On 27 March, 2014 Patrys reported the final results from its Phase I/IIa, open-label study in patients with refractory or relapsed multiple myeloma (MM) (Press release Patrys, MAR 27, 2014, View Source [SID:1234500542]).
This trial was conducted in 12 patients (10 male and 2 female, median age 71 years) with refractory or relapsed MM. On average each patient had received five prior lines of therapy, including proteasome inhibitors, immunomodulatory (IMID) drugs or stem cell transplantation.
Twelve patients (3 in each cohort) received 4 intravenous infusions of PAT-SM6 at 0.3mg/kg, 1mg/kg, 3mg/kg or 6mg/kg per dose. All patients were then assessed for a response at 36 days post final treatment.
The primary endpoint of the study was safety and tolerability. At all dose levels tested, PAT-SM6 was well tolerated with no serious adverse events (SAEs) or dose limiting toxicities being reported. A maximal tolerated dose (MTD) was not reached.
Secondary endpoints were designed to measure efficacy as determined by a series of well-established laboratory assays. Overall, 4/12 patients (33%) treated with PAT-SM6 showed evidence of stable disease (SD) according to the International Myeloma 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 154 days and is currently therapy free.
These data compare favorably with another antibody (Elotuzumab) currently in Phase 3 combination trials for MM. When tested in a Phase I trial, 26.5% (9/35) patients treated with increasing doses of Elotuzumab (0.5– 20mg/kg) responded with SD. Like PAT-SM6, this antibody was used as a single agent. The information on the clinical efficacy of Elotuzumab is publicly available.
Importantly, 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 will be used in combination with Amgen’s Carfilzomib.
11/ 12 patients went on to receive additional salvage therapy after completing the PAT-SM6 clinical trial. Remarkably, 7/ 11 patients responded very positively with a partial response (PR) while 3 others responded with SD indicating that PAT-SM6 treatment may make cancer cells more sensitive to killing by other chemotherapeutics.
Analysis of blood samples collected during the trial confirmed that no patient generated a significant adverse immune response to PAT-SM6 (immunogenicity). This is an important finding as adverse immune reactions to existing marketed antibodies is known to limit the effectiveness of these treatments.
Pharmacokinetic analysis demonstrated linear dose proportional increases in maximum serum concentration (Cmax) of PAT-SM6. Systemic exposure to the drug, demonstrated by area under the curve (AUCt) was in line with Cmax and showed similar linear behavior. Patients displayed apparent linear pharmacokinetics with a rapid distribution phase followed by a slower disposition phase and a half-life of about 7 hours. The parameters of half-life, volume of distribution and clearance were consistent across the dose levels and between cycles, indicating that higher doses do not affect the general pharmacokinetic properties of PAT-SM6.
Post treatment with PAT-SM6, malignant cells were isolated from the patient’s blood or bone marrow and analysed for the presence of the infused antibody. It was shown conclusively that PAT-SM6 specifically targeted and bound to the myeloma cells. Furthermore analysis of patient’s immune systems indicated that PAT-SM6 is capable of inducing an immune response by both stimulating and increasing the absolute number of CD8+, NK and regulatory T-cells. These cells are specifically capable of regulating the growth and dissemination of tumours. Such changes were more significant in patients who had experienced stable disease post treatment with PAT-SM6. These data may indicate specific crosstalk between PAT-SM6 and immune cells, a previously unreported finding that warrants further investigation.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On May 27, 2014 DepYmed Inc., a joint venture of Ohr Pharmaceutical, Inc. (Nasdaq:OHRP) and Cold Spring Harbor Laboratory, reported the validation of Trodusquemine (MSI-1436) as a therapeutic candidate for HER2-positive breast cancer (Press release, Ohr Pharmaceutical, MAR 27, 2014, View Source [SID:1234512310]). Trodusquemine is the Company’s inhibitor of the enzyme PTP1B (protein tyrosine phosphatase 1B). The results were published online on May 20, 2014 in Nature Chemical Biology.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. In approximately 1 out of every 4 breast cancers, tumor cells make an excess of HER2 due to a gene amplification. HER2-positive breast cancers tend to be aggressive and the prognosis for patients is poor. The drug Herceptin (trastuzumab) is a first-line treatment for many women with HER2-positive breast cancer, but in most cases resistance develops within a year. It is anticipated that alternative therapies which act either alone or in combination with Herceptin may enhance patient outcomes.

In a paper entitled "Targeting the Disordered C Terminus of PTP1B With an Allosteric Inhibitor" a multi-institution team led by Professor Nicholas Tonks of Cold Spring Harbor Laboratory reports that it has found a means of inhibiting PTP1B, expression of which is upregulated in HER2-positive breast cancer. They provide compelling evidence of PTB1B as a therapeutic target in HER2-positive breast cancer.

PTB1B is a well-characterized target for several major diseases, including diabetes and obesity. However, it has been a challenging target for therapeutic development due to the chemical properties of the enzyme at its active site. "Novel approaches are required to exploit this important target fully," Dr. Tonks observes. In the approach reported in the newly published paper, Trodusquemine has been identified as a selective, allosteric inhibitor of PTP1B that exerts its effects outside the active site of the enzyme.

Dr. Tonks and his team tested Trodusquemine in several mouse models of HER2-dependent breast cancer. They showed that in animals treated with Trodusquemine, there was extensive inhibition of tumor burden and prevention of metastasis to the lung. They also demonstrated that it was inhibition of PTP1B that antagonized signaling by HER2 proteins in the treated animals.

"We are pleased with the publication of this important paper on Trodusquemine in breast cancer," said Dr. Irach Taraporewala, President and Chief Executive Officer of Ohr Pharmaceutical. "These results build on data from earlier studies showing PTP1B to be a tumor promoter and suggest it may be a viable therapeutic target in HER2-positive breast cancer. This form of breast cancer is very aggressive and difficult to treat. Many women ultimately build up a resistance to current treatments, so it is important to identify additional therapeutic agents for intervention."

In other studies, Trodusquemine has been shown to cross the blood-brain barrier, which enhances its potential applications. It has been well tolerated in dose-escalation clinical studies completed to date in over 65 patients. Novel analogs of Trodusquemine have also been identified that are potent inhibitors of PTP1B and have potential delivery route advantages.

A Phase I clinical trial evaluating Trodusquemine in HER2-positive breast cancer patients is planned for later this year and will be conducted at North Shore-Long Island Jewish Hospital.

(Press release, Prolynx, MAR 27, 2014, View Source [SID:1234504740])

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On March 27, 2014 Cancer Research UK reported that a new cancer drug, based on further development of a discovery originally made by Cancer Research UK, has entered a clinical trial to target a wide range of cancers (Press release, Cancer Research Technology, MAR 27, 2014, View Source [SID1234523228]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The drug, RG7813, delivers a cytokine (engineered IL2) to a specific part of the carcinoembryonic antigen (CEA) protein which is exposed only on the surface of cancer cells, resulting in a narrowly-targeted treatment.

Cancer Research Technology, the commercial arm of Cancer Research UK, licensed the monoclonal antibody called PR1A3 to Roche. PR1A3 was discovered in Sir Walter Bodmer’s laboratory when he was director of the Imperial Cancer Research Fund*. Roche has subsequently engineered the antibody and incorporated it into its proprietary immunocytokine drug platform to generate the final drug candidate. Clinical trials have then been initiated.

Sir Walter Bodmer, head of the Cancer and Immunogenetics Laboratory at the University of Oxford, said: "It’s very exciting to see that a drug based on our monoclonal PR1A3 antibody is now going into the clinic. By combining these discoveries we make in the lab with the latest developments in immunotherapy, we’re expanding our arsenal of cancer drugs at a greater pace – which will ultimately benefit more patients, sooner."

Dr Phil L’Huillier, Cancer Research Technology’s director of business management, said: "We’re delighted to see the trial launch of this promising new drug, which harnesses the power of the immune system, and that potentially could treat a range of cancers.

"This drug is particularly exciting because it homes in on a new target only accessible on the surface of cancer cells, increasing its potency while sparing healthy cells. We hope that the early clinical trials prove this is a safe and effective new treatment for cancer patients – ultimately saving more lives from the disease."

On March 24, 2014 Patrys reported an update on the development programme for anti-cancer product, PAT-LM1 (Press release Patrys, MAR 24, 2014, View Source [SID:1234500541]).
PAT-LM1 is the second IgM antibody in Patrys’ pipeline to enter clinical development. PAT-LM1 is a natural human antibody that has shown great promise in preclinical development as a potential treatment for multiple types of cancer, including colon, lung, breast, ovary, pancreatic and various hematological cancers.
The most recent laboratory experiments focused on the evaluation of the efficacy of PAT-LM1 in blood cancers including different types of leukemias and lymphomas. PAT-LM1 showed very strong and specific binding to more than 90% of tested lymphoma cell lines and patients samples. PAT-LM1 was able to induce cell death in mantle cell lymphoma and histiocytic lymphoma cells. Interestingly, PAT-LM1 also bound specifically and strongly to some very rare lymphoma types like marginal zone B-cell and Burkitt lymphoma, indicating that it may have broad therapeutic application covering the whole range of different lymphomas. Despite there being numerous drugs on the market for lymphoma, there is still a significant unmet medical need especially in patients with relapsed and refractory disease. The prognosis for these patients is poor and therefore the development of novel agents, such as PAT-LM1, is urgently needed.
The cell line development of PAT-LM1 for production has been successfully completed and early data indicate that the resultant yield from a GMP manufacturing run is likely to be significantly higher than yields achieved to date. Patrys has now commenced the manufacturing process to produce PAT-LM1 for a future clinical trial in treating patients with relapsed and refractory lymphomas.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!