WEEK OF MAY 28, 2012BioCenturyTHE BERNSTEIN REPORT O N BI OB USINESS Volume 20 • Number 22 • Page A1 of 20 Product Discovery & Development Devil is in the dosing By Erin McCallister BioCentury This Week Senior Writer Data released in April suggest theCover Story tended-release antipsychotics without drug theory behind second-generation sphin- spikes to reduce side effects and improve gosine 1-phosphate receptor agonists inDevil is in the Dosing — Dosing and patient compliance compared with depot for- development for multiple sclerosis waspharmacokinetics, not specificity, are likely to mulations./A11 wrong. However, two companies are find-be the key to avoiding cardiac effects with ing that improved pharmacokinetics and/second-generation S1P agonists that are Regulation or dose titration could achieve the origi-following Gilenya for multiple sclerosis. nal goal of improving safety compared Rare Win — An FDA panel agreed with Pfizer with first-generation S1P receptor agonistProduct Discovery & Development that surrogate secondary endpoints in a failed Gilenya fingolimod from Novartis AG. Phase II/III trial justify approval of tafamidis to Gilenya, the first oral drug for relaps-c-Met’s Highs and Lows — Differences treat transthyretin familial amyloid polyneur- ing-remitting multiple sclerosis (RRMS),in tumor types and study designs may opathy, an Orphan disease./A12 was approved in September 2010, but hasexplain apparently contradictory results struggled to gain a foothold in first-line usefor two mAbs against human hepatocyte Finance due to concerns over cardiovascular safetygrowth factor/scatter factor from Amgen and (see BioCentury, Sept. 27, 2010).Aveo./A5 Ebb & Flow — Pontifex seeks shelter. Abbott In April, Novartis updated the drug’sIslet Defense — Sernova’s Cell Pouch System Biotech venturing upstream. Strategic VCs U.S. and EU labels to recommend addi-and Sertolin technology is designed to provide without carried interest. Accelerator refueling tional cardiac testing before treating pa-the necessary setting for donor islet cells to the tank. Also: Furiex; Medivation; Onyx; tients and additional cardiac monitoringproduce insulin while being protected from the Achillion; Chelsea; MediciNova; Peregrine; once dosing begins.host immune system./A8 Active Biotech; Auxilium; Veloxis, et al./A15 Gilenya’s therapeutic effect in MS is mediated by its interaction with S1PR1 on Featured links this week/A7 lymphocytes. But it binds with high affinityEmerging Company Profile Stock charts & tables/A20 to all of the five known S1P receptorsDisabling Immune Escape — iTeos is devel- Company index/A14 except S1PR2.oping small molecules to block tumor immuno- According to Gordon Francis, VP ofsuppressive mechanisms, and hopes to combine Novartis’ neurosciences and ophthalmol- BioCentury 100 Indicators TMits immunomodulators with cancer vaccines ogy clinical science unit, rodent data hadfrom the Ludwig Institute./A10 Week ended 5/25/12 suggested Gilenya’s interaction with S1PR3Implantable Antipsychotics — Delpor’s PRICES VOLUME was responsible for reductions in heartProzor implantable device aims to deliver ex- 2720.76 624.6M shrs rate and atrioventricular (AV) block. up 4% dn 7% See next page This Week on BioCentury TV This Week in SciBX ASCO Preview — ISI’s Mark Schoenebaum on investor highlights; Johns Hopkins’ Reviving Ras — Genentech and Vanderbilt teams have independently identified a new small Thomas Smith on bending the cancer cost molecule binding site that blocks activation of Ras, which has been considered undruggable. curve. Please see Program Notes on A13. Please see Table of Contents on A9. www.biocenturytv.com
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A2 OF 20Product Discovery & Development, effects.”from previous page “We’re going to have BG-12 In any case, sales of Gilenya have been rising as Novartis launches the drug in The idea behind second-generation before these new S1P ago- additional territories and as physiciansS1P receptor agonists thus was to dial in nists come online. I think become more familiar with the product.specificity for S1PR1, while dialing out Novartis reported 1Q12 worldwide salesinteraction with S1PR3. BG-12 will be hard to beat of $247 million and worldwide annual However, Phase II data reported in for a while.” sales for 2011 of $494 million, including aApril for ONO-4641 from Ono Pharma- full year of sales in the U.S. and about nineceutical Co. Ltd. and Merck KGaA, David Brandes, Hope Multiple months of sales in Europe. The drug wasshow cardiovascular signals similar to Sclerosis Center launched in Europe shortly after its ap-Gilenya’s. proval last March, followed by a Decem- ONO-4641 is selective for S1PR1 and ber launch in Japan. Novartis licensedS1PR5. With continued dosing, the heart rate rights to Gilenya from Mitsubishi Meanwhile, preclinical data on sec- returns to baseline within a month. Tanabe Pharma Corp.ond-generation compounds from Novartis The original label for Gilenya recom-and Receptos Inc., as well as additional mended that doctors observe all patientsstudies of Gilenya have negated the S1PR3 for six hours after the first dose for de- Second-generation surprisehypothesis. creases in heart rate. Baseline ECGs were Phase I and II data on second-genera- “The rodent lied,” Francis told recommended in patients at higher risk for tion S1P receptor agonists show the sameBioCentury. “We thought that was the bradyarrhythmia. The label also suggested kinds of cardiovascular signals as Gilenya,key receptor, but it turns out it is not the doctors “carefully monitor” patients on although too little data have been dis-same across species, and the same types of beta blockers, or Class Ia or Class III anti- closed to know whether the signal is ascardiac effects are seen with an S1PR1- arrhythmic drugs. strong.exclusive agonist.” In December, FDA issued a safety alert Merck and Ono presented their Phase Novartis and Receptos now believe for Gilenya after receiving a report of an II data for ONO-4641 at the Americanslowing the time to peak drug concentra- MS patient who died within 24 hours of Academy of Neurology meeting in Newtion could reduce the CV effects of sec- the first dose of the drug for unknown Orleans in April.ond-generation agonists without compro- reasons. In the double-blind, internationalmising efficacy. In January, EMA’s CHMP began a safety DreaMS trial in 407 patients with RRMS, Receptos expects the PK profile of its review following reports of serious cardio- all three doses met the primary endpointRPC1063 will accomplish this goal, while vascular events in patients receiving of reducing the number of gadolinium-Novartis is exploring dose titration in Gilenya as well as the unexplained death enhancing lesions obtained by MRI inPhase II trials of its siponimod (BAF312). of the U.S. patient. At the time, CHMP said four-week intervals for 26 weeks. Patients Actelion Ltd. also has some skin in there had been 10 additional deaths. Six, receiving 0.05 mg had a reduction of 82%the game with its second-generation S1PR1 including three sudden deaths, were un- vs. placebo. Reductions vs. placebo wereagonist, ponesimod. The company is say- explained. Three were due to heart attack, 92% for the 0.1 mg group and 77% for theing little about how it plans to mitigate the and one was due to disruption of heart 0.15 mg group (p<0.0001 for all threecardiovascular effects, but plans to start rhythm. doses).Phase III testing this year. While FDA did not conclude that In a Phase II trial of Gilenya in 281 Regardless of how the scenarios play Gilenya contributed to the patient deaths, patients with RRMS, patients receivingout, it appears likely that S1P1R-specific Novartis reached agreements with the 1.25 mg Gilenya had a reduction of 42%agonists would be used behind BG-12 agency and EMA to change the drug’s vs. placebo in the number of gadolinium-from Biogen Idec Inc. because of its label. enhancing lesions based on a mean num-cleaner safety profile and history of use. The new U.S. label recommends that ber of lesions at six months of 1.29 forFumarate, the parent compound of BG- all patients receive an electrocardiogram Gilenya and 2.21 for placebo. Reductions12, is already used in Germany to treat prior to starting Gilenya and six hours vs. placebo were 87.8% for the 5 mg dosepsoriasis without any serious side effects. after the first dose in addition to hourly where mean number of lesions was 0.27 at blood pressure and heart rate measure- six months. ments. The drug is contraindicated in The ONO-4641 data appear to beS1P signals patients with preexisting cardiac condi- comparable to Phase II data on lesions for Cardiovascular side effects emerged tions or taking concomitant anti-arrhyth- Gilenya, given that the patients in theduring clinical development of Gilenya, mic drugs. Gilenya trial were likely sicker: despiteand postmarketing reports of CV events The new European label contains lan- similar enrollment criteria, there was ahave led to increased warnings on the guage similar to the U.S. label and also higher number of mean gadolinium-en-drug’s label. recommends that monitoring be extended hancing lesions at baseline in the Gilenya In clinical trials, Gilenya was associ- for at least two hours in patients whose Phase II trial (2.8-3.4) vs. the ONO-4641ated with a mean decrease in heart rate of heart rate is lowest at six hours. trial (0.9-1.4). However, ONO-4641, like13 bpm, which occurred six hours after According to Francis, the new labels other second-generation S1P receptorthe first dose. Bradycardia following the are intended to “highlight for physicians agonists, can be given at considerablyfirst dose was reported in 0.5% of patients and patients that there are groups of lower doses.in the Gilenya groups of the clinical pro- patients for whom this drug might be less No patients in the 0.05 mg group orgram vs. none in the placebo groups. suited than others due to the heart rate See next page
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A3 OF 20Product Discovery & Development, titrated 1.25 mg dose arm had an 86.1%from previous page “The rodent lied.” reduction vs. placebo in new gadolinium- enhancing lesions on T1-weighted andplacebo group had secondary AV block. Gordon Francis, Novartis non-enhancing new/newly enlarging le-But 1% of patients in the 0.1 mg ONO- sions on T2-weighted MRI scans (p<0.001).4641 group and 3% in the 0.15 mg group The trial also tested the effect of aexperienced secondary AV block. There According to Gujrathi, RPC1063 is titrated dose vs. stable dosing of siponimodalso was a decrease in heart rate, with the not only highly specific for S1PR, but also on cardiac effects. Cohort 1 received stablemaximum mean drop of 8.4 bpm seen in has a pharmacokinetic profile that could doses of 0.5, 2, or 10 mg of siponimod orthe 0.15 mg group. help to desensitize cardiomyocytes to the placebo, over six months. A second group Andrew Galazka, Merck’s SVP of exter- compound’s heart rate-lowering effects. of patients, which included placebo pa-nal scientific affairs, global development “We have a slower time to reach the tients from cohort 1 who were allowed toand medical, declined to compare the highest therapeutic concentration, and cross over after six months, were random-ONO-4641 data on CV side effects with this allows for gradual onset of our drug,” ized to test titrated doses of 0.5, 1.25, 2data from similar placebo-controlled trials she told BioCentury. and 10 mg siponimod vs. placebo overof Gilenya. The increase in heart rate seen with three months. Cohort 2 also included a “We need to complete the analysis of Gilenya was dose dependent and occurred stable dose arm of 0.25 mg.the Phase II results. We are looking at all within the first six hours of administration. In cohort 2, siponimod was started atsorts of analyses to detect any difference Receptos therefore believes that if the 0.25 mg on day one and titrated up to thethat may be there between our compound time to peak concentration is slowed, final dose over the course of 3-10 daysand available treatments, and we will de- cardiomyocytes may not become over- depending on the final dose.sign a program around those differences,” whelmed and heart rate would not drop, In cohort 1 on day one, a dose-depen-he said. or the drop would not be as severe. dent reduction in mean heart rate was Novartis also has seen heart rate eleva- “Our goal is to make the cardiovascu- seen; secondary AV block occurred in 19tions in its Phase I and Phase II trials for lar profile of RPC1063 as benign as pos- patients in the treatment arms, includingsiponimod. The pharma designed the com- sible so that patients will not have adverse five symptomatic AV blocks.pound to be an S1PR1-specific agonist, events and only a minimal drop in heart In the titration group, the reduction inbut now believes the original hypothesis rate that could be well tolerated. If we mean heart rate was less pronounced, andwas flawed. could show a benign cardiac profile, hope- there were no symptomatic second-de- “We thought we were going to be fully we could remove the need for cardiac gree AV blocks. There were five events ofclever by getting rid of the S1PR3 compo- monitoring,” Gujrathi said. asymptomatic AV block in patients onnent,” Francis said. Receptos has completed a Phase I study, placebo and two events in the titrated 2 However, a 2007 publication by and the company plans to release the mg arm.Novartis in Pharmacology & Therapeutics pharmacokinetics data as well as safety “Although the patient numbers arenoted experiments with isolated guinea data showing “a more benign” profile at small, it appears that the titration sched-pig atrial myocytes revealed both fingolimod the European Committee for Treat- ule abrogates the cardiac effects,” Francisand an S1PR1-specific tool compound ment and Research in Multiple Scle- said.called AUY954 activated potassium ion rosis (ECTRIMS) meeting in October, Novartis expects to start Phase III test-channels, resulting in a decrease in heart Gujrathi said. ing of siponimod late this year or in earlyrate. “We are very encouraged by this data 2013. It also is considering a titration Also in 2007, Novartis realized that and we believe RPC1063 has the potential study of Gilenya, he added.S1PR1 was the dominant player behind to be best in class,” she said. Receptos also may do dose titrationCV effects based on Phase I results for Novartis hopes to achieve a similar with RPC1063, Gujrathi said. The biotechsiponimod. reduction in cardiovascular side effects is planning on an end-of-Phase I meeting The animal data, Phase I results and with titrated dosing of siponimod, without with FDA before deciding on the Phase IIresearch in human cardiovascular tissue sacrificing any of the efficacy seen with program.that showed a higher concentration of Gilenya. Merck said it is exploring possibilitiesS1PR1 mRNA and protein vs. S1PR3, led The pharma tested a titrated dosing for its Phase III program of ONO-4641,Novartis to conclude S1PR1 played a regimen in a Phase II trial in 297 RRMS including dose titration.greater role in heart rate elevation. patients. On the primary endpoint, the Actelion has its S1PR1 agonist in Phase Receptos agrees. “S1PR1 appears to II testing. Last August, the company an-be the predominant receptor in human nounced Phase IIb data for ponesimod incardiomyocytes, so any S1PR agonist is “We fundamentally believe 464 RRMS patients. The compound metlikely going to have some effect on heart that there will be a high the primary endpoint of reducing the num-rate,” said CMO Sheila Gujrathi. ber of new active inflammatory lesions as need for another effective measured by T1-weighted MRI brain scans and safe agent to go after at weeks 12, 16, 20 and 24 vs. placeboTweaking delivery (p<0.0001). Receptos and Novartis believe they BG-12 and in place of it in In 2007, the company observed first-can mitigate the cardiac effects based on dose cardiovascular effects of ponesimod some patients.” and has been studying how to adapt treat-the physiologic properties of their com-pounds and/or by tweaking the dosing ment protocols to minimize these effects, Faheem Hasnain, Receptosschedule. See next page
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A5 OF 20 Product Discovery & Development c-Met’s highs and lows By Michael Flanagan (43% vs. 40%). The combination also missed sion, where the preclinical evidence was Senior Writer the secondary endpoint of median PFS vs. unclear about which subgroup might re- Differences in the manner of c-Met inhi- Iressa alone (5.6 vs. 4.7 months). spond better, Aveo SVP and CSO Jenobition and EGFR mutation status may help In Genentech’s case, its combination of Gyuris said the company’s main hypothesesexplain apparently contradictory biomarker MetMAb and Tarcva missed the co-primary going into the study related to whether theresults in non-small cell lung cancer re- endpoint of PFS in the ITT population. But addition of ficlatuzumab to Iressa wouldported for two anti-c-Met mAbs, one from it did hit the endpoint in the high c-Met work in patients with EGFR wild-type and/Aveo Pharmaceuticals Inc. and the other subset: PFS was 2.9 months for MetMAb in or EGFR sensitizing mutations (SM+).from Genentech Inc. combination with Tarceva vs. 1.5 months “The translational research evidence was Activation of c-Met is thought to trigger for placebo plus Tarceva (p=0.04). in fact stronger in the EGFR SM+ setting,tumor cell survival, growth and metastasis In Aveo’s case, however, a post hoc where c-Met amplification or elevated HGFin a variety of tumor types. subgroup analyses showed ficlatuzumab did was demonstrated as the mechanism of Aveo’s ficlatuzumab binds human hepa- best in patients with low c-Met expression. resistance for EGFR inhibitor in SM+ tumorstocyte growth factor/scatter factor (HGF/ The Aveo analyses segmented patients at the time,” he told BioCentury. “TheSF) and prevents the ligand from interacting based on EGFR mutation status (wild-type reason for the inclusion of the exploratorywith and activating c-Met. or sensitizing mutations) and c-Met expres- c-Met biomarker was to assess if HGF/c-Met By contrast, Genentech’s MetMAb sion levels (high or low). pathway activity, as measured by c-Metonartuzumab binds c-Met directly and blocks Rather than focusing on c-Met expres- See next pageits interaction with HGF/SF. The Phase II results from Roche and itsGenentech unit showed MetMAb plus theEGFR inhibitor Tarceva erlotinib met one Amgen’s c-Met experienceco-primary endpoint by improving progres- Amgen Inc.’s rilotumumab improved survival in patients with gastric and gastroesoph-sion-free survival in patients with high c-Met ageal junction cancer whose tumors expressed high levels of c-Met, but not in patients withexpression. low c-Met expression. This month, however, Aveo said that asubset of patients with low c-Met expression Amgen selected advanced gastric cancer in part because c-Met expression is particularlyhad longer PFS than patients with high c- high in this setting, according to David Chang, VP of global oncology.Met expression in its Phase Ib/II trial of Phase II results presented at the 2011 European Multidisciplinary Cancer Congress inficlatuzumab in NSCLC. Stockholm showed a positive trend on the primary endpoint of median PFS for chemother- Aveo’s data also differed from results for apy plus rilotumumab vs. chemotherapy plus placebo (5.6 vs. 4.2 months, HR=0.64).Amgen Inc.’s rilotumumab in gastric andgastroesophageal junction cancer. The mAbs The secondary endpoint of overall survival (OS) also showed a trend in favor of thehave the exact same mechanism, and in that rilotumumab group (11.1 vs. 8.9 months, HR=0.73).case researchers expect the divergent data In an abstract released this month, Amgen reported a post hoc biomarker analysisreflect the different tumor types in which the showing that in patients whose tumors had high c-Met expression, adding rilotumumab tomolecules were tested (see “Amgen’s c-Met chemotherapy significantly improved median OS vs. chemotherapy plus placebo (11.1 vs.Experience”). 5.7 months, p=0.012). In patients with low c-Met expression, the company saw a trend toward unfavorable OSGoing low in the rilotumumab group. Data will be presented at the American Society of Clinical Aveo’s open-label study compared Iressa Oncology meeting in Chicago.gefitinib, a small molecule EGFR1 inhibitor, Amgen spokesperson Ashleigh Koss said patients were not stratified prospectivelywith and without ficlatuzumab as front-line because gastric cancer is a setting with high c-Met expression.therapy for NSCLC. The company’s rationale for combining Researchers who spoke to BioCentury agreed that different tumor types could explainficlatuzumab and an EGFR inhibitor was the seeming disconnect between results for rilotumumab and Aveo Pharmaceuticals Inc.’sbased on preclinical evidence of synergistic ficlatuzumab, which was studied in NSCLC.activity and a clinical precedent for target- Amgen plans to move rilotumumab into Phase III testing this year to treat advanceding the c-Met and EGFR pathways together gastric and gastroesophageal junction cancer in patients whose tumors have high c-Met(see BioCentury, Nov. 1, 2010). expression. Preliminary data from an intent-to-treat(ITT) analysis showed ficlatuzumab plus Earlier this year, Amgen and Dako A/S partnered to develop and evaluate the use ofIressa missed the primary endpoint of over- a companion diagnostic measuring c-Met expression in the development of rilotumumab.all response rate vs. Iressa alone in 188 Dako is being acquired by Agilent Technologies Inc.patients with previously untreated NSCLC
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A6 OF 20Product Discovery & Development, only. At high c-Met levels, tumors can be activated either byfrom previous page constitutive dimerization that occurs without needing the ligand or it can be trans-activated by EGFR itself,” or even by otherexpression levels by IHC, could also impact the activity of the oncogenes like Src kinase, said Siegfried, who is a professor ofcombination.” pharmacology and chemical biology at the university’s school of According to Gyuris, Genentech’s definition of high c-Met medicine.included all patients with tumors that were positive for c-Met “One might argue that it is the low c-Met patients who canbased on a diagnostic test, which was a achieve the best blockade of c-Met signalingmuch less stringent definition than was through inhibition of the ligand,” she added.used by Aveo. “Without the level of HGF in Jin Kim, CSO of Galaxy Biotech “Neither Genentech nor Aveo would LLC, expressed doubt as to whether thelikely have known precisely which c-Met the tumors, I do not think we efficacy signal for ficlatuzumab was real,subset, if there were one, would preferen- can make a correct interpre- noting that significance had not beentially benefit” from the respective combina- achieved in the retrospective analyses oftion, he said. tation on these data.” the biomarker data. As it turned out, the most favorable There are several possible explanationseffect of ficlatuzumab and Iressa was in 10 Seiji Yano, Kanazawa University for ficlatuzumab’s “seemingly counterintuitivepatients who were EGFR SM+ and low c- effects” in the high and low c-Met groups,Met. These patients had median PFS of 11 months vs. 5.5 months said Kim. “It is certainly possible that ficlatuzumab is simply not ain nine SM+, low c-Met patients receiving Iressa alone. The result potent drug, or that HGF is not a good therapeutic target inwas not statistically significant. NSCLC.” In the high c-Met arms, the addition of ficlatuzumab offered no Genentech’s positive MetMAb data in NSCLC seem to refute thebenefit. latter explanation, he noted. Wild-type patients receiving either regimen had PFS of 1.8 Another potential explanation, said Kim, is that the highmonths while those with EGFR SM+ had PFS of 9.2 months. Patients proportion of EGFR SM+ patients in the ficlatuzumab study had awith wild-type EGFR and low c-Met had slightly worse PFS in the negative impact on the mAb’s efficacy.combination arm (1.3 vs. 2.3 months). A total of 58% of patients in the Phase II trial of ficlatuzumab Elan Ezickson, Aveo’s EVP and COO, said an internal review of were defined as EGFR SM+ compared with only 13% of those inthe data suggested ficlatuzumab did not have an impact — positive the MetMAb arm and 11% in the placebo arm in Genentech’sor negative — on any of the groups except the EGFR SM+/low c- study.Met group. “The Aveo patient population may have been more enriched He said the slightly worse PFS in EGFR wild-type/low c-Met for EGFR mutant patients than the Genentech patient popula-patients was simply a matter of chance. tion, and it’s possible that these patients are not good candidates “This was an exploratory study designed to look at the for treatment with HGF/c-Met antagonists. After all, what isintersection of EGFR mutation status and c-Met expression levels driving the cancer in these patients is the EGFR mutation and notwith the goal of using the biomarkers to identify patient populations the HGF/c-Met pathway,” said Kim.where we could see a strong signal of activity,” said Gyuris. “We Galaxy’s TAK-701, a mAb against HGF/SF that Kim co-discov-think we have done just that.” ered, is being developed by partner Takeda Pharmaceutical Ezickson suggested there might be an inverse correlation Co. Ltd. It is in Phase I testing in solid tumors.between HGF and c-Met in NSCLC. If this were the case, then Arriola of Hospital del Mar noted that Genentech’s study had apatients with high c-Met expression might benefit less from an HGF/ high proportion of EGFR wild-type patients, a group that tends notSF inhibitor because c-Met is activated largely independently of the to achieve much benefit from use of Tarceva alone. “So it should beligand. quite easy to observe a benefit” from the addition of MetMAb, she On the flipside, it could be that tumors in patients with low c- noted.Met expression are more dependent on HGF/SF for activation, Seiji Yano, a professor of medical oncology at the Cancerwhich Ezickson said would explain why ficlatuzumab appeared Research Institute of Kanazawa University, believes an impor-more active in this subgroup. tant question that Aveo will need to answer is “whether the dose Edurne Arriola, a medical oncologist at the Hospital del Mar, of its anti-HGF antibody was enough to neutralize HGF activity insaid she is working with preclinical models of small cell lung cancer vivo.”that have high levels of HGF/SF and no c-Met expression. “This Indeed, unlike MetMAb, which binds the receptor, ficlatuzumabmight not necessarily be the case in NSCLC,” she said, but it needs to mop up all the HGF ligand in circulation.suggests there can be situations with an inverse correlation in Yano said the available data are insufficient to draw anyexpression levels of c-Met and its ligand. conclusions about whether and how ficlatuzumab’s activity differs Arriola’s group has yet to put Aveo’s theory about ficlatuzumab’s from the other mAbs. “Without the level of HGF in the tumors, I doactivity in low c-Met patients to the test. “We are trying to figure not think we can make a correct interpretation on these data,” heout if these would be sensitive to an HGF inhibitor,” she said, noting said.that the tumors have proven resistant to a small molecule inhibitorof c-Met. Jill Siegfried of the University of Pittsburgh said that if Leveling upficlatuzumab’s signal in EGFR SM+/low c-Met patients is real, then Aveo is collecting data on HGF expression levels, whichEzickson’s theory of an inverse correlation between c-Met and HGF/ Ezickson said could go a long way toward explaining the results. HeSF could make sense. hopes to report these at a scientific meeting next half. Ficlatuzumab prevents “ligand-dependent signaling of c-Met See next page
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A7 OF 20Product Discovery & Development, ceuticals Inc., now part of Astellas Pharma Inc., and elsewherefrom previous page by Roche. AstraZeneca plc markets Iressa for NSCLC in the EU. The company has not settled on a plan for moving ficlatuzumab COMPANIES AND INSTITUTIONS MENTIONEDforward in NSCLC, he said, though “based on the strength and Agilent Technologies Inc. (NYSE:A), Santa Clara, Calif.consistency of response rate and magnitude of the PFS benefit in American Society of Clinical Oncology (ASCO), Arlington, Va.mutation-positive, c-Met-low patients, we think that is a strong Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.signal of activity that warrants further development in that sub- Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japangroup.” AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K. “Going forward it will be very important to incorporate c-Met Aveo Pharmaceuticals Inc. (NASDAQ:AVEO), Cambridge, Mass.and HGF biomarker analyses in all clinical trials with this class of Dako A/S, Glostrup, Denmarkagents,” noted Gyuris. Galaxy Biotech LLC, Mountain View, Calif. In the meantime, Aveo plans to start a Phase II trial of Genentech Inc., South San Francisco, Calif.ficlatuzumab in head and neck cancer around mid-year. Hospital del Mar, Barcelona, Spain Genentech’s MetMAb is in Phase III testing to treat NSCLC in Kanazawa University, Kanazawa, Japanpatients with high c-Met expression, with marketing applications Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerlandexpected in 2014. Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, Japan Tarceva is marketed in the U.S. by Genentech and OSI Pharma- University of Pittsburgh School of Medicine, Pittsburgh, Pa. Featured links this weekLinks to the following documents reside online PDUFA that includes several amendments, Startupson the BioCentury on BioBusiness page of including one from Sen. Tom Coburn (R- Text of the Startup Act 2.0 (S. 3217) thatwww.biocentury.com. Okla.) that would require independent aims to change tax requirements for startup assessment of the drug review and ap-Epilepsy investments and amend visa regulations to proval process (see BioCentury Extra, Fri- create new businesses and jobs (see BioCen-Not-for-profit Epilepsy Therapy Project pipe- day, May 25). tury Extra, Tuesday, May 22).line documenting investigational and ap- — White House statement of administra-proved products for epilepsy. tion policy supporting S. 3187 to reautho- Product documentation rize PDUFA (see BioCentury Extra, Thursday,Heart failure May 24). — Nimenrix: CHMP EPAR for Nimenrix to vaccinate patients ages 12 months and old-European Society of Cardiology 2012 guide- Pediatric drugs er against invasive meningococcal diseaseslines for diagnosis and treatment of acute caused by Neisseria meningitidis serogroupsand chronic heart failure. Summary of actions taken at the April 11-13 A, C, W-135 and Y; from GlaxoSmith- meeting of EMA’s Pediatric Committee.Opioids Kline plc (LSE:GSK; NYSE:GSK). Pharmacovigilance — Tafamidis: Briefing documents for theNICE clinical guidelines on use of opioids May 24 meeting of FDA’s Peripheral andfor pain in palliative care. EMA Q&A on implementation of pharma- Central Nervous System Drugs Advisory covigilance legislation.Orphan products Committee, which voted 13-4 that surro- Prostate cancer gate endpoint data for tafamidis were robustSummary of actions taken at the May 10-11 enough to predict a clinical benefit in pa-plenary meeting of EMA’s Committee for U.S. Preventative Services Task Force (USP- tients with transthyretin (TTR) familial amy-Orphan Medicinal Products (COMP). STF) final recommendation against loid polyneuropathy (FAP); from Pfizer using prostate-specific antigen (PSA)-basedOvarian cancer Inc. (NYSE:PFE) (see “A Rare Win,” A12). screening for prostate cancer in all age — Vimpat: CHMP revised EPAR updatingNICE quality standard on recognizing early groups (see BioCentury Extra, Monday, May SPC to include hallucination as an adversesymptoms of ovarian cancer. 21). drug reaction for Vimpat lacosamide as anPCORI Safety adjunctive therapy for partial-onset seizures; from UCB Group (Euronext:UCB).Patient Centered Outcomes Research EMA’s CHMP draft orientation paper of — Xarelto: Briefing documents for the MayInstitute (PCORI) funding announce- 2013 priorities for adverse drug reac- 23 meeting of FDA’s Cardiovascular andment to award $120 million in grants in tion research under Framework Pro- Renal Drugs Advisory Committee, which2012 after its board voted to formally gramme 7 (FP7), including long-term voted 6-4, with one abstention, againstadopt a revised set of research priori- safety effects of antipsychotics in de- recommending approval of 2.5 mg twice-ties and agenda (see BioCentury Extra, mentia patients, long-term adverse skel- daily Xarelto rivaroxaban to reduce the riskTuesday, May 22). etal effects of bisphosphonates, and of cardiovascular events in patients with DNA collection and studies on the ge- acute coronary syndrome (ACS), non-ST-PDUFA netic causes of adverse drug reactions elevation myocardial infarction or unstable— Text of the Food and Drug Administra- such as angiotensin-converting enzyme angina; from Bayer AG (Xetra:BAYN) andtion Safety and Innovation Act (S. 3187) inhibitor-related angioedema and sta- Johnson & Johnson (NYSE:JNJ) (see Bio-passed by the U.S. Senate to reauthorize tin-induced myopathy. Century Extra, Wednesday, May 23)
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A8 OF 20 Product Discovery & Development Islet defense By Stephen Hansen All transplanted animals were positive for insulin C-peptide, a Senior Writer measure that Toleikis said shows insulin released from islet cells Sernova Corp. is developing its Sertolin cell technology is regulating glucose.and Cell Pouch System device to provide an immune-privileged, At the end of the study period, the devices were removed andvascularized environment for donor islet cells to produce insulin the pigs returned to a diabetic state. Toleikis said analysis of thein insulin-dependent diabetes patients. The approach is intended devices showed the vast majority of islet cells were still healthyto overcome problems with traditional and functioning.islet cell transplantation, including poor “Our six-month preclinical data is notrates of cell survival and engraftment, and because we lost the islets at six months.unwanted immune responses. “By combining the Sertoli That is just when the study ended,” he Standard islet transplantation involves cells with the islet cells, said.using a catheter to infuse islet cells intothe portal vein of the liver. While mini- the Cell Pouch Systemmally invasive, the procedure carries the becomes an immune- Immune privilegedrisk of portal vein thrombosis and intrap- Sernova has a second technologyeritoneal bleeding. privileged environment. dubbed Sertolin that uses the natural According to Sernova President and That’s the ideal situation ability of Sertoli cells to create an immune-CEO Philip Toleikis, about 50% of the privileged environment.cells die immediately. In addition, because for the therapeutic cells.” Sertoli cells are naturally found in thedonor islet cells are particularly sensitive testes. In addition to secreting growthto hypoxic conditions, it is unclear how Philip Toleikis, Sernova factors, they synthesize the cytokines nec-many of the remaining cells actually en- essary to protect developing spermatozoagraft and are able to provide a therapeutic benefit. from being attacked by the immune system. Toleikis said it has “The islet cells don’t like to be bathed in blood. They want been known for over 60 years that it is possible to transplant cellsto be next to microvessels so they can interact with them,” from other species into the testes without them being rejected.Toleikis said. “By combining the Sertoli cells with the islet cells, the Cell Donor cells also are recognized by the body as foreign and Pouch System becomes an immune-privileged environment.elicit an inflammatory immune response. Patients thus require That’s the ideal situation for the therapeutic cells,” Toleikis said.immunosuppressive drugs to prevent graft rejection. These “It’s local immunosuppression without the need for systemicdrugs not only carry the risk of serious infections and malignan- treatment.”cies, but also can impair the revascularization and function of The company cited unpublished data in a diabetic rat modelgrafted islets. co-transplanted with porcine islets and Sertoli cells in the kidney Sernova protects islet cells from immediate death and ensures capsule, showing the immune response was significantly inhib-sufficient oxygen is available to the cells using its Cell Pouch ited compared with rats that received only the porcine islets.System, a matchbook-sized polymer device with several cham- In co-transplanted animals, islets produced “robust” levels ofbers for therapeutic cells. insulin up to 180 days following implantation, Toleikis said. In Initially, the empty device is implanted subcutaneously in the animals receiving islets without the Sertolin technology, an IgG-abdomen with the chambers plugged. The device contains pores, mediated immune response destroyed the islets by day 14.which allow microvessels and collagen tissues to move in and Toleikis said Sernova also has unpublished data in multiplegrow up to the edge of the plugs over a period of two to 12 weeks, diabetic animal models that combine the Sertolin technology andToleikis said. islet cells in the Cell Pouch System. He said these data show that Once the device has been vascularized, the plugs are re- normal glucose levels were achieved in two weeks and main-moved in an outpatient procedure and donor islet cells are tained for the duration of the studies — more than 100 days.inserted into the chambers. Toleikis said both inserting the Beta-O2 Technologies Ltd. is developing another devicedevice and removing the plugs requires a minimally invasive one that uses a mechanical barrier to prevent the immune systemcentimeter keyhole subcutaneous incision. from reaching the implanted islet cells. The bioartificial pancreas “The islet cells naturally release growth factors when they has two chambers, one for the islet cells and another for anmove into an environment to stimulate angiogenesis and oxygen supply for the cells. Both chambers are encapsulated inmicrovessel formation,” he said. a polymer barrier with nanopores large enough to let insulin out, The microvessels not only supply the islet cells with the but small enough to prevent immune system components fromoxygen and nutrients needed to survive, but also provide the entering.connection to the host for glucose regulation. Preclinical data were recently published showing the Sernova says its unpublished preclinical data show islet cells bioartificial pancreas can restore blood glucose levels in diabeticremain viable in the Cell Pouch System after a single transplan- mice (see SciBX: Science-Business eXchange, March 22).tation. In a diabetic pig model, the Cell Pouch System maintained According to Toleikis, previous approaches that have used aglucose levels in the normal range during the six-month study. See next page
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A9 OF 20 Product Discovery & Development, from previous page mechanical barrier to sequester donor islet cells have prevented SciBX This Week the cells from interacting with microvessels, thus potentially reducing their therapeutic effect.ANALYSIS Into humansCOVER STORY In May Sernova began a Canadian open-label, single-arm Reviving Ras Phase I/II trial of the Cell Pouch System without the Sertolin Genentech and Vanderbilt teams have independently used fragment-based drug discovery to identify a new small technology. The trial will enroll 20 patients with insulin-depen- molecule binding site that blocks activation of Ras, a highly dent diabetes who will receive immunosuppressive drugs. prevalent oncoprotein that has previously been considered The primary endpoint will be safety, and the secondary undruggable. The results could reinvigorate drug discovery endpoint will be the proportion of patients who achieve and efforts against the target. maintain insulin independence at three months after transplan- tation. Data are expected this year.TARGETS & MECHANISMS Patients will be followed for up to three years to provide Cooling down AD additional information on the long-term viability of the islet cells. A Johns Hopkins University team has clinical proof-of- A second Phase I/II trial will then combine the Sertolin concept data for slowing the progression of Alzheimer’s technology with the Cell Pouch System. Toleikis said the Sertolin disease by reducing activity in the hippocampus with technology is still 12-18 months from the clinic. antiepileptic drugs. AgeneBio has licensed the IP and is While Sernova is focused on diabetes, Toleikis said other planning a Phase II trial of an antiepileptic to prevent AD. protein or hormone-producing cells, or stem cells, could be used Getting around peripartum cardiomyopathy in the Cell Pouch System. Some examples the company is A Harvard Medical School–led team has shown that a considering include human growth hormone (hGH) and Factor soluble form of FLT1 causes about one-third of peripartum VIII. cardiomyopathy cases—those associated with pre- “Essentially anything that can produce a hormone or protein eclampsia. Ongoing studies are seeking to identify small that is missing from the body, we’ll be able to work with,” he said. molecule inhibitors of the protein and determine whether “We are currently looking at neurological diseases, metabolic the mechanism also underlies the other two-thirds of diseases and blood diseases.” cases. Sernova, which is listed on the TSX Venture Exchange, raised Getting selective for g C$3.6 million ($3.5 million) in a private placement in April. Cellzome and Exelixis have independently designed the Toleikis said the company has C$5 million in cash, which should first highly selective inhibitors of the g-isoform of PI3K. provide a two-year runway. Exelixis hopes to out-license its inhibitors, whereas the recent acquisition of Cellzome by GlaxoSmithKline gives COMPANIES AND INSTITUTIONS MENTIONED the pharma a new class of compounds for inflammatory Beta-O2 Technologies Ltd., Petah Tikva, Israel and autoimmune diseases. Sernova Corp. (TSX-V:SVA), London, OntarioTHE DISTILLERY This week in therapeutics Treating melanoma by antagonizing PREX2; preventing thrombosis with PDI inhibitors; ameliorating hyperalgesia in diabetic neuropathy by blocking methylglyoxal; and more… This week in techniques The search for intelligent life High throughput sequencing of TCRs to detect minimal We know you have many choices for residual disease in T cell acute lymphoblastic leukemia; a proteomic method for developing rational combinations of headlines. But finding real intelligence is a lot kinase inhibitors; synthesis of biologically active harder. That’s why top managers and meroterpenoids; and more… investors in the life sciences community depend on BioCentury, the Bernstein Report on BioBusinessTM for its leading perspective on the strategic issues essential to the formation, FROM THE MAKERS OF BioCentury AND nature development and sustainability of life science ventures in 2012 and beyond. Request a Free Trial ‘It’s the BioCentury’TM email@example.com
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A10 OF 20 Emerging Company Profile iTeos: Disabling tumor immune escape By Kai-Jye Lou clinic and that one could be approved by Staff Writer iTeos Therapeutics S.A. the time the company is ready to start its Tumor cells exploit many signaling Phase I/II trial. He declined to providepathways to avoid detection by the host Gosselies, Belgium specific details on LICR’s vaccine candi-immune system, thereby limiting the po- Technology: Small molecule dates and the planned trial.tential of cancer immunotherapies. iTeos immunomodulators that block tumor iTeos is aiming to complete the PhaseTherapeutics S.A. is developing small immunosuppressive mechanisms I/II study and to submit an IND for amolecule immunomodulators that block Disease focus: Cancer second candidate in four years. Decisionsthese escape pathways, which could po- on whether to partner, out-license ortentially boost and prolong the effects of Clinical status: Preclinical continue developing the lead candidatecancer vaccines. Founded: 2011 by Michel Detheux in-house will be made after completing the iTeos spun out of the Ludwig Insti- and Benoit Van den Eynde Phase I/II.tute for Cancer Research Ltd. (LICR) University collaborators: Ludwig Insti- Detheux said iTeos is exploring theand the de Duve Institute at the tute for Cancer Research, de Duve possibility of developing a dual inhibitorUniversité catholique de Louvain last Institute at the Universite catholique that targets both IDO and TDO.August to translate the LICR’s scientific de Louvain In January, Van den Eynde’s groupassets into immunomodulatory cancer Corporate partners: None published data showing that tumor cellstherapies. Number of employees: 5 could express IDO, TDO or both. Those iTeos initially will focus on pancreatic, data suggest inhibition of IDO and TDO Funds raised: €3 million ($4 million)liver, lung and colorectal cancers. The could have a complementary effect (seecompany is pursuing three targets, two of Investors: Ludwig Institute for Cancer SciBX: Science-Business eXchange, Feb. 23).which have been disclosed: tryptophan Research; Hunza Ventures; Life Sci- iTeos this month raised €3 million ($42,3-dioxygenase (TDO2; TDO) and ence Research Partners; Vives Louvain million) in a series A round, which comple-indoleamine 2,3-dioxygenase (INDO; Technology Fund; and angel investors ments a €6 million non-dilutive researchIDO). The company has exclusive rights CEO: Michel Detheux grant the company received last Decem-to the targets from LICR and could receive Patents: None issued ber from Belgium’s Walloon regional gov-rights to future targets discovered at the ernment.institute. Detheux said the funding gives iTeos The rationale for targeting IDO and 1-methyl-d-tryptophan is in a pair of Phase runway until 2015 and that the funds willTDO stems from the research of iTeos co- Ib/II trials in solid tumors. allow the biotech to build out its therapeuticfounder and CSO Benoit Van den Eynde, Detheux said iTeos plans to develop platform and to discover and develop addi-who also is director of the LICR Brussels IDO inhibitors that will be more potent tional small molecule immunomodulators.Branch. Since 2003, his group and others and selective than the clinical-stage com- iTeos will outsource some drug dis-have shown that degradation of tryptophan pounds but declined to disclose whether covery efforts, such as those related toby IDO and by TDO is a strategy many the company already has candidates that medicinal chemistry, pharmacokinetics andtumors employ to disarm immune cells. meet such criteria. lead optimization. iTeos CEO Michel Detheux said the The company plans to start a proof-of-company has an undisclosed number of concept Phase I/II trial of a lead candidate COMPANIES AND INSTITUTIONS MENTIONEDsmall molecule IDO and TDO inhibitors against one of the two targets in combina- Incyte Corp. (NASDAQ:INCY), Wilmington,in preclinical development. tion with a cancer vaccine from LICR Del. Aside from iTeos, there are no dis- within two years. iTeos Therapeutics S.A., Gosselies, Belgiumclosed TDO inhibitors in development. Detheux said the company will select Ludwig Institute for Cancer Research At least two other companies, Incyte “the most advanced Ludwig Institute can- Ltd., New York, N.Y.Corp. and NewLink Genetics Corp., cer vaccine suitable for the human cancer NewLink Genetics Corp. (NASDAQ:are developing small molecule IDO inhibi- we want to target.” NLNK), Ames, Iowators. Incyte’s INCB24360 is in Phase II He said the institute already has mul- Universite catholique de Louvain, Brus-development for solid tumors. NewLink’s tiple cancer vaccine candidates in the sels, Belgium BioCentury makes people think TM There is only one journal — BioCentury, the Bernstein Report on BioBusiness — that is recognized by key decision makers as the best source of perspective, interpretation and analysis for top managers and investors in the biotech community.
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A11 OF 20 Emerging Company Profile Delpor: Implantable antipsychotics By Stephen Hansen 201, a preclinical interferon alpha implant Senior Writer Delpor Inc. to treat HCV. Similar to Prozor, DLP-201’s While extended-release antipsychotics steady PK profile could reduce side effectshave been a commercial success, they still San Francisco, Calif. associated with daily IFN alpha injections.have a limited therapeutic duration and Technology: Prozor and Nanopor drug Delpor also has DLP-202, which con-poor pharmacokinetics, resulting in poor delivery devices tains human growth hormone (hGH), incompliance. Delpor Inc. is aiming to preclinical testing. Disease focus: Neurology, infectiousimprove all three of these characteristics Intarcia Therapeutics Inc. andwith its implantable Prozor drug delivery Clinical status: Preclinical Durect Corp. are developing productsdevice. Founded: 2009 by Tassos Nicolaou, using an implantable device called Duros Prozor is a tubular device 40 mm long Frank Martin and Nick Arvanitidis under licenses from J&J’s Alza Corp. sub-and 4 mm in diameter that is subcutane- Corporate partners: None sidiary.ously implanted in the arm to provide con- Number of employees: 4 The difference between Delpor’s de-tinuous drug delivery via passive diffusion. vices and Duros implantable devices is Funds raised: Undisclosed To deliver drugs with poor water solu- that Prozor and Nanopor have no movingbility, such as antipsychotics, Delpor has Investors: Angel investors parts, while Duros is an osmotic mini-developed undisclosed excipients that CEO: Tassos Nicolaou pump that uses osmotic pressure and aerode over time, creating an acidic pH Patents: 2 issued covering Nanopor piston to slowly push drug out of theenvironment within the device. This acid technology and Delos pump technol- device.generation improves solubility and estab- ogy for drug delivery According to Nicolaou, Prozor alsolishes a concentration gradient between has a larger drug capacity and lower costthe device reservoir and the external en- of goods. Moreover, he said, if the devicevironment. The drug then passively dif- a flat PK profile. Nicolaou thinks the becomes clogged, there is no risk of drugfuses into the body at a steady rate. smooth PK profile could diminish or elimi- dumping. Delpor’s lead program is DLP-114, a nate the extrapyramidal side effects. Durect markets Alzet implantable os-Prozor device loaded with risperidone. Nicolaou added the amount of drug motic pumps for research use to deliverDelpor plans to submit an IND by year used in DLP-114 should allow for three- to drugs in animal models. Intarcia’s ITCAend. six-month dosing. This schedule should 650, a continuous subcutaneous delivery DLP-115, a Prozor device delivering improve patient compliance compared of exenatide from an implantable Durospaliperidone, is in preclinical testing. with injectable depot formulations, which device, is in Phase III testing for Type II According to President and CEO require patients to visit the doctor’s office diabetes (see BioCentury, July 11, 2011).Tassos Nicolaou, Delpor would compete for more frequent injections. Intarcia also has ITCA 638, a Duroswith depot formulations of antipsychotics Nicolaou noted the implant also could device containing IFN alpha, in Phase I fordelivered via intramuscular injection, such be safer because it can be removed if a HCV.as Johnson & Johnson’s Risperdal Consta patient has a bad reaction to the drug, Delpor also has a pump technologyrisperidone and Invega Sustenna whereas a depot cannot. called Delos that can deliver therapeuticspaliperidone palmitate. Both are approved Delpor also is developing a related at timed intervals. The company is notfor schizophrenia; Risperdal Consta is also technology for biologics, called Nanopor. developing programs using the technol-approved to treat bipolar disorder. Nicolaou said the biologics device also ogy, but Nicolaou said it could be useful In 2011, Risperdal Consta had sales of relies on passive diffusion, but unlike for fertility hormones, parathyroid hor-$1.6 billion. Sales of Invega Sustenna were Prozor, Nanopor devices have membranes mone or pain medications.not disclosed. at each end containing nanopores. The Risperdal Consta is given every two size and number of nanopores dictates COMPANIES AND INSTITUTIONS MENTIONEDweeks, and Invega Sustenna is given once how much therapeutic is released. Delpor Inc., San Francisco, Calif.monthly. Nicolaou said drug levels spike He said the challenge is to keep Durect Corp. (NASDAQ:DRRX), Cupertino,following injections, which can lead to biologics stable within the device at body Calif.extrapyramidal side effects. temperature. Nicolaou said Delpor has an Intarcia Therapeutics Inc., Hayward, Calif. The company says unpublished pre- undisclosed formulation technology that Johnson & Johnson (NYSE:JNJ), Newclinical data show Prozor can deliver prevents the proteins from aggregating. Brunswick, N.J.risperidone at a constant rate, resulting in Delpor’s lead Nanopor program is DLP- All press releases, news announcements and story inquiries should be submitted to our news room at firstname.lastname@example.org. Editorial announcements emailed to the Editor-in-Chief and/or the Publisher may not receive immediate attention and potential stories will be delayed.
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A12 OF 20 Regulation A rare win By Erin McCallister Small fiber function was one of five components of the quality Senior Writer of life endpoint; and muscle weakness was one of three compo- Pfizer Inc. saw value in a failed Phase II/III trial of tafamidis nents of disease progression.as a treatment for transthyretin familial amyloid polyneuropathy Small fiber function and muscle weakness have been usedwhen it acquired FoldRX Pharmaceuticals Inc. in 2010. Last previously in studies for diabetic peripheral neuropathy, whileweek, FDA’s Peripheral and Central Nervous System Drugs the surrogate of TTR stability was designed specifically forAdvisory Committee agreed, voting 13-4 that data on surrogate tafamidis.endpoints in the study were sufficiently robust to predict clinical Tafamidis had a statistically significant improvement on thebenefit. secondary outcomes of small nerve fiber score (p=0.005), mBMI The vote paves the way for accelerated approval in the (p<0.0001), muscle weakness (p=0.01) and TTR stabilizationOrphan disease. (p<0.0001). If FDA approves tafamidis, Pfizer would have two approved Pfizer submitted an NDA last December with the understand-Orphan drugs only two years after the ing that the regulatory pathway — tradi-pharma said it was creating a business unit tional or accelerated — would be deter-focused on rare diseases. The PDFUA date “As I understand it, mined at a later date.is June 16. Approval also would validate the surrogate data has to bepharma’s decision to purchase FoldRx for substantial and the effect Applying flexibilityan undisclosed sum, despite knowing the In briefing documents, FDA reviewerscompound had missed the primary end- reasonably likely to predict recommended that the agency issue apoints (see BioCentury, Sept. 6, 2010). benefit. One could make complete response letter because tafamidis missed the primary endpoints and the that argument for muscle clinical significance of the secondary end-Stabilizing TTR points was uncertain. strength and small TTR FAP is an autosomal dominant However, in a memo to the paneldisease characterized by deposition of fiber function.” included in the review documents and inabnormal amyloid proteins primarily in his opening statement at the meeting,the peripheral nerves and other organs. Eric Logigian, Russell Katz, director of the Division ofSymptoms include sensorimotor and auto- University of Rochester Neurology Products at the Center fornomic neuropathy as well as heart, kidney Medical Center Drug Evaluation and Research (CDER),and eye dysfunction. said FDA is “willing to apply as much According to FDA’s briefing documents, there are about flexibility as we can, but within the standards of the law.”2,500 patients with TTR FAP in the U.S. and 5,000-10,000 Katz told the panel robust clinical data from at least two well-worldwide. controlled clinical trials was necessary for full approval. Alterna- The disease is caused by mutations in the gene that codes for tively, a single well-controlled trial could satisfy the criteria fortransthyretin (TTR).The most frequent mutation leads to misfolding full approval if the results were “robust,” with a p-value 0.05,of TTR monomers, which form toxic intermediates. The result is as well as multiple subgroups and locations showing equallythe formation and deposition of amyloid. robust results. Patients die within about 11 years of onset of symptoms. Alternatively, Katz said, FDA can grant accelerated approval Current treatment in the U.S. is liver transplant, which based on an unvalidated surrogate endpoint if it believes theremoves abnormal TTR from circulation. The five-year survival effect on the surrogate is reasonably likely to predict a clinicalfor liver transplant is 80%, with about 60% who stabilize, 20% benefit.who improve and 20% who do poorly. He added that the definition of reasonably likely will depend FoldRx discovered and developed tafamidis as an alternative on a “detailed understanding of efficacy and safety and thefor patients who are not eligible for or do not respond to liver biological activity or pathophysiology of the drug.”transplant. The compound is a small molecule that stabilizes the The panel voted 13-4 that the data from Fx-005 did notTTR protein and prevents misfolding. support full approval because 58% of patients were enrolled in In 2009, tafamidis missed the co-primary composite end- a single site in Portugal, and there was a higher than expectedpoints of disease progression and quality of life in the intent-to dropout rate due to liver transplant, leaving the study underpow-treat (ITT) population in Fx-005, a randomized double-blind, ered.placebo-controlled Phase II/III trial. The ITT population included Fx-005 had 90% power to detect a significant treatment64 patients on tafamidis and 61 on placebo. difference and assumed a 5-10% dropout rate, including drop- The trial also included multiple secondary endpoints includ- outs for liver transplant.ing large nerve fiber score, small nerve fiber score, modified BMI The dropout rate from transplant alone was 20%, which both(mBMI), muscle weakness and TTR stabilization status. the agency and Pfizer agreed left the study underpowered. See next page
BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS MAY 28, 2012 P AGE A13 OF 20Regulation, neurology at the University of South the patient an early bump before progres-from previous page Florida. sion starts,” but that doesn’t mean the In response to Gooch, Katz reminded drug isn’t working, he said.Substantial surrogates the panel that FDA’s analysis showed the Gooch also noted that in diabetic neur- level of response on small nerve fiber opathy, decreases in small fiber function Despite these shortcomings, panel function peaked at 18 months, and then have been associated with “significant mor-members did feel secondary endpoints leveled off. Patients on placebo continued bidity.”pointed to some level of clinical benefit. to do worse, with the curves remaining According to FDA’s briefing documents, Temporary voting member Clifton separated, but patients on treatment also small fiber function is an objective measureGooch was especially impressed by the got worse, he said. of peripheral nerve function and a surrogatesmall nerve fiber function score. Gooch countered that it is not surpris- measure of peripheral neuropathy. “Since this is the first population of ing to see a high initial response on small The panel also felt the mean changenerve fibers to be affected in this condition, nerve fiber function followed by a plateau. from baseline in muscle weakness of 0.8 forit is, in effect, a canary in the coal mine. So “There are some nerves, in this case tafamidis vs. 3.4 for placebo (p=0.013) wasto see [efficacy] in a part of the nervous small fibers, that are barely alive, and a an important marker of clinical benefit.system where you would see the earliest drug like this salvages them and enables “As I understand it, surrogate data hassigns of disease, it is significant,” he said. the repair process to kick in, which gives to be substantial and the effect reasonably Gooch is chair of the department of likely to predict benefit. One could make that argument for muscle strength and small fiber function,” said Eric Logigian, a temporary voting member and professor of neurology at the University of Roch- ester Medical Center. The panel also was impressed with the TTR stabilization score, which measured Tens of thousands of physicians and research- the proportion of stabilized TTR protein ers are crowding into Chicago this week for in the plasma upon exposure to tafamidis “ASCO” — the annual meeting of the American vs. TTR ratio at baseline. Society of Clinical Oncology. In the treatment group, the TTR stabi- lization ratio was 97% vs. 0% for placebo In its ASCO preview, BioCentury This Week (p<0.0001). television looks beyond the medical science to Because TTR stabilization correlates the economics of cancer, from investors looking with amyloid fiber inhibition in vitro, Pfizer for upside to healthcare providers grappling considered it to be a plausible biomarker with the mounting cost of care. that could predict clinical benefit. Dr. Mark Schoenebaum, Senior Managing Director and Head of Healthcare Panel members agreed. Research at ISI Group, joins BioCentury This Week from Wall Street to “TTR stabilization was robust and just discuss the sustainability of oncology drug prices, the rise of “immune- makes sense,” temporary voting member oncology” and the showcase presentations at this year’s ASCO meeting. David Preston said. Preston is vice chairman of neurology In a Web Exclusive segment, Dr. Schoenebaum describes why drug pricing is and professor of neurology at University a “big, big overhang” on biopharma stocks, Hospitals — Case Medical Center. saying the Street sees a “declining margin Additionally, the panel felt that accel- industry.” erated approval was warranted due to the On the cost side, Dr. Thomas Smith, Director of absence of major adverse events in the Palliative Medicine and Professor of Oncology at tafamidis program and the lack of treat- Johns Hopkins University, joins BioCentury This ments beyond liver transplants. Week to preview his ASCO session on the affordability of care, and argue why and how oncologists must find ways to bend the cost Confirmation curve in medical spending. As Pfizer would need to have a confir- matory trial started prior to accelerated approval, the pharma presented three Watch Any Time on the Web potential studies. www.biocenturytv.com Donna Grogan, former CMO at FoldRx and a consultant to Pfizer, said these might include an open-label trial New weekly shows go online at 9:00 a.m. EDT on Sundays. of tafamidis vs. historical controls, or a Prior shows available 24/7 in the online Program Archive. placebo-controlled study of tafamidis in BioCentury This Week also is broadcast on Sunday in Washington, D.C. TTR FAP with muscle weakness at month Watch it on WUSA Channel 9 at 8:30 a.m. EDT 12 as the primary endpoint. Grogan also suggested the company Charter Sponsorship from BIO, Biogen Idec, and Rodman & Renshaw See next page