Technology

Overview

Heart disease has a profound negative effect on global health and is the biggest cause of death in the world, surpassing all forms of cancer combined. As per recent data, more than 500 million adults had been diagnosed with some form of heart disease, with an adult passing away from a CVD-related issue such as a heart attack every 40 seconds. Although treatments have gradually improved over time, recent analysis has indicated that after years of reduced mortality from cardiac failure, there was actually an increase in the last decade. A considerable variety of known cardiomyopathies and monogenic disorders where the primary cause for ill health and fatality relates to the heart exist today; yet there are almost no approved drugs capable of tackling their root cause. This points to greater demand for gene therapy remedies going forward.

Delivery vehicles and routes for cardiac gene therapy

⦁ An overview of the main delivery strategies for cardiac gene therapy (injection of naked plasmid DNA or gene transduction using adenoviral or adeno-associated virus [AAV]-based vectors).

⦁ A main method of reaching the heart is by injection into the coronary artery or retrograde into the coronary sinus, as on the left side panel; or intramyocardial, as on the right-side panel, after a mini-thoracotomy or bypass surgery, or after percutaneous catheterization to reach the left ventricle, followed by trans-endocardial delivery.

Clinical trials for therapeutic angiogenesis

The figure summarizes the main clinical trials for therapeutic angiogenesis, grouped according to the delivery method used (naked plasmid DNA, top or adenoviral vectors, bottom), along with the indication of the therapeutic gene and the trial name. Vascular endothelial growth factor-A is known as VEGF-A.

In the mid-1990s, gene therapy for cardiovascular disorders emerged, and with it, a series of attempts to induce therapeutic angiogenesis in those suffering from coronary or peripheral artery disease. The belief that new blood vessel formation is driven by cytokines, and therefore could be solved through over-expressing certain angiogenic cytokines in animal models, giving rise to several experiments. This process is initiated by secreted factors that act on the endothelial cells which later lead to the maturation of new capillaries. By the 2000s, over 20 clinical applications involved intramyocardial injection of plasmids encoding VEGF (Vascular Endothelial Growth Factor)- A165. Although more effective than plasmid DNA delivery vehicles for cardiac gene therapy, adenovirus vectors were used clinically as well; one example being AdGVVEGF121.10NH - a vector containing the VEGF-A121 cDNA controlled by a strong CMV enhancer/promoter - which was included in open-labeled and randomized nonplacebo controlled trials at multiple sites during bypass artery grafting and mini-thoracotomy, respectively.

Novel treatments for heart failure are urgently needed, since this condition has become pervasive, affecting 2% of adults around the world and 10% of those aged 75 and up. A significant target for treatment is to alter the way Ca2+ is handled in cardiomyocytes as normal cardiac function depends on it. Reuptake in the sarcoplasmic reticulum relies on SERCA2a, which is inhibited by de-phosphorylated PLN (phospholamban). The cAMP-dependent PKA (protein kinase A), regulated via β-adrenergic stimulation, is mainly responsible for phosphorylating PLN in cardiac cells. Inhibitor 1c's binding to PP1 (protein phosphatase 1) can be prevented to heighten PLN phosphorylation and therefore increase SERCA2a activity. For over twenty years, various animal studies have explored using gene transfer to modulate these mechanisms and enhance cardiac performance in heart failure patients.

Heart Disease Gene and Cell Therapy

A new crop of biopharma innovators emerged to advance the next generation of CGTs (Cell and Gene Therapy) for heart disease, following many failures throughout the last two decades, losing the race to find a reliable gene-therapy method or medicine able to treat heart disease patients.

Our company employs three individual platforms - Cellular Regeneration, Gene Therapy, and Precision Medicine - to build up our first-in-class product candidates. The Gene Therapy platform uses AAV vectors to deliver beneficial payloads into specific cells of the heart, mainly with the aim of treating genetic cardiomyopathies. The Cellular Regeneration platform is also implemented through AAV vectors in order to reprogram cardiac fibroblasts into cardiomyocytes for the treatment of chronic heart failure after myocardial infarction. Finally, the Precision Medicine platform works with iPSC-derived cardiomyocytes as human disease models to detect and validate new heart failure goals and screen for therapies like gene therapies and small molecules particularly aimed at genetically defined Dilated Cardiomyopathies (DCMs). Most Cell and Gene Therapy companies leverage AAV approaches in targeting the heart.

SCENARIO 1: CGTS FOR ORPHAN HEART DISEASE INDICATIONS

It is possible for biopharma companies behind a potentially curative, one-time CGT for a rare and severe genetic heart disorder to use several benchmarks to justify the value of their therapy and to try and justify a high, one-time price in order to recover their investment if a potentially curative, one-time CGT is approved.

Heart Transplants

Heart transplants are the most commonly used 'curative' approach to treating end-stage heart failure, no matter the origin, whether it be genetic or due to age and lifestyle. Despite being incredibly life-changing procedures, they are few and far between due to the limited donor hearts available globally - only ~8,000. Additionally, these procedures can cost up to $1.6M+, making them one of the most expensive medical treatments currently covered by payers. Outcomes vary greatly in children, as they may need multiple transplants during their childhood. Therefore, a CGT which could replace the need for a heart transplant and/or generate similar effects with fewer long-term side effects would be able to justify a price comparable if not higher than that of a transplant, while still being cost-effective.

LVADs

For those suffering from end-stage heart failure who are not eligible for a transplant, implantation of a left ventricular assist device (LVAD) can be their only option. In cases where the LVAD serves as a bridge towards a heart transplant, the cost will be additional. Outcomes tend to vary over time and readmissions as well as follow-up care may add substantial costs needing regular LVAD replacements. This might justify a CGT that could replace or supplement the LVAD, with an effect and safety profile superior to multiple rounds of replacement therapy.

Chronic Therapies for Orphan Heart Disease

There are only a few therapies designed for orphan diseases caused primarily by heart conditions. In recent years, gene therapy for transthyretin amyloid cardiomyopathy (ATTR-CM) was approved, which is an ultra-orphan genetic cardiomyopathy with less than 15,000 cases per year. An argument for valuing it as a one-time potentially curative therapy could be made and compared with the cost of 3–5 years of chronic therapy for a similar-sized indication. However, this logic would not be as convincing to payers if it ultimately replaces expensive existing therapies such as those used to treat hemophilia A/B or lysosomal storage disorders like MPS I and MPS II where protein replacement therapies are already being used as the standard of care.

SCENARIO 2: CGTS FOR PREVALENT HEART DISEASE INDICATIONS

For more prevalent heart disease indications, the value proposition, price, and adoption of CGTs change intensely. They fall into three broad categories:

Uncertainty in the regulatory environment and high expectations for product performance

The majority of drug development for cardiovascular diseases has typically been accomplished through large-scale outcomes studies, where a survival advantage must be demonstrated compared to the standard of care and safety risks are essentially not tolerated. Endpoints that focus on functional improvements, such as ejection fraction (EF) and 6-minute walk tests (6MWT), have not been accepted as sufficient for approval. This necessitates the use of very long and expensive randomized and placebo-controlled clinical studies. For example, one report suggests that the average size of a clinical study used to back recommendations for heart failure treatments included more than 2,300 patients, with one study having as many as 8,400 participants.

Investigations for remedies meant to tackle diabetes may necessitate very stringent assessments involving 5,000-15,000 patients to exclude cardiovascular danger. This could at least partially explain why the development of drugs for cardiovascular ailments has been hard. Many studies have determined that the total likelihood of successful drug production from Phase I through commercial launch is 4-7%, one of the lowest in all therapeutic areas. Recent analysis has indicated that, usually, biopharmaceutical companies use around $1B in clinical progress for every cardiovascular product authorization, the greatest proportion in comparison to any other therapeutic area. Some specialists think that clinical tests in cardiovascular medicine have turned out to be larger, more expansive and intricate, resulting in some pharmaceutical companies diverting away from the cardiovascular sector.

Low-cost benchmarks for standard of care treatments

First line therapies for heart failure have mostly been the realm of generic small molecules, including angiotensinconverting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARBs), beta blockers (BBs), aldosterone antagonists (AldA), and diuretics. These medications are very well accepted as safe and effectve, with proven longterm survival benefts. They are also very inexpensive. One of the most widely prescribed ACEi drugs has an annual cost of less than $500 per year, and this combination of generic first line therapies has a collective annual cost less than $2,000 per year. These therapies are considered very cost effective, and in some scenarios these medications save costs (i.e. where heart failure patents’ lives were prolonged at lower costs to the healthcare system).

Reasonable standards for conventional healthcare

Generic small molecules, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), aldosterone antagonists (AldA), and diuretics, have typically been the first-line treatments for heart failure. These drugs are widely recognized as effective and safe, with long-term survival benefits that have been demonstrated. They are also reasonably priced. These treatments are seen as being very cost-effective, and in certain cases they result in cost savings.

High price sensitivity

Heart failure is a leading cause of death and a major expense for payers, both private and public. It is estimated that the total direct and indirect costs of heart failure will reach $70 billion by 2030. With the rise in costs, payers are increasingly focusing on cost control for this therapeutic area. Most cases of heart failure are observed in individuals aged 65 or older due to aging-related weakening of the heart muscle, as well as chronic diseases that can lead to heart failure. As such, most heart failure patients are covered by medical care organizations, the primary public option. Hospital stays are a common occurrence for these patients, making heart failure one of the most expensive chronic diseases to treat.

Our gene therapy technology consists of three core elements:

• A "gene cassette" containing a therapeutic gene is used to rectify a malfunctioning or absent protein, thus restoring normality or curtailing a disease-associated effect in targeted cells.
 

Therapeutic Gene Cassettes

Constructing our own gene therapies, we introduce a transgene into cells for the production of a beneficial protein or RNA structure. This transgene is contained in a gene cassette with DNA promoters that coordinate its expression in particular tissues.

• A vector delivery system based on adeno-associated viruses (AAVs) to transport the genetic cassette.

Best-in-Class AAV-based Vector Delivery System

Our product candidates, developed for hemophilia B and Huntington's disease, rely on the AAV5 variant, or serotype, of the vector delivery system. This particular type of adeno-associated virus has been utilized in pre-clinical research and more than 80 clinical trials, where it has displayed an excellent safety profile. Furthermore, studies have demonstrated that a single treatment with AAVs can lead to long-term therapeutic gene expression. We hold exclusive, worldwide rights to AAV5 for use in therapeutic products delivered to the brain or liver, and our investigations suggest that this vector can provide greater efficacy in treating patients when compared to other AAV-based gene therapies.

Clinical trials involving nearly 80 patients with hemophilia B and other conditions have demonstrated that gene therapies based on AAV5 are safe and well-tolerated. No individual receiving the treatment in these trials has exhibited a confirmed T-cell-mediated immune response towards the capsid. Furthermore, pre-clinical and clinical data suggest that AAV5-based gene therapies may be an effective treatment for patients with existing antibodies to AAV5, potentially increasing the number of people eligible for this type of therapy.

The presence of circulating anti-AAV neutralizing antibodies, which can be present in patients beforehand and may inhibit successful gene transfer, is one of the main difficulties in AAV-based gene therapy. Preclinical evidence demonstrating successful and efficient AAV5 transduction in non-human primates with pre-existing anti-AAV5 neutralizing antibodies (NABs) has been provided. Existing anti-AAV5 antibodies did not impair the efficiency of the AAV5 vector's transduction at any of the measured levels. It indicates that patients with pre-existing anti-AAV5 NABs may still be able to be successfully treated with AAV5 gene therapies, which offers a far wider potential group of eligible patients for AAV5-based gene treatments than was previously anticipated.

We have made significant headway in improving and advancing re-administration and cross-administration strategies which we think will have a great effect on the usage of our gene therapies and possibly permit multiple administrations. We have presented preclinical results indicating successful re-administration of gene therapy with our AAV5 vector following a specific immunoadsorption technique in non-human primates (NHPs). In addition, we have published information demonstrating profitable cross-administration of gene therapies in NHPs using sequential administration of AAV5 and AAV1 vector serotypes, implying that cross-administration of AAV5 gene therapies with other vectors might be feasible in humans. Despite this progress, high levels of circulating anti-AAV neutralizing antibodies can develop after a single administration of gene therapy and can prevent successful gene transfer in patients. AAV5 is a premier vector with the capacity to deliver gene therapies more efficiently and securely to a larger number of patients in need of care.

• Implementing administrative strategies to efficiently transport the appropriate gene into the liver or central nervous system. 

Administration Technology

We and our partners are making great strides in harnessing a range of technologies to deliver our gene therapies to the right tissues and organs for the desired outcome. This includes methods such as intravenous infusion for our hemophilia B program or MRI-guided injection into the heart for our heart disease program. With our competent team and cutting-edge facilities, we have all the necessary components to create a successful gene therapy product.

The platform is intended to be modular, which may enable us to quickly develop, produce, and obtain regulatory approval for a variety of gene therapies using essentially the same basic building blocks. We anticipate that in certain circumstances, the only element that has to be altered to target a new disease in a particular tissue is the disease-specific gene cassette. As a result, we might be able to considerably reduce overall development risk, time, and expense while also reducing the amount of preclinical and possibly clinical testing needed to achieve regulatory approval.

Improvement in Gene Therapy Technology

Our platform for next-generation gene silencing is our own, exclusive technology. It is intended to inhibit the entire target organ by secondary exosome-mediated transport and degrade disease-causing genes without producing off-target damage. We have developed novel therapeutic structures for gene therapy candidates that can be administered by AAVs and may have long-lasting action. Preclinical research on gene treatments based on this technology has revealed several significant benefits, such as better tissue-specificity, improved nuclear and cytoplasmic gene suppression, and no off-target consequences linked to impact on the cellular transcriptome.