Controlling disease using a safe, nasal and oral antibody
Tiziana Life Sciences delivers its fully human therapeutic antibody, foralumab, to the gut or nose mucosal surfaces aiming to modulate the immune response. This might help to control various autoimmune diseases such as Crohn’s and Multiple Sclerosis (MS).
Foralumab has also been clinically tested with interesting results in COVID-19 patients to alleviate any immune over reaction. Mucosal delivery is an innovative approach and foralumab is in early-stage clinical development.
A licensing deal for an infused form of foralumab with Precision Biosciences on CAR T-cell therapy has been announced.
Tiziana also has a small molecule cancer therapy (milciclib) in mid-stage clinical development for solid cancers. There is a preclinical project in lung disease.
Tiziana intends to obtain a direct listing on the NASDAQ and de-list its shares in London. The company is mainly US-based. At the 2020 year-end, net cash was US$65.6mln.
Foralumab targets large, autoimmune disease indications with a novel approach. The therapies available for these conditions, although powerful, are not always able to control patients’ immune systems longer-term. Adding in a new, easy to administer the product to boost natural immune regulation might establish a lucrative adjuvant market.
If foralumab shows efficacy in Crohn’s disease, Multiple Sclerosis (MS) and in COVID-19 clinical studies now starting, it might eventually become a core therapy. Biological treatment markets including for Crohn’s disease, led by Humira (2020 sales $19.8bn) are starting to consolidate as patents expire.
In MS, a 2021 market report estimated US beta interferon sales alone as growing to US$4.8bn.
Tiziana is transferring its primary listing to NASDAQ potentially giving a higher US-style valuation. However, this still needs to be backed by robust clinical data.
Year end Dec 31 · 2019 · 2020
Revenue (£M) · 0.00 · 0.00
EBITDA (£M) · 7.8 · 19.5
Tiziana Life Sciences was founded by the current executive chairman Gabriele Cerrone as Tiziana Pharma Ltd. It licensed foralumab in 2014 and milciclib maleate in 2015. The company listed on AIM in 2014 through a reverse takeover of Alexander David Investments and raised £2mln in a public offer of 16.7 million new shares at 12p. A secondary listing on the NASDAQ followed in 2018. In May 2020, the company announced the spin-off its StemPrintER and SPARE genomics-based personalised medicine businesses into a separate company, leaving Tiziana as a pure-play biotech research company. Tiziana was admitted to the main London market in 2021.
In August 2021, Tiziana announced it would de-list its shares on the London market to seek a direct listing on NASDAQ, with new Tiziana NASDAQ tradable shares issued to holders of the current Tiziana shares. “New Tiziana” will be a Bermuda-incorporated parent company of the Tiziana Group. By gaining a direct NASDAQ listing, Tiziana can directly access US capital markets and potentially gain a US-style valuation.
Tiziana background
The full pipeline and current development progress are illustrated in Figure 1..
Tiziana Life Sciences Product Pipeline
Figure 1 - Tiziana Pipeline status
Project status with planned studies
Source: Tiziana
The main focus remains on foralumab with its unique delivery method and mode of action. Trials listed as active on the standard US database are in Table 1. There are no current active studies listed with the cancer drug milciclib although trials are being planned.
Table 1 - Tiziana current and planned studies
This table shows trial listed on the standard US database.
Source: clinicaltrials.gov
Foralumab - the lead therapeutic candidate in Crohn's, MS and COVID-19
Foralumab is a fully human monoclonal IgG1k antibody, IgG being the type of antibody usually found in the blood that neutralises viruses, bacteria and foreign molecules. Foralumab was developed using a genetically engineered mouse that had fully human antibody genes; hence foralumab is fully human. Foralumab targets the CD3 epsilon receptor. The antibody was engineered to minimise unwanted cytokine release (a side effect of older anti-CD3 antibodies) by modifying the Fc-region of the antibody with two changes. This means it is less able to bind a T-cell to another immune cell; this would normally trigger release of potent cytokines and cause an immune reaction.
Licensing to Tiziana
Tiziana licensed foralumab (formerly named NI-0401) from privately-owned Swiss drug development company NovImmune in 2014, paying an upfront of US$1.25mln, with further payments totalling $0.75mln up till 2018. In 2019, NovImmune subsequently sold most of its assets to Sobi and has since rebranded as Light Chain Therapeutics. In 2001, NovImmune licensed NI-0401 from Medarex, which was subsequently (in 2009) acquired by Bristol-Myers-Squibb. We assume that Tiziana will eventually pay any royalties directly to BMS - although the current position has not been disclosed.
Foralumab earlier clinical data using systemic delivery
Foralumab was tested using intravenous delivery in a 40-patient, randomised, placebo-controlled safety study in Crohn’s patients (NCT00630643 completed Dec 2007) and the data was published in Inflammatory Bowel Diseases in 2010.
Patients could be on steroids, methotrexate or another disease-modifying agent but not on biological agents such as anti-TNF therapy. Foralumab was given once per day for up to five days. Infusion reactions were the most serious adverse event and occurred in six cases in total, four of whom withdrew from the study.
The study, a dose-escalation design, showed that foralumab was tolerated up to 1mg / day. One patient received 2mg and had severe reactions although this was safely resolved. Another patient received 10mg; it is not clear why. Most patients received 0.5mg (11) or 1mg (12) daily doses with seven on placebo.
The study was to show dose and safety. Efficacy indications were measured using Crohn’s disease response scores and by measuring T-cell levels (both CD8+ (killer) and CD4+ (regulatory and helper). There was no change in disease scores. The data shows that T-cell levels fell and that this was dose-related. There was a 60% modulation of T-cell numbers at the 1mg dose at day five. The effect was transitory and resolved by day 21 (so just over two weeks after dosing ceased).
A further escalating dose study (NCT00805909) was run in 12 patients with Acute Renal Allograft Rejection. This completed in January 2009. We can find no published report.
Foralumab oral/ nasal formulation
The novel aspect of Tiziana is primarily the method of administering foralumab. In all current therapeutic applications, antibodies (mostly IgG types) are infused or injected to give systemic coverage. Tiziana takes a different approach. It delivers foralumab to the exterior nasal or gut surfaces.
As antibodies are very large molecules, they will not on their own penetrate the mucosal surfaces of the body: the gut wall or nasal surfaces. To cross these, they need to be transported by Fc carrier molecules into the immune cell rich layers below.
Foralumab does not enter the blood on oral or nasal administration so this is not a route for systemic disease like rheumatoid arthritis.
Immune cells (T-regs) modulated by foralumab action might cross the blood-0brina barrier to affect immune processes in the brain.
Putative mode of action
To modulate a malfunctioning immune response, like Crohn’s Disease at the surface of the gut, this approach offers the potential of localised immune control.
In theory, foralumab down regulates cell-killing T-cells and promotes calming regulatory T-cells, Figure 2.
Foralumab, by binding to a T-cell, causes internalization of the T-cell Receptor-CD3 complex. If enough complexes are bound, this down regulates the ability of the killer T-cell to become active after antigen exposure.
The potent effects of any regulatory T-cell response generated might extend to other immune cells in the brain such as microglial cells, a type of macrophage. This might have effects on neuro-degenerative diseases. These might be further indications to explore in future.
Figure 2 - Foralumab immune modulation effect
Nasal administration
Source: Tiziana
Adapted from Marasini et al, 2016
Nasal administration
In the nasal cavity and upper airways, the mucosal immune response is slightly different to the gut wall, and less understood. The same cell biology processes happen but the regulatory immune cells in the head move around a complex network of lymph nodes (small and ubiquitous tissue drainage channels used by the immune cells to move around), including tonsils and cervical lymph nodes (Waldeyer’s ring). There are specialised tissues in the nose: nasopharynx- associated lymphoid tissue. The nose, mouth and lung surface are highly exposed to potential pathogens.
From the neck (cervical) lymph nodes, regulatory T-cells might modulate the immune response in the brain. Multiple sclerosis is caused by a long-term, chronic attack on the brain by cell killing T-cells. The aim of foralumab in multiple sclerosis is to promote the calming regulatory T-cells in the brain to gain control over the malfunctioning immune response.
Preclinical data on nasal delivery
There is mouse data from other authors (Exhibit 1) indicating that anti-CD3 use promotes regulatory T-cells, these calm the immune repose to a particular threat. We note that T-cell biology is very complex, and that regulatory T-cells also use CD3. One should therefore be cautious on simplistic theory and mouse models and look to clinical outcomes.
Exhibit 1 - Mouse evidence for anti-CD3 action
Source: Tiziana
The level of the Phase 1 nasal delivery study
A small exploratory Phase 1 study was run in 2019, Exhibit 2. The data showed that given as a spray, foralumab was well tolerated up to 0.25mg/ day. This is more than twice the planned 0.1mg daily dose for the next stage of the trials.
It was also shown that T-reg numbers increased and IL-10, a potent stimulator of T-regs, was produced. This reduced the level of interferon gamma, the pro-inflammatory cytokine.
Exhibit 2 - Phase 1 nasal delivery study
Source: Tiziana
Fortalumab in Multiple Sclerosis - nasal
MS is a devastating, chronic inflammatory disease of the central nervous system, affecting approximately 2.3mln people worldwide and up to one million people in the US, according to a study conducted by the National MS Society. Generally, MS is divided into its most prevalent relapsing and remitting type (RRMS), and primary and secondary progressive forms (SPMS/PPMS). There are a limited number of other late-stage clinical programmes for progressive MS. So, if the alternative modality and mechanism of nasal foralumab are safe and efficacious, it could be an important supplementation to other treatment options. This is a particularly interesting approach given the severe side effect profile of first-line treatments such as Ocrevus (ocrelizumab, Roche), which includes infections and infusion reactions, and the acute unmet need.
Clinical development
An escalating dose study using nasal foralumab is planned in Primary and Secondary Progressive MS, NCT05029609. This should start in October 2021 and is planned to achieve its primary endpoint in late 2022. We therefore expect the outcome to be announced in Q1 2023. There will be four-dose arms run sequentially with escalation if the previous dose was safe and tolerable. Doses are not stated in the trial record. Each arm will have nine active and three placebo patients. It is estimated that 55 patients need to be recruited.
Individual patient study in MS
In March 2021, Tiziana received FDA permission for nasal dosing of foralumab in a single secondary progressing MS (SPMS) patient under an individual patient compassionate use programme. Investigators have treated this patient for three months using a repeated thee week course (two weeks of dosing three times a week then a one-week rest before restarting). Detailed safety, neurological, imaging and PET measurements have been made. This tests the rationale for activating the mucosal immunity via the cervical lymph nodes signified by modification of immunological and neurodegenerative markers. Results from this study will be presented when available, possibly in the near term.
Commercial potential
One of the biggest players in MS is Biogen. It has a range of products and generated Q2 2021 sales of US$1.8bn. However, these are falling as Tecfidera (dimethyl fumerate) has become generic in the US. The classic MS therapy is beta interferon. In MS, a 2021 market report estimated that US beta interferon sales would grow to $4.8 billion. Interferons are now generic, but Biogen still sold US$400mln in Q2 2021.
We initially see foralumab as an add-on to dimethyl fumarate (an easy to take oral product) used for relapsing-remitting MS and/ or beta interferons which are used more for active, relapsing MS. It is too early in the foralumab development process to be clear about what the label might be.
Oral administration
The small intestine surface is huge, about 400m2 or 200 times bigger than the skin surface area. Hence, it is exposed to many potential infectious agents. In the gut, the layer below this barrier epithelium is the lamina propria, a porous, elastic layer full of immune cells. The gut wall has special areas, for example, Peyer's patches, areas of lymphoid tissue full of immune cells lying just under the top layers of the wall which “sample” the contents of the intestine. This enables immune cells to detect possible threats – and be ready to destroy them. Peyer's patches connect via surface “M-cells” to the intestine to sample the gut contents for threats. Some immune cells then make IgA and secret that into the gut to neutralise pathogens directly.
In the subepithelial layer, it is believed that foralumab binds to the cell-killing CD8+ T-cells and neutralises them. this happens as T-cells kill when they see signals through their specific receptor, the TCR and its associated stimulatory receptor, CD3. If CD3 is bound by foralumab but the TCR is unbound, the T-cell becomes lethargic and can die. This process releases signalling molecules that trigger regulatory T-cells; these modulate the activity of cell killing T-cells. A key cytokine here is IL-10. That spreads widely triggering the calming response.
There is, in support, some clinical data from a small open trial with oral delivery of another anti-CD3 antibody, the mouse-derived product OKT3. This is an approved product but has major side effects and is very immunogenic.
Phase I oral trial
Tiziana conducted a small volunteer study using oral foralumab (up to 5mg doses) at the Brigham and Women’s Hospital, Exhibit 3. It was found that oral foralumab was safe and immunologically active as measured by suppression of CD8+ T cell responses (the killer T-cell type) and with induction of CD4+ IL-10 responses (these are regulatory T-cell responses).
The data are being analysed; the trial has not been published.
Exhibit 3 - Foralumab Phase I data
Source: Tiziana
Foralumab in Crohn's disease - lead oral indication
Tiziana plans to start a phase 1b dose-escalation study of oral foralumab in Crohn’s disease (NCT05028946, EU Clinical Trial 2021-002698-24 (not on database)). Oral administration uses an enteric-coated capsule. This passes unaltered through the stomach but dissolves in the small intestine. We assume the main site of action is towards the end of the small intestine in the Ileum where the Peyer’s Patches are located. This is also often the main site of Crohn's lesions.
The protocol is for dosing once a day for five days, then a two-day observation period, then a further five days of treatment. If safety and tolerability are shown in the patient cohort, then the trial moves to the next dose level. We understand that daily dose levels will be at 0.5, 1.25. 2.5 and 5.0 mg. This type of trial can be slow to run as each stage must be cleared and evaluated before the next. The trial record states that it might run till July 2023.
After this type of dose-escalation study, it is then usual to have a cohort expansion whereby a larger cohort is given the maximum tolerated dose. This enables an assessment of efficacy, but not proof. If this is successful, then a larger Phase 2 or possibly pivotal Phase 3 study is run. This normally requires a major partner.
Crohn’s market potential
Clearly, the implications are significant since the advanced CD therapy market is dominated by mAbs including Humira (adalimumab, Abbvie) and Stelara (ustekinumab, J&J). Analysts peg the prospective value of the CD market at over US$20bn in the next decade. While the landscape is dominated by big pharma, foralumab’s potential in CD could lie as an easy to add-in adjuvant to treat populations that are failing on first-line therapies.
Foralumab and COVID-19
The main opportunity for foralumab in the shorter term is as a potential symptomatic treatment for severe COVID-19. In COVID-19, the nasal cavity is a major site of infection and so immune activity. Regulating any overreaction to SARS-CoV-2 virus (but not reducing the immune response to clear the virus) might modulate the widespread immune response in the lungs, known as a cytokine storm. The extent of the immune modulation needs to be established in larger clinical trials. Initial results show that a leading inflammatory cytokine, IL-6, appears to fall after foralumab administration. In 2018, a research report showed that a nasal immune reaction against SARS-CoV (not the current COVID-19 one) could protect the lungs against a pathogen challenge.
Regulators have been willing and pressurised, at least in 2020, to fast-track clinical innovations. However, with widespread vaccination in developed countries resulting in declining numbers of severe infections, this urgency has fallen. This is likely to mean that innovations will be more rigorously examined by regulators and looked at critically by payors. However, it is also clear that SARS-CoV-2 is not going to vanish and there will be a need for a portfolio of therapies to treat patients. Further mutations and lock-downs are possible, new variants might evolve, and the number of potential patients remains high.
Background to immune regulators in COVID-19
As the immune system clears the SARS-CoV-2 virus that causes COVID-19, collateral damage can be done by an immune over reaction. Drugs known to control this include dexamethasone which reduces the recovery times in those patients needing either non-invasive or invasive oxygen (that is a pressurised mask or intubation on a ventilator). Agents that reduce the immune response are not recommended in the earlier stages of infection as this prevents it from destroying the virus.
In a 39-patient Phase 2 study in Brazil in mild to moderate COVID-19 patients, Tiziana observed reduction of serum interleukin-6 (IL-6) and C-reactive protein (CRP) when foralumab was used alone compared to either untreated patients or those treated with a combination of dexamethasone and foralumab. This was published in a paper: Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study. Frontiers in Immunology, 12 August 2021.
IL-6 is a potent driver of immune inflammation as it stimulates the acute phase response in the liver, so leading to CRP production, and causes the production of more platelets in bone marrow (which are involved in clot formation) and also drives immune responses, it also reduces regulatory T-cell activity and stimulates the production of more cytotoxic T-cells - which kill virus-containing cells - but also cause collateral tissue damage.
Brazilian study of foralumab
The study, published in August 2021 recruited 39 patients. Some key data is shown in Graph 1. It was an early-stage trial; we note that trials in Brazil at this time were not easy to organise given the pandemic and resulting confusion. The trial was in patients with confirmed SARS-CoV-2 infection but who did not need hospitalisation or oxygen.
Generally, these were younger patients, and the majority were not obese, hence they were drawn from a worried, low risk group. Socio-economic status was not described but most were white.
Lung scans were done and scored but some patients, particularly in the control group, had no obvious lung symptoms at the outset.
Trial arms were small and not balanced. Table 2 shows the breakdown.
The graphs show the fall in the inflammatory cytokine IL-6 and the acute phase protein (made by the liver) CRP in response to LIL-6 driven inflammation. Both markers fell in the foralumab only treated group, but they are biochemically associated.
Graph 1 - Brazilian Trial marker data
Source: Tiziana
Table 2 - Foralumab COVID-19 Phase 1
Brazilian data
Source: Frontiers in Immunology, 12 August 2021
Trial analysis
A confusing factor was the widespread use of prophylactic steroids. In other countries, these would not be prescribed but they seem to have been common, along with pointless antibiotics and horse medications. The foralumab group were selected from those who did not use steroids and this might have affected the results, noted the authors. The foralumab cohort were also older (44.5 years), age is a factor in the severity of COVID-19 infection, compared to controls, averaged 33.5 years. The authors noted that there were no differences in symptom scores across the groups. The trial was open-label.
More rapid clearance of lung infiltrates, as measured by CT scanning, was observed in foralumab and foralumab -dexamethasone-treated subjects compared to those that did not receive foralumab - although the authors note that the analysis was complicated by a number of patients in the control group having no lung lesions. This data was, however, compelling and lung measurements form the basis for the next trial.
Foralumab treatment was well-tolerated with no severe adverse events. The most interesting finding was that markers of immune inflammation, IL-6 and the acute phase protein CRP (made by the liver in response to IL-6) both fell faster in the foralumab group compared to control. However, IL-6 levels were twice as high in the foralumab group prior to treatment and natural recovery would presumably cause this level to fall anyway. An effect was not seen if dexamethasone was also given. Immune suppressing agents like dexamethasone are not indicted in the UK in the early stages of the infection as they suppress the natural immune clearance of the virus.
Overall, the study authors concluded that: “although we found positive effects of nasal Foralumab as measured by decreases in IL-6 and CRP and improvement on lung CT scans in mild to moderate COVID-19 patients, our results must be taken with caution, and we cannot conclude that nasal Foralumab has a beneficial effect in COVID-19 until larger studies are performed”.
Next clinical study
The proposed Brazilian Phase 2 clinical study, planned to start by the end of 2021 with results possibly announced around mid-2022, will be a rigorous double-blind, proof-of-concept study of intranasal foralumab in hospitalised subjects with severe COVID-19 and pulmonary inflammation. It will enrol 80 patients. Dosing will be 100ug/day of foralumab (50ug per nostril) for 14 days. In June 2021, Tiziana contracted FHI Clinical to conduct the study at trials at up to 7 sites in Brazil.
The primary endpoint is the effect of intranasal foralumab on the evolution of pulmonary infiltrates in hospitalized subjects with severe COVID-19 pneumonia. This is assessed by lung CT scans on day 14 (last day of treatment) and day 28 (two-week follow-up). This study is tougher than the initial mild-moderate study reported above. Patients have more severe disease and are hospitalised. Some will die over the 35-day assessment, trial and follow-up period. However, a positive result will give very strong evidence of efficacy.
Tocilizumab as an example of an immune modulator in COVID-19
In this therapeutic space, tocilizumab is an approved, recombinant humanised monoclonal antibody sold as Actemra by Roche, that inhibits binding of IL-6 to IL-6 receptors. It is not approved by national regulators for COVID-19 treatment - although it is recommended by the WHO as a treatment option. A large 4116-patient clinical trial, RECOVERY, is underway showing some benefits to COVID-19 patients treated with tocilizumab. The initial results, reported in May in The Lancet, showed an improvement in 28-day recovery and slightly lower mortality (31% vs 35%, p=0.0028). There are always problems in analysing large COVID-19 trials . In particular, the authors noted that the tocilizumab mortality at 31% is still far too high. Tocilizumab is normally used to treat an autoimmune disease like Rheumatoid Arthritis. Its patent has expired (2017) but no biosimilar products have yet been approved.
CAR T-cell therapy opportunity
The area of Chimeric Antibody Receptor (CAR) T-cell therapy is still relatively new. Current products include Yescarta (axicabtagene ciloleucel, Gilead), Kymriah (tisagenlecleucel, Novartis) and Abcema (idecabtagene vicleucel, BMS). These products are currently made by genetic modification of killer T-cells taken from the individual patients. The manufacturing process takes some weeks and is logistically complex. In addition, as each therapy is custom made, and not always successful, costs are high and prices are up to $475,000 – plus all the extra costs and hospital time.
To make a CAR T-cell, killer T-cells, a type of white blood cell are isolated from the patient’s blood. Killer T-cells sense abnormal cells and selectively kill them; one T-cell might kill up to a thousand cancer cells, so they are potent and lethal if triggered. CAR T-cells detect their cancer cell targets through a very complex genetically engineered receptor, the CAR, that is genetically inserted into the cells. This does not use cell-surface CD3 so is not bound by foramulab. Currently, approved products only target some leukaemias and lymphomas and recently multiple myeloma. Many other targets are in clinical development.
The biggest markets will develop if CAR T-cells therapies can be made general, that is allogeneic so one batch can be used to treat many different patients. this means they can be cheaper and stored in the freezer at major cancer centres. (Current products are autologous: the therapy is custom manufactured for just one patient using their own cells).
The other goal is to develop CAR T-cell therapies against solid cancers. This is proving hard as there are multiple factors affecting the efficacy of T-cells, but globally, clinical development efforts are intensive with many cancer types and targets (cancer antigens) under development.
Commercial impact on Tiziana - little now, high long-term potential
The deal is exclusive to Precision and restricted to using foralumab with Precison’s allogeneic CAR T-cell therapies. It has an upfront fee, some milestones and a royalty although these are not disclosed. As a preclinical stage project with high development costs over probably at least five years as a systemic, infused product, we do not expect significant payments soon - although potential royalties could be significant. Development times are likely to be long but are currently not disclosed. If the project shows promise, it might be extended by various routes as it is potentially broadly applicable to other CAR T-cell applications.
Accordingly, we see this deal as scientifically interesting and a potential source of considerable future value. Shorter-term, it will have a minimal financial impact. By passing all costs to Precision, the opportunity can be explored without distracting Tiziana from its core focus on oral and nasal delivery of foralumab.
Potential use of foralumab in CAR T-cell therapy
Before CAR T-cell therapy can be given, the number of natural killer T-cells in the patient has to be reduced. This enables the infused CAR T-cells to reproduce and deliver a much better therapeutic response as they kill the cancer cells.
Targeting CD3 depletes killer T-cells and foralumab is an anti-CD3 monoclonal. Foralumab has been shown, after a dose of 1mg day for five days, to reduce T-cells by up to 60% in Crohn’s disease (see above).
Currently, the depletion of existing T-cells is done by combining two toxic agents, called Cy-Flu therapy.
- Fludarabine (Flu) which can cause fevers and brain toxicity
- Cyclophosphamide (Cy) which causes haemorrhagic cystitis, pericarditis, and brain toxicity
The side effects are serious and can prevent patients from attempting CAR T-cell therapy or even kill them. They can also trigger secondary cancers.
If foralumab can be used on its own or combined with low dose Cy/Flu, it might reduce overall toxicity and enable more patients to be treated. To gain approval in this indication, foralumab will have to undergo clinical trials. As yet, it is too early to be clear on the potential approved indication.
There is a possible use in maintaining suppression of host immune cells after administration of a CAR T-cell therapy. This might potentiate the therapeutic response. However, this seems a longer-term prospect.
Clinical analogy- Allo-647
The ALPHA study (NCT03939026), used another monoclonal antibody (Allo-647) against CD52. CD52 is another T-cell marker. It was given for lymphodepletion of 22 patients with relapsed/refractory diffuse large B-cell lymphoma and administered alongside Flu/Cy.
Preliminary results showed that higher doses of Allo-647 were associated with more significant suppression of endogenous T cells and a 50% complete response rate the therapy versus 27%.
Allo-647 is now being tested at 13mg/day for three days both on its own and as an addition to Cy/Flu preconditioning in five clinical studies run by Allogene. We assume that this provides a model for potential foralumab development. Data shows better immune suppression by adding All-647 into the lymphodepletion mix.
Allogene notes that Allo-647 is intended to reduce the likelihood of the patient’s immune system from rejecting AlloCAR T cells.
Precision Biosciences
Because Precision, Tiziana's licensee, specialises in genetic modification, it designs CARs, make the genetic packages and insert them into T-cells. The T-cell normally makes a sophisticated receptor (a TCR) that is activated by an associated receptor, CD3. Precision knocks out the TCR and CD3 genes in the T-cells and inserts genes for a CAR to target a cancer. This does not use cell-surface CD3, so is not bound by foramulab.
Precision has three allogenic products in early clinical-stage development with two more approaching clinical development. All of them target blood cancers and known cancer antigens.
Precision (Nasdaq:DTIL) is a US company with a market capitalisation of $760 million.
Milciclib (TZLS-201)
Milciclib was licensed from Nerviano Medical Sciences, an Italian company, in 2015. The core patent expires in 2023. The deal had a US$3.5mln upfront payment, various milestones up to $35 million and a 3.5% royalty rate. Milciclib is a cyclin-dependent kinase inhibitor (CDK) that is positioned to treat cancers that have proved to be resistant to repeated rounds of chemotherapy or the current standard of treatment. The method of action is to inhibit cancer cell division and the potential conversion of healthy cells to cancerous ones. Milciclib has been studied in a total of eight completed Phase 1 and Phase 2 trials in 316 patients.
Cancer indications
Tiziana intends to initially focus milciclib development for liver cancer (Exhibit 4) that does not respond to sofanabib (Nexavar, Bayer). The primary risk factor for HCC is hepatic cirrhosis. The American Cancer Society predicts approximately 42,810 new cases of live cancer will be diagnosed in 2020 of whom approximately 30,160 will die.
Non-small cell lung cancer is another potential indication (Exhibit 4). Although checkpoint inhibitors work well for some patients, there is still a very high unmet need for new therapies.
Thymic carcinoma is a rare cancer that often shows no symptoms. It affects approximately 0.12 people in 10,000 in the EU - so could gain an orphan drug designation.
Exhibit 4 - Cancer targets for milciclib
Source: Tiziana
Phase 1/2 study
A study in 31 patients with HCC (EU Trials register 2017-000144-18) was completed in 2019. This study evaluated the safety and tolerability of milciclib in Child-Pugh "A" unresectable hepatocellular (liver) carcinoma (HCC) patients who failed or were not eligible for sorafenib, the standard first line therapy in this indication. This was a single arm study.
Tiziana presented the data, Exhibit 5, at the May 2020 Virtual American Society of Clinical Oncology (ASCO) conference.
Exhibit 5 - Liver cancer trial outcome
Source: Tiziana
Clinical development
Tiziana is intends to focus the development of the pan-CDK inhibitor milciclib on the treatment of hepatocellular carcinoma (HCC) in combination with a tyrosine kinase inhibitor (regorafenib or sorafenib). Tiziana anticipates initiating this Phase 2b in Q1 2022.
Milciclib is also being used in combination with regorafenib for the treatment of liver transplant patients with recurrent HCC in an investigator-initiated clinical trial, as reported in an abstract presented at the 2020 ASCO Virtual Meeting. Tiziana intends to conduct a larger trial in liver transplant patients with recurrent HCC using this drug combination.
Tiziana ran a 28 patient Phase 2 trial in recurrent or metastatic, unresectable thymic (a neck gland) cancer (NCT01011439) completing in 2018. Tiziana reported that 17 of 28 (60.7%) evaluable patients showed stable disease and that one patient (3.6%) showed a partial response.
Competition
There are multiple agents in development for HCC, many in combination with tyrosine kinase inhibitors or checkpoint inhibitors, mostly Keytruda (pembrolizumab, Merck). There are four approved CDK inhibitors, all of which are specific to CDK4/6 kinases. These are Ibrance (palbociclib, Pfizer), Kryxana (ribociclib, Novartis) and Verzenio (abemaciclib, Lilly), which are approved for hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer and Cosela (trilaciclib, G1 Therapeutics), which is approved for small cell lung cancer.
Of the first three, only Verzenio is in a study intended to support registration in another indication (prostate cancer), while Cosela is in Phase 3 trials for colorectal cancer and triple-negative breast cancer. Several companies (including Merck and Bayer) have had pan-CDK molecules in clinical trials, but these appear to have been discontinued. Cyclacel has previously pursued the development of a CDK2/9 inhibitor, seliciclib, although this has been largely discontinued in favour of a second-generation agent with the same kinase specificity, fadraciclib. Tiziana notes that as a potent cdk2 inhibitor, milciclib potentially blocks a major resistance route to cdk4/6 inhibitors.
Anti-IL 6 receptor mAb (TZLS-501)
Tiziana’s third product under development, TZLS-501, is an anti-interleukin-6-inhibitor that is the company’s second monoclonal antibody candidate after foralumab. Tiziana licensed the drug from Bristol Myers Squibb. The mAb works by binding to membrane-bound and soluble IL-6R, an inflammatory cytokine that drives the inflammation associated with autoimmune diseases and cancer. The product’s potential use in COVID-19 patients has meant an accelerated development programme, with Tiziana last year signing research agreements with several contract research organisations to begin studies. No US trials are however listed as yet although Tiziana management have indicated that a US trial starting in Q12022 is being planned.
Competitor products and market opportunity
The risks involved in the clinical trial phase stage of product development was more than amply demonstrated by the number of trial failures for potential treatments for COVID-19, in particular. Sanofi ceased development of Kevzara (sarilumab), an approved anti-IL-6 antibody, in the COVID-19 indication after high rates of side effects and low efficacy. A large Phase 3 study was run in over 400 patients that reported in September 2020.
IP Protection covering Tiziana's product portfolio
The patent portfolio is outlined in Table 3
Foralumab’s direct patent protection expires in 2024. A US formulation patent will expire in 2036. For biological therapeutics, patents are much less critical since, if approved, Foralumab as a new biological gains 12 years of biological exclusivity from the FDA. In the EU, the period is 10 years.
Biological products also have inherent IP protection since the production system is the key aspect, specifically the proprietary cell line in which it is manufactured. Because of this, any generic can only be biosimilar. This requires a complex development and clinical program which is expensive. Unless a biological achieves significant sales, no generic company will make the investment. In the US, at least four years must elapse after approval before the FDA will accept for review a biosimilar under the 351(k) pathway.
Foralumab also has various use patent applications recently filed including in COVID-19 and for CAR T-cell therapy. These expire up between 2037 and 2040 if granted.
Milciclib as a small molecule has its main patent expiry in 2023. It will obtain a five-year exclusivity from the FDA if approved. In Europe, it will have eight years of data protection, so no generic would be developed during that period, with ten years of market exclusivity. A generic could be launched after that. If other indications were developed, the exclusivity could extend to 11 years. Other use and formulation patents may extend the available period of exclusivity.
Table 3 - IP Portfolio
Source: Tiziana
Finnancial commentary
Tiziana is financially stable for the immediate future after two successful fundraising rounds in 2020 raised at a net total of £54.1mln. A realisation bonus of £10.3mln is payable to the executive chairman as a result of the successful fundraising.
In 2020, research and development expenses were £4.7mln, up from £2.9mln in 2019. Admin costs rose to £8.7mln from £4.9min in 2019. The reported 2020 loss was £20.2mln, up from a loss of £5.2mln in 2019.
In 2020, there was an operating cash outflow of £9.3mln, up from a cash outflow of £5.3mln in 2019. At the 31 December 2020 year-end, Tiziana had net cash of £48.2 mln. There was also a £2.2min tax credit due.
As further clinical trials commence, cash burn can be expected to rise over 2021 and 2022.
Primary move to NASDAQ
The company will offer one new share for two of each old Tiziana shares in a straight 2-for-1 consolidation.
The consolidation and de-listing moves investor interest to NASDAQ. Overall, we see this as a positive as it should make the shares considerably more tradable, as well as boosting Tiziana’s access to new sources of capital in the long term.
It follows in the footsteps of UK listed biotech companies such as GW Pharma; now acquired by Jazz.
Peer comparison
The most obvious peer comparator is Provention Bio (NASDAQ:PRVB) with a market cap of US$410mln (as of 13 Sept 2021). Its lead programme is humanised anti-CD3 mAb teplizumab (Phase 3) being developed for type-one diabetes. Type-one diabetes is an autoimmune disease that often manifests in pre-adolescent children as their immune systems destroy their insulin-producing cells. Anti-CD3 monoclonals have shown efficacy in this indication. It also has programmes in a vaccine (PRV-101), in lupus (PRV-3279) and in Celiac disease (PRV-015).
Hence, Provention Bio is a later stage company with a better validated clinical hypothesis and a clear market opportunity in T1D. There is also novel pipeline in other large indications. Tiziana can aim to reach this capitalisation once Phase 2 studies have shown both safety and clear efficacy indications for foralumab and pivotal studies are underway.
Risks & Sensitivities
All clinical stage smaller companies carry very high levels of risk. These can result in exceptional returns in the right circumstances, but this requires significant investment over several years. There are three broad risk categories.
Market-driven risks
Only time will tell whether developing a symptomatic COVID-19 treatment will pay off. If vaccination succeeds in most developed countries in suppressing the severity and spread of the virus, then the urgency for drug-related treatment of severe cases diminishes when compared with the established standard of care (in this case, the inexpensive steroid treatment dexamethasone). Conversely, this could also be a positive if highly infectious variants emerge that vaccination cannot generally prevent from developing into severe disease. This would open the market to novel medicines that had robust clinical efficacy.
Execution risk
The failure rate for biotech products is very high in the earlier trial phases with under 30% overall success rates; Phase 2 trials, in particular, are a big obstacle as here a product must show indications of efficacy in a realistic clinical situation. Even later stage pivotal studies still have only a 50%-60% probability of success in general, in later-stage trials. Regulatory processes can reveal clinical issues hidden from investors; the dreaded “complete response” letter from the FDA, refusing an approval, has crushed many hopes.
Tiziana must design fund and run carefully designed Phase 2 studies to convince a much larger pharmaceutical or biotechnology major to fund the later stages of its research. This will generate upfronts and potentially milestones. Eventual regulatory clinical success is usually marked by a milestone. After that, the product has to be commercially successful and marketed strongly in a competitive global marketplace to generate substantial royalties.
Sector trends
There is always the possibility that sentiment will move against biotech again, as it did in the early to mid-2000s. The IPO market for biotech was very buoyant in 2020, with total fund-raising nearly tripling in a year. That momentum has continued with the caveat that deal sizes are getting smaller, with signs of a correction in overall valuation. That may affect companies like Tiziana that need to fund their long-term operations through issuing equity. We note that the US stock market, though enormous, is very competitive for investor attention and dollars. Analysts and commentators can be brutal. Tiziana as a small market capitalisation company might find it hard to attract attention and costs can be high.