CAR T data from Novartis AG (NYSE:NVS; SIX:NOVN) and the University of Pennsylvania demonstrated much of what's already known about the challenges of moving the technology into the solid tumor setting. A presentation at the American Association for Cancer Research meeting in Philadelphia on Sunday showed no complete or partial responders among five patients receiving CART-meso.
The product is an intravenous infusion of autologous T cells transduced to express a CAR directed against mesothelin in patients with recurrent, advanced mesothelin-expressing solid tumors.
There were some signs of efficacy, such as "the clearing of malignant cells in the pleural fluid of one patient" and "radiological and clinical evidence of stable to decreased burden of disease in one patient," according to an abstract from the UPenn presentation.
Solid tumors are typically more intractable than many blood cancers where CAR T products have shown strong response rates. Solid tumors create their own microenvironment and are heterogeneous and structurally complex.
The CART-meso T cells were transiently detectable in peripheral blood for up to 28 days post-infusion. In blood cancers, other CAR T products have shown persistence for more than a year.
In solid tumors the potential to hit the right target on the wrong cell makes it difficult to find a balance between T cell persistence and safety. The greater the persistence, the more likely patients will not relapse. But greater persistence increases the chance that T cells may ultimately find and destroy normal tissues with low levels of antigens.
As reported, the Novartis/UPenn product showed no off-tumor on-target toxicities. The product did travel to tumor sites as well as off-tumor on-target sites.
In a statement to BioCentury, Novartis noted the study was not designed to show efficacy, but rather safety and feasibility of the treatment.
The data put downward pressure on CAR T therapy developers Juno Therapeutics Inc. (NASDAQ:JUNO) and Kite Pharma Inc. (NASDAQ:KITE). Juno lost $8.76 (14%) to $55.90 on Monday, while Kite dipped $6.38 (10%) to $58.68.
Both Kite and Juno are studying CAR T therapies in solid tumors, but their most advanced programs are treatments for blood cancers.
Curadev Pharma Pvt. Ltd. (New Delhi, India) and Roche (SIX:ROG; OTCQX:RHHBY) partnered to develop inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2; TDO) to treat cancer.
The deal gives Roche exclusive, worldwide rights to develop and commercialize Curadev's lead compound, CRD1152, which is a small molecule dual IDO1/TDO inhibitor. The Indian company will receive $25 million up front and is eligible for up to $530 million in milestones, plus escalating royalties up to double digits. Roche declined to say when it plans to start a clinical trial of CRD1152.
Curadev and Roche's Pharma Research and Early Development (pRED) organization also plan to discover next-generation IDO1/TDO inhibitors to treat cancer.
Last year, Roche's Genentech Inc. unit acquired exclusive, worldwide rights from NewLink Genetics Corp. (NASDAQ:NLNK) to NLG919, an oral small molecule IDO pathway inhibitor in Phase I testing for solid tumors.
Bristol-Myers Squibb Co. (NYSE:BMY) gained a discovery platform for IDO and TDO inhibitors in February, when it acquired of Flexus Biosciences Inc. (San Carlos, Calif.) for $800 million up front (see BioCentury Extra, Feb. 23).
Takeda Pharmaceutical Co. Ltd. (Tokyo:4502) said it will invest Y20 billion ($168 million) over 10 years to develop clinical applications of induced pluripotent stem (iPS) cells under a new research collaboration with the Center for iPS Cell Research Application (CiRA) of Kyoto University.
The Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA) will sponsor research projects in areas such as heart failure, diabetes, neurological disorders and cancer immunotherapy.
Takeda also is providing more than Y12 billion ($100.8 million) in in-kind support to the projects, including facilities, equipment, researchers and services. Takeda and CiRA each will dedicate about 50 researchers to the projects.
CiRA was established in 2010. Director Shinya Yamanaka won a Nobel Prize in 2012 for his research into iPS cells and adult stem cells.
Japan's discoveries in regenerative medicine are seen as a vital part of the Japan Revitalization Strategy, the country's national growth initiative, and the government has devised new strategies to translate science into commercial therapies more quickly. One such strategy is its sakigake early access pathway for regenerative medicines that could cut approval times for innovative therapies in half (see BioCentury, April 20).
Takeda spokesperson Julia Ellwanger told BioCentury last week that the company was evaluating its compounds to see which ones might qualify for the new pathway, which has been described as similar to U.S. FDA's breakthrough therapy designation.
CNS play Vanda Pharmaceuticals Inc. (NASDAQ:VNDA) named Tom Gibbs as SVP and CCO. Gibbs was VP of worldwide commercial operations at Bristol-Myers Squibb Co. (NYSE:BMY).
Pain and neurology play Purdue Pharma L.P. (Stamford, Conn.) named Alan Butcher SVP of licensing and business development. Butcher was VP of business development at Shire plc (LSE:SHP; NASDAQ:SHPG).
Metabolic disease company CymaBay Therapeutics Inc. (NASDAQ:CBAY) hired Kirk Rosemark as VP of regulatory affairs and quality assurance. Rosemark held the same position at Exelixis Inc. (NASDAQ:EXEL).
Bioinformatics company OpGen Inc. (Gaithersburg, Md.) named Kevin Krenitsky as president and Timothy Dec as interim CFO. Krenitsky was CCO and COO at Foundation Medicine Inc. (NASDAQ:FMI). Dec was CFO for Clubwidesports LLC.
Merck & Co. Inc. (NYSE:MRK) submitted an sBLA for Keytruda pembrolizumab to treat advanced squamous and non-squamous non-small cell lung cancer (NSCLC) and said it plans to submit an sBLA for the drug as first-line treatment for melanoma mid-year. The company reported data from Keytruda trials for these indications at the American Association for Cancer Research meeting in Philadephia. The humanized IgG4 mAb against programmed cell death 1 (PDCD1; PD-1; CD279) is approved to treat advanced melanoma in patients previously treated with Yervoy ipilimumab from Bristol-Myers Squibb Co. (NYSE:BMY).
Merck reported data from the Phase Ib KEYNOTE-001 trial in which Keytruda-treated NSCLC patients with ≥50% tumor cells positive for PD-L1 expression had an overall response rate (ORR) of 45.4%, compared to 16.5% of patients with1-49% tumor cells positive and 10.7% of patients with <1% tumor cells positive for PD-L1 expression. Merck said the findings showed that tumor PD-L1 expression may be a relevant biomarker to identify NSCLC patients who are more likely to benefit from anti-PD-1 therapy.
FDA approved an sBLA in March for BMS's competing anti-PD-1 therapy Opdivo nivolumab to treat metastatic squamous NSCLC (see BioCentury Extra, March 4).
Last week, BMS said it stopped a Phase III trial of Opdivo after the drug met its primary endpoint in previously treated patients with advanced non-squamous NSCLC. BMS did not disclose when it plans to seek a label extension for non-squamous NSCLC. Opdivo is marketed as second-line treatment for advanced melanoma after Yervoy (see BioCentury Extra, April 17).
Gideon Blumenthal, a clinical team leader in the Office of Hematology and Oncology Products at FDA's Center for Drug Evaluation and Research, told BioCentury TV that while FDA approved Opdivo for metastatic squamous NSCLC based on survival data, the agency would not require survival data for subsequent PD-1 modulators.
Merck intends to base its sBLA for Keytruda as first-line treatment for advanced melanoma on data from the Phase III KEYNOTE-006 trial, which the company ended in March after an interim analysis showed Keytruda was superior to Yervoy on the co-primary endpoints of progression-free survival (PFS) and overall survival (OS). Merck said Keytruda is the first anti-PD-1 therapy to demonstrate a survival advantage over Yervoy, a human mAb against CTLA-4 receptor and the standard of care in the first-line setting (see BioCentury Extra, March 24).
Patients in KEYNOTE-006 received either 10 mg/kg of Keytruda every two weeks, 10 mg/kg of Keytruda every three weeks or four cycles of 3 mg/kg of Yervoy every three weeks. The median PFS was 5.5 months in the two-week Keytruda arm and 4.1 months in the three-week Keytruda arm, compared to 2.8 months in the Yervoy arm (p<0.00001).
The one-year OS rate was 74.1% in the two-week Keytruda arm (p=0.00052) and 68.4% in the three-week Keytruda arm (p=0.00358) vs. 58.2% in the Yervoy arm. Median OS has not yet been reached in any treatment group.
The ORR was 33.7% in the two-week Keytruda group (p=0.00013) and 32.9% in the three-week Keytruda group (p=0.00002) vs. 11.9% for the Yervoy group.
In November, BMS said patients treated with Opdivo in the Phase III CheckMate -006 trial as a first-line treatment for advanced melanoma had a one-year survival rate of 72.9%. BMS spokesperson Carrie Fernandez declined to discuss the company's plans to seek a label extension for Opdivo in this indication (see BioCentury Extra, Nov. 17, 2014).
Bristol-Myers Squibb Co. (NYSE:BMY) said the combination of Opdivo nivolumab plus Yervoy ipilimumab was superior to Yervoy alone in the Phase II CheckMate -069 trial to treat treatment-naive patients with advanced melanoma.
Opdivo plus Yervoy led to an objective response rate (ORR) of 61% vs. 11% with Yervoy (p<0.001), meeting the trial's primary endpoint. The combination led to complete responses in 22% of patients without BRAF mutations (n= 72) as well as 22% of patients with BRAF mutations (n=23) vs. no CRs in the Yervoy group.
In patients with BRAF mutations, Opdivo plus Yervoy led to median progression-free survival (PFS) of 8.5 months vs. 2.7 months with Yervoy alone, while median PFS was not reached in patients without BRAF mutations.
Treatment-related grade 3/4 adverse events were more frequent with the combination regimen than with Yervoy alone (54% vs. 24%). The most common grade 3/4 AEs with Opdivo plus Yervoy were grade 3-4 colitis (17%), diarrhea (11%) and increased alanine aminotransferase (11%). BMS said about 80% of the AEs resolved with corticosteroid treatment. Trial discontinuations in the combination arm were 47% vs. 17% in the Yervoy arm.
BMS spokesperson Carrie Fernandez said the company plans to present results from the Phase III CheckMate -067 trial evaluating Opdivo plus Yervoy vs. either treatment alone at the American Society of Clinical Oncology annual meeting, which runs from May 29-June 2 in Chicago.
FDA approved Opdivo in December 2014 to treat unresectable or metastatic melanoma in patients previously treated with Yervoy, including BRAF V600 mutation-positive patients treated with Yervoy plus a BRAF inhibitor. In March, FDA approved an sBLA for Opdivo to treat metastatic squamous NSCLC in patients who have progressed on or after platinum-based chemotherapy (see BioCentury Extra, Dec. 22, 2014 and BioCentury Extra, March 4).
Opdivo is a human IgG4 mAb against programmed cell death 1 (PDCD1; PD-1; CD279). BMS's Yervoy, a human mAb against CTLA-4 receptor, is the standard of care in advanced melanoma.
The Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY) said it will advance MPDL3280A into Phase III studies for triple-negative breast cancer (TNBC) this year after reporting interim Phase Ia data showing the compound led to an overall response rate (ORR) of 19% and a 24-week progression-free survival (PFS) rate of 27%.
The human mAb targets programmed cell death 1 ligand (PD-L1; B7-H1; CD274). As presented today at the American Association for Cancer Research meeting in Philadelphia, the 21-patient cohort had ≥5% tumor cells positive for PD-L1 expression and received 15 mg/kg, 20 mg/kg or 1,200 mg of MPDL3280A IV every three weeks.
Two patients had complete responses and two had partial responses. The median duration of response has not yet been reached.
Spokesperson Holli Dickson said efficacy results for patients with PD-L1-negative tumors were not yet evaluable.
She said Genentech plans to start a Phase III trial of MPDL3280A plus nab-paclitaxel as first-line treatment for TNBC next half.
In December, Merck & Co. Inc. (NYSE:MRK) reported interim Phase Ib data from its KEYNOTE-012 trial of Keytruda pembrolizumab to treat TNBC; the 27-patient cohort demonstrated an 18.5% ORR.
The pharma's Phase II KEYNOTE-086 trial of the humanized IgG4 mAb against the PD-1 receptor (PDCD1; PD-1; CD279) in the metastatic triple-negative indication is slated to start this half (see BioCentury Extra, Dec. 10, 2014).
Ampio Pharmaceuticals Inc. (NYSE-M:AMPE) fell $5.18 (66%) to $2.69 on Monday after osteoarthritis pain relief candidate Ampion missed the primary endpoint in the Phase III STRIDE trial. Ampio said it will meet with FDA to discuss the submission of a BLA for Ampion based on data from previous clinical trials.
Ampion did reduce WOMAC-A pain subscale scores significantly from baseline in the trial, but Ampio said response to a saline control in STRIDE's placebo arm was twice as variable as observed in previous trials. The company said it will re-examine patient demographic differences between STRIDE and earlier trials.
Ampio said it thinks the earlier Phase I/II STRUT and Phase III SPRING trials will adequately meet FDA requirements to support a BLA submission, while STRIDE will allow it to reach a minimum patient exposure FDA requires for an acute therapy. The company did not respond to requests for comment.
Brandon Capital raised A$200 million ($156.3 million) for its Medical Research Commercialisation Fund (MRCF3), which the firm said is Australia's largest life science venture fund to date. Existing investors AustralianSuper and Statewide Super and new investors HESTA and Hostplus contributed to the fund.
The firm intends to invest A$50 million in 20-30 seed-stage biotech and medical device companies. It plans to invest the remainder in later rounds for those companies and other MRCF portfolio companies.
Brandon Capital closed its A$40 million MRCF2 fund in 2011 with participation from the Australian government's Innovation Investment Fund program.
Woodford Investment Management LLP raised L800 million ($1.2 billion) for its Woodford Patient Capital Trust plc fund ahead of its listing on LSE. The fund, expected to trade on LSE beginning Tuesday, was oversubscribed by about 10%. Earlier this month, Woodford raised the ceiling of its fund to L800 million from L500 million ($746.6 million) after exceeding its initial fundraising target of L200 million ($300.9 million). Woodford has said it will invest in 50-100 mid- to large cap, early growth and early stage companies, primarily in the U.K. (see BioCentury, April 13).
Acting FDA Commissioner Stephen Ostroff told BioCentury he plans to keep FDA on the course set by his predecessor, Margaret Hamburg. Ostroff, who is starting his third week as acting commissioner, presented a detailed agenda for the agency to reporters Monday, focusing on food safety and regulation of tobacco products. He said it is "hard to imagine substantial new priorities, at least in the short-term" beyond those Hamburg set over the last six years.
Ostroff reiterated concerns Hamburg had expressed publicly that a discussion draft of the 21st Century Cures Act could divert FDA resources from medical product reviews and approvals, and that provisions in the draft could lower safety and efficacy standards. He reported that FDA staff have been advising the House Energy & Commerce Committee about provisions that would be better deferred for consideration in PDUFA reauthorization negotiations rather than legislated in the 21st Century Cures Act.
Ostroff joined FDA in 2013 as CMO in the Center for Food Safety and Applied Nutrition and senior public health advisor to FDA's Office of Foods and Veterinary Medicine. He was appointed FDA Chief Scientist in January 2014. Prior to joining FDA, Ostroff was deputy director of the CDC's National Center for Infectious Diseases.
The Diagnostic Test Working Group is not part of the Personalized Medicine Coalition. The April 17 BioCentury Extra mischaracterized the affiliation.
Find a commercialization partner, or go it alone? This decision involves not only strategic questions regarding a company's identity and core competencies, but also multiple value drivers that are easy to overlook. This article examines how a value-based approach can help companies position themselves to ensure their business plans contribute to a product's success and an improved return on investment. Download your copy now!