Patrys’ second product to enter clinic trials is PAT-SM6, a natural human antibody that binds to multiple types of cancer including solid tumours such as melanoma, breast, colon and pancreatic, as well as blood-based cancers such as multiple myeloma.
Following successful preclinical safety/ toxiciology studies, Patrys advanced PAT-SM6 into a first-in-human clinical trial in melanoma patients. This was a significant milestone for Patrys in a number of ways.
From a treatment perspective, the trial represented a significant opportunity for melanoma patients as PAT-SM6 is a novel antibody that kills cancer in a completely different way to any other treatment available today, such as chemotherapy, which is often ineffective and unsafe. More specifically, PAT-SM6 kills cancer by binding to a protein called GRP78 that is found on the surface of cancer cells but not on the surface of healthy tissues. At least 30 published scientific articles have reported that high levels of GRP78 have been detected in lung, gastric, colonic, oesophageal and liver cancers and melanoma. GRP78 has been shown by independent researchers to play a key role in promoting tumour progression, metastasis and drug resistance to a variety of therapies.
Given the importance of GRP78 in cancer a product that interrupts the normal functioning of that protein offers real promise to cancer patients. Considering that no other products are in the clinic that target GRP78, this promise is only offered by Patrys’ PAT-SM6.
The outcome of the PAT-SM6 trial has broader significance for Patrys as all of the Company’s anti-cancer products come from the same natural human antibody platform. This clinical trial for PAT-SM6 was completed in February 2012. Patrys met the primary endpoint of the trial and was able to show that the product was safe when administered as an intravenous single dose. The success of this clinical result for PAT-SM6 is therefore indicative of the potential value of Patrys’ overall pipeline.
In March 2014 Patrys completed a Phase I/IIa clinical trial in multiple myeloma for anti-cancer drug PAT-SM6. The trial was an open-label multi dose escalation trial in relapsed and multi-resistant patients with multiple myeloma who have failed all currently marketed drugs and have a very poor prognosis. Twelve patients were enrolled in four dosing groups with a minimum of two cycles (four doses) of treatment. If a patient showed a partial response to treatment with PAT-SM6 an additional cycle (two doses) of treatment will be offered. The primary objective of the study was to evaluate the safety and tolerability of escalating doses of PAT-SM6 and the secondary objective to measure efficacy as determined by a series of well-established laboratory assays. Patrys is pleased to report that at all dose levels, PAT-SM6 was well tolerated with no serious adverse events or dose limiting toxicities were reported. A maximum tolerated dose was not reached. Overall, 4/12 patients (33%) treated with PAT-SM6 showed evidence of stable disease (SD) according to the International Working Group (IMWG) criteria. One patient who received 3mg/kg of PAT-SM6 was stable for 138 days before additional therapy was needed, whilst another patient, who received 6mg/kg of PAT-SM6, has been stable for 145 days and is currently therapy free. Patients treated with PAT-SM6 had a mean time to next therapy of 51 days which is considered clinically significant.
Patients who had received prior treatment with proteasome inhibitors responded much better to PAT-SM6 treatment than patients who had been previously treated with IMIDs or other chemotherapeutics. This observation is very exciting as it indicates that PAT-SM6 may act synergistically with proteasome inhibitors (such as Carfilzomib) to induce better clinical responses. Such a hypothesis will be tested in Patrys’ next clinical trial in which PAT-SM6 wil be used in combination with Amgen’s Carfilzomib.
Following on from these observations, in May 2014 Patrys reported a single patient was granted “individual use” treatment with PAT-SM6 as part of a combination therapy including Velcade and Revlimib. After 3 doses of this combination therapy, a PET-CT scan revelaed significant shrinkage of extramedullary and intramedullary lesions. Of particular note was the disappearance of the tumour in the testes. The patient has gone on to receive additional treatment for his remaining disease, these observations are very promising.
As described at the 2015 AGM and in various market updates, the Company has deferred the commencement of the combination clinical trial with Amgen until such time as the variation in manufacturing of PAT-SM6 has been resolved.
PAT-SM6 has received European orphan drug designation for multiple myeloma, which provides for 10 years market exclusivity post approval. This provides a number of opportunities including: regulatory assistance and access to grant funding schemes.
From a technology perspective, PAT-SM6 is the first product advanced to the clinic that has been manufactured using our proprietary natural human antibody production technologies.
• L Rache, L Duell, I Castro, V Dubljevic, M Chatterjee, S Knop, F Hensel, A Rosenwald, H Einsele, M Topp and S Brändlein. GRP78-directed immunotherapy in relapsed or refractory multiple myeloma – results from a Phase I trial with monoclonal antibody PAT-SM6, Haematologica, 2015, 100(3): 377-84.
A Loos, C Gruber, F Altmann, U Mehofer, F Hensel, M Grandits, C Oostenbrink, G Stadlmayr, PG Furtmuller, H Steinkellner, Expression and glycoengineering of functionally active heteromultimeric IgM in plants, 2014, PNAS, 111(17):6263-8.
• Z Rosenes, TD Mulhern, DM Hatters, LL Ilag, BE Power, CH Hosking, F Hensel, GJ Howlett, Y-F Mok. The Anti-Cancer IgM Monoclonal Antibody PAT-SM6 Binds with High Avidity to the Unfolded Protein Response Regulator GRP78. PLOS One, 2011, 7(12): 1-11 (2012)
• F Hensel, M Eckstein, A Rosenwald, S Brändlein. Early development of PAT-SM6 for the treatment of melanoma, Melanoma Research, 2013, 23(4): 264-75.
• Z Rosenes, Y-F Mok , S Yang, MD. W. Griffin, TD Mulhern, DM Hatters, F Hensel, GJ Howlett. Simultaneous Binding of the Anti-Cancer IgM Monoclonal Antibody PAT-SM6 to Low Density Lipoproteins and GRP78 PLOS ONE, 2013, 8(4): 1-8.
• L Rasche, J Düll, C Morgner, M Chatterjee, F Hensel, A Rosenwald, H Einsele, MS Topp, S Brändlein. The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78. PLOS ONE, 2013, 8(5): 1–11
• Rauschert N, Brändlein S, Holzinger E, Hensel F, Müller-Hermelink HK, Vollmers HP. A new tumor-specific variant of GRP-78 as target for antibody-based therapy, Lab Invest. 88(4), 375-86, (2008).
• Brändlein S, Rauschert N, Rasche L, Dreykluft A, Hensel F, Conzelmann E, Müller-Hermelink HK, Vollmers HP. The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein, Mol Cancer Ther. 6(1), 326-333 (2007).
• Pohle T, Brändlein S, Ruoff N, Müller-Hermelink HK, Vollmers HP. Lipoptosis: tumor-specific cell death by antibody-induced intracellular lipid accumulation, Cancer Res, 64(11), 3900-3906 (2004).