Formation Biologics Inc., a company more commonly called Forbius that's developing biologics for fibrosis and cancer, has dosed the first patient in a phase IIa study designed to evaluate its EGFR-targeting antibody-drug conjugate, AVID-100, in patients with EGFR-overexpressing squamous cell carcinoma of the head and neck (SCCHN). The primary endpoint of the trial is the number of participants with objective response or stable disease. Development of the drug, which is also being tested against advanced squamous cell non-small-cell lung cancer (NSCLC), has been supported by two grants from the Cancer Prevention and Research Institute of Texas (CPRIT) .

The study is constructed with a seamless trial design, a relatively new concept, pioneered by Merck & Co. Inc. with Keytruda (pembrolizumab), that combines the traditional three phases of trials into one. Following a phase Ia-type study defined under the same protocol, Forbius is now running three parallel but independent studies testing AVID-100 in several indications: NSCLC, SCCHN and triple-negative breast cancer (TNBC). Each study will enroll about 15 patients with the option to expand to 30 or more depending on the amount of activity investigators see with AVID-100. Responses will be measured via imaging of marker lesions. (See BioWorld, Oct. 31, 2017.)

All patients enrolled in the SCCHN and NSCLC studies will have tumors that highly overexpress EGFR, meaning more than 50 percent of cells with EGFR 3+ staining through testing with Agilent Technologies Inc.'s EGFR Pharmdx test. About 20 percent of people with SCCHN have tumors that highly overexpress EGFR, the company said. Meanwhile, the TNBC study will include two cohorts, one with EGFR 3+ and another with EGFR 2+.

"We're doing the latter for two reasons," Forbius' chief medical officer, Paul Nadler, told BioWorld. "One is logistical – 3+ positive triple-negative [breast cancer] is less common than in the other two indications – but also because we want to test with our antibody whether this expression/response relationship is critical. Because if it isn't, it will make it a lot easier for us to expand in other indications into people with less positivity," he said.

A recommended phase II dose of 240 mg/m2, or about 6 mg/kg, was established for AVID-100 in a completed phase I portion of the company's study.

Skin rash has been a consistent side effect of most EGFR inhibitors, because the protein is not just part of tumor cells but also other normal healthy epithelial cells. What makes AVID-100 special and different, Forbius' chief scientific officer, Maureen O'Connor-McCourt, told BioWorld, is the relatively high dose at which it can be provided without triggering that toxicity. The feat is enabled by the antibody the company has selected to link to the toxin it uses, DM1. "In the end, we're finding that the antibody protects cells against the toxin, but does not prevent the toxin from working on tumor cells," she said. "You have to have a fully active, fully antagonist antibody to do this," she added.

The company, founded in 2011 in Montreal as Avidbiologics with ADC technologies co-developed with the National Research Council of Canada, was formed as a management-led spinout from YM Biosciences Inc., prior to YM's acquisition by Gilead Sciences Inc. It has since grown to around 40 full-time employees. The company continues to have discovery and manufacturing staff in Montreal, but has since added a base of operations in Austin, Texas, with CPRIT's support. The company is led by President and CEO Ilia Tikhomirov.

Last year, CPRIT provided the company with an $18.8 million grant to support its phase II work, following on a $12.8 million grant provided in 2015 to support phase I development of the candidate. It's help that O'Connor-McCourt said "lets the company grow more and get to a later stage" and that, according to Nadler, comes with an approach that's relatively hands-off vs. the kind of funding and more hands-on attention attached to most venture investments.

In addition to AVID-100, the company is also developing the TGF-beta inhibitor AVID-200, which is designed to neutralize both TGF-beta1 and TGF-beta3, isoforms known to be drivers of fibrosis and tumor immune resistance. The company recently dosed the first patient in a phase Ib trial of the candidate in diffuse cutaneous systemic sclerosis.

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