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Positive Trial Result Might be Considered Negative News

On Jan. 3, 2012, AVEO announced that tivozanib demonstrated superiority over Nexavar (sorafenib) in the primary endpoint of progression-free survival (PFS) in a global, randomized Phase 3 clinical trial in 517 patients with advanced renal cell carcinoma (RCC). All patients in the trial had clear cell RCC, had undergone a prior nephrectomy, and had not previously been treated with either a VEGF or mTOR therapy.

· tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall study population

· tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib in the pre-specified subpopulation of patients who were treatment naïve (no prior systemic anti-cancer therapy); this subpopulation was approximately 70% of the total study population

· tivozanib demonstrated a well-tolerated safety profile consistent with the Phase 2 experience; the most commonly reported side effect was hypertension, a well established on-target and manageable effect of VEGFR inhibitors

On surface, the news is positive for an investigational drug against an approved drug. However, by looking at advanced RCC competitive landscape, the news might be negative.

Bayer/Onyx’s Nexavar (sorafenib) was approved first in 2005 for advanced RCC who had received one prior systemic therapy. Pfizer’s Sutent (sunitinib) was approved as a first-line treatment for RCC in 2006, and quickly established itself, and is now considered the new standard of care (SOC) for treatment-naïve patients. Pfizer’s Torisel (temsirolimus), Novartis’ Afinitor (everolimus), Roche’s Avastin (bevacizumab), GlaxoSmithKline's Votrient (pazopanib) were approved for advanced RCC subsequently. On Dec 7, 2011, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend the approval of Pfizer's Inlyta (axitinib) for the second-line treatment of patients with advanced RCC based on the results of the Phase III trial comparing axitinib and sorafenib. Note: Torisel and Afinitor inhibit mTOR while others mentioned above are VEGF inhibitors.

To crack into the crowded space for advanced RCC, new drug entering the space needs to be armed with superior or differentiated data. Tivozanib's 3-month PFS advantage over sorafenib was a significant disappointment for the market. AVEO stock ended down almost 20% to $13.83 from $17.2 on Dec. 30.

With Sutent firmly established as SOC for treatment naive patients, competition is fierce in the second and third line settings. There are currently four major targeted agents for the second line treatment of advanced RCC. Nexavar was the leading therapy but with steady declining market share, followed by Torisel, Afinitor and Avastin. Axitinib most likely will enter this space shortly. It's not entirely clear where tivozanib fits in.

The tivozanib registration trial is geared toward competition against Sutent, 70% of patients in the registration trial were treatment naive. It's not clear from the data released whether tivozanib has advantage over Sutent. If it were to compete against Nexavar and others in 2nd line setting, they should have included at least 50% patient population with prior systemic treatment. AVEO didn't breakdown number from that 30% patient population, based on other numbers provided, my guess is it didn’t achieve statistical significance, and the median PFS number didn't differ from Nexavar that much. This kind of leaves tivozanib in searching for an identity. One possible differentiation for tivozanib is safety profile, which remains to be seen when full data are presented at ASCO 2012. Tivozanib might become a niche product for treatment naïve patients with advanced RCC who cannot tolerate Sutent, rather than the leading VEGF TKI for advanced RCC many had expected before.

Posted on Jan. 4, 2012

#AVEO #RCC #TIVOZANIB #NEXAVAR #SUTENT

Follow-up on Exelixis (EXEL) Failure to Secure Cabozantinib (XL184) in mCRPC Phase III Trial (306) SPA

On Oct. 31, 2011, EXEL announced decision to initiate Cabozantinib in metastatic castration-resistant prostate cancer (mCRPC) Phase III trial (306) after failure to secure Special Protocol Assessment (SPA) from FDA. On Nov. 29, 2011 at Piper Jaffray Health Care Conference Call, EXEL CEO Mike Morrissey gave much more details on the issues raised by FDA during SPA process than previously disclosed. Here is part of the transcript:

Mike Morrissey: Yeah. Well, I think a SPA would have been certainly preferred really to go relative to having a lock in agreement on a trial which we believe is a very important part of the process relating to how we hope to again build this commercially differentiated profile for cabo. That being said, we had a very good dialogue with the FDA. We’ve gone into great detail on the call we’ve had back in October and I think in all the different documentations. We have -- in that dialogue we had two-step process, if you will. We had a pre-end of Phase 2 meetings before ASCO. We’ve got some of the documentation after ASCO. The first set of feedback that we got in the August timeframe was actually very encouraging. A number of enhancements were suggested to put a protocol around inclusion criteria, response criteria, narcotic optimization, the nature of the bone scan response and primary vs exploratory endpoint. All things that we, I think we’re very happy to deal with and include in the protocol relative to the fact that we had very high level of confidence in the bone scan response data that came from the RDT trial, as well as what we were seeing from the non-randomized trial that was recently published now at EORTC. I think the difference came into play on the second round of feedback, where I think the magnitude of the response was being to be small or too small relative to the potential for inadvertent unblinding by the differential AE profile of cabo versus mitoxantrone. We had a 17% delta in the confirmed pain response rate between cabo and mito/prednisone. The trial was designed at 25% confirmed response rate for pain for cabo, 8% was for mitoxantrone/prednisone. And the feedback was that that’s probably too small to be able to get around the idea of inadvertent unblinding. And that was a judgment issue, I think at that point in time we had pretty clear picture of what the agency was looking for in terms of the overall protocol, importantly the magnitude of the effect of 25% versus 8% was reasonable. We think we could probably beat that certainly the -- if you look at the RDT data from EORTC that the number of patients that had about a 30% reduction was about half the patients that we studied, so using that as kind of a good metric for what we might see in 306, one could imagine we had a much higher confirm pain response. We weren’t prepared to commit to a higher level, why raise the bar for a trial that obviously is important one to us, I think the issue is the data will define the utility of that lead out relative to a label and we don’t really response for that, the data will speak for itself. We’re planning to run the trial very, very carefully and collected exhaustively and we’re confident in what we’ve seen so far from a data point of view relative to this impact on pain. Again, this is a different profile from what we’re seeing some other compounds to-date. Our goal ultimately is to have a survival trial i.e. 307 and the pain trial 306 lead out at approximately the same time where we’re modeling in the first half of 2014, if that is to be the case maybe a little bit sooner, we would be able to then again have a strong foundation to go forward with a label that would support both the survival we have, but also a reduction in pain, reduction in narcotics both in response. So ultimately it’s that differentiated commercial opportunity that will drive value and we, again, based upon the data that we have from the last 275 patients its going to be pretty good as how that’s going to go.

Thus, FDA wanted much higher delta in pain response rate between Cabozantinib arm and mitoxantrone/prednisone arm due to potentially inadvertent unblinding of the trial because of significantly different adverse event profile between the two arms. However, EXEL didn't want to risk failure of the trial by raising the delta significantly in 306 trial. This implies the following:

1. FDA potentially is willing to approve Cabozantinib if 306 trial eventually produces much larger differential in pain response rate between the two arms.

2. EXEL wants to get the pain label, but doesn't want to risk failure of 306 trial if higher delta is agreed upon for the SPA. This is consistent with the point I made in previous blog on this subject that EXEL wants to preserve the two options for 306 trial, one is to file NDA based primarily on pain endpoint if the trial produces spectacular result, the other is to file NDA along with 307 trial if 306 trial just meets endpoints to have pain as part of overall label, which is an important differentiation factor for Cabozantinib from other drugs in mCRPC. If EXEL raises the bar for 306 as stand alone trial via SPA that results in failure, Cabozantinib would not get pain label even if 307 trial succeeds.

Posted on Dec. 1, 2011

#EXEL #Cabozantinib #XL184 #CRPC

Exelixis (EXEL) to Initiate Cabozantinib (XL184) in mCRPC Phase III Trial (306) Without SPA

The market was surprised with this development partially based on past guidance from EXEL management. However, it should not be entirely surprising. Cabozantinib had produced surprising data in the past year from ongoing Randomized Discontinuation Trial (RDT), especially bone scan data from CRPC cohort - partial or complete resolution of bone scans in a substantial portion of patients. There has been ongoing debate on how to interpret the bone scan data, and whether bone scan data are real or artifact. EXEL decided to seek SPA for one Phase III trial with composite endpoint from pain and bone scan. This is a novel endpoint for oncology trial. It shouldn't be a surprise FDA didn't grant SPA to 306 trial. For FDA to grant SPA, FDA not only had to endorse the trial design but also had to endorse the data interpretation of how much bone scan contributed to clinical benefit when as of today they have no data to back up such endorsement. FDA's suggestion of making bone scan as exploratory endpoint is right on the mark. Only with further data, maybe from 306 trial, would we know how much bone scan contributes to clinical benefit.

In my opinion, SPA process had improved 306 trial design. If EXEL had gone on with their original composite primary endpoint design, I don't think they would get approved even if trial significantly exceeds primary endpoint because it will be difficult to interpret the data.The new 306 trial separates pain primary endpoint from bone scan secondary endpoint, which makes data interpretation more clearly. Pain reduction is an approvable endpoint. The final 306 trial design is as following:

"The double-blind 306 trial is designed to enroll 246 patients with CRPC that is metastatic to the bone, who are suffering from moderate to severe bone pain despite optimized narcotic medication, and who have failed prior docetaxel and abiraterone in no particular order... Patients will be randomized 1:1 to receive either cabozantinib or mitoxantrone/prednisone... Alleviation of bone pain will be the primary endpoint... Overall survival will be a secondary endpoint of the ‘306 trial. The 306 trial will be deemed successful if the primary endpoint of statistically significant pain improvement is met and the overall survival analysis demonstrates that there is no adverse impact on overall survival in the cabozantinib arm. In light of not proceeding under an SPA, the Company has decided to evaluate bone scan response as a secondary endpoint rather than as an exploratory endpoint."

In addition to 306 trial, EXEL "expects to initiate the 307 trial in the first half of 2012. The primary endpoint of 307 trial will be overall survival. The trial will be conducted in patients with CRPC with bone metastases who have failed prior docetaxel and abiraterone therapies. Patients will be randomized to receive cabozantinib at 60 mg daily or prednisone."

Due to failure to secure SPA for 306 trial, many suggested EXEL should abondon 306 trial, proceed with 307 trial with OS as primary endpoint. Personally I don't mind EXEL start 306 trial with current design in current quarter. The trial size is small, 246 patients - if it were 500+ patients, I would have different opinion due to limitation of resources - not much bigger than one cohort of their RDT. Given Cabozantinib's unique data to date, it is not a bad idea to run a RANDOMIZED trial this size to explore the relationship among pain, bone scan, survival. Their existing data while compelling are post hoc, and the relationship among pain/bone scan/survival was extrapolation of post hoc data. I still don't know how to interpret the bone scan data. 306 trial will answer many if not most questions. If it meets all endpoints, including survival (80% powered for 50% inprovement in survival), take the data to FDA for approval. FDA would be much more willing to approve with very compelling data in front of them than giving SPA endorsement for a trial they didn't have enough data to endorse/interpret. If it doesn't meet OS endpoint, they'll have to wait to file along with 307 if 307 result is positive. Cabozantinib will get label including bone pain relief. During the wait, if Cabozantinib is approved in MTC, it might get some off label use. All in all, I don't see it is a bad idea to run this 246 patients exploratory registration trial. EXEL shouldn't have made this high risk 306 trial SPA as all or nothing for them in broad Cabozantinib development plan. Alternatively, EXEL could have sought SPA for both 306 and 307 trials, similar to what OGXI did with Custirsen in combination with docetaxel in CRPC. FDA could be more willing to grant SPA with one of them with conventional OS primary endpoint. In the end, it is the result of Cabozantimib trial that will determine the fate of EXEL, not whether EXEL gets SPA for a novel endpoint in one oncology trial.

Also worth noting is the dosage used for both 306 and 307 trials, 60 mg QD. Cabozantinib's original MTD was 175mg, which was used for the recently successful phase III trial in MTC. 175 mg QD had tolerability issue from early portion of phase II GBM trial, and dose was reduced to 125 mg QD in subsequent later portion of that trial. 125 mg QD regimen was used in phase II RDT. The reason 60 mg QD was chosen for 306 and 307 trials, according to EXEL management, was that >50% patients in RDT had dose reduction to 60 mg QD without adverse impact on efficacy.

Posted on Nov. 4, 2011

#EXEL #XL184 #Cabozantinib #CRPC

Depomed (DEPO) Serada Missed Several Endpoints in BREEZE 3 Trial

On Oct. 13, 2011, DEPO annonced top line results from BREEZE 3, a Phase 3 trial evaluating the efficacy and safety of Serada(R) (extended-release gabapentin tablets) for menopausal hot flashes. Efficacy data from the trial were positive and statistically significant for three of the four pre-specified primary endpoints of frequency and severity at 4 and 12 weeks. Data for the key secondary endpoints of frequency and severity at 24 weeks did not achieve statistical significance.

Most discussions afterwards centered around the trial design and statistical analysis plan (SAP), especially changes made to BREEZE 1, BREEZE 2 after similar results announced on Oct. 12, 2009. DEPO management mainly blamed placebo effects and outliers for missing some primary endpoints. They made the following changes to BREEZE 3 in addition to FDA requirement on showing efficacy in 24 weeks:

"Modifications to the design of Breeze 3 relative to Breeze 1 and 2 include: (i) a single active arm rather than two arms, and therefore a required statistical p value of .05 rather than .025 to achieve statistical significance; (ii) 65% more patients in the active treatment arm than in Breeze 1 and 2; (iii) a two-week run in period to prior to randomization, rather than one week, which is designed to reduce the regression to the mean observed in Breeze 1 and 2, resulting in a more stable baseline, and thereby potentially reducing the placebo effect; and (iv) an alternative statistical analysis method, known as a non-parametric analysis, that is designed to reduce the influence significant outliers can have on the achievement of efficacy endpoints."

Some of these changes made easier to achieve statistical siginificance. However, I had discussed the potential issues the change might not address early this year on investorhub Biotech Value Board. Here are summarization of key points from Feb 2011 discussion:

http://investorshub.advfn.com/boards/board.aspx?board_id=1418

1. The changes didn't address one issue which seemed odd in original 2 trials: the drug did much better at week 4 than week 12 for both dosage groups - if it were really placebo effect, wouldn't placebo effect be more obvious at week 4 than week 12? I'd think if the drug is really effective, placebo effect should go down rather than up over time. Could the drug work only in short term (4 weeks), but effect waned in longer term (12 weeks)?

2. DEPO claimed "While the drug effect in the studies was what we expected to see, there was an unexpectedly high placebo effect, particularly in the latter part of one of the studies." I looked at BREEZE 1 and BREEZE 2 result more closely, reduction of frequency for placebo were 62%, 56% respectively. While number from BREEZE 1 was a little bit higher than historical number for placebo effect in this indication, number from BREEZE 2 was inline with historical number. Even though placebo effects were quite different between BREEZE 1 and BREEZE 2, the overall results were remarkablely similar, at 4 weeks statistical significant, at 12 weeks some were some were not. To me, it was more than outliners from BREEZE 1 alone. So, I was not certain all those tweeks would be the answer. It would help in certain circumstance, might not in others. If BREEZE 1 had failed, BREEZE 2 had succeeded, then I would say it would most likely solve the problem. When both your drug and placebo performed in line with expectation in BREEZE 2, and sample size was correct, then you can't blame trial design.

These concerns were quite valid. Changes made to study design and statistical analysis plan resulted almost identical result to previous two trials.

Links to other blog on BREEZE 3 trial result:

http://seekingalpha.com/article/299631-what-to-do-with-depomed-now

Posted on Oct. 23, 2011

#DEPO #Depomed #Serada #Gabapentin

Optimer's Fidaxomicin In Front of FDA Advisory Panel

Optimer Pharmaceuticals (OPTR) antibiotic fidamoxicin for Clostridium difficile infection (CDI) will be in front of a U.S. Food and Drug Administration advisory panel on Tues. April 5, 2011. The general consensus is it will get positive vote from the panel because the efficacy and safety data presented in public have been solid. However, the public never get to see the full data as FDA reviewers do.

TheStreet's Biotech columnist Adam Feuerstein brought up two possible negatives http://www.thestreet.com/story/11063469/1/optimer-pharma-faces-key-fda-review-panel.html:

"1. The statistically significant increase in laboratory serious adverse events associated with fidamoxicin compared to vancomycin is a potential problem because it raises questions about one of the key attributes of fidamoxicin: The lack of systemic absorption, which is supposed to keep the drug in the gut and out of the bloodstream.

2. The lack of a statistically significant benefit in CDI disease recurrence for fidamoxicin over vancomycin in patients infected with the NAP1 strain of C. diff. The pooled data from the two studies shows a trend favoring fidamoxicin but this could still be a topic of conversation and concern at the panel."

These are excellent points. I looked at the data over and over again to see if I could spot anything. Here are my observation and caution:

1. In one of the pivotal trial, total enrollment was 629 patients, 302 were randomized to fidamoxicin while 327 were to vancomycin. There was no explanation why there was such large difference in number of patients (327 - 302 = 25) randomized to two treatment groups. Did something go wrong during randomization? Or it was nothng to worry about?

2. In detailed presentation of safety data from one of the two pivotal trials (I can't find similar data from the other trial), the change from baseline for ALT (SGPT) did get my attention: the mean change for fidamoxicin vs vancomycin was 3 vs 2.6, the range however was (-515, 262) vs (-232, 120). Thus, at least a couple of patients experienced large change from baseline in ALT for fidamoxicin group. Antibiotic has been known to cause abnormal liver enzyme levels. The question is always whether it caused liver damage (example, Antibiotic Ketek liver toxicity controversy). Without access to detailed individual patient data, it is impossible to make judgement. http://www.optimerpharma.com/gallery/OIU090733safetyPoster9_2946271_94.pdf

We'll have to wait and see what's in FDA briefing document on April 1, 2011.

Posted on Mar. 30, 2011

#OPTR #FIDAMOXICIN #CDI #OPTIMER

Lorcaserin Carcinogenicity Data Issue

FDA release advisory panel briefing document on Lorcaserin. It raised question regarding carcinogenicity data:

"A number of malignant tumor types developed in rats treated with lorcaserin for up to two years. An excess number of malignant mammary tumors developed in female rats treated with lorcaserin at doses within 7-fold of the proposed clinical dose of 10 mg BID. Male rats developed malignant mammary tumors when treated with lorcaserin at doses 17-fold higher than the proposed clinical dose. "

This is not entirely surprising to me. I raised this potential pre-clinical data issue after reading an article titled "Arena Pharmaceuticals: Locraserin and the Fallen Competitors: Analysis Part III" (http://www.gekkowire.com/?p=4186 comment by JQ on July 21, 2010).

I found suspension of ATHX-105 development for obesity due to pre-clinical toxicology data interesting since it was supposed to be selective to 5HT2c similar to Lorcaserin. I found the following from ATHX website http://bit.ly/aakDH8):

“In September 2008, we were notified by the FDA that our proposed phase II clinical trial was being placed on clinical hold, pending discussion with the FDA and resolution of several issues, some of which related to proposed trial design, and one of which related to a preclinical toxicology finding in rodents. While we were able to resolve each of the other issues regarding the clinical hold, we believe we will be unable to practically resolve the issue related to the toxicology finding in rodents, and as a result we have suspended further development of ATHX-105. The potential significance of the toxicology issue to humans remains unclear, but it appears to be a compound-specific effect that is not representative of the class of compounds we are developing. However, given that we would have to complete long-term toxicology studies in rodents and potentially other species in order to resolve the issue, and these studies may not be conclusive, we decided that further development of ATHX-105 may be too risky, expensive and time consuming, and therefore may not serve the best interests of our stockholders. Accordingly, we have withdrawn our IND application for ATHX-105, and suspended further development of this compound. ”

Posted on Sept. 14, 2010

#ARNA #LORCASERIN #ARENA #ATHX #ATHX105

Negative News Without Change in Fundamental

There are 4 types of negative news in biotech: clinical trial failure, regulatory setback, partnership dissolution, commercial launch disappointment. While clinical trial failure is a game changer, not all other negative news, however, necessarily change the fundamental of the biotech company. Recently 3 biotech companies experienced negative news without changing the fundamental of the companies.

Exelixis (EXEL) On June 21, 2010, BMS returned XL184 rights to EXEL. XL184 are currently in phase III, II for different oncology indications. The reason BMS gave up the rights to XL184 according to EXEL was "Given the recent progress of BMS' wholly-owned oncology pipeline and positive data generated by XL184, Exelixis and BMS were not able to align on the scope, breadth and pace of the ongoing clinical development of XL184." EXEL presented extensive data from XL184 at ASCO2010 (http://www.exelixis.com/asco/2010). While the data were not earth shaking, but nevertheless positive. While this news is negative, EXEL stock dropped from $4.58 on June 18, 2010 to $3.84 on June 21, 2010, then drifted futher down to $3.12 on July 30, 2010 even though July was a spectacular month for stock market overall, it doesn't change the potential of XL184, and EXEL's 19 other candidates in pre-clinical and clinical development.

ImmunoGen (IMGN) on August 27, 2010, Roche received Refuse to File from FDA on T-DM1 BLA submission based on one single arm 110 patients study for 3rd line Metastatic Breast Cancer. Roche will submit new BLA in mid 2012 based on larger randomized phase III trial. While this news is negative, IMGN stock dropped from $8.39 on August 26, 2010 to $5.16 on August 27, 2010, then recovered to $5.51 on September 10, 2010, it doesn't change the potential of T-DM1, and IMGN's ADC technology platform.

Celldex (CLDX) on Spetember 3, 2010, PFE returned CDX110 rights to CLDX. CDX110 is currently in Phase II clinical trial for GBM. The reason PFE gave up the rights to CDX110 according to CLDX was "rindopepimut program is no longer a strategic priority of Pfizer". PFE presented CDX110 promising interim data at ASCO2010 that are consistent with previous phase II trials (http://www.celldextherapeutics.com/wt/page/sci_articles). While the news is negative, CLDX stock dropped from $4.78 on September 2, 2010 to $3.53 on September 3, 2010, then stayed flat at $3.49 on September 10, 2010, it doesn't change the potential of CDX110, and CLDX's promising vaccine and ADC candidates.

After initial sharp drop in stock price, it is difficult to predict where the stock will go in short term (1-6 months) without immediate catalysts. Since the fundamental didn't change in the long term (6+ months), one strategy to mitigate this uncertainty is to sell slightly in-the-money put or out-of-the-money put 6-month into the future. If the stock price recovers or stays flat but above strike price, you can benefit from retaining the put premium sold; if the stock price drops below strike price, you will be assigned the stock at essential strike price minus option premium but well below stock price when the news was announced. In case of IMGN, the stock dropped to $5 range, you could either sell out-of-the-money APR2011 $5 put for $1.1 or APR2011 $4 put for $0.65 on August 27, 2010. If the stock price drops below $5 or $4, you will effectively buy the stock at $3.9, $3.35 respectively. Which strike price you choose ($5 or $4), and how far into the future, it depends on your risk tolerance. The higher the strike price, the higher the risk, thus higher potential return as well.

Posted on Sept. 10, 2010

#EXEL #XL184 #IMGN #T-DM1 #CLDX #CDX110

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