Three-year-old Rasna Therapeutics Inc. took the reverse merger route to the public markets, joining with Canadian travel company Active With Me Inc. to gain a listing on the Over-the-Counter Pink market, where it will continue to trade, for now, under the ticker ATVM.

Although no funds changed hands, the listing was seen as the first step in what the company envisions as a much bigger expedition.

"By this time next year, we expect to have strong clinical data in hand that will allow us to reach out to investors," said James Tripp, the company's acting CEO.

In 2013, serial biotech entrepreneur Gabriele Cerrone, founder and executive chairman of Tiziana Life Sciences plc, approached Roberto Pellicciari, the scientific founder of Intercept Pharmaceuticals Inc., and Brunangelo Falini, professor of hematology at the University of Perugia, Italy, to discuss how to apply synergies in their research to potential new treatments for leukemia and lymphoma.

Cerrone was previously involved in starting nine companies in the biopharma space, taking six of them to the Nasdaq Market and one to London's AIM. Among those startups were Synergy Pharmaceuticals Inc. and Callisto Pharmaceuticals Inc., where Cerrone served as co-founder and chairman, and Fermavir Pharmaceuticals Inc., which merged in 2007 with Inhibitex Inc., where Cerrone continued to serve as a director until that company's $2.5 billion acquisition in 2012 by Bristol-Myers Squibb Co. (See BioWorld Today, April 11, 2007, and Jan. 10, 2012.)

Pellicciari, an expert on molecular design, synthesis, mechanism of reaction and drug modeling, had amassed more than 40 patents and hundreds of publications over the course of his career. Following Intercept, he formed TES Pharma Srl, also in Perugia, which is exploring a variety of target classes, including GPCRs, enzymes and protein-protein interactions. The company's particular focus is to realize the potential of nuclear receptors as disease modulators. Falini, meanwhile, had conducted seminal work on the role of nucleophosmin protein, or NPM1, in acute myeloid leukemia (AML).

Pellicciari and Falini signed on to Rasna, becoming its scientific founders, with the goal of taking forward modulators to the largely unexplored NPM1 protein as well as the promising but still unproven target lysine-specific demethylase 1, or LSD1 – both implicated in the pathogenesis of blood cancers.

Cerrone held intellectual property on NPM1, according to Tripp, and Falini – in addition to his research – had clinical exposure to the NPM1 mechanism as a member of the scientific advisory board at molecular diagnostics firm Trovagene Inc., whose precision cancer monitoring technology is used to detect and quantitate oncogene mutations in cancer patients to improve their treatment. Trovagene – another company co-founded by Cerrone – had developed a method to incorporate NPM1 into research and clinical testing services for AML and, in 2012, inked a global nonexclusive license for the technology with Novartis AG unit Genoptix Inc.

Pellicciari and his research team at TES – a strategic partner of Intercept and co-founder of Rasna – set about designing a method to modulate NPM1, first shown to be implicated in the progression of leukemia by Falini. Rasna subsequently partnered with additional collaborator Pier Guiseppe Pelicci and his team at the European Institute of Oncology (EIO) in Milan to advance the NPM1 program using the EIO's animal models for additional studies.

Given the multiple functions of nucleophosmin and its involvement in AML, "if it's possible to develop a molecule that modulates NPM1, it not only would be a blockbuster but it also would be a game-changer for patients with leukemia," Tripp told BioWorld Today.

"Despite existing available treatments, the five-year survival rate for AML patients is only 24 percent," he pointed out. "We do not believe that any existing drug therapies address this problem. Our NPM1 program targets the subset of AML patients with the NPM1 mutation and may also benefit the general AML population."

A drug targeting NPM1 also could have implications in solid tumors, where NPM1 is sometimes overexpressed and thought to promote tumor growth by inactivation of the tumor suppressor p53/ARF pathway. When expressed at low levels, NPM1 could suppress tumor growth by inhibiting centrosome duplication during the cell cycle.

'THE QUICKEST WAY FOR US TO GET ON THE MARKET'

In terms of their LSD1 approach, the collaborators looked to findings from a 2012 Nature Medicine paper suggesting that inhibitors of LSD1 (also known as KDM1A) can make drug-insensitive forms of AML respond to treatment with all-trans-retinoic acid (ATRA) – used to treat a subtype of AML called acute promyelocytic leukemia (APL) but normally not effective in non-APL AML, Tripp explained. In their paper, the authors hypothesized that inhibiting LSD1 might facilitate ATRA-induced differentiation of AML cells, known to halt the division of those cells, and offer a therapeutic option in AML.

Working from that premise, Rasna's collaborators at EIO developed irreversible and reversible LSD1 regulators that showed beneficial effects on the LSD1 gene in vitro. In collaboration with the EIO via its tech transfer company, TTFactor, Rasna now is advancing the LSD1 inhibitor DDP-26140 in investigational new drug (IND)-enabling preclinical studies for the potential treatment of AML, according to Thomson Reuters Cortellis.

Roche AG, of Basel, Switzerland, is the farthest along with an LSD1 inhibitor, thanks to a 2014 partnering deal with Oryzon Genomics SA, of Barcelona. The companies have moved the oral small molecule RG-6016 (ORY-1001) into a phase I/II safety and pharmacokinetics study in relapsed or refractory acute leukemia that is also exploring remission rate as a secondary endpoint, according to Cortellis. (See BioWorld Today, April 9, 2014.)

In addition, London-based Glaxosmithkline plc is recruiting patients in a phase I dose-escalation study of its LSD1 candidate, GSK-2879552, in patients with AML and a second phase I in relapsed or refractory small-cell lung cancer.

The Rasna compound, Tripp said, represents a second-generation approach to LSD1.

With Rasna's work moving quickly toward the clinic – the company has identified a lead candidate and is completing safety and toxicology studies with the goal of filing its first IND with the FDA next year – the team decided it was time to move beyond an essentially self-funded model and gain more exposure to investors. A reverse merger was "the quickest way for us to get on the market," said Tripp, who also serves as Tiziana's chief operating officer and head of global clinical operations. Rasna was content to start with a small exchange with the intent of uplisting once it generates clinical data.

Rasna also relocated to New York, setting up shop in the same building as Synergy.

A reverse merger was the same mechanism used by Callisto – at the time, the parent company of Synergy – to acquire a public listing and cash to fund Synergy's development of SP-304, its guanylate cyclase C receptor agonist, for chronic constipation and constipation-predominant irritable bowel syndrome. In 2012, Synergy acquired its parent in a stock swap. (See BioWorld Today, July 22, 2008.)

The endgame for Rasna, as with Cerrone's other startups, is to take its assets through clinical proof of concept and then decide whether to commercialize or sell them, according to Tripp.

"The board is open-minded about the best way to develop the compounds," he said, noting that his role, as Rasna's only employee, is to oversee the virtual company's operations until clinical data are in hand and a permanent CEO is named to court additional investment.

London-based Tiziana is involved in a host of additional development activities. Last year, the company exclusively licensed milciclib from Nerviano Medical Sciences Group, of Nerviano, Italy. Milciclib, which blocks the action of cyclin-dependent kinases, is in phase II trials for thymic carcinoma in patients previously treated with chemotherapy and was granted orphan designation by the FDA and EMA to treat malignant thymoma and thymic epithelial tumors.

Last year, Tiziana exclusively licensed the anti-cancer stem cell agent, OH14, from Cardiff University scientists. The inhibitor of cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein, or c-FLIP, is a known suppressor of apoptosis.

Tiziana also is advancing foralumab, a fully human anti-CD3 antibody targeting graft-vs.-host disease and ulcerative colitis, under an exclusive development and commercialization license from Novimmune SA.

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