Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Chris Spivey

Tome Bioscience is developing genome-editing treatments that are based on the optimization of programmable additions via site-specific targeting elements (e.g., PASTE technology). This opens a possibility to create advanced integrative cell and gene therapies (CGTs), capable of correcting genes 

. Why is this a potentially significant company?

How Pfizer Views Partnering and Investing for Emerging Therapies

 (1), Uwe Schoenbeck, senior vice-president and chief scientific officer for emerging science and innovation at Pfizer, was asked what he’d like to see if he could wave a magic wand to have just one more tool at his disposal, to which he replied: “Target delivery, not just for RNA but also for both small and large molecules, including oligonucleotide-based therapies. We believe if you are able to deliver your therapeutic modality to your target organ or target cell, this could bring a lot of additional advantages for patients. Allowing access to new indications where we currently do not have effective therapies, but even for existing [indications] it might be able to provide a safer, lower dose, approach ... Any kind of tropism that you could introduce, that would be selective, that could be dialed in and dialed out, as desired, we would be very interested in.”

Co-founded by PASTE developers Omar Abudayyeh, PhD, and Jonathan Gootenberg, PhD, former graduate students with Feng Zhang, PhD (Broad Institute), Tome says its programmable genomic integration (PGI) platform “is designed to enable the insertion of any DNA sequence of any size into any programmed genomic location. PGI encompasses a series of genome-editing approaches, each representing enhancements over PASTE” (2). Furthermore, going back to an earlier paper, Tome outlined its potential by saying, “Beyond direct correction of hereditary disease, gene insertion provides a promising avenue for cell therapies, and efficient integration of engineered transgenes, such as chimeric antigen receptors at specific loci, can produce improved therapeutic products in comparison to random integration … By providing efficient, multiplexed integration of transgenes in dividing and non-dividing cells and in animal models, the PASTE platform builds on fundamental developments in both integrase and CRISPR [clustered regularly interspaced short palindromic repeats] biology to expand the scope of genome editing and enable new applications across basic biology and therapeutics” (3).

, Sept. 6, 2022.
2. Philippidis, A. The Next Chapter in Genome Editing? Tome Emerges from Stealth with $213M. Genet. Eng. Biotechnol. News online. Dec.19, 2023.
3. Yarnall, M. T. N.; Ioannidi, E. I.; Schmitt-Ulms, C.; et al. Drag-and-Drop Genome Insertion of Large Sequences without Double-Strand DNA Cleavage using CRISPR-Directed Integrases. 

, 500–512. DOI: 10.1038/s41587-022-01527-4

Articles

Tome Bioscience is facilitating the transition in biology from the editing phase to the cut-and-paste phase.

Tome brings $213 Million to the Programmable Genome Editing Party

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Perhaps not the headline most would first think of, but 2023 was a record year for disease elimination. A distinction between eradication and elimination, however, should be made. Eradication of a disease is seen as permanent and worldwide. Elimination of a disease, however, is only talking about a specific geographic area. “Eradication means that intervention measures are no longer required, the agent, which previously caused the disease is no longer present. 

 of a disease refers to the deliberate effort that leads to the reduction to zero of the incidence of infection caused by a specific agent in a defined geographic are … actions to prevent the disease from transmitting or re-emerging are still required once a disease is eliminated” (1).

Two diseases—smallpox and rinderpest—have been eradicated. As the World Health Organization (WHO) reaches its 75th birthday, its summary of disease burden decries increased heath perils associated with climate change and sustained urban warfare. But the summary also lists a surprising number of achievements.

Society has learned to co-exist in a world with COVID-19, but in March 2023, WHO certified Azerbaijan and Tajikistan malaria-free, followed by Belize in June, while Egypt made huge strides towards banishing Hepatitis C. More than 50 countries eliminated at least one neglected tropical disease (NTD); for example, Ghana eliminated gambiense Human African trypanosomiasis, “a life-threatening sleeping sickness transmitted by tsetse flies that causes significant harm in rural populations living in poverty in sub-Saharan Africa.” New and improved vaccines became available for malaria, dengue meningitis, and cervical cancer. These communicable diseases disproportionately affect the poorest among us (2).

Access and shortages, sometimes due to supply chain failures made obvious by COVID-19 vaccine and therapeutic rollouts, became a topic of concern for rich and poor alike. “For the 2023 update, 85 applications, encompassing over 100 medicines and formulations, were considered by the WHO Expert Committee on Selection and Use of Essential Medicines List (EML). The recommended changes bring the total number of medicines on the EML and EMLc (Essential Medicines List for Children) to 502 and 361, respectively” (3). Multiple sclerosis (MS) treatment was given a boost, with Secretariat of the WHO EML, Dr Benedikt Huttner saying, “given the evidence base and the increased affordability of rituximab, including the availability of prequalified biosimilars, it has been prioritized over on-label alternatives as an essential medicine to treat relapsing-remitting and progressive MS” (3). Two new cancer treatments, pegylated liposomal doxorubicin for Kaposi sarcoma and pegfilgrastim (to stimulate production of white blood cells and reduce the toxic effect of some cancer medicines on the bone marrow). Also of note was inclusion of various polypills for cardiovascular disease (3).

While 2023 was a turbulent year in many respects, the WHO summary report on disease burden and medicines access provides some room for optimism, despite these improvements not making major headlines throughout the year. Perhaps if they did, it would positively encourage more such advances and improvements to the way healthcare is thought of, and delivered?

Roser, M.; Ochmann, S.; Behrens, H.; Ritchie, H.; Dadonaite, B. Eradication of Diseases, Revised October 2018, Our World In Data, Global Change Data Lab. 

https://ourworldindata.org/eradication-of-diseases

https://www.who.int/news-room/spotlight/global-health-achievements-2023

WHO. WHO Endorses Landmark Public Health Decisions on Essential Medicines for Multiple Sclerosis. Press release. July, 26 2023. 

https://www.who.int/news/item/26-07-2023-who-endorses-landmark-public-health-decisions-on-essential-medicines-for-multiple-sclerosis

WHO provides a look at the world’s health as the agency turns 75.

A Record Year for Disease Elimination

Pharmaceutical Technology Europe® spoke with Fiona Bellot of Cellexus BioreactorSystems at CPHI Barcelona 2023.

A Look at New Airlift Technology in Single-Use Bioreactors Systems

Cellexus has pioneered airlift single-use disposable bioreactor systems. This new type of bioreactor airlift technology eliminates the need for mechanical mixing, instead using bubbles to move cells and nutrients, providing optimal aeration for rapid growth of cells. This method of gentle agitation is suitable for microbial fermentation and cell culture. An integrated heater/cooler allows temperatures from 16 °C to 40 °C without the need for external equipment.

Because of the low mechanical sheer forces inherent to the system (no impellers are used), phage and lentiviral production have been early use applications/adopters. Due to the large number of flasks required for adherent cell lentiviral vector production, manufacturers have turned to bioreactors and suspension-adapted cells to reduce space requirements, labor, and costs. Traditional stirred-tank bioreactors use mechanical agitation to provide mixing and aeration of the culture volume. This method of agitation can generate large shear forces that can damage the health of the cells, thus reducing lentiviral vector yields. 

The single-use airlift technology uses disposable bioreactor bags to eliminate cleaning and contamination, reducing downtime between runs and decreasing time to market. The system can work in volumes from 1.5L to 50L, with compact systems offering a comparably low footprint.

Cellexus Bioreactor Systems was featured at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023. CPHI Barcelona ran from Oct. 24–26, 2023.

Pharmaceutical Technology Europe® spoke with Fiona Bellot, sales director, Cellexus BioreactorSystems, at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023.

In sickle cell anemia mishappen and sticky hemoglobin cells cannot carry oxygen properly and frequently clump, clogging blood vessels and sometimes causing searing pain termed a vaso-occlusive crisis. It is debilitating. β-thalassemia isn’t etiologically closely related, however, similar to sickle cell disease (SCD), genetic defects are passed on from both parents, which leads to low hemoglobin production. This creates fatigue, jaundice, shortness of breath and irregular heartbeats. A fresh (Nobel prize winning) tool to redress both mutational situations was recently given Medicines and Healthcare products Regulatory Agency (MHRA) approval, in a world-first approval for complicated next-generation therapeutics (

). Clustered regularly interspaced short palindromic repeats (CRISPR) was successfully applied to both disease states, in a therapeutic called Casgevy (exagamglogene autotemcel, or exa-cel).

CRISPR is so new that this MHRA approval caused quite a stir in both the medical and pharmaceutical worlds. Even at the end of November 2023 the American society of Hematology didn’t appear to convey much about this news, nor the attendant questions and issues that must still be addressed. These include potential immunogenicity because of biology outside of the CRISPR itself, and also access alongside cost and reimbursement.

Casgevy galvanizesproduction of a form of hemoglobin normally made only in developing fetuses. “Production of this fetal hemoglobin is typically shut off soon after birth by a gene called 

, allowing fetal-hemoglobin production to resume. This provides some hemoglobin that is not misshapen and dampens the effects of the abnormal form. Vertex and CRISPR Therapeutics reported that, at nine months after treatment, 31 of 32 participants in their clinical trial had not had a single vaso occlusive crisis. Before treatment, they’d had an average of about four each year” (2).

CRISPR remains somewhat controversial for potential off-target effects. On top of this, after it makes its cut in the DNA of the 

 gene, CRISPR relies on the cell’s natural DNA repair machinery to stitch the strands back together. The step can introduce new errors. All of this is well known and becoming better understood; however, in its advisory committee briefing, Vertex stated: “There is no known or hypothesized mechanism whereby a DNA edit would revert to reduce the reactivation offetal hemoglobin (HbF) after exa-cel treatment. The long-term engraftment of edited cells also demonstrates the successful editing of long-term hematopoietic stem cell (HSCs) that are known to persist for a person’s lifetime” (3).

What is potentially equally worrisome for Casgevy are new findings from Wellcome Sanger Institute, University of York, and Boston Children’s Hospitalscientists outlining an observation that “cell competition” following gene therapy, may increase leukemia incidence. “The cause is likely not the gene therapy treatment itself, say researchers, but the therapy process, which involves gene editing outside the body and re-transplantation of stem cells back into the patient.” The authors go on to say “Instead, the process of genetically modifying these stem cells outside the body and re-transplanting them back into the patient makes blood stem cells that already have these mutations more prominent, thereby increasing their influence on the blood and immune systems.” The authors hypothesize younger patients might be an easier cohort to manage these therapies through, as their stem cells inherent have fewer mutations to “select” as triggering undesirable outcomes, and that “Continuously tracking these mutations and gaining a deeper understanding of these processes will profoundly impact the future well-being of sickle cell patients around the world.” (4)

While they are approximately 100,000 SCD patients in the United States, the disease seems related to malaria, and hence the vast majority of sufferers live in resource-poor nations. Vertex Pharmaceuticals said it had not yet established a price for the treatment in Britain and was working with health authorities “to secure reimbursement and access for eligible patients as quickly as possible. In the US, Vertex has not released a potential price for the therapy, but a report by the nonprofit Institute for Clinical and Economic Review said prices up to around $2 million would be cost-effective. By comparison, research earlier this year, showed medical expenses for current sickle cell treatments, from birth to age 65, add up to about $1.6 million for women and $1.7 million for men.” (5)

Not only cost but access to the “manufacture” of this treatment is also a barrier to widespread implementation. “In the US, there are approximately 200 specialized centers for bone marrow transplants. There are only three such centers for all of sub-Saharan Africa—in Nigeria, Tanzania, and South Africa. Making these types of CRISPR-based therapies available throughout the continent will require massive investment in clinical infrastructure. The road from now, having gene editing that is possible and implemented where most people live, it’s not that close,” said Ambroise Wonkam, a geneticist at Johns Hopkins School of Medicine and the University of Cape Town who also serves as president of the African Society of Human Genetics. “We have to put that into perspective” (6).

Casgevy was used here as synecdochic for the surging tidal wave of new modalities. The choice might well have fallen to ARCT-154, a self-amplifying messenger RNA (sa-mRNA) COVID-19 vaccine for initial vaccination and booster for adults 18 years and older, which was even more recently given approval by Japan's Ministry of Health, Labor and Welfare (MHLW). While ARCT-154 was tested on 16,000 patients compared to Casgevy in 40 patients only, and. while the cost and access is no barrier compared with Casgevy, both therapeutics herald new ways of thinking, new types of testing and validation, and new types of manufacture and end-point monitoring. Following on from the revolutionary COVID-19 vaccines, what comes next is more complicated, more difficult to price for reimbursement, and more effective in terms of cure rates. The toothpaste is out of the tube, and the industry must learn to adapt to take best advantage of what is becoming available, no matter how messy the process.

1. MHRA. MHRA Authorizes World-First Gene Therapy that Aims to Cure Sickle-Cell Disease and Transfusion-Dependent β-thalassemia. Press Release, Nov. 16, 2023
2. Ledford, H. Is CRISPR Safe? Genome Editing Gets Its First FDA Scrutiny. 

 (7986), 234–235. DOI: 10.1038/d41586-023-03317-7
3. FDA. 

Cellular, Tissue, and Gene Therapies Advisory Committee October 31, 2023 Meeting Announcement

, Oct. 31, 2023.
4. Wellcome Sanger Institute. New Research Sheds Light on Cancer Risk in Gene Therapies. 

, Nov. 16, 2023.
5. Cheng, M. The World’s First Gene Therapy for Sickle Cell Disease Has Been Approved in Britain. 

, Nov. 16, 2023.
6. Molteni, M. With CRISPR Cures on Horizon, Sickle Cell Patients Ask Hard Questions about Who Can Access Them

Chris Spivey is the editorial director for 

Exagamglogene autotemcel seen as synechdoche.

New Medicines, Markets, and Manufacture: CRISPR for Sickle Cell Disease and β-thalassemia

PTE discusses mRNA advances with Guillaume Roelandts, Head of Products and Marketing, Quantoom Biosciences, at the 11th International mRNA Health Conference.

Tackling Production Challenges through Greater Access to mRNA Technologies

, discusses messenger RNA (mRNA) advances with Guillaume Roelandts, Head of Products and Marketing, Quantoom Biosciences, at the 11th International mRNA Health Conference in Berlin, Germany. Quantoom Biosciences is a team of scientists, engineers, and clinicians committed to solving some of the biggest DNA and RNA production challenges facing vaccines and therapeutics by delivering greater access and autonomy to mRNA technology. This discussion introduces the company’s background and explores its future direction. It also covers Quantoom’s expertise in process development for mRNA synthesis and purification, and the process of validating a GMP cleanroom machine with regulators.

Quantoom Biosciences is part of Univercells, a global life sciences group with the mission of making biologics accessible to all. Launched early in the pandemic in June 2021, Quantoom entered into a strategic collaboration with eTheRNA to build an advanced, small footprint technology platform for the production of affordable RNA-based therapies. The platform can be used within existing facilities or rapidly deployed to areas of urgent need.

Milestones in Quantoom’s development include a grant from the Bill and Melinda Gates foundation and the acquisition of SynHelix, which developed a technology that, with the use of bacteria, is an alternative to DNA amplification. SynHelix, later renamed Quantoom Research France, is focusing on integrating a “new generation DNA bioreactor” that could provide great benefits in productivity and cost reduction, both for R&D and production needs. The World Health Organization (WHO) interest in Quantoom, through their tech transfer program, has led to mRNA production facilities and BioPharm technologies being placed in several emerging countries.

Chris Spivey, editorial director for Pharmaceutical Technology, discusses messenger RNA (mRNA) advances with Guillaume Roelandts, Head of Products and Marketing, Quantoom Biosciences, at the 11th International mRNA Health Conference in Berlin, Germany.

Earlier this fall the Centers for Disease Control and Prevention (CDC) gave an alert to likely shortages of drugs to treat infants with lower respiratory tract disease associated with respiratory syncytial virus (RSV). RSV itself is becoming more of a scary household name, sometimes being linked to COVID-19 and seasonal influenza in what has sometimes been dubbed a “tripledemic”.

“A big part of the flu increase in November,” said Scott Roberts MD, a Yale medicine infectious diseases specialist, in a news release on the tripledemic, “was our lack of immunity from having not been exposed to the virus for several seasons due to masking and other precautions, many of which have fallen to the wayside” (1).

COVID-19 primarily spreads through air transmission, whereas RSV spreads via contaminated surfaces. “Flu, on other hand, is somewhere in the middle, and can spread from respiratory droplets, aerosols, and through contaminated surfaces,” added Roberts in the news release (1).

It’s important, therefore, to practice what the CDC calls “respiratory etiquette,” specified Thomas Murray, MD, PhD, a Yale Medicine pediatric infectious diseases physician, in the news release (1). “That means coughing into a tissue and disposing of it immediately in the garbage.”

However, on July 17, 2023 FDA approved a new drug, Beyfortus (nirsevimab), to prevent RSV in babies and toddlers. John Farley, MD, MPH, director of the Office of Infectious Diseases in FDA’s Center for Drug Evaluation and Research, said in an FDA press release about the approval, “[This] approval addresses the great need for products to help reduce the impact of RSV disease on children, families and the health care system” (2).

Beyfortus has been approved for use in all infants up to the age of eight months old, which is different to the previous treatment, palivizumab, that was only approved for those infants considered to be at the highest risk of contracting RSV. Furthermore, Beyfortus is only required to be administered once, whereas palivizumab needs to be given once a month during RSV season (3).

This new therapy, along with other approvals and breakthrough therapy designations for alternate drugs, such as Arexvy from GSK (4),or RSVpreF from Pfizer (5), have given the public health system the feeling it was superlatively winterized. Unfortunately, supply has significantly lagged demand for Beyfortus, to the point that senate democrats are demanding answers about this shortage—lawmakers, led by Sen. Tammy Duckworth, have requested more detailed information from AstraZeneca and Sanofi about the supply issues and why there was unpreparedness for demand (3).

It’s easy to blame pharmaceutical companies, but the situation is much more nuanced than simply stating manufactured supply was too low. While that’s true, and while that’s partly because COVID-19 created an expectation for more vaccine hesitancy among parents than actually occurred, costs and payments played into readily available supplies, meaning payment and incentive systems also needs extra scrutiny in this case.

About half of pediatric vaccines in the US are paid for by the federal government through the vaccines for children program. Its main goal is to remove cost as a barrier so that eligibility is narrowed down to “Medicaid-eligible, under or uninsured, or American Indian or Alaska Native” children (6).

The remainder of vaccines are paid by private insurance; however, payment by insurance companies is made after the pediatrician has administered the dose. As a result of this method of payment, there is uncertainty as to whether the insurance company will cover the full cost of the vaccine, which is risky for the pediatrician (6).

Because most pediatric vaccines are inexpensive, the payment approach by insurers isn’t typically a dominant factor in terms of overall supply and access. However, Beyfortus is much more expensive, costing nearly $500 a dose, which is not likely to be manageable for a medium-sized practice to be able to vaccinate their patient population (6).

While it is debatable if RSV is part of a tripledemic, it is part of a perfect storm when it comes to supply and access of treatment. With demand for treatment difficult to estimate and a novel vaccine with a price tag misaligned with the vast majority of pediatric vaccine precedents; under-ordering from pediatric practices was inevitable andfurther fed into the lower demand models being used by manufacturers for production. Lastly, a lack of natural immunity from being “closeted” due to the pandemic has had a knock-on effect, inflating more cases than would otherwise have naturally occurred. The supply issues with RSV drugs have demonstrated a good case example for industry to learn from going forward.

1. MacMillan, C. ‘Tripledemic:’ What Happens When Flu, RSV, and COVID-19 Cases Collide? 

Yale Medicine Nov. 22, 2022 (Updated: Jan. 12, 2023

).
2. FDA. FDA Approves New Drug to Prevent RSV in Babies and Toddlers. 

, Press Release, July 17, 2023.
3. Weixel, N. Senate Democrats demand answers from manufacturers over RSV drug shortage. 

, Nov 17, 2023.
4. Playter, G. FDA Approves First RSV Vaccine. 

May 10, 2023.
5. Pharmaceutical Technology Editors. Pfizer Receives FDA Breakthrough Therapy Designation for Respiratory Syncytial Virus Vaccine Candidate. 

, March 2, 2022.
6. Landman, K. The RSV Shot Shortage isn’t Just a Supply Problem. 

Looking at the role that RSV and pediatric medical practices play in drug shortages.