‘Good enough’ is no longer good enough
March 2013
by Randall Willis  |  Email the author


Imagine being an Olympic high jumper, preparing for years for one performance. You stand in the block for your final jump, the one that could give you a gold medal. You run; you jump; you will your body over that bar to victory—only just as you're about to surmount the bar, the judges on either side raise it a little higher, and you fail. Or worse, you successfully jump the bar, only to have the judges change their minds and decide that the bar should have been higher—and you lose. All those years of development are now gone because of actions you could not have foreseen.  
In Olympic sport, this is unlikely to ever happen, but all too often, it seems to be happening in the pharmaceutical industry as potential new therapeutics are being rejected for being good, but not quite good enough—and possibly nowhere more than in oncology have the rules changed so much in getting a new therapeutic approved.  
When it was once good enough to simply show that your drug was efficacious and relatively safe, regulatory agencies around the world are raising the approval bar and demanding that new therapies show dramatically significant improvements over current standards of care, or risk either non-approval or relegation to late-stage (e.g., third- and fourth-line) or niche treatment. Even when you get your drug through regulatory agencies, payors can still refuse your applications, as new drugs often cost significantly more than current standards of care, which in many cases have entered the generic phase of their lifecycle.  
In response, companies are left trying to discover ways to anticipate the new thresholds, and in the absence of that information, to tip the risk-benefit balance of improvement over standard of care through a combination of therapeutic target selection, patient selection and clinical trial design.
Hedging your bets
"Cancer is one of the most complex diseases, as tumor characteristics change over time and tumors become resistant to many therapeutics," says Dr. Ingmar Hoerr, CEO of CureVac, a company developing RNA-based immunotherapies targeting cancer and infectious diseases.  
Thus, the company has focused its efforts on indications that offer antigens known to be overexpressed in diseased tissue—in CureVac's case, antigens presented in prostate cancer and non-small cell lung cancer (NSCLC).  
"Stimulating the patient's intrinsic immune response for a stronger and more effective way to attack cancer cells has been an intriguing concept for a long time," Hoerr explains. "Recent success stories, such as the cell-based immunotherapy Provenge for the treatment of prostate cancer, and positive data from several Phase II trials with different cancer vaccines for NSCLC, have spurred the interest in this approach."
CureVac's RNActive system involves the intradermal injection of self-adjuvanted mRNA molecules that code for tumor-specific (or tumor-predominant) antigens. The RNA molecules are taken up by immune cells, which then express the antigens, prompting a sustained immune response.
RNA-based vaccine specialist Argos Therapeutics had a similar approach to selecting its initial therapeutic area: renal cell carcinoma.  
"Kidney cancer was ideal because we wanted a tumor type where immunotherapies have succeeded, albeit on a limited basis, in the past," explains Doug Plessinger, Argos' vice president of clinical and medical affairs. "It was also a very important target for us because of our unique approach to how we obtain the fresh tumor tissue, isolate the RNA from the tumor and ultimately reprogram a patient's dendritic cells, re-educating a patient's immune system to be able to better recognize the antigens expressed on the surface of a tumor cell."  
Neither RNActive nor Argos' Arcelis platforms are limited to these specific cancers, both men are quick to note, but these disease states were chosen to give the companies the best chances for early success. And variability within a therapeutic category can be extreme, so knowing not just what to treat, but also who to treat, can have a significant impact on a company's likelihood of success.  
"Patient population targeting is very important to demonstrate superiority over standard of care," says Mike Sherman, chief financial officer of Endocyte, a biopharmaceutical firm developing small-molecule drug conjugates that target cytotoxic agents to tumors via highly expressed surface receptors. The company's initial targets are platinum-resistant ovarian cancer and NSCLC.  
"The reward of targeting a broader population is the ability to enter a larger market; however, without knowledge of the patient population that will respond to the drug, there is the risk of having lowered efficacy," he explains. "By identifying and targeting a selected patient population, the risk of a drug failure due to lack of efficacy is greatly reduced."  
As is the risk associated with securing attractive reimbursement, and on the flip side, utilization will likely be higher. There is also the potential for running smaller clinical trials, saving time and resources.
"Our ongoing study of vintafolide in NSCLC is only enrolling patients that express the folate receptor on all of their target tumors, which potentially eliminates half of patients who might otherwise have been included in the trial, who also would have likely diluted the benefit measured," says Sherman.  
As discussed previously in ddn ("A companion in your corner," ddn October 2012), the co-development of companion diagnostics to identify those patients most likely to benefit from treatment may also increase a new therapeutic's chances for success.
  "Several recent studies have documented that disease characteristics change over time and may be heterogeneous within one patient, which presents a challenge when obtaining single samples through methods such as a biopsy," Sherman adds. "The use of a companion imaging diagnostic allows disease characteristics to be visually identified at the time of treatment for all lesions."
As an example, he describes Endocyte's companion diagnostics, which consist of the same small targeting molecule as the corresponding SMDC linked to an imaging agent. This allows a non-invasive, full-body scan to be conducted that visually monitors the molecular target of interest before and during treatment.  
Trial and success  
The parameters and design of clinical trials are also factoring more heavily in the final decisions regarding approval, as agencies demand stronger links between the efficacy and safety results of the tested therapeutic versus standard of care. Historically, a large percentage of oncology trials have been single-arm studies involving only the therapeutic of interest. This has made it difficult to compare results against standards of care or other experimental drugs—the statistical value of meta-analyses has always been controversial—as there can be many confounding factors in how different trials have been set up and executed or results interpreted.  
As comparative results become increasingly important for approval, there seems to be a movement away from single-arm studies, particularly in the late stages of development. This trend is noted by Dr. Dirk Reitsma, vice president and therapeutic area head of oncology at Pharmaceutical Product Development LLC (PPD), a contract research organization offering discovery, development and lifecycle management services, who sees the use of multi-arm comparative studies being an area of rapid development.  
"The BATTLE and I-SPY trials designed by Berry Consultants are examples of multi-arm Phase II screening trials," he offers. "Their intent is to pair drugs and biomarkers to define which subsets of patients within a specific tumor type are likely to benefit most from which treatments. As this type of trial design gains regulatory acceptance, it is possible that results in one of the arms may be so striking and unexpected that a regulatory approval may be feasible based on such data."  
Trial design is critical to evaluate not just endpoints but how you combine therapies and against what to compare, offers Plessinger, not just for regulatory approval but also for eventual clinical and commercial success. He uses Argos' Phase III ADAPT study as an example.  
"We really wanted to design a study that had standard treatment and the evolution of standard treatment in mind," he says. "In our study, all patients are going to start with either a combination of AGS-003 plus standard sunitinib or sunitinib alone, but there's an opportunity—either due to early progression within the first year or due to intolerability to sunitinib—for our treatment investigators to switch out to other approved therapies. So we're going to gain some very valuable experience looking at the addition of AGS-003 to a variety of approved therapies."
Trial design was also critical for Argos from a technical perspective, as it potentially allows them to achieve the biggest clinical bang for their buck.  
Over the first six weeks of the trial, patients in both the combination and monotherapy arms receive sunitinib alone. This gives Argos the opportunity to manufacture patient-personalized AGS-003 (from harvested tumor samples and leukapheresed dendritic cells), but it also gives sunitinib a chance to work its magic on patient tumors.
"We know sunitinib has two potential positive impacts on these kidney cancer patients," Plessinger explains. "A percentage of these patients—25 to 30 percent—are going to see some initial tumor regression and may ultimately develop a partial response to sunitinib therapy. So sunitinib has the ability to diminish some of the overall metastatic tumor burden."
"Sunitinib also has some very well-characterized impacts on the immune microenvironment. It's been demonstrated to diminish the circulating regulatory T cells and myeloid-derived suppressor cells that are being secreted by the tumor to evade immune detection. It really sets the stage for AGS-003 to re-educate the immune system to identify and therefore destroy cancer expressing the antigens we've obtained from that tumor tissue RNA."  
The ability to adapt the parameters of a clinical trial as results come in—whether efficacy or safety—or as external factors change is also likely to become increasingly important and has become an area of specialization for companies like PPD.  
Reitsma suggests that adaptive clinical trials designs are useful in many ways, and he says he expects their use to greatly increase in the near future.  
"In a setting where a compound is being paired with a biomarker to define the optimal subpopulation in a multi-arm trial, an adaptive patient allocation process is likely to be most efficient," he offers as an example. "Based on ongoing experience in the trial, endpoints may be changed adaptively, and even accrual rates may be adjusted to the accretion rate of data to support optimal—and efficient—decision-making."
Adaptive designs are not useful in all situations, cautions CureVac's Hoerr, who is a proponent of them in principle. Cancer immunotherapies can have delayed onset, he offers, and only rarely induce objective tumor responses—but can still have significant impact on overall survival, so there has been little experience with adaptive trial designs in this area.  
"As long as there is a lack of a good early surrogate for the clinical benefit of a cancer vaccine, we do not plan trials with adaptive designs at this stage, but this may change in the future," he says.  
How significant is significant?  
Once the trials have been completed, however, the ball moves to the regulatory approval forum where questions are being raised about the significance of even significant improvements.  
PPD's Reitsma acknowledges that while there have been past approvals based on statistically significant but minor improvements in overall survival, he believes they are unlikely to occur in the future.  
"I expect that future approvals will depend on demonstrating sufficient magnitude of benefit and acceptable tolerability in the defined patient population," he suggests, adding that there will need to be some agreement on the endpoints used to demonstrate the impact of treatment. "If a delay in worsening of cancer is to be acceptable, for example, it would need to be demonstrated that such a delay is likely to lead to an increase in overall survival or that the delay itself is of benefit to the patient in some other way."  
A perfect test case for this scenario could come from the recently announced results of the TIVO-1 Phase III study in advanced renal cell cancer. The study, undertaken by AVEO Oncology and Astellas Oncology, showed that patients receiving investigational tivozanib demonstrated median overall survival of almost 28.8 months compared to the 29.3 months of patients receiving sorafenib.  
In announcing the results, the study's principal investigator, Dr. Robert Motzer of Memorial Sloan-Kettering Cancer Center, saw the overall survival results in a very positive light, suggesting, "It's encouraging to see that patients in the study who received tivozanib had a median overall survival of 28.8 months, particularly given that these patients received minimal subsequent therapy."
The fact that the overall survival results were not statistically better than those of the standard, and in fact were numerically worse, could potentially dampen enthusiasm for the therapeutic when it comes to regulatory approval, despite signs of significant improvement in other endpoints such as tumor response and progression-free survival. A U.S. Food and Drug Administration review of the tivozanib NDA is expected in late July.
Dr. Charles Drake, professor at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, suggests that not all therapies are created equal, however, and therefore cannot necessarily be held to the same standards when it comes to clinical trial endpoints. In a 2010 review in Annals of Oncology, Drake and his colleagues discussed the assessment of benefit in immunotherapy-based cancer treatment. He suggests that because immunotherapies work differently and on different timelines than typical cytotoxic agents, it may not make sense to judge them by the same endpoint criteria.  
"Response trajectories for targeted agents may include disease stabilization, delayed tumor response or transient tumor swelling followed by tumor response," Drake writes. "Using strict RECIST criteria applied at typical follow-up points in a clinical trial, such responses are not 'counted,' and patients with delayed response, or who experience a response after initial tumor growth, may be classified as non-responders."
He uses Roche's Avastin as an example, suggesting that if its development in colorectal cancer had been based strictly on RECIST criteria, its clinical approval may never have happened.
"Because of the unique patterns of clinical response that arise with immune-modulating therapies, alternative clinical trial design and endpoints are necessary to properly evaluate these targeted agents," he writes.  
That clinical and economic expectations of new therapeutics have changed, however, cannot be denied, and Argos' Plessinger describes developments in renal cell carcinoma as a model of these changes.
"If we look back at the evolution of therapies in the kidney cancer space in the mid-90s—the IL-2s, the IFN-as—approval of those agents was based solely on clinical benefit as evidenced by tumor response," says Plessinger. "High-dose IL-2 was associated with a 5-percent to 8-percent complete remission rate, which was good enough as a regulatory and even a payor threshold when there were few or no other therapies available."  
But as the advanced kidney cancer landscape evolved, so too did the surrogates for success, and progression-free survival became the new benchmark. And the winds of change are blowing once again, he says.
"In a crowded market space like advanced kidney cancer, we're moving in a direction where the regulatory threshold will be based on a much more concrete endpoint such as an overall survival," Plessinger says. "That leads to the acceptability by the payor to reimburse the use of novel therapeutics that aren't $2,000 to $3,000 a course like they used to be, but can be as expensive as $25,000 to $30,000 a dose."  
Thus, we move to the increasing influence payors are having on the commercial success of a new product.  
Payor thresholds  
In an interview with Pharmaceutical Commerce last June, Debbie Warner, vice president of commercial planning at Kanter Health, positioned the challenge very succinctly. "Payors often have a higher expectation of clinically relevant benefit compared to the level of clinical response that is required for the drug to gain regulatory approval in the first place," she said, citing statistics requiring a minimum six-month improvement in overall survival before a treatment is considered worthwhile.
"While approved drugs that deliver significantly lesser clinical benefit may still be covered," she added, "they may face a much higher level of scrutiny in the prior authorization process to help control costs."  
Avastin (bevacizumab) is experiencing such a challenge now in the United Kingdom. At the end of January, the National Institute for Health and Clinical Excellence (NICE) issued a draft decision recommending against Avastin in advanced ovarian cancer that has returned six months or more after treatment with platinum-based chemotherapy. In announcing the draft rejection, NICE CEO Andrew Dillon said: "Although bevacizumab may help to delay the spread of a patient's cancer for a limited time, the evidence did not show that bevacizumab justifies its very high cost and could not be recommended."  
Roche is working with NICE to reverse this decision as the latter continues its consultations in preparation for the next draft guidance.  
Companies like Sanofi and Regeneron Pharmaceuticals may want to watch the NICE proceedings intently. In early February, the two companies announced European approval of ZALTRAP, an antiangiogenic VEGF- and PIGF-inhibitor, in combination with FOLFIRI (a standard chemotherapy cocktail) in patients with metastatic colorectal cancer. The approval, given last August in the United States, was based on the results of the Phase III VELOUR study that showed patients receiving the combination demonstrated significantly improved overall survival compared to patients receiving FOLFIRI alone.
Dr. Eric Van Cutsem, study lead investigator from Belgium's University Hospitals Leuven, enthused, "ZALTRAP is the first and only agent to demonstrate a survival improvement in a Phase III trial in patients previously treated with an oxaliplatin-based regimen who are being treated with FOLFIRI for their metastatic disease."
In light of the recent events with the NICE refusal of Avastin in ovarian cancer, however, the question is raised as to whether payor organizations will see ZALTRAP's absolute improvement in overall survival (13.5 months versus 12.1 months) as sufficient to merit the likely dramatic increase in treatment cost versus the fully generic FOLFIRI.  
"We have to be able to bring therapies forward that provide significant efficacy and safety benefit versus standard of care but also are economically viable for the healthcare system," says Endocyte's Sherman. "Clinical trials that are more focused and show enhanced benefit in targeted patient populations enable this goal to be achieved."
The bar continues to move on oncology therapeutics, not just up and down, but left and right, back and forth. Companies will have to be creative in finding ways to give themselves a leg up if they are to succeed in bringing new products to market and achieving commercial success.                                                 lib/modules/linktrack.php?url=http://www.ppdi.com Berry Consultants lib/modules/linktrack.php?url=http://www.berryconsultants.com AVEO Oncology lib/modules/linktrack.php?url=http://www.aveooncology.com/ Astellas Oncology lib/modules/linktrack.php?url=http://www.us.astellas.com/therapeutic/product/oncology.aspx Memorial Sloan-Kettering Cancer Center lib/modules/linktrack.php?url=http://www.mskcc.org/ U.S. Food and Drug Administration lib/modules/linktrack.php?url=http://www.fda.gov/ Johns Hopkins Sidney Kimmel Comprehensive Cancer Center lib/modules/linktrack.php?url=http://www.hopkinsmedicine.org/kimmel_cancer_center/ Annals of Oncology lib/modules/linktrack.php?url=http://annonc.oxfordjournals.org/content/21/10/1944 Roche lib/modules/linktrack.php?url=http://www.roche.com/index.htm Kanter Health lib/modules/linktrack.php?url=http://kanterhealth.org/ National Institute for Health and Clinical Excellence (NICE) lib/modules/linktrack.php?url=http://www.nice.org.uk/ Sanofi lib/modules/linktrack.php?url=http://www.sanofi.us/l/us/en/index.jsp Regeneron Pharmaceuticals lib/modules/linktrack.php?url=http://www.regeneron.com/ University Hospitals Leuven lib/modules/linktrack.php?url=http://www.uzleuven.be/en
Code: E031305

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