FDA Approves Wainua (eplontersen) for the Treatment of Adults with Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) announced  the U.S. Food and Drug Administration (FDA)   approval of  Ionis and AstraZeneca's Wainua™ (eplontersen) for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, commonly referred to as hATTR-PN or ATTRv-PN. Wainua is the only approved medicine for the treatment of ATTRv-PN that can be self-administered via an auto-injector.

"Many people living with hereditary transthyretin-mediated amyloid polyneuropathy are unable to fully enjoy their lives because of the relentless, progressive and debilitating  effects of the disease," said Michael J. Polydefkis, M.D., professor of neurology at Johns Hopkins University School of Medicine and an investigator in the NEURO-TTRansform study. "Approval of Wainua represents a meaningful advancement in treatment, one that gives those who are living with transthyretin-mediated amyloid polyneuropathy help managing the disease."

ATTRv-PN is a debilitating disease that leads to peripheral nerve damage with motor disability within five years of diagnosis and, without treatment, is generally fatal within a decade. Wainua is a ligand-conjugated antisense oligonucleotide (LICA) medicine designed to reduce the production of TTR protein at its source.

"The FDA approval of Wainua marks an important milestone for people living with hereditary transthyretin-mediated amyloid polyneuropathy, who will now have an effective, well-tolerated treatment that can be self-administered via auto-injector to combat this devastating disease," said Brett P. Monia, Ph.D., chief executive officer at Ionis. "It is also a pivotal moment for Ionis as Wainua will be the first in a steady cadence of potential commercial launches for the company. We are proud to have discovered and, together with AstraZeneca, developed Wainua, and are grateful to the patients, caregivers and investigators who participated in our clinical studies, as well as for the dedication of our scientists and researchers."

"People with hereditary transthyretin-mediated amyloid polyneuropathy, and other forms of amyloidosis, are often misdiagnosed since symptoms can mirror other conditions," said Isabelle Lousada, President and CEO, Amyloidosis Research Consortium "The path to getting an accurate diagnosis can often be a long, arduous journey and it is critical that a timely and accurate diagnosis is made not only for the individual experiencing symptoms but for their families and loved ones. It is exciting to see new innovations coming through and increased efforts to raise awareness in an area that has often been overlooked or neglected."

Ref : https://en.wikipedia.org/wiki/Eplontersen

Ref : https://go.drugbank.com/drugs/DB16199

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FDA Approves Wainua (eplontersen) for the Treatment of Adults with Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

FDA Approves Amondys 45 (casimersen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 45

In continuation of my update on antisense oligonucleotides 

Sarepta Therapeutics, Inc. the leader in precision genetic medicine for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved Amondys 45 (casimersen). Amondys 45 is an antisense oligonucleotide from Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 45 skipping. This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Amondys 45, which is reasonably likely to predict clinical benefit for those patients who are exon 45 amenable. Consistent with the accelerated approval pathway, the continued approval of Amondys 45 may be contingent on confirmation of a clinical benefit in confirmatory trials.

The ESSENCE trial – a placebo-controlled confirmatory trial to support the Amondys 45 approval – is ongoing and expected to conclude in 2024.

Although kidney toxicity was not observed in the clinical studies with Amondys 45, kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking Amondys 45. In the clinical trial, the most common adverse reactions observed in at least 20% of patients treated with Amondys 45 and at least 5% more frequently than in placebo were (Amondys 45, placebo): upper respiratory tract infections (65%, 55%), cough (33%, 26%), fever (33%, 23%), headache (32%, 19%), joint pain (21%, 10%), and pain in mouth and throat (21%, 7%).

“This is an important day for Sarepta and, far more importantly, for the patients that we serve. After years of scientific commitment, investment and development, the approval of Amondys 45, Sarepta’s third approved RNA therapy, offers treatment to the 8% of the DMD community who have a confirmed exon 45 amenable mutation,” said Doug Ingram, president and chief executive officer, Sarepta. “Along with our other approved RNA therapies, we can now offer treatment options for nearly 30% of Duchenne patients in the U.S. And our commitment to bring therapies to the greatest percentage of the DMD community as soon as possible continues.”

“Decades of research and commitment have fueled and now accelerate our progress towards new treatments for Duchenne,” said Marissa Penrod, founder of Team Joseph and parent of an 18-year old with Duchenne. “The extraordinary diligence and persistence of the Duchenne community – patients and families, clinicians and researchers – have led us to today’s approval, where we now have exon-skipping treatments for almost a third of those with Duchenne.”   

FDA Approves Vyondys 53 (golodirsen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 53

In continuation of my update on oligonucleotide.

Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved Vyondys 53™ (golodirsen). Vyondys 53 is an antisense oligonucleotide from Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 53 skipping. This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Vyondys 53, which is reasonably likely to predict clinical benefit for those patients who are exon 53 amenable. Consistent with the accelerated approval pathway, the continued approval of Vyondys 53 may be contingent on confirmation of a clinical benefit in this post-marketing confirmatory trial.

Sarepta’s placebo-controlled, post-marketing confirmatory trial to support the Vyondys 53 accelerated approval – titled ESSENCE – is currently enrolling and expected to conclude by 2024.

Hypersensitivity reactions, including rash, pyrexia (fever), pruritis, urticaria (hives), dermatitis, and skin exfoliation have occurred in patients who were treated with Vyondys 53. Renal toxicity was observed in animal studies. Although not observed in the clinical studies with Vyondys 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. The most common adverse reactions that occurred in at least 20% of Vyondys 53-treated patients and more frequently than in placebo-treated patients were headache (41%), pyrexia (41%), fall (29%), abdominal pain (27%), nasopharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%).

Following a New Drug Application (NDA) submission to and review by the Division of Neurology Products (the Review Division) for Vyondys 53, which the Review Division recommended for approval, the Office of Drug Evaluation 1 issued a complete response letter (CRL) in August of 2019. Thereafter, Sarepta made a formal dispute resolution request as outlined in relevant FDA Guidance. With the support of the Review Division, the matters raised in the CRL were rapidly evaluated and resolved by Dr. Peter Stein, Director of the Office of New Drugs (OND). OND granted the Company’s appeal and Sarepta re-submitted its NDA to the Review Division, which worked expeditiously to review and approve Vyondys 53.

“Today is monumental for Sarepta and, more importantly, for the DMD community,” said Doug Ingram, president and chief executive officer, Sarepta. “Vyondys 53, our second approved exon-skipping RNA therapy for DMD, may treat up to 8% of the DMD community, representing those patients who have a confirmed exon 53 amenable mutation. Along with EXONDYS 51® (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the U.S.”

Ingram continued, “In the span of four months, we commenced and completed the formal dispute resolution process culminating in the grant of our appeal, resubmitted our NDA and obtained an approval – a great benefit to DMD patients awaiting treatment. This unprecedented timing could not have been achieved without the commitment of the Review Division under the leadership of Dr. Billy Dunn, and the Office of New Drugs, which expeditiously heard and granted our appeal. Along with the DMD community, we owe our gratitude to both the Review Division and the OND for their objective, evidence-based approach to this review, for their fairness, and for the sense of urgency with which they addressed and resolved the CRL and granted this approval.”

“With the approval of Vyondys 53, up to another 8% of Duchenne families will have a therapy to treat this devastating disease,” said Pat Furlong, founding president and chief executive officer, Parent Project Muscular Dystrophy (PPMD). “For 25 years, PPMD has been working with researchers, clinicians, industry, and the Duchenne community to find treatments for all people living with Duchenne. And while we need to ensure that these approved therapies are accessible for patients, today we celebrate this approval and thank Sarepta for their continued leadership in the fight to end Duchenne.”

Vyondys 53 is priced at parity to EXONDYS 51, the price of which has not increased since its launch in 2016. Patients and physicians can access more information at www.SareptAssist.com or by calling 1-888-727-3782.

About Vyondys 53

Vyondys 53 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Vyondys 53 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.

https://www.rxlist.com/vyondys-53-drug.htm

New approach to kill specific bacteria could be alternative to antibiotics

A new approach to killing C. difficile that silences key bacterial genes while sparing other bacteria may provide a new way to treat the most common hospital-acquired bacterial infection in the United States, according to researchers.

While conventional antibiotics treat bacterial infections, they can also cause a condition in the colon called C. difficile infection, due to the drug killing both good and bad bacteria in the gut.

In a lab, researchers created three new antibiotics that kill C. difficile by preventing the expression of bacterial genes that are important for its survival. This approach -- called antisense therapy -- allows the drug to kill only C. difficile, unlike many antibiotics that kill multiple forms of bacteria.

"We were able to show that these drugs can zero in on and kill C. difficile bacteria while leaving other bacteria alone," said Arun Sharma, associate professor of pharmacology, Penn State College of Medicine. "We're still working to refine these drugs and make them even better, with the eventual goal of testing them clinically."

David Stewart, an associate professor of surgery at the University of Arizona who along with Sharma is a co-principal investigator on this study, said the drug works in a completely different manner than the antibiotics currently used.

"These drugs are organism specific, meaning that they target only one kind of bacteria, kind of like smart antibiotics," Stewart said. "They're precise. And that's especially important with C. difficile infections because this bacteria is uniquely, selectively advantaged to exploit ecological disturbances in the human gut."

While C. difficile is normally present in the gut, other "good" bacteria are also present, and all these bacteria contribute to a person's microbiome. When a person's microbiome is healthy and balanced, it keeps bad bacteria like C. difficile under control.

But if a patient takes an antibiotic for another condition, the antibiotic kills many different types of bacteria, including the good ones keeping C. difficile under control. This allows C. difficile to thrive, causing an infection that can result in severe gastrointestinal symptoms. Since antibiotics can contribute to C. difficile infections, the researchers said a new, alternative treatment for these infections is desirable.

"Ideally, a treatment for C. difficile would have no effect on other bacteria," Stewart said.

The researchers, who recently published their findings in the Journal of Antibiotics, said that while most antibiotics lack organismal specificity -- the ability to target just one type of organism -- antisense treatments show great potential for being able to target only specific bacteria.

"Our antisense antibiotics contain genetic material which is complementary to bacterial genetic material, so we designed our genetic material to target specific genes in C. difficile," Stewart said. "And when our genetic material binds to the bacterial genetic material, it prevents the expression of bacterial genes. And that can cause C. difficile to die."

The drug tested in the study consisted of two components: the antisense compound that targeted the genetic material in C. difficile -- referred to as an antisense oligonucleotide (ASO) -- and a carrier compound that transported the ASO into the bacteria, referred to by the research team as a CAB. The researchers tested three versions of the drug, each with a different version of CAB.

The researchers tested each compound to see how much of the drug was required to kill C. difficile bacteria, whether it was toxic or not to human colon cells, and whether it also harmed other bacteria normally found in the gut -- like E. coli.

"Ultimately, we wanted these compounds to deliver the drug into the C. difficile bacteria without hurting other bacteria or the patient," Sharma said. "After testing these three, we found that one carrier in particular -- CYDE-21 -- was the best at delivering an effective dose of the drug into the bacteria."

 

In the future, the researchers said they will conduct further studies to continue to refine the carriers to increase their capacity and minimize their effect on other bacteria and human cells.

"In this study, as a first effort, the carrier is pretty good, and we'd like to do even better," Stewart said. "It has minimal antibacterial activity, minimal toxicity and it's an effective carrier of our cargo. So what we're working on now is modifying our carriers for future testing in preparation for animal studies."

Ref : https://www.nature.com/articles/s41429-018-0056-9

FDA Advisory Committee Votes in Favor of Waylivra (volanesorsen) for Treatment of Familial Chylomicronemia Syndrome

Akcea Therapeutics, Inc. (NASDAQ:AKCA), an affiliate of Ionis Pharmaceuticals, Inc., and Ionis Pharmaceuticals, Inc. (NASDAQ:IONS)   announced that the U.S. Food and Drug Administration’s (FDA) Division of Metabolism and Endocrinology Products Advisory Committee voted 12-8 to support approval of Waylivra (volanesorsen) for the treatment of people with familial chylomicronemia syndrome (FCS). The committee’s non-binding recommendation will be considered by the FDA in its review of Akcea’s New Drug Application for Waylivra. The PDUFA date for completion of the review of Waylivra is August 30, 2018.

3’—A*—G*—mC*—T*—T*—dmC—dT—dT—dG—dT—dmC—dmC—dA—dG—dmC—T*—T*—T*—A*—T*—5’




* = 2’-O-(2-methoxyethyl)

m = 5-methyl

d = 2’-deoxy

“We thank the committee members for their time and their comments today. The Committee’s majority vote in favor of approval is an important positive step to bring Waylivra to people with FCS who have no adequate treatment options,” said Paula Soteropoulos, chief executive officer of Akcea Therapeutics. “We look forward to working with the FDA to complete the final stages of regulatory review for Waylivra. We are committed to the FCS community and will continue to focus on bringing Waylivra, potentially the first and only treatment, to people living with this serious and potentially fatal disease.”

“Given the severity of FCS and the burden it places on patients, the need for a therapy is critical. The progress in development of a potential first-ever treatment is very encouraging. The planned efforts in monitoring and education are designed to achieve the highest levels of patient adherence, compliance and safety,” said Dr. Seth Baum, president, American Society for Preventive Cardiology. “The medical community is eager to have a medicine to treat our patients with FCS.”

The Advisory Committee reviewed data from two Phase 3 clinical trials, APPROACH and COMPASS, as well as the ongoing APPROACH Open Label study for Waylivra. Results from the phase 3 APPROACH trial, the largest study ever conducted in patients with FCS, show that patients with FCS treated with Waylivra achieved a statistically significant mean reduction in triglycerides of 77% from baseline and decreased risk of pancreatitis. The most common adverse events in the APPROACH study were injection site reactions and platelet declines. The Committee's input will be considered by the FDA in its review of the New Drug Application for Waylivra. The FDA is not bound by the Committee's guidance, but takes its advice into consideration when reviewing investigational medicines. Waylivra is also under regulatory review in the European Union and Canada.

“People with FCS have severely elevated triglycerides, which lead to multiple severe daily and chronic symptoms, such as abdominal pain and increased risk for pancreatitis, which can be fatal. Waylivra is the first drug to demonstrate substantial triglyceride lowering in clinical trials in people with FCS,” said Brett P. Monia, chief operating officer at Ionis. “Waylivra illustrates how our antisense technology can create targeted drugs for people living with severe diseases who currently have no available therapeutic options.”

Ref : http://ir.akceatx.com/news-releases/news-release-details/fda-advisory-committee-votes-favor-waylivra-treatment-familial

New drug shows promising results for treating spinal muscular atrophy

A drug developed by an Iowa State University biomedical researcher as a potential treatment for spinal muscular atrophy showed promising results in a recently published study.

Ravindra Singh, a professor of biomedical sciences in the ISU College of Veterinary Medicine, has been studying spinal muscular atrophy, a leading genetic cause of infant mortality, for years. His lab helped to identify a drug known as A15/283, an antisense oligonucleotide, as a potential treatment for spinal muscular atrophy..

In a study recently published in the peer-reviewed scientific journal Molecular Therapy, Singh and his co-authors showed the drug helped to combat the effects of the disease in mice with mild levels of the disorder.

Spinal muscular atrophy results from the loss or mutation of a gene called Survival Motor Neuron 1, often referred to as SMN1. If SMN1 is deleted or doesn't function properly, not enough SMN protein is produced, giving rise to the disease.

The study found that mice that were given the treatment on the first and third days after birth increased SMN levels and alleviated some of the genetic effects of the disease. The study looked in particular at sex-specific symptoms, such as underdeveloped testes, and found the drug helped to normalize testicular growth in male mice. Singh said previous studies failed to control for how males and females may respond differently to the treatment, and this study provides insight into such questions.


"These results in the mouse model are very promising for the possible treatment of mild spinal muscular atrophy cases in children," Singh said. "We're hoping this line of research could someday lead to clinical trials, but more work remains before that can happen."

Ref : http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(17)30157-0

https://www.ncbi.nlm.nih.gov/pubmed/28412171

New drug shows promising results for treating spinal muscular atrophy

New drug shows promise against Huntington's disease

A drug that would be the first to target the cause of Huntington's disease (HD) is effective and safe when tested in mice and monkeys, according to data released today that will be presented at the American Academy of Neurology's 68th Annual Meeting in Vancouver, Canada, April 15 to 21, 2016. A study to test the drug in humans has begun.

Huntington's disease is a rare, hereditary disease that causes uncontrolled movements, loss of intellectual abilities, emotional problems and eventually death. The disease is passed from parent to child through a mutation in the huntingtin gene. The mutation results in the production of a disease-causing huntingtin protein. Each child has a 50/50 chance of inheriting the gene mutation. Everyone who inherits the mutated gene will eventually develop the disease.

The new drug, called IONIS-HTTRx, is an antisense drug that acts as a "gene silencer" to inhibit the production of huntingtin protein in people with Huntington's disease.

"It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease," said clinical study principal investigator Blair R. Leavitt, MD, of the University of British Columbia in Vancouver. "Right now we only have treatments that work on the symptoms of the disease." Leavitt notes the drug is still years away from being used in human clinical practice.

Earlier studies in mouse models of Huntington's disease showed that treatment with antisense drugs delays disease progression and results in sustained reversal of the disease phenotype. In YAC128 mice, a transgenic model of HD, motor deficits improved within one month of initiating antisense treatment and were restored to normal at two months after treatment termination. Motor skills of antisense-treated BACHD mice, another transgenic model of HD, improved eight weeks after initiation of treatment and persisted for at least nine months after treatment termination. In monkeys, dose-dependent reductions in HTT mRNA and Htt protein throughout the central nervous system were observed after intrathecal administration of an antisense drug. Reduction of cortical huntingtin levels by 50 percent was readily achieved in monkeys and correlated with 15 to 20 percent reduction in the caudate. In further tests in rodents and monkeys, IONIS-HTTRx was found to be well-tolerated without any dose-limiting side effects.

New drug shows promise against Huntington's disease

Sense oligonucleotide antidote reverses actions of antisense antithrombotic drug, prevents bleeding

Researchers from Isis Pharmaceuticals (Carlsbad, CA) and Prysis Biotechnologies (Pudong, Shanghai, China) have demonstrated proof-of-concept for using a sense oligonucleotide to undo the effects of an antisense drug, an antithrombotic agent in this novel study. The sense oligonucleotide antidote reversed the actions of the antisense antithrombotic drug in the mouse model and prevented the bleeding that commonly occurs with anti-coagulation therapy, as described in an article in Nucleic Acid Therapeutics, a peer-reviewed journal from Mary Ann Liebert, Inc. publishers. The article is available free on the Nucleic Acid Therapeutics website until November 13, 2015.

Jeff Crosby, Chenguang Zhao, Hong Zhang, A. Robert MacLeod, Shuling Guo, and Brett Monia treated mice with an antisense oligonucleotide drug designed to suppress the ability of liver and blood cells to produce prothrombin, a protein required for blood to coagulate. Subsequent treatment with a prothrombin sense oligonucleotide antidote led to a dose-dependent reversal of the antisense drug activity and the return of prothrombin to normal levels. The authors describe the study design and the implications of their findings in the article "Reversing Antisense Oligonucleotide Activity with a Sense Oligonucleotide Antidote: Proof of Concept Targeting Prothrombin."

"An elegant demonstration of the feasibility of reversing the effects of an antisense oligonucleotide in vivo by administering an antidote oligonucleotide," says Executive Editor Graham C. Parker, PhD, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI. "It will be fascinating to now see how the chemistry can be optimized to achieve translation to clinical efficacy."

Sense oligonucleotide antidote reverses actions of antisense antithrombotic drug,
prevents bleeding

Sense oligonucleotide antidote reverses actions of antisense antithrombotic drug, prevents bleeding

Isis Pharmaceuticals starts Phase 1 clinical study of ISIS-PKKRx to treat patients with HAE

Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced  that it initiated a Phase 1 clinical study of ISIS-PKKRx.  ISIS-PKKRx is an antisense drug in development to treat patients with hereditary angioedemia (HAE).  HAE is a rare genetic disease that is characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and trachea.  HAE affects approximately 20,000 patients in the United States and Europe and can be fatal if swelling occurs in the larynx.  ISIS-PKKRx is designed to alter the course of HAE and therefore has the potential to be best-in-class for the treatment of HAE.  

Isis Pharmaceuticals starts Phase 1 clinical study of ISIS-PKKRx to treat patients with HAE

Compound reverses symptoms of Alzheimer's disease in mice

"It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer's disease," Farr said. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer's disease."

Farr cautioned that the experiment was conducted in a mouse model. Like any drug, before an antisense compound could be tested in human clinical trials, toxicity tests need to be completed.

Antisense is a strand of molecules that bind to messenger RNA, launching a cascade of cellular events that turns off a certain gene.

In this case, OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the over expression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in
the brain of patients who have Alzheimer's disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Previously they had tested the substance in a mouse model that has a natural mutation causing it to overproduce mouse amyloid beta. Like people who have Alzheimer's disease, both types of mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus  the part of the brain responsible for learning and memory.

"To be effective in humans, OL-1 would need to be effective at suppressing production of human amyloid beta protein," Farr said.

Scientists compared the mice that were genetically engineered to overproduce human amyloid beta protein with a wild strain, which served as the control. All of the wild strain received random antisense, while about half of the genetically engineered mice received random antisense and half received OL-1. 

The mice were given a series of tests designed to measure memory, learning and appropriate behavior, such as going through a maze, exploring an unfamiliar location and recognizing an object. 

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. Learning and memory were the same among genetically engineered mice that received OL-1 and wild mice that received random antisense.

They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

Ref http://iospress.metapress.com/content/px72758w0158103u/?issue=4&genre=article&spage=1005&issn=1387-2877&volume=40

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Compound
reverses symptoms of Alzheimer's disease in mice  

OGX-427 Improves PFS in Prostate Cancer | News | Drug Discovery and Development Magazine

In continuation of my update on OGX-427 

OncoGenex Pharmaceuticals Inc. announced data from a Phase 2 study of its investigational compound OGX-427 in chemotherapy-naive metastatic castration resistant prostate cancer (mCRPC) patients. Preliminary results show a higher number of patients taking OGX-427 plus prednisone without disease progression at 12 weeks and with declines in prostate-specific antigen (PSA), compared with those taking prednisone alone.

Sixty-four of 72 planned patients have been randomized to the study and data on 42 patients [22 who received OGX-427 plus prednisone and 20 who received prednisone alone] are now available at or beyond the 12 week assessment time point. Highlights are as follows: 

Antisense Pharma presents data from trabedersen Phase I/II cancer study at ASCO 2012

In continuation of my update on antisense drugs

Trabedersen, is an antisense compound that specifically inhibits expression of transforming growth factor beta 2 (TGF-β2) – a protein which is overexpressed in advanced tumors and which triggers key cancer pathomechanisms, i.e. suppression of antitumor immune response and metastasis. 

Antisense Pharma presents data from trabedersen Phase I/II cancer study at ASCO 2012: The biopharmaceutical company Antisense Pharma today presents trabedersen complete data from its clinical Phase I/II study in patients with advanced pancreatic cancer, malignant melanoma or colorectal cancer at the international cancer congress ASCO 2012 in Chicago, USA.

Ebola, Marburg Virus Treatments Safe in Phase 1 Studies

In continuation of my update on antisense drugs and RNAi

AVI BioPharma Inc. announced positive safety results from the first five cohorts of Phase 1 single ascending dose trials of AVI-6002 and AVI-6003, AVI's lead drug candidates being evaluated for the treatment of the Ebola virus and Marburg virus.

Data were evaluated by an independent Data and Safety Monitoring Board (DSMB), which issued recommendations for both studies to progress as planned to the next highest dosing level after no safety concerns were identified. The Phase 1 single ascending dose trials are designed to characterize the safety, tolerability, and pharmacokinetics of each therapeutic candidate in healthy adult volunteers.

"We are very encouraged that these two drugs, which use our advanced PMOplus chemistry, have demonstrated a favorable safety profile through five cohorts in our dose-escalation studies,”says Chris Garabedian, president and chief executive officer of AVI BioPharma...

Ref : http://phx.corporate-ir.net/phoenix.zhtml?c=64231&p=RssLanding&cat=news&id=1619940

To date, 25 healthy human subjects (five per group) have been enrolled into five sequential dose groups in each of the two studies. Within each group, four subjects received the indicated dose of the therapeutic and one subject received placebo. For each group, safety, clinical laboratory and renal biomarker results through five days after treatment were reviewed by a DSMB. Subjects enrolled in the sixth group for the drug studies will receive 9.0 mg/kg of the therapeutic or placebo. Final, un-blinded safety and pharmacokinetic results for all subjects will be available upon completion of the trial.

Both candidates employ AVI's patented PMOplus technology that selectively introduces positive charges to its phosphorodiamidate morpholino oligomer (PMO) backbone to improve interaction between the drug and its target.

Isis Initiates Phase 1 Study in Patients With Cancer With the First Generation 2.5 Antisense Drug, ISIS-STAT3Rx

 In continuation of my update on antisense drugs...

Isis Pharmaceuticals, Inc.  announced the initiation of a Phase 1 study of ISIS-STAT3Rx, a Generation 2.5 antisense drug designed to treat cancer.  ISIS-STAT3Rx specifically reduces the production of signal transducer and activator of transcription 3 (STAT3). Because STAT3 is over expressed in numerous types of cancers, ISIS-STAT3Rx has the potential to be broadly useful for both solid and liquid tumors.  The ISIS-STAT3Rx development plan is initially focused on key cancers where there is a high unmet medical need and a strong link to STAT3, such as hepatocellular carcinoma (HCC) and ovarian cancer.  Advancements in Isis' technology platform have resulted in the improved potency of Generation 2.5 antisense drugs creating opportunities for drugs like ISIS-STAT3Rx to be effective in the more difficult to treat types of cancer. 

 

"The role of STAT3 as a key factor critical for tumor cell growth and survival of cancer cells has made STAT3 widely viewed as an important target of interest," said David S. Hong, M.D., Assistant Professor, Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center.  "STAT3 is a well understood transcription factor involved in multiple survival mechanisms that intersect with the growth, metastasis and invasiveness of cancer. The ability to selectively inhibit STAT3 could allow us to effectively treat some of the most difficult to treat cancers."

 
Isis Initiates Phase 1 Study in Patients With Cancer With the First Generation 2.5 Antisense Drug, ISIS-STAT3Rx

Ref : http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1691711&highlight=

Isis receives $5M milestone payment from GSK for initiating ISIS-TTRRx Phase 1 study

In continuation of my update on "antisense drugs"....
Isis receives $5M milestone payment from GSK for initiating ISIS-TTRRx Phase 1 study

Idera's gene-silencing oligonucleotide studies published in Journal of Medicinal Chemistry

In continuation of my update on antisense drugs and nucleotides

Idera's gene-silencing oligonucleotide studies published in Journal of Medicinal Chemistry

Ref : JMC 

Regulus present advancements in microRNA platform at Oligonucleotide Therapeutics Society meeting

Recently, I did write an article regarding the future of antisense drugs for BlogNotions (wherein I did mention about the Regulus plans for mRNA platform)...


Regulus present advancements in microRNA platform at Oligonucleotide Therapeutics Society meeting

Japanese patent for Archexin (a novel anti-cancer drug)....

Rexahn Pharmaceuticals, Inc., a clinical stage pharmaceutical company commercializing potential best in class oncology and CNS therapeutics, announced that the Japanese Patent Office has issued a patent for its novel anti-cancer compound, Archexin. As per the claim by the company,  Archexin is a first in class, potent inhibitor of Akt protein kinase in the treatment of cancer. 

The AKT pathway is an important therapeutic target for cancer drug discovery as it functions as a main point for transducing extracellular and intracellular oncogenic signals. Moreover, alternations of the AKT pathway have been found in a wide range of cancers. Akt regulates signal processes of cell proliferation and survival, angiogenesis, and drug resistance in cancer. Archexin is being developed to treat solid tumors and has FDA Orphan drug designation for RCC, pancreatic, stomach, glioblastoma, and ovarian cancers. Archexin is in Phase II clinical development for pancreatic cancer as lead indication.

Archexin(R) was fromerly named as RX-0201, is  an oligonucleotide compound that  inhibits the expression of human Akt-1. I am really happy for this approval because, in my opinion this will boost the new field of drugs (ologonucleotides/antisense). I have covered some developments in this field, those interested can read earlier articles...

SPC3649 ( LNA- locked nucleic acid) - a new hope for hepatitis C.....

When  I was working with Innovasynth Technologies, Khopoli, I had an opportunity to do literature survey about  Lock Nucleic Acids (LNAs) and Peptide Nucleic Acids (PNAs) (we were supposed to work on the preparation of  some of the LNAs & PNAs for US based companies). In my opinion though these class of compounds (including oligonucleotides) are  still emerging,  I think in the days to come there will be more and more drugs from oligonucleotides, Locked Nucleic Acids (LNAs) and Peptide Nucleic Acids, (PNAs) class of compounds.

LNAs : A locked nucleic acid (LNA) (see the right side general structure), is a modified RNA nucleotide. Ribose moiety of an LNA nucleotide is modified with an extra bridge

connecting the 2' oxygen and 4' carbon. The bridge "locks" the ribose  in the 3'-endo (North) conformation, which is often found in the A-form of DNA or RNA. LNA nucleotides can be mixed with DNA or RNA bases in the oligonucleotide whenever desired. This locking  significantly increases the thermal stability (mp) of oligonucleotide.

LNA nucleotides are used to increase the sensitivity and specificity of expression in DNA microarrays, FISH probes, real-time PCR probes and other molecular biology techniques based on oligonucleotides. For the in situ detection of miRNA the use of LNA is currently the only efficient method. A triplet of LNA nucleotides surrounding a single-base mismatch site maximizes LNA probe specificity unless the probe contains the  G-T mismatch. We have already seen some antisense drugs (oligonucleotides from Geron & Isis) and some are into clinical trials.

Now its interesting to see that Santaris Pharma   is currently advancing LNA based compounds within infectious diseases, metabolic disorders, oncology, inflammatory and rare genetic disorders.

Santaris Pharama, has developed a LNA,  SPC3649 - which captures a small RNA molecule in the liver, called microRNA122, that is required for HCV replication.

As per the claim by the company, SPC3649 works by altering the environment in the host liver cell to inhibit viral replication rather than inhibiting the virus itself. This subtle difference (in comparison  with other therapies) may have significant implications, as it may reduce the risk of the virus becoming resistant to therapy – a major concern with current therapies.

As per the claim by Dr. Robert Lanford,  (who has collaboration with Santaris Pharma), that in a preclinical study  SPC3649 successfully inhibited miR-122, a liver-expressed microRNA important for Hepatitis C viral replication. By inhibiting miR-122, SPC3649 dramatically reduced Hepatitis C virus in the liver and in the bloodstream in chimpanzees chronically infected with the Hepatitis C virus. Four HCV chronically infected chimpanzees were treated weekly with 5 or 1 mg/kg of SPC3649 for 12 weeks followed by a treatment free period of 17 weeks. The two animals that received the 5 mg/kg dose had a significant decline in viral levels in the blood and liver of approximately 2.5 orders of magnitude or approximately 350 fold. Hope the new therapy could potentially replace interferon (interferon and ribavirin is  approved by FDA for hepatitis C and this treatment is very toxic, requires 48 weeks with 50% success) in future cocktails, since it provides a high barrier to resistance. This antiviral could be used alone to treat disease progression and there are indications that it can convert interferon non-responders to responders, so that non-responders to the current therapy could be treated with the combination of this drug with interferon.   More....

Those interested  can see the video demo with the link

Positive results from mipomersen- a new hope for FH sufferers...

About Familial hypercholesterolemia :

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a genetic disorder characterized by high cholesterol levels, specifically very high low-density lipoprotein (LDL, "bad cholesterol") levels, in the blood and early cardiovascular disease. Many patients have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.

Heterozygous (FH) is normally treated with statins, bile acid sequestrants or other hypolipidemic agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

Recently, Genzyme Corp. and Isis Pharmaceuticals Inc have come up with some intresting results from the drug mipomersen [mipomersen - is an antisense oligonucleotide, with phosphorothioate linkage at 5'- postion and 2'-O-methoxymethyl moety] ( phase 3). As per the claim by the companies, the study met its primary endpoint in an intent-to-treat analysis, with a 25 percent reduction in LDL-cholesterol after 26 weeks of treatment, vs. 3 percent for placebo (p<0.001)>.

The trial met all of its secondary and tertiary endpoints, suggesting that mipomersen may offer potential benefits to patients beyond LDL-C reduction. Patients treated with mipomersen experienced a 27 percent reduction in apolipoprotein B vs. 3 percent for placebo; a 21 percent reduction in total cholesterol vs. 2 percent for placebo; and a 25 percent reduction in non-HDL cholesterol vs. 3 percent for placebo (all p<0.001).>Mipomersen patients’ HDL-C levels increased 15 percent (p=0.035 vs. placebo), which combined with the LDL-C reductions observed, resulted in improved LDL/HDL ratios, a ratio considered an important measure of cardiovascular risk. Mipomersen patients’ LDL/HDL ratios decreased by 34% (p<0.001>Mipomersen a representative of Isis’ leadership in the field of RNA targeted therapeutics will bring a sigh of relief to the sufferers of FH, in the days to come.

I had an opportunity to work with ISIS (as contract R & D, Innovasynth Technologies Limited, Khopoli) and really excited to see the results..

Ref : http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1356364&highlight=