Category Archives: Gene Medicine

Completing an investigational new drug (IND) application can be a long and tedious process, one known to bog down timelines and frustrate sponsors looking to take their cell or gene therapy (CGT) to the clinic. In a tight race to trials, program sponsors look for efficiencies from bench to bedside.

Using off-the-shelf materialssuch as plasmid DNA products and CRISPR-associated nucleases is one way to potentially speed things up particularly if they come with a drug master file, or DMF.

Drug master files are reference packages that report to the FDA information about the processes involved in new drug products. Theyre not FDA-required nor approved nor denied but they can help supplement INDs and other applications as a way to cross-reference new processes with pre-filed submissions.

And as a concept, DMFs arent new. Download the DMF list and youll see tens of thousands of submissions, some dating to 1939. Theyve always been used to support various materials, even ibuprofen and acetaminophen. But as normalized as theyve become, DMFs are still novel among CGTs, which only recently began using off-the-shelf materials that would benefit from a DMF.

With the growing standardization of cell and gene therapies, interest has emerged in DMFs as a tool to expedite the path to clinical trials. If you use an off-the-shelf reagent that has a DMF, the application links to that preexisting file without the filer having to provide redundant information.

As more off-the-shelf materials such as plasmids become available for cell and gene therapies, suppliers are submitting DMFs for those products as a benefit to customers. Doing so gives researchers a dual offering: They can not only access standardized materials at GMP-grade with the cost and time savings that come with that but they can also cross-reference their INDs to the already prepared DMF.

Two examples of these DMF-ready products are Aldevrons SpyFi Cas9 nuclease and pALD-X80 helper plasmid, each available from research grade to GMP. When new cell and gene therapy products use these materials, users automatically get the benefit of a pre-filed DMF that references Aldevrons manufacturing processes involved in making them.

The reason IND submissions have long embraced DMFs is the same reason DMFs are likely to rapidly expand among CGT applications in the months and years ahead: Theyre not just efficient in saving time, but theyre also potentially more comprehensive with less of a risk of missed information.

If you use the SpyFi Cas9 nuclease, for example, or others offered from Aldevron, you can skip the drug substance part for the Cas9 product when filing the IND because Aldevron has already prepared the DMF.

And when linking to the DMF, the FDA gets complete access to manufacturing information without the filer having to do so. This avoids overlooking information the FDA might need, which can delay application review.

Moreover, translational medicine organizations may find particular value in DMF-ready products because they overcome resource barriers inherent to hospitals and academic institutions. Unlike big pharma or biotech companies, many such organizations may not have easy access to field experts. Turning to DMFs gives academic outfits the economies of scale they might not get otherwise.

By 2025 thats just two years away the FDA expects to approve up to 20 cell and gene therapy products per year. With all that IND activity in a crowded market, sponsors will need any differentiating efficiency they can get along the pathway to clinical trials and beyond.

By taking advantage of pre-filed DMFs, researchers benefit from the value, time savings and reduced complexities of having someone else do the heavy lifting for key components of the final drug product. After all, this concept isnt new in drug development. However, the science in this so-called new frontier of medicine is. As it becomes more standardized, everyone wins including future patients.

Looking for other ways to standardize processes and accelerate your path to market? Stay tuned for Aldevrons next post, where well explore how plasmid backbones can simplify development logistics and reach your goals faster.

See the rest here:
Expediting IND applications with drug master files - BioPharma Dive

Led by Sam McLean, MD, MPH, University of North Carolina at Chapel Hill researchers and collaborators were awarded $3 million from the U.S. Department of Defense for to evaluate the efficacy of a therapeutic to reduce the frequency and severity of acute stress disorder and posttraumatic stress disorder.

The UNC Institute for Trauma Recovery in the UNC Department of Psychiatry has been awarded a $3-million grant from the U.S. Department of Defense (DoD) to investigate the potential of a therapeutic agent to reduce the frequency and severity of acute stress disorder and post-traumatic stress disorder (PTSD). Acute stress disorder refers to the bodys immediate response to trauma, whereas PTSD is the long-term effects of trauma.

Historically, we have been able to provide emergency care to address immediate and long-term problems after visible wounds using tools such as sutures and antibiotics. However, we still have nothing to offer trauma survivors, whether in the emergency department or on the battlefield immediately after trauma, to prevent the development of invisible wounds, said principal investigator Samuel McLean, MD, MPH, professor of psychiatry and emergency medicine and director of the Institute for Trauma Recovery at the UNC School of Medicine. We need to investigate potential treatments like ACER-801 in an effort to better address these challenges.

The proposed OASIS trial will examine the safety and efficacy of ACER-801 (osanetant) to reduce acute stress response symptoms, posttraumatic stress disorder symptoms and behavioral changes among patients presenting to the emergency department after a motor vehicle collision.

Participating sites will include Washington University in St. Louis, University of Massachusetts Chan Medical School, Rhode Island Hospital, University of Florida College of Medicine Jacksonville, and Indiana University School of Medicine. The study, proposed to begin in the first half of 2023, will evaluate the efficacy of ACER-801, which Acer Therapeutics licensed from Sanofi in 2019.

The OASIS trial builds upon a foundation of knowledge and infrastructure developed through the UNC-led, $40 million AURORA initiative. The AURORA study is a major national research initiative to improve the understanding, prevention, and recovery of individuals who have experienced a traumatic event. AURORA is supported by funding from NIH, One Mind, private foundations, and partnerships with leading tech companies such as Mindstrong Health and Verily Life Sciences, the healthcare arm of Googles parent company Alphabet.

We are proud to be partnering with a leading academic institution in the field of trauma recovery as we begin exploring ACER-801 as a treatment option to reduce the frequency and severity of acute PTSD, said Adrian Quartel, MD, FFPM, Chief Medical Officer of Acer. The data from thousands of motor vehicle collisions collected through the AURORA initiative should allow us to better predict the correlation of the emergence of acute stress disorder or PTSD symptoms following a motor vehicle collision.

Added Brandon Staglin, President of One Mind We are thrilled to see how our funding to the AURORA initiative over the last five years is accelerating further advancements such as the OASIS Trial. The targeted outcomes of the OASIS Trial are the types of results that One Mind supports and of incredible value to anyone who experiences trauma and traumatic stress.

Acute and chronic stress disorders can affect both civilian and military populations. According to the National Center for PTSD, in the US about 60% of men and 50% of women experience at least one trauma in their lives. In the United States alone, one-third of emergency department visits (40-50 million patients per year) are for evaluation after trauma exposures, and in a 2014 study involving 3,157 US veterans, 87% reported exposure to at least one potentially traumatic event during their service.3 Moreover, as many as 500,000 US troops who served in wars between 2001 and 2015 were diagnosed with PTSD.

Scientific rationale for OASIS:

TheTacr3gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, Neurokinin B (NKB), which is encoded by the Tac3 (human) gene.

The role ofNKB-NK3R in growth and reproduction has been extensively studied, butNKB-NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system. In animal models, Tac2 mRNA levels are rapidly up-regulated during fear consolidation 30 minutes after fear conditioning, and subsequent NKB-NK3R activation can lead to over stress sensitization and the consolidation of fear, and treatment with osanetant has been shown to block a critical fear/stress sensitization step in the brain. An effective therapeutic to reduce acute and persistent/long-term psychological and somatic symptoms would fulfill a large unmet need.

Media Contact: Mark Derewicz, 919-923-0959

Originally posted here:
UNC School of Medicine Awarded $3 Million to Lead Study to Reduce PTSD Frequency, Severity | Newsroom - UNC Health and UNC School of Medicine

In 2018, when he was 13, Ethan Ralstons eyesight started to get blurry. The diagnosis was devastating. He had been born with Leber Hereditary Optic Neuropathy (lhon), a rare genetic disorder that eats away at the cells of the optic nerve until it causes blindness.

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Given that America and Europe between them see just 800 cases of lhon a year young Mr Ralston was very unlucky. In another way, though, he could be counted fortunate. GenSight, a French biotech company, had for years been working on a gene therapy for lhon. The condition is caused by a mutation in a gene called nd4 which causes the bodys cells to make a faulty protein. The therapy, called Lumevoq, sought to resolve the problem by adding the canonical version of nd4 to cells in the retina and optic nerve. By 2018 Lumevoq was in clinical trials. Shortly after his diagnosis Mr Ralston was treated with it.

Today his eyesight has almost returned to normal. He can work on a computer, drive a car, go bowling with his friends. He would seem to be cured.

Such stories are becoming increasingly common. In the 2010s a whole year might see only one new gene-therapy approval from regulators. This August alone saw two, one for beta thalassaemia and one for haemophilia a, both diseases of the blood. The Alliance for Regenerative Medicine, an international industry group for cell and gene therapies, says that 1,369 groups are developing such treatments and just over 2,000 clinical trials are under way. Most of those in their earliest stages and may well progress no further: many are cell therapies which do not require changes to the patients genes. Still, according to scientists from the Centre for Biomedical Innovation in Cambridge, Massachusetts, there are enough trials under way that 40-50 new gene therapies could be approved for clinical use by 2030.

A lot of these will be used in the fight against cancer. Removing from the body some of the t-cells which the immune system uses to fight cancer, giving them a gene that lets them recognise a cancer-specific trait and putting them back is the basis of car-t therapies, one of the hottest approaches around (the car stands for chimeric antigen receptor). But there will also be lots that tackle inherited diseases. There are clear signs that this surge has begun. Janet Lambert, the boss of the Alliance for Regenerative Medicine, anticipates that Europe and America will see a record number of such gene therapies approved this year (see table).

In a world where saying that something is in some person or other entitys dna has become a shorthand for seeing it as part of their very essence, dealing with inherited diseases this way looks truly revolutionary. It is one of the most compelling concepts in modern medicine as a recent review paper put it. The ability to provide someone with a single treatment that will alleviate a terrible condition for a decade or moreperhaps even for lifeis an intervention without any obvious parallel.

But it comes with a number of challenges. The techniques being used still carry risks. The therapies themselves are enormously expensive, not just because of the research required to develop themthat is expensive all across the biotech worldbut because the cost of making them is particularly high. What is more, some may face stiff competition from other approaches, some of them equally novel. These may allow some of the conditions gene therapy seeks to fix to be treated in cheaper ways.

This raises the possibility that, impressive as they are, gene therapies might be relegated to a niche treating a small number of patients in rich countries. That would be a poor outlook for millions around the world who suffer from more common genetic diseases, such as sickle-cell disease, and other conditions. It could also scupper the chances of gene therapy moving beyond the realm of single-gene disorders to tackle more complex conditions. For many more people to experience the sort of benefits that have changed Mr Ralstons prospects, the ability to produce miracles will not be enough. They have to be produced affordably in ways that can be adapted to conditions far removed from the elite hospitals where trials typically take place today.

To design a gene therapy, you need a gene you want to add to the patients cells and a way of getting it into them. Finding the first is, in principle, easy: thousands of diseases, most of the worst thankfully rare, come about because of a garbled copy of a single gene. That means they might in principle be alleviated by the addition of the normal version. The second is normally the job of a modified virus that can no longer reproduce but that can get a new gene into its target cells: a viral vector.

Sometimes cells are taken out of the body, transformed by a vector and put back in, as they are in car-t cancer therapies. Zynteglo, a gene therapy for beta thalassaemia made by bluebird bio, a startup with an aversion to capital letters, works this way. On August 17th it became the third gene therapy for an inherited disease to be approved by Americas Food and Drug Administration (fda). In other cases the vector does its work inside the body. Lumevoqauthorised for use in France in 2021, but not yet by the European Medicines Agency (ema) or the fdawas injected directly into Mr Ralstons eyes.

The first gene-therapy trial, which treated a single child with a specific and severe immunodeficiency called ada-scid, got under way in 1990. It did not lead quickly to a commercial product (a different gene therapy for ada-scid, Strimvelis, was eventually approved in 2016) but it paved the way for a number of successors. Unfortunately in 1999 the nascent field was rocked by the death of Jesse Gelsinger, an 18-year-old, four days after he had been given a gene intended to fix his inherited inability to metabolise ammonia.

His death was caused by his immune systems response to the adenovirus used as a vector. That knowledge drove the hunt for safer vectors; James Wilson, a gene-therapy pioneer at the University of Pennsylvania, where the trial during which Mr Gelsinger died was based, uncovered the potential of adeno-associated viruses (aav). These are widespread in humans and are not known to cause any sort of disease; they provoke little or no immune response. Similar advantages are sought by vaccine-makers when they look for vectors. (The Oxford AstraZeneca covid-19 vaccine works in this way, using an adenovirus to put dna describing a telltale viral protein into the bodys cells.)

For gene therapies, aavs have the big advantage of coming in more than 100 different flavours, or serotypes, each of which has different preferences when it comes to which sorts of cell to infect. Vectors derived from aavs are able to home in on specific tissues such as the optic nerve, or the central nervous system, or the muscles.

However, aav-based vectors are not without problems. A recent analysis of almost 150 gene-therapy trials using them found that 35% had seen serious adverse events, including brain-imaging findings of uncertain significance. Large doses of the vector have also been linked to safety concerns. In 2018 Dr Wilson warned that high doses of aav caused life-threatening toxicity in piglets and monkeys. At the same time he resigned from the scientific advisory board of Solid Biosciences, a gene-therapy firm focused on muscular dystrophy, citing emerging concerns about the possible risks of too much aav. The firm says his resignation was due to findings in experiments that were unrelated to its work. Nonetheless its regulatory filings acknowledge that the high dosing requirements for the therapy it is developing may increase the risk of side-effects.

In August Novartis, a Swiss drug company, reported two liver-related deaths in children who were treated with its gene therapy for spinal muscular atrophy (sma). Trials of a therapy being developed by Astellas, a Japanese drug company, for a rare muscle disease called x-linked myotubular myopathy produced some spectacular results, but also saw three children die with sepsis and gastrointestinal bleeding as a consequence of liver failure and a fourth from other liver-related complications.

Bernhardt Zeiher, who is about to retire as Astellass head of development, recently told Endpoints, an online publication, that the company thinks the deaths were caused by a combination of a reaction to the aav vector used and an underlying risk of liver disease. The transformational nature of the therapy itself, he added, means that the firm is committed to finding a way forward in the field.

There have also been concerns over the potential for some vectors to trigger cancers in the long term. You are giving [patients] quadrillions of vector particles, says David Lillicrap, a professor at Queens University in Kingston, Ontario, who works on haemophilia. A very, very small percentage are going to get into the host genome [in] susceptible areas. In 2020 a patient who was being treated for ada-scid with Strimvelis, which uses an rna-based retrovirus as a vector, developed leukaemia. Orchard Therapeutics, the company marketing Strimvelis, has said it may be attributable to the way the gene integrated itself into the genome.

Nicole Paulk of the University of California, San Francisco, says that despite some worrying headlines the aav vector is extraordinarily safe. She says it has been or is being used in over 250 clinical trials with tens of thousands of patients, and that, compared with cancer drugs, it has been remarkably well tolerated.

Given that patients can have terrible experiences with cancer drugs that might not seem reassuring. But there are two other factors to bear in mind. One is that the patients in gene-therapy trials are often very unwell to begin with, and may come into them on other quite arduous treatment regimes. Adverse events are to be expected. More importantly, they may have little if anything by way of other options.

Karen Pignet-Aiach is the founder and boss of Lysogene, a French gene-therapy firm which concentrates on errors in the central nervous system. Firms like hers, she says, have to battle to make sure that regulatory agencies stick to the principle that the risks attached to a treatment have to be balanced against the benefits that a therapy for something lethal and untreatable could bring. In 2020 Lysogene had to deal with the difficult death of a child during a trial, putting a temporary halt to its clinical work. Ms Pignet-Aiach says the death may have been caused by medication given outside the trial but that there was no link with the treatment that was actually being investigated. As to the possible benefits, when she says Our patients have nothing [else] available she knows what she is talking about: she lost a daughter to Sanfilippo syndrome, one of the disorders the company is tackling.

Hold-ups when patients die are understandable, but they increase the cost, and risk, of developing these medicines. And there are other hurdles. Because no one yet knows how many years of duty can be expected from gene therapies, long-term studies are needed; regulators will often insist on them continuing after approval. Because the conditions involved are often progressive and untreatable by other means there are real ethical concerns about randomising trials, something often seen as the best way to clear-cut results.

These problems go some way to explaining the remarkable price of the therapies which make it to marketand which, because of those prices, sometimes leave it soon afterwards. When Glybera, a therapy developed by uniQure, a Dutch company, to address an error in the way fat is processed in a particularly rare condition, got the nod from the ema in 2012 it became the first gene therapy to be approved by a stringent regulator. It also became the first medical treatment with a price tag of $1m. The first approval by the fda, in 2017, was for Luxturna, a gene therapy to prevent another form of progressive vision loss. Roche, a big-pharma company, priced it at $425,000. Per eye. In 2019 Zolgensma, Novatiss treatment for sma, went on sale at $2.1m. Last year the mother of a baby being treated with Zolgensma remarked that everyone who touched the drug, or was around it, had to be trained to handle it: it was like carrying gold. Libmeldy, approved by the ema in 2020 to treat a disorder which degrades the nervous system, costs 2.8m ($3.3m) a dose.

Pharmaceutical companies do not discuss the basis of drugs prices. In America the approach is typically taken to be an assessment of what the market will bear, which has led to an environment accustomed to high prices. The problem with gene therapies is that the price being charged seems in some cases well beyond what the market will bear.

Take Glybera, the first-approved therapy. Only a single dose was ever sold. It has been withdrawn from the European market. According to Stat, another online publication, after the ema approved Zynteglo in 2019 bluebird bio offered it in Germany for $1.8m a treatment; Germany offered to pay $950,000 in cases where it worked, $790,000 when it didnt. The firm subsequently withdrew it from the European market; it has done the same with eli-cell, which treats an irreversible nerve disease. The price it has set for Zynteglo in America is $2.8m.

Some companies are getting out of the market altogether, suggesting they see no way forward. Amicus Therapeutics, a biotech firm which had been working on a number of gene therapies at one point, got out of the field completely earlier this year. Within two years of having put the ada-scid therapy Strimvelis on the market in Europe, gsk, a big drug company, offloaded the treatment to Orchard.

If the makers are worried, so are the buyers. Health systems and insurance firms can cope with one or two such therapies at the far end of the price spectrum. Britains nhs, quite capable of ruling out therapies on the basis of cost, has bought both Zolgensma and Libmeldy (it negotiated a significant discount). But as the number of approved treatments grows the economics are looking more challenging.

A study published this February by the Aspen Institute, a think-tank, and the Blue Cross Blue Shield Association, an association of American insurance companies, looked at the expected arrival of 90 gene therapies and cell therapies. By 2031 the annual acquisition cost for 550,000 patients would be $30bn. With the countrys total prescription-drug bill currently at $577bn, that is relatively small; but it is still significant. Virtually all the buyers for health care in America have warned about the cost burden they expect as the numbers of these products grow.

I think everyone agrees that the pricing of gene therapies is a crisis, says Dr Paulk. The crisis has two main drivers: the amount of work needed to develop and make the therapies and the lack of good models for pricing one-off interventions which could obviate the need for lifelong treatment.

The costs of gene therapies are not just down to arduous research and development and long-drawn-out trials. Making the material which gets put into the patient is not for the faint of heart says Jay Bradner, president of the Novartis Institutes for BioMedical Research. Gene therapies are like snowflakes, says Dr Paulk. Every aav program and every lot is completely unique. Bespoke, though, does not mean small scale. She says that for diseases where you need to get the vector into a particularly large number of cells, such as Duchenne muscular dystrophy, It is not uncommon that we need to use at least a 50 litre, if not a 200 litre, bioreactor to make a single dose for a single patient.

Analysts at the Boston Consulting Group recently estimated that the cost of manufacturing gene therapies ranges from $100,000 to $500,000 per dose. A lot of this manufacturing is done by third parties, and the difficulties of the process can be seen in the limited capacity they offer. Biotech firms that want to get into gene therapy can have to wait up to three years for manufacturing capacity to become available, according to insiders.

On the other side of the coin is the difficulty of calculating benefits. If a $2m treatment really does provide decades of life then the cost per year is down in the tens of thousands of dollarshardly out of line with many other modern therapies. This has led some to suggest that payment might be in annual instalments. In the long term that could make the total larger, but it would spread it out. Another possible innovation is to couple such an approach with the option of stopping paying if the therapy stops working.

The question as to whether the therapy is worth the price has to be answered in the context of what if anything the competition can offer. Take sma, which is caused by a faulty version of a gene called smn1. Zolgensma treats this problem by providing cells with an extra copy of smn1 which works. A treatment called Spinraza uses a method that increases the amount of protein made from a very similar but normally much less productive gene, smn2: its active agent is a molecule called an antisense oligonucleotide.

Antisense treatments are being tried against various conditions which look as if they can be alleviated by getting an existing gene expressed more or less. They are not permanent; Spinraza needs to be administered every four months. Moreover, although the cost of manufacture is far lower than for gene therapies, they are still not cheap. Biogen, the biotech company that makes Spinraza, charges up to $125,000 per dose. But such treatments may well be easier to scale up, and thus see their costs reduced.

Haemophilia, for a form of which Roctavian, made by Biomarin, a biotech company, received ema approval on August 24th, is another condition where alternative approaches have made huge strides, according to Dr Lillicrap. One of the newest antibodies used in its treatment needs to be given only every two to four weeks, rather than every few days, as used to be the case. Artificial versions of the clotting factors haemophiliacs cannot make have been engineered so as to last longer in the blood. There are also clever new ways of lowering the expression of proteins which suppress coagulation.

It is not just what the competition can offer now that matters. It is what it might offer in five or ten years time. Spending a lot on a gene therapy today may prove a good investment if it provides many years of reasonably healthy life. But at the same time it is a bet against the real possibility that a cheaper and possibly better treatment is on the way.

The answer to that conundrum is to make sure that gene therapies get better and cheaper, too. Various companies are looking at ways to improve manufacturing. 64x Bio, based in San Francisco, is testing millions of possible cell lines to try and find those that will grow vectors like aav most efficiently. Others are looking at the vectors themselves, trying to make them less arousing to the immune system, better targeted and more likely to actually carry the gene of interest. Current procedures leave a lot of the vectors empty; increasing the proportion that is filled would reduce dose size and costs.

Ideas for making better things to put in the vectors abound. The field started with basic tools; would-be therapists could put a gene into the genome but had little control over where it went and thus how it might be controlled and what collateral damage it might cause. In the past decade, though, great advances have been made in gene editing, a set of techniques which allow the message in an existing gene to be rewritten. As Fyodor Urnov, a professor at the University of California, Berkeley, puts it, gene therapy is like adding a fifth wheel to a car with a flat tyre; gene editing is repairing the flat.

At present, gene editing is a particularly promising route for therapies in which blood-cell-making stem cells are removed, fiddled with and reinserted into the patients bone marrow. Two clinical trials in which this sort of editing is used against sickle-cell disease, which is brought about by mutations in haemoglobin which make red blood cells deformed and defective, are already well under way. One is for a treatment from Vertex Pharmaceuticals, based in Massachusetts and crispr Therapeutics, the other is by bluebird bio.

More than a dozen patients are reported to have been cured, and it is possible that one of the treatments could be ready for approval next year. There are other gene therapies for the condition at earlier stages. There is also, again, competition from other approaches. On August 8th Pfizer, another big drug company, announced its intention to acquire Global Blood Therapies, a biotech company, for $5.4bn. For that it gets Oxbryta, a drug that stops the mutant haemoglobins from sticking together, and some other therapies.

A similar gene-therapy approach is being used to tackle aids by editing into cells traits that make them immune to hiv. But here the price issue, already confounding, becomes all but lethal. Most people with aids, like most people with sickle-cell disease, live in low- and middle-income countries. According to Mike McCune of the Bill & Melinda Gates Foundation, in countries where antiretroviral therapy for aids costs between $70 and $200 a year an all-out cure for the disease, even if it were possible, would need to come in at $2,000 or less.

If this sounds staggeringly unlikely, it is worth considering that there is a partial precedent. The cost of making target-specific monoclonal antibodies was enormous when they were first developed. But between 1998 and 2009 manufacturing improvements brought about a 50-fold reduction in the cost of goods. Matching that would allow gene therapies to move into middle-income countries, if not low-income ones.

As Mr Ralston can testify, gene therapies border on the miraculous. But they remain miracles of science, their creation incredibly time-intensive [and] people-intensive, as Dr Paulk puts it. Now they must become routinely applicable miracles of medicine. That requires extending the range of conditions they address, learning how long they last and expanding the number of patients they help. In many ways that effort will be more demanding than the work to date. It will have to go well beyond the labs currently tinkering, the charities currently raising funds for rare diseases and the companies desperately trying to find a way to sell the remarkable things they have created. But their remarkable work has made it possible for that second miracle-making effort to begin.

Editors note (September 1st 2022): Due to an editing error, the print and earlier online versions of this article wrongly stated that Lumevoq had been approved by the ema and that Oxford AstraZeneca vaccine used an AAV vector rather than an adenovirus. Sorry.

More:
Gene therapies must become miracles of medicine | The Economist

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.

Methods: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 61013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.

Results: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.

Conclusions: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

Go here to see the original:
Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A

Cell and gene therapies seek to correct the root cause of an illness at the molecular level. These game-changing medicines are reshaping how we address previously untreatable illnesses transforming peoples lives.

Cell and gene therapy represent overlapping fields of research with similar therapeutic goals developing a treatment that can correct the underlying cause of a disease, often a rare inherited condition that can be life-threatening or debilitating and has limited treatment options.

While these technologies were initially developed in the context of treating rare diseases caused by a single faulty gene, they have since evolved towards tackling more common diseases, says Professor Rafael J. Yez-Muoz, director of the Centre of Gene and Cell Therapy (CGCT) at Royal Holloway University of London.

A powerful example is the chimeric antigen receptor (CAR) T-cell therapies, which have been approved for treating certain blood cancers. The approach involves genetically modifying a patients T cells in the laboratory before reintroducing them into the body to fight their disease.

For the first time, we had an example of gene therapy to treat a more common disease demonstrating that the technology has wide applicability, enthuses Yez-Muoz.

To date, 24 cellular and gene therapy products have received approval from the US Food and Drug Administration (FDA) including life-changing treatments for patients with rare diseases, such as inherited forms of blindness and neuromuscular conditions. A variety of gene and cell-based therapies for both rare and common diseases are also currently in development across many therapeutic areas, offering hope for many more families in coming years.

This webinar will provide an introduction to the regulatory framework for cell and gene therapies and highlight the importance of chemistry, manufacturing and controls. Watch to learn about regulatory concerns, safety and quality testing throughout the product lifecycle and key acronyms and terminology.

Gene therapies seek to introduce specific DNA sequences into a patients body to treat, prevent or potentially cure a disease. This may involve the delivery of a functional gene into cells to replace a gene that is missing or causing a problem or other strategies using nucleic acid sequences (such as antisense oligonucleotides or short interfering RNAs [siRNAs]) to reduce, restore or modify gene expression. More recently, scientists are also developing genome-editing technologies that aim to change the cells DNA at precise locations to treat a specific disease.

The key step in successful gene therapy relies on the safe and efficient delivery of genetic material into the target cells, which is carried out by packaging it into a suitable delivery vehicle (or vector). Many current gene therapies employ modified viruses based on adenoviruses, adeno-associated viruses (AAV), and lentiviruses as vectors due to their intrinsic ability to enter cells. But non-viral delivery systems such as lipid nanoparticles (LNPs) have also been successfully employed to deliver RNA-based therapeutics into cells.

A big advantage of using viral vectors for gene delivery is they are longer lasting than non-viral systems, states Dr. Rajvinder Karda, lecturer in gene therapy at University College London. Many of the rare diseases were aiming to tackle are severe and we need to achieve long-term gene expression for these treatments to be effective.

While improved technological prowess empowers the development of CRISPR-edited therapies, supply-chain and manufacturing hurdles still pose significant barriers to clinical and commercialization timelines. Watch this webinar to learn more about the state of CRISPR cell and gene therapies, challenges in CRISPR therapy manufacturing and a next-generation manufacturing facility.

Viral-vector gene therapies are either administered directly into the patients body (in vivo), or cells harvested from a patient are instead modified in the laboratory (ex vivo) and then reintroduced back into the body. Major challenges for in vivo gene delivery approaches are with the safe and efficient targeting of the therapeutic to the target cells and overcoming any potential immune responses to the vectors.

As well as getting the genetic material into the affected cells, we also need to try and limit it reaching other cells as expressing a gene in a cell where its not normally active could cause problems, explains Dr. Gerry McLachlan, group leader at the Roslin Institute in Edinburgh.

For example, the liver was identified as a major site of toxicity for an AAV-based gene therapy approved for treating spinal muscular atrophy (SMA), a type of motor neuron disease that affects people from a very young age.

Unfortunately, these viruses are leaky as theyre also going to organs that dont need therapy meaning you can get these off-target effects, says Karda. Theres still work to be done to develop and refine these technologies to make them more cell- and organ-specific.

It is also important to ensure the gene is expressed at the right level in the affected cells too high and it may cause side effects and too little may render the treatment ineffective. In a recent major advancement in the field, scientists developed a dimmer switch system Xon that enables gene expression to be precisely controlled through exposure to an orally delivered small molecule drug. This novel system offers an unprecedented opportunity to refine and tailor the application of gene therapies in humans.

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In 1989, a team of researchers identified the gene that causes the chronic, life-limiting inherited disease cystic fibrosis (CF) the cystic fibrosis transmembrane conductance regulator (CFTR). This was the first ever disease-causing gene to be discovered marking a major milestone in the field of human genetics. In people with CF, mutations in the CFTR gene can result in no CTFR protein, or the protein being made incorrectly or at insufficient levels all of which lead to a cascade of problems that affect the lungs and other organs.

Our team focuses on developing gene therapies to treat respiratory diseases in particular, were aiming to deliver the CTFR gene into lung cells to treat CF patients, says McLachlan.

The results of the UK Respiratory Gene Therapy Consortiums most recent clinical trial showed that an inhaled non-viral CTFR gene therapy formulation led to improvements in patient lung function.

While this was encouraging, the effects were modest and we need to develop a more potent delivery vehicle, explains McLachlan. Weve also been working on a viral-based gene therapy using a lentiviral vector to introduce a healthy copy of the CTFR gene into cells of the lung.

Kardas team focuses on developing novel gene therapy and gene-editing treatments for incurable genetic diseases affecting the central and peripheral nervous system and Yez-Muoz is aiming to develop new treatments for rare neurodegenerative diseases that affect children, including SMA and ataxia telangiectasia (AT).

But a significant barrier for academic researchers around the world is accessing the dedicated resources, facilities and expertise required to scale up and work towards the clinical development and eventually the commercial production of gene and cell therapies. These challenges will need to be addressed and overcome if these important advancements are to successfully deliver their potentially life-changing benefits to patients.

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After many decades of effort, the future of gene and cell therapies is incredibly promising. A flurry of recent successes has led to the approval of several life-changing treatments for patients and many more products are in development.

Its no longer just about hope, but now its a reality with a growing number of rare diseases that can be effectively treated with these therapies, describes Yez-Muoz. We now need to think about how we can scale up these technologies to address the thousands of rare diseases that exist and even within these diseases, people will have different mutations, which will complicate matters even further.

But as more of these gene and cell-based therapies are approved, there is a growing urgency to address the challenge of equitable access to these innovative treatments around the world.

Gene therapies have the dubious honor of being the most expensive treatments ever and this isnt sustainable in the longer term, says Yez-Muoz. Just imagine being a parent and knowing there is an effective therapy but your child cant access it that would be absolutely devastating.

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Biopharma focuses on streamlining biomanufacturing and supply chain issues to drive uptake of cell and gene therapies.

Cell and gene therapies (CGTs) offer significant advances in patient care by helping to treat or potentially cure a range of conditions that have been untouched by small molecule and biologic agents. Over the past two decades, more than 20 CGTs have been approved by FDA in the United States and many of these one-time treatments cost between US$375,00 and US$2 million a shot (1). Given the high financial outlay and patient expectations of these life-saving therapies, it is essential that manufacturers provide integrated services across the whole of the supply chain to ensure efficient biomanufacturing processes and seamless logistics to reduce barriers to uptake.

The following looks at the who, what, when, and why of biomanufacturing and logistics in CGTs in the bio/pharmaceutical industry in more detail.

According to market research, the global gene therapy market will reach US$9.0 billion by 2027 due to favorable reimbursement policies and guidelines, product approvals and fast-track designations, growing demand for chimeric antigen receptor (CAR) T cell-based gene therapies, and improvements in RNA, DNA, and oncolytic viral vectors (1).

In 2020, CGT manufacturers attracted approximately US$2.3 billion in investment funding (1). Key players in the CGT market include Amgen, Bristol-Myers Squibb Company, Dendreon, Gilead Sciences, Novartis, Organogenesis, Roche (Spark Therapeutics), Smith Nephew, and Vericel. In recent years, growth in the CGT market has fueled some high-profile mergers and acquisitions including bluebird bio/BioMarin, Celgene/Juno Therapeutics, Gilead Sciences/Kite, Novartis/AveXis and the CDMO CELLforCURE, Roche/Spark Therapeutics, and Smith & Nephew/Osiris Therapeutics.

Many bio/pharma companies are re-considering their commercialization strategies and have re-invested in R&D to standardize vector productions and purification, implement forward engineering techniques in cell therapies, and improve cryopreservation of cellular samples as well as exploring the development of off-the-shelf allogeneic cell solutions (2).

The successful development of CGTs has highlighted major bottlenecks in the manufacturing facilities, and at times, a shortage of raw materials (3). Pharma companies are now taking a close look at their internal capabilities and either investing in their own manufacturing facilities or outsourcing to contract development and manufacturing organizations (CDMOs) or contract manufacturing organizations (CMOs) to expand their manufacturing abilities (4). Recently, several CDMOsSamsung Biologics, Fujifilm Diosynth, Boehringer Ingelheim, and Lonzahave all expanded their biomanufacturing facilities to meet demand (5).

A major challenge for CGT manufacturers is the seamless delivery of advanced therapies. There is no room for error. If manufacturers cannot deliver the CGT therapy to the patient with ease, the efficacy of the product becomes obsolete. Many of these therapies are not off-the-shelf solutions and therefore require timely delivery and must be maintained at precise temperatures to remain viable. Thus, manufacturers must not only conform to regulations, but they must also put in place logistical processes and contingency plans to optimize tracking, packaging, cold storage, and transportation through the products journey. Time is of the essence, and several manufacturers have failed to meet patient demands, which have significant impacts on the applicability of these agents.

Several CAR T-cell therapies have now been approved; however, research indicates that a fifth of cancer patients who are eligible for CAR-T therapies pass away while waiting for a manufacturing slot (6). Initially, the manufacture of many of these autologous products took around a month, but certain agents can now be produced in fewer than two weeks (7). Companies are exploring new ways to reduce vein-to-vein time (collection and reinfusion) through the development of more advanced gene-transfer tools with CARs (such as transposon, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) among others, and the use of centralized organization with standardized apheresis centers (5). Others are exploring the use of the of allogeneic stem cells including Regen Biopharma, Escape Therapeutics, Lonza, Pluristem Therapeutics, and ViaCord (7).

Several gene therapies have also been approved, mainly in the treatment of rare disease (8). Many companies are evaluating novel gene therapy vectors to increase levels of gene expression/protein productions, reduce immunogenicity and improve durability including Astellas Gene Therapies, Bayer, ArrowHead Pharmaceuticals, Bayer, Bluebird Bio, Intellia Therapeutics, Kystal Biotech, MeiraGTx, Regenxbio, Roche, Rocket Pharmaceuticals, Sangamo Therapeutics, Vertex Pharmaceuticals, Verve Therapeutics, and Voyager Therapeutics (8).

While many biopharma companies have established their own in-house CGT good manufacturing practice (GMP) operation capabilities, others are looking to decentralize manufacturing and improve distribution by relying on external contracts with CDMOs and CMOs such as CELLforCURE, CCRM, Cell Therapies Pty Ltd (CTPL), Cellular Therapeutics Ltd (CTL), Eufets GmbH, Gravitas Biomanufacturing, Hitachi Chemical Advances Therapeutic Solutions, Lonza, MasTHerCell, MEDINET Co., Takara Bio, and XuXi PharmaTech (6, 9, 10).

The top 50 gene therapy start-up companies have attracted more than $11.6 billion in funds in recent years, with the top 10 companies generating US$5.3 billion in series A to D funding rounds (10). US-based Sana Biotechnology leads the field garnering US$700 million to develop scalable manufacturing for genetically engineered cells and its pipeline program, which include CAR-T cell-based therapies in oncology and CNS (Central Nervous System) disorders (11). In second place, Editas Medicine attracted $656.6 million to develop CRISPR nuclease gene editing technologies to develop gene therapies for rare disorders (12).

Overall, CGTs have attracted the pharma industrys attention as they provide an alternative route to target diseases that are poorly served by pharmaceutical and/or medical interventions, such as rare and orphan diseases. Private investors continue to pour money into this sector because a single shot has the potential to bring long-lasting clinical benefits to patients (13). In addition, regulators have approved several products and put in place fast track designation to speed up patient access to these life-saving medicines. Furthermore, healthcare providers have established reimbursement policies and manufacturers have negotiated value- and outcome-based contracts to reduce barriers to access to these premium priced products

On the downside, the manufacture of CGTs is labor intensive and expensive with manufacturing accounting for approximately 25% of operating expenses, plus there is still significant variation in the amount of product produced. On the medical side, many patients may not be suitable candidates for CGTs or not produce durable response due to pre-exposure to the viral vector, poor gene expression, and/or the development of immunogenicity due to pre-exposure to viral vectors. Those that can receive these therapies may suffer infusion site reactions, and unique adverse events such as cytokine release syndrome and neurological problems both of which can be fatal if not treated promptly (14).

Despite the considerable advances that have been made in the CGT field to date, there is still much work needed to enhance the durability of responses, increase biomanufacturing efficiencies and consistency and to implement a seamless supply chain that can ensure these agents are accessible, cost-effective, and a sustainable option to those in need.

Cleo Bern Hartley is a pharma consultant, former pharma analyst, and research scientist.

BioPharm InternationalVol. 35, No. 10October 2022Pages: 4951

When referring to this article, please cite it as C.B. Hartley, "Growth in Cell and Gene Therapy Market," BioPharm International 35 (10) 4951 (2022).

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Growth in Cell and Gene Therapy Market - BioPharm International