Problems that led to the capsizing of Dendreon Corp.’s Provenge prostate cancer immunotherapy are particular to the company and product, some cancer vaccine makers are quick to say. Nevertheless, what the Street saw as a commercial disaster for the pioneering treatment bears lessons for those who follow in the budding space.

After many years of regulatory hurdles and patient protests demanding access, in April 2010, Provenge (sipuleucel-T) became the first active cancer immunotherapy approved by FDA for castration-resistant prostate cancer. A personalized, tough-to-manufacture product, Provenge hit the market at the whopping price of $93,000, for a regimen including three infusions given over one month. It went on to get a national endorsement for Medicare coverage, hitting the reimbursement bull’s eye of the target patient population.

Before Provenge, there had been numerous late-stage failures in the development of active cancer immunotherapies, a field often referred to as cancer vaccines. The thumbs-up from FDA appeared to be a rising tide that could lift all ships (Also see "Provenge Nod Lifts Spirits And Stocks, But Also Sets High Bar For Success" - Pink Sheet, 17 May, 2010.).

But in the summer of 2011 the tide turned, leaving some companies to accentuate their differences, rather than the similarities, to Provenge. In early August, Dendreon missed its forecasts, explaining that compared to academic centers, take-up in community practices was lower than expected, mainly, due to fears about reimbursement and uncertainty about the appropriate patient population (Also see "Disappointing Provenge Sales Stir Doubts About Demand" - Pink Sheet, 4 August, 2011.).

The company’s withdrawal of revenue projections of $350 million to $400 million for 2011 caused its stock to plummet by more than 65% between Aug. 3 and Aug. 4. Yearly revenue is actually more likely to be in the $200 million range, based on quarterly revenue of about $50 million per month, the company subsequently told analysts.

According to the Cancer Research Institute, a non-profit provider of funding for cancer immunotherapy research, some 40 active cancer immunotherapies are in development (some companies refer to their products as vaccines and others prefer the term cancer immunotherapeutic). The products diverge dramatically in terms of mechanism of action, manufacturing and administration. Twelve of the therapies in development are autologous, or developed using patients’ own cells. The others are off-the-shelf treatments.

Provenge is a complex, autologous immunotherapy. Each dose relies on cells that are altered using a process called leukopheresis and the treated cells are given intravenously back to the patient.

Dendreon faced many unique hurdles because of Provenge’s complexity, but nevertheless, the company has been a “bellwether for the entire space,” and so when it comes to perception, the disappointment has a broad impact, according to Rainer Laus, executive VP and director of cancer vaccines at Bavarian Nordic.

“We tend to celebrate victories in cancer immunotherapy a little prematurely,” commented Michael Becker, founder of the consultancy MD Becker.

Great Expectations

The Dendreon launch experience underscores the importance of managing expectations, commented Kantar Health Oncology CEO Richard Martin. Given that the drug is from a new class, its uptake so far may be reasonable and appropriate, he said. This may not actually be a bad launch, despite the missed financial expectations, he said.

Companies are best advised to be positive about expectations internally, but conservative when it comes to external communications, he said.

Similarly, Bavarian Nordic’s Laus noted that the launch has been portrayed as a “massive failure,” but that another way to look at it is that the guidance was too aggressive.

The treatment breaks new ground on a number of counts. In addition to being the first active cancer immunotherapy, the target customer base has some unique characteristics. Prostate cancer patients have traditionally been managed by urologists, who, unlike oncologists, do not typically administer complex infusion therapies. Initially, the company targeted large academic centers and faced challenges in moving into the community environment, where 70% of cancer patients are managed by urologists and oncologists.

“Cost-density” The Culprit?

During an earnings call, Dendreon execs said that the “cost-density” of the product proved to be an obstacle, because the physicians needed to pay a high dollar figure in a short period of time, in an uncertain reimbursement environment.

But addressing the cost of an expensive drug is a typical issue with a new product launch and can usually be managed with extended payment programs. Dendreon offers financing to doctors but was not specific about the details.

McKesson, which is the exclusive distributor of the product, declined to comment specifically on Dendreon or Provenge. Generally, however, it said it buys pharmaceutical products and sells them to physicians, allowing extended payback periods, which typically are from 45 to 120 days. If the physicians don’t pay within the contracted period, McKesson charges a 1% to 1.5% financing fee.

Urologists are less accustomed to purchasing expensive pharmaceuticals and taking advantage of such programs.

Oncologists have traditionally managed chemotherapy, due to the side effects. But cancer vaccines typically have cleaner safety profiles, and data suggest they are better suited to earlier stages of disease, when the tumor burden is lighter. Consequently, in the future, vaccines are likely to be used beyond oncology by a broader range of medical doctors, commented James Gulley, director of the Clinical Trials Group at the National Institutes of Health’s Laboratory of Tumor Immunology and Biology.

“As long as they [doctors] understand when to use them, there is very little downside to using a vaccine,” Gulley said.

Logistical Hurdles

Dendreon’s withdrawal of sales guidance raised questions about demand. At the time, some clinicians commented that the treatment involves extensive coordination and administrative work to manage the infusions, steps that don’t occur in routine patient management, Becker said.

“Physicians are put off by that, particularly community physicians. They don’t want to go through that complex process,” said Rachel Webster, an analyst at Decision Resources.

Among other biotechs, Agenus has worked to minimize the hassles of delivering personalized cancer vaccines.

Agenus Inc. (formerly called Antigenics) noted the importance of streamlining administration of patient-specific cancer therapies. The company’s Prophage (heat shock protein peptide complex-96) vaccine is in Phase II for glioblastoma and is commercially available in Russia for advanced kidney cancer under the trade name Oncophage.

As part of routine treatment for glioblastoma, tumors are removed surgically. The company provides a kit for packaging the tumor specimen in dry ice and arranges for courier pick-up to the company’s manufacturing facility in Lexington, Mass. The personalized treatment is made within 10 hours and transported back to the hospital, where it is stored in the pharmacy.

“From a hospital and physician perspective, there’s really no burden at all,” said Garo Armen, CEO.

In an Aug. 10 press release, Northwest Biotherapeutics Inc. pointed out many differences between its autologous dendritic cell vaccine DCVax, which is in development for multiple cancers, and Provenge. Dendreon is a fresh product given by intravenous injection, in contrast with DCVax, which is given by intradermal injection and can be frozen and therefore has a much longer shelf life, the release pointed out. Northwest argues that because its production costs are lower – they are based on batch manufacturing and cryopreservation techniques – DCVax is cheaper to produce and will be priced at roughly $37,000 per year, which is competitive with monoclonal antibodies, as well as Provenge.

“It’s really important that pricing and reimbursement issues not cause disillusionment with all of the immune therapies emerging”– Northwest Biotherapeutics CEO Linda Powers

“It’s really important that pricing and reimbursement concerns with certain immune therapies, such as Provenge, not cause disillusionment with all of the immune therapies emerging,” CEO Linda Powers noted in the statement.

Off-The-Shelf Options

Nowadays, interviews with physicians suggest, more enthusiasm exists for off-the shelf vaccines compared to patient-specific products, said Decision Resources’ Webster.

Although twice as many non-autologous active immunotherapies have failed in trials, Big Pharma seems to have a preference for off-the-shelf immunotherapies, noted a post-ASCO 2011 report from MD Becker and the Cancer Research Institute.

Of the 40 active cancer immunotherapies in development, Big Pharma developed or is partnered on six candidates, all of which are non-autologous. GlaxoSmithKline’s MAGE-3 ASCI, which was in-licensed from the Ludwig Institute for Cancer Research, is one of the most advanced, with a large Phase III trial ongoing in non-small-cell lung cancer. Meanwhile, Merck Serono SA and partner Oncothyreon Inc. have Stimuvax in Phase III for NSCLC.

In collaboration with the National Cancer Institute, Bavarian Nordic has an off-the-shelf prostate cancer vaccine called PROSTVAC in Phase III. The company raised DKK655 million ($123 million) in a rights issue of new shares in May, and will not need additional cash to finance its Phase III program, which targets a similar patient population as Provenge. Compared to Provenge, the vaccine is much simpler to use, said the NIH’s Gulley, who is the trial’s lead investigator.

“You just take it out of the freezer and inject it,” he said.

In a randomized Phase II study of 125 patients with metastatic prostate cancer after failure of initial hormone therapy, a similar patient population targeted by Provenge, the drug offered an 8.5 month overall survival advantage over placebo. If the vaccine showed even half that reduction in Phase III, it would match the survival benefit of Provenge, Gulley commented.

And if potency is equal between an individualized and off-the-shelf vaccine, “one would clearly go with off-the-shelf,” he added.

In theory, lower manufacturing costs for an off-the shelf product could allow more competitive pricing, as the Northwest press statement attests. But the $93,000 price for Provenge is not actually that high in the oncology space, and products that cost the same or more have been received favorably, commented Kantar Health’s Martin.

Bristol-Myers Squibb’s Yervoy (ipilimumab) is a prime example. An off-the-shelf passive cancer immunotherapy, the ipilimumab regimen includes four $30,000 injections at the total cost of $120,000. The drug generated revenues of $95 million in its first three months of launch, exceeding expectations ([A#1216099165884]).

However, noteworthy differences exist between Yervoy and Provenge. Unmet need is higher in advanced metastatic melanoma, which doctors have treated with a handful of older medicines, approved more than a decade ago. Yervoy was the first approved drug to show a survival benefit for the disease, all the more remarkable given the advanced stage of disease for patients in the trials supporting approval. The mechanism of action is also well-understood. And compared to the Provenge label, the Yervoy label is very broad when it comes to patient eligibility. As an off-the-shelf product, Yervoy is also simpler to produce and distribute.

A Crowded Therapeutic Space

By the time Provenge hit the market, the landscape for treating CRPC was getting crowded.

Sanofi's new chemotherapy Jevtana (cabazitaxel) was approved soon after Provenge.

Johnson & Johnson’s hormone therapy Zytiga (abiraterone) is now cleared for patients following chemotherapy and is being positioned for earlier-stage patients after failure of primary androgen deprivation therapy and prior to chemotherapy, which is the same population targeted by Provenge.

The generic oral ketoconazole has a similar mechanism of action as abiraterone and, among other options, has been used for many years as a as a second-line hormonal treatment prior to chemotherapy.

The National Comprehensive Cancer Network guidelines include adrenal/paracrine androgen synthesis inhibitors abiraterone and ketoconazole as options for patients after initial castration therapy has failed. The guidelines specify that abiraterone may be used for metastatic CRPC patients who have not received prior chemotherapy, though it isn’t the standard of care.

Many other treatments are in development for CRPC and have shown promise.

“It’s what you could call ‘competition-density,'” Becker said.

Weighing Costs And Benefits

Hormonal and chemotherapeutic treatments just approved and coming down the pike for CRPC work in ways that are more familiar to physicians, with clear signs that a drug is working, such as tumor shrinkage, delay in time-to-progression and declining prostate specific antigen levels.

With cancer vaccines, however, the effect on tumors is delayed and may not register a clear sign of response after treatment.

“Many medical oncologists and urologists are still uncertain as to how to explain how a drug is working,” Gulley said.

In the case of prostate cancer, the PSA may still be rising, and this raises questions about the cost-benefit trade-offs of treatment.

Decision Resources’ Webster noted that the Provenge experience has shown the importance of hitting secondary endpoints in trials, such as time-to-progression – not for regulatory approval but in order to maximize uptake following approval.

The message still needs to get out that cancer vaccines can improve outcomes with fewer side effects, Laus said. However, the exec also acknowledged that physicians want to see effects on conventional markers. It’s easier to demonstrate a cancer vaccine’s effect on tumor size and progression in earlier stage disease. While this research may not be needed or accepted by regulatory officials, it could be gathered and used to support use and explain how the drug works, he said.

It will take time to move physicians toward an understanding of immunotherapy, he said: “It’s a multi-step process to re-educate the entire oncology community and that’s hard. That’s why there’s one drug out there and it’s highly debated. It might take more than one to change the space.”

An interim analysis from Stimuvax in the Phase III START study of NSCLC is due out by the first quarter of 2012. But the release could prove a double-edged sword – the vaccine was not successful in breast cancer and a failure in NSCLC could further taint the field of immunotherapy, Becker said. Data for GSK’s MAGE-3 ASCI is expected by the end of 2012.

“Hopefully, right around the corner from the Dendreon debacle will be some positive data coming from an off-the-shelf [product] developed by Big Pharma, to provide investors and observers with some other cancer immunotherapy metric to point to as a success,” Becker said.

By Emily Hayes

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