SPECIAL REPORT: An aside on side effects

Are we really making things better for cancer patients?

Randall C Willis
Hair loss. Nausea and vomiting. Weakness. Tiredness.Frailty.
Put the words "cancer," "chemotherapy" or "radiation" infront of anyone in the public, and these are the phrases you are likely to hearin response.
 
Sure, all drugs carry the risk of side effects, but oncologytherapeutics hold a special place in people's psyches. At the same time, whenpresented with the diagnosis of cancer, few patients are going to say, "thanks,but no thanks."
 
Side effects are the new normal when it comes to having yourcancer treated—part of the risk-benefit equation—and it is accepted.
 
Cost of doingbusiness?
 
Even in clinical circles, there has become a certainexpectation when treating patients with oncology therapeutics. When presentedwith a new therapeutic on the market, oncologists can look at a safety profilethat includes 75 percent of patients experiencing some degree of neutropenia(for example), and respond that this is within normal parameters for otherdrugs in the same category and/or for the same condition.
The clinicians aren't necessarily blasé about the sideeffects. They simply don't feel like there are any alternatives out there.
Unfortunately, this belief itself can have a cost when a newdrug enters even the research phase.
 
One of the major side effects associated withimmuotherapeutics targeting the EGFR tyrosine kinase (e.g., gefitinib and erlotinib) is a significant, if not necessarilydebilitating, rash. And despite a lack of supporting evidence—at leastinitially—many oncologists believed the rash was a sign that the drug wasworking, and sold the benefit to patients.
 
Over the last handful of years, further studies on these twodrugs have shown that patients with non-small-cell lung cancer (NSCLC) whoexperience the rash do seem to perform better in treatment, so there may havebeen some merit to this belief.
But then came the introduction of another member of thisfamily, nimotuzumab, an anti-EGFR for which rash was not a significant sideeffect. Anecdotally, while the absence of rash might have been hailed as a stepforward, it met with resistance. Without the rash, some clinicians found ithard to believe that the drug was actually providing benefit, despite clinicalevidence in conditions such as glioma.
 
The expectation of side effects has become so deeplyingrained in this category that the absence of a key side effect was groundsfor disbelief by some.
The development of new drugs has typically focused onefficacy first (benefits), safety second (risks). But as was discussed lastmonth (see "Good enough is no longer good enough," ddn March 2013), efforts to raise the efficacy bar have become moredifficult in recent years.
 
So, if the industry can't necessarily raise the benefitsside of the equation, can it lower the risks side? Do side effects have to bethe new normal? Or is there a way to either prevent or better ameliorate someside effects?
 
Easy dose it
 
Some companies have refused to give up completely on theefficacy side of the equation, believing there is still room to improvetherapeutic efficacy without necessarily increasing side effects. For LawsonMacartney, CEO of La Jolla, Calif.-based Ambrx, it's about finding the rightbalance between the two sides, and his company is betting on improvingtherapeutic potency.
 
Often when cancer patients experience debilitating orlife-threatening side effects, their oncologists will either reduce their doseor stop therapy—"a treatment vacation"—until they can recover. Ambrx is takinga similar approach in the development of its therapeutics, but rather than waitfor something to go wrong before lowering a drug dose, the company wants to useminimal dosing ahead of time by making its drugs that much more specific andpotent.
 
"The old cancer medicines were notoriously non-specific,"Macartney explains. "They've been basically toxins and have had horrible sideeffects. Modern agents are much more targeted, which means that you can giveless of it. Unfortunately, in the old days, not until you were able to showefficacy and safety were you then able to move molecules like Herceptin orTykerb upstream in the treatment paradigm, to say, adjunctive therapy or inchemo-naïve patients."
 
Macartney sees antibody-drug conjugates (ADCs) as the nextstep in this evolution, smart bombs that use tumor-directed antibodies todeliver a chemotherapeutic payload, the two held together with a chemicallinker.
 
ADCs are not new. What is new is the specificity with whichthey are constructed.
 
"In traditional molecules that are currently available, thelinker attaches at several different sites on the antibody, which on the plusside means that you potentially get lots of therapy molecules," Macartney says."On the down side, however, you may get none or you may get so many that itactually interferes with the antibody binding."
 
You end up with a really heterogeneous population ofmolecules that can be difficult to characterize and may interfere with specificityand potency.
 
Rather than rely on the native amino acids for chemicallinkage, Ambrx engineers the antibody with a specific non-natural amino acidlocated optimally for greatest therapeutic potency.
 
"The goal is to decrease the dosage necessary for efficacy,increase the relative efficacy and by doing this, improve the therapeuticwindow between where we start to see efficacy and where we start to see sideeffects," adds Macartney.
 
Perhaps the poster-child for ADCs currently is SeattleGenetics' Adcetris (brentuximab vedotin), which has been FDA-approved forHodgkin lymphoma and systemic ALCL, but is actively being tested in a varietyof other cancers.
 
Several other companies are following closely behind,however, including the Phase III programs of Genentech/Roche's trastuzumabemtansine ADC against HER2+ metastatic breast cancer and Pfizer's inotuzumabozogamicin ADC against relapsed/refractory acute lymphoblastic leukemia (ALL)and relapsed/refractory non-Hodgkin lymphoma.
 
The true test of Ambrx's lead oncology product,αHER2-ADC, is still to come as it isin preclinical phases, but the company is in active discussions with severalpharmaceutical companies to bring it into the clinical domain.
 
As Macartneyexplains, to increase the likelihood of success and proof of concept, theobvious first target is breast cancer, but as HER2 is expressed in a number ofother tissues, other cancers are viable targets downstream.
 
Looking for trouble
 
The ultimate goal, of course, would be to build atherapeutic product that only hit its intended target and offered few sideeffects from off-target interactions or its own intrinsic toxicity.
Over the last decade or so, computational scientists andinformatics companies like ACD/Labs and Simulations Plus have tried to find waysof predicting potential side effects, at least at the small molecule level, byperforming comparative analyses of known and experimental molecules, usingtechniques such as quantitative structure-activity relationship (QSAR), withvarying degrees of success.
One potential reason for the variable success of many ofthese methods for identifying off-target effects by drugs may be theinadvertent separation of a therapeutic's molecular identity and itspharmacological effects.
 
"In the modern era of molecular biology, we can look at thestructures and sequences of protein targets, and perhaps say, I know this is aserotonin type 1 receptor, I know what it looks like and I can see what drugsbind to it," says Michael Keiser, founder and chief operating officer ofSeaChange Pharmaceuticals. "Because of that ability, however, we've kind offorgotten how to organize therapeutics by their pharmacological effect. So youmight look at the highly related targets for a particular drug, but you mightnot think to look for a different sort of target."
 
Keiser and his colleagues at University of California-SanFrancisco (UCSF) and the Novartis Institute of BioMedical Research (NIBR) havedecided to go back to the older idea of looking at the chemical structures ofsmall molecules rather than a protein target and comparing that small moleculeto all of the ligands of each of a panel of pharmacologically importanttargets.
 
"On the one side, we have a single drug, and on the otherside, we have all of the known ligands for a single target, and we comparethose two-dimensional structures in a statistical way," he says. "If we do thecomparison right, then the shape of the probability distribution is what'scalled an extreme value distribution."
 
Their similarity ensemble approach (SEA) allows SeaChange tolink potential drugs to an entire panel of molecular targets and predictwhether the drug might interact with one or some of those targets. Once theyhave the target profile, they then ask out of those target profiles, which targetsare associated with particular side effects.
 
As presented in Naturein last year, the group tested SEA on a panel of 656 prescribed drugsagainst 73 known targets and identified 1241 potential side effect targets, ofwhich 348 were known in NIBR's proprietary data. A further 151 side effects,previously unidentified, were later confirmed through lab testing at NIBR.
Said UCSF professor Brian Shoichet when the results wereannounced, "The biggest surprise was just how promiscuous the drugs were, witheach drug hitting more than 10 percent of the targets, and how often the sideeffect targets were unrelated to the previously known targets of the drugs.That would have been hard to predict using standard scientific approaches."
 
Other groups are following a similar path to preemptivelyidentifying potential side effects in drug candidates, including VéroniqueStoven and colleagues at the Mines ParisTech Centre for Computational Biology.
 
The group examined the chemical substructures and known sideeffects of almost 1,000 drugs to identify statistical links between the two,and then used this information to identify potential side effects for compoundsthat did not have side-effect data. In one example, they noted a link betweenthe anti-obesity compound rimonabant and key phrases such as "borderline personalitydisorder" and "PTSD."
 
In 2008, rimonabant was pulled from the European marketfor side effects that included severe depression.
Both Stoven and Keiser see strong utility for their methodsearly in the drug discovery process.
 
"A toxicologist has a hard position, because more often thannot, you don't get to evaluate or even see any of the compounds until they'requite a ways along," Keiser says. In other words, a point at which many choiceshave been made and you're faced with a decision to kill a program: "One of thereasons for this is that the assays needed to make sure there are no negativeeffects are expensive," Keiser notes.
 
"Computationally, instead of only being able to evaluatefour compounds, you can contribute earlier on when you are still looking at athousand candidates, and differentiate them not just on efficacy but also onpotential off-targets," he adds. "You aren't replacing safety assays, but youare highlighting what products to test."
 
But even if you could limit the potential side effects ofdrugs coming down the discovery and development pipeline, those drugs won'tlikely hit the market for another decade. What can we do for patients now?
 
Shielding patients
 
With the advent of personalized medicine came theopportunity to identify what patients would most likely benefit from whatdrugs. But even here, with all of the diagnostic tools at our disposal and anexpanding arsenal of targeted therapeutics, the focus has been on the cancer,rather than the patient.
 
"Everyone is looking at the genomics of tumors, and they'retrying to develop therapies based on that," says Ed Rubenstein, president andCEO of InformGenomics. "One fundamental problem with this approach is thatcancer by its nature is a fundamental instability of DNA, so what people may belooking at is the consequence, rather than the cause of cancer."
 
Furthermore, he stresses, cancer is constantly evolving,responding to Darwinian pressures. When you expose a heterogeneous populationof malignant cells to chemotherapy, you kill off the easy ones. The moreunstable, harder-to-treat ones continue to evolve.
 
InformGenomics looks at the problem from anotherperspective.
 
"A patient's inherent DNA is relatively stable, aside fromepigenetic changes, but there are probably genetic bases for every sideeffect," Rubenstein explains. "And there is lots of evidence to support thatthe biologic pathways responsible for these side effects are under geneticcontrol."
 
Thus, like SeaChange Pharmaceuticals and the group at MinesParisTech, InformGenomics is applying biological networks with its OnPartplatform, but in its case, to side-effect pathology and risks, rather thansmall-molecule characterization.
 
Rubenstein is quick to point out, however, that this is notthe typical biomarker diagnostics effort typically associated with personalizedmedicine (see "A companion in your corner," ddnOctober 2012).
 
"Genes work together in networks," he says. "If you look atmost of the predictive biomarkers or genetic markers, they're notnetwork-based, they're standard-frequency statistically based. Genes talk toeach other, there's lots of biologic feedback and interaction, so we are usingadvanced Bayesian networks to discover those genes that interact with oneanother. The way we're doing that is using SNPs as markers."
 
By linking patterns of SNPs to various biological networks,the company found it could create individual networks for individual sideeffects. Thus, Rubenstein explains, the nausea-vomiting networks hadneurotransmitter and neurosignaling terms, which said they were on the righttrack. Similarly, some of the genes that were mapped by the diarrhea networkhave been implicated in other inflammatory diarrhea pathologies like Crohn'sdisease and ulcerative colitis.
 
For InformGenomics, however, it is not just aboutstatistics. It is also very much about the patient and his or her desires,concerns and fears.
 
Thus, a key component of OnPart is a validated patientquestionnaire—the Preference Assessment Inventory—that quantifies the patient'sattitudes about potential side effects.
 
"It empowers patients because not only does OnPart determinetheir own genomic risks, but it also captures how they view those side effects,how important they are to them in their day-to-day life," Rubenstein explains,giving the example of a concert pianist or computer coder whose biggest fear isperipheral neuropathy. "That information goes back to the oncologist so theycan have that real informed-consent discussion about the risks and benefits ofchemotherapy options."
 
At the ASCO Gastrointestinal Cancers Symposium in January,InformGenomics presented the findings of a study of OnPart in 384 patients whoreceived the modified FOLFOX regimen +/- bevacizumab for a variety of cancersto see how accurately the platform could predict a set of side effects. Theirpredictive networks had accuracies beyond 90 percent.
 
In announcing the findings, Lee Schwartzberg, leadinvestigator and Medical Director of The West Clinic, said, "This allows us tocustomize our chemotherapy regimens and side effect control interventions forbest patient care. These side effects can impair function, create inefficienciesin medical practice and are costly to patients and payers."
 
InformGenomics is also developing a similar system forpatients receiving stem cell transplants. According to Rubenstein, about 40 percent of patientsreceiving high-dose chemotherapy and stem cell transplant will develop seriousoral mucositis, meaning lesions of the mouth, serious infection, prolongedhospitalization and an increased risk of mortality, but it is impossible topredict which patients using clinical factors.
 
"Prophylactic drugs are available to prevent the oralmucositis, but they are very expensive, and if only four out of 10 patients aregoing to benefit, it is hard to justify the use of that agent," he says. "If wecan predict who is going to get serious oral mucositis, then it allows analready approved drug to be targeted appropriately to the patients who are goingto benefit. We see that as another way to take cost out of the system."
 
So where are we with those prophylactic treatments?
 
Making things better?
 
As founding chair of the NCCN Febrile Neutrogena Panel,member of the NCCN Antiemetic Guidelines Panel and member of the MASCC board ofdirectors, Rubenstein is well positioned to understand the armamentarium ofside effect treatments.
 
In the earliest days of oncology, drug toxicity essentiallyforced oncologists to develop supportive care as patients were almost as likelyto die from their treatments as from their cancer, he explains.
 
"That led tothe advent of prophylactic antibiotic therapy for neutropenic fever and thedevelopment of pheresis machines and blood component therapy."
 
"The second wave of cancer supportive therapy was thedevelopment of effective antiemetics, which was usually a combination of thingsthat had lots of side effects, but then the 5-HT3 receptor antagonists weredeveloped," he adds. "Around the same time, you got better advances in antibioticsand then the development of blood cell growth factors."
 
Those advances continue. As mentioned earlier, oralmucositis can be an incredibly debilitating side effect of many chemo andradiation therapies, afflicting almost 500,000 cancer patients each year in theUnited States alone. At present, there are few therapeutic options available topatients other than pain management, Access Pharmaceuticals' MuGard being amajor player.
 
Last summer, at the MASCC conference, Access presentedPhase IV studies of MuGard in patients undergoing chemoradiation therapy forhead-and-neck cancer, showing significant reduction in mouth and throatsoreness and delay in mucositis onset, as well as reductions in weight loss anduse of opioid medications.
 
Less advanced in development is the defensin mimeticbrilacidin from PolyMedix, which is just entering Phase I trials. Part of a newclass of antibiotics, brilacidin has shown antibacterial, antibiofilm andanti-inflammatory activity in various animal models, leading to an NCI grantlast September for the Phase I study the company hopes to initiate this year.
 
Slightly ahead of brilacidin is Soligenix's oral mucositiscandidate SGX942, a fully synthetic pentand radiation therapy. The companydescribes the product as an innate defense regulator that stimulates the innateimmune response to damage. In preparation for its Phase II study, which thecompany expects to initiate in the second half of 2013, Soligenix announced theformation of a mucositis medical advisory board in February.
 
As Rubenstein suggests, great strides were made in thetreatment of chemotherapy-induced nausea and vomiting (CINV) with the advent ofthe 5-HT3 receptor antagonists, the most recent entrant being Eisai's Aloxi(palonosetron), but even here, companies continue to seek improvements.
 
For example, last September, A.P. Pharma resubmitted its NDAto the FDA for its lead product, APF530. Essentially the 5-HT3 receptorantagonist granisetron, APF530 has been formulated for a more durable responseon a single injection. The hope is to extend granisetron's current indicationfor acute-onset CINV (first treatment day) to include delayed-onset CINV (up tofive days), putting it more on par with Aloxi, which is indicated for bothacute and delayed onset.
 
OPKO Health, meanwhile, in partnership with Tesaro, iscurrently in Phase III trials with its CINV candidate rolapitant, aneurokinin-1 receptor antagonist that it is testing in three studies ofpatients receiving highly- and moderately-emetogenic chemotherapy with standardof care, which includes a 5-HT3 receptor antagonist and the steroiddexamethasone. The company expects the results of the trials for late 2013.
 
And of course, several companies continue to push variousmarketed supportive care products through clinical trials, looking for expandedapplications. Such is the case with Amgen, which continues to test Neulasta(pegfilgastrin) against febrile neutropenia. In January, the company announcedthe results of its Phase III PAVES trial in metastatic colorectal cancer,showing significant reduction in the incidence of grade 3/4 febrile neutropeniaversus placebo.
 
Alder Biopharmaceuticals took a step back, however, anddecided there had to be something better than the current whack-a-mole approachto tackling side effects; that is, hitting them as they arise, or are expectedto arise. The company took a more holistic approach by looking forcommonalities in the root causes of many side effects.
Alder focused on the pathways controlling inflammation, andspecifically on the cytokine interleukin-6 (IL-6).
 
"There's a number of places where inflammation plays a rolein a negative sense for cancer patients," explains Randall Schatzman, companypresident and CEO. "First and foremost, the cancers themselves releasepro-inflammatory molecules like IL-6, which cause a lot of inflammationsecondary to the tumor. And this inflammation is really responsible for a largepercentage of the morbidity and mortality."
 
The second place inflammation plays a role is in tumorigenesisitself and how certain chemotherapies work on the tumor, such as in thedevelopment of resistance. And finally the problems that chemotherapy itselfcauses—e.g., anemia and oralmucositis—side effects of chemotherapy that Alder believes are driven bypro-inflammatory cytokines.
 
"What we're trying to do is tease out the role ofinflammation within this remit of paraneoplastic issues and chemotherapy sideeffects, because at the end of the day, oncologists want to get as many cyclesof chemotherapy into a patient as possible to increase their chances of gettinga complete response," adds Jeffrey Smith, Alder's senior vice president oftranslational medicine. "If the patient is saying time out after, say, threecycles out of six because of the side effects, then clearly, the oncologistisn't winning. It's a suboptimal treatment of the patient's cancer."
 
As Smith sees it, it's about more than simply controllingside effects to improve patients' quality of life, and therefore makingtreatment easier. It's also about getting more cycles into the patient toimprove the chances of killing the cancer off. It's about both efficacy andsafety.
 
Alder's lead cancer product, ALD518, currently in severalPhase II studies, is a humanized anti-IL-6 monoclonal antibody that keeps thecytokine from interacting with its receptor and triggering a variety ofcancer-related conditions such as catexia (wasting), anemia, oral mucositis andacute graft-versus-host disease.
 
Smith sees opportunities for ALD518 not only in preventingsome of the side effects of chemotherapy, but also in helping to modulate thebody's response to immunostimulatory regimens, using the recent case ofchildren being treated for ALL as almost a proof of concept.
 
In that study, patients received modified T-cells designedto attack the leukemia, but in some cases, the patient's immune system wasoverstimulated and the therapy triggered a cytokine storm that threatened tokill the patient. When one oncologist noted that a patient's IL-6 levels hadspiked, he prescribed her Actemra (tocilizumab), an antibody used in rheumatoidarthritis that targets the IL-6 receptor. Within hours, the patient stabilized.
 
Smith thinks a day is approaching when this type of regimenbecomes the paradigm, not the anecdote.
 
"I could foresee more of that, where agents such as ananti-TNF or anti-IL-6 or other agents that modify the immune system are used todamper down unwanted effects of immunostimulatory regimens," he says.
 
Schatzman also sees the holistic approach as paying off froma payor perspective.
 
"It's one thing to have an agent that makes patients feelbetter, and it's another to have an agent that improves outcomes," he says. "Ithink the burden is on us to do the latter because when you improve clinicaloutcomes rather than just patient-reported outcomes, payors are more willing topay."
 
And at the end of the day, as with any industry, it's aboutgetting paid.

Randall C Willis

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