Imagine being an Olympic high jumper, preparing for yearsfor one performance. You stand in the block for your final jump, the one thatcould give you a gold medal. You run; you jump; you will your body over thatbar to victory—only just as you're about to surmount the bar, the judges oneither side raise it a little higher, and you fail. Or worse, you successfullyjump the bar, only to have the judges change their minds and decide that thebar should have been higher—and you lose. All those years of development arenow gone because of actions you could not have foreseen.
In Olympic sport, this is unlikely to ever happen, but alltoo often, it seems to be happening in the pharmaceutical industry as potentialnew therapeutics are being rejected for being good, but not quite goodenough—and possibly nowhere more than in oncology have the rules changed somuch in getting a new therapeutic approved.
When it was once good enough to simply show that your drugwas efficacious and relatively safe, regulatory agencies around the world areraising the approval bar and demanding that new therapies show dramaticallysignificant improvements over current standards of care, or risk eithernon-approval or relegation to late-stage (e.g.,third- and fourth-line) or niche treatment. Even when you get your drug throughregulatory agencies, payors can still refuse your applications, as new drugsoften cost significantly more than current standards of care, which in manycases have entered the generic phase of their lifecycle.
In response, companies are left trying to discover ways toanticipate the new thresholds, and in the absence of that information, to tipthe risk-benefit balance of improvement over standard of care through acombination of therapeutic target selection, patient selection and clinicaltrial design.
Hedging your bets
"Cancer is one of the most complex diseases, as tumorcharacteristics change over time and tumors become resistant to manytherapeutics," says Dr. Ingmar Hoerr, CEO of CureVac, a company developingRNA-based immunotherapies targeting cancer and infectious diseases.
Thus, the company has focused its efforts on indications thatoffer 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 astronger and more effective way to attack cancer cells has been an intriguingconcept for a long time," Hoerr explains. "Recent success stories, such as thecell-based immunotherapy Provenge for the treatment of prostate cancer, andpositive data from several Phase II trials with different cancer vaccines forNSCLC, have spurred the interest in this approach."
CureVac's RNActive system involves the intradermal injectionof self-adjuvanted mRNA molecules that code for tumor-specific (ortumor-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 asimilar approach to selecting its initial therapeutic area: renal cellcarcinoma.
"Kidney cancer was ideal because we wanted a tumor typewhere immunotherapies have succeeded, albeit on a limited basis, in the past,"explains Doug Plessinger, Argos' vice president of clinical and medicalaffairs. "It was also a very important target for us because of our unique approachto how we obtain the fresh tumor tissue, isolate the RNA from the tumor andultimately reprogram a patient's dendritic cells, re-educating a patient'simmune system to be able to better recognize the antigens expressed on thesurface of a tumor cell."
Neither RNActive nor Argos' Arcelis platforms are limited tothese specific cancers, both men are quick to note, but these disease stateswere chosen to give the companies the best chances for early success. Andvariability within a therapeutic category can be extreme, so knowing not justwhat to treat, but also who to treat, can have a significant impact on acompany's likelihood of success.
"Patient population targeting is very important todemonstrate superiority over standard of care," says Mike Sherman, chieffinancial officer of Endocyte, a biopharmaceutical firm developingsmall-molecule drug conjugates that target cytotoxic agents to tumors viahighly expressed surface receptors. The company's initial targets areplatinum-resistant ovarian cancer and NSCLC.
"The reward of targeting a broader population is the abilityto enter a larger market; however, without knowledge of the patient populationthat will respond to the drug, there is the risk of having lowered efficacy,"he explains. "By identifying and targeting a selected patient population, therisk of a drug failure due to lack of efficacy is greatly reduced."
As is the risk associated with securing attractivereimbursement, and on the flip side, utilization will likely be higher. Thereis also the potential for running smaller clinical trials, saving time andresources.
"Our ongoing study of vintafolide in NSCLC is only enrollingpatients that express the folate receptor on all of their target tumors, whichpotentially eliminates half of patients who might otherwise have been includedin the trial, who also would have likely diluted the benefit measured," saysSherman.
As discussed previously in ddn ("A companion in your corner," ddn October 2012), the co-development of companion diagnostics toidentify those patients most likely to benefit from treatment may also increasea new therapeutic's chances for success.
"Several recent studies have documented that diseasecharacteristics change over time and may be heterogeneous within one patient,which presents a challenge when obtaining single samples through methods suchas a biopsy," Sherman adds. "The use of a companion imaging diagnostic allowsdisease characteristics to be visually identified at the time of treatment forall lesions."
As an example, he describes Endocyte's companiondiagnostics, which consist of the same small targeting molecule as thecorresponding SMDC linked to an imaging agent. This allows a non-invasive,full-body scan to be conducted that visually monitors the molecular target ofinterest before and during treatment.
Trial and success
The parameters and design of clinical trials are alsofactoring more heavily in the final decisions regarding approval, as agenciesdemand stronger links between the efficacy and safety results of the testedtherapeutic versus standard of care. Historically, a large percentage ofoncology trials have been single-arm studies involving only the therapeutic ofinterest. This has made it difficult to compare results against standards ofcare or other experimental drugs—the statistical value of meta-analyses hasalways been controversial—as there can be many confounding factors in howdifferent trials have been set up and executed or results interpreted.
As comparative results become increasingly important forapproval, there seems to be a movement away from single-arm studies,particularly in the late stages of development. This trend is noted by Dr. DirkReitsma, vice president and therapeutic area head of oncology at PharmaceuticalProduct Development LLC (PPD), a contract research organization offeringdiscovery, development and lifecycle management services, who sees the use ofmulti-arm comparative studies being an area of rapid development.
"The BATTLE and I-SPY trials designed by Berry Consultantsare examples of multi-arm Phase II screening trials," he offers. "Their intentis to pair drugs and biomarkers to define which subsets of patients within aspecific tumor type are likely to benefit most from which treatments. As thistype of trial design gains regulatory acceptance, it is possible that resultsin one of the arms may be so striking and unexpected that a regulatory approvalmay be feasible based on such data."
Trial design is critical to evaluate not just endpoints buthow you combine therapies and against what to compare, offers Plessinger, notjust for regulatory approval but also for eventual clinical and commercialsuccess. He uses Argos' Phase III ADAPT study as an example.
"We really wanted to design a study that had standardtreatment and the evolution of standard treatment in mind," he says. "In ourstudy, all patients are going to start with either a combination of AGS-003plus standard sunitinib or sunitinib alone, but there's an opportunity—eitherdue to early progression within the first year or due to intolerability tosunitinib—for our treatment investigators to switch out to other approvedtherapies. So we're going to gain some very valuable experience looking at theaddition of AGS-003 to a variety of approved therapies."
Trial design was also critical for Argos from a technicalperspective, as it potentially allows them to achieve the biggest clinical bangfor their buck.
Over the first six weeks of the trial, patients in both thecombination and monotherapy arms receive sunitinib alone. This gives Argos theopportunity to manufacture patient-personalized AGS-003 (from harvested tumorsamples and leukapheresed dendritic cells), but it also gives sunitinib achance to work its magic on patient tumors.
"We know sunitinib has two potential positive impacts onthese kidney cancer patients," Plessinger explains. "A percentage of thesepatients—25 to 30 percent—are going to see some initial tumor regression andmay ultimately develop a partial response to sunitinib therapy. So sunitinibhas the ability to diminish some of the overall metastatic tumor burden."
"Sunitinib also has some very well-characterized impacts onthe immune microenvironment. It's been demonstrated to diminish the circulatingregulatory T cells and myeloid-derived suppressor cells that are being secretedby the tumor to evade immune detection. It really sets the stage for AGS-003 tore-educate the immune system to identify and therefore destroy cancerexpressing the antigens we've obtained from that tumor tissue RNA."
The ability to adapt the parameters of a clinical trial asresults come in—whether efficacy or safety—or as external factors change isalso likely to become increasingly important and has become an area ofspecialization for companies like PPD.
Reitsma suggests that adaptive clinical trials designs areuseful in many ways, and he says he expects their use to greatly increase inthe near future.
"In a setting where a compound is being paired with abiomarker to define the optimal subpopulation in a multi-arm trial, an adaptivepatient allocation process is likely to be most efficient," he offers as anexample. "Based on ongoing experience in the trial, endpoints may be changedadaptively, and even accrual rates may be adjusted to the accretion rate of datato support optimal—and efficient—decision-making."
Adaptive designs are not useful in all situations, cautionsCureVac's Hoerr, who is a proponent of them in principle. Cancerimmunotherapies can have delayed onset, he offers, and only rarely induce objectivetumor responses—but can still have significant impact on overall survival, sothere has been little experience with adaptive trial designs in this area.
"As long as there is a lack of a good early surrogate forthe clinical benefit of a cancer vaccine, we do not plan trials with adaptivedesigns at this stage, but this may change in the future," he says.
How significant issignificant?
Once the trials have been completed, however, the ball movesto the regulatory approval forum where questions are being raised about thesignificance of even significant improvements.
PPD's Reitsma acknowledges that while there have been pastapprovals based on statistically significant but minor improvements in overallsurvival, he believes they are unlikely to occur in the future.
"I expect that future approvals will depend on demonstratingsufficient magnitude of benefit and acceptable tolerability in the definedpatient population," he suggests, adding that there will need to be someagreement on the endpoints used to demonstrate the impact of treatment. "If adelay in worsening of cancer is to be acceptable, for example, it would need tobe demonstrated that such a delay is likely to lead to an increase in overallsurvival or that the delay itself is of benefit to the patient in some otherway."
A perfect test case for this scenario could come from therecently announced results of the TIVO-1 Phase III study in advanced renal cellcancer. The study, undertaken by AVEO Oncology and Astellas Oncology, showedthat patients receiving investigational tivozanib demonstrated median overallsurvival of almost 28.8 months compared to the 29.3 months of patientsreceiving sorafenib.
In announcing the results, the study's principalinvestigator, Dr. Robert Motzer of Memorial Sloan-Kettering Cancer Center, sawthe overall survival results in a very positive light, suggesting, "It'sencouraging to see that patients in the study who received tivozanib had amedian overall survival of 28.8 months, particularly given that these patients receivedminimal subsequent therapy."
The fact that the overall survival results were notstatistically better than those of the standard, and in fact were numericallyworse, could potentially dampen enthusiasm for the therapeutic when it comes toregulatory approval, despite signs of significant improvement in otherendpoints such as tumor response and progression-free survival.
A U.S. Food and Drug Administration review of the tivozanibNDA is expected in late July.
Dr. Charles Drake, professor at Johns Hopkins Sidney KimmelComprehensive Cancer Center, suggests that not all therapies are created equal,however, and therefore cannot necessarily be held to the same standards when itcomes to clinical trial endpoints.
In a 2010 review in Annalsof Oncology, Drake and his colleagues discussed the assessment of benefitin immunotherapy-based cancer treatment. He suggests that becauseimmunotherapies work differently and on different timelines than typicalcytotoxic agents, it may not make sense to judge them by the same endpointcriteria.
"Response trajectories for targeted agents may includedisease stabilization, delayed tumor response or transient tumor swellingfollowed by tumor response," Drake writes. "Using strict RECIST criteriaapplied at typical follow-up points in a clinical trial, such responses are not'counted,' and patients with delayed response, or who experience a responseafter initial tumor growth, may be classified as non-responders."
He uses Roche's Avastin as an example, suggesting that if itsdevelopment 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 thatarise with immune-modulating therapies, alternative clinical trial design andendpoints are necessary to properly evaluate these targeted agents," he writes.
That clinical and economic expectations of new therapeuticshave changed, however, cannot be denied, and Argos' Plessinger describesdevelopments in renal cell carcinoma as a model of these changes.
"If we look back at the evolution of therapies in the kidneycancer space in the mid-90s—the IL-2s, the IFN-as—approvalof those agents was based solely on clinical benefit as evidenced by tumorresponse," says Plessinger. "High-dose IL-2 was associated with a 5-percent to8-percent complete remission rate, which was good enough as a regulatory andeven a payor threshold when there were few or no other therapies available."
But as the advanced kidney cancer landscape evolved, so toodid the surrogates for success, and progression-free survival became the newbenchmark. 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 amuch more concrete endpoint such as an overall survival," Plessinger says."That leads to the acceptability by the payor to reimburse the use of noveltherapeutics that aren't $2,000 to $3,000 a course like they used to be, butcan be as expensive as $25,000 to $30,000 a dose."
Thus, we move to the increasing influence payors are havingon the commercial success of a new product.
In an interview with PharmaceuticalCommerce last June, Debbie Warner, vice president of commercial planning atKanter Health, positioned the challenge very succinctly.
"Payors often have a higher expectation of clinicallyrelevant benefit compared to the level of clinical response that is requiredfor the drug to gain regulatory approval in the first place," she said, citingstatistics requiring a minimum six-month improvement in overall survival beforea treatment is considered worthwhile.
"While approved drugs that deliver significantly lesserclinical benefit may still be covered," she added, "they may face a much higherlevel of scrutiny in the prior authorization process to help control costs."
Avastin (bevacizumab) is experiencing such a challenge nowin the United Kingdom.
At the end of January, the National Institute for Health andClinical Excellence (NICE) issued a draft decision recommending against Avastinin advanced ovarian cancer that has returned six months or more after treatmentwith 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 alimited time, the evidence did not show that bevacizumab justifies its veryhigh cost and could not be recommended."
Roche is working with NICE to reverse this decision as thelatter continues its consultations in preparation for the next draft guidance.
Companies like Sanofi and Regeneron Pharmaceuticals may wantto watch the NICE proceedings intently. In early February, the two companiesannounced European approval of ZALTRAP, an antiangiogenic VEGF- andPIGF-inhibitor, in combination with FOLFIRI (a standard chemotherapy cocktail)in patients with metastatic colorectal cancer. The approval, given last Augustin the United States, was based on the results of the Phase III VELOUR studythat showed patients receiving the combination demonstrated significantlyimproved overall survival compared to patients receiving FOLFIRI alone.
Dr. Eric Van Cutsem, study lead investigator from Belgium'sUniversity Hospitals Leuven, enthused, "ZALTRAP is the first and only agent todemonstrate a survival improvement in a Phase III trial in patients previouslytreated with an oxaliplatin-based regimen who are being treated with FOLFIRIfor their metastatic disease."
In light of the recent events with the NICE refusal ofAvastin in ovarian cancer, however, the question is raised as to whether payororganizations will see ZALTRAP's absolute improvement in overall survival (13.5months versus 12.1 months) as sufficient to merit the likely dramatic increasein treatment cost versus the fully generic FOLFIRI.
"We have to be able to bring therapies forward that providesignificant efficacy and safety benefit versus standard of care but also areeconomically viable for the healthcare system," says Endocyte's Sherman."Clinical trials that are more focused and show enhanced benefit in targetedpatient populations enable this goal to be achieved."
The bar continues to move on oncology therapeutics, not justup and down, but left and right, back and forth. Companies will have to becreative in finding ways to give themselves a leg up if they are to succeed inbringing new products to market and achieving commercial success.
http://www.ppdi.comBerry Consultantshttp://www.berryconsultants.comAVEO Oncologyhttp://www.aveooncology.com/Astellas Oncologyhttp://www.us.astellas.com/therapeutic/product/oncology.aspxMemorial Sloan-Kettering Cancer Centerhttp://www.mskcc.org/U.S. Food and Drug Administrationhttp://www.fda.gov/Johns Hopkins Sidney Kimmel Comprehensive Cancer Centerhttp://www.hopkinsmedicine.org/kimmel_cancer_center/Annals of Oncologyhttp://annonc.oxfordjournals.org/content/21/10/1944Rochehttp://www.roche.com/index.htmKanter Healthhttp://kanterhealth.org/National Institute for Health and Clinical Excellence (NICE)http://www.nice.org.uk/Sanofihttp://www.sanofi.us/l/us/en/index.jspRegeneron Pharmaceuticalshttp://www.regeneron.com/University Hospitals Leuvenhttp://www.uzleuven.be/en