LONDON – Synthon Biopharmaceuticals NV is making final preparations to advance its lead antibody drug conjugate (ADC) based on Herceptin (trastuzumab) into phase I, after completing a preclinical head-to-head comparison with the Herceptin ADC Kadcyla (ado-trastuzumab emtansine, T-DM1).

In both in vitro and in vivo tests Synthon’s product, SYD985 “clearly outperformed” Roche AG’s Kadcyla. Unlike Kadcyla, SYD985 was effective in breast cancers expressing low levels of the HER2 receptor (human epidermal growth factor receptor2) against which Herceptin is targeted.

“The compound was more potent in this indication, and far more importantly, patients with HER2 1+ and HER2 2+ breast cancers who are not eligible for T-DM1 could be treated,” said Marco Timmers, CSO.

“This would at least double the patient population,” he told BioWorld Today.

Both SYD985 and T-DM1 showed antitumor activity in high HER2-expressing models, with SYD985 being slightly more active. However, SYD985 demonstrated very potent activity in tumor cells expressing low levels of HER2, where T-DM1 was completely inactive. In these low-expressing HER2 tumor models, SYD985 was able to induce complete tumor remission after a single dose of 3 mg/kg.

In eight cell lines expressing different levels of HER2, both SYD985 and T-DM1 showed similar potencies in high-expressing lines. However, in cell lines with low HER2 expression, SYD985 was substantially more potent than T-DM1.

Synthon, of Nijmegan, the Netherlands, is presenting the data today at the American Association for Cancer Research Annual meeting. The company initially will treat patients with high HER2 expression in a dose escalation trial, expanding the cohort to include patients with tumors expressing low levels of the receptor once the maximum dose is established.

The key reason for SYD985’s superiority to Kadcyla in preclinical testing is the mode of action of the cytotoxic payload, according to Timmers. As a tubulin binder, emtansine manifests its effect when cells are undergoing mitosis, while the duocarmycin payload in SYD985 binds to the minor groove of DNA, disrupting the DNA of tumor cells at any stage of the cell cycle. This increases efficacy in cancers with low levels of HER2 expression.

In addition, SYN985 had a significantly better side effect profile than Kadcyla in the preclinical evaluation. Timmers attributed that to low circulating levels of the toxin payload, as demonstrated in animal models, and said target-mediated toxicity will be the dose-limiting factor.

While Synthon advanced a biosimilar version of Herceptin to phase III before outlicensing it to Watson Pharmaceuticals Inc. (now Actavis) in 2012, it does not view SYD985 as in any sense a generic or biosimilar version of Kadcyla.

“This is a new molecular entity; we’ve used available technology and chemistry, combined with our expertise in biologics and biosimilars to create a new drug class,” Timmers said. “It’s not similar to T-DM1 because it has unique linker technology.”

In common with other generics companies such as Actavis and Momenta Pharmaceuticals Inc., Synthon has used the opening up of the biosimilars pathway to diversify away from its traditional chemical generics business into biologics.

Although Synthon decided to outlicense its biosimilar Herceptin on the grounds that doing phase III would be too expensive, the company has invested in a two-year 796-patient phase III trial of its generic version of the multiple sclerosis treatment Copaxone (glatiramer acetate).

At the end of March, Synthon reported its generic met the main endpoint of demonstrating equivalent safety and efficacy with Copaxone, owned by Teva Pharmaceuticals Inc., which is reaching the end of its patent life.

The $4.3 billion-selling treatment for relapsing-remitting multiple sclerosis currently is the subject of intensive patent litigation in the U.S. as Teva fights to extend exclusivity from May 2014 to September 2015.

Generic versions of Copaxone filed for approval under the FDA’s abbreviated new drug approval (ANDA) pathway, by Synthon, Mylan Inc. and Momenta, are under review.

Copaxone consists of a mixture of peptides with variable molecular weight and amino acid sequences, which is rapidly degraded to free amino acids on administration. As a result it is hard, if not impossible, to demonstrate either pharmaceutical equivalence or bioequivalence of generic formulations.

As a result the European Medicines Agency (EMA) has required proof of therapeutic equivalence in a large-scale trial comparing Synthon’s generic with Copaxone and placebo. Synthon now is finalizing the phase III study report, which it expects to file with the EMA by mid-2014. The European patents on Copaxone expire in May 2015.

Timmers said it remains to be seen what stance the FDA will take on abbreviated approvals for Copaxone generics. “In Europe we will be the only generic; in the U.S. maybe there will be competition.” Having a product that is clinically validated will be important in building the market, both encouraging switching from Copaxone and from interferon drugs, Timmers added.