I have long considered Senesco Technologies Inc (OTCQB:SNTI) an agricultural biotechnology company. For over a decade, Senesco had been working on technologies to increase the crop yield and shelf life of fruits. It formed partnerships with a group of well-known agriculture technology companies such as Monsanto Company (MON) and Bayer (BAYRY). Senesco's key target is the eukaryotic translation initiation factor 5A (eIF5A). In eukaryotic cells, eIF5A is an abundant protein involved in protein synthesis and is one of the most conserved proteins during evolution. Senesco's team found that eIF5A acts at a critical point in the process of cell death. By controlling or changing the process of senescence (cell death in a plant cell), Senesco could modify the taste, texture and other consumer traits of a crop's seeds or fruits.
Senesco is no longer an agricultural company but focused on human diseases as many biological mechanisms are conserved between plants and animals. Some "hot" biological phenomena were actually first discovered or utilized in plant biology. Fortunately for Senesco, its expertise in eIF5A has potential in cancer therapy. I believe Senesco's work on eIF5A has both scientific and commercial potential.
Construction of Unique Cell-Specific Weapon Against Cancers
Life is beautiful and all living things share the same essential characteristics. All life is composed of cells, which are programmed to die to ensure the overall health of the organism. The senescence in plants turned out to have a counterpart word in animals, i.e. apoptosis. If we could induce cancer cells to apoptosis, then we would potentially find a therapy for that cancer. While programmed cell death is a complicated process, researchers have found that eIF5A plays an important role in that it is the only protein that contains the special amino acid hypusine. In humans, eIF5A has a lysine at the 50 amino acid position. After eIF5A is synthesized, almost the entire lysine residue is modified to hypusine. This post-translational modification from lysine to hypusine is necessary for cell growth. When this modification is stopped, cells enter into apoptosis and die.
In collaboration with scientists at Waterloo University, the company constructed a mutant eIF5A. The lysine(K) at the 50 position was changed to a similar amino acid arginine resulting in eIF5AK50R. The mutation prevents eIF5A from the post-translational modification of lysine to hypusine. The mutant eIF5AK50R functions similarly to nascent eIF5A before modification. What this means for cancer cells is that the over expression of eIF5AK50R leads to cell death.
To test the anti-tumor activities in humans, the mutant protein must be specifically expressed in targeted cancer cells to avoid the death of normal cells. The company chose to initially test its activity in B cell cancers. A B cell-specific promoter and enhancer were introduced into the plasmid containing the mutant eIF5AK50R gene and it was later confirmed that the mutant protein accumulates very little in non-B cells.
Introduction of exogenous mutant eIF5AK50R may still not reduce endogenous eIF5A that contains hypusine, so the company used RNA interference technology to knock out the endogenous eIF5A expression with a small inhibitory RNA (siRNA). These two components are combined in a fixed ratio with a polymer, polyethyleneimine (PEI), which enables self-assembly of the DNA and RNA into nanoparticles with enhanced delivery to tissues and protection from degradation in the blood stream.
Preclinical Trials Showed Striking Anti-Tumor Activities
SNS01 was found to significantly inhibit tumor growth in mice and the results of SNS01 in a multiple myeloma murine models were published in Molecular Therapy. The research had a number of important implications.
First, it was confirmed the additive therapeutic potential of co-administering an eIF5A siRNA and eIF5AK50R expression plasmid using PEI nanoparticles. Intratumoral injection of the eIF5A siRNA inhibited multiple myeloma tumor growth by >80% compared to control animals. The eIF5AK50R plasmid inhibited tumor growth by >70% but when both the siRNA and plasmid were delivered in combination, it resulted in a 92% reduction in growth.
Second, SNS01 demonstrated striking dose dependent anti-tumor activities when tested against a KAS-6/1 multiple myeloma model. The data are shown in the following figure.
SNS01 dosed at 1.5 mg/kg resulted in a 95% (p = 0.026) reduction in tumor growth with no evidence of tumor burden upon excision. Decreasing the dose of SNS01 by half resulted in a 91% (p = 0.03) decrease in tumor volume. The percent change in tumor volume of mice treated with SNS01 at 0.75 mg/kg and 1.5 mg/kg was -244% and -245%, respectively (indicating tumor regression occurred following SNS01 treatment). In contrast, the tumors of control mice increased in size by more than 2,000%.
The study also tested a second model of multiple myeloma, RPMI 8226. Mice treated twice weekly with 1.5 mg/kg SNS01 by intravenous administration exhibited a 59% growth inhibition (p <0.05) compared to mice treated with 1.5 mg/kg of a control nanoparticle. The data are shown in the following figure.
In general, SNS01 has shown encouraging signals in animal models but the real question is the efficacy in humans.
Dose Escalating Clinical Trial Demonstrates Safety And Early Clinical Signals
The company slightly changed its formulation and took SNS01-T into a phase I/IIa clinical trial. The clinical study is an open-label, multiple-dose, dose-escalation study, which is evaluating the safety and tolerability of SNS01-T when administered by intravenous infusion to relapsed or refractory multiple myeloma, mantle cell lymphoma (MCL) or diffuse large B cell lymphoma (DLBCL) patients. The study design calls for four cohorts of three to six patients each. Patients in each cohort receive twice-weekly dosing for six weeks followed by up to a four-week safety data review before the company can escalate to a higher dose level in the next cohort. The company has completed the first 3 cohorts and is moving to the highest dose cohort. The following table summarizes the preliminary results.
Safe and well tolerated.
Stabilization of serum monoclonal protein levels observed in 3 of 5 evaluable multiple myeloma patients.
Safe and well tolerated.
Safe and well tolerated.
More robust effects observed: Of 3 evaluable patients, one myeloma patient had reductions in disease-related proteins, and a second patient with DLBCL had tumor shrinkage.
Basically, there is no dose limiting toxicity observed up to 0.2 mg/kg tested and more robust molecular or tissue level responses were observed as the dose escalated. While the signals are promising, data points are still few. Encouraged by results, management is adding new clinical sites to speed up the trial. It should be noted that the doses in these trials are at the low end of what was used in the murine models, so the lack of strong efficacy is not surprising. This could very well change as the doses increase.
Potential Expansion to Other Cancer Targets and Combination Therapies
Considering how well eIF-5A is conserved as well as its uniqueness in regulating cell growth and apoptosis, it has broad applicability.
a) Expanding to other cancer targets
Evidence is growing that eIF5A plays a role in other cancers. For instance, it was shown that eIF5A and hypusine forming enzymes are over-expressed in glioblastoma. The paper suggests that the pharmacological inhibition of eIF5A may represent a novel concept for the treatment of glioblastomas and help to substantially improve the clinical course of this tumor. Other published papers suggest that eIF5A is involved in liver, colon, ovarian and cervical cancers.
b) Combination therapies
The company has demonstrated in human multiple myeloma cell lines that there may be additional benefit to combining SNS01-T with other approved myeloma drugs, such as bortezomib (Velcade marketed by Takeda) and lenalidomide (Revlimid marketed by CELG). In vitro, these drugs are up to forty (40) times more effective in inhibiting cell growth when used in combination with SNS01-T. While SNS01-T performed well by completely eliminating tumors in 40% of the animals, complete tumor eradication was achieved in five out of six animals that received SNS01-T combined with the optimal study dose of lenalidomide.
The median survival of mice treated with control nanoparticles was 21 days and mice treated with lenalidomide or SNS01-T had a median survival of 28 days (33% increase) and 37 days (76% increase), respectively. Mice treated with the drug combination had a median survival of 52 days (an increase of 148 %). In addition, the survival difference was statistically significant even when compared to SNS01-T alone (p = 0.002) or lenalidomide (p = 0.007) alone.
The benefit of combining SNS01-T with bortezomib was also demonstrated. In a mouse model of human multiple myeloma, SNS01-T as a monotherapy achieved 59% tumor growth inhibition, which exceeded that of bortezomib at either the 0.2 mg/kg dose (22% inhibition) or the 0.5 mg/kg dose (39% inhibition). The combination of SNS01-T with 0.5 mg/kg of bortezomib resulted in an 89% tumor inhibition.
Continuous Dilutive New Share Offering Stymies Stock Price
While Senesco is definitely moving in the right direction, its low market valuation and constant need for cash constitute an undeniable risk. After a recent 1:100 reverse split in October, its stock is trading at about $5 per share (about a $12M market cap). By end of September 2013, the company had cash of only $1M and its milestone payments from its agriculture partners are drying up. In December 2010, the company entered into an At Market Issuance Sales Agreement (the "ATM") under which the company, from time to time, may issue and sell shares of its common stock with an aggregate offering price of up to $5,500,000. The stock price, however, has been so depressed that the company did not use ATM this year. Instead, the company has used private placements to raise cash. There have already been three equity financings in 2013 raising $3.0M at $12/share, $1.255M at $3/share, and $1.725M at $2.5/share. It is expected that capital raising will continue. The phase I/IIa trial may not conclude until early to mid 2014 and the best scenario is a clear molecular or clinical response will spark interest from established biotech companies. A partnership could be a catalyst that not only revalues the stock higher but also addresses many of the near term funding needs.
A recent Seeking Alpha article pointed out that Senesco Technologies has strong financial backing from its chairman and director. Strong support from insiders, especially those of famous pedigree, helps build investor confidence. Nevertheless, the dilutive effect of the new share offering will last for a few years. Unless we see clear and strong clinical responses from phase I/IIa trial, this small and early trial may have difficulty securing a large investment from a partner. The company may have to raise tens of millions dollars to do a larger phase II trial to demonstrate efficacy as either a mono-therapy or as part of a combination therapy.
In summary, Senesco is transforming itself from an ag biotech company to a therapeutic cancer company. It holds the composition of matter and other patents to what appears to be broadly applicable eIF5A related technologies. This company is definitely worth a closer look. There are certainly risks associated with micro cap companies but there is a good chance that the newest dose cohort shows a more definitive effect and acts as a proof of concept for the company.