TLSA: November’s Investor Day
NASDAQ:TLSA
SPMS and Strategic Direction
Tiziana Life Sciences PLC (NASDAQ:TLSA) hosted an investor day on Thursday, November 10th which addressed the company’s lead program in secondary progressive multiple sclerosis (SMPM) and its future focus on CNS diseases. Other items covered include the status of previous pipeline programs, future capital raises and the standing of Tiziana’s stock on the NASDAQ exchange. Tiziana executives Gabriele Cerrone, CEO and Matthew Davis, CMO, led the call and answered questions from investors.
Tiziana’s SPMS program, which was launched in 2021 has shown favorable initial results with its expanded access program (EAP) subjects EA1 and EA2. The positive results were discussed in depth in a previous note that we published in October. A positron emission tomography (PET) scan of the expanded access SPMS patients showed a reduction in microglial activity coincident with improvements in mobility.
The positive results supported FDA clearance to conduct additional studies that will be completed in two four-patient cohorts, the first of which has begun enrollment. This open label study will be able to expand dosages from 50 mcg to 100 mcg and will examine both biomarker and disability scale measurements. A Phase II study in SPMS using nasal foralumab is in the works, which is slated to begin in 2023.
SPMS Phase II
Tiziana expects to soon request a Type C meeting with the FDA to obtain guidance on Phase II trial design and to clarify safety assuming the expanded access cohorts return favorable results. If all goes to plan, the Phase II could start in 2Q:23. Preliminary plans call for a multicenter, double-blinded, placebo controlled, dose ranging proof of concept study for intranasal foralumab for treatment of non-active SPMS. While enrollment targets will depend on a statistical analysis, 40 – 60 patients appear to be a reasonable number. Three to five sites that offer the necessary imaging capability will serve to enroll the subjects. A futility analysis will be conducted at an interim timepoint to determine whether or not the trial should continue in an effort to efficiently use capital. Further work will stop if results do not achieve a pre-defined improvement in the reduction of microglial activity. If results meet interim goals, the study will continue and maintain the double blind.
Alzheimer’s Disease and Amyotrophic Lateral Sclerosis
Early work that has been conducted in CNS disease other than multiple sclerosis has shown early promise. This includes neurodegenerative diseases such as Alzheimer’s Disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Animal studies have been conducted that suggest activity in humans including rodent work conducted by Dr. Howard Weiner. A common feature of neurodegenerative disease is excessive inflammation. Foralumab is able to address this inflammation and, using nasal administration, can provide localized rather than systemic treatment allowing for fewer side effects. Programs outside of SPMS will likely be funded by partners, such as the ALS Association which provided a grant to researchers at Brigham and Women’s Hospital to study foralumab nasal spray as a potential treatment for ALS.
Other Programs
Crohn’s disease using foralumab and solid tumors using milciclib were active indications that previously appeared in Tiziana’s pipeline. Now that initial results for SPMS are supportive of further work and the capital raising environment is less attractive, Tiziana plans to deprioritize programs outside of CNS disease. This will conserve capital and provide partnership opportunities for others that may wish to advance the candidates.
Financial and Trading
CEO Gabriele Cerrone anticipates a sufficient level of cash on the balance sheet to support operations without further capital raises until 1Q:24. He anticipates an update on the SPMS program prior to this time that, if favorable, could support a revaluation of the company and minimize dilution. Funds are also sufficient to complete the recently launched 8-patient expanded access program.
Tiziana shares have traded below $1.00 since early April 2022 and the company has received a delisting notice from the NASDAQ in June notifying it that the shares were not in compliance with minimum bid requirements. Tiziana initially has 180 days to cure the deficiency and may request an additional 180 days to comply. Management plans to attain compliance either through generating sufficient supportive data from its SPMS trial to produce a market response or through other actions as necessary by the anticipated deadline in May 2023.
Research Article
On behalf of foralumab, Tiziana published the article “Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects” in the journal Frontiers of Immunology on November 23, 2022. The article reviewed the results of a study that examined the results of 27 subjects evaluated in a placebo-controlled trial measuring the safety of the anti-CD3 monoclonal antibody foralumab. Of the 27 healthy volunteers, nine were in the placebo group, and six each were in the 10 µg, 50 µg, and 250 µg foralumab dosing groups.
The study concluded that foralumab was safe with only modestly higher non-serious treatment emergent adverse events (TEAEs) in comparison with the placebo group. Notable is that the proportion of TEAEs declined in subjects as the dosage increased (see Table 2)1. Immune effects were observed mostly at the 50 µg dose with lesser effect at the 10 µg and 250 µg doses. This “sweet spot” in dosing was attributed to the partial signaling that occurs at intermediate doses which favors the induction of regulatory cells. Nasal administration offered different biologic effect as compared to intravenous (IV) delivery. IV anti-CD3 is associated with modulation of CD3 from the cell surface, a decrease in CD3 cells and side effects that include cytokine release syndrome and, in some instances, activation of Epstein-Barr Virus (EBV). Nasal administration avoided EBV activation and entry of the drug into the bloodstream reducing the systemic effect that is observed with IV administration.
The study also summarized in vitro work that found foralumab preferentially induced CD8+ T cell stimulation, reduced CD4+ T cell proliferation and lowered expression of IFNg, IL-17 and TNFa. In vivo studies showed that nasal Foralumab did not modulate CD3 from the T cell surface at any dose. The article concluded that nasal Foralumab is safe and immunologically active in humans and presents a new avenue for the treatment of autoimmune and CNS diseases.
SPMS Background
Tiziana enrolled its first SPMS subject in May 2021 through the Individual Patient Expanded Access program. The effort is investigating lead candidate, foralumab, using an innovative, intranasal formulation. The biologic is able to bring balance to the immune system by stimulating Tregs and reducing proinflammatory cytokines. Dysregulation in these elements is present in a number of neurodegenerative diseases, including multiple sclerosis. In the first patient, investigators observed the upregulation of Tregs and the suppression of cytokines after six months of treatment.
SPMS represents an advanced stage of multiple sclerosis with few treatment options and has a severe impact on a patient. Three-month results released in January of this year provided sufficient evidence of safety and efficacy to justify the enrollment of a second SPMS subject. On March 10, 2022, topline data for the full six months of evaluation was reported, and a key opinion leader (KOL) event was held to further detail results and offer discussion with the study’s principal investigators.
Milestones
➢ Submit request to hold Type C meeting with FDA on SPMS Phase 2 – 4Q:22
➢ Begin foralumab six-month toxicology study – 4Q:22
➢ Enroll four new patients and baseline PET scan – 4Q:22
➢ Six- and nine-month PET scan results on first two expanded access patients (EA1 & EA2) - 1Q:23
➢ Three-month PET scans on first four-patient SPMS cohort (EA3 to EA6) – 2Q:23
➢ FDA Type C meeting feedback on SPMS program – 1Q:23
➢ Results from first four-patient SPMS cohort – 2Q:23
➢ Start of Phase II SPMS study – 2Q:23
➢ Enrolling, imaging and dosing second four-patient SPMS cohort – 3Q:23
➢ Futility analysis for Phase II – 4Q:23
➢ File foralumab IND for Type 1 Diabetes - 2023
Summary
The update by Tiziana management on the company’s strategic direction was welcome. Early success with its first two patients in the expanded access SPMS trial support expansion of the program into additional SPMS cohorts to further substantiate the reduction in microglial activity and improvements in mobility. An active timeline is expected over the next few months as the first two four person cohorts are evaluated, FDA meetings take place and preparations for a Phase II begin. If all goes to plan, before year end 2023, a futility analysis will be conducted for the Phase II to evaluate the success of foralumab in a larger population. Additional efforts are expected to be made in other neurodegenerative diseases including AD and ALS that will be financially supported by partners. We expect to hear further updates on the SMPS enrollment progress and advancements in other programs as we move into 2023.
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1. Note that this was a small sample that is not statistically significant.
