FDA Action Alert: Sanofi, Motif Bio and Merck

Over the next two weeks, the U.S. Food and Drug Administration (FDA) has three upcoming decisions. Here’s a look.

Sanofi’s Biologics License Application for Caplacizumab for aTTP

France’s Sanofi has a target action date of February 6 for its caplacizumab for acquired thrombotic thrombocytopenic purpura (aTTP), a life-threatening, autoimmune-based blood clotting disorder. The disease is marked by extensive blood clot formation in the small blood vessels of the body. This can lead to severe thrombocytopenia, which is a very low platelet count, microangiopathic hemolytic anemia, which is red blood cell destruction, and restricted blood supply throughout the body, or ischemia. This can cause widespread organ damage, particularly in the heart and brain.

The drug was approved under the brand name Cablivi by the European Commission in August 2018. The drug was developed by Ablynx, a Sanofi company. It is the company’s first Nanobody-based drug to receive approval and the first newly approved product that is part of Sanofi Genzyme’s Rare Blood Disorders franchise.

Motif Bio’s Antibiotic for Skin Infections

Motif Bio, with offices in New York and London, has a target action date of February 13 for its New Drug Application (NDA) for iclaprim, a targeted, Gram-positive investigational antibiotic for the treatment of acute bacterial skin and skin structure infections. The company also plans to develop the antibiotic for hospital-acquired pneumonia (HABP), including ventilator-associated bacterial pneumonia (VABP). A Phase II trial in patients with HABP has been completed and a Phase III trial is planned.

Iclaprim has received Qualified Infectious Disease Product (QIDP) designation from the FDA along with Fast Track designation for the ABSSSI indication.

The company presented iclaprim data in October at the IDWeek conference in San Francisco, showing it was non-inferior to vancomycin in a pooled analysis of a subgroup of patients in the REVIVE Phase III clinical trials in patients with wound infections.

G. Ralph Corey, Gary Hock Professor at Duke University School of Medicine and principal investigator of the REVIVE-2 trial, stated at the time, “Wound infections, including surgical site infections, can be difficult to treat and it was important to see that iclaprim was non-inferior to standard of care in treating these types of infections. Additionally, in the iclaprim treatment arm, there was no evidence of nephrotoxicity, while two patients in the vancomycin arm demonstrated high serum creatinine levels.”

Merck’s Checkpoint Inhibitor Keytruda Up for Another Indication

Merck & Company has a target action date of February 16 for its supplemental Biologics License Application (sBLA) for Keytruda, its anti-PD-1 therapy. It is being reviewed as adjuvant therapy in patients with resected, high-risk stage III melanoma. The sBLA is based on data from the pivotal Phase III EORTC1325/KEYNOTE-054 trial, which showed significant benefit in recurrence-free survival. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting 2018 and published in The New England Journal of Medicine.

In June, when the acceptance of the sBLA was announced, Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories, stated, “EORTC1325/KEYNOTE-054 was the first trial with Keytruda to demonstrate a recurrence-free survival benefit in the adjuvant setting, and we continue to actively investigate Keytruda in the adjuvant or neoadjuvant setting across our broad clinical development program.”

On Jan. 3, Merck announced that Keytruda had been approved for this indication by the Japan Pharmaceuticals and Medical Devices Agency (PMDA), as well as for four other indications: in combination with pemetrexed and platinum-based chemo for first-line unresectable, advanced/recurrent nonsquamous NSCLC regardless of PD-L1 expression; in combination with carboplatin and paclitaxel or nab-paclitaxel for first-line treatment of unresectable, advanced/recurrent squamous NSCLC regardless of PD-L1 expression; monotherapy in first-line treatment of PD-L1-positive unresectable, advanced/recurrent NSCLC; and as monotherapy for advanced/recurrent MSI-H solid tumors that have progressed after chemotherapy.

https://www.biospace.com/article/fda-action-alert-sanofi-motif-bio-and-merck/

Moderna’s Not the Only One: A Look at the mRNA Market

Although Moderna gets the lion’s share of attention in the mRNA market, it’s not the only company working to break away with this potentially disruptive technology.

Messenger RNA (mRNA) is a family of RNA molecules that transport genetic information from DNA to the ribosome, where it specifies the amino acid sequence that creates proteins. In theory, by coding your own mRNA, it should be possible to insert it into the cells and turn them into protein factories churning out whatever drug or molecule you program it to.

Moderna is the most prominent player in the field although it has yet to get a product to market. In December, the company went public, raising $604 million with its IPO. The company’s value is tagged at around $7.5 billion.

The company has a development pipeline of 21 programs. Ten are in the clinic and another three have open Investigational New Drug (INDs) submissions. Nine of those in the clinic are in Phase I and one is in Phase II, according to a July 2018 update.

But Moderna is not alone.

In August 2018, Pfizer entered a collaboration deal with Mainz, Germany-based BioNTech to develop mRNA-based vaccines to prevent influenza (flu). The two companies will jointly conduct research and development to advance the vaccines. Pfizer paid BioNTech $120 million upfront along with equity and near-term research payments. Another $305 million in milestones is up for grabs and if the vaccines make it to market, BioNTech will receive up to double-digit tiered royalties.

Earlier this month, Paris-based Sanofi extended a deal with BioNTech to co-develop and co-commercialize a cancer vaccine based on mRNA. And this deal follows a July deal Sanofi made with Lexington, Mass.-based Translate Bio to develop an mRNA vaccine for up to five infectious diseases. Sanofi Pasteur paid Translate Bio an upfront payment of $45 million. Translate Bio is eligible for up to $805 million in payments, including a $45 million upfront payment and various milestone payments and royalties.

On January 3, Translate Bio announced that its Phase I/II clinical trial of MRT5005, an mRNA treatment for cystic fibrosis, was ongoing. It also announced that its MRT5201, an mRNA candidate for patients with OTC deficiency, a common urea cycle disorder, was advancing, with the trial expected to begin in the first half of this year. However, on January 22, the company indicated the U.S. Food and Drug Administration (FDA) had requested more information about the IND submission for MRT5201.

Another company making waves in the mRNA market is CureVac, based in Tubingen, Germany and Boston. On October 23, 2018, the company announced it had initiated its Phase I dose-escalation trial of its mRNA-based rabies vaccine, CV7202. CV7202 is a “prophylactic mRNA-based vaccine encoding the rabies virus glycoprotein, RABV-G, formulated with the next generation LNP.”

LNP stands for Lipid Nanoparticle, which is a type of delivery system for mRNA.

On Jan. 8, 2019, the U.S. Patent and Trademark Office (USPTO) granted CureVac a fundamental patent for the use of MRNA for the Respiratory Syncytial Virus (RSV) F-protein to be used to vaccinate infants.

CureVac also has deals with Sanofi, Eli Lilly, and Boehringer Ingelheim.

In theory, mRNA could be used to treat any disease. However, it’s not all that simple. The major challenge is getting the mRNA to the right cells in order to express the protein. As a result, companies have tended to focus on what is often deemed “low-hanging fruit,” such as vaccines and cancer immunotherapies. That’s the case of CureVac, BioNTech and Moderna, but Translate Bio is focusing on a significantly more difficult challenge of cystic fibrosis.

https://www.biospace.com/article/moderna-s-not-the-only-one-a-look-at-the-mrna-market/

Turning Negative Emotions Into Positive Motivation

Social awkwardness, shyness: most of us have experienced such feelings at one time or another. In a recent post, I drew upon the unusual America’s Got Talent performance of Courtney Hadwin to illustrate how an immersion in our talents can transform us, making us “a different person.” In her performance zone, Courtney is able to do something more than simply overcome her reticence: she finds her assertive, empowered voice.

The implications for performance psychology are significant. It is one thing to cope with our frailties; quite another to channel them through our strengths to achieve unique heights. Yes, we can use psychological techniques to reduce our negative emotional experience. But could it be that, in directly facing our greatest negatives, we find our distinctive positives?

In my work with traders and portfolio managers in financial markets, I’ve seen most of the negatives that interfere with optimal performance. That includes, not only the classic fear and greed, but also frustration, overexcitement, boredom, and pessimism. Invariably these are viewed as problems to be overcome. As a result, traders focus on their problems and lose sight of their strengths and successes. If Courtney came onto the stage to be a less nervous singer, she would be mediocre at best. She makes her way to Champions by becoming a different kind of singer: one that lies on the other side of her “weakness”. The trader prone to frustration (and frustrated decision-making) can try to be a less agitated money manager–or could learn to become frustrated with his or her agitation and use the negative experience to double down on the positive motivation to stay market-focused and clear-minded. It is when we are most in touch with the negatives–and most distressed by them–that we can find the motivation to discover and maximize our positives.

Indeed, if we don’t use our most negative emotional experiences for positive transformation, all we’ll be left with is pain.

Recent writings and research in positive psychology suggest that there indeed are benefits to our negative emotions. As the Positive Psychology Program site notes, negative emotions can be motivators and can become powerful prods for mindfulness. For example, fear of consequences and vivid memories of past failures can help an alcoholic recognize and avoid urges to drink that might otherwise lead to relapse. Even more dramatically, those negative experiences can channel the alcoholic’s motivation toward helping others in support groups, transforming antisociality into very prosocial outcomes.

I was socially reticent in my young adult years, so my college friends played a prank on me, voting me social chairperson of the dormitory at a meeting where I was absent. Once voted in, I became extremely competitive, vowing to put together more successful parties than the other dorms. I polled students for their preferences and organized wine and cheese tasting events over the usual beer keg offerings. At the parties, I made sure to introduce people to each other and keep things lively. Before long, I adopted the identity of social organizer and later used those skills in leadership roles. Like Courtney, I drew on a strength (my competitive drive) to transform a weakness (reticence) into becoming a different person (social engaged).

In their book The Upside of Your Downside, Todd Kashdan and Robert Biswas-Diener introduce the concept of wholeness: the ability to tolerate distress as an important component of happiness. They advance the idea that all emotions are beneficial and can be channeled constructively, as in the case of anger helping us identify and advance our needs. Indeed, working through negative emotions can lead to more positive outcomes, as in the case of confused students who work through their confusion scoring better on tests than non-confused students. To perform at our best, the authors suggest, we need emotional wholeness: awareness and acceptance of all emotional experience. It is in the working through of the negativity that we achieve unique positives.

Ivtzan, Lomas, Hefferon, and Worth refer to “second wave” positive psychology as one that embraces adversity and negative experience in the building of resilience and growth. They note that the hero’s journey is one of overcoming obstacles, not one of unlimited joy and success. Self-transcendence through spirituality, they explain, is yet another example of overcoming limitations and negative experiences to achieve qualitative change. Most of the world’s great spiritual traditions, for example, incorporate rituals for repentance. In coming to terms with what we’ve done wrong, we connect to a deep sense of who we want to be, creating motivations that transcend ordinary, daily wants and needs.

The common theme here is that our most promising paths to growth may be through our negative traits and experiences and not around them. I would further add the possibility that our greatest negatives occur when we are most alienated from the values, talents, and meanings that underlie our strengths. If I’m not in my competitive mode of succeeding by helping others, I’m just a socially awkward person. If I’m not in my caring mode of training and helping developing traders, I’m simply another punter riding the emotional ups and downs of riding profits and losses. Perhaps you’ve experienced the unique loneliness of being in a group of people who do not and cannot connect emotionally. That can be painful; it can also become a prod to develop our most meaningful relationships.

All of us have a dark side. Cover it over and it merely becomes darker. Or we can recognize that the darkness is only possible in the absence of light. Who we are at our worst is simply the shadow of our best selves.

https://www.forbes.com/sites/brettsteenbarger/2019/01/31/turning-negative-emotions-into-positive-motivation/#3d96c95e78c0

Chugai, Roche get positive Hemlibra opinion from Euro panel

Chugai said that Roche has received notification that the EU Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for Hemlibra^®, a treatment for hemophilia A created by Chugai, for routine prophylaxis of bleeding episodes in adults and children with severe hemophilia A without factor VIII inhibitors, administered once weekly, every two weeks, or every four weeks. The CHMP has also adopted a positive opinion for additional dosing options of every two weeks or every four weeks in adults and children with hemophilia A with factor VIII inhibitors.

“We are thrilled that Hemlibra is expected to be approved shortly for people with severe hemophilia A without inhibitors in the Europe Union (EU). Also, I’m very pleased that people in the EU with hemophilia A will soon be offered multiple options of Hemlibra’s dosing interval regardless of their inhibitor expression,” said Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit, Dr. Osamu Okuda. “Hemlibra is co-promoted by Chugai and Roche in Germany, France, and the United Kingdom, as is the case with the anti-rheumatic agent RoActemra^®. We are committed to pursue our efforts in collaboration with Roche so that Hemlibra may further contribute to the treatment of hemophilia A.”

This positive opinion is based on results from two Phase III studies HAVEN 3 (NCT02847637) and HAVEN 4 (NCT03020160), conducted jointly with Roche and Genentech. HAVEN 3 study was conducted to evaluate the reduction of bleed rate of Hemlibra subcutaneous injection once a week and once every two weeks in people with hemophilia A (12 years of age or older) without inhibitors to factor VIII. HAVEN 4 study was conducted to evaluate efficacy, safety, and pharmacokinetics of Hemlibra subcutaneous injection every four weeks in people with hemophilia A (12 years of age or older), with and without inhibitors to factor VIII.

In Japan, Chugai obtained regulatory approval for Hemlibra from the Ministry of Health, Labour and Welfare in December 2018 for an additional indication of prophylactic treatment for people with hemophilia A without inhibitors to factor VIII, as well as for additional dosage and administration as a biweekly or every four-week treatment for people with hemophilia A with inhibitors to factor VIII.

https://www.marketscreener.com/CHUGAI-PHARMACEUTICAL-CO-6491165/news/Chugai-Pharmaceutical-Hemlibra-Gains-Positive-CHMP-Opinion-in-Severe-Hemophilia-A-Without-Inhibit-27957459/

Stem cell growth accelerated by tropoelastin surgical glue protein

Tropoelastin, the raw material used to create ‘MeTro’ elastic surgical glue developed with the University of Sydney, has been found to encourage stem cell growth—with the potential to ultimately help the body repair itself.

Stem cells are vital for therapeutic treatments to repair and build human tissue including skin and muscles. Researchers are constantly looking for ways to make stem cells work better, with worldwide demand for the cells far outstripping supply.

Now researchers have discovered a way to generate more stem cells cheaply and quickly, using tropoelastin – a protein that gives living tissues the ability to stretch and retract.

Published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), co-authors Dr. Giselle Yeo and Professor Anthony Weiss – from the University of Sydney’s Charles Perkins Centre, School of Life and Environmental Sciences and Bosch Institute – said the study describes a new and cost-effective method of growing and recruiting mesenchymal stem cells rapidly and efficiently.

“Stem cells are increasingly being used as cell therapies for a range of diseases that cannot be reliably treated by conventional medicine including skeletal tissue injuries, heart attacks, degenerative diseases and organ failure,” Dr. Yeo explained.

“Unfortunately, a lack of supply is hindering widespread use of such cell therapies.”

“Such technologies can help significantly lower the currently prohibitive cost of many cell therapies.”

Tropoelastin is a key component of MeTro, the groundbreaking ‘squirtable’ elastic surgical glue that can seal wounds in 60 seconds when exposed to UV light, developed by Professor Weiss in conjunction with researchers in the United States. Professor Weiss won the Eureka Prize for Innovation in Medical Research for his development and commercialisation of tropoelastin protein biomaterials.

Using human stem cells from donors, the researchers found that when small amounts of tropoelastin were applied it encouraged more cells to be produced, creating a better environment for growth compared to other commonly used proteins for stem cell cultures.

“Stem cells need a home to live and grow, and we’ve essentially created a nice environment for them live in,” Professor Weiss said.

“Making stems cells requires a process a bit like cooking soup – the more complex the culture or ‘soup’, the more difficult it is to control the growth of the cells and the more expensive it is to make.”

“Tropoelastin also encourages other stem cells to join the ‘soup’ – further increasing the rate of growth of the cells.”

Professor Weiss said the next stage of research would be to test the efficacy of tropoelastin inside the body.

“We expect that once these stem cells are inside a living body they will actually help trigger repair, encouraging other cells to come to the damaged area and supporting the body to repair itself,” he said.

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It’s all about the (stem cell) neighborhood

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More information: Giselle C. Yeo et al. Soluble matrix protein is a potent modulator of mesenchymal stem cell performance, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1812951116

https://medicalxpress.com/news/2019-02-stem-cell-growth-tropoelastin-protein.html

Senseonics reports preliminary Q4 revenue $8M, consensus $7.73M

Reports preliminary FY18 revenue $19.7M, consensus $19.46M. As of December 31, 2018, cash and cash equivalents were $136.8M and outstanding indebtedness was $67.7M. Foresees revenue for FY19 to be in the range of $28M-$32M.

https://thefly.com/landingPageNews.php?id=2858050

Senseonics announces extension of agreement with Roche Diabetes Care

Senseonics (SENS) announced an extension of its distribution agreement with Roche Diabetes Care (RHHBY). As extended, the agreement now runs through January 31, 2021. Under terms of the extended agreement, Roche will continue its role as Senseonics exclusive distributor in Europe, the Middle East and Africa, excluding Scandinavia and Israel. In addition, the agreement has been expanded to provide Roche with exclusive distribution rights in 17 additional countries, including Brazil, Russia, India and China, as well as select markets in the Asia Pacific and Latin American regions.
https://thefly.com/landingPageNews.php?id=2858049