Rampart Bioscience investment analysis

Rampart Bioscience is a private biotechnology firm developing next-generation DNA-based medicines. Based in La Jolla, California, the company's HALO platform aims to address the main limitations and safety concerns associated with viral and early non-viral gene approaches. HALO is geared towards creating therapies that are potent, enduring, and can be redosed.

Rampart's lead therapy program targets hypophosphatasia (HPP), a rare genetic disease that hinders bone mineralization, which can be fatal. Beyond this, the firm has several other programs in the pipeline.

Rampart's DNA medicines have unique structural elements that enhance nuclear trafficking and retention while evading immune reactions. This advancement could potentially address challenges of potency and durability faced by earlier approaches.

The company raised a $40M seed round from Orbimed and, in October 2023, raised an $85M Series A from Orbimed, RA Capital Management and HealthCap.

Gene therapy is a medical technique that treats or prevents diseases by modifying an individual's genes. Instead of drugs or surgery, it introduces, removes, or replaces genetic material within cells, offering potential solutions for genetic disorders, certain cancers, and some viral infections.

Basics of gene therapy

Viral vectors are used in gene therapy as delivery tools to introduce therapeutic genes into cells, leveraging the virus's natural ability to penetrate and integrate genetic material into host cells.

However, despite their potential, there are several challenges and concerns associated with their use:

• Immunogenicity: One of the main challenges with viral vectors is the potential for an immune response. The patient's immune system might recognize the viral vector as foreign and mount an immune response, which could inactivate the vector and decrease the efficiency of gene transfer. This response could also lead to adverse side effects in the patient.
• Insertional Mutagenesis: Viral vectors can integrate their genetic material into the host's genome. While this can be beneficial for long-term expression, there's a risk that the integration might disrupt vital genes or activate oncogenes, potentially leading to diseases like cancer.
• Limited Payload Capacity: Some viral vectors have a limited capacity for the amount of DNA they can carry, which restricts their use for delivering larger genes.
• Production Difficulties: Large-scale production, purification, and titration of viral vectors can be challenging, making it difficult to generate the quantities needed for widespread clinical use.
• Re-administration Issues: Due to the potential immune response against the viral vector, it might be challenging to re-administer the same vector to a patient if needed, as the body could have developed neutralizing antibodies against it.
• Potential Toxicity: Some viral vectors might have inherent toxicities or can induce an inflammatory response, leading to complications. High doses of gene therapies have caused severe liver tox and patient deaths.
• Tissue Specificity: While some viruses naturally target specific tissues, others might require modifications to target the desired cells or tissues, which adds to the complexity of vector design.
• Loss of Therapeutic Effect: For non-integrating viral vectors, the therapeutic effect might be temporary, as the delivered gene might get diluted out during cell divisions or might degrade over time.
• Difficulty in Regulation and Control: Once administered, it's challenging to control the expression levels of the introduced gene. Overexpression or unregulated expression might lead to unwanted side effects.
• Safety Concerns: The use of certain viral vectors derived from pathogenic viruses can raise concerns about the potential reversion to a disease-causing form or causing disease in individuals with specific vulnerabilities.
• Cost: The production and purification processes for viral vectors are labor-intensive, which can make treatments based on them expensive.

Despite these challenges, ongoing research is continually improving viral vector designs and addressing the associated risks. Techniques like targeted integration, use of self-inactivating vectors, and development of synthetic or hybrid vectors are being explored to enhance safety and efficacy.

Rampart's opportunity in non-viral gene therapy

Non-viral gene therapy offers an alternative to viral methods by delivering therapeutic genes without the potential complications of immune responses, limited DNA payload capacity, and integration-associated risks linked to viral vectors, thereby aiming for a safer and more controlled gene transfer approach.

However, there are inherent challenges and limitations associated with non-viral vectors. Here's a discussion on the limitations of non-viral gene therapy in the context of diseases like HPP:

• Limited DNA Payload Capacity: Non-viral vectors typically have a lower capacity to carry genetic material compared to viral vectors. This may pose challenges for diseases where larger genes or multiple genes need to be delivered.
• Transient Gene Expression: One of the main challenges with non-viral vectors is achieving long-term, stable gene expression. Unlike viral vectors which can integrate into the host genome and provide sustained gene expression, non-viral vectors often lead to transient gene expression that diminishes over time, requiring repeated administrations.
• Efficiency of Delivery: Non-viral vectors tend to have lower transfection (gene delivery) efficiency compared to their viral counterparts. This can be attributed to barriers at various steps of the delivery process, from cellular uptake to nuclear entry.
• Immune Responses: While non-viral vectors are generally considered to evoke lesser immune responses compared to viral vectors, certain formulations can still induce unwanted immune reactions. This can compromise the safety and efficacy of the therapy.
• Cell Targeting: Achieving specificity in terms of which cells the genetic material is delivered to can be more challenging with non-viral vectors. While certain modifications can enhance targeting, it's still an area of active research.
• Challenges in Manufacturing and Scalability: Producing consistent and high-quality non-viral vectors at a scale suitable for clinical applications can be complex. Ensuring the reproducibility and standardization of these vectors remains a technical challenge.
• Safety Concerns Over Integration: Even though non-viral vectors are less likely to integrate into the host genome (which is seen as an advantage in terms of avoiding potential mutagenesis), the lack of integration can also be a limitation when aiming for long-term therapeutic effects.

Rampart's claims regarding its proprietary HALO platform, in light of the known limitations of non-viral gene therapy, provide hints about the innovative techniques and technologies they might be employing. While the exact mechanisms remain proprietary to Rampart, we can make some educated speculations based on the provided information:

• Enhanced Nuclear Trafficking: One of the significant barriers for non-viral vectors is the delivery of the therapeutic DNA into the cell nucleus. Rampart's mention of "enhanced nuclear trafficking" suggests they might be using specialized sequences or chemical modifications that facilitate efficient transport of DNA across the nuclear envelope.
• DNA Retention: The mention of DNA "retention" implies the platform's ability to maintain therapeutic DNA within cells for extended periods, potentially addressing the transient gene expression challenge. This could involve techniques to enhance episomal maintenance of the introduced DNA or even controlled integration into safe harbor sites within the genome.
• Evading Immune Reactions: To achieve this, Rampart may be employing stealth technologies or encapsulation techniques that protect the therapeutic DNA from detection and degradation by the immune system. This could involve lipid-based nanoparticles, polymer encapsulation, or other advanced delivery systems that shield the therapeutic material.
• Structural Elements in DNA Medicines: Rampart's claim about "novel structural elements" in their DNA medicines may point to specialized DNA constructs or configurations that enhance therapeutic potency. This could include optimized promoter sequences for higher gene expression, multi-gene cassettes for synergistic effects, or even scaffold/matrix attachment regions (S/MARs) for improved episomal retention.
• Redosing Capabilities: The ability to redose suggests that the platform either has minimal immunogenicity or has a mechanism to circumvent or suppress immune reactions upon subsequent administrations. This is crucial for ensuring long-term treatment efficacy, especially if the therapy's effects diminish over time.
• Potency and Durability: Achieving both potency and durability may involve a combination of high transfection efficiency, optimized gene expression levels, and long-term cellular retention. Rampart might be utilizing advanced delivery systems, like nanoparticles or other carrier molecules, combined with optimized DNA constructs to achieve this balance.

Gene therapy in HPP

Hypophosphatasia is a rare genetic disorder caused by mutations in the ALPL gene leading to deficient activity of the tissue-nonspecific alkaline phosphatase enzyme, affecting bone mineralization. For a disease like HPP, where long-term correction is needed to reverse or halt the progression of the disease, the transient nature of non-viral gene expression might be inadequate.

To address HPP through gene therapy, the primary cells that would need to be targeted are osteoblasts, chondrocytes and liver cells.

Osteoblasts are the bone-forming cells responsible for producing the extracellular matrix of the bone and initiating its mineralization. Since HPP manifests as impaired bone mineralization due to a buildup of pyrophosphate (an inhibitor of mineralization), delivering functional ALPL genes to osteoblasts is crucial to restore normal bone formation.

These are the cells found in cartilage, which is a precursor to bone in the growth plate. Chondrocytes undergo a maturation process, eventually leading to apoptosis and replacement by bone. Proper function of the TNSALP enzyme is essential in this cartilage-to-bone transformation, so targeting chondrocytes could also be beneficial in treating HPP.

While the ALPL gene is tissue-nonspecific and its product, the TNSALP enzyme, is expressed in various tissues, the liver is a significant producer of circulating alkaline phosphatase. Some gene therapy approaches might aim to target liver cells to increase systemic levels of the enzyme, especially for forms of HPP that manifest systemically and not just in bones.

The approach to targeting might vary depending on the severity and type of HPP. Perinatal/Infantile HPP is the most severe form and manifests shortly after birth. Addressing this would likely require systemic delivery of the therapeutic gene to ensure widespread enzyme availability. Childhood/Adult HPP is less severe and might be addressed by more localized delivery, although a systemic approach could still be beneficial.

Key data Rampart would need to demonstrate

While Rampart has not disclosed any data on its platform or HPP program, we can speculate at the data that would potentially be required for investors to gain confidence in the program.

For a non-viral gene therapy targeting hypophosphatasia (HPP) to be deemed promising, several key experiments and results would be essential. Here's a suggested set of experiments and anticipated results:

In addition to these experiments, it would also be essential to see pre-clinical safety data (toxicology, off-target effects) before advancing the therapy to clinical trials. Successful outcomes in these experiments would bolster confidence in the therapeutic potential of Rampart's non-viral gene therapy for HPP.

Choosing the right species for testing is critical to obtain meaningful preclinical data. For a disease like hypophosphatasia (HPP), which is a genetic disorder that affects bone mineralization, the selected animal models should ideally possess similarities in bone physiology to humans and should be able to recapitulate key aspects of the human disease phenotype when genetically manipulated. Rabbits have closer bone physiology to humans compared to rodents, but there are less genetic information and tools available, more expensive, longer reproductive cycle compared to rodents. Large mammals have closer physiological similarity to humans, especially in terms of size, bone structure, and turnover, but the cost and complexity of these studies are higher than rodents or rabbits.

Market overview

Hypophosphatasia (HPP) is a rare, inherited metabolic disorder characterized by defective mineralization of bones and teeth due to mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). This leads to a deficiency or inactivity of this enzyme, resulting in an accumulation of its substrates, like inorganic pyrophosphate, which inhibits mineralization. Symptoms range from skeletal deformities, respiratory complications, and fractures in severe forms present in neonates, to dental problems and muscle weakness in milder adult forms.

The standard of care for HPP has been largely supportive, addressing the symptoms and complications of the disease. Treatments can include pain management, physical therapy, and orthopedic procedures for skeletal issues. For severe pediatric cases, respiratory support might be necessary. In 2015, the U.S. Food and Drug Administration (FDA) approved asfotase alfa (Strensiq®) - an enzyme replacement therapy (ERT) - which provides the missing TNSALP enzyme, showing significant efficacy in improving bone mineralization and survival in pediatric patients.

Strensiq is one of the most expensive drugs in the world. The annual cost for Strensiq can vary depending on the patient's weight and dosage, as it's dosed by patient weight. The annual price can range from six-figures to millions of dollars. It's important to note that these are list prices and may not reflect what patients actually pay after insurance, discounts, or any patient assistance programs.

Strensiq generated $958M in worldwide revenue in 2022.

While enzyme replacement therapy has provided a treatment avenue, it's not a cure. There's a need for therapies that can address the underlying genetic cause of the disease, potentially offering a one-time treatment. Moreover, the high cost of ERT, lifelong treatment regimen, and potential for the body to develop resistance or adverse reactions underscore the necessity for alternative therapies.

Given the rarity of HPP, the patient population is limited. However, due to the severity of the disease and the high cost of treatments like ERT, the market value can be significant. The precise market size can vary based on geographic region and data source, but with the approval of asfotase alfa, the market has seen growth.

Clinical development

While Rampart has not progressed into the clinic or provided detail on their development plan, we can use Strensiq's development in HPP as a blueprint. Based on the clinical trials and natural history studies for Asfotase Alfa, here's a potential development plan for Rampart Bio's non-viral gene therapy in HPP:

Key efficacy measurements would likely include:

• Overall survival
• Ventilator-free survival
• Growth
• RGI-C
• Rickets Severity Scale
• Fractures
• Bayley Scale of Infant and Toddler Development
• Peabody Developmental Motor Scales
• Bruininks-Oseretsky Test of Motor Proficiency
• modified Performance Oriented Mobility Assessment-Gait
• 6MWT
• DEXA scan
• Bone biopsy
• Hand Held Dynamometry
• PODCI
• CHAQ

The development of asfotase alfa did not encompass a large Phase 3 trial. However, Rampart's program may require one. Rampart's clinical development pathway may look different depending on the quality of early clinical data, in light of the fact that there is an approved therapy in Strensiq that reduces the unmet need compared to when Strensiq was in development. Further, due to the added layers of risk for gene therapy, including integration risks, immune responses, and unknown and potentially irreversible long-term effects, egulatory bodies often require more extensive data for gene therapies compared to conventional treatments. However, the exact clinical trial requirements would be contingent on discussions with regulatory agencies, the nature of the gene therapy, its mechanism, and the results from early-phase trials.