PRINCETON, N.J. — Three years ago, a small New Jersey biotech called Advaxis was on the brink of ruin.
Its cancer drug AXAL was in the middle of clinical trials, but the company was out of money and trading as a penny stock.
Today, Advaxis is on the upswing. In the past few weeks, the company has earned two big wins — its cancer drug has been fast-tracked for approval to treat cervical cancer by US Food and Drug Administration and the company has inked a valuable partnership with Amgen for another tumor-killing technology.
The rapid resurrection of Advaxis is the work of both man and microbe — chief executive officer Daniel O’Connor, who was hired at the company’s rock bottom, and a bacterial species called listeria that’s best known for causing food poisoning.
A sinking ship
When O’Connor took over as CEO of Advaxis in August 2013, the company was in debt to several service providers and unable to make payroll for its half-dozen employees, he said. But O’Connor had ushered ImClone’s embattled cancer drug, Erbitux, to market in 2006, in the wake of an insider trading scandal that sent the CEO and Martha Stewart to jail. He believed he could pull off a similar turnaround at Advaxis.
“Advaxis was similar to ImClone in that it had a lot of problems that needed to be addressed,” O’Connor said. “But I believed the underlying technology was sound and should have an opportunity to move forward.”
That technology uses an engineered form of listeria monocytogenes to prompt patients’ immune systems to attack cancer. In the case of its first treatment, AXAL, that coaxing is blunt force — the system attacks cervical cancer by recognizing a common tumor marker in HPV-infected cells. Its second technology, under development, is called MINE, My Immunotherapy Neo-Epitopes. How listeria coaxes the immune system to attack will be specific to the genetic make-up of each patient’s cancer.
AXAL is now in Phase 3 trials. The Amgen deal for MINE breaks down like this: a $25 million purchase of Advaxis stock, $40 million in cash, and $475 million in potential milestone payments. On the day the Amgen deal was announced, Advaxis’s stock jumped 31 percent.
But, as in most drug development, it hasn’t been an easy path.
Using the immune system to fight cancer
AXAL and MINE are technologies that allow the immune system to recognize that cancer cells are not normal and must be destroyed.
Tumors have figured out how to evade the body’s immune system, allowing them to grow and spread under what could be called an invisible cloak. AXAL works by unveiling that cloak.
Listeria infections generate a potent immune response on their own. In AXAL treatment, weakened listeria are loaded with DNA that codes for a specific protein found in nearly all patients with HPV-associated cancer. Infection with these engineered listeria help prime T cells to recognize and kill tumors, where they wouldn’t have been able to before.
For MINE, the listeria-based technology is tweaked to identify hundreds of tumor-specific mutations, or neo-epitopes, from a biopsy of each patient’s tumor and a blood sample, using DNA sequencing to distinguish cancer cells from normal cells. The DNA corresponding to the neo-epitopes is used to bioengineer a patient-specific treatment that will allow T cells to recognize that patient’s mutations and attack the tumors.
Because MINE will be tailored to each patient’s tumor mutations, the company will have some technology hurdles to overcome.
“The technology to identify neo-antigens that deliver a potent immune response is in place, but it requires months to do,” said Jill O’Donnell-Tormey, chief executive officer of the Cancer Research Institute in New York. “Reducing that timeframe and making it scalable is where this field needs to move.”
The hazards of listeria
Amgen’s support of MINE is a vote of confidence, said Dr. Elliott Levy, senior vice president of global development at Amgen. The Advaxis team says they have cut to six weeks the amount of time needed to produce a batch of drugs precisely tailored to a patient’s tumor. MINE won’t be ready for human trials until next year, though, and Advaxis has had to overcome issues with AXAL.
O’Connor and Advaxis’s chief scientific officer, Robert Pettit, had to spend hours explaining the merits of listeria as a cancer-killing vector to investors. They touted their less-pathogenic listeria as a better delivery system than viruses because the bacteria could get past a part of the immune response that often cripples viruses, and head straight to the part of the immune response that it was targeting to wipe out tumors.
After a small Phase 2 trial in India with 109 patients, the overall cervical cancer survival rate at 12 months of patients taking AXAL was 32 percent, whereas another test group, given AXAL plus the chemotherapy drug cisplatin, showed no additional survival over AXAL alone.
The Advaxis C-suite raised $26.5 million and paid off the company’s debts. The team got to work planning Phase 3 trials for AXAL in HPV-driven cancers.
But in October 2015, the FDA forced Advaxis to halt four trials of AXAL after a patient with end-stage cervical cancer who died of her disease was found to have listeria in her bloodstream.
The stock plummeted.
Advaxis submitted a new plan to the FDA, which included administering antibiotics to patients after treatment. Two months later, the FDA lifted the clinical hold.
Advaxis is now recruiting for Phase 3 trials.
The promise of MINE
Levy said Amgen was inspired to make an early bet on Advaxis’s MINE technology because it has the potential to complement one-size-fits-all immunotherapy drugs like Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo. And Advaxis’s listeria platform is similar to Amgen’s recently approved melanoma drug Imlygic, which also uses an engineered pathogen — in that case herpes virus — to engender an immune response against cancer. But those drugs don’t work for all patients, highlighting the need for rapid and more personalized approaches, Levy said.
“Patients with cancer can’t wait forever for treatment,” he said.
O’Connor has built the company back up, but knows Advaxis still has a long way to go to prove the value of its technology.
“Patients are depending on us to move forward,” he said. “That counter-balances the fear.”
This story has been updated with more information on the MINE technology.