Category Archives: Genetic Medicine

BLA Includes Substantial Body of Data from Pivotal Phase 3 and Ongoing Phase 1/2 Studies

If Approved, Would Be 1st Gene Therapy in U.S. for Treatment of Severe Hemophilia A

SAN RAFAEL, Calif., Sept. 29, 2022 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced today that the Company resubmitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for its investigational AAV gene therapy, valoctocogene roxaparvovec, for adults with severe hemophilia A. The resubmission incorporates the Company's response to the FDA Complete Response (CR) Letter for valoctocogene roxaparvovec gene therapy issued on August 18, 2020, and subsequent feedback, including two-year outcomes from the global GENEr8-1 Phase 3 study and supportive data from five years of follow-up from the ongoing Phase 1/2 dose escalation study.

BioMarin anticipates an FDA response by the end of October on whether the BLA resubmission is complete and acceptable for review. Typically, BLA resubmissions are followed by a six-month review procedure. However, the Company anticipates three additional months of review may be necessary based on the number of data read-outs that will emerge during the procedure. If approved, valoctocogene roxaparvovec would be the first commercially-available gene therapy in the U.S. for the treatment of severe hemophilia A.

The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to valoctocogene roxaparvovec in March 2021. RMAT is an expedited program intended to facilitate development and review of regenerative medicine therapies, such as valoctocogene roxaparvovec, that are expected to address an unmet medical need in patients with serious conditions. The RMAT designation is complementary to Breakthrough Therapy Designation, which the Company received for valoctocogene roxaparvovec in 2017.

In addition to the RMAT Designation and Breakthrough Therapy Designation, BioMarin's valoctocogene roxaparvovec also received orphan drug designation from the EMA and FDA for the treatment of severe hemophilia A. Orphan drug designation is reserved for medicines treating rare, life-threatening or chronically debilitating diseases. The European Commission (EC) granted conditional marketing authorization to valoctocogene roxaparvovec gene therapy under the brand name ROCTAVIAN on August 24, 2022 and endorsed the recommendation from the European Medicines Agency (EMA) to maintain orphan drug designation, thereby granting a 10-year period of market exclusivity in the European Union.

"We are pleased to reach this point in the development program for valoctocogene roxaparvovec and look forward to working with the FDA with the goal of bringing a potentially transformative therapy to people with severe hemophilia A in the United States," said Hank Fuchs, M.D., President of Worldwide Research and Development at BioMarin. "This large and robust data set provided in this BLA resubmission shows an encouraging efficacy profile. We remain committed to sharing these data with the public, along with even longer-term data generated through our ongoing clinical trials and any post-approval studies, to further our understanding of AAV gene therapy in severe hemophilia A and of gene therapies more broadly."

The resubmission includes a substantial body of data from the valoctocogene roxaparvovec clinical development program, the most extensively studied gene therapy for severe hemophilia A, including two-year outcomes from the global GENEr8-1 Phase 3 study. The GENEr8-1 Phase 3 study demonstrated stable and durable bleed control, including a reduction in the mean annualized bleeding rate (ABR) and the mean annualized Factor VIII infusion rate. In addition, the data package included supportive evidence from five years of follow-up from the 6e13 vg/kg dose cohort in the ongoing Phase 1/2 dose escalation study. The resubmission alsoincludesaproposedlong-term extension studyfollowingall clinicaltrialparticipantsfor up to 15years, as well astwo post-approval registry studies.

Robust Clinical Program

BioMarin has multiple clinical studies underway in its comprehensive gene therapy program for the treatment of severe hemophilia A. In addition to the global Phase 3 study GENEr8-1 and the ongoing Phase 1/2 dose escalation study, the Company is also conducting a Phase 3, single arm, open-label study to evaluate the efficacy and safety of valoctocogene roxaparvovec at a dose of 6e13 vg/kg with prophylactic corticosteroids in people with severe hemophilia A (Study 270-303). Also ongoing are a Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with severe hemophilia A with pre-existing AAV5 antibodies (Study 270-203) and a Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with severe hemophilia A with active or prior Factor VIII inhibitors (Study 270-205).

Safety Summary

Overall, to date, a single 6e13 vg/kg dose of valoctocogene roxaparvovec has been well tolerated with no delayed-onset treatment related adverse events. The most common adverse events (AE) associated with valoctocogene roxaparvovec have occurred early and included transient infusion associated reactions and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae. Alanine aminotransferase (ALT) elevation, a laboratory test of liver function, has remained the most common adverse drug reaction. Other adverse reactions have included aspartate aminotransferase (AST) elevation (101 participants, 63%), nausea (55 participants, 34%), headache (54 participants, 34%), and fatigue (44 participants, 28%). No participants have developed inhibitors to Factor VIII, thromboembolic events or malignancy associated with valoctocogene roxaparvovec.

About Hemophilia A

People living with hemophilia A lack sufficient functioning Factor VIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Additionally, people with the most severe form of hemophilia A (Factor VIII levels <1%) often experience painful, spontaneous bleeds into their muscles or joints. Individuals with the most severe form of hemophilia A make up approximately 50 percent of the hemophilia A population. People with hemophilia A with moderate (Factor VIII 1-5%) or mild (Factor VIII 5-40%) disease show a much-reduced propensity to bleed. Individuals with severe hemophilia A are treated with a prophylactic regimen of intravenous Factor VIII infusions administered 2-3 times per week (100-150 infusions per year) or a bispecific monoclonal antibody that mimics the activity of Factor VIII administered 1-4 times per month (12-48 injections or shots per year). Despite these regimens, many people continue to experience breakthrough bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.

Hemophilia A, also called Factor VIII deficiency or classic hemophilia, is an X-linked genetic disorder caused by missing or defective Factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a new mutation that was not inherited. Approximately 1 in 10,000 people have hemophilia A.

About BioMarin

BioMarin is a global biotechnology company that develops and commercializes innovative therapies for people with serious and life-threatening genetic diseases and medical conditions. The Company selects product candidates for diseases and conditions that represent a significant unmet medical need, have well-understood biology and provide an opportunity to be first-to-market or offer a significant benefit over existing products. The Company's portfolio consists of eight commercial products and multiple clinical and preclinical product candidates for the treatment of various diseases. For additional information, please visitwww.biomarin.com.

Forward-Looking Statements

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including without limitation, statements about: BioMarin anticipating an FDA response by the end of October on whether the BLA resubmission is complete and acceptable for review, BioMarin's expectations regarding the duration of the review procedure, valoctocogene roxaparvovec being the first commercially-available gene therapy in the U.S. for the treatment of severe hemophilia A, if approved, BioMarin's commitment to sharing longer-term data generated through its ongoing clinical trials and any post-approval studies. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: the results and timing of current and planned preclinical studies and clinical trials of valoctocogene roxaparvovec; additional data from the continuation of the clinical trials of valoctocogene roxaparvovec, any potential adverse events observed in the continuing monitoring of the participants in the clinical trials; the content and timing of decisions by the FDA and other regulatory authorities, including decisions to grant additional marketing registrations based on an EMA license; the content and timing of decisions by local and central ethics committees regarding the clinical trials; our ability to successfully manufacture valoctocogene roxaparvovec for the clinical trials and commercially; and those and those factors detailed in BioMarin's filings with the Securities and Exchange Commission (SEC), including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's Quarterly Report on Form 10-Q for the quarter ended June 30, 2022 as such factors may be updated by any subsequent reports. Stockholders are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise.

BioMarin is a registered trademark of BioMarin Pharmaceutical Inc and ROCTAVIAN is a trademark of BioMarin Pharmaceutical Inc.

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BioMarin Resubmits Biologics License Application (BLA) for Valoctocogene Roxaparvovec AAV Gene Therapy for Severe Hemophilia A to the FDA - PR...

The study also identified a new prostate cancer taxonomy.

Two groundbreaking studies recentlypublished in the journalsNature and Genome Medicine found genetic signatures that explain ethnic disparities in the severity of prostate cancer, notably in Sub-Saharan Africa.

By genetically analyzing prostate cancer tumors from Australian, Brazilian, and South African donors, the team developed a new prostate cancer taxonomy (classification scheme) and cancer drivers that not only distinguish patients based on their genetic ancestry but also predict which cancers are likely to become life-threatening, a task that is currently difficult.

Our understanding of prostate cancer has been severely limited by a research focus on Western populations, said senior author Professor Vanessa Hayes, genomicist and Petre Chair of Prostate Cancer Research at the University of Sydneys Charles Perkins Centre and Faculty of Medicine and Health in Australia. Being of African descent, or from Africa, more than doubles a mans risk for lethal prostate cancer. While genomics holds a critical key to unraveling contributing genetic and non-genetic factors, data for Africa has till now, been lacking.

Professor Vanessa Hayes examining a blood sample from a prostate cancer patient that was used in the study. Credit: Stefanie Zingsheim, University of Sydney

Prostate cancer is the silent killer in our region, said University of Pretorias Professor Riana Bornman, an international expert in mens health and clinical lead for the Southern African Prostate Cancer Study in South Africa. We had to start with a grassroots approach, engaging communities with open discussion, establishing the infrastructure for African inclusion in the genomic revolution, while determining the true extent of prostate disease.

Over two million cancer-specific genomic variants were identified in 183 untreated prostate tumors from males residing throughout the three research zones using advanced whole genome sequencing (a method of mapping the full genetic code of cancer cells).

We found Africans to be impacted by a greater number and spectrum of acquired (including cancer driver) genetic alterations, with significant implications for ancestral consideration when managing and treating prostate cancer, said Professor Hayes.

Using cutting-edge computational data science which allowed for pattern recognition that included all types of cancer variants, we revealed a novel prostate cancer taxonomy which we then linked to different disease outcomes, said Dr. Weerachai Jaratlerdsiri, a computational biologist from the University of Sydney and first author on the Nature paper.

Combining our unique dataset with the largest public data source of European and Chinese cancer genomes allowed us to, for the first time, place the African prostate cancer genomic landscape into a global context.

As part of her Ph.D. at the University of Sydney, Dr. Tingting Gong, the first author of the Genome Medicine paper, painstakingly sifted through the genomic data for large changes in the structure of chromosomes (molecules that hold genetic information). These changes are often overlooked because of the complexity involved in computationally predicting their presence, but are an area of critical importance and contribution to prostate cancer.

We showed significant differences in the acquisition of complex genomic variation in African and European derived tumors, with consequences for disease progression and new opportunities for treatment, said Dr. Gong.

This cancer genome resource is possibly the first and largest to include African data, in the world.

Through African inclusion, we have made the first steps not only towards globalizing precision medicine but ultimately to reducing the impact of prostate cancer mortality across rural Africa, explains Professor Bornman.

A strength of this study was the ability to generate and process all data through a single technical and analytical pipeline, added Professor Hayes.

The research featured in the Nature and Genome Medicine paper is part of the legacy of the late Archbishop Emeritus Desmond Tutu. He was the first African to have his complete genome sequenced, data which would be an integral part of genetic sequencing and prostate cancer research in southern Africa.

The results of the sequencing were published in Nature in 2010.

Diagnosed at age 66 with advanced prostate cancer, to which he succumbed in late December 2021, the Archbishop was an advocate not only for prostate cancer research in southern Africa, but also the benefits that genomic medicine would offer all peoples, recollected Professor Hayes.

We hope this study is the first step to that realization.

References:

African-specific molecular taxonomy of prostate cancer by Weerachai Jaratlerdsiri, Jue Jiang, Tingting Gong, Sean M. Patrick, Cali Willet, Tracy Chew, Ruth J. Lyons, Anne-Maree Haynes, Gabriela Pasqualim, Melanie Louw, James G. Kench, Raymond Campbell, Lisa G. Horvath, Eva K. F. Chan, David C. Wedge, Rosemarie Sadsad, Ilma Simoni Brum, Shingai B. A. Mutambirwa, Phillip D. Stricker, M. S. Riana Bornman, and Vanessa M. Hayes, 31 August 2022, Nature.DOI: 10.1038/s41586-022-05154-6

Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers by Tingting Gong, Weerachai Jaratlerdsiri, Jue Jiang, Cali Willet, Tracy Chew, Sean M. Patrick, Ruth J. Lyons, Anne-Maree Haynes, Gabriela Pasqualim, Ilma Simoni Brum, Phillip D. Stricker, Shingai B. A. Mutambirwa, Rosemarie Sadsad, Anthony T. Papenfuss, Riana M. S. Bornman, Eva K. F. Chan and Vanessa M. Hayes, 31 August 2022, Genome Medicine.DOI: 10.1186/s13073-022-01096-w

Professor Hayes acknowledges the foresight of The Petre Foundation and donor Daniel Petre who has supported her vision for inclusive genomic research for over eight years.

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Ancestral Heritage and Cancer: New Connection Discovered - SciTechDaily

ALAMEDA, Calif.--(BUSINESS WIRE)--Scribe Therapeutics Inc., a molecular engineering company pioneering a CRISPR by Design platform for genetic medicine, today announced a strategic collaboration with Sanofi for the use of Scribes CRISPR genome editing technologies to enable genetic modification of novel natural killer (NK) cell therapies for cancer.

The agreement grants Sanofi non-exclusive rights to Scribes proprietary CRISPR platform of wholly owned enzymes to create ex vivo NK cell therapies. Scribes suite of custom engineering genome editing and delivery tools called CasX-Editors (XE), based on novel foundations such as the CasX enzyme, will support Sanofis expanding pipeline of NK cell therapeutics for oncology.

Were pleased to provide Sanofi with access to Scribes proprietary and enhanced gene editing technologies for use in ex vivo oncology applications distinct from our current pipeline, said Benjamin Oakes, Ph.D., co-founder and CEO of Scribe. Scribe is proud to expand the use of our XE CRISPR technologies with the team at Sanofi, whose commitment to deep scientific rigor and clinical development experience will enable the rapid advancement of novel ex vivo cell therapies for patients in need.

At Sanofi, we are pushing the boundaries of science by developing a diverse range of next-generation therapies based on natural killer (NK) cells, which could have broad applications across solid tumors and blood cancers, said Frank Nestle, Global Head of Research and Chief Scientific Officer, Sanofi. This collaboration with Scribe complements our robust research efforts across the NK cell therapy spectrum and offers our scientists unique access to engineered CRISPR-based technologies as they strive to deliver off-the-shelf NK cell therapies and novel combination approaches that improve upon the first generation of cell therapies."

Deal Terms

Under the terms of the agreement, Scribe will receive $25 million in upfront payment and be eligible to potentially receive more than $1 billion in payments based on development and commercial milestones, as well as tiered royalties on net future sales on any products that may result from this research agreement.

About Scribe Therapeutics

Scribe Therapeutics is a molecular engineering company focused on creating best-in-class in vivo therapies that permanently treat the underlying cause of disease. Founded by CRISPR inventors and leading molecular engineers Benjamin Oakes, Brett Staahl, David Savage, and Jennifer Doudna, Scribe is overcoming the limitations of current genome editing technologies by developing custom engineered enzymes and delivery modalities as part of a proprietary, evergreen CRISPR by Design platform for genetic medicine. The company is backed by leading individual and institutional investors including Andreessen Horowitz, Avoro Ventures and Avoro Capital Advisors, OrbiMed Advisors, Perceptive Advisors, funds and accounts advised by T. Rowe Price Associates, Inc., funds managed by Wellington Management, RA Capital Management, and Menlo Ventures. To learn more about Scribes mission to engineer the future of genetic medicine, visit http://www.scribetx.com.

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Scribe Therapeutics Announces Research Collaboration with Sanofi to Accelerate Breakthrough CRISPR-based Cell Therapies for Cancer - Business Wire

As we know, there are three major categories of medicines according to their sources, including natural medicines, chemically synthesized drugs, and biological therapeutics.

Among them, biological therapeutics (aka. biologics) are drugs developed and manufactured through biotechnology, such genetic engineering, cell engineering, and protein engineering. Two major categories of biopharmaceuticals have been small molecule- and protein/antibody-based biologics.

Recently, fueled by the global use of mRNA-based COVID-19 vaccines and nucleic acid-based testing for the SARS-CoV-2 virus, the new wave of nucleic acid-based medicine development and production has started taking off (pdf). Furthermore, the increasing number of nucleic acid drugs approved by the U.S. Food and Drug Administration (FDA) demonstrates the potential to treat diseases by targeting the genes responsible for them.

Nucleic acid therapeutics are based on nucleic acids or closely related chemical compounds, and they are completely different from small molecule drugs and antibody drugs.

Instead of targeting protein causes of diseases, they target disease on a genetic level.

Nucleic acid drugs are currently classified into four categories, including medicines based on antisense oligonucleotides (ASOs), small interfering nucleic acids (siRNAs), microRNAs (miRNAs), and nucleic acid aptamers (aptamers).

siRNA and miRNA drugs are called RNA interference (RNAi) medicines.

ASO and siRNA drugs have been approved, and both mainly act on cytoplasmic messenger RNAs (mRNA) to achieve regulation of protein expression through base complementary recognition and inhibition of target mRNAs for the purpose of treating unmet medical needs.

According to the central dogma of molecular biology, DNA is transcribed into RNA, which is then translated into proteins. In some specific cases, RNA can be reverse transcribed into DNA. So, we can see that RNA is critical, because it determines what proteins can be expressed.

Therefore, scientists are trying to see if the process of gene expression can be regulated. That is, instead of interfering at the DNA level, scientists try to regulate the RNA, which is produced in the nucleus and then moves to the cytoplasm. The production of proteins is also carried out in the cytoplasm. If drugs can be absorbed by cells, enter the cytoplasm, and influence the process of translating RNA into proteins, then these drugs can also treat related diseases.

Nucleic acid drugs are designed around this rationale to interfere with the synthesis of disease-causing proteins to treat certain diseases.

ASO is a single-stranded oligonucleotide molecule that enters the cell and binds to the target mRNA through sequence complementation. Then, under the action of ribonuclease H1 (RNase H1), this piece of RNA will be degraded and the expression of the disease-causing proteins will be inhibited consequently.

Both siRNA and miRNAtreat diseases through RNA interference, but their molecules have different properties.

siRNAs are encoded by transposons, viruses, and heterochromatin; whereas miRNAs are encoded by their own genes.

miRNAs can regulate different genes, while siRNAs are called the silencing RNAs, as they mediate the silencing of the same or similar genes from which they originate.

miRNAs are single RNAs and have an imperfect stem-loop secondary structure.

siRNA is a class of double-stranded short RNA molecules that bind to specific Dicer enzymes to degrade one strand. Then the other strand will bind to other enzymes including Argonaute Proteins (AGO) to assemble into a RNA-induced silencing complex (RISC).

In the RISC, the single strand RNA will bind to a target mRNA through the principle of base complementary pairing. Subsequently, the target mRNA will be degraded in the RISC complex, thus blocking the expression of the target protein for the purpose of treating a disease.

This mechanism of inhibiting protein expression via siRNA is called RNA interference. The scientists that had discovered RNA interferencegene silencing by double-stranded RNAwere awarded the Nobel Prize in Physiology or Medicine in 2006.

In terms of therapeutic areas, ASO drugs are mostly developed to cure cancers, infections, as well as neurological, musculoskeletal, ocular, and endocrine diseases.

For instance, fomivirsen, manufactured by Ionis/Novartis, was the first FDA-approved ASO drug, and it is currently used as a second-line treatment for cytomegalovirus (CMV) retinitis. Second-line treatment is used after the first-line (initial) treatment for a disease or condition fails or has intolerable side effects.

Several ASO drugs are also used for treatment of certain rare diseases, including Kynamro (phosphorothioate oligonucleotide drug for the treatment of the rare disease of Homozygous familial hypercholesterolaemia [HoFH]), Exondys 51 (for the treatment of a rare disease called Duchenne muscular dystrophy [DMD]), and Spinraza (for the treatment of spinal muscular atrophy [SMA], a rare inherited disease).

Prior to the development of these medicines, these rare diseases didnt have any effective drugs for treatment.

siRNA drugs therapeutic areas include cancers, infections, as well as neurological, ocular, endocrine, gastrointestinal, cardiovascular, dermatologic, and respiratory diseases.

For instance, patisiran, produced by Alnylam/Genzyme, is the first siRNA drug, and it is used for the treatment of polyneuropathy caused by hereditary transthyretin amyloidosis (haTTR). And the worlds second siRNA drug, Givlaari, produced also by Alnylam, was designed and developed for the treatment of acute hepatic porphyria (AHP), which is a family of ultra-rare disease in adults.

The main manufacturer of ASO drugs is the California-based Ionis Pharmaceuticals. The other major ones include ProQR, Sarepta, WAVELife Sciences, Biogen, and Exicure.

The largest manufacturer of siRNA drugs is Alnylam, a Massachusetts-based biopharmaceutical company specializing in the development and manufacturing of RNA interference therapeutics. The other major producers of these medicines include Dicerna, Quark, and Arrowhead.

In terms of the current status of ASO drug development, most of the therapeutics are in the preclinical stage, with their therapeutic areas mainly focused on oncological, neurological, and muscular diseases. The second largest group of ASO drugs are still in their discovery stage, during which medicines are being designed and undergoing preliminary experiments.

The situation with siRNA drugs (pdf) is similar to that of ASO medicines, with the largest group of medicines being in the preclinical stage, and the second largest group in the discovery stage. Currently, five siRNA drugs have been approved, including patisiran, givosiran, inclisiran, lumasiran, and vutrisiran. In addition, around a dozen other drugs are in late stages of phase III clinical trials.

Therefore, in both categories, only a small percentage of drugs have already been launched.

Nucleic acid drugs are considered novel therapeutic modalities, as they have great potential to treat diseases that cannot be treated effectively in the past, such as certain cancers, and some rare diseases for which no small molecule or protein/antibody-based biologics were developed.

In comparison with small molecule drugs and antibody-based biologics, nucleic acid-based therapeutics have high specificity towards RNAs.

Furthermore, they have simple designs and rapid and cost-effective development cycles (which would later translate into lower costs for patients), as their preclinical research and development starts with gene sequence determination and reasonable designs for disease genes, the genes can be targeted and silenced, thus avoiding unnecessary development and greatly saving research and development time.

They can also quickly alter the sequence of the mRNA construct for personalized treatments or to adapt to an evolving pathogen.In addition, they have abundant targets, so they can potentially make a breakthrough for some special targets that were previously undruggable, to treat certain genetic diseases. And the RNA interference technology has already matured in terms of target selection and small RNA segment synthesis.

However, getting the small RNA segment generated is only the initial step of drug development. In order for nucleic acid drugs to be applied clinically, the next important issue is delivering the nucleic acids to target tissues and cells. Since nucleic acids are highly hydrophilic and polyvalent anionic, it is not easy for cell uptake.

The selection of different delivery mechanisms of genes or RNA agents can impact the increase or decrease the expression of proteins in a cell.

The commonly used (pdf) nucleic acid drug delivery systems include drug conjugates (such as antibody-siRNA conjugates and cholesterol-siRNA conjugates), lipid-based nanocarriers (such as stealth liposomes and lipid nanoparticles), polymeric nanocarriers (such as nanoparticles base on degradable or non-degradable polymers and dendrimers), inorganic nanocarriers (such as silica nanoparticles and metal nanoparticles), carbon-based nanoparticles, quantum dots, and natural extracellular vesicles (ECVs).

Just like almost all drugs, nucleic acid therapeutics also have side effects and risks, some of which stem from their delivery methods.

The common adverse drug reactions (ADRs) of FDA-approved ASO drugs include injection site reactions (e.g. swelling), headache, pyrexia, fever, respiratory infection, cough, vomiting, and nausea (pdf). Individual ASO drugs have their own respective side effects. For instance, fomivirsen can potentially increase intraocular pressure and ocular infection. Pegaptanib can cause conjunctival hemorrhage, corneal edema, visual disturbance, and vitreous floaters. The ADRs of mipomersen (Kynamro) resemble flu symptoms. Nusinersen can cause fatigue and thrombocytopenia. And inotersen can also cause contact dermatitis.

Users of ASO drugs should also be aware of hepatotoxicity, kidney toxicity, and hypersensitive reactions (pdf).

Inotersen (Tegsedi) even carries black box warnings, which are required by the FDA for medications that carry serious safety risks, against its severe side effects, including thrombocytopenia, glomerulonephritis, and renal toxicity. Furthermore, users of inotersen are warned against possible reduced serum vitamin A, stroke, and cervicocephalic arterial dissection.

Side effects of siRNA drugs are similar to those of ASO drugs, including nausea, injection site reactions, heart block, vertigo, blurred vision, liver failure, kidney dysfunction, muscle spasms, fatigue, abdominal pain, and the potentially life-threatening anaphylaxis.

Specifically, during clinical trials of givosiran, one siRNA drug, 15 percent of subjects reported alanine aminotransferase (ALT) elevations three times above the normal range, and 15 percent reported elevated serum creatinine levels and reductions in estimated Glomerular Filtration Rate (eGFR), both signs of poor kidney function. Therefore, liver and kidney toxicity was reported during these clinical trials.

The use of siRNA drugs by pregnant mothers may entail risks for their unborn children. So far, although data on using givosiran, patisiran, and lumasiran have not been reported, certain ADRs of these drugs can serve as warning signs for use during pregnancy. For instance, patients using patisiran (Onpattro) will experience a reduction in their vitamin A levels. Vitamin A is essential for the unborn babys developing organs such as eyes and bones, as well asits circulatory, respiratory, and central nervous systems. Also, givosiran is shown to cause unfavorable developmental effects on animals. Furthermore, inclisiran therapy is not recommended for pregnant mothers, as it may harm the fetus.

In order for nucleic acid drugs to be effective, their design and development need to overcome a number of challenges, such as nuclease degradation, short half-life, immune recognition in circulation, accumulation in target tissues, transmembrane transport, and endosomal escape. Although nuclease stability and avoidance of immune recognition can be greatly reduced by combining chemical modifications, other problems remain to be solved.

Since carrier systems can greatly solve the problems that cannot be solved by chemical modifications and enhance the effectiveness and safety of nucleic acid drug therapeutics, these carrier systems are considered by many as the most important for development and overcoming the aforementioned challenges.

Currently, siRNA drug development faces several challenges (pdf), such as efficacy in siRNA delivery, safety, biocompatibility/biodegradability, and issues of their production, standardization, and approval as multi-component systems.

For example, in the case of lipid nanoparticles (LNPs; one type of lipid-based nanocarriers), only 1 to 2 percent of the internalized siRNAs are released into the cytoplasm. Therefore, research should be focusing on making nanoparticles capable of increasing the release of siRNAs.

However, it should also be noted that the safety, biodistribution, biokinetics, clearance or accumulation of LNPs in different tissues and organs are not well characterized for different types of LNPs. Therefore, the side effects or adverse reactions triggered by this delivery system should also be carefully studied.

The unprecedented global usage of mRNA vaccines under the context of pandemic has given a very unusual momentum to drive more RNA-based therapeutic development. However, clear and calm minds are still needed to see the challenges and explore the safety and risks issues comprehensively and longitudinally for any newly designed RNA-based therapeutic drugs.

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COVID mRNA Jabs and Testing Kicked Off This Industry of Drug Development: Here's What You Need to Know - The Epoch Times

The Nobel Prize for medicine is awarded to the person who shall have made the most important discovery within the domain of physiology or medicine.

Alfred Nobels vision puts responsibility for deciding the winner on the Karolinska Institutet. Since 1901, there have been 112 prizes awarded and nine years where no one won with 224 laureates, 12 of whom were women.

The youngest winner was Canadian Frederick G. Banting, 32, when he won in 1923 for the discovery of insulin. American Peyton Rous is the oldest winner, who was 87 when his discovery of tumour-inducing viruses was honoured.

No one has yet been awarded the prize for medicine more than once and no one has received it posthumously.

2021

David Julius and Ardem Patapoutian for their discoveries of receptors for temperature and touch.

2020

Harvey J. Alter, Michael Houghton and Charles M. Rice for the discovery of Hepatitis C virus.

2019

William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza for their discoveries of how cells sense and adapt to oxygen availability

2018

James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation

2017

Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discoveries of molecular mechanisms controlling the circadian rhythm

2016

Yoshinori Ohsumi for his discoveries of mechanisms for autophagy

2015

William C. Campbell and Satoshi mura for their discoveries concerning a novel therapy against infections caused by roundworm parasites

Tu Youyou for her discoveries concerning a novel therapy against malaria

2014

John OKeefe, May-Britt Moser and Edvard I. Moser for their discoveries of cells that constitute a positioning system in the brain

2013

James E. Rothman, Randy W. Schekman and Thomas C. Sdhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells

2012

Sir John B. Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent

2011

Bruce A. Beutler and Jules A. Hoffmann for their discoveries concerning the activation of innate immunity

Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity

2010

Robert G. Edwards for the development of in vitro fertilisation

2009

Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase

2008

Harald zur Hausen for his discovery of human papilloma viruses causing cervical cancer

Franoise Barr-Sinoussi and Luc Montagnier for their discovery of human immunodeficiency virus

2007

Mario R. Capecchi, Sir Martin J. Evans and Oliver Smithies for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells

2006

Andrew Z. Fire and Craig C. Mello for their discovery of RNA interference gene silencing by double-stranded RNA

2005

Barry J. Marshall and J. Robin Warren for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease

2004

Richard Axel and Linda B. Buck for their discoveries of odorant receptors and the organisation of the olfactory system

2003

Paul C. Lauterbur and Sir Peter Mansfield for their discoveries concerning magnetic resonance imaging

2002

Sydney Brenner, H. Robert Horvitz and John E. Sulston for their discoveries concerning genetic regulation of organ development and programmed cell death'

2001

Leland H. Hartwell, Tim Hunt and Sir Paul M. Nurse for their discoveries of key regulators of the cell cycle

2000

Arvid Carlsson, Paul Greengard and Eric R. Kandel for their discoveries concerning signal transduction in the nervous system

1999

Gnter Blobel for the discovery that proteins have intrinsic signals that govern their transport and localisation in the cell

1998

Robert F. Furchgott, Louis J. Ignarro and Ferid Murad for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system

1997

Stanley B. Prusiner for his discovery of Prions a new biological principle of infection

1996

Peter C. Doherty and Rolf M. Zinkernagel for their discoveries concerning the specificity of the cell mediated immune defence

1995

Edward B. Lewis, Christiane Nsslein-Volhard and Eric F. Wieschaus for their discoveries concerning the genetic control of early embryonic development

1994

Alfred G. Gilman and Martin Rodbell for their discovery of G-proteins and the role of these proteins in signal transduction in cells

1993

Richard J. Roberts and Phillip A. Sharp for their discoveries of split genes

1992

Edmond H. Fischer and Edwin G. Krebs for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism

1991

Erwin Neher and Bert Sakmann for their discoveries concerning the function of single ion channels in cells

1990

Joseph E. Murray and E. Donnall Thomas for their discoveries concerning organ and cell transplantation in the treatment of human disease

1989

J. Michael Bishop and Harold E. Varmus for their discovery of the cellular origin of retroviral oncogenes

1988

Sir James W. Black, Gertrude B. Elion and George H. Hitchings for their discoveries of important principles for drug treatment

1987

Susumu Tonegawa for his discovery of the genetic principle for generation of antibody diversity

1986

Stanley Cohen and Rita Levi-Montalcini for their discoveries of growth factors

1985

Michael S. Brown and Joseph L. Goldstein for their discoveries concerning the regulation of cholesterol metabolism

1984

Niels K. Jerne, Georges J.F. Khler and Csar Milstein for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies

1983

Barbara McClintock for her discovery of mobile genetic elements

1982

Sune K. Bergstrm, Bengt I. Samuelsson and John R. Vane for their discoveries concerning prostaglandins and related biologically active substances

1981

Roger W. Sperry for his discoveries concerning the functional specialisation of the cerebral hemispheres

David H. Hubel and Torsten N. Wiesel for their discoveries concerning information processing in the visual system

1980

Baruj Benacerraf, Jean Dausset and George D. Snell for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions

1979

Allan M. Cormack and Godfrey N. Hounsfield for the development of computer assisted tomography

1978

Werner Arber, Daniel Nathans and Hamilton O. Smith for the discovery of restriction enzymes and their application to problems of molecular genetics

1977

Roger Guillemin and Andrew V. Schally for their discoveries concerning the peptide hormone production of the brain

Rosalyn Yalow for the development of radioimmunoassays of peptide hormones

1976

See original here:
Nobel Prize for medicine: the full list of winners - The National

The industry revisits the pros and cons of microbial fermentation at scale for biotherapeutics.

Microbial fermentation has its place in the biomanufacturing industry, despite the prevalence of mammalian-based cell culture processes for the production of biologics. However, despite the lower costs and potential for substantial product yield with microbial fermentation, this process has challenges. This article discusses the advantages and challenges of microbial fermentation and looks ahead at what place fermentation may hold in the biomanufacturing industry moving forward.

Industry sources note that fermentation has played a role in manufacturing biologics for quite some time. The first biopharmaceutical, insulin, was produced in the early days via microbial fermentation in Escherichia coli (E. coli), and is now also produced in yeast, says Gregor Awang, PhD, director, Biologics Process Development, BioVectra, a contract development and manufacturing organization (CDMO).

In addition to insulin, many other biologic drug substances are now made via fermentation, including human growth hormone (HGH), enzymes, cytokines, monoclonal antibodies, antibody fragments, and bioconjugates, Awang enumerates. Furthermore, plasmid DNA, which is the intermediate needed to make messenger RNA (mRNA) for vaccines and therapeutics, is also produced in bacteria, and some bacteria have been modified as a product themselves to be used in nutritional supplements, Awang states.

Fermentation is a key technology at the core of all biologics, whether it is antibodies, complex proteins, or genetic medicines, says Jess Tytell, director of Technical Business Development, Ginkgo Bioworks, a US-based biotechnology company specializing in bioengineering microorganisms. Tytell explains that cell lines that have historically been employed for biologics production have been mammalian in origin, but with advances in cell engineering and development of new formats of biologics, microbial platforms will start to become more relevant.

In the meantime, more biosimilar products are expected to come onto the market in the next decade, so the question is whether fermentation will hold a place in the manufacture of these biosimilars. Tytell believes that fermentation will continue to remain a fundamental technology enabling the manufacturing of biosimilars as much as they have been for novel biologics. In the context of biosimilars, microbial platforms can enable the improvement of access to much-needed therapies because these platforms can help make the manufacturing of biologics much more cost effective, she notes.

Awang points out that, since most of the non-glycosylated biosimilars on the marketsuch as HGH and insulinare made in either E. coli or yeast, fermentation will continue to be important in the manufacture of biosimilars. However, one limitation of fermentation for biosimilars is the proteins needing glycosylation, which adds polysaccharides to the protein to improve stability and potency. Protein glycosylation is specific to mammalian cells, and microbes, as a rule, dont add polysaccharides to proteins. If a product requires glycosylation, you would use mammalian cells. Specifically, you need to ensure human or human-like glycosylation to avoid an adverse immune response, Awang explains.

Traditionally, biosimilars have been cultured in Chinese hamster ovary (CHO) cells, and, even when glycosylated, these protein products tend to be compatible with the human systemthough there are human cell lines now available that provide fully human glycosylation.

It is sometimes possible to make the protein with E. coli, then chemically add a carbohydrate moiety in vitro. This has the benefit of reducing costs of protein production as fermentation is less costly than mammalian cell culture. It depends on whether the protein is amenable to this approach, depending on the complexity of the required glycan. For example, some proteins can be PEGylated, which adds a relatively less complex carbohydrate, Awang says.

Pichia pastoris (P. pastoris) is a yeast that combines high-yield production and is capable of some post-translational modifications, including glycosylation, Awang adds, noting that companies have engineered P. pastorisand many other yeaststo mimic the human glycosylation pathway.

As with most manufacturing processes, a particular process will have both its pros and cons when it comes to scale up, and microbial fermentation is no exception. When comparing fermentation to mammalian cell production, Cameron Graham, senior manufacturing and science technology (MST) process engineer, BioVectra says that scale up of a microbial process benefits from the fact that microbes are usually more resistant to shear than mammalian cells; however, microbial fermentation has the challenges of needing adequate oxygen transfer and mixing as well as the removal of excess metabolic heat.

Typically, for microbial scale up, well pursue a more robust scale up strategy in terms of the power per unit volume input and kLa (volumetric oxygen transfer coefficient), to maximize the efficiency of oxygen transfer into the fermentation broth. Particularly at larger scales (>1000 L) of high-growth cultures, the amount of heat can be more than what jacket cooling can handle since single-use bags dont have the same conductivity as a stainless-steel surface. This can also be challenge in traditional stainless-steel vessels, explains Graham.

Graham notes that there are options to lower the jacket coolant temperature, but the ratio of jacket heat transfer area to fermenter volume typically becomes more unfavorable as vessel volume increases. In those cases, you have to explore internal surface area additions to the vessel itself. For example, we are exploring an upgrade to our 17,000-L stainless steel fermenter to include internal baffles that will allow us to achieve about 300 mmol/L/hour OTR [oxygen transer rate] at 30 C broth temperature, and up to 450 mmol/L/hour OTR at 37 C. Such an upgrade will allow us to maximize the microbial process while reducing the risk to product quality due to uncontrolled temperature rise, Graham states.

Awang observes that media costs are lower for microbial fermentation, making scale up less expensive than with mammalian cultures, which can have up to 20 different ingredientsa few of which are extremely expensive and sensitive to certain conditions.

Yields tend to be much better with mammalian cell cultures (up to 10 g/L), than for fermentation (13 g/L). However, fermentation process development is faster and less technically challenging since there are a lot of tried-and-true methods for optimizing the process in E. coli, Awang says.

Awang continues that the key for both microbial fermentation and mammalian cell culture is getting the correct type of DNA inserted into the cells to ensure a high titer and yield of product. For example, transferring DNA into E. coli and selecting a suitable clone with the intact DNA is much simpler than transfecting mammalian cells. In the latter case, it is necessary to screen thousands of mammalian cell clones to get one that has the desirable combination of traits, depending on where in the cell genome the inserted DNA (transgene) has located, and how many copies. In the past decade, DNA editing using CRISPR [clustered regularly interspaced short palindromic repeats] and other techniques has made inserting DNA precisely into stable hot spots in mammalian cells much more precise, resulting in higher stability and product yield, says Awang.

Fermentation, however, has shorter processing times. According to Awang, a good microbial process can take as little as one to three days, as opposed to the weeks necessary for mammalian cell culture. This faster process has the added benefit of reducing the risks associated with contamination. Not only is the risk lower with fermentations, but if you do have a contaminated fermentation, the loss of worker hours is a lot less. A contamination two weeks into a mammalian culture can be a massive financial loss, Awang emphasizes.

Tytell concurs that microbial fermentation advantages include significantly lower costs for microbial hosts, less expensive media, and fewer issues with contamination. The latter can mean less downtime and higher productivity. In addition, optimizing microbial hosts is faster, leading to a shorter turnaround time to develop the final production strain, which can decrease overall production timelines, she adds. In comparison, mammalian hosts require more screening (e.g., for viral infections).

The disadvantages of microbial fermentation that Tytell sees include the fact that post-translational modifications are different, and this difference is relevant for more complex biologics. In addition, there are fewer approved biologics from non-Chinese hamster ovary hosts, so there may be higher regulatory hurdles for newer biologics produced via microbial fermentation; however, these hurdles are expected to go away quickly after the first few approvals, says Tytell.

With a rich pipeline of emerging therapy drug candidates, what place will fermentation-based processes hold in the biomanufacturing industry as these more highly complex biomolecules move towards commercialization?

Fermentation has a place in a range of therapeutics in development. For example, plasmid DNA produced in E. coli can be used as both a therapeutic or an intermediate to make mRNA vaccines, gene therapies, and for gene editing, says Awang.

Conjugated protein therapeutics, in which a protein and another chemical entity, such as polyethylene glycol, are linked to improve the function of a biologic, is another area in which microbial fermentation has application, says Awang. Bioconjugation had died out around the turn of the century but is coming back with a bang. Products in development include PEGylated hormones, such as GM-CSF [granulocyte-macrophage colony-stimulating factor], which can be made in bacteria or yeast, and is then PEGylated to improve its stability. Or mAb protein fragments made in E.coli, which can be conjugated to therapeutic payloads to direct the payload to specific disease cells, Awang explains.

Tytell says that many current biologics do not require post translational modifications. For those biologics, and because of cost of goods and development timelines, microbial fermentation is poised to become a workhorse (e.g., nanobodies, aglycosylated antibodies, other protein based biologics, etc.). As microbial hosts continue to develop, they will become more valuable for complex biologics, she anticipates.

As microbial engineering continues to develop and microbial strains can be produced that can mimic key mammalian features, such as glycosylation, these fermentation-based processes will become extremely valuable in more complex biologics. The faster turnaround to testing and higher titers will be especially valuable for the discovery and validation phases, which become more critical as molecules get more complex, Tytell states.

Meanwhile, another current popular trend in biomanufacturing, single-use technologies, may have a place in fermentation processes, but stainless-steel systems will likely remain the core setup for microbial fermentation. Single-use microbial technologies can be conducive to fermentation-based biomanufacturing if certain criteria are met, Jeremy Kerrick, head of Process Development and Engineering at Ginkgo Bioworks emphasizes.

For instance, scale matters. If the output of a process is a commodity, then scaling up is often the approach that drives down cost of manufacturing and the final product. This typically means that the best option is stainless-steel, since there are currently no single-use fermentation options beyond 50 L, and these are only just now showing up on the market, says Kerrick. Thus, scaling up into a single use microbial fermentation-based platform to drive down cost is not currently possible.

The availability of single-use platforms is also a factor. High-value mammalian-based therapeutics such as CGTs rely heavily on single-use reactors. Yet, these single-use reactors typically scale to up to 2000 L. While they may incrementally increase in size in the future and perhaps marginally drive down the cost of manufacturing, it seems unlikely that they can get much larger than what is on the market now. It seems logical that once single-use technology reaches this scale for microbial fermentation, it will also be limited, and then the economics of scaling will again steer one toward stainless steel, says Kerrick.

In terms of titer, novel approaches to increasing the expression of the modality of interest could swing the pendulum back to smaller-sized fermenters and, thus, to single-use technology. According to Kerrick, superior producer cell lines, induction or transfection advances, and genetically modified organisms are all means being explored across industries to increase titers. He explains that, if a process currently provides 2 g/L of product and is produced in a 20,000-L reactor, which suddenly sees an increase of 10 fold titer, then 1000-L or 2000-L single-use fermenters are a viable option. Further, single-use technology has some advantages over stainless-steel at this scale, which could make single-use the superior choice.

Meanwhile, development at the bench and pilot scale needs to be taken into consideration. Until recently, mammalian and microbial development laboratories were dominated by glass and stainless-steel reactors, Kerrick points out. With the introduction of high throughput bioreactor systems many mammalian development teams have made the move from stainless-steel to single-use technologies.

Breaking down a dirty reactor, autoclaving, reassembly, cleaning in place (CIP), and steaming in place (SIP) are required [with stainless-steel bioreactors], which are time consuming and lead to downtime. Systems are often contaminated because a single step in the cleaning process was not done perfectly, leading to more downtime. Single use systems are typically provided in gamma-irradiated bags and arrive sterile. Single use systems greatly reduce the need for laborious cleaning and downtime. As more and larger single use microbial fermentation technologies are introduced onto the market, more microbial teams will follow the trend of their mammalian counterparts, Kerrick states.

Meanwhile, Awang notes that single-use fermenters have many benefits, including the rapid changeovers between batches (which can occur within one day) as well as the previously mentioned decreased risk of contamination and the elimination of costly and time-consuming cleaning and sterilization between batches that is essential with stainless-steel equipment. Single-use processes can also be large enough for a client that wants to do some fast clinical runs, since it will be much less expensive, and there are efficiencies with single-use up to 2000 L that arent available with stainless-steel systems, Awang says. One caveat being, however, that for biologics produced in the range of tons per year, stainless steel remains the preferred option.

Graham points out that biopharmaceuticals made by single-use fermentation units require purpose-built fermenters with a bottom radial impeller for adequate mixing/power per unit volume input. These fermenters must also be capable of one to two vessel volumes per minute at commercial scale. It is also advised that single-use fermenters have oxygen supplementation available for increased driving force in lieu of the lack of head pressure capability for single-use fermenters to optimize microbial growth and, ultimately, yield of drug substance, he states.

Choosing the best equipment will depend on scale and the type of product being manufactured, Awang continues. A good example is the autologous therapeutics used in personalized medicine. These require small-scale runs of 50 L or less with batch segregation. For these, single-use fermentation is great because one vessel is dedicated for each patient. There is no need to clean it, leading to faster turnarounds. This increases speed, reduces costs, and, most importantly, prevents cross-contamination, empasizes Awang.

In addressing the current viability of microbial fermentation for the anticipated influx of new emerging therapies, Graham points to work BioVectra has been doing. The company has been testing a new 100-L single-use fermenter to verify their ability to deliver suitable power per volume and mixing. In our experience, we can increase oxygen supplementation, but, without sufficient mixing to properly disperse the oxygen and achieve the desired transfer rate, oxygen supplementation can have limitations. Recently, we were excited to test a 400 mmol/L/hour process and completed the run while maintaining fermentation broth temperature within the expected specification. This is an important consideration for our clients in terms of the feasibility of single-use fermenters for use in high growth microbial processes, Graham explains.

A final selling point for using single-use systems is that they also tend to have lower utility needs, and single-use has faster equipment qualification than stainless-steel bioreactors, Graham concludes.

While fermentation has roots in ancient history, it has a bright future in the world of emerging therapeutics. Depending on the product being considered, the scale required and the need to speed a process to market, fermentation-based manufacturingwhen reconfigured for nuanced requirementsholds a valuable and flexible position within the manufacturers toolbox.

BioPharm InternationalVol. 35, No. 10October 2022Pages: 1822

When referring to this article, please cite it as F. Mirasol, Weighing the Benefits of Fermentation for New Biotherapies, BioPharm International 35 (10) 1822 (2022).

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Weighing the Benefits of Fermentation for New Biotherapies - BioPharm International