Every hour, two more people are diagnosed with Parkinson’s in the UK and the global patient population continues to rise. To date, there are no disease-modifying therapies available on the market for Parkinson’s (PD) patients. Pharmaceutical company Bayer is simultaneously launching stem cell therapy and gene therapy trials for Parkinson’s patients. The aim of this is to reverse the decline in motor control caused by the disease.

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Introduction

Parkinson’s is a progressive neurodegenerative disease in which depletion of the dopamine neurons in a region known as the substantia nigra causes a multitude of symptoms. The most notable of these symptoms include tremors, slowed movement, memory difficulties and behavioural changes.  

Parkinson’s clinical trials are one of the most challenging areas of research with a lack of therapeutics achieving desired disease modification. One of the major causes for treatment failing to progress to market is the placebo effect. 

The patients’ desire to retain independence and basic functions means that the placebo effect reduces symptoms even beyond experimental treatment. As a result, drugs fail to achieve the end-point as the observed improvements are primarily psychological and outweigh the efficacy of the drug. 

Gene therapy 

Over the last decade, Parkinson’s research has shifted towards cell and gene therapy (CGT). Current treatment is designed to replace the dopamine lost in the brain which, long-term, causes a multitude of side effects and does not modify the disease. 

Gene therapy is a broad term which covers methods that improve the genetic profile of an organism by “means of the correction of altered (mutated) genes or site-specific modifications that have therapeutic treatment as target”. 

The introduction of gene therapy for Parkinson’s has been split into possible targets classed as disease-modifying or non-disease modifying. Disease modifying strategies revolve around stopping PD-mediated cell death and/or regenerating lost neurons.

Previous Parkinson’s clinical trials of CGT have been based on viral vectors to deliver therapeutic transgenes to neurons within the basal ganglia. This delivery system remains a popular choice in the field and at the forefront of gene therapy. 

Bayey has initiated a gene therapy unit through Asklepios Biopharmaceutical which is currently recruiting patients for a phase 1b trial of a gene therapy using an adeno-associated viral (AAV) vector. This delivery system is designed to “deliver a gene for human glial cell line-derived neurotrophic factor (GDNF) into the neurons in the putamen”. GDNF is a naturally occurring protein in the body, previously shown to support the growth, survival, and maturation of dopaminergic neurons. This supports the rationale of delivering GDNF which could stimulate the growth of dopaminergic neurons and recover the loss of dopaminergic signalling which is essential for symptom recovery. 

Stem cell therapy 

BlueRock Therapeutics, a subsidiary of Bayer Pharmaceutical is utilising an alternative approach for Parkinson’s CGT.  According to a recent industry article,” in the BlueRock trial the first patient has been administered the first dose of pluripotent stem cell-derived dopaminergic neurons – MSK-DA01. The drug was delivered via surgical transplant procedures into the putamen area of the brain”. 

Pluripotent stem cells are cells that have the capacity to self-renew and develop into any cell of the adult body. By dividing and developing into the three primary germ cell layers of the early embryo, pluripotent stem cells can differentiate into any tissue type. 

Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons have remained at the forefront of Parkinson’s CGT research. Midbrain dopaminergic neurons can be efficiently induced from human embryonic stem cells and iPSCs and, when grafted into the target brain region, can improve the impaired behaviour of rodent and non-human primate (PD) models. 

The success of preclinical studies supporting the efficacy of stem cell transplantation for dopaminergic restoration in PD models has played a huge part in accelerating clinical studies of CGT in humans.  

Potential CGT challenges – delivery system 

The delivery system of CGT varies across the pharmaceutical industry, but is usually divided into viral- and non-viral vectors. Traditional viral vector-based gene therapy is achieved by in vivo delivery of the “therapeutic gene into the patient by vectors based on retroviruses, adenoviruses (ADs) or adeno-associated viruses (AAV)”. 

The ideal delivery system for gene therapy in the central nervous system (CNS) will aim to follow a specific criteria: (1) minimally invasive delivery (2) target specific tissue (3) achieve long-life treatment following a single, low dose. One of the main obstacles for gene therapy in the CNS is the blood brain barrier (BBB). 

As a protective measure, the BBB prevents the diffusion of drugs (delivered intravenously) into the brain. This was a particular issue raised for AAV vectors, highlighted in a journal review. However, direct delivery into the CNS is one method of bypassing the BBB. This appears to be the direction for Bayer’s gene therapy, which will be administered directly into the putamen region.

This is known as an intraparenchymal injection, and a number of preclinical studies have demonstrated successful circumvention of the BBB. There are, of course, a number of challenges with this method of viral vector gene delivery highlighted in the aforementioned review:

• This method is highly invasive which may not be an appropriate method for clinically vulnerable patients who may find this distressing 
• Previous studies have demonstrated the distribution of AAV particles within the brain (of higher order animals) is restricted 
• Intracranial delivery is correlated with a lower probability of therapeutic efficacy in larger mammals 

For CGT, one of the greatest barriers is the immune system, which could attack the stem cells/genes delivered into the brain. For AskBio’s gene therapy, this is a potential risk. Humoral immune responses, derived from antibody-producing B cells, can develop against AAV. Humoral immunity refers to antibody-mediated immune responses. This is also a challenge for BlueRock Therapeutics stem cell therapy, in which the transplanted cells will be destroyed by the immune system as a protective mechanism against foreign bodies. 

However, the transition from preclinical to Bayer’s clinical trials infers that there is potential for success and safety for both cell and gene therapy. The phase one trial for Bayer’s stem cell therapy “primarily examines the safety and tolerability of cell transplantation a year after the procedure. Secondary goals include assessing evidence of cell survival following transplant and motor effects one and two years after surgery”. In other words, this will determine the efficacy of the delivery system with regards to symptom improvement and highlight any potential safety issues. 

These clinical trials represent a huge milestone in Parkinson’s research. For the first time, there is potential to develop therapies which could overcome the short-lived efficacy and extensive side effects of current Parkinson’s treatment. For a significantly unmet clinical need, this could offer a hope for a growing patient population. Furthermore, successful disease modification within these CGT trials could potentially lead to the development of CGT for other diseases of the CNS.

• thus specific gene expression silencing is obtained 

siRNAs have been described as the most promising type of RNA-based therapeutic oligonucleotide drug. The ability to inactivate RNA molecules in a sequence-specific reinforces potential for precision medicine in specific RNAi therapies. 

One of the main advantages of siRNAs over small molecules and monoclonal antibody drugs is the simpler execution of function. siRNAs work by complete Watson-Crick base pairing with mRNA, whereas small molecule and monoclonal antibody drugs need to recognise the complicated spatial conformation of certain proteins. 

As a result, there are many diseases, especially rare forms, that are not treatable by small molecule and monoclonal antibody drugs due to the complexity of the pathology in which a target molecule with high activity, affinity and specificity cannot be identified. 

Despite this significant advantage, there remain a number of barriers for siRNA to their targets. Firstly, siRNAs are unable to directly penetrate the cell membrane and can enter the cell only by endocytosis or pinocytosis. However, in order to implement the silencing effect, siRNA must penetrate the membrane and exit into the cytoplasm.

When siRNA enters the cytoplasmic space via endo/pinocytosis, there is also a risk it will be cleaved by cytoplasmic ribonucleases or its concentration can decrease due to the division of target cells. This is an obvious issue when it comes to optimising the bioavailability of the drug for two reasons: (1) concentration is affected by internal cellular mechanisms, and 2) is susceptible to degradation by enzymes. 

The high specificity of action which makes siRNA so desirable can also cause off-target effects. As a result this limits its use in high concentrations due to the induced toxicity. The most significant non-targeted effect of siRNA is unwanted activation of the system of innate immunity under the action of certain motifs in the siRNA sequence. 

Fortunately, research in this area has led to chemical modifications that may affect the properties of siRNA. 

One of the most saturated areas of interest is the use of bioconjugates, like with ASOs, which enables a more direct delivery system to target cells. A stable linker binding siRNA and biomolecules together prevents a decrease in the efficiency of RNAi associated with the inhibition of RISC assembly. Lipids and cholesterol were some of the first ligands suggested for conjugation with siRNAs as they can overcome the issue of the hydrophobic cell membrane barrier.

On-going research is determined to address some of the challenges with siRNAs and ASOs through chemical modifications to improve bioavailability and reduce toxicity. Despite these challenges, the efficacy of these drugs remains evident with an increasing number reaching the market. The end goal is optimise the delivery of these drugs to the point where they can be potentially developed for effective precision therapeutics.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Latest Advancements in Parkinson’s Treatment: CGT Shows Potential to Reverse Disease appeared first on Proventa International.

Cell and gene therapies have remained at the forefront of biomedical research for the last decade. While the mechanisms of these therapies differ, both approaches have shown potential across a range of conditions to alleviate symptoms or potentially cure the underlying disease. The latest research is focusing on the future for viral- and non-viral based vectors for cell and gene therapy.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

Introduction

Gene therapy is a broad term which covers methods that improve the genetic profile of an organism by “means of the correction of altered (mutated) genes or site-specific modifications that have therapeutic treatment as target”. Cancer gene therapy is an example of this therapeutic technique which continues to show potential in cancer research for treatment. 

A number of innovations and findings came from CGT research in 2020, as highlighted in a recent Nature article. One interesting finding was that a new genetic signature was identified for acute myeloid leukemia. This genetic signature is important in detecting AML-specific stem cells that are responsible for tumor relapse and therapy resistance. 

A recent study used machine learning algorithms to develop a method of identifying genes associated with stem cells. These genes were considered as specific biomarkers for leukemia stem cells. This could have a fundamental impact on future gene therapy design, in terms of optimising cancer stem cell identification and validation through biomarkers. 

Stem cell therapy is also an example of a cellular therapeutic technique which has shown potential as a regenerative strategy for a multitude of diseases. Cell therapy is characterised as the “prevention or treatment of human disease by the administration of cells that have been selected, multiplied, and pharmacologically treated or altered outside the body (ex vivo)”. The cells may be derived from the patient known as autologous cells or from a donor (allogeneic cells). 

In ophthalmology, stem cell therapy has seen a significant improvement in the vision of patients suffering from a condition known as macular degeneration. This was reported after patients of a particular study received a transplant “patient-derived induced pluripotent stem cells (iPSCs) that were induced to differentiate into pigment epithelial cells of the retina”. 

Viral vector-based therapy

Traditional viral vector-based gene therapy is achieved by in vivo delivery of the “therapeutic gene into the patient by vectors based on retroviruses, adenoviruses (ADs) or adeno-associated viruses (AAV)”. 

ADs continue to be used as a vector for CGT due to a number of advantages. Firstly, they show high transduction efficiency for a broad range of cell types. Transduction refers to the entry of viral vectors into the target cells. In the case of AD this is a rapid, simple process which allows “sufficient expression of the encoded sensor to permit detection and analyses”. Secondly, they have the ability to infect a broad range of cell types and tissue, known as viral tropism. 

Third-generation AD vectors, known as high-capacity AD viral vectors (HCAds), are the latest versions of developed viral vectors for gene therapy. HCAds are characterised as high capacity due to their ability to accommodate ~36 kb of space for cargo genes. In comparison with previous generations, HCAds offer a number of improvements. 

One of the main improvements is that HCAds demonstrate a reduced immunogenicity. Immunogenicity refers to the ability of therapeutic products to trigger an immune response. While this may be desirable in the context of vaccines, it is an unwanted effect with viral vectors which are then cleared or neutralised by the immune system. In addition, immunogenicity of gene therapy products “can cause diverse immune related toxicities”.

The future for AD viral vectors is further refinement with elimination of the current limitations. While the immunogenicity has been reduced in third generations, AD viral vectors pose a concern over the safety in the long term. In 2019, a ten-year follow up study in dogs receiving gene therapy vectors, found that “the vector genomes were found to be stably integrated into the host genome”. This presents some obvious concerns with regards to the risk of oncogenic mutations. Lentiviruses, another type of viral vector, are emerging as a platform of choice for genetic vaccines. Recent advances in the development of non-integrating lentiviral vectors have greatly reduced insertional mutagenesis.

Non-viral approach 

The main advantage of moving towards non-viral vectors in CGT is the biosafety. In comparison to viral vectors which pose a risk for immunogenicity and cytotoxicity, non-viral vectors offer a significant safety advantage. 

In terms of manufacturing, they are also more cost-effective and easier to produce than viral vectors. The major approaches to non-viral gene delivery involve naked DNA, plasmids, conjugate complexes and cationic polymers. 

Plasmids

A plasmid is a small, circular, double-stranded DNA molecule that is distinct from a cell’s chromosomal DNA. Researchers can insert genes into a plasmid vector creating a recombinant plasmid. The plasmid is transferred into a bacterium in a process called transformation, which then undergoes rapid division and can be used as factories to copy DNA fragments in large quantities. 

One of the main problems with plasmid vectors is translocation from the cytosol to the nucleus. The cytosol is typically the desired location for transported cargo to induce a therapeutic effect, the nucleus is often avoided due to the risk of genetic alterations. 

Cationic polymers

In the last decade, molecular biology has seen significant development in the engineering of non-viral vectors. Plasmid vectors, while originally popular, are decreasing in prevalence in CGT. Cationic polymers are now among the most utilised non-viral vectors for gene transfer. 

This class of non-viral, lipid-based vectors includes polyethyleneimines (PEI). PEIs have demonstrated good gene delivery performance with regards to a high cation charge density. A high cation charge refers to a density of positively charged ions, which shows great attraction for DNA and RNA, which are both negatively charged.

Polysaccharides

In terms of future development, bioengineering appears to be moving towards polysaccharides as gene delivery systems. Polysaccharides are long chains of subunits called monosaccharides – glucose is a prime example of an important polysaccharide. 

A number of natural polysaccharides such as chitosan and hyaluronic acids have been widely used as polymeric backbones for the formation of nanoparticles, which can be provided as valuable gene delivery carriers. They show substantial promise for cell therapy, “effectively transporting the drug molecules across the membrane“. In addition, their biodegradability ensures the release of the encapsulated drug molecules, which minimises the side effects caused by a burst release of the cargo therapeutics. 

Despite the innovations improving viral-vectors for molecular medicine, non-viral vectors appear to offer significant advantages. In addition to minimising safety concerns, the manufacturing process of non-viral vectors is overall more simple and cost-effective. However, further research is required to refine non-viral vectors to meet the therapeutic efficacy of viral vectors should they become an alternative.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Oncology Strategy Meeting, set for 17 June 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post A Review of CGT: Viral and Non-Viral Approaches appeared first on Proventa International.

Given the considerable seismic shifts occurring in the pharmaceutical and life sciences sectors recently, it is no surprise that the major trends and investments of 2021 have seen a similar change in focus. Alzheimer’s Disease, genome editing and cellular therapy are three areas which will see increased investment from the pharma industry in the coming months. 

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

R&D: Alzheimers 

Dementia is an umbrella term to describe degenerative neurological disorders which result in significant cognitive impairment that impacts daily life. Symptoms often manifest as problem-solving issues, short-term memory impairment and language difficulties. Alzheimer’s is a specific cause of dementia characterised by early clinical symptoms including depression and difficulty remembering short-term conversations. Late symptoms include confusion, poor judgement, behavioural changes and eventually walking. With an ageing global population, Alzheimer’s presents an unmet clinical condition. As of 2021, there is no cure for Alzheimer’s disease, with only poor symptom management available for patients. 

The current drugs available on the market aim to manage the symptoms of Alzheimer’s, but none can “slow or stop the damage and destruction of neurons that cause Alzheimer’s symptoms”. Psychosis is a particularly difficult symptom that can present in Alzheimer’s with disease progression. Psychosis is a psychiatric symptom in which an individual fails to distinguish fiction from reality. It can include vivid visual and auditory hallucinations. Unfortunately, ”no drugs are specifically approved by the FDA to treat behavioral and psychiatric symptoms”. Psychosis is one of multiple behaviour and psychiatric symptoms that manifest in “almost all patients with dementia in the course of their disease”. 

Aducanumab is the only drug of the five approved by the FDA which shows potential to slow progression of the disease. Hence, a significant amount of time and resources are being funneled into Alzheimer’s research to better understand the pathophysiology. A study published May 15, 2021 a new comprehensive model of Alzheimer’s was published. The longitudinal model is to be used as a prognostic tool which “effectively reproduces the observed course of AD from an initial visit assessment”. The aim of which allows clinicians to project “coordinated developments for individual patients of multiple disease features.” 

Alzheimer’s has recently seen significant investment for novel drug trials in rare forms of the disease. The Alzheimer’s Association, in partnership with the GHR Foundation, has committed $14 million to Tau Next Generation. Tau Next Generation is an expansion of the Inherited Alzheimer Network Trials Unit at Washington University. The aim of this unit is to investigate the efficacy of a class of Azheimer’s drugs known as anti-tau, in individuals with “dominantly inherited Alzheimer’s disease (AD), a rare form of younger‐onset AD caused by inherited genetic mutations.”

Biotech: Genome editing

Genome editing is a powerful tool of genetic engineering in which DNA is inserted, modified, substituted, or replaced within an organism’s genome. According to a 2019 review, the mechanism of genome editing is based on the use of “highly specific and programmable nucleases, which produce specific changes in regions of interest in the genome by introducing double-strand breaks (DSBs) that are later repaired by cellular mechanisms.” 

Nucleases are a broad class of enzymes that cleave nucleic acids. Genome editing has evolved rapidly over the last decade, showing its utility in biotechnology and biomedical research. This method of genetic engineering can be performed in vitro or in vivo in a wide variety of experimental models. The most popular system for genome editing is the CRISPR/Cas9 system. The system performs sequence-specific cleavage through interaction of crRNA by base pairing at the target site. After joining the target site, “the two DNA strands are cleaved by the nuclease domain of Cas9”.

The system has shown significant therapeutic potential for a multitude of diseases. These diseases are primarily caused by some form of known genetic dysfunction. The therapy of genome editing is based on the direct modification of pathological genetic sequences. Whether it be the knock-out of a target gene, introducing a protective mutation, or adding a therapeutic transgene, CRISPR/Cas9 has shown great diversity in its ability to edit the human genome. 

Oncology is one therapeutic area which continues to use genome editing as a therapeutic tool for treating cancer. The current goal of cancer therapy with CRISPR/Cas9 for the coming years “is to remove malignant mutations and replace them with normal DNA sequences.” According to a 2020 Nature article, the screening of functional genes using genome editing is the future direction for precision medicine. The aim is to “reveal changes in gene expression after cancer drug therapy and help to investigate drug-gene interactions by adding small molecules as perturbations”. The hope is that novel targets will be targeted for precise treatment and provide insight into disease development.

Personalised medicine: Cell and gene therapy

Gene therapy is a broad term which covers methods that improve the genetic profile of an organism by “means of the correction of altered (mutated) genes or site-specific modifications that have therapeutic treatment as target”. One of the most recognised gene therapy techniques is recombinant DNA technology. In this technique, a target/healthy gene is inserted into a vector which is then transported into the genome in order to replace an abnormal gene causing a disease. 

Recombinant DNA technology has facilitated many important clinical techniques including genetic screening and clinical technique known as genetic counselling. It appears now that the advances in gene therapy are being applied to “correct inherited genetic disorders such as hemophilia, cystic fibrosis, and familial hypercholesterolemia”. 

In July 2020, a nature article was published suggesting that “gene therapy could offer an inclusive cure for cystic fibrosis”. In the same article, it was highlighted that in October 2019, the Cystic Fibrosis Foundation (US) announced a funding of $500 million “for research into treatments for cystic fibrosis, including gene-therapy approaches”. Over the next six years this function will be used to explore different genetic therapies for cystic fibrosis patients whose condition cannot be treated with existing drugs on the market like Trikafta.Stem cell therapy is an example of a cellular therapeutic technique which has shown potential as a regenerative strategy for a multitude of diseases. In a news release by Yale University, “Yale scientists repair injured spinal cords using patients’ own stem cells”. Stem cell therapy has shown potential over the years to restore nerve damage, up until now however, the results have been less than sold. In the news article, it was stated that additional studies will need to confirm the results of this “preliminary, unblinded trial”, however they remain optimistic. This shows one of many applications for cellular therapies which show potential to treat diseases or injuries not previously thought possible.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Medicinal Chemistry and Biology Strategy Meeting, set for 29 June 2021

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Future Trends for Pharma and Life Sciences 2021 appeared first on Proventa International.

Cell and Gene Therapies (CGTs), experimental technologies to treat or cure diseases using the body’s cells, have been on the ascendant for some time now. As promising as they are, CGTs have consistently moved forward faster than regulatory agencies can keep up: despite the first CGT products only receiving approval in 2017, new types of CAR-T therapies are already being examined. 

The European Medicines Agency (EMA) in Europe and Food and Drug Administration (FDA) in the USA are responsible for the regulation of CGTs. Since the first CGT approvals, applications in the space have been skyrocketing. In 2018 the regulators saw around 500 active gene therapy applications.

Despite this, CGT treatments are still a more risky proposition than other, more established therapies. One of the first in vivo gene therapies, Roche’s Luxturna, can create a short-term immune response in the liver that must be treated by steroids. Questions still exist around giving a patient with previous exposure to AAV viruses a further dose through gene therapy. Similarly studies such as Sangamo’s 2018 trials have failed to demonstrate clinical benefit for patients.

In light of these issues regulatory agencies are constantly changing and adapting to the new environment. New guidance is constantly being produced, with the EMA and FDA working more closely together to ‘avoid digressions between the two’. 

Standardisation and Other Issues

One of the major issues within CGT today is the lack of standardisation in processes. A major regulatory concern are the manufacturing processes involved when creating CGT medicines, and how changes could affect the product’s safety and efficacy. 

Creating CGTs is an extremely complex process. Due to the need to use biological materials, manufacturing must ensure very high quality throughout the production. This in turn requires expensive equipment and technical expertise, something many labs – especially smaller companies – lack. While companies often turn to contract manufacturing organisations (CMOs) to provide these functions, they are now considerably overburdened by the number of therapies heading towards trials. 

This issue is made worse by organisations’ need to change and update their processes for greater returns, which strains the ability to keep their products consistent and efficacious. 

Current and Future Regulation 

The USA and EU have markedly different regimes for overseeing the approval of CGTs. The U.S.’ FDA oversees its clinical trials, while the EMA in Europe does not. For a CGT clinical trial to occur in Europe, approval must be received from a competent authority and ethics committee in the Member State, as well as approval to use a genetically modified organism. 

Despite this, the two organisations use similar data-heavy approaches to assessing safety and efficacy of drugs, often working together through teleconferences. 

Since 2017, when Luxturna was first approved by the FDA, regulatory standards and guidelines have evolved at a rapid pace. In August 2018, the U.S. National Institutes of Health ruled that gene therapies no longer needed a regulatory review before the start of clinical trials could begin, eliminating duplicative oversight with the FDA. From that point, the Recombinant DNA Advisory Committee focused on emerging biotechnology issues. It was in this year that the FDA published six proposed new guidelines on gene therapy, with two more published in 2019. 

The EMA also updated its frameworks in 2018, changings its guidance on design, manufacture, characterisation and testing of delivery mechanisms. 

This is a rapidly-changing field, made swifter by the efforts of trial sponsors within the area. Generally, CGT sponsors work with regulators from the earliest stages of development, sometimes even during preclinical development. The talks with regulators on how to design the drug programme allows for easier approval when the drug is set for manufacture. 

Despite this, concerns have been expressed that the agencies lack the necessary expertise to fully deal with the influx of new therapies sent to them for approval. With estimates suggesting that by 2021 over a thousand CGTs will be expecting regulatory approval, this seems a genuine concern that so far has no solution. 

Automation as a Solution

Before the industrialisation of CGTs can fully commence, a number of issues must be addressed. Processes must be made more efficient and more cost-effective, and standardised in such a way that regulation becomes less burdensome or stringent. 

Automation is one way to address these problems, and open the door to greater commercialisation of CGTs. Providing greater control over bioprocesses via more efficient and fast readouts, automating CGT manufacturing can easily lead to the optimisation the sector so desperately needs. 

Automation would immediately remove human error and the variation caused by manual handling. It would also allow for the precise determination of process parameters and timings to be saved, and the for integration of process analytics, which would eliminate the subjectivity of which processing decisions are currently based. This would allow for better processing rules. 

With full automation of a process, greater understanding will be had of how individual processes affect cell quality. The optimisation that comes about through these various positives means that manufacturing costs will be hugely reduced. 

From here, the introduction of AI and Machine Learning to these automated processes could improve their efficiency and ability to handle more complex tasks, as well as to perceive cell quality better through a learning feedback loop. 

Conclusion

For CGTs, the regulatory field has advanced in leaps and bounds over the last three years, becoming increasingly more effective and targeted with each new guidance update. It is clear that sponsors and manufacturers have no issue with the direction that regulatory agencies are going in: only that their budgets and means are not equipped to deal with the scale of the CGT revolution to come. 

Automation is the tool of the near future that can change this. With the ability to standardise processes to a regulatorily satisfactory manner, remove human error and increase efficiencies across the manufacturing chain, automation would immediately increase the ability of regulators to work with CGTs and approve life-saving therapies. Companies are certainly implementing small-scale automation in their companies: but it is clear that full automation of CGT manufacturing cannot come fast enough. 

Joshua Neil, Editor
Proventa International

To ensure you remain up-to-date on the latest in clinical development and biotech conferences, sign up for Proventa International’s online Biomanufacturing Strategy Meeting 2020.

The post Solving Regulatory Issues in Cell and Gene Therapies appeared first on Proventa International.

The COVID-19 pandemic proved how ill-equipped the world was for a virus of that scale and potency. In the first months of the pandemic, businesses across all sectors scrambled to prepare their processes and supply chains for the coming disruption, caught unawares by the sudden and enormous changes.

Naturally, one of the sectors most affected by COVID-19 was the pharmaceutical industry, and within pharma biomanufacturing had the potential to be hit hardest. Reliant not only on global travel and well-planned timelines, biomanufacturing also deals with products central to solving the pandemic threat: vaccines.

It is inevitable that change at this scale will revolutionise the field. But how will biomanufacturing shift in the years after COVID has faded from the headlines? Ahead of its Biomanufacturing Strategy Meeting this October, Proventa finds out more.

Transport and Supply

Almost every industry’s transport and supply chains have suffered during the COVID-19 pandemic, including in biomanufacturing, where tight timescales and sensitive payloads are commonplace. Though the impact has largely been less critical than was feared, drug shortage worries and the problem of export embargoes have meant that managing the supply chain has been a greater worry than ever. 

During the height of the pandemic, air traffic to and within the United States was heavily disrupted: according to one report almost 50% of flights were cancelled between mid-March and April 2020. As a large percentage of cell therapy products travel via commercial airways, these cancellations had a significant effect on the sector’s supply chain, exacerbated by the potential for couriers to be unable to travel internationally, either due to health reasons or border restrictions. 

A key contributor to this challenge is the fact that many pharma companies have concentrated their manufacturing centres in one or two places, often either in China or in India – two countries where considerable lockdowns were or are imposed and much of the workforce unable to work. 

Over the coming years, it is expected that this problem will be dealt with by moving manufacturing to less-impacted markets, avoiding critical delays when a major manufacturing country is hit with export difficulties. Spreading factories across a few countries will avoid this risk, though in the short term it will cause greater difficulties due to the tight regulations and need for precise capabilities involved in setting up a factory. 

This will certainly increase complexity within the supply chain. Paired with extra regulatory burdens on working with partners, it is important that pharma companies work to digitise their supply chain as soon as possible, to ensure track and trace, monitoring and licensing requirements are sufficiently met. 

Vaccines under COVID-19

Naturally, vaccines are the area most directly affected by the COVID-19 pandemic. The rush to produce a solution to the virus has driven pharma companies to unprecedented speed in vaccine research: but it is not only the speed of the development that will change post-COVID but how the industry looks at vaccine creation more widely. 

Traditional vaccines, made in eggs or from blood plasma, lack the swift creation and simplicity that is needed today. The industry has turned from these older forms to more modern developments including recombinant antigen-, DNA- and mRNA-based solutions which are not only safer but can respond rapidly to future pandemics with high rates of mortality. 

The changes made during COVID will also enable pharma experts to re-examine other products that in the past have seemed too expensive to run. Such vaccines would use established bioprocess operations that have already been thoroughly tested across a number of modalities, but have so far been too expensive to consider over current vaccine production methods.

The pandemic has changed the cost-risk-benefit balance of vaccines, however: now, area professionals are working ceaselessly to create new biomanufacturing operations that can make more advanced and cost-effective vaccines in large quantities. This will continue as these fields continue to receive additional resources, creating new vaccine possibilities in the wake of the virus. 

In which direction the vaccine field goes will depend somewhat on which of the potential COVID-19 vaccines proves effective; but it is also certain that this period in history has changed how stockholders view the importance of vaccine creation. It is also inevitable that the speed with which these vaccines have been made will not be a passing trend: with the knowledge that vaccines can go from initial stages to phase 3 in under a year, a new standard will be set that future vaccines will be held up to. 

Cell Therapies

The cell therapy space has also been dramatically altered by the onset of COVID-19. Autologous cell therapies, which collect cells directly from the patient rather than from a healthy third party, have naturally been impacted by the need for social distancing. Beyond the difficulty of patients visiting apheresis centres, there is also the difficulty of undertaking treatment regimes which weaken immune systems. 

Beyond this, the supply chain for cell therapies has been particularly interrupted by COVID, depending as it does on strict timeframes for delivery of cells to centralised manufacturing facilities. Due to the variable nature of supply in the pandemic, more patients than ever are opting to delay their therapies where possible to ensure greater safety, with companies like Eli Lilly and Pfizer announcing delays to their trials for patient safety reasons. 

To counter these difficulties, the future will see a broader base of cell donors from which to draw. This will create greater resilience in the supply chain, removing the need for companies to rely on a small number of ‘super donors’ from which cells are sourced. 

Another change that could ensure greater industry robustness is greater use of cryopreservation. Storing cell material will allow patients to have access to therapies even during times of disruption, as well as potentially allowing for cell collection nearer to the patient themselves, thus cutting down the potential for interruptions to the process. While uncertainties still exist around the implications of freezing cells for therapy, the process offers a potential solution to the severe disruptions pandemics can cause in cell therapies. 

Business Decisions 

Beyond area-specific changes that will follow in the years to come, there are a number of business-specific modifications that companies should or will be adopting to prevent future difficulties during a pandemic.

The first of these will be patient-centric: in line with the current trend in the sector, focusing considerably more on the patient’s thoughts and feelings is critical for companies facing the public, particularly those dealing with trials. Understanding how patients are dealing with the pandemic, their difficulties and in what way they feel safe undertaking trials is key to maintaining a working trial during times of crisis. 

This also applies to stakeholders. Understanding what healthcare providers need and when they are able to engage further in the business chain is vital to working together. 

This change has seen, and will continue to see, a rapid positive change in the use of digital equipment for more hybridised trials. The use of econsent and eCOA software to digitally sign patients up and increase understanding, as well as the use of wearable technology, video discussions and social media can all increase patient compliance and retention without the need to breach social distancing measures or put lives at risk. A survey conducted in April 2020 pointed to a 6x increase in patient engagement remotely across a number of specialties and geographies. 

Conclusion

The impact of COVID-19 will not disappear alongside the virus. Whether or not the wider world will be changed by this virus, as many have suggested it might be, is unknowable. But it is certain that biomanufacturing will never go back to what it was before the creation of the COVID-19 vaccine. In terms of supply chain planning, vaccine creation and business decision-making, the pandemic of 2019 has pushed the field into new and exciting territories, from which it will not return. 

Joshua Neil, Editor
Proventa International

To ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s online Biomanufacturing Strategy Meeting 2020.

The post How will COVID-19 Change Biomanufacturing? appeared first on Proventa International.

Safety is one of the most important aspects of drug development. The need for a drug to be efficacious, consistent and non-harmful to humans is vital for its success. And where a treatment is new, highly variable, and can involve introducing viral vectors into the human body, safety must be ensured more than ever. 

The chemistry, manufacturing and controls (CMC) processes are key to ensuring at every stage that a drug is safe and effective. But given the novelty and variability of cell and gene therapies, what challenges does CMC face in this field? 

Ahead of our CMC / Regulatory Affairs online Strategy Meeting on 2/3 June, we looked more at the challenges of CMC in cell and gene therapies.

Cell and Gene Therapies

Cell and gene therapies (CGTs) are two distinct but overlapping treatments in modern medicine, whose potential is only now beginning to be fully explored. In both cases, cells are extracted either from a patient (autologous approach) or from a healthy donor (allogeneic approach). They are then altered to contain a corrected or modified version of the damaged genes, and returned to the patient’s body. There they will propagate and hopefully solve the issue. As a result of this method, CGTs have the potential to be extremely long-lasting solutions. Some require only one or two treatments in a lifetime. 

So far, CGTs have been used primarily to treat rare and currently untreatable diseases, such as motor neuron disease and some types of cancer. Their efficacy can be excellent: One treatment for B-cell acute lymphoblastic leukaemia showed an 83% remission rate after three months. 

As with any new treatment, a number of difficulties have arisen around the development and manufacture of CGTs. These range from development to manufacture, and include: 

– design of facilities, as the single-use and highly bespoke nature of CGTs reduces a number of standard processes to redundancy

– a much more complex supply train, in which a number of biological elements must be tracked, monitored and kept safe at the same time

– additional training for healthcare staff, who must learn new CGT methods and techniques

– the development of new payment models to deal with the high cost of CGTs and their more specialised targets

The Regulatory Challenge for CMC

But it is in the CMC arena that CGT is facing one of its most difficult challenges. The area’s natural need for flexibility and adaptability could potentially be solved by a strong risk-based CMC framework. But this is only recently appearing, both in the U.S. and within the European Union. In addition to this, the grant of breakthrough and ‘Regenerative Medicine Advanced Therapy’ status to a number of CGTs means that any CMC development process is sped up, causing further issues.

The newness of CGT is not, however, an excuse for reduced CMC compliance. The FDA has stated that by phase 2 of a CGT study there is increasing expectation for product characterisation and compliance with cGMPs. For licensure, full compliance with all applicable regulations is required. The FDA expectations for late-stage product development include having:

– sufficient manufacturing experience to narrow acceptance limits

– a controlled manufacturing process and planning for future scale-up

– a biologically relevant potency assay

The FDA released CMC guidelines for CGT manufacturing in January 2020. This covers CMC expectations for both early-stage and late-stage product development, as well as accelerating product developments through the FDA. 

To get around the sparsity of firm CMC frameworks, greater awareness of the current situation and better communication must occur. All parties must take care to share knowledge as early in the process as possible, to determine where quality/clinical connections are, and how to manage potential risks as they occur. 

More information on CMC requirements for CGT IND applications can be found here. 

Manufacturing Challenges for CMC in CGT

Across manufacturing, CGT faces issues that hinder CMC. An incomplete understanding of some therapies’ mechanism of action means data is limited. This in turn makes it more difficult to link clinical outcomes to critical quality attributes and process control parameters.

Additionally, the inherent variability of starting materials, changing from patient to patient, can affect process performance and efficacy of the final product. Other problems in manufacturing include:

– The need for segregating products in facilities, and the numerous inherent safety risks of viral vectors and (often-manual) work during manufacturing

– The short shelf-life of sampling, which can impact release testing strategies

– Accelerated approval pathways negatively impacting manufacturing timescales and process design

– Difficulty during comparability exercises based on lack of data 

Facility-specific safety challenges can be solved by giving significant thought to facility design, staff training and chain of custody procedures for any manual steps in the process. For those processes which do not need manual work, closed systems and automation are highly recommended to reduce cost, increase safety and limit error. 

Regarding comparability, one solution is to create process development and technology transfer procedures suitably early in production as a vital part of the life-cycle. Creating suitable analytical methods to assess batches of products can allow comparability of a product before and after changes to a batch. 

Other Challenges for CMC in CGT

Legislation and guidance are not the only area pharma companies must be aware of. Selection of raw materials is a particular challenge when such a degree of variability exists in extracted biologics. Poor or unlucky selection will become a particular problem later in the process, reducing efficacy or potentially harming the patient. To combat this issue, high-grade materials should be ascertained and used. 

This issue is further compounded by the lack of clarity surrounding the terminology for ‘‘raw materials’. In the U.S., raw materials can include starting materials, ingredients, reagents, processing aids and many other ingredients. There is a disparity between the United States and stedEurope around what exactly ‘ancillary materials’ covers as a term. 

Beyond this, a number of other challenges exist around raw materials, including the potential variability and risk of using animal-derived materials, the use of Research Use Only materials such as growth factors that are labelled ‘not for clinical use, for research purposes only’, and the lack of simple characterisation tests for many raw materials. With every challenge, a risk-based approach to assessing and using raw materials is suggested, as detailed in USP Chapter 1043  and European Pharmacopoeia General Chapter 5.2.12.

Another challenge is the need for versatility where novel products are being created. The diversity of CGTs means that often, standard practices and processes will not work – for example, some viral vectors are too large or sensitive for terminal sterile filtration, a necessary part of purification. To surmount such an issue, companies must determine the best possible alternative, using risk- and science-based justifications for new control strategies. 

Seeking Regulatory Approval

Regulator feedback on product development strategies is enormously helpful for winning product approval. Pre-IND meetings can be a source of understanding and collaboration that can hugely improve CMC efforts early on in the development process. Where guidance does not cover certain issues, regulators can assist companies who show that they are aware of potential gaps in knowledge and are eager to address them. 

Analytical methodology is a useful area to receive feedback on, especially where a CGT’s mechanism of action may not be fully understood. Companies must take all possible chances to ensure methodologies are sufficient for the current stage of development, and that if the mechanism of action isn’t known that surrogate assays can be utilised for further insight. Regulators can help with this by recommending particular attributes to evaluate. 

Keep an eye out for Proventa International’s upcoming Biomanufacturing White Paper, looking at the challenges surrounding CGT Manufacturing and their possible solutions. 

Joshua Neil, Editor
Proventa International

To ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s online Clinical Operations, Supply Chain & Pharmacovigilance Strategy Meeting 2020.

The post The Challenges of CMC in Cell and Gene Therapies appeared first on Proventa International.

The Potential of Cell and Gene Therapies 

Until very recently, cell and gene treatments saw limited uptake in the pharmaceuticals industry, due to their relatively new and untested status. But with greater coverage and increased research around the world, CGT has quickly becoming one of the more exciting fields pharma can invest in. CAR-T therapies have already seen some big names, most notably Novartis and Gilead, finding success at the forefront of the technology’s usage with the approval of both Kymriah and Yescarta.

Most large pharma companies are now investing in CGT: Novartis acquired commercial gene therapy company AveXis for $8.7 billion last year, while gene therapy expert Spark Therapeutics was bought up by Roche for around half that earlier in 2019. Global investment in cell therapies rose by 64% in 2018 compared to the previous year.

Despite this, investment in CGT is not evenly distributed across the board. Roche has shown reduced interest in cell and gene therapy compared with its contemporaries, though it has recently begun working with T-cell engaging bispecific antibodies. Eli Lilly, too, has seen limited takeup of CGT innovation, avoiding CAR-T therapies and only last year announcing a collaboration with Sigilon to develop encapsulated cell therapies at all.

The benefits of investing in the promising CGT field are numerous and evident, shown most clearly in the extreme sector takeup over the last few years: the area was valued at $6 billion in 2017, with a projection for it to exceed $35 billion by 2026. But the reasons for delay in investment, while more subtle, do still exist: and it is worth noting the main reasons for some companies’ reticence to invest in CGT even as the need to do so becomes more urgent than ever.

Challenges

Part of the reason for the hesitancy expressed by companies with a slow CGT takeup is the number of unaddressed issues the sector faces at present. While CGTs have only grown in safety and efficacy as demonstrated by both lab and clinical trials, obstacles remain that limit takeup from some pharma giants.

MANUFACTURING ISSUES – Regulatory requirements specify that cell and gene therapies do not materially change through the manufacturing process. However, due to the stringent commercial incentives to optimise manufacturing processes and evolve constantly through to commercial launch, companies must maintain a careful balance between state-of-the-art processes and ones which do not change the product in any meaningful way. 

TRANSPORTATION DIFFICULTIES – Any biological material is difficult both to grow and transport: a reliable manufacturing system is key to effective management of CGT. 

FEARS OVER SAFETY – Proventa recently covered Google’s ban on experimental CGT advertisements on its sites, a story that represented a number of fears in the professional world over the safety and utility of the therapies. For the most part, this fear is entirely unfounded: 

NEED FOR SUCCESSFUL ASSAYS – Meeting regulatory standards for safety and efficacy is vital in any pharmaceutical area, but creating a specific mechanism of action for CGT is difficult. Even when this is done, a further challenge then exists of showing the assay actually measures for the critical specifications set out. Often a company is left with no choice but to develop its own assays or assay panels due to a lack of suitable commercial choice. 

Of course, these are only high-level solutions to problems preventing companies from investing. To fully understand the issue and receive expert insight into solving key CGT challenges and better integrating and implementing CGT processes within a business, come to Proventa’s Cell & Gene Therapy Strategy Meeting 2019, hosted on 8th October in Zurich, Switzerland.

Talk topics include optimising CAR-T cell therapies, adopting CRISPR to modulate immunosuppressive pathways in CAR-T products, the challenge of clinical manufacture of modified cells and avoiding toxicity when administering large drug doses.

The Need to Invest

However, while these challenges do exist and are continuing to act as a brake on pharma investment in CGT, solutions are already beginning to appear to solve the worst such issues. 

For example, truth that almost every expert shares is that innovation in CGT is coming largely from startups and smaller companies. This is certainly the case where the manufacturing bottleneck is concerned, with companies such as Oxford Genetics and TreeFrog Therapeutics creating an improved system for culturing and transporting stem cells to ensure maximum growth, and devising automation technologies to improve the logistical aspect of the manufacturing supply chain. 

The number of companies dedicating effort to creating solutions for CGT, and certainly the number of pharma giants investing huge amounts in the area, both show that now is the time to be investing. 

More than $550 million was raised by companies working with CAR-T projects between 2011 and 2016, with $2.2 billion in investment raised by the ten biggest cancer immunotherapy startups alone. Between June 2013 and May 2015 the six largest companies working with CAR-T were valued collectively at $962 million at IPO; now, they are worth more than $30 billion in total. 

The CGT sector has reached the point of rapid expansion, with both the price of innovative, inventive startups skyrocketing and the hunger of big pharma for CGT portfolios growing by the day. The time is now to invest in CGT: a later investment could well be too late. 

Joshua Neil
Editor, Proventa International

To ensure you remain up-to-date on the latest in biomanufacturing, sign up for Proventa International’s Cell & Gene Therapy Strategy Meeting 2019, hosted on 8th October in Zurich, Switzerland.

The post Time to invest in CGT: Its Benefits for Pharma appeared first on Proventa International.