Hepatotoxicity

• North America and Europe Dominate, Asia-Pacific Witnesses Rapid Growth
  Steady Increase in Average Drug Development Cost and Efforts to Mitigate Late-Stage Drug Failure Rates Highlights the Role of ADME-Toxicology Testing: Average Cost of Drug Development (in US$ Billion) in the US since 1980s
  actors Leading to Failure of Drugs in Phase III Clinical Trials: Percentage Breakdown of Number of Cases for Efficacy, Pharmacokinetics, Toxicity and Others
  Drug Withdrawals Due to Toxicity Issues (1990-early 2010s): Percentage Share Breakdown of Number of Drugs Withdrawn Due to Cardiotoxicity, Hepatotoxicity and Others
  World R&D Market by Geographic Region (2020): Percentage Breakdown of R&D Spending for Asia, Europe, Middle East & Africa, North America and South America
  Growth Momentum Shifts Away from In Vivo Technologies; In Vitro Technologies to Lead the Charge
  Global Cell-based Assays Market by Segment (2020): Percentage Share Breakdown of Value Sales for Consumables, Instruments, Software, and Services
  Global Market for Cell-based Assays by End-User (2020): Percentage Share Breakdown of Value Sales for Pharma & Biotech Companies, Government & Academic Institutes, CROs, and Others
  World Cell-based Assays Market by Application (2020): Percentage Breakdown of Revenue for ADME, Basic Research and Drug Discovery
  Personalized Treatments & Computational Tools: Intriguing Facets of ADME R&D ADME Pharmacogenomics to Power Personalized Treatments

• AGEN2373 demonstrated objective responses, clinical benefit, and was well tolerated in heavily pre-treated patients with solid tumors.
• “AGEN2373 has shown meaningful single agent activity and a favorable safety profile without evidence of liver toxicity in patients with heavily pretreated cold and immunotherapy resistant tumors,” said Dr. Steven O’Day, MD, Chief Medical Officer at Agenus.
• “AGEN2373 is designed to selectively boost tumor immunity while limiting hepatotoxicity and off-target effects associated with systemic CD137 activation.
• Presently, AGEN2373 is being evaluated in combination with botensilimab (multi-functional anti-CTLA-4) at a dose of 10 mg/kg in patients with PD-(L)1 refractory melanoma.

• The CRL raised a concern regarding the increased risk of thromboembolic events, driven by vascular access thrombosis (VAT).
• Accordingly, Akebia plans to include post-approval data from Japan in the NDA resubmission, where tens of thousands of Japanese patients with CKD have been exposed to vadadustat to date.
• The OND's letter provides guidance on a path for the resubmission of our NDA and potential approval of vadadustat for dialysis dependent patients in the U.S. without suggesting the need to generate additional clinical data.
• We appreciate the FDA's engagement with us throughout the appeal process," said John P. Butler, Chief Executive Officer of Akebia.

• But arriving at the beach to find water that’s green, red or brown, and possibly foul-smelling, can instantly spoil the party.
• I’ve conducted research into early detection of harmful algal blooms, or HABs, which are an increasing threat to humans, animals and the environment.
• Toxins produced during these blooms have been implicated in human and animal illnesses in at least 43 states.

Tiny organisms, big impacts

• Algae and cyanobacteria – often called blue-green algae – are simple, plantlike organisms that live in water.
• They can grow out of control, or “bloom,” especially when the water is warm and slow moving.
• Climate change is making water bodies warmer, increasing the risk of HABs.
• The other major factor that drives blooms is high levels of nutrients like nitrogen and phosphorus, which fertilize algae.

An array of toxins

• As with many environmental exposures, children and older people may be especially sensitive to HAB toxins.
• People who regularly consume seafood caught in HAB-prone areas are also at risk of long-term health effects from potentially frequent, low-level exposures to HAB toxins.

Recognizing and responding to HABs

• If you are unsure whether a bloom is harmful or not, contact your local health department or environmental agency for guidance.
• If you see signs of a bloom, stay out of the water and keep your pets out of the water.
• It’s important to be aware that cooking contaminated seafood or boiling contaminated water does not destroy the toxins.

Be informed

• The U.S. Centers for Disease Control and Prevention provides resources and recommendations related to HABs and ways to stay safe.
• Pet owners should also learn how to protect their dogs from HABs.
• Many states conduct HAB monitoring programs, especially in areas that are known to be vulnerable to blooms, such as western Lake Erie.

What’s being done about HABs?

• Many efforts are underway to prevent, control and mitigate HABs and provide early warnings to water system managers and health officials.
• One example in the U.S. is the
  Cyanobacteria Assessment Network, or CyAN, a collaborative effort across several government agencies to develop an early warning indicator system to detect algal blooms in freshwater systems.
• At the global scale, the Harmful Algal Information System will eventually include harmful algal events and information from harmful algae monitoring and management systems worldwide.