Category Archives: Gene Medicine

In 1976, a letter to the editor thanked this publication for its coverage of the genetic disease Tay-Sachs, and for regularly promoting opportunities to get tested.

At the time, Tay-Sachs remained a scourge in the Jewish community. Since then, in a victory of community willpower over genetic destiny, a concerted push for early testing has virtually eradicated the disease reducing the number of Ashkenazi children born with Tay-Sachs from 60 per year, to 3 to 5 per year.

But while the incidence of Tay-Sachs among Ashkenazi Jews has fallen, a host of genetic disorders still threatens the community, necessitating genetic screening.

We need to plan and be proactive about it, said Estie Rose, a genetic counselor with JScreen, an Atlanta-based nonprofit that offers testing and education.

In 2008, the U.S. Senate named September Tay-Sachs Awareness Month, but Tay-Sachs is only one of the genetic diseases for which Ashkenazi Jews are more likely to carry a recessive gene. (A recessive gene, as opposed to a dominant one, is expressed only when inherited from both parents.)

According to Rose, about 75 percent of those with Ashkenazi Jewish heritage carry a recessive gene for at least one of a number of genetic conditions. Besides Tay-Sachs, the most common include Gaucher disease, cystic fibrosis, familial dysautonomia and Canavan disease. (According to the Jewish Genetic Disease Consortium, there are also various genetic diseases that are more prevalent among Sephardic Jews.) One in 30 Ashkenazi Jews carries the gene for Tay-Sachs, while among the general population, 1 in 300 is a carrier (the number is also high among those of Cajun descent).

While a recessive gene does no harm, a child with Tay-Sachs is more likely to be born to a couple who are both Ashkenazi Jews.

Its really only a problem if the person youre having a child with has the same gene, explained Mary Norton, an MD and professor of perinatal medicine and genetics at the University of California, San Francisco.

The reason Ashkenazi people are more likely to carry the Tay-Sachs gene is interwoven with the many calamities in the history of the Jewish people. Think the Crusades; think the Holocaust; think the Spanish Inquisition, Rose said. The size of the community shrunk, then it regrew.

For genetics, such circumstances exemplify a population bottleneck and the founder effect. In laypersons terms: Many Jews were killed at various times in history, leaving a smaller pool of genes to replenish the population. Also, Jews in Europe were endogamous, meaning they tended to marry other Jews.

The mutations become copy and pasted over and over and over again, Rose said.

Tay-Sachs was discovered toward the end of the 19th century, and even back then its prevalence among Ashkenazi Jews was noted.

The most common form becomes noticeable in infants around 6 months old. Symptoms include reduced vision and an exaggerated startle response, and then progress to slow growth, listlessness, neural degeneration and seizures by age 2, with death coming by age 5. The disease has no cure.

A carrier of a genetic disorder may have no family history of the disease or have the disease themselves. Pregnancy is often the first time many people get tested to see if they are carriers for a range of genetic disorders. Some dont get tested at all.

JScreens mission is to encourage people not to wait until pregnancy to get tested.

Thats what Rose did, and it changed her life. While in college, she and her partner got tested to see which genetic disorders they carried. It turned out they were both carriers for cystic fibrosis, a life-threatening disease. If shed had children with her then-partner, they could have faced some tough choices.

We decided to break up and avoid all of those things, she said.

Today, as a genetic counselor, Rose helps couples consider their options when faced with similar scenarios. She said JScreen tests for 225 diseases and works closely with the primary health care provider and genetic counselors.

I can serve my own community, which is really important to me, she said. The Jewish community unfortunately faces a lot of genetic health issues.

About 75 percent of those with Ashkenazi Jewish heritage carry a recessive gene for at least one of a number of genetic conditions.

Rose said if a pregnant couple finds they both carry the same disease gene, the next step is to test the fetus. If the fetus has the disorder, the couple has to choose whether or not to carry the baby to term. Even better is to do the testing before pregnancy, Rose said: In case there is a problem, they have more options.

The couple can explore IVF (in which each embryo can be tested before implantation) or egg donation, or they may decide not to have children or even go their separate ways, as Rose and her then-partner did.

Sophia Pesotchinsky is all in favor of testing before pregnancy. Her daughter Vera, 49, has Late Onset Tay-Sachs, a rare form of the disease.

The Pesotchinskys came to the Bay Area from Russia in 1976. Vera later developed motor function problems that turned out to be the first signs of LOTS. Sophia had never been tested to see if she was a carrier, neither in Russia nor here in the U.S. when she was considering having more children. Thats a huge oversight, she said.

If people have come from a different country, they have to be asked, Did you have that test? she said.

Thats particularly true for people who come from the former Soviet Union. Very often they didnt know they had Jewish roots, she pointed out.

Sophia said it took more than a decade to diagnose Vera (along the way, Sophia was told that her daughters problems, ranging from slurring to klutziness, came from having an overbearing immigrant mother). Vera, who earned an MBA from Santa Clara University and a BA from Wellesley College, is currently in a wheelchair and cannot live alone, but mother and daughter are active in patient advocacy through the National Tay-Sachs and Allied Diseases Association.

JScreen isnt the only Jewish organization trying to get people to screen early.

New York-based Dor Yeshorim screens potential couples in the Orthodox community by running tests for over 50 diseases. According to their most recent quarterly report, of more than 9,000 people who have used the service, 120 were found to be genetically incompatible.

Like JScreen, Dor Yeshorim advises people to get tested well before pregnancy. When a match is suggested its time for a compatibility check. Dor Yeshorim, rabbanim and experienced shadchanim urge everyone to check compatibility before a couple or the parents meet to avoid unnecessary heartache! the site says.

To that end, Dor Yeshorim often tests at Orthodox schools. JScreen works with Hillel and Birthright, Rose said.

Advances mean that genetic tests once reserved for Ashkenazi Jews can now be accessed by the population at large, further reducing the likelihood that children will be born with a disease like Tay-Sachs.

Tests used to cover only 25 or so gene disorders, but now hundreds can be identified.

Rose said its important to test no matter what ethnicity you are. While Ashkenazi Jews have their own set of risks, other ethnic groups have theirs. You never know what a test result will bring, Rose noted.

We all have things we dont know about our family history, she said.

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Work remains on Tay-Sachs and other Ashkenazi genetic disorders J. - The Jewish News of Northern California

Newswise The first large-scale genomic study of musicality published on the cover of todays Nature Human Behaviour identified 69 genetic variants associated with beat synchronization, meaning the ability to move in synchrony with the beat of music.

An international team of scientists, including the Vanderbilt Genetics Institute and 23andMe, demonstrated that human capacity to move in synchrony with a musical beat (termedbeat synchronization) is partially coded in the human genome.

Many of the genes associated with beat synchronization are involved in central nervous system function, including genes expressed very early in brain development and in areas underlying auditory and motor skills, according to co-senior author Reyna Gordon, PhD, associate professor in the Department of Otolaryngology - Head and Neck Surgery and co-director of the Vanderbilt Music Cognition Lab.

Rhythm is not just influenced by a single gene, it is influenced by many hundreds of genes, Gordon said. Tapping, clapping and dancing in synchrony with the beat of music is at the core of our human musicality.

The studyalso discovered that beat synchronization shares some of its genetic architecture with other traits, including biological rhythms such as walking, breathing and circadian patterns.

This is novel groundwork toward understanding the biology underlying how musicality relates to other health traits, said co-senior author Lea Davis, associate professor of Medicine.

23andMes large research dataset provided study data from more than 600,000 customers who consented to participate in research allowed researchers to identify genetic alleles that vary in association with participants beat synchronization ability.

The large number of consented study participants offered a unique opportunity for our group to capture even small genetic signals, said David Hinds, PhD, a research fellow and statistical geneticist at 23andMe. These findings represent a leap forward for scientific understanding of the links between genetics and musicality.

First author Maria Niarchou, PhD, research assistant professor in the Department of Medicine, said the study findings made new connections between the genetic and neural architecture of musical rhythm, thus improving our understanding of how our genomes tune our brains to the beat of the music.

The work was supported in part by an NIH Directors New Innovator award #DP2HD098859. Visit the FAQ of the study to learn more.

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Study Shows Genetic Link to Moving to the Beat of Music - Newswise

The Republican Party has created quite a political and scientific mess in its chaotic and contradictory legislative maneuverings in the wake of the overturning of Roe v Wade. Sen. Lindsey Graham spent much of the last weekdefending his proposed federal ban on all abortionsafter 15 weeksa law that also allows any state to set even more restrictive standard, including refusing to allow a woman to terminate a pregnancy in cases of incest or to protect her health.

The proposal was seen by many as an attempt to deflect growing concerns that Republicans are out of step with most Americans who want to preserve some version of choice in every state.

Grahams proposal to try to deflate the backlash against Dobbs has drawn criticism and even ridicule from the right and the left, both of whom call it ham-handed but for different reasons.

Senate Minority Leader Republican Mitch McConnell, referencing the ban, said that most of the members of my conference prefer that this be dealt with at the state level which in Republican-dominated states mostly means complete bans even in cases of incest or health complications.

Democrats were no less incensed. House speaker Nancy Pelosi called Grahams proposal the latest, clearest signal of extreme MAGA Republicans intent to criminalize womens health freedom in all 50 states and arrest doctors for providing basic care. Make no mistake: if Republicans get the chance, they will work to pass laws even more draconian than this [Graham] bill just like the bans they have enacted in states like Texas, Mississippi and Oklahoma.

The over-riding issue for most Americans is government overreach, once a sacred conservative principle: Republicans are increasingly inserting of the government into the private relationship between patients and their clinicians in guiding health decisions, says the American College of Obstetrics and Gynecology in a joint statement representing more than 75 health care organizations:

Abortion care is safe and essential reproductive health care. Keeping the patientclinician relationship safe and private is essential not only to quality individualized care but also to the fabric of our communities and the integrity of our health care infrastructure. As leading medical and health care organizations dedicated to patient care and public health, we condemn this and all interference in the patientclinician relationship.

Ive published 38 editions of several college life science textbooks since 1982. All have covered human prenatal development and assisted reproductive technologies (ARTs).

My books have chronicled the progress in reproductive medicine: from Louise Joy Brown, the first test tube baby; through the fading of amniocentesis as checking circulating fetal DNA offered a far less invasive way to detect extra chromosomes; to selecting the earliest embryos for one or two free of a familys disease-causing mutation, circumventing a lethal legacy.

Im now revising the final chapter of the fourteenth edition of my human genetics textbook, entitled Reproductive Technologies. Its a crazy time to be doing that.

I read most of the decision, to reach my own conclusions. I was astonished at how profoundly the justices skirt the health field that bloomed into existence with Louise Joy Brown four decades ago. I dont pretend to know anything about the law. How can the justices presume medical expertise in telling a woman what she can and cannot do to her body, with such hubris?

The tone of the Supreme Court decision stunningly evokes the thinking of another century and I dont mean the twentieth.

About halfway through the213 pages, seeing no words from modern reproductive medicine, I started doing word searches to speed things up.

A search forin vitro fertilization called up one mention, but in the dissent. Actual. Medical. Facts.

Further, the Court may face questions about the application of abortion regulations to medical care most people view as quite different from abortion. What about the morning-after pill? IUDs? In vitro fertilization? And how about the use of dilation and evacuation or medication for miscarriage management?

Next I searched for a fundamental distinction in developmental biology: embryo versus fetus.

Embryogets 3 hits in the decision. The first is part of embryology in a footnote. More telling is the second mention, part of a quote within a quote (In contemplation of law life commences at the moment of quickening, at that moment when the embryo givesthe first physical proof of life, no matter when it first received it, emphasis added). Thats from an 1872 decision The third mention of embryo is as part of Embryos in the title of a paper cited in a footnote. Not a lot of coverage.

Embryos by definition do not yet have rudiments of all body parts. The period of the embryo extends from fertilization (aka conception) to the end of the 8th week. Obstetricians and politicians count the weeks from the last menstrual period, which tacks on two non-pregnant weeks at the start. Maybe thats because 40 weeks is easier to remember than 38 weeks. More likely, perhaps the erroneous timetable is a legacy from when most obstetricians and politicians were people who could not become pregnant.

In the decision, a word search for fetus brings 54 hits, compared to the 3 indirect ones for embryo, although most abortions are in fact done on embryos. The 2019CDC Abortion Surveillance finds that the majority of abortions took place early in gestation: 92.7% performed at 13 weeks gestation; a smaller number of abortions (6.2%) at 1420 weeks gestation, and even fewer (<1.0%) at 21 weeks gestation.

Next I searched for terms familiar to people seeking reproductive health care. It was enlightening.

First, I looked for mention of some stages of early development beyond the familiar embryo and fetus:

0 hits each for zygote, blastocyst, and inner cell mass.

Then I looked for ARTs other than the lone IVF mention:

0 hits each for gamete intrafallopian transfer (GIFT), preimplantation genetic diagnosis (PGD), and zygote intrafallopian transfer (ZIFT).

I began to think of Dean Wormers comment to John Belushis character Bluto Blutarsky in Animal House abouthis grade point average: Mr. Blutarsky. ZERO POINT ZERO.

The decision mentions the stages of prenatal development in very vague terms, focusing at great length on quickening, when a woman first feels fetal movement. Its all from an historical perspective. And that is a part of pregnancy that a man might imagine. He might wax less sentimental over the barfing, exhaustion, back pain, and labor.

What terrifies me the most is that repealing Roe v Wade doesnt affect just those seeking abortion services. Consider a woman having a miscarriage.

My word search for miscarriage brought up 66 references to the phrase procure the miscarriage.The two instances of produce abortion or miscarriage reveal that procure the miscarriage is doublespeak for abortion. Thats dangerous, because the two drugs used to safely manage a miscarriage are the same used to induce abortion. Ditto the scraping of the uterine lining. The dissent reminds of these facts.

What effect will the decision have on a woman experiencing a spontaneous abortion in a state that doesnt allow the treatment she needs? Will a woman in those states entering a clinic with bleeding and cramping become a criminal suspect? In Alabama, for example, performing an abortion is a Class A felony a provider faces from 10 to 99 years in prison. InTexas, treating infection in a pregnant woman may be delayed because doctors fear punishment, even if they know that live birth is impossible, risking septicemia or even death of the woman.

No one facing a medical crisis should have to fear their physician pausing, or even halting, when in the midst of doing what the patient needs in order to resolve or avoid the threat of prosecution, said Jen Villavicencio, MD, representing the American College of Obstetricians and Gynecologists. Imagine that happening during cardiac bypass or an appendix removal. Or vasectomies, which are unsurprisingly on the rise in the wake of the decision.

Villavicencio also questions the judges expertise to rule on medical matters, reaching the same conclusions that I did:

The individuals writing these laws are not medical experts. Laws like abortion restrictions and bans are not based in science or evidence and, therefore, the language does not coincide within the practice of the highest quality, evidence-based care. The language is often incorrect, not clinically meaningful, and therefore confusing to those practicing medicine Pregnancy, complications of pregnancy, and the treatment of those complexities require nuanced, individualized caresomething that is very difficult when faced with unscientific, non-medical laws.

In vitrofertilization is also complex, requiring nuanced, individualized care. Its painful (daily injections) and drawn out over weeks, with a few months off between attempts. Several embryos must be created in order for one or sometimes two to divide enough times to transfer to a womans uterus. The embryo then is a blastocyst, a hollow ball of cells not the comma-shaped tiny humanoid that some might envision, nor the magnified, mangled fetuses that festoon anti-abortion placards meant to terrorize women at a traumatic time of their lives.

In an increasingly common procedure done with IVF to up the odds of success, a blastocyst cell is removed and tested for mutant genes. If its free of the mutation, the remaining still-microscopic blob is transferred to the womans uterus. This procedure is called preimplantation genetic diagnosis, or PGD.

The first case of IVF with PGD enabled a family to conceive a child who did not inherit the cystic fibrosis that both parents carried. That was 30 years ago.

Extra embryos generated through IVF, with or without PGD, may be donated to other women, for research, discarded, or frozen. More than a millionhuman embryos are currently frozen. Whats to be done with the ones in states where women cant choose what happens to their bodies? Charge the women with a crime? Charge the men, who contributed one genome copy to each cell of each embryo on ice? Fine them? Lock them up? Or defrost thousands of embryos in suspended animation? Then what?

Katie Moser has the mutation that causes Huntingtons disease. She wants to have a child that doesnt inherit the mutant gene, and IVF with PGD could make that happen.

TheNew York Timeshas chronicled Katies experience and shes told her story as an advocate for people with movement disorders. Shell likely develop symptoms before age 50. She turns 41 on July 14 also Woody Guthries birthday, perhaps the most famous person to have HD.In 2011, Katie underwent two rounds of IVF. Eighteen embryos resulted, eight viable. But they all had inherited the HD gene.

HD is dominant, so the embryos arent just carriers. Theyre destined, and so hold clues to the earliest manifestations of the disease. Thats why Katie donated them for research a decade ago to researchers in another state. How will the abortion decision affect the transport of genetically-doomed frozen IVF embryos? Will flights need to be rerouted over states with more liberal laws, like people carrying cannabis on planes, avoiding the forbidden zones? That may sound like the Planet of the Apes, but its what the US is becoming, in terms of reproductive rights: a mosaic of forbidden zones.

Katie Moser had genetic testingbecause she knew she has a family history of a single-gene disease. Millions of pregnant women have geneticscreening, which means without such a history, with a simple blood test,NIPT(noninvasive prenatal testing).

NIPT is done after 9 weeks, in obstetric-speak. If the number of fetal DNA pieces corresponding to a chromosome far exceeds or is below the number of maternal pieces, then the fetus has an extra or missing chromosome, respectively.

The test has replaced much more invasive amniocentesis and chorionic villus sampling. A bad result an extra chromosome 13 or 18, for example, which rarely leads to a live birth brings up the choice to end the pregnancy. Will overturning Roe force women in some states to endure a pregnancy with a near 100 percent likelihood of ending in tragedy? Yes.

The dissenting opinion from justices Breyer, Sotomayor, and Kagan directly addresses the issue of a fetus with a hopeless diagnosis:

So too, after todays ruling, some States may compel women to carry to term a fetus with severe physical anomaliesfor example, one afflicted with Tay-Sachs disease, sure to die within a few years of birth.

Again, medical facts and details.

I looked through the final chapter of my human genetics textbook, Reproductive Technologies. I will not allow the Roe v Wade reversal to impact my coverage of this essential information.

The chapter opening case history is true, about a couple seeking IVF with PGD to select an embryo free from the devastating brain disease for which they are each carriers, as well as for a clotting abnormality the man has. If they select a disease-free embryo, what will happen to the others?

The first section of the chapter discusses savior siblings, relating the famous story of Adam Nash. He was chosen, as an 8-celled-embryo, to be transferred to his mother-to-bes uterus so that he could eventually donate umbilical cord stem cells to save his 6-year-old sister Molly from Fanconi anemia. Adam did not inherit the mutant genes and was a perfect tissue match for Molly. He was born in 2000 this technology is hardly too new for the justices to be unaware.

After the section on IVF, my book covers the aforementioned GIFT and ZIFT. Both are used to treat infertility.

In GIFT, a few eggs are retrieved and introduced with sperm into a fallopian tube, past a blockage. Fertilization takes place in vivo, so theres nothing to outlaw. (And of course donating eggs is painful; donating sperm, well, not so much.)

In ZIFT, sperm meet eggs in a dish, like regular IVF, and then a fertilized ovum is placed into the tube. In regular IVF, it divides a few times first.

So, a physician who fumbles and drops the pipette bearing the precious cargo of GIFT is just making a mess. But a physician who drops the pipette bearing a fertilized ovum is committing murder, ending the life of an unborn child, albeit one who is just one cell.

The slippery slope that comes with this archaic, religion-tainted Supreme Court decision is going to cost many postnatal lives.

The dissenting opinion sums up the situation:

The majoritys refusal even to consider the life-altering consequences of reversing Roe and Casey is a stunning indictment of its decision. With sorrowfor this Court, but more, for the many millions of American women who have today lost a fundamental constitutional protectionwe dissent.

Ricki Lewis has a PhD in genetics and is a science writer and author of several human genetics books.She is an adjunct professor for the Alden March Bioethics Institute at Albany Medical College.Follow her at herwebsiteor Twitter@rickilewis

A version of this article was originally posted atPLOSand has been reposted here with permission. PLOS can be found on Twitter@PLOS

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Viewpoint: In the post Roe v Wade world, what changes should a biology textbook writer make to address the medical repercussions of Dobbs? - Genetic...

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the European Commission (EC) has granted marketing authorization for AMVUTTRA (vutrisiran), an RNAi therapeutic for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy. The EC approval is based on positive 18-month results from the HELIOS-A Phase 3 study, where AMVUTTRA significantly improved the signs and symptoms of hATTR amyloidosis, with more than 50 percent of patients experiencing halting or reversal of their polyneuropathy manifestations.

On behalf of patients across Europe, we could not be prouder to announce the approval of AMVUTTRA, our second RNAi therapeutic for hATTR amyloidosis. We are committed to delivering continued innovation to people affected by rare, life-limiting conditions where high unmet need still exists. Todays decision now means we can progress working with health authorities across Europe to achieve responsible and sustainable access arrangements that allow us to bring AMVUTTRA to patients as quickly as possible. Our thanks go to the patients, families, investigators and study staff who have enabled us to reach this significant milestone, said Kasha Witkos, SVP, Head International Region at Alnylam.

Although the considerable research into hATTR amyloidosis over the past few years has resulted in a more positive outlook for those diagnosed with the condition, there remain unmet needs in treatment for patients living with this rapidly progressive, multi-system disease, said Professor David Adams, Head of the Neurology department at Bictre hospital AP-HP, University of Paris-Saclay and Lead Investigator for the HELIOS-A Study. RNAi therapeutics are changing the future of medicine and I am honored to have contributed to these research efforts that have enabled us to bring an innovative new medicine to patients. Results from the HELIOS-A study have shown the potential AMVUTTRA has to benefit patients with hATTR amyloidosis with stage 1 or stage 2 polyneuropathy, whilst also helping reduce treatment burden through subcutaneous dosing once every three months.

HELIOS-A was a global, randomized, open-label, multicenter, Phase 3 study that evaluated the efficacy and safety of AMVUTTRA across a diverse group of patients with hATTR amyloidosis with stage 1 or stage 2 polyneuropathy. Results of the HELIOS-A study were published in Amyloid in July, 2022.

In the HELIOS-A study, AMVUTTRA met the primary and all secondary endpoints of the study at both 9 months and 18 months, demonstrating reversal in neuropathy impairment and an encouraging safety and tolerability profile. AMVUTTRA demonstrated improvement in the mean change from baseline in modified Neuropathy Impairment Score + 7 (mNIS+7) at 18 months (the primary endpoint for the EU), as compared to external placebo data from the landmark APOLLO Phase 3 study of patisiran.

After 18 months of dosing, the most frequently occurring adverse reactions in AMVUTTRA-treated patients were arthralgia (joint stiffness) and pain in extremity (pain in arms and legs). Other less frequent adverse reactions reported with AMVUTTRA were dyspnea (shortness of breath), injection site reaction and an increase in blood alkaline phosphatase (a liver enzyme).

Vutrisiran was previously granted Orphan Drug Designation in the European Union (EU) and U.S. for the treatment of ATTR amyloidosis and in Japan for transthyretin type familial amyloidosis with polyneuropathy. In June 2022, AMVUTTRA was approved by the U.S. Food and Drug Administration (FDA) for the treatment of the polyneuropathy of hATTR amyloidosis in adults. Vutrisiran is under review by the Brazilian Health Regulatory Agency (ANVISA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).

About AMVUTTRA (vutrisiran)

AMVUTTRA is an RNAi therapeutic, which is designed to target and silence specific messenger RNA (mRNA), blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. AMVUTTRA utilizes Alnylams Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability to allow for quarterly, and potentially biannual, subcutaneous administration. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy, which encompasses both hereditary ATTR (hATTR) and wild-type ATTR (wtATTR) amyloidosis.

About hATTR Amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as a major scientific breakthrough that happens once every decade or so, and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylams RNAi therapeutic platform, function upstream of todays medicines by silencing messenger RNA (mRNA) the genetic precursors that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

IMPORTANT SAFETY INFORMATION

Reduced Serum Vitamin A Levels and Recommended Supplementation

AMVUTTRA treatment leads to a decrease in serum vitamin A levels. Supplementation of approximately, but not exceeding, 2500 IU to 3000 IU vitamin A per day is advised for patients taking AMVUTTRA. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

Adverse Reactions

The most frequently occurring adverse reactions in patients treated with AMVUTTRA were arthralgia and pain in extremity. Other commonly reported adverse reactions with AMVUTTRA were dyspnoea, injection site reaction and increase in blood alkaline phosphatase.

About Alnylam Pharmaceuticals

Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the potential treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylams has developed RNAi therapeutic products which are licensed for the treatment of hATTR amyloidosis, acute hepatic porphyria, primary hyperoxaluria type 1 and primary hypercholesterolemia / mixed dyslipidemia. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its Alnylam P5x25 strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylams views with respect to the safety and efficacy of AMVUTTRA, a quarterly subcutaneous injection, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, the potential of AMVUTTRA to significantly improve the signs and symptoms of polyneuropathy, and potentially halt or reverse disease manifestations for some patients, the potential of AMVUTTRA to help reduce treatment burden through subcutaneous dosing once every three months, plans to progress working with health authorities across Europe to achieve responsible and sustainable access arrangements to bring AMVUTTRA to patients as quickly as possible, continued regulatory review of vutrisiran in multiple jurisdictions, and Alnylams aspiration to become a leading biotech company and the planned achievement of its Alnylam P5x25 strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylams business, results of operations and financial condition and the effectiveness or timeliness of Alnylams efforts to mitigate the impact of the pandemic; the potential impact of the recent leadership transition on Alnylams ability to attract and retain talent and to successfully execute on its Alnylam P5x25 strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylams ability to obtain and maintain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally, including AMVUTTRA; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylams ability to successfully expand the indication for ONPATTRO, AMVUTTRA and OXLUMO in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylams ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the Risk Factors filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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Alnylam Receives Approval in Europe for AMVUTTRA (vutrisiran) for the Treatment of Hereditary Transthyretin-mediated (hATTR) Amyloidosis in Adult...

A new gene therapy being developed by CSL for haemophilia B has the potential to overhaul patient treatment times and, according to market watchers, unlock significant market share for the ASX-listed biotech giant

CSL started developing the treatment, known as EtranaDez, after inking a $655 million deal with genomic medicine company Uniqure back in 2020. The US Food and Drug Administration is expected to make a call on whether to give the product the green light by the end of this year.

CSL boss Paul Perreault told this masthead earlier this year he hoped to launch the product in the next calendar year. Credit:Jason South.

Patients with haemophilia B lack the blood clotting protein Factor-IX, and currently have to undergo regular intravenous treatments. EtranaDez aims to free up patients from the need for frequent treatment sessions, by instructing their cells to produce the clotting factor that they lack.

As the date of the FDAs decision approaches, experts have started to run the ruler over the potential benefits of the drug, with Boston-based independent non-profit, the Institute for Clinical and Economic Review (ICER), publishing a draft report on the treatment last week.

The groups panel of experts have reviewed the evidence for the treatment and run models for the cost-effectiveness of the drug, assuming a placeholder price of $2.5 million in the US market.

No prices are set yet for the product because it has not yet been approved, but the draft report suggests EtranaDez offers cost savings for a patient across their lifetime compared with other available treatments.

The ICER report also notes that gene therapies for haemophilia are a major step forward for patients who otherwise need regular and time-consuming injections.

CSL boss Paul Perreault told this masthead earlier this year the company was very excited for the treatment to be one of the next CSL research and development projects to hit the market.

It will be in the second half of this fiscal year when we look to hopefully get the approvals and launch that project, he said.

View post:
CSL flexes gene therapy muscle with latest drug - Sydney Morning Herald

image:Cover art to "The Exquisite Machine" view more

Credit: The MIT Press, 2022.

The Exquisite Machine: The New Science of the Heart (20th September) offers unique and astonishing revelations about the human heart, uncovered by data from the very latest scientific advances. Sian E. Harding, a world leader in cardiac research, reveals some truly fascinating things that you probably didnt know about the heart:

Harding describes this explosion of new science including ultrafast imaging, gene editing, stem cells, artificial intelligence, and advanced sub-light microscopyand the crucial, real-world consequences they have for our health and well-being.

Sian E. Harding is Emeritus Professor of Cardiac Pharmacology in the National Heart and Lung Institute at Imperial College London, where she led the Division of Cardiovascular Sciences and the British Heart Founsation Centre for Cardiac Regeneration.

How the heart works, how it fails and what can be done about it. A remarkable read from a world renowned researcher.Stephen Westaby, author of theSunday Timesbest sellersFragile LivesandThe Knifes EdgeThis lively account on recent advances in heart research stands out by its accessibility to a broader audienceI just loved her analogies to pastry or "the heart as a city!Elisabeth Ehler, Professor of Cardiac Cell Biology, Kings College London, author ofCardiac Cytoarchitecture

Exquisitely packed with facts, this book relates all you need to know about the heart and shares a scientist's crystal ball of future treatments.Roy Taylor, Professor of Medicine and Metabolism, University of Newcastle, and author ofLife Without Diabetes

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Continued here:
The MIT Press releases new book on the science of the heart from cardiac expert Dr. Sian Harding - EurekAlert

Visiongain Reports Ltd

Visiongain has launched a new report on theGlobal Pharmaceutical Contract Manufacturing MarketForecast 2022-2032: - Market Segment by Services {Pharmaceutical Manufacturing Services (Pharmaceutical API Manufacturing Services, Pharmaceutical FDF Manufacturing Services), Drug Development Services, Biologics Contract Manufacturing Services, (Biologics API manufacturing services, Biologics FDF Manufacturing Services}; End User (Big Pharmaceutical Companies, Small & Medium-Sized Pharmaceutical Companies, Generic Pharmaceutical Companies, Other End Users) Plus analysis of leading regional/national markets and leading companies in the market.COVID-19 Impact Recovery Analysis(V-shaped recovery, W-shaped recovery, U-shaped recovery, L-shaped recovery)

Global Pharmaceutical Contract Manufacturing Market Outlook

According to Visiongain analysis,Global pharmaceutical contract manufacturing marketwas valued at $115.8 billion in 2021, and is projected to reach $329.7 billion in 2032, registering a CAGR of 10.1% from 2022 to 2032. Europe Pharmaceutical Contract manufacturing market was the highest contributor to the global market generating $43.9 billion in 2021, and is projected to reach $113.9 billion in 2032, registering a CAGR of 9.1% from 2022 to 2032.

Download Exclusive Sample of Report @https://www.visiongain.com/report/pharma-contract-manufacturing-market-2022/#download_sampe_div

Key Questions Answered by this Report:

What is the current size of the overall global pharmaceutical contract manufacturing market? How much will this market be worth from 2022 to 2032?

What are the main drivers and restraints that will shape the overall pharmaceutical contract manufacturing market over the next ten years?

What are the main segments within the overall pharmaceutical contract manufacturing market?

How much will each of these segments be worth for the period 2022 to 2032?

How will the composition of the market change during that time, and why?

What factors will affect that industry and market over the next ten years?

What are the largest national markets for the world Pharmaceutical Contract Manufacturing?

What is their current status and how will they develop over the next ten years?

What are their revenue potentials to 2032?

How will market shares of the leading national markets change by 2032, and which geographical region will lead the market in 2032?

Who are the leading companies and what are their activities, results, developments and prospects?

What are some of the most prominent Pharmaceutical Contract Manufacturing currently in development?

What are the main trends that will affect the world pharmaceutical contract manufacturing market between 2022 and 2032?

What are the main strengths, weaknesses, opportunities and threats for the market?

What are the social, technological, economic and political influences that will shape that industry over the next ten years?

How will the global pharmaceutical contract manufacturing market evolve over the forecasted period, 2022 to 2032?

What will be the main commercial drivers for the market from 2022 to 2032?

How will market shares of prominent national markets change from 2022, and which countries will lead the market in 2032, achieving highest revenues and fastest growth?

How will that industry evolve between 2022 and 2032, especially in R&D?

Story continues

What are the Market Drivers?

Patent Expiry and Increasing Demand for Generic Drugs

Generics are low-cost medications with therapeutic efficacy and safety profiles that are comparable to those of their branded equivalents. One of the primary elements driving the generics market demand is the push to decrease rising healthcare costs. Patent expiry paved the way for a slew of less expensive generic alternatives to enter the market. Patent expiration is a good predictor of market growth since generic manufacturing businesses subcontract roughly 80% of their production to CDMOs. Some of the major drugs whose patents expired in 2021 were Roches Lucentis, Galens Adasuve, Mylans Perforomist, Lundbecks Northera, and Emergent BioSolutions Narcan.

Currently, several CDMOs are expanding their facilities to tap the growth opportunities in the expanding generics market. In December 2021, SGS had acquired Quay Pharma that helped the company expand its business in the CDMO industry. Additionally, in December 2021, Adare Pharma Solutions acquired Frontida BioPharm that will help the company expand into CDMO offerings such as high potency compound handling and packaging services.

Investments in Pharmaceutical R&D

The global pharmaceutical industry is research-intensive, with innovative firms spending on average about 15% of their sales on R&O. Also, the increasing R&D expenditure on early-stage development, as well as an increase in the number of potential drugs in the preclinical phase, is driving the demand for preclinical services among life science companies.

Some of the top pharmaceutical companies have increased the R&D expenditure that help promote product innovation and drug development. For instance, in 2020, Incyte spent $2.2 billion, Regeneron Pharmaceuticals spent $ 2.7 billion, Biogen spent $3.9 billion, and Bristol Myers Squibb spent $ 11.1 billion as R&D expenditure. According to the Congressional Budget Office, around $ 83 billion was devoted to pharmaceutical R&D expenditure in 2019 in the United States. The growth in the R&D pharmaceutical expenditure is expected to increase the opportunities of outsourcing services provided by CROs, thus boosting thedemand of pharmaceutical contract manufacturing market.

Advancements in biotechnology have made it necessary to outsource various drug development stages in order to develop cost-effective and efficient medicines. With compounded timeline savings, investment savings can reach more than US$0.5 Billion post its success in Europe. This compounded timeline savings models advantages are now being realized in the US, the worlds largest R&D market. Thus, outsourcing drug development activities improves trial efficiency and productivity and helps drug development companies deliver new medicines faster.

What are the Market Opportunities?

Increasing Demand for Biological Therapies

The introduction of new biologics-based therapies and increased revenues from current biologics are expected to boost biologics, biosimilars, and large-molecule drug shares in the coming years. Over 200 biologics have been authorised by the US FDA in the previous decade. In addition, biologics accounted for 27% of all treatments authorised between 2018 and 2021, while biopharmaceuticals account for 65-75 percent of all drugs now in clinical research. The FDA of the United States authorised 46 new medicines and biologics in 2021.

However, these products (mostly parenteral medications) need a higher focus on dosage form stability as well as novel techniques to overcome biological obstacles to distribution at the target region. Since such formulations are difficult to produce, biologics manufacturing outsourcing has grown in popularity.

Growth in the Nuclear Medicine Sector

The contract manufacturing of nuclear medicines includes the development and manufacturing of radioisotopes and radiopharmaceuticals. Recent corporate acquisitions and share offerings have created renewed interest in the radiopharmaceutical industry. The takeovers of Endocyte and Advanced Accelerator Applications (AAA) by Novartis in 2020, for USD 2.1 billion and USD3.9 billion, respectively, have raised the profile of radiopharmaceutical (products that act as both diagnostic and therapeutic agents) products and radiopharmaceuticals in general. Additionally, in May 2021, Curium completed the acquisition of IASON that helped the company expand its business in European region and expand its product portfolio of life saving diagnostic solutions. The growing emphasis on cancer management has accelerated the growth of this market due to the need for new and effective diagnostic and treatment options for common and rare cancers.

Companies involved in the production of nuclear medicines prefer having all the processes integrated under one roof to foster the effective development of new products. For this, they outsource to CDMOs that have the expertise and manufacturing capabilities, all under one roof, thereby saving time and overall production costs.

Growing Demand for Cell and Gene Therapies

Cell and gene therapies has the ability to meet unmet medical requirements associated with treating a variety of illnesses. Many pharmaceutical firms and investors have put substantial resources into researching and commercialising these medicines because of their strong therapeutic potential. Several companies are strategically expanding in the cell and gene therapy market by acquiring facilities with major expertise. For instance, in April 2019, Catalent acquired Paragon Bioservices Inc. (US), one of the leading cell and gene therapy contract manufacturing companies, for USD 1.2 billion. In March 2019, Thermo Fisher Scientific acquired Brammer Bio (a CMO) for USD 1.7 billion. This enabled Thermo Fisher to accelerate its activities in the cell and gene therapy CDMO marketplace. Major players such as Lonza and Catalent have also entered this market through similar strategic developments.

COVID-19 Impact Analysis on Pharmaceutical Contract Manufacturing Market

The COVID-19 pandemic had a favourable influence on the pharmaceutical contract development and manufacturing business. The outbreak sparked the development of coronavirus-related vaccines, antiviral vaccines, antibody therapies, and a variety of pharmaceutical products, prompting pharmaceutical companies to hire contract development and manufacturing organisations for pharmaceutical drug development and manufacturing in order to ensure their business's long-term viability.

Most pharmaceutical firms, contract research organisations, and research institutions are working together to transfer research into useful pharmaceutical products. For example, Catalent Inc. and AstraZeneca PLC announced a deal in August 2020 to increase manufacturing support for the University of Oxford's adenovirus vector-based COVID-19 vaccine AZD1222 at the Harmans, Maryland production plant. In addition, Thermo Fisher Scientific Inc. (US) teamed with Inovio Pharmaceuticals, Inc. (US) in September 2020 to produce INOVIO's DNA COVID-19 vaccine candidate INO-4800 and improve commercial manufacturing.

Furthermore, several vaccines are still in development, despite the fact that some COVID vaccines are now accessible. According to the World Health Organization (WHO), 149 vaccines were in clinical development, 195 vaccines were in pre-clinical development, and 37 vaccinations have been approved across many countries as of March 18, 2022. As a result of the increased demand for effective treatments to treat COVID-19, worldwide production of chloroquine, vaccines, antibodies, and other pharmaceuticals is likely to rise in the future years, bolstering the CDMOs market.

Get Detailed TOC @https://www.visiongain.com/report/pharma-contract-manufacturing-market-2022/#download_sampe_div

Regional Analysis

North America, comprising the US and Canada, accounted for over 30% of the pharmaceutical contract manufacturing market in 2021. Factors such as increasing R&D investments, increased competition among drug manufacturers, shrinking profit margins of pharmaceutical companies, and the presence of major pharmaceutical companies such as ThermoFisher Scientific (US), Catalent (US), and AbbVie (US), are driving the growth of the Pharmaceutical Contract manufacturing market in North America.

The rising demand for state-of-the-art procedures and production technologies in the pharmaceutical sector, which have proved very successful in satisfying regulatory criteria, is one of the primary drivers driving the expansion of the contract manufacturing market in North America.

In 2021, the Asia Pacific region is anticipated to witness highest growth rate in the global pharmaceutical contract manufacturing market. The Asia Pacific region is the most dynamic emerging market globally due to its large base of generic drug manufacturers, growing scientific base and capability (due to the establishment of R&O centres), and the establishment of enhanced manufacturing facilities by major players in the past 2-3 years.

Growth in the emerging markets of China and India is mostly driven by low labour and manufacturing costs, which have drawn huge investments by pharma giants. Despite the capital-intensive nature of biologics, significant capacities have been built by CDMOs in Asia. In 2020, Lonza (Switzerland) expanded its capsule manufacturing capacity in eight sites, including Indonesia and India. In 2019, Fujifilm (Japan) planned to invest USD 90 Billion to expand its Bio Contract Development and Manufacturing Organization business.

Competitive Landscape

Some of the companies profiled in the globalpharmaceutical contract manufacturing marketare AbbVie Inc., Aenova Group, Albany Molecular Research Inc. (AMRI), Almac Group, Boehringer Ingelheim International GmbH, Cambrex Corporation, Catalent, Inc., CordenPharma International, Evonik Industries AG, Famar Health Care Services, Fujifilm Corporation, Lonza Group Ltd., Recipharm AB, Samsung Biologics, Siegfried Holding AG, Thermo Fisher Scientific Inc., Vetter Pharma International GmbH, and WuXiAppTec among other prominent players. To gain a competitive edge, Pharmaceutical Contract Manufacturing companies adopt a variety of strategies. These include product launch, partnerships, investment in R&D, mergers & acquisitions, regional business expansion, and facility expansion among others.

Discover sales predictions for the global pharmaceutical contract manufacturing market and submarkets.

Along with revenue prediction for the overall world market, there are 2 segmentations of the pharmaceutical contract manufacturing market, with forecasts for 3 services, and 4 end-users, each forecasted at a global, regional, and country level, along with COVID-19 impact recovery pattern analysis for all segments.

Find quantitative and qualitative analyses with independent predictions. Receive information that only our report contains, staying informed with this invaluable business intelligence.

To access the data contained in this documentplease emaildev.visavadia@visiongain.com

Information found nowhere elseWith this new and exclusive report, you are less likely to fall behind in knowledge or miss out on opportunities. See how our work could benefit your investment, research, analyses, and decisions. Visiongain's study is for everybody needing commercial analyses for thepharmaceutical contract manufacturing marketand leading companies. You will get the most recent data, opportunities, trends, and predictions.

Do you have any custom requirements we can help you with?Any need for a specific country, geo region, market segment or specific company information?Contact us today, we can discuss your needs and see how we can help:dev.visavadia@visiongain.com

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Visiongain is one of the fastest growing and most innovative, independent, market intelligence around, the company publishes hundreds ofmarket research reportswhich it adds to its extensive portfolio each year. These reports offer in-depth analysis across 18 industries worldwide. The reports cover a 10-year forecast, are hundreds of pages long, with in depth market analysis and valuable competitive intelligence data. Visiongain works across a range of vertical markets, which currently can influence one another, these markets include automotive, aviation, chemicals, cyber, defense, energy, food & drink, materials, packaging, pharmaceutical and utilities sectors. Our customized and syndicated market research reports means that you can have a bespoke piece of market intelligence customized to your very own business needs.

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Global Pharmaceutical Contract Manufacturing Market is projected to reach a market value of US$329.7 Billion in 2032: Visiongain Reports Ltd - Yahoo...

FRAMINGHAM, Mass.--(BUSINESS WIRE)--Alzheon, Inc., a clinical-stage biopharmaceutical company developing a broad portfolio of product candidates and diagnostic assays for patients suffering from Alzheimers disease (AD) and other neurodegenerative disorders, today reported statistically significant and clinically relevant plasma biomarker reduction, robust preservation of brain volume, and positive memory effects in Alzheimers patients following 12 months of treatment with investigational agent ALZ-801 in its Phase 2 biomarker trial.

ALZ-801 (valiltramiprosate) is an oral agent in Phase 3 development as a potentially disease modifying treatment for AD that blocks formation of neurotoxic soluble beta amyloid (A) oligomers causing cognitive decline in Alzheimers patients. In mechanism of action studies, ALZ-801 fully inhibited the formation of amyloid oligomers at the Phase 3 clinical dose. ALZ-801 has shown potential for robust efficacy in the highest-risk Alzheimers population patients with two copies of the apolipoprotein 4 allele (APOE4/4 homozygotes), and favorable safety with no events of brain vasogenic edema, seen in trials with plaque-clearing antibodies. This population is the focus of Alzheons pivotal Phase 3 APOLLOE4 trial and has the highest likelihood of demonstrating successful efficacy outcomes.

The ongoing, fully enrolled Phase 2 biomarker study is evaluating ALZ-801 in Early AD patients, who carry either one or two copies of the 4 allele of apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively), representing two thirds of Alzheimers patients. APOE4 genotype, the leading risk factor for AD after aging, is associated with a several-fold higher brain burden of neurotoxic amyloid oligomers.

Phosphorylated tau (p-tau) levels in plasma are a sensitive and specific marker of neuronal stress and brain injury in AD, and considered a highly reliable biomarker of disease pathology. P-tau is produced by neurons as a reaction to formation of toxic beta amyloid oligomers, the key driver of AD pathology and neurodegeneration. P-tau181 levels rise with AD progression and clinical deterioration of patients, and have been shown to fall in response to clinically effective disease modifying treatments in Alzheimers.

The several-fold greater reduction on the p-tau181 biomarker in plasma compared to plaque-clearing anti-amyloid antibodies provides further support for the robust clinical benefits observed in Alzheons prior Alzheimers studies. Combined with preservation of brain hippocampal volume and a favorable safety profile with no events of vasogenic edema, these new biomarker data and their positive correlations with cognitive benefits further validate the disease modifying effects of ALZ-801 in Alzheimers patients, said Martin Tolar, MD, PhD, Founder, President, and CEO of Alzheon. Importantly, rather than slowing the cognitive decline of patients as seen in trials with other agents, subjects treated with ALZ-801 demonstrated cognitive gain from baseline status on memory tests and maintained their cognitive skills over 1 year. These well-differentiated results position ALZ-801 to potentially become the first oral agent that can slow or even stop and prevent Alzheimers pathology in patients and healthy individuals at risk for the disease.

Alzheons Phase 2 AD biomarker study (NCT04693520) enrolled 84 patients with Early AD, who carry either the APOE4/4 or APOE3/4 genotype and received oral ALZ-801 265 mg twice daily. All analyses of plasma biomarkers were performed at the laboratory of Professor Kaj Blennow at University of Gothenburg in Molndal, Sweden, audited according to Good Laboratory Practice. A total of 75 patients (mean age 69 years, 52% female) completed the Week 52 visit and were included in this pre-specified analysis. In this population, ALZ-801 demonstrated a significant 41% reduction from baseline in plasma p-tau181 (p=0.016) at 52 weeks. ALZ-801 also significantly reduced the plasma p-tau181/A42 ratio by 37% at 52 weeks (p=0.032). Given the importance of p-tau181 and A42 as biomarkers of core AD pathology, these results support a disease modifying effect of ALZ-801 in Alzheimers patients.

Alzheon has pioneered precision medicine in Alzheimers disease targeting neurotoxic amyloid oligomers, and now very promising biomarker, imaging and clinical data with ALZ-801 provide further support for this approach, said Kaj Blennow, MD, PhD, Professor of Clinical Neurochemistry at the University of Gothenburg, Sweden, a member of Alzheons Scientific Advisory Board and developer of the p-tau181 assay. Across many trials of anti-amyloid treatments, p-tau181 has emerged as a consistent plasma biomarker that correlates with clinical benefit. Upon analysis of the plasma p-tau181 data in our laboratory, we have observed an unprecedented reduction in this leading biomarker of Alzheimers pathology in patients taking ALZ-801 tablet for 12 months. This suggests a downstream effect on neuronal function and the potential for clinical efficacy of this novel treatment.

ALZ-801 shows rapid and robust plasma p-tau181 reductions at 13, 26 and 52 weeks that correspond with preservation of hippocampal volume and improvements in memory tests. These early p-tau181 effects are enabled by the robust 40% brain penetration of ALZ-801 compared to approximately 1% brain penetration of plaque-clearing antibodies. As p-tau181 is primarily of brain origin and is actively cleared from brain into plasma, the significant lowering of p-tau181 in response to ALZ-801 treatment validates the drugs target engagement and action in AD brain.

These positive results represent the latest evidence confirming the promise of ALZ-801, extending other key discoveries made by Alzheon scientists over the last 9 years. The significant effect on plasma p-tau181, combined with hippocampus volume preservation and clinical stabilization after 12 months of treatment, support the anti-amyloid oligomer action of ALZ-801 in brains of patients with Alzheimers disease. Consistency across these three outcomes, including structural effects, is very encouraging and supports the disease modifying profile of ALZ-801 in Alzheimers patients, said Susan Abushakra, MD, Chief Medical Officer of Alzheon. Alzheon has developed a well-differentiated approach to both treatment and prevention of Alzheimers disease with the small molecule ALZ-801, which acts upstream on the same pathway as anti-amyloid antibodies, preventing the formation of neurotoxic soluble amyloid oligomers without disrupting the insoluble plaque deposits in brain tissue and small vessels. ALZ-801 is, therefore, in a class of its own as an easy to administer oral tablet that has shown the potential for robust efficacy with a favorable safety profile, avoiding the vascular complications of brain edema and microbleeds seen with infusions of plaque-clearing antibodies.

With support from the National Institute on Aging in the form of a $47M grant to fund the APOLLOE4 Phase 3 study with ALZ-801, Alzheons drug candidate is well positioned to become one of the first disease-modifying treatments approved for slowing and even preventing cognitive decline in Alzheimers patients. Pioneering a precision medicine approach in Alzheimers, the APOLLOE4 Phase 3 trial is enrolling the highest-risk homozygous APOE4/4 AD patients and incorporates the latest volumetric MRI measures and biomarkers to track patient benefit levels of p-tau181 and beta amyloid in plasma and cerebrospinal fluid, hippocampal volume, and other volumetric brain measures, along with the gold-standard primary clinical endpoint, ADAS-Cog 13 (Alzheimer's Disease Assessment Scale-Cognitive Subscale).

About ALZ-801

ALZ-801 (valiltramiprosate) is an investigational oral agent in Phase 3 development as a potentially disease modifying treatment for AD.1,3 In mechanism of action studies, ALZ-801 has been shown to fully inhibit the formation of neurotoxic soluble beta amyloid oligomers at the Phase 3 clinical dose.5,6 ALZ-801 acts through a novel enveloping molecular mechanism of action to fully block formation of neurotoxic soluble amyloid oligomers in the human brain7 associated with the onset of cognitive symptoms and progression of AD.14 ALZ-801 received Fast Track designation from the U.S. Food and Drug Administration in 2017. The clinical data for ALZ-801 and Alzheons safety database indicate a favorable safety profile.57,9 The initial Phase 3 program for ALZ-801 is focusing on Early AD patients with the APOE4/4 genotype, with future expansion to AD treatment and prevention in patients carrying one copy of the APOE4 gene and noncarriers.14

ALZ-801 APOLLOE4 Phase 3 Study

An Efficacy and Safety Study of ALZ-801 in APOE4/4 Early Alzheimer's Disease Subjects (NCT04770220): This ongoing study is designed to evaluate the efficacy, safety, biomarker and imaging effects of 265 mg twice daily oral dose of ALZ-801 in Early AD subjects with the APOE4/4 genotype, who constitute approximately 15% of Alzheimer's patients. This is a double-blind, randomized trial comparing oral ALZ-801 to placebo treatment over 78 weeks. The APOLLOE4 trial is supported by a $47 million grant from the National Institute on Aging.

ALZ-801 Phase 2 Biomarker Study

Biomarker Effects of ALZ-801 in APOE4 Carriers With Early Alzheimer's Disease (NCT04693520): This ongoing study is designed to evaluate the effects of 265 mg twice daily oral dose of ALZ-801 on biomarkers of Alzheimer's pathology in subjects with Early AD, who have either the APOE4/4 or APOE3/4 genotypes, who together constitute 65-70% of Alzheimer's patients. The study also includes evaluation of clinical efficacy, safety, tolerability, and pharmacokinetic profile of ALZ-801 over 104 weeks of treatment.

About Alzheon

Alzheon, Inc. is a clinical-stage biopharmaceutical company developing a broad portfolio of product candidates and diagnostic assays for patients suffering from Alzheimers disease and other neurodegenerative disorders. We are committed to developing innovative medicines by directly addressing the underlying pathology of neurodegeneration. Our lead Alzheimers clinical candidate, ALZ-801 (valiltramiprosate), is an oral agent in Phase 3 development as a potentially disease modifying treatment for AD. ALZ-801 is an oral small molecule that fully blocks formation of neurotoxic soluble amyloid oligomers in the brain. Our clinical expertise and technology platform are focused on developing drug candidates and diagnostic assays using a precision medicine approach based on individual genetic and biomarker information to advance therapies with the greatest impact for patients.

Alzheon Scientific Publications

1 Tolar M, et al: Neurotoxic Soluble Amyloid Oligomers Drive Alzheimers Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression, International Journal of Molecular Sciences, 2021; 22, 6355.2 Abushakra S, et al: APOE 4/4 Homozygotes with Early Alzheimers Disease Show Accelerated Hippocampal Atrophy and Cortical Thinning that Correlates with Cognitive Decline, Alzheimers & Dementia, 2020; 6: e12117.3 Tolar M, et al: Aducanumab, Gantenerumab, BAN2401, and ALZ-801the First Wave of Amyloid-Targeting Drugs for Alzheimers Disease with Potential for Near Term Approval, Alzheimers Research & Therapy, 2020; 12: 95.4 Tolar M, et al: The Path Forward in Alzheimers Disease Therapeutics: Reevaluating the Amyloid Cascade Hypothesis, Alzheimers & Dementia, 2019; 1-8.5 Hey JA, et al: Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain, CNS Drugs, 2018; 32(9): 849-861.6 Hey JA, et al: Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimers Disease, Clinical Pharmacokinetics, 2018; 57(3): 315333.7 Abushakra S, et al: Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimers Disease Suggest Disease Modification Potential, Journal of Prevention of Alzheimers Disease, 2017; 4(3): 149-156.8 Kocis P, et al: Elucidating the A42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimers Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data, CNS Drugs, 2017; 31(6): 495-509.9 Abushakra S, et al: Clinical Benefits of Tramiprosate in Alzheimers Disease Are Associated with Higher Number of APOE4 Alleles: The APOE4 Gene-Dose Effect, Journal of Prevention of Alzheimers Disease, 2016; 3(4): 219-228.

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Alzheon Reports Industry-Leading Biomarker, Brain Preservation and Clinical Effects Following 12 Months of Treatment in Phase 2 Trial of Oral ALZ-801...

The drug Tagrisso is showing promise for lung cancer patients, yet again. So, what should people with lung cancer be asking their doctors? SurvivorNet has the answers for you.

Updated results from the phase III ADAURA study presented at the European Society for Medical Oncology (ESMO) Congress 2022 showed that AstraZenecas drug osimertinib, brand name Tagrisso, demonstrated more exciting results for lung cancer patients with a mutation in the Epidermal Growth Factor Receptor (EGFR) gene. The study results further support the idea that this targeted drug, which is already approved for certain lung cancer patients with EGFR mutations, can bring precision medicine to patients with earlier, and thereby more curable, stages of lung cancer.

If a lung tumor harbors an alteration of the EGFR gene, patients can respond to certain medications that block the function of the EGFR gene, Dr. Balazs Halmos, director of the Multidisciplinary Thoracic Oncology Program at Montefiore Health Systems, explained to SurvivorNet. Tagrisso is one of the very effective EGFR targeting agents used widely in cases of advanced/stage 4 EGFR-positive lung cancer.

Dr. Geoffrey Oxnard explains the importance of genetics in lung cancer.

The EGFR gene mutation is present in about 10-15 percent of lung cancers in the United States and generally appears in the adenocarcinoma subtype of non-small cell lung cancer, according to the American Lung Association.

It is an oral medication which binds EGFR primarily on lung cancer cells, Dr. Salman Punekar, an oncologist at NYU LangonesPerlmutter Cancer Center, told SurvivorNet of Tagrisso. It blocks the ability of EGFR to support the survival and proliferation of these cancer cells.

RELATED: In Certain Types of Lung Cancer, Targeted Drug Tagrisso Slashed Recurrence Rates, Study Says

Side effects of the drug can include GI disturbance and skin changes, according to Dr. Punekar.

Now, for the ADAURA study. Participants in this clinical trial were nonsmall-cell lung cancer (NSCLC) patients who had certain EGFR mutations and had their cancer surgically removed meaning their cancers were at earlier stages where the cancer could in fact, be removed.

These participants then either received Tagrisso or a placebo pill for up to three years so investigators could determine how long these patients could remain disease-free, which is referred to as disease-free survival, or DFS. Studying the DFS of this patient population being treated with Tagrisso is important because even though some people with earlier stage lung cancers may have their disease cured, recurrence is still common.

The DFS of the studys participants who received Tagrisso was improved compared to those who received the placebo. A median DFS of nearly five and a half years (65.8 months) was seen in the overall population treated with Tagrisso versus 28.1 months with the placebo, and the risk of disease recurrence or death of the studys participants was decreased by 73 percent in the overall trial population.

In the overall study population, at 3 years, 85 percent of patients who received osimertinib [Tagrisso] were disease free (and alive) compared to 44 percent of patients who received placebo, Dr. Punekar explained.

Dr. Ronald Natale explains how precision medicine is changing lung cancer treatment

Additionally, less people in the Tagrisso group developed the cancer in their central nervous system (CNS) which is made up of the brain and spinal cord.

There was a reduction in the risk of CNS disease of about 24% in patients who received osimertinib [Tagrisso], Dr. Punekar told SurvivorNet. This is significant because nonsmall-cell lung cancer (NSCLC) can travel to the brain, and when it does so, it is more difficult to treat. The fact that osimertinib had an effect here shows that the medication can enter the brain.

First off, its important to know that this study is part of an ongoing effort to evaluate the effectiveness of using Tagrisso in this subset of lung cancer patients.

Osimertinib [Tagrisso] has shown efficacy in patients who have metastatic EGFR mutant NSCLC in the past, Dr. Punekar explained. This trial provides more evidence that it is effective even in patients who have had their EGFR mutant lung cancers surgically removed to reduce the risk of it coming back.

Dr. similarly expressed the positive nature of this studys results, but he also cautioned that we are still waiting to see how Tagrisso affects overall survival for these patients.

Of course, side effects always have to be considered as well fortunately, Tagrisso is generally quite safe and the quality of life in patients receiving Tagrisso did not seem adversely impacted, Dr. Halmos told SurvivorNet. So overall, this study is viewed as practice changing as even if overall survival is not impacted, delaying the recurrence of cancer by years is viewed as clinically impactful by most patients and providers and has therefore been approved by the FDA, however further data will be important to be able to fine tune our approach even better.

This study highlights many important things for people with lung cancer to discuss with their doctor. First off, it shows just how important it can be to make sure you and your care team knows exactly what type of lung cancer you have.

I believe the most important issue that patients should be asking their doctors is has my tumor been tested in detail for biomarkers [such as an EGFR mutation] and have the biomarker tests helped define a precision medicine based approach? Dr. Halmos explained. Indeed, now we have a spectrum of tests and excellent treatment options for patients with advanced lung cancer, so we need to ensure each and every patients care is carefully tailored to help reach the best outcomes.

If the tumor tests positive for the EGFR biomarker yes, it should be asked whether an EGFR targeting medicine, such as Tagrisso, might be the best approach for patients both with advanced and, thanks to the promising results of the ADAURA study, now also earlier stage disease.

That being said, below are some specific questions to consider asking your doctor if you have lung cancer:

Learn more about SurvivorNet's rigorous medical review process.

Originally posted here:
Do You Have Lung Cancer With An EGFR Mutation? If So, The Drug Tagrisso Might Be Right For You Based On New Results From A 'Practice Changing' Trial -...

video:Scientists elucidate the regulatory mechanisms underlying autophagy mediated competitive elimination of cancer cells. view more

Credit: Tokyo University of Science

The maintenance of a healthy cell population is a dynamic process, whereby unhealthy cells are eliminated by a defense mechanism called cell competition. This process is crucial as unhealthy cells or cells that have accumulated detrimental genetic mutations (defects in genes) over time, can initiate the formation of cancer. Cell competition is achieved by healthy normal cells that surround mutant cancer cells through various mechanisms that trigger cell removal. In addition, epithelial cells (a type of cell that constitutes external and internal body surfaces such as skin and internal organs) adopt a cell-death-independent mechanism known as apical extrusion to recognize and eliminate transformed cells. While the role of apical extrusion in cell competition has been well elucidated, the regulatory mechanisms underlying this complex dynamic process remain elusive.

Autophagy is a process by which cells degrade and recycle cellular components. Dysregulation of autophagy has been implicated in various diseases, including several cancers. While autophagy is known to facilitate the growth and survival of cancer cells at advanced stages, previous studies have indicated that autophagy may have a preventive role in early stages of cancer. Does autophagy regulate the early destruction of cancer cells through cell competition?

Building on this hypothesis, Dr. Shunsuke Kon, a junior associate professor at Tokyo University of Science along with Eilma Akter and a team of researchers, has now explored the potential regulatory role of autophagy in cell competition, in a new study recently published in Cell Reports.

Probing deeper into the possible interplay between autophagy and cell competition, the researchers used cell lines, in which cell competition is triggered by RasV12 (a cancer-causing protein). Dr. Kon explains, We have previously shown that when a small number of mutant cells are produced in the normal epithelial layer by activating the cancer-causing gene Ras, the mutant cells are eliminated into the lumen as loser cells. This happens as a result of cell competition between the normal epithelial cells and the Ras mutant cells.

Using the RasV12-induced mosaic (healthy + mutant cancer cells) cell competition model and fluorescent-protein labeling, the team uncovered a fascinating set of results. They showed that the RasV12-transformed cells had an increased number of autophagosomes (structures containing degradable cytoplasmic contents). Further, they noted impairment of lysosomes, the structures that fuse with autophagosomes and mediate the breakdown of their contents; which likely, caused the increase in autophagosomes. This in turn, perturbed the autophagic flux (a measure of autophagic degradation) in RasV12-transformed cells.

Next, they showed that the accumulated autophagosomes and the impaired lysosomes facilitated apical elimination of the transformed (cancer) cells via cell competition. These results suggest that the intact or non-degradable autophagosomes are important for the elimination process. Interestingly, when the researchers ablated the autophagy gene, ATG-5 in RasV12-induced cells, they noted impairment in autophagy mediated cell competition and elimination of the transformed cells. Similarly, autophagy impaired cells exhibited resistance to elimination in a mouse model, and eventually led to chronic pancreatitis or inflammation of ducts in the pancreas, thus, corroborating their earlier findings.

Together, these findings highlight the role of autophagy in competitive elimination of mutant cancer cells and tissue homeostasis (balance). The study sheds light on the role of autophagy in cancer prevention during early stages and opens avenues for the development of novel anti-cancer therapeutics.

In this context, Dr. Kon remarks, The development of anti-cancer drugs targeting autophagy is being intensely pursued worldwide. Since the role of autophagy has been found to differ depending on the stage of cancer progression, anti-cancer strategies that take into account the stage of cancer progression can enhance treatment efficacy.

Autophagy is surely emerging as the unsung hero that aids the removal of cancer-causing rogue cells!

***

Reference

DOI: https://doi.org/10.1016/j.celrep.2022.111292

About The Tokyo University of ScienceTokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Dr. Shunsuke Kon from Tokyo University of ScienceDr. Shunsuke Kon is a Junior Associate Professor in the Cancer Biology Department of the Research Institute for Biomedical Sciences. He obtained his Ph.D. from the Tohoku University Graduate School of Life Sciences in 2008. He was previously associated with the Institute of Genetic Medicine at Hokkaido University. His primary research interest has been in the field of tumor biology. He has more than 20 publications to his credit. In addition, he has received the Best Articles of the Year award.

Funding informationThis study was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research on (B) 20H03166, JSPS Grant-in-Aid for Scientific Research on Innovative Areas 20H05347, the Princess Takamatsu Cancer Research Fund, the MSD Life Science Foundation, the Inamori Foundation and the Uehara Memorial Foundation (to S.K.), and by JST SPRING, Grant Number JPMJSP2151 (to E.A.).

Experimental study

Animals

Non-degradable autophagic vacuoles are indispensable for cell competition

30-Aug-2022

The authors declare no competing interests.

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Getting rid of unwanted transformed cells: Possible new directions in cancer therapy - EurekAlert