by NAMPT inhibitors are a class of investigational drugs that work by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), an enzyme that regulates NAD+ biosynthesis in the body. NAMPT catalyzes the rate-limiting step in one of the primary NAD+ salvage pathways in mammals. By blocking NAMPT, these drugs aim to decrease cellular NAD+ levels and disrupt various NAD+-dependent processes and pathways involved in diseases.
How Do Nicotinamide Phosphoribosyltransferase Inhibitors Work?
Inside human cells, there are two main routes for generating NAD+ – de novo biosynthesis pathway and salvage pathway. The salvage pathway, which utilizes nicotinamide (NAM) as a precursor, is the major source of NAD+ production under normal physiological conditions. NAMPT plays a key role in this salvage pathway by catalyzing the synthesis of nicotinamide mononucleotide (NMN) from NAM and 5-phosphoribosyl-1-pyrophosphate (PRPP).
Nicotinamide phosphoribosyltransferase inhibitors work by selectively binding to and blocking the active site of NAMPT Inhibitors, inhibiting its enzymatic activity. This leads to reduction of NMN and subsequently NAD+ levels inside cells as the salvage pathway is disrupted. With decreased NAD+, various NAD+-dependent processes and pathways regulated by NAD+ consuming enzymes like sirtuins and PARPs cannot function optimally. This metabolic alteration forms the basis of how Nicotinamide phosphoribosyltransferase inhibitorsexert their pharmacological effects.
Potential Applications Of NAMPT Inhibitors
Considering the central role of NAD+ in cellular metabolism and various diseases, Nicotinamide phosphoribosyltransferase inhibitors are being studied for their therapeutic potential in several clinical areas:
Cancer
Rapidly proliferating cancer cells have increased demand for NAD+ to support biosynthesis and maintain redox homeostasis. Nicotinamide phosphoribosyltransferase inhibitors can selectively induce cancer cell death by further depleting their NAD+ levels. Studies show these drugs have preclinical activity against various solid and hematological tumor types as single agents or in combination with standards of care. Several Phase I/II trials in different cancers are ongoing.
Inflammatory Diseases
NAD+-metabolizing enzymes that regulate inflammation like CD38 and PARPs depend on NAD+ levels. NAMPT inhibitors hold promise for autoimmune and inflammatory diseases by calming hyperactive immune responses. Preclinical studies demonstrate their potential in arthritis, colitis, multiple sclerosis, etc. Phase I trial results in psoriasis showed acceptable safety profile.
Metabolic Diseases
Maintenance of NAD+ and its effector pathways is crucial for metabolic regulation. Preliminary evidence indicates Nicotinamide phosphoribosyltransferase inhibitors may improve glucose homeostasis, lipid metabolism, mitochondrial function in obesity, diabetes and non-alcoholic fatty liver disease models. More research is warranted to establish their roles as therapeutic options.
What Are The Clinical Trial Results So Far?
The lead NAMPT inhibitors clinical candidate is FK866, developed by Forma Therapeutics. Here are some key results from FK866 trials to date:
– Phase I studies established its safety, tolerability and pharmacokinetics in over 200 healthy volunteers and cancer patients. Dose-dependent NAD+ depletion was seen.
– Monotherapy Phase Ib/II trial in acute myeloid leukemia showed anti-leukemic activity, especially in IDH mutant and FLT3-ITD positive subgroups.
– Phase II trial in combination with axitinib for advanced renal cell carcinoma met its primary efficacy endpoint with manageable safety.
– Phase I trial combining FK866 with PD-1 inhibitor pembrolizumab in advanced solid tumors reported encouraging response rates and durability.
– Ongoing Phase I trial is assessing FK866 combined with standard regimens in lung, breast and other cancers.
– Phase Ib trial results presented for FK866 in psoriasis showed relief from skin lesions and acceptable safety at tested doses.
Overall, FK866 appears reasonably well-tolerated with mostly low-grade adverse effects. Clinical efficacy signals warrant its further development alone or with other agents. More data is awaited from ongoing trials.
- By targeting the crucial NAD+ salvage enzyme NAMPT, NAMPT inhibitors represent an innovative therapeutic approach with broad applicability. Although still in early stages of clinical research, they have demonstrated preliminary anti-cancer activity and effects on inflammation. With their novel mechanism of metabolic modulation, these oral drugs may offer an efficacious treatment option, either alone or in combinations, for cancers and other diseases in the future. Further clinical studies are expected to better characterize the full potential of this new drug class.
*Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author - Alice Mutum
Alice Mutum is a seasoned senior content editor at Coherent Market Insights, leveraging extensive expertise gained from her previous role as a content writer. With seven years in content development, Alice masterfully employs SEO best practices and cutting-edge digital marketing strategies to craft high-ranking, impactful content. As an editor, she meticulously ensures flawless grammar and punctuation, precise data accuracy, and perfect alignment with audience needs in every research report. Alice's dedication to excellence and her strategic approach to content make her an invaluable asset in the world of market insights. LinkedIn
