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MethylGene Reports Encouraging Clinical And Preclinical Data

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Encouraging Clinical Data on MGCD265 Presented at the ESMO 2012 Congress

 By Grant Zeng, CFA

On October 1, 2012, MethylGene Inc. () presented clinical data from its MGCD265 Met/VEGFR-targeted oncology program at the European Society for Medical Oncology (ESMO) 2012 Congress, held in Vienna, Austria.  Three poster presentations provided updates on the ongoing monotherapy, combination therapy and healthy volunteer trials.

As a reminder, MGCD265 is an oral, multi-targeted kinase inhibitor rationally designed to target the Met, VEGFR, RON and Tie-2 RTKs, key kinases involved in cancer and angiogenesis.

MethylGene has completed a Phase I monotherapy study (Trial 265-102, intermittent dosing) for MGCD265. Another monotherapy Phase I study (Trial 265-101, continuous dosing) and a Phase I/II (Trial 265-103 combination study with two arms: MGCD265+full dose docetaxel, or MGCD265+full dose erlotinib) are ongoing.

Source: Company presentation as of March 2012

At the ESMO Congress, MethylGene presented updated data on the two ongoing Phase I clinical trials (101 and 103) and on the recently completed Phase I Trial 265-105.

Update on trial 101:

The trial 101 poster is entitled “A Phase I, dose-escalation study of MGCD265, a multi-targeted oral tyrosine kinase receptor inhibitor, for treatment of advanced solid tumors” (abstract 471P), which documented the safety profile, pharmacokinetics, pharmacodynamics and clinical response observed as of October 1, 2012, in the ongoing monotherapy trial 265-101. MGCD265 continues to exhibit a favorable safety profile with drug-related adverse events being mostly mild to moderate. The maximum tolerated dose (MTD) has not yet been reached. Drug-related grade 3 adverse events seen in more than one patient were diarrhea, fatigue and elevated lipase (n=2 for each). Stable disease was achieved in 36% of patients (24/67 patients).  No objective responses have been seen to date. Dose-dependent Met inhibition was demonstrated using samples of patient plasma, and drug exposures have reached the range shown to have antitumor effects in animal models.

Update on trial 103:

Data from the ongoing combination trial 265-103 was presented in the poster entitled “Clinical effects of MGCD265, an oral tyrosine kinase inhibitor, in combination with erlotinib or docetaxel for treatment of advanced gastroesophageal and NSCLC tumors” (abstract 492P). This poster highlighted the clinical responses seen in patients with non-small cell lung cancer (NSCLC, n=12) or gastro-esophageal cancer (GE, n=9) treated with MGCD265 in combination with docetaxel or erlotinib in an ongoing dose-escalating Phase I study. Among twelve patients with NSCLC treated with MGCD265 (up to 600 mg / m2), nine achieved disease control (seven stable disease and two partial responses). Four NSCLC patients were progression-free for 7-11 months. In the GE cohort, five of nine patients treated with MGCD265 (up to 324 mg / m2) achieved disease control (all stable disease). Three of these patients remained stable for 11-22 months, an increase of 6-11 fold compared to the length of time on prior therapy. The safety profile of MGCD265 in combination with docetaxel or erlotinib was acceptable at doses up to 600 mg / day with no apparent increase in frequency of the adverse events that are commonly associated with docetaxel and erlotinib, respectively.  Dose escalation is ongoing and the MTD has not been defined for either combination.

Update on trial 105:

The third poster entitled “Pharmacokinetic profile of MGCD265, an oral tyrosine kinase inhibitor, with or without food in healthy volunteers” (abstract 493P) described the recently completed Phase I Trial 265-105 which assessed the effect of food on MGCD265 pharmacokinetics. This study showed that administration of MGCD265 in the presence of food increased drug exposure significantly, with no added toxicity. Based on these findings, food has been incorporated into all ongoing MGCD265 clinical trials.

Our Takeaways from the ESMO Presentation

We think the data presented at the ESMO Congress are encouraging. These data have demonstrated further favorable safety and efficacious clinical activity of MGCD265 as a single agent as well as in combination with other anticancer agents.  

We are especially encouraged by the safety profile and clinical benefits of MGCD265 in combination with erlotinib or docetaxel for treatment of advanced gastroesophageal and NSCLC tumors. We believe MGCD265 plus erlotinib or docetaxel has the potential to provide additional treatment options for patients of NSCLC and gastroesophageal cancers as well as other cancer types.

MGCD290 New Preclinical Data Presented at the 2012 the ICAAC Conference

On September 11, 2012, MethylGene presented preclinical data for its novel clinical-stage antifungal, MGCD290, at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, California.

The poster, entitled “MGCD290, an Oral Fungal Hos2 Inhibitor, Enhances the Antifungal Properties of Fluconazole following Multiple or Single Oral Dose Administration in Pre- and Post-Infection Settings” (Presentation #M-1711), demonstrated that MGCD290 plus fluconazole was superior to fluconazole alone in a murine model of systemic candidiasis under multiple dosing schedules.

This poster details how, under different dosing schedules in a mouse model of systemic candidiasis, the combination of MGCD290 plus fluconazole significantly decreased the fungal kidney burden versus fluconazole alone. The combination of MGCD290 plus fluconazole was superior in both fluconazole-sensitive candidiasis and fluconazole-resistant candidiasis. Dosing schedules tested included a single dose of fluconazole plus MGCD290 administered after infection, or prophylactic dosing followed by a second post-infection treatment.

The preclinical data reported here demonstrates the activity of MGCD290 under conditions relevant to mucosal and life-threatening systemic antifungal indications, as well as supporting the ability of MGCD290 to overcome azole resistance, an increasing problem.

As a reminder, based on previous preclinical and Phase I results, in October 2011, MethylGene initiated a Phase II (Study 290-005) clinical study evaluating MGCD290 in combination with fluconazole vs. fluconazole alone in patients with moderate to severe acute vulvovaginal candidiasis (AVVC).

This study is a multicenter, randomized, double-blinded, placebo-controlled trial and is currently enrolling subjects at sites in the US and Canada with moderate to severe AVVC. This trial focuses on the most severe infections and therefore patients with mild disease are excluded. The purpose of the trial is to evaluate the safety and efficacy of fluconazole versus fluconazole + MGCD290.

  • Subjects will be randomized in a 1:1 ratio to one of two arms of this study as follows: 150mg fluconazole + 540mg MGCD290, or 150mg fluconazole + placebo;
  • 75 evaluable patients will be enrolled in each treatment arm; about 200 patients will be enrolled to get 150 evaluable patients in two arms;
  • Subjects will be dosed on Day 1, and followed for one month after dosing;
  •  The primary endpoint for the study will be the Therapeutic Cure Rate, a composite endpoint of Clinical Cure (a resolution of clinical signs and symptoms) plus Mycologocial Cure (negative results on microscopy and culture) at Day 28;
  • The primary endpoint population for this study will be based on the Modified Intent To Treat (MITT) population, which removes those patients who have been determined by screening not to have a fungal infection from analysis;
  • Secondary endpoints will be:
•    Clinical Cure and Mycological Cure at 28 days;
•    Therapeutic Cure, Clinical Cure and Mycological Cure at 14 days;
•    Time to Resolution of Symptoms;
•    Safety of the combination of MGCD290 and fluconazole compared to fluconazole alone;

Dr. Jack Sobel, Chief of Infectious Diseases, Distinguished Professor of Medicine, Department of Internal Medicine, Wayne State University School of Medicine is the lead investigator for this study.

While 90% cure rate is observed in the mild patients group for fluconazole,  we are expecting the control group in this moderate to severe patient subset to have a 30-50% cure rate and the trail is powered to show (roughly, without going into the stats) a 20% absolute improvement i.e. improvement from 40% control to 60% treatment.

Enrollment in this Phase II trial is over 50% complete. Topline data from this trial is expected around the end of 2012.

We are very pleased to see MethylGene has made great progress in clinical development in recent months. Current share price should be boosted based on the Company’s strong fundamentals.

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