Navitor Pharmaceuticals age gracefully

[Photo by Glen Hodson on Unsplash]

Officials at Navitor Pharmaceuticals (Cambridge, Mass.) think they could help people increase their healthy years by developing more targeted therapeutics.

Products from its pipeline may soon pave the way for more effective treatments for conditions such as kidney disease, but how could the company shape the way we look at “aging gracefully?”

Drug Discovery & Development recently interviewed Navitor CEO Thomas E. Hughes for more insight into the organization and specifically, NV20494 — one of its lead product candidates.

Drug Discovery: Can you describe your personal background and the role you play at Navitor?

Hughes: I’ve spent the majority of my career [in] drug discovery and development, with a focus on diseases that have a basis in aging and nutrition. … I joined Novartis as a postdoctoral fellow in the late 1980s and worked there for almost 21 years. I spent the bulk of that time working in metabolic diseases: Type 2 diabetes, obesity, NASH, and related disorders. … I left Novartis in 2008 to start a more entrepreneurial chapter, as CEO of Zafgen Pharmaceuticals, a Cambridge startup focused on a novel strategy for the treatment of obesity (also diabetes and rare diseases including Prader Willi syndrome). Together with the Zafgen team we took the company public in 2014, and advanced the lead molecule into pivotal trials. Unfortunately, we encountered a series of serious adverse events that led to closure of the program, and ultimately the company. Given that I was advising a number of metabolic — and age-related disease biotechs — I was in a good position to move to a company in the area (Navitor) that is focused on the importance of dysregulated cellular metabolism in a range of diseases that are impacted by mTORC1, which is the target we are focused on at Navitor. We’ve set the company strategy around renal and brain indications and are moving our second program to the clinic in the coming months.

Drug Discovery: What is the primary mission of Navitor Pharmaceuticals?

Hughes: Navitor is dedicated to developing targeted therapeutics designed to help patients increase their healthy years for uninterrupted quality of life. Navitor’s proprietary drug discovery platform enables specific modulation of mTORC1, the gatekeeper of cellular metabolism and renewal, to address the disease processes that underlie a wide range of diseases, including prevalent conditions like depression, heart failure, chronic kidney disease and less common genetic disorders like polycystic kidney disease or rare forms of epilepsy. Research has shown that increased mTORC1 activity lies at the center of a wide range of diseases including age-related diseases such as chronic kidney diseases, diabetes, heart failure, neurodegenerative disorders and more.

Drug Discovery: What are some of the diseases with an unmet medical need that your company’s mTORC1 inhibitors could potentially treat? 

Hughes: Our propriety Navalog platform is oriented to the discovery of fully selective mTORC1 inhibitors that have unique tissue distribution characteristics.  This allows us to target conditions impacting certain organs like the brain, liver, kidney, and skeletal muscle. Beyond kidney diseases, there is a very strong mechanistic rationale for mTORC1 inhibition as a strategy to treat a range of brain disorders.  Navitor’s program is unique in that it will generate the first fully selective mTORC1 inhibitor that has meaningful and reliable brain exposure. There is a very strong rationale for inhibiting mTORC1 in the brain, both for rare genetic forms of epilepsy and focal cortical dysplasia that are driven by activating mutations in the genes that constitute the mTORC1 regulatory mechanisms, and for prevalent neurodegenerative disorders. Strategically, the company is focused initially on rare diseases with genetic links to mTORC1; broader indications provide life-cycle management options.

Drug Discovery: Can you explain Navitor’s ‘Navalogs’ and elaborate on the functionality of NV-20494?

Hughes: mTORC1 selectivity allows full titration of desired mTORC1 inhibition by avoiding limitations related to mTORC2 inhibition such as dyslipidemia and insulin resistance, immunosuppression and adverse effects on some cell types in the kidney. Current compounds lack selectivity and as such cannot be used at doses leading to robust mTORC1 inhibition. Our Navalogs are unique and leverage chemical modifications of the core rapamycin structure that were identified during a very thorough evaluation of the mTORC1 structure. By accessing unique interactions in the complex, we achieve complete selectivity for mTORC1, which has previously not been possible. The individual molecules in our Navalog class have a range of properties that differentiation of molecules for use in different indications. Our initial indication focus — for our lead inhibitor NV-20494 — is autosomal dominant polycystic kidney disease (ADPKD). There is a uniquely strong fit to this indication for NV-20494, given that it addresses the kidney well after oral administration, and given the genetic linkage between the key gene implicated in ADPKD and mTORC1 dysregulation. Treatment of animal models of kidney disease including ADPKD with well-tolerated doses of NV-20494 leads to reduction of inflammation and fibrosis, and a reduction of cyst volume in the setting of ADPKD.

Drug Discovery: Can you provide more insight into the potential of NV-20494 and how it may address various kidney diseases?

Hughes: Polycystin 1 (PKD1) genetic mutations underlying ADPKD substantially increase mTORC1 activity, causing progressive enlargement and ultimately failure of the kidneys through formation of cysts and fibrous tissue. Patients with ADPKD experience a range of life-limiting effects of the disease and often progress to dialysis or kidney transplants at some point in their life. Today there are few treatment options for patients with ADPKD, and there is substantial need for new therapies. Human trials have shown reduced cyst volume following treatment with everolimus, a non-selective mTORC1/mTORC2 inhibitor, but at doses that were either not well-tolerated or were only marginally effective due to dosing limitations associated with mTORC2 inhibition. Navitor believes that NV-20494, the selective mTORC1 inhibitor from the Navalog class of compounds, will be better tolerated and allow for more effective kidney mTORC1 inhibition than non-selective inhibitors. This could represent a breakthrough in the treatment of ADPKD both as a potential standalone agent and in combination with current standard of care.

Drug Delivery: Can you explain how and why you believe NV-20494 will be better tolerated and more effective in patients, compared to the use of non-selective inhibitors?

Hughes: Early mTORC inhibitors have shown limited clinical benefits due to side effects related to the non-selectivity of these compounds for mTORC2 vs. mTORC1. Dose-limiting side effects include metabolic issues like hypertriglyceridemia and insulin resistance/diabetes, immunosuppression, and adverse effects on kidney function. By eliminating the mTORC2 effects we anticipate that the compounds will be significantly better tolerated and that it will be possible to attain a more reliable inhibition of mTORC1 activity. In animal models, we are able to dose to much higher levels with our compounds without the dose-limiting effects seen with prior generations of mTORC inhibitors, such as everolimus and rapamycin.

Drug Discovery: What else is Navitor focused on right now? (e.g., age-related diseases, kidney diseases, mental health-related conditions)

Hughes: While we see a broader opportunity to address age-related diseases, our current strategy is to focus on readying NV-20494 for clinical studies next year and development in ADPKD and to establish the breadth of the chemical class, especially for CNS indications.  We have also recently partnered with Supernus for NV-5138; the two companies will jointly conduct a Phase 2 clinical program for NV-5138 in treatment-resistant depression (TRD).

Drug Discovery: Which areas have already shown the most promise? What have been the most challenging diseases for Navitor to address?

Hughes: The most challenging aspect of mTORC1 have proven to be selectivity, which is something we now have a handle on with the Navalog class.  This opens up diseases for which mTORC1 inhibition simply wasn’t possible due to the lack of complete selectivity of prior generations of compounds, especially the kidney which is very sensitive to mTORC2 inhibition. NV-20494 has the potential to be a very exciting molecule.  It will be the first fully selective mTORC1 inhibitor to be studied in humans. So far, the data in animal models is very encouraging, especially for the treatment of ADPKD. The second challenge — which represents the final frontier for mTORC1 — is achieving reliable and fully selective inhibition in the brain. Existing compounds are poorly exposed to the brain. Our next-generation Navalogs may represent the first example of compounds that provide access to the brain, opening up the possibility of treating a range of challenging diseases. It’s an exciting time at Navitor.