After promoting one of his top execs to president and bringing in two new board members, Unum Therapeutics CEO Chuck Wilson ended the week by putting the first snapshot of positive human data from their lead cell therapy for cancer on display in an $86 million IPO filing. But with just a handful of patients in the first round of clinical trials, Unum is also revealing publicly for the first time that it ran squarely into lethal rates of dose-limiting toxicity that killed two patients in one arm and forced it to abandon their high dose after the FDA slapped a clinical hold on the study.
That hold was only recently lifted sometime last month, according to the filing. Unum kept word of the deaths and the hold out of the news for three months while it was on a road show for the IPO.
In response to a query, president and CFO Christiana Stamoulis said in an email:
As you know we are in the quiet period and unfortunately we cannot provide any comments at this point.
The biotech — one of many that has built a rep around a top team and reliable venture backers — has been building a new cell therapy that engineers patient’s T cells into a double whammy on cancer cells. The cells are first designed to express ACTR, a chimeric protein encompassing proteins from T cells and natural killer cells, then combined with another tumor-specific drug, whipping up a cytotoxic assault on cancer cells.
The lead drug is ACTR087, and Unum is already comparing it to Gilead’s Yescarta and Kymriah, the two pioneering CAR-Ts on the market. A combination with Rituxan, researchers tested a low dose (0.5 x 106 ACTR T cells/kg) in 7 NHL patients and tracked 6 responses, including two complete and a partial response. That looks good compared to 39% and 32% complete response rates reported at three months for Yescarta and Kymriah. And they reported no serious adverse events.
The high dose (1.5 x 106 ACTR T cells/kg) was lethal, killing 2 of just 9 patients in that arm. That’s not the first time severe toxicity has killed patients in an exploratory early-stage cell therapy study, but the lengthy delay between the deaths and the SEC filing is likely to spur intense criticism. The FDA responded by putting the study on hold, something Unum never previously disclosed. From the S-1:
The severe ACTR087-related SAEs we observed in Dose Level Two resulted in the FDA placing this trial on clinical hold in December 2017 pending submission of certain information relating to the ATTCK-20-2 clinical trial. The clinical yyhold was removed in February 2018, following review of this information by the FDA. Several protocol and dosing changes were made in early 2018, which we expect to reduce the incidence of adverse events and better manage those events that do occur.
Researchers concluded that there were two cases of ACTR087-related severe CRS — one fatal — and one patient died from ACTR087-related neurotoxicity. There was one fatal case of enterococcal sepsis considered related to ACTR087 and “one patient subsequently experienced a fatal case of sepsis considered not related to ACTR087,” according to the S-1.
Cytokine release storms and neurotoxicity are not new in the cell therapy world, as Juno found out through a string of deaths linked to their first deadly, and now discarded, CAR-T. Gilead’s Kite and Novartis, though, were able to complete registration studies without raising the same concerns.
Safety concerns are a key feature in cell therapy research, but the FDA rules put a wall around information and prevent the agency from discussing any of this, leaving biotechs some wide discretion on how they handle this information. As we saw with Solid Bioscience’s 11th hour update about a partial trial hold for their Duchenne MD gene therapy due to safety concerns, private biotechs can rely on the FDA’s silence to keep safety issues a secret, waiting until SEC rules require a disclosure. And for prominent bioethicists in the field, that’s a problematic issue.
I asked bioethicist Arthur Caplan at New York University’s Langone Medical Center what his perspective was. His answer, by e-mail:
Don’t know Unum case, but I do know of numerous instances in which companies had deaths during early clinical trials that they chose not to publicly disclose. They told the FDA but FDA does not reveal information including deaths that are offered as part of commercial development.
Absurdly more weight is given to keeping deaths a secret in order to bolster the financial prospects of new companies and their investors than to protecting the welfare of human subjects and ultimately the safety of the public should drugs or therapies be approved in the USA or other nations.
At a minimum researchers ought to know if a path they are pursuing has resulted in death(s) so as not to replicate the risks for their subjects. How best to do this I am not sure but putting trade secrecy over human welfare is a sad ordering of priorities.
Unum has three different Phase I programs in the clinic, with another headed to human studies in the near future. The biotech has a collaboration deal in place with Seattle Genetics which combines a BCMA therapy with ACTR087 for multiple myeloma.
Seattle Genetics has paid over $32.5 million in the deal so far, with venture backers coming up with $77.3 million.
One of the big advantages that Unum hopes to prove is that by concentrating on CD16 binding they can use the same basic approach for all their therapies, making it simpler to design and manufacture than the breakthrough drugs now on or close to the market.
For a venture-backed company, Unum also revealed an unusually high reserve of stock for two key players at the biotech: Dario Campana, the scientific founder and a well known cell therapy expert, and CEO Wilson. Each owns 21.7% of the stock.
Atlas, meanwhile, owns 13.9% while F-Prime is in it for 9.9%.
Karen Ferrante and Robert Perez joined Uum’s board last week, while CFO Christiana Stamoulis added the president’s title to her resume. Bruce Booth at Atlas is chairman of the board.
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