OREANDA-NEWS. Molecular Partners AG (ticker: MOLN) today announced the first demonstration in patients of the potential role of DARPin-based therapy in oncology at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, Mass., USA. In a poster presentation titled “First-in-human Phase I study to evaluate MP0250, a DARPin® blocking HGF and VEGF, in patients with advanced solid tumors,” a team of independent researchers presented preliminary Phase I data showing that MP0250, a multi-DARPin blocking vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), was well-tolerated in patients with solid tumors, while also providing favorable pharmacokinetics (PK) and sustained exposure over multiple applications.

“Treatment with MP0250 was well-tolerated in these patients and resulted in sustained drug exposure. We were very encouraged to see patients with prolonged stable disease. DARPins may represent a new class of molecules with the potential to specifically inhibit multiple critical pathways with just one drug,” commented Prof. Jordi Rodon, Institute of Oncology, Vall d’Hebron in Barcelona, Spain, who presented the poster. “Results from this ongoing study are a first example of the feasibility of the DARPin approach in oncology, and we look forward to confirming these results in further research of this promising compound.”

In a poster session at the AACR-NCI-EORTC conference – a joint meeting of the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC) – researchers presented data from a Phase I, multi-centre, open-label, repeated-dose, dose-escalation study assessing the safety, tolerability, PK, and immunogenicity of MP0250 in patients with advanced solid tumors. Preliminary results in 15 patients show that MP0250 is well-tolerated following repeated bi-weekly administration at doses ranging from 0.5 to 8 milligrams per kilogram of body weight (mg/kg). Repeated doses led to sustained exposure of MP0250 throughout the treatment periods analyzed, with a half-life of approximately 12 days. Anti-drug antibody (ADA) assessment of patients off study suggest a low immunogenic potential. Additionally, two patients exhibited stable disease for greater than 12 months and 8 months, respectively.

“The data from this ongoing phase I study are the first demonstration that DARPins can be administered systemically to patients with good tolerability and that sustained exposures over multiple treatment cycles can be achieved,” said Andreas Harstrick, MD, Chief Medical Officer of Molecular Partners. “By binding to specific oncologic targets with high affinity, DARPins may offer synergies with standard-of-care drugs as well as with novel approaches such as immunotherapy. These preliminary results will inform our Phase II strategy for MP0250 and the overall strategy for our DARPin technology platform, which may help reshape anticancer treatment.”

Study details

The primary objectives of the ongoing Phase I study are to evaluate the safety and tolerability of MP0250; to determine the maximum tolerated dose (MTD), recommended biological dose (RBD), and dose-limiting toxicities (DLTs) of MP0250; and to characterize the PK of the compound. Secondary objectives are to characterize the immunogenicity of MP0250; to make a preliminary assessment of biomarkers and genetic markers; and to evaluate the anti-tumor activity of MP0250. To be eligible, patients must have advanced or metastatic solid tumors refractory to at least one prior regimen of standard treatment or for which no curative therapy is available; progressive disease (PD) or stable disease (SD) documented in the four weeks prior to screening; and presence of a measurable or evaluable tumor.

Fifteen patients have been enrolled into the first four dose groups: 0.5 (n=3), 1.5 (n=3), 4 (n=6), and 8 mg/kg (n=3); a fifth dose cohort is to receive 12 mg/kg. Patients are to receive up to 12 intravenous (IV) infusions of MP0250 every two weeks, administered over three hours. Reasons for withdrawal include disease progression and DLT. Patients are allowed to continue treatment beyond 12 infusions in case of benefit.

Dr. Rodon and colleagues reported that MP0250 has been well-tolerated and an MTD has not been reached. They observed a single DLT at 4 mg/kg (significant reduction in cardiac ejection fraction after the first infusion) in a patient with multiple cardiac risk factors. The most frequent adverse events (AEs) in the preliminary data set were transient hypertension (47%), diarrhea (40%), fatigue (40%), and nausea (40%). A total of 116 infusions of MP0250 have been administered in 15 patients. Infusions were well-tolerated, except for mild nausea and diarrhea occurring in some patients. One patient experienced a temporary drop in blood pressure and bradycardia during his first infusion; these effects resolved spontaneously. Although these reactions were not “classical”, investigators could not exclude an infusion-related reaction in this patient. One patient with a nasopharyngeal carcinoma of the head and neck has stable disease after 12 months and continues to receive treatment. Another patient with a cervical adenocarcinoma achieved stable disease for eight months.

In terms of PK parameters, the investigators observed sustained exposure for all patients throughout the treatment periods analyzed, with the longest period to-date being 12 months. The mean half-life of MP0250 is approximately 12 days (range: 9-18 days). In line with the long half-life of MP0250, the investigators observed slight accumulation (factors 1.3-3). Plasma concentration-time data show low-to-moderate inter-subject variability (<factor 2-3). In an interim ADA analysis performed on all patients coming off the study, investigators observed an increasing titer of binding antibodies in only one patient, while no impact on exposure could be shown.

About Molecular Partners in Oncology

Molecular Partners is advancing a growing proprietary pipeline of DARPin therapies in oncology. The most advanced systemic DARPin, MP0250, is in Phase I clinical studies in patients with solid tumors. MP0250 inhibits both VEGF and HGF from binding to their receptors, thereby blocking tumor growth and tumor spreading. The second most advanced oncology DARPin is MP0274, which has broad anti-HER activity, inhibiting both downstream HER2 and HER3-mediated signaling and leading to induction of apoptosis. MP0274 is currently in preclinical development. The current focus of Molecular Partners in research is immuno-oncology.

About Molecular Partners AG

Molecular Partners is a clinical-stage biopharmaceutical company that is developing a new powerful class of therapies known as DARPins. DARPins are potent, specific, and versatile small-protein therapies, which have the potential to offer benefits over conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology has the potential to offer a multi-specific approach to treatment, which enables DARPins to target multiple pathways, or multiple epitopes on a single target to achieve substantial patient benefit. DARPins have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders.

Molecular Partners has four compounds in various stages of clinical and preclinical development and several more in the research stage, with a current focus on ophthalmology and oncology. The company has ongoing research and development partnerships with leading pharmaceutical companies, including Allergan and Janssen, and is backed by established biotech investors.