NAMPT (nicotinamide phosphoribosyltransferase), also known as visfatin or pre-B cell colony-enhancing factor (PBEF), is an enzyme involved in mammalian NAD+ biosynthesis. NAMPT catalyzes the rate-limiting step in the mammalian NAD+ salvage pathway by converting nicotinamide to nicotinamide mononucleotide (NMN). Nicotinamide phosphoribosyltransferase inhibitors are a new class of drugs that work by inhibiting this NAMPT enzyme, thereby blocking NAD+ biosynthesis in cancer cells.
Impact On Cancer Metabolism
Cancer cells exhibit increased metabolic needs compared to normal cells to support their rapid proliferation. They meet these high metabolic demands partly by upregulating the NAD+ salvage pathway mediated by NAMPT. Inhibiting NAMPT Inhibitors impairs this crucial source of NAD+ for cancer cells, significantly impacting their metabolism and survival. Depriving cancer cells of NAD+ is an attractive therapeutic strategy since NAD+ plays a central role in many cellular processes like glycolysis, mitochondrial function, and DNA repair - all of which are dysregulated in cancer.
Potential As Anti-Cancer Agents
Several preclinical studies have demonstrated potent anti-tumor activity of NAMPT inhibitors as single agents and in combination with other anti-cancer drugs across various cancer types. They cause metabolic catastrophe in cancer cells by depleting NAD+ levels, inhibiting glycolysis and disrupting mitochondrial function. This results in increased reactive oxygen species production, DNA damage, and eventual cancer cell death through mechanisms like necrosis or autophagy. The promising anti-tumor efficacy of Nicotinamide phosphoribosyltransferase inhibitors seen in animal models has translated to early clinical trials establishing their potential as anti-cancer therapeutics.
Leading Nicotinamide Phosphoribosyltransferase Inhibitors Drugs
FK866 (APO866) was the first Nicotinamide phosphoribosyltransferase inhibitors developed. It demonstrated robust anti-tumor activity in preclinical studies. However, it had formulation challenges and troublesome side effects in clinical trials. This led to the development of next-generation orally bioavailable Nicotinamide phosphoribosyltransferase inhibitors with improved pharmacokinetic and safety profiles.
Some Of The Leading NAMPT Inhibitors Drugs Currently In Clinical Trials Include:
- GMX1777 (EŌS-850) - Developed by Gemogenetics and currently in Phase 1/2 trials for solid tumors and lymphoma. It has shown an acceptable safety profile and signs of clinical responses.
- BMN673 - Developed by BioMedicine and currently in Phase 1 trials for solid tumors and lymphomas. It has a favorable pharmacokinetic profile and signals of clinical anti-tumor activity.
- CHS-828 - Developed by Calithera Biosciences and currently in Phase 1 trials. It has shown preliminary anti-cancer activity and tolerability in patients with advanced solid tumors.
Clinical Trial Progress And Outcomes
While trials with early generation Nicotinamide phosphoribosyltransferase inhibitors FK866 and GMX0120 saw dose-limiting toxicities, next-gen candidates have exhibited better safety profiles in ongoing Phase 1 studies. They are generally well-tolerated with mostly low-grade adverse events reported. Dose escalation is ongoing to establish maximum tolerated and recommended Phase 2 doses.
Some patients with diverse cancer types including hepatocellular carcinoma, colorectal cancer, lymphoma, etc. have shown clinical responses and disease stabilization based on immune-related response criteria. Promising Phase 1 efficacy results have prompted expansion cohorts to further evaluate responses. Combination studies evaluating Nicotinamide phosphoribosyltransferase inhibitors along with immunotherapy or other metabolic modulating agents are also actively recruiting patients.
Based on accumulating clinical data, NAMPT inhibitors appear to be differentiating themselves from earlier candidates and demonstrating therapeutic potential. Developers are optimistic these agents could offer meaningful clinical benefits either as monotherapy or in combination regimens, pending outcomes from ongoing and planned late-stage trials.
Future Directions And Commercial Prospects
With novel mechanisms targeting cancer metabolism, Nicotinamide phosphoribosyltransferase inhibitors represent a promising new class of anti-cancer drugs. If ongoing and planned clinical studies establish their safety and efficacy profiles, major pharmaceutical companies may become interested in these assets given the large oncology opportunities. Developers are hoping to progress lead candidates into pivotal trials and partnerships over the next few years based on Phase 1 results.
While more research is still needed, NAMPT inhibitors could potentially help address unmet needs across several cancer types either as single agents or in combinations. Their commercial prospects will depend on demonstrating meaningful clinical benefits compared to existing standard-of-care regimens. Developers and research institutions worldwide continue advancing this new therapy class through collaborative clinical trials and projects aimed at fully elucidating the role of NAMPT inhibition in cancer treatment.
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Author Bio:
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: www.linkedin.com/in/alice-mutum-3b247b137 )
*Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it