Molecular Partners has a strong focus on creating differentiated therapies for retinal diseases including wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME), two diseases leading to loss of vision.
Wet AMD causes significant and irreversible loss of central vision in severe cases. Over one million Americans are affected by wet AMD. Anti-VEGF therapies, the current standard of care for wet AMD, inhibit abnormal growth and leakage of new blood vessels, and are administered by injection into the eye monthly or bi-monthly.
DME can lead to blurred vision, severe vision loss and blindness. Approximately 10% of people with diabetes will develop DME during their lifetime. Current treatments include steroids, laser and anti-VEGF treatment. Anti-VEGF treatments are administered by injection into the eye monthly or bimonthly or by an implant.
“Despite the fact that there are well-recognized treatments for wet AMD and DME, there is still a significant unmet medical need for the development of new therapies that have less frequent injections and result in greater and longer-lasting vision gains.”
Wet AMD and DME can carry a high patient burden. Most of the patients are elderly and require an increasing amount of support from caregivers depending on their level of blindness. These conditions can also put physical, social and emotional strain on family members as they provide care for the patients. Our most advanced program is abicipar, an anti-VEGF DARPin in late-stage development in partnership with Allergan. Abicipar is currently in Phase 3 clinical trials for neovascular AMD (started July 2015) and in Phase 2 trials for DME (started July 2014). Clinical data for abicipar has shown it has the potential to provide at least equal and potentially higher vision gains with fewer injections in wet AMD compared to standard of care treatment LucentisÂ® (ranibizumab) and that it can reduce retinal edema in DME for up to 12-16 weeks.
Another ophthalmology compound under development in association with Allergan is the multi-VEGF/PDGF DARPin® therapeutic which pairs our VEGF-targeting DARPin® compound abicipar with another potent DARPin® compound that targets PDGF; this combination can create a next-generation therapy that has the potential to treat several aspects of wet AMD at once.
Molecular Partners is developing DARPin® products for use in oncology. Cancer is a complex disease with multiple disease factors and mechanisms that often evade single approach therapies. Our DARPin® proteins with specificities for multiple targets within one molecule (multi-DARPin® proteins) have the potential to induce additive and synergistic anti-tumor affects. Thereby, multi-DARPin® therapeutics have the potential to address the significant unmet needs for cancer patients and provide a fundamentally different therapeutic window compared to monoclonal antibodies or antibody fragments.
The high-specificity, potency and robustness of DARPin® proteins in principle allows us to simultaneously select and act on many targets found in tumors as a single therapy which could further be combined with conventional treatments. DARPin®proteins allow for excellent tumor enrichment, tumor tissue penetration and high contrast over healthy tissue.
Our research focuses on indications where known pathways were shown to have a significant effect and where monotherapies have failed. MP0250 is our most advanced oncology DARPin® drug candidate and recently completed a Phase I clinical study. MP0250 inhibits both VEGF and HGF from binding to their receptors.
On October 9, 2016, the company presented completed Phase 1 dose escalation interim results of MP0250 at the Conference of the European Society of Medical Oncology (ESMO) in Copenhagen. These data, based on the enrollment of a total of 24 patients, are an important milestone in the development of DARPin® proteins as anticancer agents and expand the results that had been published following a poster presentation at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, Mass. on Saturday, November 7, 2015
- MP0250, used as single agent, is the first DARPin® drug candidate to be studied in humans as systemic treatment
- MP0250 was well tolerated at the higher dose levels (up to the maximally tolerated dose of 8 mg/kg administered every 2 weeks)
- This is an important milestone because it proves that DARPin® proteins do not negatively impact the immune system of humans and can be engineered to have a systemic half-life of around two weeks
- The drug is well tolerated and the side effect profile is consistent with profound inhibition of the VEGF pathway
- MP0250 has the potential to become a new therapeutic in treating various tumor types
Phase 2 strategy for MP0250: Initiation for two phase 2 trials planned for 2017
The first phase 2 study will examine MP0250 in combination with bortezomib (Velcade®) and dexamethasone in patients with multiple myeloma who have failed standard therapies. The first regulatory submission for such study is planned for 4Q 2016 with first safety data expected in 2017 and efficacy data in 2018.
Based on the encouraging data from Phase 1 in solid tumors, Molecular Partners committed to run an additional phase 2 trial for a solid tumor indication. Study details will be disclosed in H1 2017.
- In a preclinical model of MM, the combination of MP0250 and bortezomib showed substantial antitumor activity in settings where bortezomib had very little effect as a single agent. In addition to inhibiting tumor growth, the combination of MP0250 and bortezomib resulted in a significant reduction in bone destruction, one of the most important clinical hallmarks of this disease.
In addition, several preclinical studies have demonstrated the power of MP0250. We believe that MP0250 has the potential to become a valuable treatment option for solid tumors and hematological malignancies.
MP0274 for breast cancer
The second most advanced oncology DARPin® drug candidate is MP0274 and has broad anti-HER activity inhibiting both downstream HER1 (EGFR), HER2 and HER3-mediated downstream signaling, leading to induction of apoptosis.
- MP0274 is currently in preclinical development with the goals to develop a powerful alternative for HER 2+ breast cancer patients.
The company plans the first regulatory submission for the envisaged Phase 1 trial of MP0274 in 1Q 2017.
Immuno-Oncology: An Unlimited Potential
Immuno-oncology is a revolutionary approach to anti-cancer treatment that redirects the body’s immune system to fight cancer cells. Investigators are studying many different ways to modulate immune checkpoints used by the body to regulate the immune system. While many of these clinical studies are yielding promising results, novel approaches are needed.
Enhancing the activity of validated checkpoint antagonists
The first proprietary product in Molecular Partners’ immuno-oncology pipeline is a multi-DARPin® protein that blocks the checkpoint target PD-1, inhibits VEGF-A and binds to human serum albumin (HSA). The purpose of this tri-functional DARPin®protein is to normalize the tumor vasculature by inhibiting VEGF, consequently allowing for more efficient inhibition of PD-1 and more tumor-infiltrating T-cells (TIL). In addition, the DARPin® domain binding to HSA should result in a long half-life and allow for potentially increased tumor penetration.
Local Activation in immuno-oncology
Molecular Partners is also developing multi-DARPin® proteins that bind to co-stimulatory activators (agonists) on the surface of T-cells without activating them when bound in circulation. While one DARPin® domain binds to an agonistic target, another DARPin® domain binds to a densely expressed target in the tumor stroma leading to clustering of agonists and potential activation.
Co-stimulatory activators of T-cells are attractive but very difficult targets in the field of immuno-oncology. Current anti-body-based approaches are often limited by severe side effects as they tend to cluster throughout the body thereby activating T-cells systemically. This approach aims at activating T-cells only in the tumor microenvironment when the multi-DARPin® protein clusters the agonist via the stroma.
Immunology and other Indications
Molecular Partners is developing DARPin® proteins against several targets important for the treatment of inflammatory and auto-immune diseases. Its lead compound targets both IL-13 and IL-17 with long systemic half-life and potential use in pulmonary indications. Multi-DARPin® proteins have the potential to become next generation anti-inflammatory therapies and may open new ways how to treat diseases like rheumatoid arthritis and asthma.
DARPin® is a registered trademark owned by Molecular Partners AG.