Periodic Reporting for period 1 - RAPID (The first effective remedy for acute pancreatitis disease)
Berichtszeitraum: 2019-05-01 bis 2019-10-31
The project RAPID is based on a family of small molecules called Pyrtriazoles, able to work actively on SOCE process. SOCE mechanism relates to the cross-talk between intracellular organelles and the plasma membrane, and allows for the refilling of the depleted organelles, through calcium ion-flux. The principal components of SOCE are a Ca2+-sensor on the ER membrane (STIM) and a plasma membrane Ca2+-channel (ORAI).
It has been reported that SOCE hyper-activation leads to calcium overload in pancreatic acinar cells (PACs), representing a key trigger for injury and necrosis in Acute Pancreatitis (AP). Furthermore, genetic defects of STIM and ORAI proteins can lead to genetic disorders to skeletal muscles and platelets. Pathologies associated are mainly four:
• Acute Pancreatitis (AP)
• Stormorken syndrome (STRMK)
• York platelet syndrome (YPS)
• Tubular Aggregate Myopathy (TAM)
While AP affects over 10 million people worldwide, the other three syndromes are extremely rare (estimates of about 1/250.000 for TAM and 1/1.000.000 for Stormorken and York platelet syndromes).
Acute Pancreatitis (AP) is the most common gastroenterology discharge diagnosis in Europe and in the US, leading to tremendous emotional, physical, and financial burden.
Gallstones are the most common cause, together with alcohol abuse, hypertriglyceridemia, genetic causes and drug intake. AP is associated with significant disease burden, emergency room visits, frequent hospitalizations, and patients often undergo endoscopic and surgical procedures and are admitted to intensive care.
Despite the great advances in critical care medicine over the past 20 years, the mortality rate of AP has remained high, between 1.5% and 4.2% and deaths are mainly due to failure of multiple organ systems (respiratory, cardiovascular or renal), exacerbation of pre-existing disorders and pancreatic and extra-pancreatic infections. The main clinical and societal need is that for this disease there is no effective pharmacological treatment. Indeed, the current management of AP is supportive, symptomatic and limited to pain relief, nutritional support and fluid resuscitation. Surgery is useful, but limited to pancreatitis due to gallstones, while antibiotics may help only in those episodes where an infection isdocumented.
Finally, invasive techniques indicated for AP management, such as endoscopic retrograde cholangiopancreatography (ERCP), can themselves trigger further episodes of pancreatitis. Overall, long hospitalizations, high-quality supportive and intensive care, surgical and diagnostic procedures, complications and relapses lead to disproportionately high healthcare costs, and it is estimated that about 2.5 B€ are spent annually in Europe in taking care of patients with AP.
Therefore, AP is a disorder with a high medical need, and the introduction of an effective pharmacological treatment would provide high value to patients as well as be cost-effective for payers as it would (i) prevent relapses or chronicization in those patients at high risk; (ii) reduce mortality rate and disability; (iii) reduce direct hospitalizations costs in intensive care units.
It has been reported that SOCE hyper-activation leads to calcium overload in pancreatic acinar cells (PACs), representing a key trigger for injury and necrosis in Acute Pancreatitis (AP). Furthermore, genetic defects of STIM and ORAI proteins can lead to genetic disorders to skeletal muscles and platelets. Pathologies associated are mainly four:
• Acute Pancreatitis (AP)
• Stormorken syndrome (STRMK)
• York platelet syndrome (YPS)
• Tubular Aggregate Myopathy (TAM)
While AP affects over 10 million people worldwide, the other three syndromes are extremely rare (estimates of about 1/250.000 for TAM and 1/1.000.000 for Stormorken and York platelet syndromes).
Acute Pancreatitis (AP) is the most common gastroenterology discharge diagnosis in Europe and in the US, leading to tremendous emotional, physical, and financial burden.
Gallstones are the most common cause, together with alcohol abuse, hypertriglyceridemia, genetic causes and drug intake. AP is associated with significant disease burden, emergency room visits, frequent hospitalizations, and patients often undergo endoscopic and surgical procedures and are admitted to intensive care.
Despite the great advances in critical care medicine over the past 20 years, the mortality rate of AP has remained high, between 1.5% and 4.2% and deaths are mainly due to failure of multiple organ systems (respiratory, cardiovascular or renal), exacerbation of pre-existing disorders and pancreatic and extra-pancreatic infections. The main clinical and societal need is that for this disease there is no effective pharmacological treatment. Indeed, the current management of AP is supportive, symptomatic and limited to pain relief, nutritional support and fluid resuscitation. Surgery is useful, but limited to pancreatitis due to gallstones, while antibiotics may help only in those episodes where an infection isdocumented.
Finally, invasive techniques indicated for AP management, such as endoscopic retrograde cholangiopancreatography (ERCP), can themselves trigger further episodes of pancreatitis. Overall, long hospitalizations, high-quality supportive and intensive care, surgical and diagnostic procedures, complications and relapses lead to disproportionately high healthcare costs, and it is estimated that about 2.5 B€ are spent annually in Europe in taking care of patients with AP.
Therefore, AP is a disorder with a high medical need, and the introduction of an effective pharmacological treatment would provide high value to patients as well as be cost-effective for payers as it would (i) prevent relapses or chronicization in those patients at high risk; (ii) reduce mortality rate and disability; (iii) reduce direct hospitalizations costs in intensive care units.
From a scientific point of view, ChemICare demonstrated the drug-likeness of the compound RAPID was verified in vivo by evaluating different parameters, in particular pharmacokinetics and its tolerability
All the findings obatined demonstrated that RAPID was suitable as a lead compound for systemic use as it appeared stable, selective for SOCE and tolerated in vivo.
Furthermore, other milestones achieved in this Phase 1 project are the following:
- Feasibility Study: the team interacted with different stakeholders involved in the AP treatment sector, in particular gastroenterologists, patients and CROs. Moreover, a deep literature research was performed to better understand the global impact of AP, with the aim to analyse if this indication could become of interest for ChemiCare business.
- ChemiCare started the process toward the Orphan Drug Designation to the COMP in 20/06/2019. To do this the company registered an EMA account and ChemiCare was recognized as SME. It took about two months to be able to access the IRIS platform, which is required to submit a new application.
- IP Strategy:ChemiCare is working toward the protection of a new compound family able to modulate the SOCE mechanism. According to the reported claims, the new products can have a large pool of indications, including AP, TAM, STRMK, YPS, but even others such as inflammatory diseases, autoimmune diseases, cancer and other proliferative diseases, neurodegenerative disorders, myelodysplastic syndromes. The patent will be submitted in January 2020 by the Università degli Studi del Piemonte Orientale, with which ChemiCare already has a commercial deal for exploitation of IP.
All the findings obatined demonstrated that RAPID was suitable as a lead compound for systemic use as it appeared stable, selective for SOCE and tolerated in vivo.
Furthermore, other milestones achieved in this Phase 1 project are the following:
- Feasibility Study: the team interacted with different stakeholders involved in the AP treatment sector, in particular gastroenterologists, patients and CROs. Moreover, a deep literature research was performed to better understand the global impact of AP, with the aim to analyse if this indication could become of interest for ChemiCare business.
- ChemiCare started the process toward the Orphan Drug Designation to the COMP in 20/06/2019. To do this the company registered an EMA account and ChemiCare was recognized as SME. It took about two months to be able to access the IRIS platform, which is required to submit a new application.
- IP Strategy:ChemiCare is working toward the protection of a new compound family able to modulate the SOCE mechanism. According to the reported claims, the new products can have a large pool of indications, including AP, TAM, STRMK, YPS, but even others such as inflammatory diseases, autoimmune diseases, cancer and other proliferative diseases, neurodegenerative disorders, myelodysplastic syndromes. The patent will be submitted in January 2020 by the Università degli Studi del Piemonte Orientale, with which ChemiCare already has a commercial deal for exploitation of IP.
The Phase 1 study helped ChemiCare to better understand the potential value of RAPID and carry out the activities related to drug development and Orphan Designation application. During this period the team was able to interact with many stakeholders that have been working for years in this sector and therefore evaluated different strategies to exploit RAPID potential value.
The future Roadmap of ChemiCare includes different steps and milestones.
The main focus today is to validate through systematic preclinical and clinical trials on animals and humans the efficacy of RAPID on the identified treatment of pathologies such as AP, STRMK, YPS and TAM.
To this aim, the first step is the completion of Orphan Drug Designation, which is expected to take about 6-9 months. In parallel the company will continue the preclinical trials on animals (mainly mice) with the objective to be ready to start clinical trials in 2021. After 1 year of Phase 1 and two years of Phase 2/3 trials, if results confirm the safety and efficiency of the drug, RAPID will receive the CE mark allowing ChemiCare to start selling in Europe. The revenue stream coming from this first line of sales will fuel the continuation of activities towards company enlargement. This activity will include the FDA submission to enlarge the target market to the US.
Moreover, ChemiCare started studying the cost-benefit ratio of RAPID compared to existing treatments, in order to be eligible for National Reimbursement in many countries, lowering the price burden on patients.
The future Roadmap of ChemiCare includes different steps and milestones.
The main focus today is to validate through systematic preclinical and clinical trials on animals and humans the efficacy of RAPID on the identified treatment of pathologies such as AP, STRMK, YPS and TAM.
To this aim, the first step is the completion of Orphan Drug Designation, which is expected to take about 6-9 months. In parallel the company will continue the preclinical trials on animals (mainly mice) with the objective to be ready to start clinical trials in 2021. After 1 year of Phase 1 and two years of Phase 2/3 trials, if results confirm the safety and efficiency of the drug, RAPID will receive the CE mark allowing ChemiCare to start selling in Europe. The revenue stream coming from this first line of sales will fuel the continuation of activities towards company enlargement. This activity will include the FDA submission to enlarge the target market to the US.
Moreover, ChemiCare started studying the cost-benefit ratio of RAPID compared to existing treatments, in order to be eligible for National Reimbursement in many countries, lowering the price burden on patients.