3-D ‘Heat Map’ Animation Shows How Seizures Spread in the Brains of Patients with Epilepsy (Neuroscience)

For 29 years, from the time she was 12, Rashetta Higgins had been wracked by epileptic seizures – as many as 10 a week – in her sleep, at school and at work. She lost four jobs over 10 years. One seizure brought her down as she was climbing concrete stairs, leaving a bloody scene and a bad gash near her eye.

A seizure struck in 2005 while she was waiting at the curb for a bus. “I fell down right when the bus was pulling up,” she says. “My friend grabbed me just in time. I fell a lot. I’ve had concussions. I’ve gone unconscious. It has put a lot of wear and tear on my body.”

Rashetta Higgins after surgery in the UCSF Medical Center
Rashetta Higgins at the UCSF Helen Diller Medical Center at Parnassus Heights after surgery to implant more than 150 electrodes to monitor her seizures. Photo courtesy of Rashetta Higgins

Then, in 2016, Higgins’ primary-care doctor, Mary Clark, at La Clinica Vallejo, referred her to UC San Francisco’s Department of Neurology, marking the beginning of her journey back to health and her contribution to new technology that will make it easier to locate seizure activity in the brain. Medication couldn’t slow her seizures or diminish their severity, so the UCSF Neurology epilepsy team recommended surgery to first record and pinpoint the location of the bad activity and then remove the brain tissue that was triggering the seizures.

In April, 2019, Higgins was admitted to UCSF’s 10-bed Epilepsy Monitoring Unit at UCSF Helen Diller Medical Center at Parnassus Heights, where surgeons implanted more than 150 electrodes. EEGs tracked her brain wave activity around the clock to pinpoint the region of tissue that had triggered her brainstorms for 29 years.

In just one week, Higgins had 10 seizures, and each time, the gently undulating EEG tracings recording normal brain activity jerked suddenly into the tell-tale jagged peaks and valleys indicating a seizure.

To find the site of a seizure in a patient’s brain, experts currently look at brain waves by reviewing hundreds of squiggly lines on a screen, watching how high and low the peaks and valleys go (the amplitude) and how fast these patterns repeat or oscillate (the frequency). But during a seizure, electrical activity in the brain spikes so fast that the many EEG traces can be tough to read.

“We look for the electrodes with the largest change,” says Robert Knowlton, MD, professor of Neurology, the medical director of the UCSF Seizure Disorders Surgery Program and a member of the UCSF Weill Institute of Neurosciences. “Higher frequencies are weighted more. They usually have the lowest amplitude, so we look on the EEG for a combination of the two extremes. It’s visual – not completely quantitative. It’s complicated to put together.”

Measuring the Lines

Enter Jonathan Kleen, MD, PhD, assistant professor of Neurology and a member of the UCSF Weill Institute of Neurosciences. Trained as both a neuroscientist and a computer scientist, he quickly saw the potential of a software strategy to clear up the picture – literally.  

“The field of information visualization has really matured in the last 20 years,” Kleen said. “It’s a process of taking huge volumes of data with many details – space, time, frequency, intensity and other things – and distilling them into a single intuitive visualization like a colorful picture or video.”

Kleen developed a program that translates the hundreds of EEG traces into a 3-D movie showing activity in all recorded locations in the brain. The result is a multicolored 3-D heat map that looks very much like a meteorologist’s hurricane weather map.

Video: This video shows the OPSCEA (or “Ictal Cinema”) technology developed at the UCSF Epilepsy Center. It converts the usual complex “traced-based” recordings of brain waves that doctors see (on the right) into an intuitive heat map projected on the patient’s own 3D reconstructed brain (right hemisphere of brain show in main view). Each trace (line) on the right is from a single intracranial electrode (black dots in the brain view). The seizure intensity is calculated automatically from the traces (specifically from the location of the arrow) and converted into color intensity (using a “line length” algorithm), revealing how activity in a given seizure moves in space and time. The technology also applies “slice views” (example shown halfway through the video) so that activity from electrodes deep in the brain can be seen in addition to the brain surface. © UCSF

The heat map’s cinematic representation of seizures, projected onto a 3-D reconstruction of the patient’s own brain, helps one plainly see where a seizure starts and track where, and how fast, it spreads through the brain.

The heat map closely aligns with the traditional visual analysis, but it’s simpler to understand and is personalized to the patient’s own brain.

“To see it on the heat map makes it much easier to define where the seizure starts, and whether there’s more than one trigger site,” Knowlton said. “And it is much better at seeing how the seizure spreads. With conventional methods, we have no idea where it’s spreading.”

Researchers are using the new technology at UCSF to gauge how well it pinpoints the brain’s seizure trigger compared with the standard visual approach. So far, the heat maps have been used to help identify the initial seizure site and the spread of a seizure through the brain in more than 115 patients.

Kleen’s strategy is disarmingly simple. To distinguish seizures from normal brain activity, he added up the lengths of the lines on an EEG. Seizures show up as high peaks and low valleys that make their cumulative length quite long, while gently undulating brain waves make much shorter lines. Kleen’s software translated these lengths into different colors, and the visualization was born.

The technology proved pivotal in Higgins’ treatment.

“Before her recordings, we had feared that Rashetta had multiple seizure-generating areas,” Kleen said. “But her video made it plainly obvious that there was a single problem area, and the bad activity was rapidly spreading from that primary hot spot.”

The journal Epilepsia put Kleen’s and Knowlton’s 3-D heat map technology on the cover, and the researchers made their software open-source, so others can improve upon it.

“It’s been a labor of love to get this technology to come to fruition” Kleen said. “I feel very strongly that to make progress in the field we need to share technologies, especially things that will help patients.”

A Fresh Start

Higgins has been captivated by the 3-D heat maps of her brain.

“It was amazing,” she said. “It was like, ‘That’s my brain. I’m watching my brain function.’”

And the surgery has been a life-changing success. Higgins hasn’t had a seizure in more than two years, feels mentally sharp, and is looking for a job.

“When I wake up, I’m right on it every morning,” she said. “I waited for this day for a long, long time.”

Featured image: Animation shows a 3D heat map of a where a seizure is occuring in the brain © UCSF


Reference: Kleen, J.K., Speidel, B.A., Baud, M.O., Rao, V.R., Ammanuel, S.G., Hamilton, L.S., Chang, E.F. and Knowlton, R.C. (2021), Accuracy of omni-planar and surface casting of epileptiform activity for intracranial seizure localization. Epilepsia, 62: 947-959. https://doi.org/10.1111/epi.16841


Provided by UCSF

How Planets Can Affect The Sun? (Planetary Science)

The Institute of Astrophysics of Andalusia (IAA-CSIC) is involved in developing a theory that supports the hypothesis that planets affect the Sun’s magnetic activity. It shows how the small influence of the planets could set a rhythm in a system like the Sun that, if confirmed, would allow events such as solar storms to be predicted more accurately 

In 2012, a study in which the Institute of Astrophysics of Andalusia (IAA-CSIC) participated published the hypothesis that the planets could influence the Sun: the solar magnetic activity during the last ten thousand years was reconstructed by analyzing the concentration of beryllium -10 and carbon-14 in ice from Antarctica and Greenland and compared with the movement of the planets around the Sun. Coincidences were found that suggested a link, a result opposed to the general conviction that the influence of the planets on the Sun is negligible. A theoretical explanation of how this could happen is published today, a new model that, if confirmed, will allow more accurate predictions of solar phenomena.

NEW EXPLANATION FOR A CONTROVERSIAL HYPOTHESIS

An international scientific team comprising researchers from the IAA-CSIC, the EAWAG of the Swiss Federal Institute of Technology (ETH) and the Zurich University of Applied Sciences (ZHAW) proposes an explanation for how the small tidal effect of the planets could influence the Sun’s magnetic activity: stochastic resonance. Under certain conditions, this phenomenon can amplify weak, mostly periodic signals to the point where they produce significant consequences.

The stochastic resonance mechanism was proposed in 1981 to explain the alternation between terrestrial glacial and interglacial periods as a consequence of the variation of the Earth’s orbital parameters (known as the Milankovitch theory), and is related to the concept of bistability.

The Sun has an eleven-year cycle, during which its magnetic activity (manifested in the form of spots, explosions and ejections of matter into interplanetary space) ranges from a minimum to a maximum. But there are other cycles of longer periods. “We have been able to show that the Sun has two stable states of activity: an active state with great amplitude and high solar activity, and a calmer state with a small amplitude and less solar activity –indicates Carlo Albert, an EAWAG-ETH researcher involved in the study–. It would be a bistable system: we suppose that the Sun jumps between these two states due to the turbulence in its interior”. And, since turbulence occurs randomly, these changes would be expected to occur in a completely irregular and unpredictable way.

Data for measuring solar activity suggest, however, that the jump from one state to another does not occur randomly, but often has a rate of about two hundred years. It would be a cycle superimposed on the eleven-year cycle, which the 2012 work attributed to the influence of the planets but without explaining how such small bodies could affect the Sun, whose mass constitutes 99.86% of the entire Solar System.

In the work published today in the Astrophysical Journal Letters, a way to amplify that influence is proposed. “The ingredients of our model are three: bistability, a periodically modulated signal (coming from the weak tidal force exerted by the planets), and noise in the system, caused by the turbulent convection existing in an area of ​​the Sun that goes from the surface to a depth of about 200,000 kilometers –indicates Antonio Ferriz Mas, IAA-CSIC researcher and professor at the University of Vigo who participates in the work–. There is an optimal noise intensity such that the weak signal from the planets’ tidal forces is amplified enough to influence the generation of the Sun’s magnetic field.

Image of the Sun combining data at various wavelengths and showing the complexity of the solar magnetic field. A large active region can be seen in the center of the solar disk. Credit: ESO/P. Horálek/SOHO (NASA&ESA)/SDO (NASA).

TOWARDS A NEW GRAND SOLAR MINIMUM?

In a next step, the team will study to what extent observations of solar activity over the past centuries can be reproduced with this method. This would confirm the theory and also allow one more step: to predict solar activity for the next decades and centuries.

Such a prediction would be of great interest, since it seems that we are facing a turning point in solar activity. According to the 2012 hypothesis, now supported by this work, the Sun is at the end of an active phase and slowly moving towards a calmer one, and the first signs that the eleven-year cycle is weakening have been observed.

These quiet phases are known as great minima, and the data suggests that the Sun has experienced several over the past millennia. The last occurrence of a great minimum, which took place between approximately 1645 and 1715, coincided with the most intense stage of an especially cold period in much of Europe, known as the Little Ice Age (although it is not clearly demonstrated that there is a cause-effect relationship between both phenomena). It will, however, be a few more years before we know for sure whether the Sun will enter a new grand minimum.

Filament of solar material ejected into space during a coronal mass ejection, one of the phenomena associated with solar magnetic activity. Credit: NASA.

Reference: 

C. Albert, A. Ferriz-Mas et al. “Can Stochastic Resonance explain Recurrence of Grand Minima?”. Astrophysical Journal Letters, July 2021. https://iopscience.iop.org/article/10.3847/2041-8213/ac0fd6


Provided by IAA CISC

WVU Engineers Develop New Geothermal Energy Technology (Engineering)

As alternative energy sources have become necessary to decrease global carbon emissions and meet growing energy demands, researchers at West Virginia University had ideas that came bubbling to the top—literally.

 As part of the American-Made Geothermal Manufacturing Prize competition, a challenge designed to spur innovation and address manufacturing challenges in geothermal environments, associate professor Terence Musho and Berry Chair Emeritus Nigel Clark in the Statler College of Engineering and Mineral Resources, have developed a new airlift approach to optimize current geothermal pump technologies.

 The two most common methods of bringing geothermal fluids to the surface are by using a line shaft pump or a submersible pump, although both methods have limitations. The method proposed by the engineers employs a 3D-printed device—a sparger head— to generate bubbles and lift water to the surface.

 “Improved design of the sparger head for airlifts will revolutionize what the industry has been doing and eliminate the line shaft pump,” Musho said. “We can access much deeper geothermal wells, which typically have higher temperatures, which is better for direct usage and energy generation type applications.”

 By injecting air deep into a geothermal well, it then rises to interact with geothermal fluids. As the air bubbles rise to the top of the well, an exchange in momentum causes the geothermal fluids to rise.

 According to Musho, the technology works in a similar way to an automatic drip coffee maker. Typically, the water boils and travels up a tube to the top; instead of boiling the water, this method injects air into the water relying on the same buoyancy force to bring fluids up to the surface. 

 “The focus of this project relies on the efficient creation of bubbles,” Musho said. 

“The software-based optimization will provide a more efficient operating environment by tailoring bubble generation for a given well condition.”

 The advantages of geothermal energy production are many: unlike wind and solar, geothermal power plants produce electricity around the clock, modern plants emit no greenhouse gases and have a smaller physical footprint than other energy-generating plants, according to the DOE.

 Musho and Clark teamed up with industry collaborators Dan Hand, a professional engineer from Sustainable Engineering LLC, and Roy Mink from Mink GeoHydro Inc, for the competition. The researchers are working within the Oak Ridge National Laboratory’s Manufacturing Demonstration Facility to utilize their state-of-the-art 3D metal printers.

 As semifinalists of the competition, the team will make their submission for the Make Phase of the competition in November, if their technology is selected, it will be tested on working geothermal wells and the Statler College team will be eligible for up to $250,000 in cash prizes and up to $50,000 in vouchers.

Featured image: Ansan Pokharel, mechanical and aerospace engineering graduate student, tests the improved sparger design created by West Virginia University engineers. (WVU Photo/Paige Nesbit)


Provided by WVU Today

Study Shows Masks Can Prevent COVID-19 (Medicine)

Mayo Clinic researchers recently published a study that shows the proper use of masks reduces the spread of respiratory droplets. The findings strongly support the protective value and effectiveness of widespread mask use and maintaining physical distance in reducing the spread of COVID-19.

Reporter Jason Howland has more in this Mayo Clinic Minute.

Watch: The Mayo Clinic Minute

Journalists: Broadcast-quality video (0:59) is in the downloads at the end of this post. Please courtesy: “Mayo Clinic News Network.” Read the script.

Do face masks work at preventing COVID-19 transmission?

“Masks don’t work unless we wear them,” says Dr. Elie Berbari, a Mayo Clinic infectious diseases physician.

That’s what Mayo Clinic researchers say they proved in a recent study.

“We found objectively that masks are critically important. They’re very effective at protecting the people around you. If you’re wearing a mask, you’re protecting others. If they’re wearing masks, they’re protecting you,” says Dr. Matthew Callstrom, a Mayo Clinic radiologist and one of the study’s authors.

The experiments used masked and unmasked mannequins that simulated the spread of respiratory droplets and measured it at various distances.

“The most important transmission of a COVID-19 particle is a respiratory droplet. We measured the aerosol particles which are even smaller. And we found that masking was very effective even for those particles, the smallest ones,” says Dr. Callstrom.

The study showed that disposable paper medical masks and two-layer cloth masks reduced droplet transmission.

“We’re all tired of wearing masks. But I think this is really highlighting the importance of it,” says Dr. Berbari.

Featured image credit: Getty Images


Reference: Jonathan R. Tomshine, Kendall D. Dennis, Russell E. Bruhnke, James H. Christensen, Tom G. Halvorsen, Christopher J. Hogan, John C. O’Horo, Laura E. Breeher, Matthew R. Callstrom, Mark B. Wehde, Combined Effects of Masking and Distance on Aerosol Exposure Potential, Mayo Clinic Proceedings, Volume 96, Issue 7, 2021, Pages 1792-1800, ISSN 0025-6196, https://doi.org/10.1016/j.mayocp.2021.05.007. (https://www.sciencedirect.com/science/article/pii/S0025619621004018)


Provided by Mayo Clinic

Regenerative Pipeline For Spinal Cord Repair (Medicine)

Mayo Clinic research is learning how stem cell therapy can treat neurodegenerative diseases. Mayo is among the first to study whether stem cell therapy might trigger healing for spinal cord injury.

Research is ongoing in preclinical models, but it also has advanced from discovery science to early clinical trials. It’s a complex question, because different forms of stem cells can be derived from different biologics within the body. Mayo Clinic’s Center for Regenerative Medicine is driving the research that seeks new ways to restore form and function for patients with debilitating injuries and diseases.

Stem cells for spinal cord injury investigated

In a recent article published in Spinal Cord, Mayo Clinic researchers found that rats with spinal cord injury have improved movement after applying stem cells. The authors hope this preclinical data will support the eventual development of regenerative therapy for spinal cord healing.

Mohamad Bydon, M.D. © Mayo Clinic

“Spinal cord injury affects many patients, and current treatments are often limited and supportive in nature,” says Mohamad Bydon, M.D., a Mayo Clinic neurosurgeon and senior author of the paper. “This research is an opportunity to impact a significant disease that causes a great burden to so many patients.”

When the spine is injured, the electrical signal it carries from the brain is stopped at the point of injury, and the patient experiences paralysis. Unlike skin or muscle cells, injured cells of the spinal cord, called “neurons,” don’t repair or replace themselves very quickly or at all, especially as the body ages. To see if the healing process could be jump-started, Dr. Bydon’s team examined if the cells that help regenerate other tissues could help in the spine, as well.

Stem cells are a kind of cellular template. In an embryo, these are the cells that can divide into more stem cells or become other tissues in the body. In adults, stem cells are more limited, but they are also less controversial in terms of ethical use. They can be harvested from bone marrow or fat tissue, and then engineered back into a stem cell-like state and called “mesenchymal stem cells.” Less invasively, stem cells can be gathered from umbilical cord blood saved after pregnancy. These cells are, as Dr. Bydon and his co-authors write, easier to work with and divide more actively than mesenchymal stem cells collected from bone marrow or fat.

Stem cells are a kind of cellular template. In an embryo, these are the cells that can divide into more cells or become other tissues in the body. © Shutterstock

The team, which is led by Dr. Bydon and F.M. Moinuddin, Ph.D., a Mayo Clinic scientist, used rat umbilical cord stem cells to treat six of the 12 rats in the study one week after spinal cord injury. The rats were evaluated for 14 weeks after injury, and the authors found that the procedure resulted in improved motor function, compared to the control rats.

“Umbilical cord-derived mesenchymal stem cells may have a neuroprotective function,” says Dr. Bydon, citing better healing in the insulation around the nerve cells, smaller injury size, fewer immune cells flocking to the area and reduced scar formation.

In subsequent work, the team plans to clarify the regenerative properties of mesenchymal stem cells to create a targeted therapy for spinal cord healing.

“At Mayo, we focus on the needs of the patient, and in the case of patients with spinal cord injury, there is a significant area of unmet need,” says Dr. Bydon. “We have the opportunity and potential to create new paradigms of treatment.”

In addition to Drs. Bydon and Moinuddin, other authors currently at Mayo are Yagiz Yolcu, M.D.; Bingkun Chen, Ph.D.; Mohammed Ali Alvi, M.B.B.S; Anshit Goyal, M.B.B.S; Jarred Nesbitt; and Anthony Windebank, M.D. Funding for this work was provided, in part, by the Sabes Family Foundation. For a complete list of authors, see the paper published in Spinal Cord.

Center for Regenerative Medicine supports stem cell research. Earlier research at Mayo documented stem cell intervention in the lower back offers hope for people with spinal cord injury. © Mayo Clinic

Move toward clinical trials at Mayo Clinic

Earlier research at Mayo Clinic documented that stem cell intervention in the lumbar, or lower back, offers hope for people paralyzed from spinal cord injury. A Mayo Clinic case study found mesenchymal stem cells derived from a patient’s own fat injected after standard surgery, and physical and occupational therapy, are safe, and these cells restored bodily function in the first person tested.

Much like early trials in general, Dr. Bydon adds that stem cell trials are going to show variable response rates. Therefore, it’s too early to consider stem cell therapies as a treatment or cure for paralysis from spinal cord injury.

Dr. Bydon has advanced his research into stem cell therapy into a phase two clinical trial that is testing the effectiveness of stem cell therapy in treating spinal cord injury. It could be years before there are conclusive results that could be applied to daily clinical care. Dr. Bydon’s research is supported by the Sabes Family Foundation.


Provided by Mayo Clinic

High-precision Frequency Measurement (Physics)

Many scientific experiments require highly precise time measurements with the help of a clearly defined frequency. Now, a new approach allows the direct comparison of frequency measurements in the lab with the atomic clock in Bern, Switzerland.

For many scientific experiments, today’s researchers require a precise reference frequency that allows them to calibrate the time measurements made by their equipment. Such experiments include spectroscopy investigations – in which chemical reactions between molecules are examined in real time – and physical studies on natural constants.

Access to exactly this kind of highly precise reference frequency could soon become standard for Swiss research institutions. In a joint project funded as part of the Swiss National Science Foundation’s Sinergia programme, researchers at ETH Zurich, the University of Basel, the Swiss Federal Institute of Metrology (Metas) – Switzerland’s «guardian of measurement units» – and the Switch Foundation, which operates Switzerland’s academic data network, have demonstrated that such a precision reference signal can be sent via conventional telecommunications infrastructure.

«Initial results show that this permits chemical spectroscopy analyses that are 100 times more accurate than before», reports Stefan Willitsch, Professor of Physical Chemistry at the University of Basel and coordinator of the project. «With this precision, the laws of nature are verified by spectroscopic measurements on molecules with unprecedented accuracy,» adds Frédéric Merkt, Professor of Physical Chemistry at ETH Zurich.

Continuous correction

Specifically, the project established a trial network that connects the METAS site in Wabern near Bern with the University of Basel and ETH Zurich. A clever process synchronises the output signal with the Metas atomic clock. This signal is transmitted via the fibre-optic network operated by Switch – which manages IT network infrastructures for Swiss universities – to Basel and Zurich, where researchers can use it to calibrate their measuring devices.

«To ensure that the signal reaches the researchers with the desired level of precision, transmission must be continuously adjusted. Even the slightest variation in the length of the fibre-optic cable – caused by vibrations or temperature changes – affect the frequency», explains Jacques Morel, Head of the Photonics, Time and Frequency Laboratory at Metas. Therefore the signal is bounced back from Basel and Zurich to Bern, where the output signal is corrected as required.

High quality, lower costs

«In Switzerland, we’re only now beginning to establish this kind of network,» says Jérôme Faist, Professor at the Institute for Quantum Electronics at ETH Zurich, who contributed his expertise in laser technology to the project. «Other countries like Italy, Germany and France are already a step ahead in this area.»

In these countries, the reference frequencies have, up to now, been transmitted in one of two ways – each with its own specific drawbacks. Either the signal is sent via a dedicated cable, which produces an optimum physical result but is expensive, or the signal is transmitted via the telecommunications provider’s existing infrastructure. While this is much cheaper, it is technically inferior because the reference signal for measuring time is transmitted within the C band, in other words at a similar base frequency to data traffic. Not only does this leave the reference signal open to potential disruption by the rest of the data traffic, it blocks a channel that would normally be used for data transmission, which in turn complicates operation.

«We’ve now developed a third option,» explains Fabian Mauchle, project manager at Switch: «For reasons of cost, we use the existing Switch network. But instead of transmitting the reference signal within the physically optimum C band – which is largely taken up by data traffic – we use the L band, which is still mostly uncongested and has a different base frequency.» The results now show that the L band is also a viable option for transmitting reference signals at excellent quality without encountering disruption from data traffic. This did, however, require Switch to make certain modifications to its network infrastructure.

International networking

The next step will be to further expand the network to include other Swiss institutions such as Cern in Geneva, EPFL or the University of Neuchâtel. There are also plans to take the network to an international level. The goal is to establish a transnational network capable of comparing signals from various atomic clocks.

This would pave the way for an even more precise time measurement for defining the second as an SI unit. To ensure consistent time measurement worldwide, atomic clocks are currently compared with satellite signals in the gigahertz range. Synchronising atomic clocks using optical signals in the terahertz range would allow measurements of the second up to 18 decimal places instead of the «mere» 16 decimal places previously achieved. But the only way this can work is if the signals used to compare these optical clocks are transmitted as light via fibre optics.

Interesting for other disciplines

Faist also points out that it’s not just chemists and physicists who could benefit from the new network. It could provide geoscientists with new insights, too. Geoscientists might not require highly precise time signals for their experiments, but since even the tiniest disruption will affect the signal frequency, they could use the approach to detect subsurface vibrations that are too subtle for today’s measuring devices to register.

Featured image: Close-up of the optical components used to stabilise the light of the infrared laser for the precise reference frequency. (Image: Metas)


Reference

Husmann D et.al.: SI-traceable frequency dissemination at 1572.06 nm in a stabilized fiber network with ring topology. Vol. 29, No. 16 /2 August 2021. doi: 10.1364/OE.427921


Provided by University of Basel

FDA Grants Breakthrough Therapy Designation for Venclexta in Combination With Azacitidine For Myelodysplastic Syndromes (Medicine)

FDA Grants Breakthrough Therapy Designation for Venclexta in Combination With Azacitidine for the Treatment of Patients With Myelodysplastic Syndromes

  • Every year in the United States, approximately 10,000 people are diagnosed with myelodysplastic syndromes (MDS), and there remains a high unmet need for new treatment options.
  • The designation is based on interim results from the Phase Ib M15-531 study investigating Venclexta plus azacitidine in people with previously untreated higher-risk MDS.
  • This is the 11th Breakthrough Therapy Designation for Genentech’s hematology medicines and the sixth for Venclexta, demonstrating its potential across multiple blood cancers.

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that Venclexta® (venetoclax) in combination with azacitidine has been granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with previously untreated intermediate, high- and very high-risk myelodysplastic syndromes (MDS) based on the revised International Prognostic Scoring System (IPSS-R). MDS are a rare group of blood cancers that gradually affect the ability of the bone marrow to produce normal blood cells. This can lead to weakness, frequent infections, anemia and debilitating fatigue that can profoundly affect a person’s quality of life. In some cases, MDS can also progress into acute myeloid leukemia (AML). Every year in the United States, approximately 10,000 people are diagnosed with MDS, and the median survival for those with higher-risk MDS is approximately 18 months.

“Higher-risk MDS is associated with poor prognosis, reduced quality of life, and limited treatment options,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “We are pleased that the FDA has granted Venclexta its sixth Breakthrough Therapy Designation in recognition of its potential to improve outcomes for people with MDS in combination with azacitidine.”

This designation was granted based on interim results from the Phase Ib M15-531 study investigating Venclexta plus azacitidine in people with previously untreated, higher-risk MDS. BTD is designed to accelerate the development and review of medicines intended to treat serious or life-threatening conditions with preliminary evidence that indicates they may demonstrate a substantial improvement over existing therapies. This is the 38th BTD for Genentech’s portfolio of medicines, and the 11th designation for its hematology portfolio.

This most recent designation reinforces the potential of Venclexta-based combinations across several blood cancers, including MDS. In the United States, Venclexta has been granted six BTDs by the FDA: one for previously untreated chronic lymphocytic leukemia (CLL), two for relapsed or refractory CLL, two for previously untreated AML, and one for MDS. Venclexta is already approved in the United States in combination with azacitidine, decitabine or low-dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, and in the European Union in combination with hypomethylating agents, azacitidine and decitabine, for the treatment of adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy. Venclexta is also approved in the United States and European Union in combination with Rituxan® (rituximab) for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with Gazyva® (obinutuzumab) for the treatment of adult patients with previously untreated CLL; and as a monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in people who are unsuitable for or have failed a B-cell receptor pathway inhibitor.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States.

About Myelodysplastic Syndromes (MDS)

MDS are a rare group of blood cancers that gradually affect the ability of the bone marrow to produce normal blood cells. This can lead to weakness, frequent infections, anemia and debilitating fatigue. In some cases, MDS can also progress into acute myeloid leukemia (AML). Every year in the United States, approximately 10,000 people are diagnosed with MDS, and the median survival for those with higher-risk MDS is approximately 18 months.

There are several classifications of MDS – very low-risk to very high-risk – determined by the composition of the bone marrow, blood cell counts, and chromosomal alterations. Higher-risk disease is defined as intermediate, high- or very high-risk based on the revised International Prognostic Scoring System (IPSS-R), which is a risk assessment scale that uses five prognostic indicators to predict the course of a patient’s disease. Approximately half (45%) of patients present with higher-risk MDS, which is associated with a poorer prognosis and short life expectancy.

About the M15-531 study

The M15-531 [NCT02942290] study is a Phase Ib, open-label, non-randomized, multicenter, dose-finding study evaluating Venclexta® (venetoclax) in combination with azacitidine in treatment-naïve patients with higher-risk myelodysplastic syndromes (MDS) comprising a dose-escalation portion and a safety expansion portion. The primary objectives of the study are to assess the safety profile and pharmacokinetics and determine the recommended Phase II dose and dosing schedule of Venclexta in combination with azacitidine. The response criteria specified in the M15-531 study are based on the modified International Working Group 2006 response criteria for MDS.

About Venclexta

Venclexta is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to help restore the process of apoptosis.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States. Together, the companies are committed to research with Venclexta, which is currently being studied in clinical trials across several types of blood cancers.

Venclexta Indications
Venclexta is a prescription medicine used:

  • to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
  • in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:

‒ are 75 years of age or older, or

‒ have other medical conditions that prevent the use of standard chemotherapy.

It is not known if Venclexta is safe and effective in children.

Important Safety Information
What is the most important information patients should know about Venclexta?

Venclexta can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. The patient’s doctor will do tests to check their risk of getting TLS before they start taking Venclexta. The patient will receive other medicines before starting and during treatment with Venclexta to help reduce the risk of TLS. The patient may also need to receive intravenous (IV) fluids into their vein.

The patient’s doctor will do blood tests to check for TLS when the patient first starts treatment and during treatment with Venclexta. It is important for patients to keep appointments for blood tests. Patients should tell their doctor right away if they have any symptoms of TLS during treatment with Venclexta, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Patients should drink plenty of water during treatment with Venclexta to help reduce the risk of getting TLS.

Patients should drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before the first dose on the day of the first dose of Venclexta, and each time a dose is increased.

The patient’s doctor may delay, decrease the dose, or stop treatment with Venclexta if the patient has side effects. When restarting Venclexta after stopping for 1 week or longer, the patient’s doctor may again check for the risk of TLS and change the patient’s dose.

What patients should not take Venclexta?

Certain medicines must not be taken when the patient first starts taking Venclexta and while the dose is being slowly increased because of the risk of increased TLS.

  • Patients should tell their doctor about all the medicines they take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Venclexta and other medicines may affect each other causing serious side effects.
  • Patients must not start new medicines during treatment with Venclexta without first talking with their doctor.

Before taking Venclexta, patients must tell their doctor about all of their medical conditions, including if they:

  • Have kidney or liver problems.
  • Have problems with body salts or electrolytes, such as potassium, phosphorus, or calcium.
  • Have a history of high uric acid levels in the blood or gout.
  • Are scheduled to receive a vaccine. Patients should not receive a “live vaccine” before, during, or after treatment with Venclexta, until the patient’s doctor tells them it is okay. If the patient is not sure about the type of immunization or vaccine, the patient should ask their doctor. These vaccines may not be safe or may not work as well during treatment with Venclexta.
  • Are pregnant or plan to become pregnant. Venclexta may harm an unborn baby. If the patient is able to become pregnant, the patient’s doctor should do a pregnancy test before the patient starts treatment with Venclexta, and the patient should use effective birth control during treatment and for at least 30 days after the last dose of Venclexta. If the patient becomes pregnant or thinks they are pregnant, the patient should tell their doctor right away.
  • Are breastfeeding or plan to breastfeed. It is not known if Venclexta passes into the patient’s breast milk. Patients are instructed to not breastfeed during treatment with Venclexta and for 1 week after the last dose.

What to avoid while taking Venclexta:
Patients should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while they are taking Venclexta. These products may increase the amount of Venclexta in the patient’s blood.

What are the possible side effects of Venclexta?

Venclexta can cause serious side effects, including:

  • Low white blood cell counts (neutropenia). Low white blood cell counts are common with Venclexta, but can also be severe. The patient’s doctor will do blood tests to check their blood counts during treatment with Venclexta and may pause dosing.
  • Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with Venclexta. The patient’s doctor will closely monitor and treat the patient right away if they have a fever or any signs of infection during treatment with Venclexta.

Patients should tell their doctor right away if they have a fever or any signs of an infection during treatment with Venclexta.

The most common side effects of Venclexta when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell count; low platelet count; low red blood cell count; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of arms, legs, hands, and feet.

The most common side effects of Venclexta in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

Venclexta may cause fertility problems in males. This may affect the ability to father a child. Patients should talk to their doctor if they have concerns about fertility.

These are not all the possible side effects of Venclexta. Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at 1-888-835-2555.

Please see the Venclexta full Prescribing Information, including the Medication Guide, for additional Important Safety Information.

About Genentech in Hematology
For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit http://www.gene.com/hematology.

About Genentech
Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.


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FDA Accepts Application for Genentech’s Faricimab for the Treatment of AMD and DME (Medicine)

FDA Accepts Application for Genentech’s Faricimab for the Treatment of Wet Age-Related Macular Degeneration (AMD) and Diabetic Macular Edema (DME)

  • Across four Phase III studies, approximately half of patients receiving faricimab could extend treatment time to every four months – the first time this level of durability has been achieved in Phase III wet AMD and DME studies
  • If approved, faricimab would be the first and only medicine designed to target two distinct pathways that drive retinal diseases that can cause vision loss
  • The European Medicines Agency has also validated the faricimab Marketing Authorization Application submission in wet AMD and DME.

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has accepted the company’s Biologics License Application (BLA), under Priority Review, for faricimab for the treatment of wet, or neovascular, age-related macular degeneration (AMD) and diabetic macular edema (DME). The FDA has also accepted the company’s submission for diabetic retinopathy.

Faricimab will be the first and only bispecific antibody designed for the eye, if approved. It targets two distinct pathways – via angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A) – that drive a number of retinal conditions that can cause vision loss.

“If approved, faricimab would be the first in a new class of eye medicines targeting two key pathways that drive retinal disorders, with the potential to offer durable vision outcomes with fewer eye injections than the current standard of care,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “Therefore, we hope faricimab will become a new treatment option for millions of people living with wet AMD and DME.”

Wet AMD and DME are two leading causes of vision loss among adults in the United States. The BLA submission is based on positive results across four Phase III studies in wet AMD and DME. The studies consistently showed that faricimab, given at intervals of up to four months, offered non-inferior vision gains compared with aflibercept, given every two months. Approximately half of people eligible for extended dosing with faricimab were able to be treated every four months in the first year in the TENAYA and LUCERNE studies in wet AMD and the YOSEMITE and RHINE studies in DME. Faricimab is the first injectable eye medicine to achieve this length of time between treatments in Phase III studies for wet AMD and DME. Furthermore, approximately three-quarters of people eligible for extended dosing with faricimab were able to be treated every three months or longer in the first year. Faricimab was generally well-tolerated in all four studies, with no new or unexpected safety signals identified.

Genentech also has long-term extension studies underway for faricimab. These include AVONELLE X, an extension study of TENAYA and LUCERNE evaluating the long-term safety and efficacy of faricimab in wet AMD, and RHONE X, an extension study of YOSEMITE and RHINE evaluating the long-term safety and efficacy of faricimab in DME. Additionally, the COMINO and BALATON trials are also underway, evaluating the efficacy and safety of faricimab in people with macular edema secondary to two types of retinal vein occlusion (RVO): central RVO and branch RVO.

The European Medicines Agency has also validated the faricimab Marketing Authorization Application for the treatment of wet AMD and DME.

About the TENAYA and LUCERNE Studies

TENAYA (NCT03823287) and LUCERNE ( NCT03823300) are two identical, randomized, multicenter, double-masked, global Phase III studies evaluating the efficacy and safety of faricimab compared to aflibercept in 1,329 people living with wet age-related macular degeneration (671 in TENAYA and 658 in LUCERNE). The studies each have two treatment arms: faricimab 6.0 mg administered at fixed intervals of every two, three, or four months, selected based on objective assessment of disease activity at weeks 20 and 24; and aflibercept 2.0 mg administered at fixed two-month intervals. In both arms, sham injections were administered at study visits when treatment injections were not scheduled, to maintain the masking of investigators and participants.

The primary endpoint of the studies is the average change in best-corrected visual acuity (BCVA) score (the best distance vision a person can achieve – including with correction such as glasses – when reading letters on an eye chart) from baseline through week 48. Secondary endpoints include: safety; the percentage of participants in the faricimab arm receiving treatment every two, three and four months; the percentage of participants achieving a gain, and the percentage avoiding a loss, of 15 letters or more in BCVA from baseline over time; and change in central subfield thickness (CST) from baseline over time.

Both studies met their primary endpoint, with faricimab consistently shown to offer non-inferior visual acuity gains to aflibercept. In TENAYA and LUCERNE, the average vision gains from baseline in the faricimab arms were +5.8 and +6.6 letters, respectively, compared to +5.1 and +6.6 letters in the aflibercept arms.

The studies also measured the proportion of people in the faricimab arm that were treated on dosing schedules of every three or four months during the first year. Importantly, 46% (n=144/315) of patients in TENAYA and 45% (n=142/316) in LUCERNE were able to be treated every four months in the first year. An additional 34% (n=107/315) of patients in TENAYA and 33% (n=104/316) in LUCERNE were able to be treated every three months. Combined, nearly 80% of faricimab-treated patients were able to go three months or longer between treatments during the first year. In both studies, faricimab given at intervals of up to four months offered reductions in CST comparable to aflibercept given every two months. Faricimab was generally well-tolerated in both studies, with no new or unexpected safety signals identified.

About the YOSEMITE and RHINE Studies

YOSEMITE (NCT03622580) and RHINE (NCT03622593) are two identical, randomized, multicenter, double-masked, global Phase III studies evaluating the efficacy and safety of faricimab compared to aflibercept in 1,891 people with diabetic macular edema (940 in YOSEMITE and 951 in RHINE). The studies each have three treatment arms: faricimab 6.0 mg administered at personalized treatment intervals (PTI) of up to four months; faricimab 6.0 mg administered at fixed two-month intervals; and aflibercept 2.0 mg administered at fixed two-month intervals. In all three arms, sham injections were administered at study visits when treatment injections were not scheduled, to maintain the masking of investigators and participants.

The primary endpoint of the studies is the average change in BCVA score from baseline at one year. Secondary endpoints include: safety; the percentage of participants in the personalized dosing arm receiving treatment every one, two, three and four months, at week 52; the percentage of participants achieving a two-step or greater improvement from baseline in diabetic retinopathy severity at week 52; the percentage of participants achieving a gain, and the percentage avoiding a loss, of 15 letters or more in BCVA from baseline over time and change in central subfield thickness (CST) from baseline over time.

Both studies met their primary endpoint with faricimab consistently shown to offer non-inferior visual acuity gains to aflibercept. In YOSEMITE, the average vision gains from baseline were +11.6 and +10.7 eye chart letters in the faricimab PTI and two-month arms, respectively, and +10.9 letters in the aflibercept arm. In RHINE, the average vision gains from baseline were +10.8 and +11.8 letters in the faricimab PTI and two-month arms, respectively, and +10.3 letters in the aflibercept arm.

A secondary endpoint in both studies measured the proportion of people in the faricimab PTI arm that achieved dosing schedules of every three or four months at the end of the first year. Importantly, 53% (n=151/286) of faricimab PTI patients in YOSEMITE and 51% (n=157/308) in RHINE achieved four-month dosing at one year. An additional 21% (n=60/286) of faricimab PTI patients in YOSEMITE and 20% (n=62/308) in RHINE achieved three-month dosing. Combined, more than 70% of faricimab PTI patients were able to go three months or longer between treatments at the end of the first year. In both studies, faricimab given at intervals of up to four months demonstrated greater reductions in CST compared to aflibercept given every two months. Faricimab was generally well-tolerated in both studies, with no new or unexpected safety signals identified.

About Wet Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a condition that affects the macula, the part of the eye that provides sharp, central vision needed for activities like reading, and is a leading cause of blindness for people aged 60 and over in the United States. Wet, or neovascular, AMD is an advanced form of the disease that can cause rapid and severe vision loss. Approximately 11 million people in the United States have some form of AMD, and of those, about 1.1 million have wet AMD.

Wet AMD is caused by growth of abnormal blood vessels, also referred to as choroidal neovascularization (CNV), into the macula. These vessels leak fluid and blood and cause scar tissue that destroys the central retina. This process results in a deterioration of sight over a period of months to years.

About Diabetic Macular Edema

Affecting approximately 750,000 people in the United States, diabetic macular edema (DME) is a vision-threatening complication of diabetic retinopathy (DR). DR is the leading cause of blindness among adults aged 20 to 74 and affects nearly 7.7 million people in the United States. It occurs when damage to blood vessels and the formation of new blood vessels cause blood and/or fluid to leak into the retina – a part of the eye that sends information to the brain, enabling sight. This leads to swelling, as well as blockage of blood supply to some areas of the retina. DME occurs when the damaged blood vessels leak into and cause swelling in the macula – the central area of the retina responsible for the sharp vision needed for reading and driving. The number of people with DME is expected to grow as the prevalence of diabetes increases. The condition is associated with blindness when left untreated and decreased quality of life. There remains a significant unmet need for more effective, longer-lasting therapies for people with DME.

About faricimab

Faricimab is the first investigational bispecific antibody designed for the eye. It targets two distinct pathways – via angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A) – that drive a number of retinal conditions. Ang-2 and VEGF-A contribute to vision loss by destabilizing blood vessels, causing new leaky blood vessels to form and increasing inflammation. By simultaneously blocking both pathways involving Ang-2 and VEGF-A, faricimab is designed to stabilize blood vessels, potentially improving vision outcomes for longer for people living with retinal conditions.

About Genentech in Ophthalmology

Genentech is researching and developing new treatments for people living with a range of eye diseases that cause significant visual impairment and blindness, including wet age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy (DR), geographic atrophy (GA) and other retinal diseases. The company is also investigating platforms for sustained ocular drug delivery, including Port Delivery System with ranibizumab (PDS).

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.


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Evrysdi (risdiplam) Showed Significant Improvement in Survival & Motor Milestones in Babies With Type 1 Spinal Muscular Atrophy (Medicine)

  • FIREFISH Part 2 study showed treatment with Evrysdi helped babies stay free of permanent ventilation, sit without support and improve across a range of motor milestones.
  • Evrysdi has proven efficacy in adults, children and babies 2 months and older with over 4,000 patients treated to date.
  • SMA is the leading genetic cause of death in infants.

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the New England Journal of Medicine (NEJM) has published data from FIREFISH Part 2, a pivotal global study evaluating the efficacy and safety of Evrysdi® (risdiplam) in babies aged 1-7 months old with symptomatic Type 1 spinal muscular atrophy (SMA). The study met its primary endpoint with 29% of infants (12/41) sitting without support for at least 5 seconds* by month 12, a milestone not seen in the natural course of the disease. Safety for Evrysdi in the FIREFISH Part 2 study was consistent with its known safety profile.

“Without treatment, babies with Type 1 SMA are unlikely to survive beyond two years of age,” said Professor Laurent Servais, M.D., Ph.D., FIREFISH investigator and Professor of Pediatric Neuromuscular Diseases at the MDUK Oxford Neuromuscular Center. “Important motor milestones, such as sitting, rolling over and swallowing, are the fundamental building blocks that can help these babies achieve optimal outcomes with Evrysdi, potentially reducing the need for ventilation and increasing the rate of survival.”

At the time of the data analysis, the median duration of treatment with Evrysdi was 15.2 months and the median age was 20.7 months. At month 12, 93% (38/41) of infants were alive and 85% (35/41) were free from permanent ventilation. Without treatment, the median age of death or permanent ventilation was 13.5 months in a natural history cohort. Ninety percent (37/41) had a CHOP-INTEND** score increase of at least 4 points, with 56% (23/41) achieving a score above 40; the median increase was 20 points.

In addition, the study met one of its secondary endpoints with 78% (32/41) of infants classified as HINE-2*** responders, which evaluated motor function through head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing and walking. Infants were classified as HINE-2 responders if more motor milestones showed improvement than worsened.

“These data published in the New England Journal of Medicine validate results from Part 1 of the FIREFISH study that showed Evrysdi can help babies with SMA reach the significant milestone of sitting without support for at least five seconds,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. “These results have been further confirmed in the recently presented 24-month data showing Evrysdi continued to improve motor function, doubling the number of babies able to sit without support from month 12. We will continue to work closely with governments and the SMA community to bring Evrysdi to as many people as possible.”

Safety for Evrysdi in the FIREFISH Part 2 study was consistent with its known safety profile. The most common adverse events were upper respiratory tract infection (68%), pneumonia (39%), pyrexia (39%), constipation (20%), diarrhea (10%) and maculopapular rash (10%). The most common serious adverse events were pneumonia (32%), bronchiolitis (5%), hypotonia (5%) and respiratory failure (5%). Three infants experienced fatal complications of their disease within the first 3 months of treatment. None of these were attributed by the investigator as related to Evrysdi.

In February 2021, 12-month results from the dose finding Part 1 of the FIREFISH study were published in NEJM.

Genentech leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics.

*As assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III)

**Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders

***Hammersmith Infant Neurological Examination 2

About Evrysdi® (risdiplam)

Evrysdi is a survival motor neuron 2 (SMN2) splicing modifier designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency. Evrysdi is administered daily at home in liquid form by mouth or by feeding tube.

Evrysdi is designed to treat SMA by increasing and sustaining the production of the SMN protein. SMN protein is found throughout the body and is critical for maintaining healthy motor neurons and movement.

Evrysdi was granted orphan designation by the European Medicines Agency (EMA) in 2019, PRIME designation by the EMA in 2018 and Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) in 2017. Evrysdi has been approved in 54 countries and submitted in a further 33 countries.

Evrysdi is currently being evaluated in four multicenter trials in people with SMA:

  • FIREFISH (NCT02913482) – an open-label, two-part pivotal clinical trial in infants with Type 1 SMA. Part 1 was a dose-escalation study in 21 infants with the primary objective of assessing the safety profile of Evrysdi in infants and determining the dose for Part 2. Part 2 is a pivotal, single-arm study of Evrysdi in 41 infants with Type 1 SMA treated for 2 years, followed by an open-label extension. Enrollment for Part 2 was completed in November 2018. The primary objective of Part 2 was to assess efficacy as measured by the proportion of infants sitting without support after 12 months of treatment, as assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III) (defined as sitting without support for 5 seconds). The study met its primary endpoint.
  • SUNFISH (NCT02908685) – SUNFISH is a two-part, double-blind, placebo controlled pivotal study in people aged 2-25 years with Types 2 or 3 SMA. Part 1 (n=51) determined the dose for the confirmatory Part 2. Part 2 (n=180) evaluated motor function using the total score of Motor Function Measure 32 (MFM-32) at 12 months. MFM-32 is a validated scale used to evaluate fine and gross motor function in people with neurological disorders, including SMA. The study met its primary endpoint.
  • JEWELFISH (NCT03032172) – an open-label exploratory trial designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in people with SMA aged 6 months to 60 years (inclusion criteria) who received other investigational or approved SMA therapies for at least 90 days prior to receiving Evrysdi. The study has completed recruitment (n=174).
  • RAINBOWFISH (NCT03779334) – an open-label, single-arm, multicenter study, investigating the efficacy, safety, PK and PD of Evrysdi in babies (~n=25), from birth to 6 weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. The study is currently recruiting.

About SMA

SMA is a severe, progressive neuromuscular disease that can be fatal. It affects approximately one in 10,000 babies and is the leading genetic cause of infant mortality. SMA is caused by a mutation of the survival motor neuron 1 (SMN1) gene, which leads to a deficiency of SMN protein. This protein is found throughout the body and is essential to the function of nerves that control muscles and movement. Without it, nerve cells cannot function correctly, leading to muscle weakness over time. Depending on the type of SMA, an individual’s physical strength and their ability to walk, eat or breathe can be significantly diminished or lost.


Reference: Basil T. Darras, Riccardo Masson, Maria Mazurkiewicz-Bełdzińska, Kristy Rose, Hui Xiong, Edmar Zanoteli, Giovanni Baranello, Claudio Bruno, Dmitry Vlodavets, Yi Wang, Muna El-Khairi, Marianne Gerber, Ksenija Gorni, Omar Khwaja, Heidemarie Kletzl, Renata S. Scalco, Paulo Fontoura, Laurent Servais, “Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls
The New England Journal of Medicine  (IF91.245),  Pub Date : 2021-07-29, DOI: 10.1056/nejmoa2102047


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