The landscape for rare pediatric diseases has long been overshadowed by the success stories of treatments for common adult conditions. However, a Florida-based radiopharmaceutical company, Advanced Innovative Partners (AIP), is venturing into uncharted territories, determined to bridge the gap for the thousands of children grappling with rare and often overlooked illnesses.

The Orphaned Battle: AIP’s Mission in Rare Pediatric Diseases

A rare or orphan disease is characterized by its low prevalence, affecting less than 6.5–10 cases in 10,000 people. The National Organization for Rare Disorders (NORD) and Orphanet are dedicated organizations working towards the betterment of individuals grappling with such rare conditions. Orphan drugs, designed for the diagnosis, prevention, or treatment of these orphan diseases, play a pivotal role in addressing the unique healthcare needs of this underserved population.

Highest Orphan Drug Prices as of 2016. Tribble, S.J., Lupkin, S. & Kaiser Health News. (2017). Drugmakers manipulate orphan drug rules to create monopolies. Spectrum News. Retrieved from spectrumnews.org/news/drugmakers-manipulate-orphan-drug-rules-create-monopolies.

The US Food and Drug Administration (FDA) actively contributes to the field by maintaining a comprehensive list of orphan drug designations and approvals. Within this realm, partial orphan drugs emerge, showcasing dual indications—serving both orphan and non-orphan purposes.

Top 10 Best-Selling Drugs in the U.S. as of 2015 – 7 of which were Orphan Drugs. Tribble, S.J., Lupkin, S. & Kaiser Health News. (2017). Drugmakers manipulate orphan drug rules to create monopolies. Spectrum News. Retrieved from spectrumnews.org/news/drugmakers-manipulate-orphan-drug-rules-create-monopolies.

So far, a staggering 7,000 rare pediatric diseases have been identified, yet a mere 5% boast FDA-approved pharmacotherapies. The term “orphan diseases” aptly characterizes these conditions, as the small patient populations render them commercially unattractive to pharmaceutical giants. This unfortunate reality translates into a lack of viable treatments, leaving afflicted children to contend with debilitating symptoms and truncated life expectancies.

Available diagnostic rates based on whole-exome sequencing in classes of paediatric genomic diseases. Wright, C., FitzPatrick, D. & Firth, H. Paediatric genomics: diagnosing rare disease in children. Nature Review Genetics 19, 253–268 (2018). doi: 10.1038/nrg.2017.116.
Technologies and methods to diagnose rare diseases when ES is unrevealing. Many of these technologies complement each other, fill the missing gaps, and should be analyzed in an integrated manner. The selection between metabolomics, proteomics, methyl profiling, and immune assays should be guided by the patient’s clinical presentation and existing candidate genes identified through sequencing. Functional studies can be used to validate strong candidate variants or elucidate the underlying molecular mechanism of the disease after identifying the causative gene. ES: Exome Sequencing, GS: Genome Sequencing, UN: unstimulated. These challenges can be at the level of interpretation or detection. GS: genome sequencing, ASE: allele-specific expression, VUS: variant of unknown significance. Marwaha, S., Knowles, J.W. & Ashley, E.A. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Medicine 14, 23 (2022). doi: 10.1186/s13073-022-01026-w.
Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland. New England Journal of Medicine (NEJM).

In response to this unmet need, AIP has positioned itself as a pioneer, harnessing its expertise in radiochemistry and drug development to craft a beacon of hope for families navigating the tumultuous waters of rare pediatric diseases. Dr. Stanley “Stan” Satz, Co-Founder, Chairman & Chief Scientific Officer of AIP, underscores the promise of radiopharmaceuticals in this domain, stating, “Radiopharmaceuticals are ideally suited for rare disease applications as they can selectively deliver radiation payloads directly to organs of interest.”

Challenges in identifying causal variants using exome or genome sequencing and the potential solutions and alternate approaches. These challenges can be at the level of interpretation or detection. GS: genome sequencing, ASE: allele-specific expression, VUS: variant of unknown significance. Marwaha, S., Knowles, J.W. & Ashley, E.A. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Medicine 14, 23 (2022). doi: 10.1186/s13073-022-01026-w.

Precision Beyond Measure: AIP’S Radiopharmaceutical Arsenal

AIP’s arsenal is built upon the strategic use of radioisotopes, including lutetium-177, copper-64, and gallium-68. These elements form the crux of diagnostic scans and treatments that hold the potential to revolutionize the landscape of rare pediatric diseases. By employing precision-targeted radiomedicines, AIP aims to unleash a profound impact on the lives of children grappling with these devastating conditions.

Schematic representation of the decay process. (a) Decay scheme of 177mLu to 177Lu. (b) Process of bond rupture. The metastable isomer 177mLu is coordinated to a very stable complex (left side). During the decay via internal conversion the nucleus excess of energy is transferred to an inner electron causing an auger electron cascade (center). After the cascade the atom is in a highly charge state, the chemical bonds are broken and the freed 177Lu can be separated (right side). Bhardwaj, R., van der Meer, A., Das, S., de Bruin, M., Gascon, J., Wolterbeek, H.T., Denkova, A.G. & Serra-Crespo, P. (2017). Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects. Scientific Reports 7, 44242 (2017). doi: 10.1038/srep44242
One of the first examples using in vivo positron emission tomography (PET) for noninvasive monitoring of copper-64 (64Cu)-radiolabeled polyethylene glycol (PEG)-modified exosomes, achieving excellent imaging quality and quantitative measurement of blood residence and tumor retention. PEGylation not only endowed exosomes with a superior pharmacokinetic profile and great accumulation in the tumor versus traditionally reported native exosomes but also reduced premature hepatic sequestration and clearance of exosomes, findings that promise enhanced therapeutic delivery efficacy and safety in future studies. Shi. S., Li, T., Wen, X. Wu, S.Y., Xiong, C., Zhao, J., Lincha, V.R., Chow, D.S., Liu, Y., Sood, A.K. & Li, C. (2019). Copper-64 Labeled PEGylated Exosomes for In Vivo Positron Emission Tomography and Enhanced Tumor Retention. Bioconjugate Chemistry 2019, 30(10): 2675-2683; doi: 10.1021/acs.bioconjchem.9b00587.
68Ga-radiolabeling of a DOTA-precursor. First, the reaction mixture is prepared by adding 68Ga eluate to a mixture consisting of a suitable buffer, precursor, and additives if necessary. Second, the reaction mixture is incubated for a specific reaction time and temperature to achieve 68Ga chelation. Third, the reaction mixture can be purified using a solid phase extraction (SPE) method. The 68Ga-radiopharmaceutical is trapped on the column while free 68Ga, 68Ge impurity, and buffer pass through the column and are discarded. Finally, the product is eluted and passed through a sterile filter as the fourth step (Meisenheimer et al. 2019). Nelson, B.J.B., Andersson, J.D., Wuest, F. & Spreckelmeyer, S. (2022). Good practices for 68Ga radiopharmaceutical production. EJNMMI Radiopharmacy and Chemistry 7, 27 (2022). doi: 10.1186/s41181-022-00180-1.

Targeting the Unseen Enemy: AIP’s Focus on Neuroendocrine Cancers

Among the array of rare pediatric diseases, AIP has zeroed in on the challenging terrain of rare neuroendocrine cancers, such as pheochromocytoma. Afflicting approximately 300 pediatric patients annually in the United States, these cancers demand innovative solutions.

A diagnostic algorithm for pheochromocytomas and paragangliomas (PPGLs). CT computed tomography, MRI magnetic resonance imaging, PET positron emission tomography, SPECT single-photon emission computed tomography, ¹²³I-MIBG¹²³iodine metaiodobenzyl guanidine. The 2016 European guidelines also recommend plasma or urine 3-methoxytyramine measurement in the initial biochemical screening. If metanephrines and 3-methoxytyramine are negative, plasma chromogranin A is recommended for screening in cases with a clinical probability. Pappachan, J.M., & Tun, N.N., Arunagirinathan, G. & Sodi, R. (2018).
Pheochromocytomas and Hypertension. Current Hypertension Reports 20(1). doi: 10.1007/s11906-018-0804-z.
Large right adrenal totally cystic pheochromocytoma. MRI coronal images represented by T1-WI FS enhanced (A) and T2-WI (B) show a cystic large adrenal mass with capsular contrast enhancement measuring 7 cm (arrows). Planar adrenal scintigraphy with 131I MIBG in anterior view at 48 h after tracer injection (C) shows inhomogeneous tracer uptake in the adrenal lesion, more evident in the capsular rim thickened on the left side (arrow). 18FDG PET-CT coronal image shows a hypodense large adrenal mass with regular margins (arrow) on unenhanced CT scan (D); hybrid fused PET-CT image (E) shows faint increased irregular FDG uptake only in the peripheral rim of the lesion as also confirmed by the extracted FDG image (F) (double arrows). Roberta Galatola, R., Attanasio, L., Romeo, V., Mainolfi, C., Klain, M., Simeoli, C., Modica, R., Guadagno, E., Aprea, G., Basso, L., Nicolai, E., Salvatore, M. & Maurea, S. (2021). Characterization of Atypical Pheochromocytomas with Correlative MRI and Planar/Hybrid Radionuclide Imaging: A Preliminary Study. Applied Sciences 2021. 11(20): 9666; doi: 10.3390/app11209666.

AIP’s foray into peptide receptor radionuclide therapy (PRRT) represents a promising avenue, honing in on receptors overexpressed on tumor cells to deliver targeted radiation. Check out this AIP – PRRT article for more details.

Navigating Unchartered Waters: AIP Explores Rare Metabolic Disorders

Beyond cancer, AIP is navigating uncharted waters in the realm of rare metabolic disorders. Wilson disease, characterized by toxic copper accumulation in the liver and brain, presents a formidable challenge.

Copper toxicity in the pathogenesis of WD. Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., Rybakowski, J.K., Weiss, K.H. & Schilsky, M. (2018). Wilson disease. Nature Reviews Disease Primers 4, 21 (2018). doi: 10.1038/s41572-018-0018-3.

AIP envisions a solution through copper-64 labeled agents, enabling both imaging and treatment. While the business case is undeniably challenging, AIP Co-Founder, CEO & President Roseanne “Rose” Satz, asserts the company’s commitment, stating, “For children and families afflicted with these conditions, new safe and effective therapies are nothing short of life-changing.”

Overview of the synthesis workflow from cyclotron to finished product. Tengzhi Liu, T., Redalen, K.R. & Karlsen, M. (2022). Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications. Journal of Labelled Compounds and Radiopharmaceuticals. doi: 10.1002/jlcr.3973.

AIP’s Radiopharmaceutical Symphony: A Creative Overture in Pediatric Medicine

AIP’s creative approach to radiopharmaceutical research and development emerges as a distinctive and harmonious melody in the grand symphony of pediatric medicine. The company’s unwavering commitment to innovation embodies the spirit of hope and progress, promising a brighter future for the countless children whose lives hang in the balance of groundbreaking treatments. As AIP takes center stage, it beckons a new era in pediatric medicine—one where precision and compassion converge to reshape the narrative of rare pediatric diseases.

About Advanced Innovative Partners (AIP)

Advanced Innovative Partners (AIP) emerges as a prominent global clinical-stage biotechnology company, standing at the forefront of diagnostic and therapeutic advancements in the realm of targeted radiation. Founded in 2017, AIP boasts a skilled team with expertise spanning biotechnology, nuclear medicine, and molecular biology. Their commitment lies in the development of next-generation diagnostic and therapeutic radiopharmaceuticals, addressing critical needs in oncology, rare pediatric diseases, infectious diseases, and biomedical countermeasures.

At the heart of AIP’s operations is a robust pipeline, extending its reach to breast, lung, brain, and solid tumor cancers, as well as rare diseases. AIP navigates this expansive landscape with a reliable, secure global supply chain and a collaborative network, ensuring the seamless progression of their innovative products from development to delivery.

With lead programs advancing through Phase I/II/III clinical trials, AIP positions itself as a leader in the emerging market space of radiopharmaceutical diagnostics and therapeutics. The company’s success is underpinned by patented platform technologies that underscore their commitment to excellence in treatment and clinical management. AIP’s approach is product-centric, reflected in the creation of a pipeline comprising multiple drugs strategically targeting areas with significant market opportunities.

AIP’s mission revolves around expediting the discovery, development, and global availability of transformative therapies. Their focus extends beyond innovation, emphasizing the importance of rigorous clinical trials mandated by regulatory bodies. By navigating these regulatory pathways and obtaining approvals, AIP aims to make their investigational products accessible to patients worldwide.

Central to AIP’s identity is a dedication to pioneering targeted therapies and advancing disease detection and treatment. This commitment unfolds through a comprehensive, integrated approach encompassing proprietary tech platforms, strategic partnerships, and an unwavering patient-centric focus. AIP’s ultimate goal is to profoundly impact patient journeys by enabling accurate diagnoses at an earlier stage and providing treatments that are not only more powerful but also gentler, thereby offering patients the best chance for improved outcomes. In essence, AIP aspires to make a meaningful difference for individuals grappling with complex, aggressive, rare, and infectious diseases worldwide.

Learn more about AIP from their Official Website.

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES

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