INDUSTRY OVERVIEW

COVID-19

The COVID-19 pandemic has brought to light the devastating effect of cytokine storms. Healthy individuals with strong immune systems are falling ill or dying not to the disease itself, but rather, the hyper inflammatory response that results. There are currently no products approved by the FDA for the prevention of cytokine release syndrome or cytokine storms associated with COVID-19. There are, however, numerous products currently in development for COVID-19; these products can be broadly categorized as direct-acting antivirals, immunomodulators, anticoagulants and other preventative strategies such as vaccines and neutralizing antibodies.

Remdesivir (a direct-acting antiviral) was approved by FDA for COVID-19. There is no evidence that suggests remdesivir offers a mortality benefit and the largest remdesivir-based global study conducted by the World Health Organization (“WHO”) failed to show benefit from the remdesivir treatment. Other direct-acting antiviral agents such as lopinavir/ritonavir and hydroxychloroquine (with or without a macrolide) have not demonstrated efficacy in randomized controlled trials. Published data to date from randomized controlled clinical trials in the setting of COVID-19 and the two leading IL-6 inhibitors, Actemra (tocilizumab) and Kevzara (sarilumab) have been mixed. The current treatments available under EUA include baricitinib (Olumiant) in combination with remdesivir (Veklury), bamlanivimab with Etesevimab, and REGEN-COV (casirivimab and imdevimab).

Recently published results from The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial have demonstrated that an anti-inflammatory treatment, tocilizumab, reduces the risk of death when given to hospitalized patients with severe COVID-19. The study also showed that tocilizumab shortens the time until patients are successfully discharged from hospital and reduces the need for a mechanical ventilator. A total of 2,022 patients were randomly allocated to receive tocilizumab by intravenous infusion and were compared with 2,094 patients randomly allocated to usual care alone. 82% of patients were taking a systemic steroid such as dexamethasone. Treatment with tocilizumab significantly reduced deaths: 596 (29%) of the patients in the tocilizumab group died within 28 days compared with 694 (33%) patients in the usual care group (rate ratio 0·86; [95% confidence interval [CI] 0·77 to 0·96]; p=0·007), an absolute difference of 4%. Tocilizumab also increased the probability of discharge alive within 28 days from 47% to 54% (rate ratio 1·23, [95% CI 1·12 to 1·34], p<0·0001). These benefits were seen in all patient subgroups, including those requiring oxygen via a simple face mask through to those requiring mechanical ventilators in an intensive care unit. Among patients not on invasive mechanical ventilation when entered into the trial, tocilizumab significantly reduced the chance of progressing to invasive mechanical ventilation or death from 38% to 33% (risk ratio 0·85, [95% CI 0·78 to 0·93], p=0·0005). However, there was no evidence that tocilizumab had any effect on the chance of successful cessation of invasive mechanical ventilation. In June 2020, the RECOVERY trial found that the inexpensive and widely available steroid dexamethasone reduces death for patients with severe COVID-19. Dexamethasone became part of standard-of-care given to all such patients. In this trial, the benefits of tocilizumab were seen to be in addition to those of steroids.

We believe that, as an upstream regulator of cytokine storm, GM-CSF neutralization with lenzilumab may offer advantages over other immunomodulator strategies that either target downstream cytokines such as IL-1, IL-6, CCR5, MCP-1, IP-10, TNF-α, or MIP-1α (the ligand for the CCR5 receptor) or are broadly immune-suppressive and target cytokine signaling pathways non-selectively through JAK inhibition or steroids which have well documented lympholytic properties. In addition, we believe, lenzilumab is the only immunomodulator that was in an active clinical trial in a non-COVID indication to prevent cytokine storm prior to embarking upon the Phase 3 COVID-19 trial. Not only is lenzilumab involved in COVID-19 related pneumonia, but lenzilumab may also have additional benefits on T-cell function as demonstrated in preclinical models with CAR-T.

Lenzilumab is being studied in patients with confirmed COVID 19 infection and pneumonia who are hospitalized not requiring IMV and blood oxygen (SpO2) levels below 94%. We believe the market potential for lenzilumab to be significant as shown in the following graphic. According to the COVID Tracking Project, as of May 21, 2021, weekly hospitalizations are approximately 3,438 patients.

CAR-T

Development and implementation of individualized treatments based on T-cell therapies has the potential to revolutionize the fight against cancer. Four CAR-T therapies have been approved by the FDA (Kite’s Yescarta, Tecartus, Novartis’s Kymriah, and Bristol Myers Squibb’s Breyanzi) to treat forms of B-cell cancers such as various types of Non-Hodgkin Lymphoma (“NHL”), including Diffuse Large-B-Cell Lymphoma (“DLBCL”), mantle cell lymphoma, and acute lymphoblastic leukemia (“ALL”) in patients that have failed two or more lines of systemic therapy. According to the Surveillance, Epidemiology, and End Results (“SEER”) program of the National Cancer Institute, it is estimated that nearly 20,000 patients per year in the U.S. will die from all forms of Non-Hodgkin Lymphoma, including patients with relapsed or refractory (r/r) B-cell NHL and ALL. Common side effects of CAR-T therapy include Cytokine Release Syndrome (“CRS”) and Neurologic Toxicities (“NT”). We believe agents that address the CRS and NT side effects of CAR-T therapies will greatly expand the use of CAR-T therapies.

The global CAR-T therapy market is projected to grow to greater than $2 billion in 2021, with continued growth up to $8.5 billion in 2028, according to ‘Evaluatepharma’.

GvHD

In addition to CAR-T therapy, we are advancing our platform for GM-CSF suppression for a broad range of other T-cell engaging therapies, including for the prevention and/or treatment of Graft versus Host Disease (“GvHD”) in patients undergoing allogeneic Hematopoietic Stem Cell Transplantation (“HSCT”), which involves transferring stem cells from a healthy donor to the patient. Allogeneic HSCT has demonstrated effectiveness in treating hematological cancers, and as a result, the overall number of allogeneic HSCT treatments continues to increase annually in the U.S. and in Europe. Unfortunately, many of these treatments lead to serious side-effects and have ample room for improved efficacy.

Allogeneic HSCT is a potentially curative therapy for patients with hematological cancers. Although a potentially life-saving treatment for patients suffering from hematological cancers, between 40-60% of patients receiving HSCT treatments experience acute or chronic GvHD, which together carries a 50% mortality rate. After being transplanted into the patient, donor-derived T cells are responsible for mediating the beneficial Graft versus Leukemia (“GvL”) effect. In many cases, however, donor-derived T cells that remain within the graft itself have also been linked to destruction of healthy tissue in the patient (the host), with particular risk of destroying cells in the patient’s skin, gut, and liver, resulting in GvHD. Although depleting donor grafts of T cells can prevent or reduce the risk of GvHD, this results in a reduced GvL effect, thereby having a detrimental impact on the efficacy of the allogeneic HSCT treatment itself and leading to increased relapse rates. We expect that the use of allogeneic HSCT may be hampered by GvHD complications. A recent study published in ‘blood advances’ an official journal of the American Society of Hematology suggests that neutralizing or blocking GM-CSF may limit or prevent GvHD in the gastrointestinal tract (Gartlan, K., et al, October 8, 2019, vol 3, no.19).

There are currently no FDA-approved agents for the prevention of GvHD, and there is a significant unmet medical need for an agent that can uncouple the beneficial GvL effect from harmful GvHD. At this time, pre-conditioning regimens for HSCT treatments vary significantly by treatment centers, including by unapproved, or “off-label”, use of agents that have been approved by the FDA for other uses only. We believe there to be a significant unmet medical need and lenzilumab, if proven to be able to prevent GvHD in allogeneic HSCTs, may offer a solution. GM-CSF neutralization with lenzilumab has the potential to prevent or reduce GvHD without compromising, and potentially improving, the beneficial graft-versus-leukemia effect in patients undergoing allogeneic HSCT, thereby making allogeneic HSCT safer.