Madison Vaccines Rides Immunotherapy Wave With Early-Stage Prostate Drug

Xconomy Wisconsin — 

Most men suffering from prostate cancer can be essentially cured if their tumors are caught early enough and their prostate glands are surgically removed or destroyed by radiation therapy before the disease spreads.

But for some men, removing the prostate gland isn’t enough. Months or years after surgery or treatment, levels of prostate-specific antigen (PSA) may begin to climb again—an indication that prostate cells, possibly cancerous, are still lurking in the body, poised to multiply and spread to the bones or other organs.

For those men, there are few treatment options, and they’re not ideal, says Rick Lesniewski, co-founder, president, and CEO of Madison Vaccines, a Madison, WI-based startup developing prostate cancer drugs. The patients can “watch and wait” with their rising PSA levels before pursuing further, more radical treatment, or they can move ahead with hormone deprivation therapy that depletes their testosterone levels and can ultimately end in surgical or chemical castration. Hormone deprivation can slow metastasis (the spread of cancer), but it also carries a host of undesirable side effects, including hot flashes, loss of muscle mass, increased amounts of fat, libido loss, and growth of breast tissue, Lesniewski says.

“It’s a hard tradeoff for these men,” Lesniewski says. “And these side effects are not only uncomfortable and they really affect their quality of life significantly, but they may be physiologically very important because we do know that their insulin levels climb, their incidence of cardiovascular disease can increase—it accelerates that process.”

That’s why Madison Vaccines (MVI) is working to develop a new treatment option for early-stage prostate cancer patients—after their prostates have been removed, but before the cancer has spread to the bones or other organs. The idea is to prevent, or at least delay, the onset of metastases and the need for castration by priming the immune system to recognize cancerous cells and kill them.

Building on research from the lab of Douglas McNeel, an oncologist and professor of medicine at the University of Wisconsin-Madison, MVI is creating vaccines from tiny circular bits of DNA called plasmids. The company’s lead DNA vaccine, MVI-816, contains instructions for a protein named prostatic acid phosphatase (PAP), which is made by prostate cells. When injected into the skin, the DNA is taken up by the body’s cells (the company is still researching exactly which types of cells do the absorbing), which use the DNA to make copies of the PAP protein. That protein, in turn, acts as an antigen to stimulate an immune response against PAP, the company has shown in Phase I trials.

The company will now test MVI-816 in a Phase II trial in prostate cancer patients to learn whether or not the immune response against PAP is strong enough to delay the spread of cancer. The hope is that the primed immune system will find and kill lurking prostate cells that are making the protein. If so, then prostate cancer that recurs after surgery “becomes a manageable disease, rather than a disease which is ultimately fatal,” Lesniewski says.

The startup has raised about $9 million from investors, who include Venture Investors, the Wisconsin Alumni Research Foundation (WARF), the State of Wisconsin Investment Board, Venture Management, Wisconsin Investment Partners, and Gen6 Capital Partners. WARF contacted Lesniewski, a biopharmaceutical veteran who had held various leadership positions at Abbott Laboratories near Chicago and GlaxoSmithKline in Philadelphia, in 2011 to gauge his interest in turning McNeel’s research into a business.

But MVI is hardly the first company to try to harness the immune system to fight cancer or to create DNA vaccines. Scientists have been trying for decades to improve the immune system’s ability to find and destroy cancer cells. And ever since researchers discovered in the early 1990s that injecting DNA plasmids into mice could stimulate an immune response, DNA vaccines have been tested against everything from HIV and influenza to malaria and cancer.

Yet despite immense promise of these approaches and hundreds of millions of dollars of investment, these fields are littered with failures and dashed dreams. GlaxoSmithKline’s MAGE-A3, a vaccine based on a protein made by melanoma cells, and Merck KGaA’s Stimuvax, a similar protein vaccine for lung cancer, are just two of the efforts that failed in late-stage trials, although Merck is taking another stab with the Stimuvax technology in a new Phase III trial.

Only one cancer vaccine, Seattle-based Dendreon’s sipuleucel-T (Provenge), has been approved by the Food & Drug Administration. Provenge uses the same PAP protein as MVI does, in a procedure that requires withdrawing a prostate cancer patient’s blood, exposing immune system cells to PAP, and infusing the cells back into the patient. But it has struggled mightily in the marketplace since its 2010 approval because of its $93,000 cost per patient and because of doubts over whether it offers meaningful benefits.

Meanwhile, DNA-based cancer vaccines have shown efficacy in animals like mice, but translating the same immune response to humans has proven difficult, says Rob Johnson, a co-founder and partner with life sciences consultant Alacrita in Cambridge, MA. Johnson worked for 10 years at a VC-backed startup, Onyvax, which was developing prostate and colorectal cancer immunotherapies. The company’s lead drug candidate failed Phase II trials, he says, and the intellectual property was sold to a South Korean company.

“Many companies have tried to develop cancer vaccines,” Johnson says. “The vast majority have failed.” Some skeptics question whether cancer vaccines will ever be successful.

This long history of disappointment means that overcoming the stigma toward cancer vaccines will be one of MVI’s challenges, says Jill O’Donnell-Tormey, CEO and director of scientific affairs of the New York-based Cancer Research Institute.

So why does Lesniewski think MVI stands a chance to succeed where bigger, better funded companies have failed?

For one, MVI is targeting the disease at an earlier stage than most therapeutic approaches, which (like Dendreon’s Provenge) are designed to fight prostate cancer after it has metastasized and is resistant to castration therapy, Lesniewski says.

“We believe the time to engage the immune system is when you have time to train it up over six to 12 weeks, and the battle it has to fight is against a relatively small number of tumor cells,” Lesniewski says.

Johnson likes MVI’s earlier-stage approach because it gives the immune system a fighting chance to control the disease, he says. He also thinks that the company’s clinical goal of delaying metastases is a sensible one that has an opportunity to get FDA approval.

MVI’s approach has other advantages over competitors. Its vaccines are designed to be “off-the-shelf,” meaning that they can be mass-produced and administered via a simple injection into the skin of the upper arm, in contrast to the multi-step, personalized process of an “autologous” treatment like Provenge. In addition, plasmid DNA vaccines are cheaper and faster to manufacture and are more stable in storage than protein or peptide vaccines, MVI says, so they wouldn’t have to be manufactured as frequently. It’s way too early to talk pricing of an unapproved MVI vaccine, but Lesniewski says, in theory, it “could be cost-effective.”

“Hopefully off the shelf would be more economical” than Provenge, says Matthew Cooperberg, a urologist and associate professor at University of California, San Francisco. “But that remains to be seen.”

To win approval from the FDA, MVI has a long, expensive road ahead. The early data show promise. In two separate Phase I trials treating a small number of patients at slightly different stages of prostate cancer, the lead vaccine showed the ability to trigger an immune response in some patients, without any major side effects. The planned 106-patient Phase II trial will attempt to show the vaccine delays metastases.

The company’s pipeline also includes a DNA vaccine that codes for part of the androgen receptor, which is often produced in higher volumes by prostate cancer cells as the disease progresses. That vaccine could enter a 40-patient Phase I trial by the end of the year. MVI is also developing a pre-clinical companion diagnostic test intended to help identify the patients that are most likely to respond to the company’s vaccines.

One of the challenges the company faces, though, is that prostate cancer often takes at least a year or two to reappear in patients after surgery, even in men with fast-rising PSA levels like those targeted by MVI. As a result, the trials also will take years to prove that the treatment delays the spread of cancer. The Phase II trial, for example, is planned to last for at least two years. That’s different from a typical cancer drug that may be approved because of its ability to shrink a tumor in a matter of a few months, Lesniewski says.

“We’re trying to prevent the appearance of this disease, rather than measure if we can shrink it,” he says. “For some investors, it’s too long.”

Investors may also worry that using just one antigen in the vaccine increases the risk of tumors learning to defend against the vaccine. “I do believe that targeting just one antigen is not as good as targeting more than one antigen,” Johnson warns.

And even if the company’s lead drug hits the market, there are no guarantees it will gain traction with doctors and patients.

“This is potentially a step above Provenge from a logistical standpoint” because it’s an off-the-shelf vaccine, Cooperberg says. “But how it stacks up against Prostvac or others” remains to be seen.

Prostvac is Bavarian Nordic’s immunotherapy drug candidate that is in a Phase III trial. Like MVI, it’s designed as an off-the-shelf vaccine, but it’s intended to treat patients at a later stage of the disease—after the cancer has metastasized and doesn’t respond to castration therapy, but before the patients show pervasive symptoms.

Still, there may be room for a number of approaches, Cooperberg adds, because the answer to successfully attacking cancer will almost certainly involve combinations of treatments. In fact, McNeel is already conducting a small Phase I study exploring synergies between MVI’s lead vaccine and Provenge, Lesniewski says.

“It’s not to say that we couldn’t be surprised and the vaccine by itself could be efficacious in preventing and delaying bone” metastases, Lesniewski says. “That would be a wonderful outcome. But history teaches us that many, if not most, of the agents that are successful end up being used in some type of combination therapy.”

That adds yet another set of challenges for companies like MVI. “The problem is there’s probably an infinite number of combinations that could be done, so how do we intelligently do this in the most efficient way?” says O’Donnell-Tormey of the Cancer Research Institute. “Combinations are the future, but what those combinations are is still the question.”