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Curis Announces Removal of FDA Partial Clinical Hold on CUDC-427

On March 31, 2014 Curis reported that the U.S. Food and Drug Administration (FDA) has notified the Company that its complete response submission to the November 2013 partial clinical hold on CUDC-427 has been reviewed and that the FDA has determined that it is safe to proceed under the IND (Press release Curis, MAR 31, 2014, View Source [SID:1234500345]). The FDA also indicated that detailed official correspondence regarding the determination will be released in the near future. Curis will provide additional details, if applicable, based upon further communications from the FDA as they become available.
In November 2013, CUDC-427’s Phase 1 study (NCT01908413) in patients with solid tumors or lymphoma was placed on partial clinical hold following the death of a patient who progressed to liver failure approximately one month following the discontinuation of CUDC-427 dosing. Under the partial clinical hold, no new patients were to be enrolled in the study until Curis provided the FDA with the requested data and analyses of all patients treated with CUDC-427, together with a protocol amendment found to be acceptable to the FDA.

DepYmed Announces Validation of Trodusquemine as a Therapeutic Candidate for HER2-positive Breast Cancer

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.

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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])

Betalutin™ successful completion of phase I part of phase I/II study

On March 27, 2014 Nordic Nanovector reported that its lead product candidate Betalutin has achieved the two major objectives from the Phase I portion of the ongoing Phase I/II clinical trial (NCT01796171) (Press release Nordic Nanovector, MAR 27, 2014, View Source [SID:1234500623]). The ongoing trial has demonstrated that Betalutin is safe and well tolerated in patients suffering from Non-Hodgkin Lymphoma and that the product has a clinically relevant effect in this patient population.

"We are pleased that the ongoing trial already has demonstrated that Betalutin is safe and well tolerated in patients suffering from Non-Hodgkin Lymphoma" stated Jan A. Alfheim, CEO of Nordic Nanovector.

"We are furthermore excited to note that the product candidate has shown a clinically relevant antitumor effect at all dose levels administered to date."

The positive results from Phase I has enabled the company to establish the dose interval for the Phase II part of the clinical trial, which will assess the efficacy of Betalutin in patients suffering from relapsed Non-Hodgkin Lymphoma.

Final Data Confirms Successful PAT-SM6 Clinical Trial

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.