Rexahn combines small and large molecules with Keytruda collab

According to the agreement, clinical stage biopharma, Rexahn, will study RX-5902 (supinoxin), an orally administered, small molecule inhibitor of phosphorylated-p68 (P-p68) – which is selectively overexpressed in cancer cells and absent in normal tissue – in combination with monoclonal antibody, Keytruda (pembrolizumab).

As a standalone therapy, Keytruda – marketed by Merck (known as MSD outside of North America) – is approved for several indications, including for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, and refractory classical Hodgkin lymphoma.

The Rexahn/Merck collaboration will evaluate the investigational therapy’s effectiveness in a Phase II trial in patients with metastatic triple negative breast cancer (TNBC), a cancer Rexahn CEO Peter Suzdak told us is notoriously difficult to treat.

in-PharmaTechnologist (IPT) ​spoke with Suzdak (PS) ​to discuss all things immunotherapy, including challenges faced in immune-oncology development, and the prospective of RX-5902 as ‘potential first-in-class’ therapy.

IPT: ​What are some of the challenges involved in current immunotherapeutic approaches to treating metastatic TNBC?​

PS: ​Broadly speaking, the immunotherapeutic approach in metastatic triple negative breast cancer, as well as in other cancers, is akin to taking the "brake" off the immune system, which can result in various treatment challenges.

For example, it causes the immune system to kill not only cancer cells but healthy tissue as well. This can result in patients developing grade three and four toxicity. In addition, immunotherapy also only works in 9-16% of patients for reasons that have not yet been determined by the scientific and medical community. 

For metastatic TNBC, the specific indication we are targeting – and which represents 20% of breast cancer diagnoses – there is no approved therapy and the prognosis is poor.

IPT: How can selectively targeting specific molecules in cancer cells serve as an adjunct therapy to standard immunotherapies?​

PS: ​While standard immunotherapies are active against some of the toughest cancers and are synergistic with existing therapies, they do not selectively target cancer cells and there can be adverse events.  

Our compound, RX-5902 (Supinoxin), is an orally administered, potential first-in-class, small molecule inhibitor of a unique cancer protein, P-p68. P-p68 is believed to increase the activity of multiple cancer-related genes including cyclin D1, c-jun and c-myc, and to play a prominent role in tumour progression and metastasis. Overexpression of P-p68 has been observed in many solid tumours, including melanoma, colon, ovarian and lung tumours.

Research conducted at the University of Colorado that evaluated RX-5902 indicated that it was able to enhance cancer cells’ susceptibility to the patient's immune system. When a cancer cell is impacted in this way, there is an increase in tumour-infiltrating lymphocytes (TILs) or T cells that enter the cancer cell. Because of this, we are optimistic that the combination of RX-5902 with an anti-PD-1 therapy may provide meaningful benefit in patients with metastatic TNBC.

IPT: How easily could targeted therapies be integrated into standard immunotherapies?​

PS: ​The rationale for combining a drug with immunotherapy is to enhance the overall response rate/efficacy of an immunotherapy agent. The key question for any specific agent is whether or not there is a good pharmacological rationale for the combination that would lead to the expectation of enhanced efficacy. Of course, safety is key – you would not want to use anything in combination with a checkpoint inhibitor that would augment the inflammation side effects.

There is a sound rationale for the use of Rexahn’s compounds in combination with checkpoint inhibitors and we have seen very nice synergistic effects in animal models. RX-5902 inhibits P-p68, which modulates beta catenin, a protein that is associated with shutting down the body’s natural tumour immunity. By inhibiting P-p68 and thereby regulating beta catenin, RX-5902 improves the ability of the immune system to kill tumour cells and this enhances the effectiveness of checkpoint inhibitors, as shown in animal models. 

IPT: Which specific types of cancers are considered particularly hard to treat with existing therapies and why? ​

PS: ​Unfortunately, there are a lot. TNBC is one, and in fact, there are no US Food and Drug Administration-approved drugs for metastatic TNBC. If you look at bladder or skin cancer that has metastasized, immunotherapy only works in 20-30% of patients.