Cystic Fibrosis Therapy Developer Announces Initial Public Offering

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by Charles Moore |

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Boulder, Colorado based Nivalis Therapeutics, Inc., a clinical stage pharmaceutical company focused on treating people with cystic fibrosis (CF), recently announced its initial public offering (IPO) which included 5.5 million shares of common stock priced at $14.00 per share before underwriting discounts and commissions.

Nivalis additionally granted underwriters a 30-day option to purchase up to an additional 825,000 shares of common stock at the IPO price, less underwriting discounts and commissions. All shares of the common stock in this offering are being sold by Nivalis, and trading commenced on the NASDAQ Global Market on June 17, 2015 under the ticker symbol “NVLS.”

Cystic fibrosis is a rare, genetic, life-shortening disease that affects the lungs and digestive systems. Approximately 30,000 Americans are living with CF. Patients with CF typically have a shorter lifespan because of the disease, although average life expectancy is increasing with greater understanding of the disease and development of better treatments.

The reason why news of Nivalis’ IPO is significant to the CF community is that the company’s lead product candidate, N91115, represents a new inhibitor of S-nitrosoglutathione reductase (GSNOR) for treatment of cystic fibrosis that could treat the underlying cause of the disease. N91115 is an investigational small molecule that addresses the CFTR defect, which results from mutations in the CFTR gene, and is the underlying cause of CF. The company believes that N91115 is a first-in-class CFTR stabilizer that modulates CFTR activity through a novel mechanism of action that their researchers expect to be complementary to existing and future CFTR modulators.

Nivalis states that N91115 is the only clinical stage product candidate they know of designed to stabilize CFTR inside the cell and at the cell surface, and that they have shown in preclinical studies that the stabilizing effect of N91115 increases and prolongs CFTR activity when added to other CFTR modulators. The company’s clinical program initially targets CF patients who are homozygous of (have two copies of) the F508del-CFTR mutation or the F508gdel mutation. Currently, Nivalis is conducting a Phase 1b clinical trial evaluating the safety of N91115 when used as a single CFTR modulator in that cohort of patients.

N91115 orally administered in healthy volunteers has proven to be well-tolerated by CF patients with the F508del-CFTR mutation, which affects approximately 90 percent of all CF patients, causing them to produce an abnormal form of the CFTR protein, leading to an inability to properly transport fluid. Nivalis Therapeutics expects N91115 to not only increase CFTR function, but also restore the adequate hydration to critical organs, particularly in the lungs. Other preclinical studies had already demonstrated the compound’s efficiency in increasing the function of F508del-CFTR. “N91115 is the first oral GSNOR inhibitor to enter clinical development, representing an important step towards identifying treatments to address a disease with significant unmet need,” comments Nivalis Therapeutics board of directors chairman Howard Furst, M.D.

Nivalis has also developed a broad portfolio of proprietary, investigational, small molecule inhibitors of S-nitrosoglutathione reductase (GSNOR) which they say have been shown in preclinical studies to significantly increase and prolong CFTR activity and to decrease inflammation. The company’s drug candidate portfolio consists of multiple compounds suitable for oral, intravenous (IV), or inhaled administration. Endogenous S-nitrosoglutathione (GSNO) plays a critical role in modulating protein function through transfer of nitric oxide to a protein thiol group, or S-nitrosation.

In addition to developing innovative solutions that extend and improve the lives of people with cystic fibrosis, Nivalis plans to utilize its proprietary S-nitrosoglutathione reductase (GSNOR) inhibitor portfolio to develop therapeutics for patients with other diseases. Nivalis (formerly known as N30 Pharmaceuticals, Inc.) began operations in 2008 with an initial focus on administering exogenous GSNO as a potential therapeutic agent in asthma and CF. The company’s current name, Nivalis Therapeutics, is derived from the Latin term that means of snow — the relevance being that in the same way each individual snowflake is unique, the company believes that so too is each person with CF unique. With more than 1,800 known mutations of the gene responsible for CF, treating the disease requires solutions as unique as snowflakes.

Nivalis recently completed Phase 1 testing of an inhaled formulation of GSNO, as well as applied for and were granted Orphan Drug designation related to potential use of GSNO to treat CF in the United States.

While evaluating GSNO as a potential therapeutic intervention, Nivalis’s discovery efforts resulted in their identifying several novel small molecule inhibitors of GSNOR, the enzyme that breaks down naturally occurring GSNO in the human body. These small molecule inhibitors provided advantages as drug candidates, compared to the direct administration of GSNO, because GSNO is limited by route of administration, instability, and lack of intracellular penetration.

Although administering GSNO directly has shown potential as a therapeutic intervention in preclinical models of cystic fibrosis and other diseases, it is limited as a chronic therapy for several reasons including difficulty in formulation and administration. Depleted GSNO levels are believed to contribute to loss of airway function and pathology in CF lung disease due to dysregulated S-nitrosation. The S-nitrosation of certain proteins has been shown to modulate CFTR activity and decrease inflammation in preclinical human airway and animal models of disease. These targeted effects have been demonstrated to modify certain molecular chaperones, such as Hsp70/Hsp90 organizing protein or HOP which affect trafficking and stability of the F508del CFTR protein.

GSNO concentrations are regulated by GSNO reductase (GSNOR) an enzyme that breaks down GSNO. GSNOR, through its regulation of GSNO levels, plays a key role in pulmonary, gastrointestinal, and cardiovascular physiology and pathophysiology. Accordingly, Nivalis’s drug development strategy is based on the premise that inhibition of GSNOR will increase intracellular levels of GSNO by preventing its degradation, particularly in the setting of cystic fibrosis and other diseases that have decreased levels of GSNO and/or increased GSNOR.

Cowan and Company and Stifel are acting as joint lead book-running managers for the Nivalis IPO. Baird and H.C. Wainwright & Co. are acting as co-managers for the offering.

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Nivalis Therapeutics, Inc.
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