Historically, developing rare disease cures and treatments has been challenging. The small, globally dispersed patient population made it difficult and expensive to bring together enough individuals for a clinical-stage trial. The small patient population of fewer than 1% of the population also made it impossible to recoup the investment in research and development costs required for a cure utilizing the chemical-based approach of traditional pharmaceuticals. Additionally, the long research and testing phases left little time to recoup the money invested before the patent ran out.

Today, advances in remote trial technology and the financial benefits that come with an Orphan Drug Designation are helping to overcome these obstacles. This has led to the development of cutting edge new therapies, yet, there’s no escaping the fact that after decades of research, testing, and development, only 5% of the 7,000 known rare diseases have a cure. This abysmal success rate is due not only to the factors cited but also because 80% of rare diseases are genetic disorders. Traditional pharmaceuticals are not the best fit for developing new treatments for genetic errors. It is only by turning to biopharmaceutical companies that we are seeing significant progress in therapies for genetic disorders such as cystic fibrosis and sickle cell disease. Gene therapy companies are transforming rare genetic disease cures by using patients’ own genes. These pioneering treatments hold great promise for improving the lives of patients by significantly slowing the progression of a disease and sometimes providing a durable – lasting – cure.

1. Genetic testing opens new possibilities

Researchers have long suspected that some diseases had a hereditary basis while others were due to mutations in an individual’s DNA. For hereditary diseases like cystic fibrosis and sickle cell disease, the faulty gene or sequence is in the germline. As a result, the potential for developing the disease is passed to each new generation. Today, we are not quite ready to perform gene editing that will affect future generations, but we can screen to determine if a couple carries the genes for known hereditary diseases and counsel them about the statistical outcome, as is the case with the BRCA gene and breast cancer. We can also test patients without a known hereditary component to determine if they have one of the 7,000 other known rare diseases, including those that are neurodegenerative. Since 80% of rare diseases are monogenic – due to a genetic error in a single gene – it is often possible to identify the faulty gene through sequencing. Unfortunately, until very recently in pharma, identifying and curing have been two different things.

In a 2015 paper, Evolution of Genetic Techniques: Past, Present, and Beyond, Asude Alpman Durmaz et al. wrote, “Due to rapid advances in genomic technologies, genetics analyses have become essential in clinical practice and research. During the past decade, a great stride has been made to unravel underlying mechanisms of genetic-related disorders.” With the increasing access and sophistication of genetic testing and diagnosis has come increased interest in and availability of tools to explore possible “fixes” for these genetic conditions through the use of gene therapy. (A timeline of significant events is included as a timeline in Fig. 1)

2. Promise of delay in disease progression, if not a durable cure, where there was once no hope

Gene therapy treatments are in their infancy. Early research has shown that it is now possible to introduce genes to take over the function of or “turn off” the faulty gene. “The ideal target for gene therapy [has been] Mendelian diseases caused by defined single-gene mutations, such as hemophilia or Duchenne muscular dystrophy. That has been its initial focus, bolstered by approvals of drugs such as Luxturna (for a type of Leber’s congenital amaurosis, an inherited blindness disorder) and Zolgensma (for spinal muscular atrophy). Now, gene therapy is taking on more complex, multigene diseases such as central nervous system diseases, neuropathic pain, sleep apnea, and cancer. Beyond correcting genes, gene therapy is revolutionizing cell-specific delivery of therapeutic proteins and synthetic drugs, as well as inspiring basic research into unanswered questions on immunogenicity.” [Sarkar, 2020]

The progression of the diseases treated with Luxturna and Zolgensma have so far been arrested. Whether this will ultimately result in a “durable” cure that goes the distance won’t be known until more time has passed. Despite the fact that gene therapy is neither a sure thing nor completely safe, as seen in the death of two young pediatric patients last summer in an experimental trial for an, otherwise deadly, rare muscular disorder [Sarkar, 2020], hopes for gene therapy remain an important part of the future for biopharma. (Fig. 2)

3. Shorter research and development phases reduce the cost of development 

The research and development phases of traditional pharmaceutical treatments take years and costs billions of dollars. By the time the drugs reach the market, there is not enough time to recover those costs while the drug is under patent and free from competitors. One of the benefits of gene therapy is a shorter development phase resulting from the nature of the research. With biopharma, researchers begin with a specific delivery mechanism, meaning there is no need for a drug discovery phase. With a delivery mechanism in hand, testing for efficacy can be done before formal trials are begun.

According to a 2019 webinar on the promise of gene therapy presented by the American Society of Gene + Cell Therapy (ASGCT) and the National Organization for Rare Disorders (NORD), starting with a specific therapeutic agent and skipping the drug discovery phase reduces the time for development from 9.5 to 15 years to 8 to 10 years. (Fig. 3) This quicker route benefits both the pharmaceutical company and the patient. (Read more in 9 Reasons Treatment of Rare Disease Will be Big in 2025.)

4. The Orphan Drug Act provides benefits for drugs with Orphan Drug Status

Benefits that include tax credits, market exclusivity, and waiver of significant fees (Fig.4) are definitely an incentive.

However, the rising cost of R&D is one looming problem for traditional pharmaceuticals that will not be remedied by the Orphan Drug Act. A recent report by BioPharmaTrend on The Evolution of Pharmaceutical R&D Model [Buvailo, 2020] stated, “There is a plethora of analytics reports, including ones by Deloitte, DKV Global, and Ernst and Young, all pointing to the declining business performance of the pharmaceutical industry. They all convey a similar bottom-line message: The decline is not due to a lack of innovation (the innovations are growing). And not because sales are falling or markets are shrinking (revenues are growing in general, and the markets are expanding with the expanding and aging population). The key reason for the declining financial performance is the fact that research and development (R&D) costs are growing substantially faster over an average investment period than the actual revenues over the same period. This kills operational profits, leading to a decline in the overall business gain.” These increases in R&D costs will likely not impact gene therapy companies as dramatically due to their shorter R&D window.

5. Greater interest and FDA Guidances and approvals for rare diseases

With 80% of the 7,000 known rare diseases caused by a single gene, growth in the number of rare disease trials and FDA approvals are another indicator of the growing interest in gene therapy treatments for rare disorders.

In January 2020, FDA released six final guidance documents on gene therapy manufacturing and clinical development of products. It also released draft guidance, Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations. These guidances were released as a signal of strong support for the development of gene therapy products for the unmet medical needs of patients. The guidances provide answers to the questions asked by those developing gene therapy products and the orphan-drug designation. [FDA]

Chemical & Engineering News reported in 2019, the US Food and Drug Administration says it is preparing for a coming wave of experimental cell and gene therapies. By 2020, the agency expects it will see more than 200 applications a year requesting permission to begin cell and gene therapy trials. The agency already has more than 800 such applications on file and plans to hire some 50 clinical reviewers to handle the surge. [C&EN]

As of October 2020, FDA had approved five gene therapy products for six diseases. (Fig. 5) Earlier this year, the FDA announced that it “anticipates many more approvals in the coming years, as there are more than 900 investigational new drug applications for ongoing clinical studies in this area. [Sakar]

Furthermore, FDA announced in May 2020, that it is establishing a rare disease clinical trials network to provide a more cooperative approach in supporting the drug development pipeline for rare diseases. [RF]

Conclusion

The ability to test the human genome and pinpoint genetic errors brought with it a desire to “fix” those errors. That desire went hand-in-hand with the drive to develop tools and methodologies that would make this possible through gene therapy. As gene therapy treatments came to be viewed as ideal for monogenic disorders, the push for human trials increased. The outcomes of these trials have largely shown that the progression of the diseases can be favorably impacted. With a shorter research and development time than that for traditional therapies, gene therapy has the advantage of a lower cost to market than traditional therapies. This is especially important because the patient population for these drugs is definitely smaller than that for the average disease. As another factor in reducing the net cost of bringing a gene therapy to market, the Orphan Drug Designation confers a number of financial benefits. The increased number of applications and trials is further evidence of a new approach to rare disease cures. The possibility of a cure for diseases for patients who were previously without hope, combined with reduced costs and greater FDA support, is bringing energy and momentum to gene therapy as a way to halt if not cure rare diseases thought to have a genetic basis. It is at the nexus of these factors that gene therapy companies are transforming rare disease cures.

Take Away

American Gene Technologies is dedicated to the pursuit of cures and treatments for infectious diseases, cancers, and monogenic disorders. AGT’s platform allows it to pursue therapies for large and orphan indications and complex diseases. The company has developed individual, intellectual property protected gene therapeutics that are breakthroughs in medicine. AGT’s pipeline includes Phenylketonuria (PKU), one of the most common monogenic rare diseases with an annual incidence in the United States of approximately 1 case among 13,500 live births.

PKU is caused by loss of function mutations in the gene Pah that encodes the enzyme phenylalanine hydroxylase (PAH). The loss of PAH function leads to excess accumulation of the amino acid phenylalanine (Phe), which reaches toxic levels in blood without strict dietary control. AGT is targeting PKU with a therapeutic strategy based on proprietary lentivirus vectors for modifying the liver to restore normal PAH activity and reduce Phe levels. The general nature and efficiency of lentivirus vectors plus unique features of our proprietary modifications are particularly suitable for permanent correction of PKU after a single therapeutic dose. The estimated North American and European markets for PKU treatments including medical food and supplements, exceeding $1 billion annually, could be replaced with AGT’s lentivirus vector gene therapy.

Published on AGT

With years of experience and expertise with pipettes, Gustavo Chavarria outlines pipetting factors and practices that lead to success and reproducibility in the lab…

Lab managers and PIs looking to improve the quality and consistency of their data should start with pipetting. Pipetting is fundamental to most life science labs, yet it is surprising how few researchers understand the importance of good pipetting practices to the success and reproducibility of their experiments. No matter how precise a pipette may be, it is the skill and knowledge of the user that ultimately determine the accuracy and reliability of the results.

Q: How did you come to be the global product manager for instruments?

A: My love of chemistry and math drew me to a career in STEM. Working in biochemistry and cell biology used both. I soon discovered that statistics was fundamental to effective experiment design, clinical trial data collection, and validation of the research results. I was working as a scientist for a company, developing bioanalytical assays to detect metabolites in human samples, when this product manager opportunity came up. Five years later, I’m still a product manager. I love my job because I learn the newest trends in the life sciences without doing the experiments while using data science to make better decisions and bring new solutions that help the current and upcoming generation of scientists.

Q: Pipetting seems so straight forward. How do errors slip into the process?

A: Pipetting is a manual process. As a result, it’s not surprising that it’s prone to small errors during the process. In some ways, pipetting is like driving a car. People ‘know’ how to drive, but many forget to turn on the blinker when changing lanes!

 Q: What are some of the most common mistakes and some simple steps to avoid them?

A: The three most common errors involve matching the pipette to the sample, maintaining a slow yet steady aspiration rate, and attaining the necessary inversion angle.

Q: What’s an effective way to improve pipetting technique overall?

A: Proper training is the key to better pipetting technique. It’s as critical as having a calibrated pipette or high-quality tips. Often people receive training when a new instrument, like a plate reader or sequencer, is purchased. Yet there is very little done to train lab workers on pipetting techniques and how to maintain these instruments. It would be ideal if new hires and lab members received formal training that explained the basics of pipetting, followed by a proficiency test to verify their skills against a standard curve or dedicated pipetting verification system. Annual refresher courses should be mandatory for all pipette users. In the long run, these simple practices will result in better and more consistent pipetting performance while reducing the costs associated with inconsistent or irreproducible results.

Q: Is there anything else you’d like to add about pipetting?

A: The pipette, pipette tip, and operator are three components that comprise a system: the pipetting system. Each part must be appropriate for the application to deliver the desired outcome: accurate volumes. An uncalibrated pipette can skew results by delivering inconsistent volumes. An incorrect or low-quality tip can contaminate or damage the sample. An improper technique can also deliver incorrect volumes. For these reasons, pipetting should always be considered as a system rather than as individual components.

Avoiding common errors

Matching the pipette to the sample

Not all samples are created equal. As a result, a forward-pipetting technique cannot be used at all times. A good rule of thumb for air displacement pipettes is to use a reverse technique for viscous and volatile liquids and a forward technique for aqueous-based solutions. Compared to air displacement pipettes, positive displacement pipettes offer greater accuracy and consistency when handling highly viscous or volatile liquids. 

Maintaining a slow yet steady aspiration rate

Releasing the plunger too quickly while aspirating can produce a ‘fountain effect’ or introduce air pockets inside the tip. These errors will affect pipetting accuracy through the formation of bubbles and inconsistent volumes, respectively. Splash-back can also occur, contaminating the pipette and/or damaging its internal working. Any of these mistakes will ultimately affect the delivered volume’s accuracy and will often make it necessary to repeat some or all of the protocol. 

Attaining the necessary inversion angle

Failing to hold the pipette as close to a vertical position as possible is not always easy, especially when pipetting small volumes. In these cases, it’s very common to hold the pipette and vessel at an angle, even at angles parallel to the bench. The pipette and vessel are often held this way to reach the bottom of a small vessel while looking through the content. Or, they’re held this way because it’s simply more comfortable for the lab worker’s arm to hold the pipette and vessel at an angle. Research shows that the problem with extreme angles of greater than 20 degrees is that they can significantly affect accuracy. Re-learning to hold the pipette as close to vertical can solve this.

Published on LabNews

Welcome to my weekly blog about BioTech, Health-Tec, Sci-Tech, and New Tech. Each Thursday you’ll find a new post, written for those who are working in tech or are curious about the exciting introduction of technology into our daily lives. I selected these topics because they are the ones I cover as a freelance writer in my work for clients in these fields.

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These five biotechnology companies in Maryland may make history in 2021 because they have multiple therapeutic programs in trials for a variety of genetic diseases.

REGENXBIO is a publicly-traded company that develops products for one-and-done, single-dose solutions addressing genetic defects. Their products use adeno associated virus (AAV) viral vectors that make up their proprietary NAV Technology Platform, which utilizes novel AAV (NAV) for retinal, metabolic, and neurodegenerative diseases. To accomplish this, the NAV Vectors deliver genes to cells, making it possible for cells to produce the proteins that will impact the disease.

Platform

The NAV Technology Platform is a patented set of AAV (adeno-associated virus vectors), which neither replicate nor are known to cause disease. The REGENXBIO NAV Vectors deliver a healthy copy of the gene, located inside the AAV capsid. As described in this video, once inside the body, the capsid travels to the targeted tissue where the NAV Vector inserts the healthy copy of the gene into a cell before dissolving. The inserted DNA is transcribed into RNA in the nucleus of the cell, which encodes the missing protein. As this gene continues to replicate, it produces sufficient quantities of the essential protein to impact the disease.

Pipeline

The REGENXBIO pipeline includes product trials ranging from preclinical to Phase II for four program areas. The company has worldwide rights to ten of these, with co-commercialization for one. Of particular interest are the Fast Track Designations granted for neurodegenerative diseases and the Orphan Drug Designation for one retinal disease and three neurodegenerative diseases because these bring an advantage to those trials. The Rare Pediatric Disease Designation for four of the trials is equally significant because of the financial benefits that go with the designation as well as the fact that these treatments will fill an unmet need for a portion of the 350 million people worldwide with one of 7,000 rare diseases. In addition, the REGENXBIO trials are for a mix of AAV-mediated antibodies for chronic diseases (6) and monogenic gene replacement,  providing more than one area of opportunity for REGENXBIO.

Promise

REGENXBIO (NASDAQ: RGNX), located in Rockville, uses its proprietary NAV Vector Platform with a range of treatments in trials that are at various stages. The products in development meet a variety of patient needs, while the company retains worldwide rights for these products that will serve a global population that has significant unmet needs.

Precigen is a publicly-traded biopharmaceutical company working in the discovery and clinical-stage space with both cell and gene therapy programs. Their focus is on the urgent and intractable diseases in immuno-oncology, autoimmune disorders, and infectious diseases. The company is pursuing multifunctional gene and cell therapy that will work together for more efficacious, safer treatments.

Platform

Precigen has a proprietary viral vector, the AdenoVerse with several advantages when compared to other vectors. These include a/an:

• Capacity to carry a larger genetic payload – significant because it makes it possible to include more than one gene for expression, as well as because it makes it possible to deliver the large gene required for some genetic disorders without having to manipulate that gene to accommodate the smaller capacity of the viral vectors currently available.
• Ability to repeat the treatment – significant because with many adenoviral vectors, there is a concert that the patient builds antibodies that make a second treatment with that vector impossible.
• Lack of replication – significant because the fact that there is no in vivo replication reduces the risks associated with the therapy.
• Durable response – significant because the antigen-specific immune response is lasting.

Their UltraVector platform blends gene therapy technologies with computational models to incorporate genetic components into an optimized expression of multiple genes. Their methodology and library of characterized genetic components and associated functional characterization data are the foundation of this platform.

Precigen also has a product known as the ActoBiotics Advantage. This is a food-grade bacteria that makes it possible to deliver biologics via mouthwash, capsule, or a topical formulation. The bacteria, L. lactis, has a long history of safe use. The process for inserting and delivering the therapeutic agent is described in the illustration below.

Pipeline

Precigen’s pipeline includes therapies in both clinical and preclinical stages. Their gene therapies in clinical trials include one for Type 1 Diabetes using ActoBiotics as a delivery mechanism and one using non-viral UltraVector biotechnology for heart failure. In the preclinical stage, the company is exploring therapeutic products for solid tumors, infectious diseases, and celiac disease.

Promise

Precigen (NASDAQ: PGEN), located in Germantown, has a range of treatments in its pipeline. Several are currently in clinical trials, with many more in the preclinical phase. It is encouraging that Precigen has many promising therapies based on their products and platforms. Their larger vector, and their alternate delivery route for biologics, differentiate the company’s therapies and puts Precigen in the position to make history in 2021.

MacroGenics is a publicly-traded biopharmaceutical company that develops and commercializes monoclonal antibody-based therapeutics for cancer. In December 2020, MacroGenics received FDA approval for Margenza, a targeted therapy to be used in conjunction with chemotherapy to treat patients with metastatic HER2-positive breast cancer. It is the first FDA approval for MacroGenics.

Platform

The company has two platforms, DART and TRIDENT, that make it possible to create single-molecule medicines that simultaneously bind to two or more targets with antibody-like specificity. The result is an environment that produces a more significant biological effect than other forms of targeted binding.

Pipeline

MacroGenics has 7 products in their pipeline. Two are in the pre-approval stage and the others are in various stages leading to possible approval. The company has major market rights as indicated in the table below.

MacroGenics also holds more than 30 patents for product candidates relating to hematological malignancies and solid tumors.

Promise

MacroGenics (NASDAQ: MGNX), located in Rockville, may make history in 2021 due to FDA approval of Margenza. Flotetuzumab for refractory AML and Retfanlimab for NSCLC, Anal are nearing approval. These therapies, in addition to the others in Phase 1 of clinical trials and the many patents the company owns, positions MacroGenics for history-making approvals and commercialization in 2021.

OpGen is a publicly-traded biotechnology company in the gene therapy sector. Their focus is on genomic diagnostics to reduce the spread of infections caused by multidrug resistant microorganisms (MDROs).

Platform

OpGen has a suite of products designed to ensure OpGen a position as what the company calls “a steward for today’s antibiotics.” Their platform includes tools to predict, track, and identify drug-resistant microbes. Two of them are cloud-based and offer identification of pathogens in a few hours rather than several days:

• Acuitas Lighthouse is the first cloud-based software working at the molecular level with genotype and phenotype data collected from hospitals around the world. By working at the molecular level, OpGen is able to identify, track, and predict antibiotic-resistant infections. The information generated by Acuitas Lighthouse can be used by healthcare systems for real-time treatment and mitigation decisions.
• Acuitas Tests is their proprietary testing panel. It can return pathogen identification in hours, rather than days by using Merck & Co’s Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program – a curated library of more than 250,000 bacterial isolates. 

Pipeline

OpGen does not have a pipeline of therapies because its business model uses proprietary platforms to save lives around the globe. This is accomplished by reducing the number of deaths each year from undiagnosed bacterial infections or drug-resistant infections. Their approach is not only diagnostic but also uses AI to suggest treatments to healthcare workers in real-time. OpGen is working to prevent the number of people affected as indicated below.

Promise

OpGen (NASDAQ CM: OPGN), located in Gaithersburg, has developed a cloud-based system that integrates genomic information from healthcare partners with rapid testing of patients for pathogen identification and AI suggestions for treatment in real-time. The market for its service is global. With increasing alarm at the number of antibiotic-resistant infections, OpGen is poised to reap the benefits of its technology and make history in 2021.

American Gene Technologies (AGT) is a private biotechnology company developing genetic medicines through the application of proprietary viral vector technology. Its programs are focused on an HIV functional cure, effective gene therapy treatment of phenylketonuria (PKU), and immuno-oncology products to bring about cancer cures.

Platform

AGT’s strength lies in its viral vectors. These vectors have been developed, tested, and banked for use with gene therapy for specific diseases. When a company approaches AGT with an approach, AGT pairs the requirements for that approach with the appropriate vector. This leaves the researchers as CEO Jeff Galvin says, “80% of the way on day one.” By focusing on the delivery of the genetic cargo, AGT has created a layer in the tech stack that will be needed by all firms intending to deliver gene therapy.

The company also holds several patents related to its programs.

Pipeline

Currently, AGT is beginning the first phase of clinical trials for its HIV Cure Program. Early indications suggest that this cell therapy will be the first successful one-and-done therapy resulting in a functional cure for those with HIV. For the millions of individuals living with HIV, this will mean the end of ongoing treatment. The PKU program is a gene therapy that will introduce a functioning gene to replace the mutated gene at the heart of PKU. Again, this is intended to provide a one-and-done cure. The immuno-oncology program is developing a therapy that will activate innate T cell immunity to kill all tumor cells with its vector.

Promise 

American Gene Technology, located in Rockville, has over 10 patents and an Orphan Drug Designation for its programs. With Orphan Drug Status for the PKU Program that is currently nearing the IND stage and the HIV Cure Program in Clinical Trials. If its HIV Cure Program is successful, AGT will have the first functional cure for individuals living with HIV.

Published on AGT

Pharmaceutical companies have been developing therapies to treat or prevent disease since the end of the 19th century. Chemical compounds are used to create these drugs and medications. The resulting small-molecule drugs – think aspirin – are ingested, metabolized and circulate through the blood. Because it’s not possible to target these drugs, they have a systemic effect that can lead to unwanted adverse events. Biopharma companies use genetic material to create genomic – gene, cell, and gene editing – treatments that repair genetic mutations or introduce functioning genes to take the place of or inhibit the mutated gene. These treatments can be targeted, causing minimal unwanted side effects.

Since the mapping of the human genome was completed in 2003, interest in biopharmaceuticals has increased. To date, several gene therapies have gone through trials and received approval from the FDA, with hundreds more proposed therapies in the pipeline. In 2020, FDA published guidance for gene therapy trials, signaling that a significant change in traditional healthcare and drug development is underway. As a result, gene therapy companies are vital to the future of biopharma for 5 reasons.

1.  Small-molecule drugs alone are not effective treatments for genetic diseases.

Genetic diseases are caused by one or more mutations in a person’s genetic code. Small-molecule drugs can alleviate the symptoms, akin to aspirin and headaches, but they can neither repair, replace, nor inhibit the function of the mutated gene. In other words, traditional pharma drug development can only provide palliative treatments for genetic disorders, in the same way that an error in a computer code cannot be fixed by switching out components; it can only be fixed by correcting the code or writing a subroutine that bypasses that segment of the code. There are many small-molecule drugs that are in development for use with targeted delivery and/or in conjunction with RNA, and these will have their place in the market, yet with nearly 400 gene and cell therapy treatments in development in 2020 (Fig. 1), pharma is clearly looking to gene therapy for next-generation, new treatment options.

2.  Biopharma treatments fulfill an unmet need for rare disease patient populations

PhRMA estimates that only 5% of rare diseases have an approved treatment option, Global Market Insights forecasts a rare disease treatment market of  $317 billion by 2026. (Fig. 2) For those with Duchenne muscular dystrophy, hemophilia, spinal muscular atrophy, and nearly 7,000 other rare diseases, the new therapies possible through the use of viral vectors, or gene editing with CRISPR or other modalities, will be life-changing. Each individual rare disease affects a small population, but the more than 350 million individuals worldwide represent a significant opportunity for life science companies. As more work is done and more about individual genes is understood, there may be opportunities to leverage off the work done for one disease to treat another, reducing the cost of the treatment in the process

Within the biotech biopharmaceutical pipeline for rare diseases (Fig. 3), genetic disorders (148/596) represent 24% of the medicines in development. With the cost of individual “one-and-done” treatments, in which one treatment is anticipated to have a lifelong effect, in the millions of dollars, these rare disease candidates can be lucrative. There is also some early evidence that treatments for one genetic disorder may apply to others. If this proves to be so, modification of existing treatments will add to the profitability of new treatments for the companies bringing them to market.

3.  Treatment of cancer using gene therapy holds promise

Cancer is the second leading cause of death worldwide with 17 million new cancer cases worldwide in 2018, according to the International Agency for Research on Cancer (IARC). Of the 400 medicines for cell and gene therapy in 2020, (Fig. 1) nearly half (173/387) are for cancer. The traditional form of treatment for cancer is chemotherapy, which introduces toxins into the body without the ability to act on one specific target. As a result, severe side effects are common. Efforts are being made to control the area affected by the chemo through a variety of methods. However, a 2006 paper from Marshfield Clinic cites gene transfer as “a new treatment modality that introduces new genes into a cancerous cell or the surrounding tissue to cause cell death or slow the growth of the cancer. This treatment technique is very flexible, and a wide range of genes and vectors are being used in clinical trials with successful outcomes.”

The PhRMA Medicines in Development 2020 Report for Cancer treatments includes more than 1,300 medicines and vaccines biopharmaceutical research companies have in clinical trials for cancer. (Fig. 3) Included in these are treatments for several types of leukemia, lung cancer – the leading cause of cancer death in the U.S., lymphoma, breast cancer, prostate cancer, multiple myeloma, brain tumors – including gliomas, and ovarian cancer.

4.  Biopharma is far too lucrative for traditional pharma to overlook

Forecasts for the biopharma industry from sources within the industry as well as those tracking the industry call for robust growth, reaching global market revenue of between $446 billion and $526 billion by 2025. The ability to sequence an individual’s genes brought the ability to pinpoint the site of the problem in genetic disorders. This information led to a number of potential approaches for new gene therapy products that could be taken to correct or override the error. More and more of these gene therapy approaches are now reaching the clinical trial stage.

In 2018, the Journal of Gene Medicine cited an FDA chart that described the indications being addressed in gene therapy clinical trials,(Fig. 4), ranging from 67% for cancer diseases to .5% for inflammatory diseases. The trials for cancer and monogenetic diseases, comprising nearly 80%, are of special interest because they signify a population with an unmet need since there are no effective treatments at this time.

5.  Mergers and acquisitions are an expedient vehicle for entry to biopharma

Traditional, big pharma companies can enter the biopharma area by hiring their own talent, creating infrastructure, and dedicating the time required to build a pipeline of promising cures. Alternatively, they can form external partnerships with drug discovery startups or academic institutions, acquire smaller firms with an approach and proof of concept and take it the rest of the way, or outsource R&D activities. In conjunction with entry into genomic medicine, BiopharmaTrend envisions a necessary revision of the current pharmaceutical business model in which the R&D is done without a specific target (Fig. 5), resulting in what Standish Fleming points out is a “high-quality, low-volume, high-cost strategy” of early drug discovery.” This model is inherently costly since R&D is costly even when a product results, much less when the R&D effort fails to yield a marketable result. The new model BiopharmaTrend describes will be a “low-cost, high-quantity strategy” with biopharma at the heart.

Bottom Line

Gene therapy is vital to biopharma. Gene therapy offers advanced therapy and treatments where none have been viable with traditional pharma and small-molecule drugs. Gene therapy also provides an opportunity for big pharma to enter the estimated $317 billion global rare disease market by meeting the needs of the 350 million people with genetically-based rare diseases. Gene therapy is also vital to biopharma because of the new, targeted approaches it brings to cancer treatments. With a forecast for a global oncology/cancer drug market of $176 billion by 2025, there is room for many players – but they will require gene therapy capabilities to access and hold a position in that market. With a forecast of about $500 billion by 2025, the biopharma market overall is equally attractive. The FDA recorded a significant number of diseases – from cancer to inflammatory diseases –  addressed by gene therapy clinical trials in 2018, with a greater number forecast in the coming years. Finally, recent partnerships or mergers with gene therapy startups have proven to be the fastest way for big pharma to enter the growing and lucrative biopharma sector.

Take Away

In 2020, the FDA issued regulatory guidance related to the cellular and gene therapy industry. Release of the guidance is a significant indicator that regulators anticipate an increase in preclinical activity and requests for clinical trials in the coming years. A full listing of the guidance documents is available.

Published on AGT

Gene therapy companies are powering a revolution in rare disease cures by offering treatments that target the genetic cause of the disease. Rather than try different combinations of chemicals to create a small-molecule treatment as is the case with traditional pharmaceuticals, gene therapy uses genetic material in drug development to repair or replace the genetic cause. Here are 3 gene therapy companies changing the face of healthcare as they strive to serve the unmet medical needs of the 350 million people worldwide with rare diseases.

01. Spark Therapeutics

Spark Therapeutics, now a part of Roche, started the ball rolling in 2017 with FDA approval of Luxturna, their gene therapy to treat pediatric and adult patients with an inherited form of vision loss/blindness. Approval for Luxturna was a game-changer, as it was not only the first gene therapy treatment approved but also the first treatment in the U.S. that targets a genetic disease. At the time of the approval, FDA Commissioner Scott Gottlieb, M.D. said in his remarks, “I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses.” Luxturna was the first treatment to deliver a normal copy of an incorrect gene (RPE65) directly to the retinal cells through the use of an adeno-associated viral (AAV) vector. As the gene replicates, it produces sufficient quantities of the requisite protein to restore vision. The mechanism of action is illustrated in Fig. 1.

Peter Marks, director for FDA’s Center for Biologics Evaluation and Research (CBER), noted that “patients with biallelic REP65 mutation-associated retinal dystrophy now have a chance for improved vision, where little hope previously existed.”

02. Avexis

Avexis, now part of Novartis AG, received the second FDA gene therapy approval for Zolgensma in 2019. Zolgensma is also the second drug approved for use with spinal muscular atrophy (SMA). The first, Biogen’s Spinraza, was designed to meet the needs of those with SMA Type 2 and is neither a gene therapy nor a one-and-done. Zolgensma is intended to meet the needs of those with SMA Type 1 and is a gene therapy used to treat children under the age of two diagnosed with spinal muscular atrophy (SMA). Targeting the genetic root cause of SMA, it is a one-and-done, single-dose solution. Zolgensma replaces the function of the SMN1 gene with a working copy of the SMN gene.

The treatment is still too new to determine if it is a durable cure for those with this most common, very serious form known as SMA Type 1. However, it is notable that SMA Type 1 is usually fatal within the first two years of life, and children treated during clinical trials four years ago are alive and healthy today. In Fig. 2, below, a graph of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) indicates that the historic high score of 40 points was surpassed by the majority of the participants.

One objection to Zolgensma has been its cost per dose of over $2 million. In an opinion piece addressing the cost of Zolgensma, Nathan Yates, an adult with SMA, points out that “critics of the eye-popping cost of Zolgensma need to take into account its long-term benefits. Zolgensma’s approval, and that of Spinraza, is the beginning of a new paradigm for treating SMA and for the fight against muscular dystrophy in general. Without any treatments, SMA would remain the top genetic killer of children under 2.”

03. uniQure

On December 21, 2020, uniQure and partner CSL Behring received a clinical hold by the U.S. FDA on their one-and-done hemophilia B AMT-061 gene therapy trial. The hold was due to a form of liver cancer in a patient who was dosed more than a year ago. Citing uniQure, FIERCE Biotech reported that the patient “has multiple risk factors” for liver cancer, Including a twenty-five-year history of hepatitis C, hepatitis B virus, evidence of nonalcoholic fatty liver disease, and advanced age. Given the risk factors, it is possible the lesion could be a result of those factors and not uniQure’s therapy. There is concern among those with hemophilia B because this treatment was intended to preclude the use of transfusions and ongoing treatment for his inherited bleeding disorder. Despite the fact that the trial is on hold until further information can be gathered, the potential for a single-dose treatment for hemophilia is part of the revolution in rare disease cures.

Bottom Line

Luxturna, Zolgensma, and the AMT-061 trial were for new therapies that were significant advances in rare disease cures through the use of gene therapy. Each of these treatments is envisioned by gene therapy companies as a one-and-done, one-time treatment that will enable the patient’s body to create the protein needed to address the genetic mutation causing a central nervous system, neurological, cardiovascular disease, or neurodegenerative disease. Whether the treatment will be durable – will last a lifetime – is not known with certainty because these cutting-edge treatments are so new. Where there are treatment alternatives, there is some concern that if a treatment doesn’t last, it will make it impossible to use other treatments – a serious consideration. For those without any treatment options, the prospect of a pioneering therapy that clears regulatory hurdles and results in a new treatment that can change the lives of patients is significant.

Take Away

American Gene Technologies (AGT) is dedicated to developing cures for monogenic diseases like phenylketonuria (PKU). PKU is one of the most common monogenic rare diseases, affecting approximately 1 among 13,500 live births in the United States each year. AGT’s PKU Therapy uses a non-integrating viral vector to introduce a synthetic PKU gene into the patient’s liver cells. This synthetic gene not only directs the production of PAH but also blocks the inappropriate production of mutant PAH, thereby enabling normal metabolism of PHE. AGT has compelling preclinical data for therapeutic vectors capable of correcting the PKU defect. Further, AGT has developed proprietary combination vectors designed to enhance potency of the genetic medicine. These vectors are advancing through preclinical development and we are ready to begin interacting with the FDA as we plan for clinical development and testing of our genetic medicines. As part of that process, we recently received US FDA Orphan Drug Approval #DRU-2018-6572 for the treatment of PKU using proprietary, lentiviral vector-based technology.

Published on AGT