Breakthrough Clinical Results
Be Biopharma presented preclinical data for BE-102, a B cell medicine, showing continuous secretion of active alkaline phosphatase (ALP) for up to six months after a single administration in animal models. This novel approach addresses limitations of current enzyme replacement therapy (ERT) for Hypophosphatasia (HPP), a genetic disease characterized by deficient ALP activity. The data, presented at the ASGCT annual meeting, showed no safety concerns and demonstrated BE-102's potential as a disease-modifying therapy. Be Biopharma plans further preclinical studies before submitting an Investigational New Drug (IND) application for a first-in-human clinical trial.
Key Highlights
- Single administration of BE-102 provides continuous ALP secretion for up to 6 months in vivo.
- No safety concerns observed in preclinical studies.
- Data presented at the ASGCT 28th Annual Meeting.
- BE-102 offers a potential disease-modifying therapy for Hypophosphatasia.
Incidence and Prevalence
Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP) activity. Its incidence and prevalence vary based on disease severity and available data. Several studies provide insights into the epidemiology of HPP:
Incidence:
- A 2015 study focusing on pediatric-onset HPP reported an incidence ranging from 1:100,000 to 1:300,000 live births. This aligns with a 2008 study that estimated the incidence of severe HP in Canada at 1/100,000. It's important to note that severe forms of HPP are rarer than moderate forms.
Prevalence:
- A 2020 study found that among rheumatology patients with persistently low ALP levels, 7 out of 19 (36.84%) had HPP signs and pathologic ALP mutations. This suggests a higher proportion of affected individuals in this specific patient population.
- A 2011 study estimated the prevalence of severe HP in European populations at 1/300,000 based on cases tested in a French laboratory. The same study estimated the prevalence of moderate HPP (mHPP), including HP with moderate bone features and odontohypophosphatasia, at 1/6370, indicating that mHPP is considerably more frequent than severe HP.
- A 2015 study reported the estimated prevalence of the less severe adult form of HPP to be between 1:3100 to 1:508 in different European countries.
Challenges in Estimating HPP Epidemiology:
HPP's rarity and broad range of clinical presentations pose challenges in accurately estimating its incidence and prevalence. Many cases, especially milder forms, may go undiagnosed, leading to underestimation. Furthermore, variations in diagnostic criteria and data collection methods across studies contribute to the variability in reported figures. Genetic testing and biochemical markers like elevated pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA) are crucial for accurate diagnosis and could improve future epidemiological studies. More research with standardized methodologies is needed to better understand the true global burden of HPP.
Economic Burden
Limited information is available regarding the direct economic burden of hypophosphatasia (HPP) in the USA and Europe. The provided PubMed articles primarily focus on the clinical aspects of the disease, including its genetic basis, clinical manifestations, diagnostic criteria, and management, particularly with the recent development of enzyme replacement therapy.
One article mentions the development of clinical practice guidelines for HPP by a Japanese task force, highlighting the varied clinical manifestations and classification of HPP based on age of onset and severity. While this article does not provide specific cost estimates, it underscores the importance of appropriate management and treatment, which can have implications for healthcare resource utilization and costs.
It is important to note that HPP is a rare disease, and this rarity can make it challenging to collect sufficient data for comprehensive cost-of-illness studies. However, the availability of enzyme replacement therapy and the development of clinical practice guidelines suggest a growing recognition of the need for effective HPP management, which can have both clinical and economic benefits.
To gain a better understanding of the economic burden of HPP, future research should focus on conducting cost-of-illness studies specifically for HPP in the USA and Europe. These studies should consider both direct medical costs (e.g., diagnosis, treatment, hospitalizations) and indirect costs (e.g., lost productivity, informal caregiving) associated with the disease. Given the rarity of HPP, international collaborations may be necessary to pool data and obtain more robust estimates of the economic burden. Furthermore, research should explore the potential cost-effectiveness of enzyme replacement therapy and other management strategies for HPP, which can inform resource allocation decisions and improve patient access to optimal care.
Mechanism of Action
While the provided text discusses various drug mechanisms of action and clinical trials, it does not specifically mention Hypophosphatasia or the most common mechanisms of action in trials for this condition. Therefore, I cannot provide a direct answer to your question.
However, I can offer some related information gleaned from the text regarding drug development and clinical trials:
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Drug Mechanisms of Action: The text extensively covers different drug mechanisms of action, including:
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Enzyme inhibition: Many drugs work by inhibiting specific enzymes involved in disease processes. Examples include proteasome inhibitors, kinase inhibitors, histone deacetylase inhibitors, and monoamine oxidase inhibitors.
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Receptor modulation: Drugs can act as agonists, antagonists, or partial agonists at various receptors, affecting cellular signaling pathways. Examples include β-blockers, antipsychotics, glutamate receptor modulators, and GLP-1 receptor agonists.
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RNA interference: Antisense oligonucleotides (ASOs) and siRNAs can target RNA molecules, leading to mRNA degradation or altered protein production.
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Targeted drug delivery: Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic drugs specifically to cancer cells.
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Gene therapy: This approach involves using genetic material to treat or prevent disease.
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Clinical Trials: The text emphasizes the importance of clinical trials in evaluating drug efficacy and safety. It discusses different phases of clinical trials, trial designs, and the challenges associated with drug development.
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Drug Resistance: The text also highlights the issue of drug resistance, which can limit the effectiveness of therapies. Various mechanisms of resistance are discussed, including drug efflux, target alteration, and activation of compensatory pathways.
To find information specifically about Hypophosphatasia drug trials and their mechanisms of action, I recommend searching reputable sources such as PubMed, ClinicalTrials.gov, and the websites of organizations focused on Hypophosphatasia research.
Drug used in other indications
BE-102, also known as asfotase alfa, is currently not being formally trialed for indications other than hypophosphatasia (HPP). While some preclinical studies have explored its potential in other bone-related conditions, these have not progressed to human clinical trials.
Preclinical Studies:
One preclinical study investigated the effects of intermittent PTH (1-34) on the skeletal phenotype of TNAP-deficient Alpl mice, a model for HPP. The study found that PTH increased long bone volume but did not alter the skull phenotype. The authors suggested that PTH may have therapeutic value for adults with TNAP deficiency-associated osteoporosis. However, this has not been tested in human clinical trials.
Off-Label Use:
Although not part of formal clinical trials, there have been reports of off-label use of asfotase alfa in adults with HPP for the treatment of osteoporosis. One study mentioned the off-label use of teriparatide and anti-sclerostin antibody in selected adult HPP cases, demonstrating benefit in accelerating fracture healing and in concomitant treatment of osteoporosis. However, these are isolated cases and not part of systematic clinical trials.
Current Clinical Trials:
The vast majority of clinical trials involving asfotase alfa focus on HPP. These trials investigate different aspects of the disease, including:
- Efficacy and safety in different age groups: Trials have been conducted in infants, children, adolescents, and adults with HPP to evaluate the effectiveness and safety of asfotase alfa.
- Long-term outcomes: Studies have followed patients for up to 7 years to assess the long-term benefits and safety of asfotase alfa treatment.
- Pharmacokinetics and pharmacodynamics: Trials have investigated the pharmacokinetic and pharmacodynamic properties of asfotase alfa in different patient populations.
- Impact on specific clinical manifestations: Studies have evaluated the effects of asfotase alfa on respiratory function, growth, cognitive and motor function, and other clinical manifestations of HPP.
- Gene therapy: Preclinical studies have explored the use of gene therapy as an alternative to ERT for the treatment of HPP, and these may lead to future clinical trials.
It is important to note that off-label use or preclinical studies do not provide the same level of evidence as randomized controlled clinical trials. Therefore, while asfotase alfa may have potential in other conditions, further research is needed to confirm its efficacy and safety beyond HPP.