Therapeutic Differentiation

Galera Therapeutics (GRTX) is a privately-held company that recently filed for an IPO. Its clinical focus is on developing Phase 3 lead investigative drug candidate, avasopasem manganese (formerly GC4419), to treat severe oral mucositis (SOM) associated with head and neck cancer (HNC) radiotherapy.

Oral mucositis (OM) occurs when radiotherapy induces the production of superoxide that attacks and breaks down the epithelial cells lining the mouth. The severity of OM is commonly measured using the WHO scale consisting of five Grades: Grade 0 through Grade 4 with SOM is commonly defined as Grade 3 or Grade 4 OM (discussed later).

Therapeutically, the annual addressable market for oral mucositis in G8 countries was estimated to be $638.8M in 2016 with a subsequent global annual projection of $2.6B in future years. In the US, ~500,000 individuals are diagnosed with OM annually and the prevalence is expected to rise in parallel with an increasing incidence of HNC projected at 65,000 every year.

SOM is a serious non-hematological complication of cancer associated with both chemotherapy and radiotherapy treatments. When caused by chemotherapy, mucositis is usually due to the low white blood cell count. In contrast, radiotherapy mediated mucositis is usually due to necrotic and inflammatory effects of radiation energy on oral mucosa.

In Q1/2018, Superoxide dismutase (SOD) mimetic, avasopasem manganese (formerly GC4419), received FDA Breakthrough Therapy Designation for the reduction of the duration, incidence, and severity of SOM induced by radiotherapy. GRTX thesis is that avasopasem manganese is therapeutically differentiated from the only FDA approved therapeutic for SOM, Kepivance, because it:

has the potential to address and mitigate the root cause of radiotherapy-induced mucositis, including OM and esophagitis. By removing superoxide, GC4419 is designed to reduce the damage radiotherapy causes to the patient's normal tissue, and thereby reduce the incidence and severity of mucositis.

In 2004, Kepivance (formerly palifermin), a recombinant human keratinocyte growth factor developed by Amgen (AMGN), was approved to reduce the incidence and duration of SOM in patients with certain types of blood cancer (i.e. hematologic malignancy) who are being treated with high-dose chemotherapy and radiation therapy followed by a stem cell transplant. It protects the epithelial cells that line the mouth and throat from the damage caused by chemotherapy and radiation and by stimulating the growth and development of new epithelial cells to build up the mucosal barrier.

The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies and this represents an important clinical differentiation from GC4419. Since its approval in 2004, Amgen has advanced the clinical development of Kepivance (palifermin) for other hematological indications as reflected in ongoing clinical trials.

Specifically, it is being studied in the prevention and treatment of common side effects in other types of cancer. If clinically successful, this would expand the addressable market for Kepivance.

At the end of Q3/2019, AMGN reported cash and investments of $20.9B and free cash flow of $3.2B. Total revenues in Q3/2019 decreased by 3% to $5.7B relative to Q3/2018. Analysts recommend a buy with a 12-month price target of $220.79. Institutional ownership stands at 78.91% based on 13F filings and accounting for 1,969 Institutional holders with 468,873,044 total shares.

Superoxide dismutases (SODs) are protein enzymes that provide antioxidant defense against the pathophysiological effects of reactive oxygen species (ROS)/oxidative stress in diverse disease states. These protein enzymes convert superoxide to molecular oxygen and hydrogen peroxide (Fig. 1). Hydrogen peroxide is much less toxic than superoxide to normal tissue but more toxic to cancer cells. Radiotherapy induces a large burst of superoxide in the irradiated tissues, which can overwhelm these SODs, damaging normal cells.

Figure 1: (A) The generally accepted catalytic mechanism for dismutation of O2 - by superoxide dismutase (SOD). (B) Subunit structure of bovine Cu, Zn-SOD (Protein Data Bank Entry, 2 SOD).

Elevated ROS/Oxidative stress has been implicated in cancer progression. Furthermore, targeting antioxidant enzymes is increasingly perceived as an important radiosensitizing strategy to reduce the resistance of cancer cells to radiotherapy. Pharmacologically, GRTX describes GC4419 as selective, stable in vivo and does not react with other oxygen species, and its low molecular weight contributes to its ability to access a cell's cytosol and mitochondria. Notably, GRTX notes that:

The ability to develop a low-molecular-weight synthetic enzyme that harnesses the power of dismutase mimetics to function as a radiation response modifier, with efficient chemical synthesis and stability, offers a new paradigm for drug design.

By rapidly converting superoxide to oxygen and hydrogen peroxide, GC4419 works to reduce elevated levels of superoxide caused by radiation, which can damage noncancerous tissues and lead to serious side effects, including oral mucositis.

The WHO scale description of Mucositis manifestation is as erythema (Grade 1), edema and/or ulceration but patients can swallow solid food (Grade 2) to ulceration with extensive erythema and patients cannot swallow solid food (Grade 3) and large and painful ulcers that worsen patient quality of life and limit basic oral functions such as speech, the swallowing of solid or liquid is not possible (Grade 4).

The data from a Phase 2b study of GC4419 in SOM associated with HNC demonstrated a reduction in:

the duration of SOM from 19 days to 1.5 days (92 percent), the incidence of SOM through completion of radiation by 34 percent and the severity of patients' OM by 47 percent, while demonstrating acceptable safety when added to a standard radiotherapy regimen.

In addition, in multiple preclinical studies, GC4419 demonstrated an increased tumor response to radiation therapy while preventing toxicity in normal tissue.

The Phase 3 confirmatory, randomized, placebo-controlled registrational trial of a 90 mg dose of GC4419 in patients with locally advanced head and neck cancer receiving radiotherapy was initiated in Q4/2018 with topline data anticipated in the first half of 2021.

At the end of Q2/2019, GRTX reported cash and cash equivalents and investments of $81.2M (S-1/A prospectus). Investors include Novo Ventures, Novartis Venture Fund and many more. GC4419 has multiple shots on goal with its Phase 1/2 clinical evaluation for pancreatic cancer (Fig. 2).

Fig. 2: Clinical Development of GC4711.

GRTX retains worldwide rights to GC4419. The IPO of 5M common shares has been set at $14 - 16.

In Q4/2019, GRTX reported on the long-term clinical effects of GC4419 in a two-year tumor outcome assessment:

As part of its Phase 2b clinical trial of GC4419 in patients with locally advanced head and neck cancer, Galera assessed tumor outcomes of the patients over a two-year period following radiotherapy. Patients in the trial received seven weeks of radiation therapy plus cisplatin, and were treated with either 30 mg or 90 mg of GC4419 or placebo by infusion on the days they received their radiation treatment. At both the one-year interim assessment and final two-year mark, tumor outcomes were maintained across all four measures - overall survival, progression-free survival, locoregional control and metastasis-free survival - in both GC4419 dose groups (30 mg and 90 mg) compared to placebo.

We are pleased with these data, which demonstrated GC4419, when added to a standard radiotherapy regimen, maintained the efficacy of treatment for head and neck cancer and reduced debilitating radiation-induced oral mucositis," said Mel Sorensen, M.D., President and CEO of Galera Therapeutics. "GC4419 achieved meaningful reductions in the duration, incidence and severity of SOM in the completed Phase 2b trial. These two-year tumor data further reinforce the potential of GC4419 to be a promising treatment to reduce radiation toxicities and complement standard radiotherapy regimens in head and neck cancer.

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