Expansion into new clinical indications
Tiziana has disclosed plans to file INDs (Investigational New Drug applications) aiming to expand the clinical indications of its lead product, intranasal foralumab, into mild-to-moderate Alzheimer’s Disease (AD) and long COVID-19. These could represent the second and third clinical indications for foralumab. The drug is a fully-human anti-CD3 monoclonal antibody.
Foralumab is currently in a ten-patient expanded access study for secondary progressive multiple sclerosis (SPMS). Following two initial enrolments, in January, Tiziana recruited and dosed four more patients. The three-month results on this cohort may become available soon. A further cohort of four is expected to be dosed from Q223 onwards so could become available in Q3. A Phase 2a is being planned and might start in Q3, pending an IND and final preclinical work on the formulation. However, the IND does not depend on the full data set from the current expanded access study.
The proposed AD study will be a Phase 2a (ie a relatively small proof-of-concept trial in patients) and will be part-financed by $3mln of non-dilutive funding expected from a philanthropic source. This study could, in our view, start in 2024 subject to an IND. Tiziana expects to submit an application for the funding shortly with the outcome known in Q3.
Separately, Tiziana has also initiated an early preclinical project exploring the potential of foralumab for Type 1 diabetes (T1D). This follows the approval of Provention Bio's Tzield (teplizumab), a humanised anti-CD3 antibody, for T1D in 2022. Unlike Tzield, which is given by daily IV infusions over a 14-day course, foralumab would be given on a chromic basis which may position it slightly differently. Of interest to investors is the fact that Provention Bio was recently the subject of an agreed takeover offer from Sanofi valued at $2.9bln.
Moving into Alzheimer's, long-Covid and Type 1 diabetes
Tiziana has seen its share price rise in recent weeks with increased investor interest in foralumab heightened by the read-across from its mechanistic similarity to Tzield especially after the takeover offer from Provention Bio. This means it has regained compliance with the NASDAQ minimum bid price rule. The work leading to AD is promising and the drug may attract non-dilutive funding from a prestigious philanthropic source adding to value. AD is currently a focus of intense interest from biotech investors after the approval of the first disease-modifying products over the last 12 months.
Tiziana has sufficient cash to initiate the planned Phase 2b trial in SPMS, which it considers likely to be a key value inflection point. At this point, it can then evaluate its options, including potentially partnering. Cash on 31 December 2022 was US$18.1mln after a reported loss of $19mln; this included $13mln of R&D costs.
New indications for foralumab elicit investor interest
Tiziana plans to take foralumab into a Phase 2a study in mild to moderate Alzheimer's disease, backed by non-dilutive funding expected from a foundation. The study could start in early 2024 and is likely to have a three-month treatment period, so could render data in 2025, assuming the funding is confirmed.
The company believes foralumab may be able to reduce the known neuro-inflammatory component of the disease, caused by the activation of microglia triggered by amyloid beta plaques that are a hallmark of Alzheimer's. As most drugs that are in development for AD target amyloid, foralumab could be complementary to this approach. Tiziana's collaborators have presented supporting data on foralumab at various scientific meetings, including from an animal model of Alzheimer's at the recent AD/PD conference.
Mild to moderate AD (which is when symptoms are first becoming apparent) is the stage of the disease when most pharmaceutical agents have historically been tested, although it is commonly believed that intervening earlier (if possible) would give drugs a better chance to show an effect. Biogen/Eisai's recently approved Leqembi (lecanemab) is indicated for patients at an earlier stage of with mild cognitive impairment or mild dementia and has to be confirmed by the presence of amyloid beta pathology.
AD looks to become the second indication tested
Plans are also taking shape to conduct a Phase 2 study of foralumab in post-COVID-19 syndrome (or "long-Covid"), starting in 2024. Few details have been disclosed. The programme is based on the hypothesis that a key pathogenic component of long-Covid is the activation of microglial cells. Tiziana anticipates running a placebo-controlled Phase 2a trial over three months with PET Scans used to determine if foralumab can decrease activated microglia. An IND for this is expected to be filed in Q4 2023, so the study could take place in 2024.
There are numerous patients who experience persistent fatigue, neurological or other debilitating symptoms consequent to Covid infection. This is sometimes called post-acute sequelae of Covid-19 or post-Covid syndrome. In some patients, these symptoms have not resolved more than two years after the original infection.
Long Covid study planned for 2024
Tiziana has initiated a preclinical programme to explore the potential of foralumab in Type 1 diabetes (T1D). This follows the recent approval of Provention Bio's Tzield (teplizumab), which is an antibody to the same target, for delaying the onset of T1D in 2022. Tzield is the only product approved for delaying the onset of type 1 diabetes and is priced at $194,000 for a 14-day course. There are an estimated 65,000 patients eligible for treatment per year.
Because foralumab is a low-dose nasal spray and is given chronically, we speculate that Tiziana could try to position it as a long-term therapy to maintain immune control for a longer period after the initial "reset" given by Tzield therapy.
Type-I diabetes project
Long-Covid background
Foralumab has been previously studied in Covid patients. During the pandemic, a pilot study of foralumab (100ug/day for 10 consecutive days) in 39 COVID-19 patients was conducted in Brazil, which showed a reduction of serum IL-6 and C-reactive protein, inflammatory biomarkers.
Given the large number of people exposed during the Covid pandemic, this represents a potentially large market opportunity and there is very little competing development activity. There are probably only two active development by other pharma/biotech companies: temelimab from GeNeuro and Vyvgart (efgartimod) from Argenx. Both are in Phase 2 studies. Temelimab is an anti-Human Endogenous Retrovirus (HERV) mAb and interestingly is also in development for MS.
In addition, a UK based academic group is conducting a large study that will test multiple drugs (initially ones already approved for other indications) for long Covid. The first two treatment arms are testing the anticoagulant, Eliquis (apixaban, Bristol Myers Squibb) and the statin atorvastatin (generic). Further treatment arms are likely to be added. A Canadian academic group is testing the antidepressant Trintellix/Brintellix (vortioxetine, Lundbeck/Takeda) specifically for the cognitive deficits in post-COVID-19 conditions.
Type 1 diabetes exploratory programme
Both Tzield and foralumab are anti-CD3 monoclonal antibodies. Tzield is humanised and given systemically and intravenously whereas foralumab is fully human.
Tzield is given by 30 min IV infusion once per day over 14 days, with the dose-escalating from 65mcg/m2 to 1,030 mcg/m2 (equivalent to c 1.1mg/day for a typical 10 year old child). Typically, it would be given to children/adolescents who have shown the initial symptoms, caused by the autoimmune attack on their pancreatic islet cells (which produce insulin). Treatment with Tzield has been shown to delay the onset of T1D by a median of two years. The intranasal route of administration used by Tiziana could be more convenient for patients but also may allow it to be positioned differently, possibly as a maintenance therapy in patients who have previously received Tzield.
Tiziana is considering using the same treatment regime to that expected to be used in MS and AD. This would be in three-week cycles of 50 mcg given on alternate days over two weeks followed by a one-week holiday. When delivered intranasally, foralumab binds to T-Cells in the cervical (neck) lymph nodes boosting IL-10-producing, FoxP3+ T-regs (T-regulatory cells). These will need to exert general systemic control for efficacy. Foralumab does not itself enter the systemic circulation whereas Tzield is given intravenously.
MS to remain main focus
The MS field is crowded and highly competitive, but Tiziana's targeting of non-active secondary progressive disease (SPMS) represents a niche where there is very little competition in addition to the fact that intranasal delivery may also provide a patient-friendly feature.
Non-active SPMS is an advanced stage of this disease where patients continue to deteriorate but do not experience the characteristic sudden flares associated with earlier stages of the disease. There are two drugs approved for a slightly less advanced stage of active secondary progressive disease (where flares still occur): Ocrevus (ocrelizumab, Roche), which is given by infusion (and is considered the more effective drug) and Mayzent (siponimod, Novartis), an oral product. Both have strong side effects. No product is specifically approved for non-active SPMS and only one other product in competing for this use (AB Science's masitinib, which is in Phase 3). The key hypothesis is that by administering foralumab to the mucosal surfaces in the nose, the drug can boost regulatory T-cell (T-reg) responses and thereby control disease progression without unacceptable immune system side effects that would be likely to arise if a molecule of this class were delivered systemically.
Given the unmet need, Tiziana has been allowed by regulators to treat a small number of SPMS patients with foralumab in an expanded access study. So far two patients have presented results, both encouraging but anecdotal. These patients received 50mcg; three times a week for two weeks (followed by one week off). The dose can be increased to 100mcg on the same schedule if needed.
A January 2023 update reported that after 11 months of dosing, additional clinical improvements were evident in the second patient. On the EDSS (expanded disability status scale, a standard MS scoring system), a score on enrolment of 6.0 had fallen (improved) to 5.5 by September and was 5.0 by December 2022, by which point the patient could walk 200 metres without a cane. Further, imaging results showed a reduction in microglial activation; microglial cells are the brain's immune cells and cause MS so lower activation is encouraging. The results were also consistent with previously reported data from the first SPMS patient; the first patient had also failed on Ocrevus.
These data are suggestive of possible efficacy in SMPS patients who have exhausted all other therapeutic options. The three-month data from the next cohort of four patients, dosed January 2023 so data due in Q2 2023, will therefore be important. A further four patients might be enrolled and dosed in Q22023, If so, they should report data by late summer 2023. However, the Phase 2b proposed does not rely on the full data set from these patients to start. This study is expected to recruit 108 patients and test two doses (50 and 100mcg) vs placebo over six months.
Finances and cash
Cash on 31 December 2022 was US$18.1mln after a reported loss of $19mln; this included $13mln of R&D costs. Tiziana states that it has sufficient cash reserves to initiate the Phase 2 trial in MS.