In conversation with Mohit Trikha
As chief scientific officer, EVP and head of closely held Triphase Accelerator, Mohit Trikha has parlayed a successful 20-year track record in oncology drug development into a home run, selling Triphase’s first asset, a proteasome inhibitor known as marizomib, to Celgene (NASDAQ:CELG). Prior to joining Triphase, Dr. Trikha was associate VP of clinical development at Ambit Biosciences; director of BioOncology and early development at Genentech; and assistant director of oncology research at J&J’s Centocor. Over the course of his career, he has been involved in multiple discovery research programs, helped file 12 oncology INDs, initiated multiple Phase 1 and Phase 2 clinical trials, and had responsibility for translational medicine, project management and companion diagnostics. Dr. Trikha has extensive experience in developing small molecules, monoclonal antibodies and companion biomarkers. In this interview with BioTuesdays, Dr. Trikha discusses Triphase’s marizomib program and what’s next for the company.
Let’s begin with a brief history of Triphase Accelerator.
We were spun out from the Ontario Institute for Cancer Research and MaRS Innovation in 2011. We now have operations in Toronto and San Diego. As our name implies, we accelerate development of oncology drugs. Specifically, our goal is to acquire programs that are one-to-two years away from an IND and take a drug to clinical proof-of-concept, which is what we have done with marizomib. We are most proud of our people and making scientific and data driven decisions to move the program forward and, just as importantly, knowing when to discontinue development of an asset. While we have no proprietary in-house drug discovery intellectual property to invent drugs, our strength is finding novel drug candidates, manufacturing the drug product, filing INDs, conducting early-stage clinical trials, and partnering with key opinion leaders to quickly bring new products to clinical proof-of-concept.
What is marizomib?
Marizomib is a natural product, isolated from the marine bacteria, salinospora tropica. It was first discovered by the Scripps Institute of Oceanography at the University of California, San Diego. Marizomib is an irreversible inhibitor of all three proteasome subunits: the chymotrypsin-like, the trypsin-like and the caspase-like, which translate into longer duration of effect and potentially improved clinical activity. We initially began working with marizomib in relapsed and refractory multiple myeloma. But what differentiated this proteasome inhibitor from other proteasome inhibitors is that it's the only one that crosses the blood-brain barrier, a key characteristic that led us to suggest to Celgene its potential application in malignant glioblastoma, or brain cancer. We have orphan drug designation from the FDA and from the EU for marizomib in multiple myeloma, and orphan drug designation from the FDA for glioblastoma. The recent clinical data from our ongoing glioblastoma clinical studies, coupled with our ability to manufacture marizomib and rapidly conduct clinical trials in the U.S., Canada and Australia was the basis for Celgene to acquire this asset.
What’s the nature of the Celgene-Triphase collaboration?
In October 2012, we established a three-program funding deal with Celgene that lead to the recent sale of marizomib. Under the terms of the marizomib deal, Celgene will pay us to complete three ongoing trials: a Phase 1 study in relapsed refractory multiple myeloma, a Phase 2 study in recurrent glioblastoma and a Phase 1 study in newly diagnosed glioblastoma. Celgene will take full responsibility for further development and carry the program through to potential commercialization. The ongoing programs are for intravenous administration of marizomib but we have also developed an oral version of the drug, which is in preclinical development.
What prior clinical data do you have for marizomib?
Marizomib has demonstrated activity in a Phase 1 study in patients with multiple myeloma refractory to lenalidomide and/or bortezomib. An IV formulation has been evaluated in more than 300 patients in multiple clinical studies in patients with solid and hematologic malignancies, either as a single agent or in combination with dexamethasone or an HDAC inhibitor.
At the Society of Neuro Oncology meeting in November, we announced encouraging results from a proof-of-concept study, evaluating marizomib in combination with bevacizumab (BEV), or Avastin, in patients with WHO grade IV malignant glioblastoma. The Phase 1 open-label study included three dose escalation cohorts plus an expansion cohort, for a total of 36 recurrent glioblastoma patients. They received marizomib on days 1, 8, and 15, with standard dose of BEV at 10mg/kg on days 1 and 15, of a 28-day cycle. The marizomib plus BEV combination was well tolerated with no dose limiting toxicity at 0.8 mg/m2, which was the highest dose of marizomib evaluated in the study.
The response rate was 42% (14/33) in efficacy evaluable patients, with 34% of patients achieving six months progression-free survival (PFS) and 55% achieving nine months overall survival (OS). The six and nine months PFS in patients with unmethylated MGMT – a marker of poor prognosis and resistance to standard-of-care in glioblastoma - were 34% and 23%, respectively. These data are comparable to PFS in all patients (34% PFS six months, 22% PFS nine months), suggesting a potentially unique clinical benefit of marizomib plus BEV in this difficult to treat segment of glioblastoma. To date, the nine months OS in unmethylated MGMT patients is 44%, with data collection continuing for most patients.
In an ongoing Phase 2 (marizomib monotherapy) portion of the study, 15 recurrent glioblastoma patients have been enrolled to date, receiving 0.8 mg/m2 marizomib on days 1, 8, and 15 of a 28-day cycle. Marizomib monotherapy in these patients has resulted in a partial remission in one patient, and stable disease in two additional patients, demonstrating activity of marizomib as a single agent. Based on these data, the study will continue enrollment up to 30 patients. Marizomib is generally well tolerated in combination with BEV and as monotherapy. The most common study treatment-related adverse events across both phases of the study include fatigue, headache, nausea, diarrhea, dysphonia, hypertension, vomiting, hallucination and weakness.
Triphase recently licensed a novel antibody drug conjugate (ADC), TRPH-222, from Catalent. What’s the potential?
The marizomib deal, in addition to providing validation of our approach to drug development, allows us to focus on new assets, such as the ADC for B-cell malignancies, which we in-licensed from Catalent Pharma Solutions in October of this year. TRPH-222 is a novel, site-specific ADC targeting CD22, a B-cell-restricted sialogycoprotein that is an important modulator of B-cell signaling and survival, which is expressed on nearly all B-cell malignancies. CD22 is a validated ADC target for non-Hodgkin’s lymphoma and acute lymphoid leukemia. The compound itself combines a site-specific modified antibody conjugated to a cytotoxic payload.
The goal here is targeted chemotherapy for cancer. The chemotherapy is specifically attached to the antibody, which binds to CD22, a cell surface receptor that is expressed on lymphoma cells. The targeted payload is then internalized into the cell, resulting in selective delivery of chemotherapy.
On Dec. 21, we announced a new strategic agreement with Celgene on TRPH-222. Under the agreement, Celgene has an option to acquire all of Triphase’s assets relating to TRPH 222. We received an upfront payment from Celgene, will control development and retain all commercial rights to TRPH-222. If Celgene exercises its option to acquire TRPH 222, much like the marizomib deal, Celgene will become responsible for development and commercialization, and Triphase will be eligible to receive development, regulatory and sales milestone payments.
Where do you see Triphase over next few years?
Our near-term goal is to develop TRPH-222 to clinical proof of concept and then achieve a successful exit as we did with marizomib. I am also hoping to acquire some new drugs from companies in the Toronto area and advance them to IND and/or clinical proof-of-concept. Toronto is a premier biotech staging area, similar to Boston and San Francisco, with a very impressive talent pool and some innovative new programs.
[Editor’s note: Raphael Hofstein, president and CEO of MaRS Innovation of Toronto, says, "Triphase’s goals fit very well with our mission statement as an enabler of new companies and their development. MaRS Innovation, which is the commercialization agent for 15 of Ontario’s leading academic institutions, continues to advance its 60-plus companies, including Triphase, in areas such as therapeutics, medical devices, clean technology and information technology. Triphase has been a success story for our institution, and I am confident the company will continue to advance novel programs using its proven approach to drug development."]