San Antonio is poised to add 1,000 well-paying jobs over the next five years.

Stay connected with The University of Texas Health Science Center at San Antonio onFacebook,Twitter,LinkedIn,InstagramandYouTube.

Experimental study

Animals

Boosting liver mRNAs curbs appetite, body weight in obese mice

5-Apr-2022

See more here:
Boosting liver mRNAs curbs appetite, body weight in obese mice - EurekAlert

The festival commemorated the 30 year anniversary of the UC Davis Center for Neuroscience

By ISABELLA KRZESNIAK campus@theaggie.org

On March 12, the UC Davis Center for Neuroscience hosted NeuroFest 2022, a free event where faculty and graduate students shared neuroscience research with the public. The event took place at the UC Davis Conference Center and marked the centers 30-year anniversary. It also coincided with Brain Awareness week, a campaign organized by the Dana Foundation to bring attention to neurological research.

The festival featured four keynote speakers whose respective fields, according to Center for Neuroscience Director Kimberley McCallister, highlighted the strengths of neurological research at UC Davis. The presentations covered neurodevelopmental disorders, mental health issues, memory and brain-computer interfaces.

The event was this really nice community-centered learning opportunity, said Christina Kim, a keynote speaker and an associate professor for neurology. Neuroscience-related faculty gave a really broad overview of their respective fields and what advances weve made in understanding over the past 30 years, how their research is trying to fill in existing gaps and envisioning what the next 30 years are going to look like.

Kims research is centered on imbalances in neurochemicals and neural activity and how these can contribute to mood changes. She prefaced a discussion of her current research with a history of discoveries in pharmacology, as they relate to neuropsychiatric disorders. Kim said she enjoyed presenting to both community members and scientists.

Typically, when you are training to be a scientist, you dont get much practice in giving these kinds of talks where youre speaking to the public and figuring out the best way to distill your research in a way thats understandable and interesting, Kim said. The majority of presentations that we normally give are geared more toward purely scientific audiences, so its a big change to give a public talk.

David Segal, a keynote speaker and a professor of biochemistry and molecular medicine, spoke about his work with gene therapy and treating rare neurological diseases such as Angelman Syndrome, which results in a host of cognitive impairments and communication issues. Despite the relative infrequency of a given rare disease, these diseases as a whole affect more people than cancer and AIDS combined, according to Segal.

The government cant fund research for these rare diseases and companies arent as interested in trying to develop therapies for this, so I think theres an important role for an academic center for interventional genetics that we put together here at UC Davis, Segal said.

The festival also offered interactive booths organized by graduate students for attendees to learn about neurobiology. The booths, which were available throughout the event, featured activities that ranged from monitoring ones brain activity to observing neurons on a microscopic level.

The event also featured NeuroBlitz, a competition where graduate students presented their research and audience members voted for the best presentation.

NeuroBlitz challenges our graduate students to sum up their research in a succinct talk, similar to an elevator pitch, that is geared toward a general audience, Kostas Zarbalis, an associate professor of pathology and laboratory medicine who worked with the contestants, said.

Neuroscientists were also invited to submit art that represents their research. The NeuroFest Committee selected the eight best submissions, displayed them at the event and invited attendees to vote for their three favorites.

The NeuroFest concept is really unique, and its not something that I had an opportunity to participate in at any other institution Ive been at, Kim said. Other universities dont really have this kind of openness, and I appreciate this blend between Davis community members and Davis researchers.

Written by: Isabella Krzesniak campus@theaggie.org

More here:
NeuroFest celebrates 30 years of neurological research at UC Davis - The Aggie - The Aggie

4D Molecular Therapeutics, Inc.

EMERYVILLE, Calif., April 04, 2022 (GLOBE NEWSWIRE) -- 4D Molecular Therapeutics, Inc. (4DMT) (Nasdaq: FDMT), a clinical-stage biotherapeutics company harnessing the power of directed evolution for targeted genetic medicines, announced that the first patient has been dosed in its Phase 1/2 clinical trial of 4D-710 in patients with cystic fibrosis.

The dosing of the first patient in the 4D-710 Phase 1/2 clinical trial in cystic fibrosis marks an important milestone for our company and for the patients we aim to benefit, said Robert Fishman, M.D., Chief Medical Officer and Pulmonology Therapeutic Area Head of 4DMT. 4D-710 utilizes the aerosol-delivered A101 vector developed at 4DMT through our proprietary Therapeutic Vector Evolution platform. To date, our platform has produced five clinical-stage product candidates that incorporate three different proprietary and novel capsids. We are seeking to unlock the full potential of genetic medicines through our platform and to fulfill the promise of transformative biotherapeutics to benefit patients.

4D-710 is designed for aerosol delivery to achieve CFTR expression within lung airway epithelial cells, said Jennifer L. Taylor-Cousar, M.D., M.S.C.S, Professor of Medicine and Pediatrics at National Jewish Health and lead principal investigator for the Phase 1/2 clinical trial. This therapy has the potential to treat a broad range of people with cystic fibrosis independent of their specific CFTR mutations. It could benefit both people with cystic fibrosis who arent able to take CFTR modulators as well as those who have a substantial residual deficit in lung function in spite of modulator therapy.

The Phase 1/2 clinical trial is a multicenter, open-label, dose-escalation and dose-expansion trial of 4D-710 in patients (n=~18) with cystic fibrosis who are ineligible for CFTR modulator therapy or who have discontinued therapy due to adverse effects. In the dose-escalation phase, two dose levels of 4D-710 will be examined in a 3+3 design. The primary endpoint of the study is safety and tolerability. Secondary endpoints include assessments of clinical activity including lung function, plus exploratory endpoints on the feasibility of detecting transgene transfer and microCFTR expression as measured in bronchoscopic biopsies and brushings.

Story continues

About 4D-710 and Cystic Fibrosis

4D-710 is comprised of our targeted and evolved vector, A101, and a codon-optimized microCFTR transgene. 4D-710 has the potential to treat a broad range of patients with cystic fibrosis, independent of the specific CFTR mutation, and is designed for aerosol delivery to achieve CFTR expression within lung airway epithelial cells. 4D-710 is being initially developed in the approximately 10-15% of patients whose disease is not amenable to existing medicines targeting the CFTR protein. In patients with CFTR mutations whose disease is amenable to modulator medicines, the improvement in lung function is variable. We therefore expect to potentially develop 4D-710 in this broader patient population, as a single agent and/or in combination with these CFTR modulator small molecule medicines.

Cystic fibrosis is a major inherited disease caused by mutations in the CFTR gene. According to the CF Foundation, more than 30,000 people in the United States and more than 70,000 people worldwide are living with cystic fibrosis, with approximately 1,000 new cases of cystic fibrosis diagnosed in the United States each year. Cystic fibrosis is a multisystem disorder affecting the lungs, digestive system and reproductive tract. Lung disease is the leading cause of morbidity and mortality. Cystic fibrosis causes impaired lung function, inflammation and bronchiectasis and is commonly associated with persistent lung infections and repeated exacerbations due to the inability to clear thickened mucus from the lungs. Patients with cystic fibrosis require lifelong treatment with multiple daily medications. These complications result in progressive loss of lung function and hospitalizations, and ultimately lead to end-stage respiratory failure.

About 4DMT

4DMT is a clinical-stage company harnessing the power of directed evolution for targeted genetic medicines. 4DMT seeks to unlock the full potential of gene therapy using its platform, Therapeutic Vector Evolution, which combines the power of directed evolution with approximately one billion synthetic capsid sequences to invent evolved vectors for use in targeted genetic medicine products. The company is initially focused on five clinical-stage products in three therapeutic areas: ophthalmology, cardiology (including Fabry disease) and pulmonology. The 4DMT targeted and evolved vectors are invented with the goal of being delivered through clinically routine, well-tolerated and minimally invasive routes of administration, transducing diseased cells in target tissues efficiently, having reduced immunogenicity and, where relevant, having resistance to pre-existing antibodies. The five 4DMT product candidates in clinical development are: 4D-310 for Fabry disease, 4D-150 for wet AMD, 4D-125 for XLRP, 4D-110 for choroideremia and 4D-710 for cystic fibrosis.

4D-310, 4D-150, 4D-125, 4D-110 and 4D-710 are in clinical trials and have not yet been approved for marketing by the US FDA or any other regulatory authority. No representation is made as to the safety or effectiveness of 4D-310, 4D-150, 4D-125, 4D-110 or 4D-710 for the therapeutic use for which they are being studied. 4D Molecular Therapeutics, 4DMT, Therapeutic Vector Evolution, and the 4DMT logo are trademarks of 4DMT.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended. In some cases, you can identify forward-looking statements by terminology such as aim, anticipate, assume, believe, contemplate, continue, could, design, due, estimate, expect, goal, intend, may, objective, plan, positioned, potential, predict, seek, should, target, will, would and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. All statements other than statements of historical facts contained in this press release are forward-looking statements. These forward-looking statements include, but are not limited to, statements about 4D-710s potential as a therapeutic product, including its potential to effectively treat a broad range of patients with cystic fibrosis independent of their specific CFTR mutations and the companys plans for developing 4D-710. Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, risks and uncertainties related to: the companys history of net operating losses and limited operating history; the companys ability to obtain necessary capital to fund its clinical programs; the risk and uncertainties inherent in the clinical drug development process; the early stages of clinical development of the companys product candidates and the limited regulatory and clinical experience to date for novel AAV gene therapy product candidates; the effects of COVID-19 or other public health crises on the companys clinical programs and business operations; the companys ability to obtain regulatory approval of and successfully commercialize its product candidates; any undesirable side effects or other properties of the companys product candidates; the companys reliance on third-party suppliers and other service providers; the outcomes of any current or future collaboration and license agreements; and the companys ability to adequately maintain intellectual property rights for its product candidates. These and other risks are described in greater detail under the section titled Risk Factors contained in the companys most recent Annual Report on Form 10-K filed as of March 28, 2022, as well as any subsequent filings with the Securities and Exchange Commission . Any forward-looking statements that the company makes in this press release are made pursuant to the Private Securities Litigation Reform Act of 1995, as amended, and speak only as of the date of this press release. Except as required by law, the company undertakes no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise.

Contacts:

Media:

Ingrid MezoCanale Communicationsingrid.mezo@canalecomm.com

Investors:

Mike ZanoniVP, Investor Relationsmzanoni@4dmt.com

See the article here:
4D Molecular Therapeutics Announces First Patient Dosed in Phase 1/2 Clinical Trial of 4D-710, an A101 AAV Vector-based, Aerosol-delivered Genetic...

In the presence of pancreatic tumors, certain immune cells break down structural proteins into molecules that trigger the building of dense tissue, a known barrier to therapy, a new study finds.

Led by researchers from NYU Grossman School of Medicine, the study revolves around the dense protein meshwork that supports organs and helps to rebuild damaged tissue. Collagen protein fibers, the major component of the mesh, are continually broken down and replaced to maintain tensile strength, and as part of the wound-healing process.

Past studies had shown that immune cells called macrophages contribute to a process called desmoplasia, which is caused by the abnormal turnover and excessive deposition of collagen that insulates pancreatic cancer. In this environment, macrophages are also known to engulf and break down collagen through the action of a protein called the mannose receptor (MRC1).

Published online April 4 in the Proceedings of the National Academies of Sciences, the current study found that the degraded collagen increased the amount of arginine, an amino acid that is used by the enzyme nitric oxide synthase (iNOS) to produce compounds called reactive nitrogen species (RNS). This, in turn, caused neighboring, supportive stellate cells to build collagen-based meshes around tumors, say the study authors.

Our results revealed how pancreatic tumors program macrophages to contribute to the construction of fibrotic barriers, says first study author Madeleine LaRue, PhD. At the time of the study, Dr. LaRue was a graduate student in the lab of senior study author Dafna Bar-Sagi, PhD, the Saul J. Farber Professor of Biochemistry and Molecular Pharmacology and vice dean for science at NYU Langone Health. This molecular framework could be harnessed to counter pro-cancer changes in structural tissues surrounding tumors, adds Dr. LaRue.

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States, with a 5-year survival rate of 10 percent. Pancreatic cancer remains difficult to treat in large part due to the extensive network of fibrotic tissue around tumors. This network not only blocks access by therapies, but also promotes aggressive growth.

For the current study, experiments showed that macrophages grown in dishes of nutrients (cultures), and converted into their cancer-tolerant setting (M2), broke down far more collagen than macrophages that attack cancer cells (M1). Further, the team confirmed with a series of tests that M2 macrophages have higher levels of enzymes that generate RNS, such as iNOS.

To confirm these findings in live mice, the team implanted stellate cells that were either pre-fed with collagen, or maintained in an unfed state, into the flanks of the study animals along with pancreatic cancer cells. The team observed a 100 percent increase in the density of intra-tumoral collagen fibers in tumors derived from cancer cells co-implanted with stellate cells pretreated with collagen.

Importantly, the study showed for the first time that macrophages near pancreatic cancer cells, not only take in and break down more collagen as part of scavenging for proteins that feed abnormal growth, but also are changed by the scavenging, such that their energy processing system (metabolism) is rewired and signals for fibrotic buildup.

Our team uncovered a mechanism that connects collagen turnover to the building of a treatment-resistant environment around pancreatic tumors, says Dr. Bar-Sagi. As this dense environment is a major reason why pancreatic cancer is so deadly, a better understanding of links between protein scavenging and the building of protective barriers will be needed to improve the treatment of this devastating malignancy.

Along with Dr. Bar-Sagi and Dr. LaRue, study authors from the Department of Biochemistry and Molecular Pharmacology at NYU Langone Health were Seth Parker and Joseph Puccini. Other authors were Alec Kimmelman, MD, PhD, chair of the Department of Radiation Oncology and a clinician and researcher at NYU Langones Perlmutter Cancer Center, and Michael Cammer of the Microscopy Laboratory, Division of Advanced Research Technologies, at NYU Grossman School of Medicine. The study was funded by National Institutes of Health grants T32GM066704, CA210263, P01CA117969, and CA232124, as well as by the Lustgarten Foundation and Stand Up To Cancer (SU2C).

Dr. Kimmelman has financial interests in Vescor Therapeutics, and is listed on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, and the autophagy control of iron metabolism. Dr. Kimmelman is on the scientific advisory board for Rafael/Cornerstone Pharmaceuticals, and consults for Deciphera and AbbVie. Dr. Bar-Sagi is on the Scientific Advisory Board of Rafael/Cornerstone Pharmaceuticals and Samumed LLC, and is also on the board of the Pancreatic Cancer Action Network. These relationships are being managed in keeping with the policies of NYU Langone Health.

Greg WilliamsPhone: 212-404-3500gregory.williams@nyulangone.org

More:
Pancreatic Cancer Cells Harness Tissue Turnover to Build Protective Barriers - NYU Langone Health