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1) According to the study, ALK translocations were found in 2.6% of BM of adenocarcinomas
2) ALK is rearranged in approximately 5% of adenocarcinomas
3) Dividing 2.6% by 5% = 52%
At ASCO, Ariad commented that 50% of patients that progress on Xalkori have brain mets. A recent study published by Comprehensive Cancer Center at the MedUni Vienna found that ALK translocations were found in 2.6% of NSCLC patients with brain mets. Since the ALK incidence rate is approximately 5%, my guess is that this how the 50% of ALK patients number is being derived.
The big unanswered question is whether the ALK rearrangement is present all along or whether this is a function of resistance. In the Vienna study researchers found that "changes to the ALK gene are also demonstrable in the brain metastases of lung cancers – and not just in the lung tumour itself" which seems to imply that the brain mets are present in ALK+ patients all along. If this is true, then using the drug that shows the best reponse against brain mets first, should lead to better overall outcomes for roughly half of ALK+ patients. The separate brain met cohort will hopefully tell us whether AP26113 is that drug.
ALK gene translocations and amplifications in brain metastases of non-small cell lung cancer
JQ, it's great to have your voice added to the ARIA discussion...especially now that you're long :)
While anecdotal, there are numerous reports that patients are finding it difficult to stay on LDK378 at the full 750mg dose. These early patient reports are starting to be borne out by the trial data. For example, at ASCO, Novartis reported a 60% overall response rate in 78 patients taking LDK378 at 750mg. But when you look at the 36 patients who received doses between 400mg-750mg, the response rate dropped to 52%. As patients don’t live in the abstract, I would imagine responses will be even lower outside of a clinical trial setting.
While AP26113 exceeds IC50s for all 11 EML4-ALK mutants for which it was tested, LDK378 appears to have a much narrower efficacy/toxicity window. Based on the pre-clinical data , this really shouldn't be all that surprising, particularly when it comes to the L1152R mutation (additional info on the role L1152R has in Xalkori resistance can be found at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278914/. Relative to LDK378, 113 also has a lower IC50 for wild-type EGFR which could translate into less severe AEs for both diarrhea and skin rash.
While it is true LDK378 has shown activity against brain mets, I'd be very interested to see the dose response relationship. According to Ariad, 50% of crizotinib resistant patients progress with brain mets so this could end up being a key point of differentiation between the two drugs. It also may afford AP26113 a possible path to a first-line setting.
As far as valuation goes, I believe the current market cap barely reflects Iclusig's value in 2/3rd line CML. As such, AP26113 is basically a free option - one that I believe will ultimately translate into significant upside to ARIA's share price.
Then again, the only thing I truly know for certain is that it will be interesting to see how this all plays out over the next 6-12-18 months.
Thanks for the heads up. I'll update the XOMA RMF to reflect same.
XOMA ReadMeFirst
(Update: XOMA’s May 10, 2013 Credit Suisse Presentation)
Hopefully, this RMF will save folks some time and make it easier to research the company. It is meant to be a convenient jumping off point but, of course, it's not a substitute for your own dd.
Company Overview
#msg-87804025 XOMA’s May 10, 2013 Credit Suisse Presentation
#msg-87745998 Q1 2013 Results and CC Notes
#msg-83090011 Archived Company Presentations
#msg-83090054 Credit Suisse Investment Thesis
#msg-83090160 Servier Partnership Terms
#msg-83091150 Recent Financings and Baker Bros Investment
#msg-85039491 RBC Capital Markets Global Healthcare Conference Notes
#msg-85514239 XOMA Major Shareholders
XOMA 052 (Gevokizumab) Overview
#msg-83090144 XOMA/Servier to commercialize gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders
#msg-83091229 IL-1B has emerged as a therapeutic target for inflammatory disorders
#msg-83091258 Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?
#msg-83090127 Current Clinical Trials
Uveitis Program
#msg-83091071 Uveitis Market Forecast
#msg-83090431 Uveitis of Behçet’s Disease Pilot Trial Results
#msg-83090221 FDA Grants Orphan Drug Status to Gevokizumab
#msg-83090262 Servier Initiates Behçet's Phase 3 Clinical Trial (EYEGUARD-B)
#msg-83090953 Phase 3 clinical trial in patients with non-infectious uveitis intermediate, posterior, or pan-uveitis (NIU) (EYEGUARD-C)
Proof of Concept Program
#msg-83106427 Phase 2 Study of gevokizumab in moderate to severe acne vulgaris
#msg-83122761 Results of Phase 2 Study for Moderate to Severe Acne Vulgaris
#msg-83091380 Phase 2 study of gevokizumab in active inflammatory, erosive osteoarthritis of the hand
#msg-83091342 Non-Infectious Anterior Scleritis selected as next PoC candidate
Diabetes Program
#msg-83090114 Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint
#msg-83091405 XOMA Discovers Two New Classes of Insulin Receptor-Regulating Antibodies
Cardiovascular Program
#msg-83091327 PoC Gevokizumab Study in Patients With a History of Acute Coronary Syndrome
Aceon Program (Perindopril/Amlodipine)
#msg-83091483 Aceon Phase 3 PATH Trial Meets Primary Endpoint
#msg-83091538 Credit Suisse' Take on the Aceon Opportunity
Competition
i#msg-83091092 Lux Biosciences declares intent to halt application efforts for uveitis treatment
#msg-83091763 Eyegate Pharma's pivotal Phase III study of EGP-437 in patients with anterior uveitis
#msg-83091599 XBiotech Announces Positive Phase II Results in Acne Vulgaris
XOMA ReadMeFirst
(Update: XOMA Q1 2013 Results and CC Notes)
Hopefully, this RMF will save folks some time and make it easier to research the company. It is meant to be a convenient jumping off point but, of course, it's not a substitute for your own dd.
Company Overview
#msg-83090011 Archived Company Presentations
#msg-83090054 Credit Suisse Investment Thesis
#msg-83090160 Servier Partnership Terms
#msg-83091150 Recent Financings and Baker Bros Investment
#msg-85039491 RBC Capital Markets Global Healthcare Conference Notes
#msg-85514239 XOMA Major Shareholders
#msg-87745998 Q1 2013 Results and CC Notes
XOMA 052 (Gevokizumab) Overview
#msg-83090144 XOMA/Servier to commercialize gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders
#msg-83091229 IL-1B has emerged as a therapeutic target for inflammatory disorders
#msg-83091258 Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?
#msg-83090127 Current Clinical Trials
Uveitis Program
#msg-83091071 Uveitis Market Forecast
#msg-83090431 Uveitis of Behçet’s Disease Pilot Trial Results
#msg-83090221 FDA Grants Orphan Drug Status to Gevokizumab
#msg-83090262 Servier Initiates Behçet's Phase 3 Clinical Trial (EYEGUARD-B)
#msg-83090953 Phase 3 clinical trial in patients with non-infectious uveitis intermediate, posterior, or pan-uveitis (NIU) (EYEGUARD-C)
Proof of Concept Program
#msg-83106427 Phase 2 Study of gevokizumab in moderate to severe acne vulgaris
#msg-83122761 Results of Phase 2 Study for Moderate to Severe Acne Vulgaris
#msg-83091380 Phase 2 study of gevokizumab in active inflammatory, erosive osteoarthritis of the hand
#msg-83091342 Non-Infectious Anterior Scleritis selected as next PoC candidate
Diabetes Program
#msg-83090114 Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint
#msg-83091405 XOMA Discovers Two New Classes of Insulin Receptor-Regulating Antibodies
Cardiovascular Program
#msg-83091327 PoC Gevokizumab Study in Patients With a History of Acute Coronary Syndrome
Aceon Program (Perindopril/Amlodipine)
#msg-83091483 Aceon Phase 3 PATH Trial Meets Primary Endpoint
#msg-83091538 Credit Suisse' Take on the Aceon Opportunity
Competition
i#msg-83091092 Lux Biosciences declares intent to halt application efforts for uveitis treatment
#msg-83091763 Eyegate Pharma's pivotal Phase III study of EGP-437 in patients with anterior uveitis
#msg-83091599 XBiotech Announces Positive Phase II Results in Acne Vulgaris
XOMA Q1 2013 Results and CC Notes
1) The company discussed, for the first time, the results of the Servier Ph2 follow-on trial in Behçet's. Of 21 pts enrolled, 17 were considered acute and 4 were "at risk." 11 pts had a vitreous haze score at enrollment that was greater than or equal to 2 which is also the enrollment threshold in the Eyeguard-A Ph3 trial. 8 of 11 patients (72%) experienced a 2 unit reduction. For reference, the primary endpoint for Eyeguard-A is the proportion of patients to see 2 unit improvement in their vitreous haze score day 56. The Ph3 Eyeguard-A trial is powered to show a 40% response so the 72% seen in this Ph2 data is quite encouraging. As pointed out in #msg-87720750 the assessment period in both Ph2 trial and the Ph3 are essentially the same: 56 days in EYEGUARD-A and 56 days after the 14-day loading-dose filtering period in the phase-2 study (i.e. 70 days in all in the phase-2 study).
For reference, the EYEGUARD program consists of three pivotal trials; EYEGUARD-A in patients with active disease is expected to read-out by year end; data from EYEGUARD-C, which is studying the effects of gevokizumab in a maintenance setting, is expected in 1Q14; and, EYEGUARD-B which is enrolling patients with Behçet's is expected to read-out last, in 2Q14. Per discussions with the FDA, the company will likely need to meet the primary endpoint in two of the three trials. The risk is that even though all three trials are in NIU, Eyeguard A and C have a different intent-to-treat population than that actually studied in the Ph2 trial. Of course, the trial for which we have the most data, Eyeguard-B, actually reads out last. However, even though the company is running three separate Ph3 trials, the trials are all in non-infectuous inveitis of which Behçet's uveitis is one of the most severe forms. As an investment, it seems logical that if Gevokizumab works in the most severe form of NIU (Eyeguard B) then it should work in the less severe forms (Eyeguard A,C) of the disease as well. Time will tell.
The company has expanded the number of trial sites in the US from 60 to 80 and expects to have a total of 140 sites in over 20 countries up and running in the next few weeks.
2) Of the 27 million people in the U.S. with osteoarthritis, approximately 1.8-2.2 million have erosive osteoarthritis of the hand (EOA). The company noted that recent research has highlighted the role of IL-1 beta in EOA disease progression. There are no therapeutic options available that work well for these patients, let alone a drug that can modify their disease.
The current PoC is targeting the 500,000 patients who have inflammatory EOA as evidenced by elevated C reactive protein (CRP). However, only about a quarter of the patients being screened for the Ph2 trial have elevated CRP levels. Consequently, the company announced a second PoC trial for EOA patients who do not meet the "active inflammatory" CRP threshold. According to the company, "This study will tell us if gevokizumab works in the broader EOA population as estimated to be 1.8 to 2.2 than people in the U.S. or they may tell us gevokizumab only works in the patients who are in inflammatory stage of the disease which might approximate about 500,000 patients." The second EOA trial in low CRP patients should provide better insight into the validity/necessity of the CRP biomarker.
To date, the company has enrolled 67/90 pts in the initial Ph2 EOA trial and anticipates top-line data by Labor Day.
3) The company continues to explore a commercial path forward in moderate to severe acne and, to that end, has consulted with ~100 dermatologists. The feedback has been positive and the company sees a possible role for gevokizumab in treating patients who have not yet been prescribed acutane, which has known toxicities. The company stated that next Ph3 trial will be in either erosive osteoarthritis or acne.
4) In 1Q13, the company burned ~ $15M and, as of March 31, 2013, had $70.4M in cash. The company expects to use $50M this year which would leave them with ~ $35M by year-end. Although the company stated they have sufficient funding through FY14, I would not be surprised if the company raised funding on a positive Eyeguard-A result (see previous discussion in #msg-85603458).
A copy of the 1Q14 transcript may be found on seeking alpha.
Once I have a chance to re-listen to the cc, I'll post an update to the XOMA RMF however here's my initial take-away:
1) For the first time, the company discussed the results of the Servier Ph2 follow-on trial in Behçet's. Of 21 pts enrolled, 17 were considered acute and 4 were "at risk." 11 pts had a vitreous haze score at enrollment that was greater than or equal to 2+ which is also the enrollment threshold in the Eyeguard A Ph3 trial. 8 of 11 patients (72%) experienced a 2 unit reduction. For reference, Eyeguard A is powered to show a 40% response. The primary endpoint for Eyeguard A is the proportion of patients to see 2 unit improvement in their vitreous haze score day 56.
2) The company announced a parallel PoC trial in erosive osteoarthritis (EOA) of the hand in patients who do not meet the "active inflammatory" enrollment threshold. If Gevokizumab proves active in this broader patient population, the market opportunity in EOA could expand from 500k to 1.8M.
Considering the Eyegate Ph3 trial only matched SOC, I'm wondering if XOMA will eventual run a trial in anterior uveitis?
I agree Berger definitely has a blind spot especially when it comes to taking company criticism (whether valid or not) as a personal attack. I think some of this can be explained by the fact that he's the founding CEO. This wouldn't be the first time a founder ends up defining their self-worth by the company they've created. Of course, the upside is that founding ceo's also often have the drive, focus and discipline needed to achieve some pretty amazing results.
I like the fact that Berger has put his $ where his mouth is....I don't know too many biotech CEO's who have invested their entire net worth in their company. It is what it is...just another plus/minus to factor into your investment decision.
Ok, I see that now. I still don't appreciate being lumped in with other peoples comments. I stand by my posts, not theirs.
Please do me the favor of responding to my specific posts because I think your criticism is way out of line.
I can't begin tell you how much I resent being compared to PPHM.
I have no problem with the anonymity. I have a problem with an unsubstantiated, over-the-top, opinion going unchallenged. Adam is no mere reporter, you don't get to hide behind the reporter label when you interject your own opinion. Case in point, after the article came out, Adam, not the anonymous source, tweeted that Iclusig is "Dirty" = toxic/intolerable and "won't gain enough 1st/2nd line use to justify $3.4B mktt cap".
btw, the reason I didn't offer an opinion on the sell-side analyst is because I really don't care what he/she said.
edit: Welcome Aboard!
Given the 20% drop in ARIA over the last week, I'm currently living in a bunker. Will let you know when I re-establish postal delivery.
Over the first 11 weeks, Iclusig NRx has totaled 331 or 30 a week. Over the last 4wks, NRX has averaged 44. Ariad estimates that ~ 2500 U.S. patients will switch their TKI this year. I believe the company only had ~ 150 US patients in its early access program so every indication is that Iclusig is taking market share; however, a weekly NRx of 30 (let alone 44) simply isn't sustainable.
Starting with the current NRx of 331 and assuming a weekly NRx of 30 for the rest of the year would result in Iclusig ending its first 12 months with an NRx of 1,561. Assuming NRx is a rough proxy for subscribers, this would mean that Iclusig would have to capture 60% of the patients who switch therapy. This isn't going to happen, consequently, I suspect over the short-term Iclusig NRx will decline from current levels. At that point, perhaps AF will write another article claiming a weak launch, however, the reality is the launch remains ahead of even the most optimistic analyst estimates.
Claiming Iclusig is "dirty drug" based solely on AEs seen in a 3/4 line setting is a really weak bear thesis (and poor journalism, imo). What matters as much to me as total scrips is the composition of those scrips. For example, how many are CP vs AP vs BP? What line of therapy? How many have the T315I mutation?
Here is what we do know. In a 3rd line CP setting, sprycel achieved a 16 month CCyR of 31% (i'm using sprycel data because the tasigna numbers were worse). In 2L, sprycel achieved a 15mo CCyR of 49% (which is a 58% improvement over the 31% CCyR sprycel got in 3L). In the PACE trial 93% of patients were third-line and 58% were fourth-line. Even though most of these patients had failed 3 prior TKIs, Iclusig still achieved a 46% CCyR at 15.3 months. So will Iclusig also see a significant improvement in a 2L setting? The short answer is we don't know yet however there were 19 second-line CP patients in the PACE trial (13 had previously been treated with imatinib only, 6 had previously received either sprycel or tasigna. Of these 19 patients, 84 percent achieved a MCyR.
Ultimately, this issue will only be resolved once Iclusig demonstrates that it can take 1/2L market share from sprycel/tasigna in CML-CP patients who do not have the T315I mutation. I believe the EPIC trial interim results will demonstrate both the superiority and safety necessary to achieve this result.
JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths
http://bloodjournal.hematologylibrary.org/content/119/12/2721.full.pdf
If Curis pursues CUDC-907 in B-cell lymphoma or multiple myeloma, the company would owe a royalty of 2.5X the total amount funded by LLS.
http://www.businesswire.com/news/home/20111130005368/en/Curis-Announces-Agreement-Leukemia-Lymphoma-Society-Develop
Clark here's the pertinent section from the GERN SA transcript:
The ET study was closed to new patients enrollment in December last year when we determined that we have sufficient number of patients to be confident that the hematologic and molecular response data that we had observed and reported at Ash. A total of 20 patients have been enrolled in the trial, which includes 18 patients with ET and 2 patients with polycythemia vera. Patients on the study may continue to receive imetelstat for up to 3 years according to the study protocol. We expect to report periodic updates from the study at future scientific meetings.
Most ET patients are served well with currently available therapies. The purpose of the study in ET was to provide proof of concept for the potential use of imetelstat as a treatment for various other hematologic myeloid malignancies, including myelofibrosis, myelodysplastic syndromes and acute myeloid leukemia. However, the ET data exceeded our expectations, and we are currently working with expert advisers to assess whether there is any potential for the further development of imetelstat in ET.
http://seekingalpha.com/article/1270581-geron-management-discusses-q4-2012-results-earnings-call-transcript?part=single
Unless i misheard the cc, they enrolled 18 ET and 2 PV and that's it. There was mention of the ET results exceeding expectations and as a result they were now considering actually pursuing ET...how novel, lol.
Nope, they stopped the ET trial at 20 pts. So other than setting-up ISTs in AML and MDS and monitoring the MF IST, they aren't doing anything. About the only good news in this scenario is that they aren't wasting the $90M chasing solid tumors.
The GERN CC was frustrating. An updated analysis of the NSCLC data using a new assay to measure telomere length found that the "magnitude of the treatment effect in patients whose tumors had short telomeres was not reproduced." Also, despite early positive data, the company has decided not to pursue multiple myeloma due to the difficulty in combining Imetelstat with existing SOC due to potential overlapping toxicity issues.
The company is waiting to start a myelofibrosis trial until they get a read-out from the myelofibrosis IST. This data is not expected until year-end so a company sponsored trial is not likely until 2014.
Investigator sponsored trials in AML and MDS are anticipated in 2013 but with the company sitting on $90M, I am surprised by the decision not to run any company sponsored trials in 2013.
XOMA ReadMeFirst
(Update: XOMA Major Shareholders)
Hopefully, this RMF will save folks some time and make it easier to research the company. It is meant to be a convenient jumping off point but, of course, it's not a substitute for your own dd.
Company Overview
#msg-83090011 Recent Company Presentations
#msg-83090054 Credit Suisse Investment Thesis
#msg-83090160 Servier Partnership Terms
#msg-83091150 Recent Financings and Baker Bros Investment
#msg-85039491 RBC Capital Markets Global Healthcare Conference Notes
#msg-85514239 XOMA Major Shareholders
XOMA 052 (Gevokizumab) Overview
#msg-83090144 XOMA/Servier to commercialize gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders
#msg-83091229 IL-1B has emerged as a therapeutic target for inflammatory disorders
#msg-83091258 Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?
#msg-83090127 Current Clinical Trials
Uveitis Program
#msg-83091071 Uveitis Market Forecast
#msg-83090431 Uveitis of Behçet’s Disease Pilot Trial Results
#msg-83090221 FDA Grants Orphan Drug Status to Gevokizumab
#msg-83090262 Servier Initiates Behçet's Phase 3 Clinical Trial (EYEGUARD-B)
#msg-83090953 Phase 3 clinical trial in patients with non-infectious uveitis intermediate, posterior, or pan-uveitis (NIU) (EYEGUARD-C)
Proof of Concept Program
#msg-83106427 Phase 2 Study of gevokizumab in moderate to severe acne vulgaris
#msg-83122761 Results of Phase 2 Study for Moderate to Severe Acne Vulgaris
#msg-83091380 Phase 2 study of gevokizumab in active inflammatory, erosive osteoarthritis of the hand
#msg-83091342 Non-Infectious Anterior Scleritis selected as next PoC candidate
Diabetes Program
#msg-83090114 Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint
#msg-83091405 XOMA Discovers Two New Classes of Insulin Receptor-Regulating Antibodies
Cardiovascular Program
#msg-83091327 PoC Gevokizumab Study in Patients With a History of Acute Coronary Syndrome
Aceon Program (Perindopril/Amlodipine)
#msg-83091483 Aceon Phase 3 PATH Trial Meets Primary Endpoint
#msg-83091538 Credit Suisse' Take on the Aceon Opportunity
Competition
i#msg-83091092 Lux Biosciences declares intent to halt application efforts for uveitis treatment
#msg-83091763 Eyegate Pharma's pivotal Phase III study of EGP-437 in patients with anterior uveitis
#msg-83091599 XBiotech Announces Positive Phase II Results in Acne Vulgaris
So ala Jim Carey you're telling me there's a chance. :)
Clearly these are two very different MOAs. However, given the sheer number of MPN-associated mutations my guess is that it is going to take more than just targeting JAK2 which is one of the reasons I find GERNs approach of targeting neoplastic progenitor cells so interesting. Now, whether this will actually translate from ET to MF is the big question but like mcbio i have a soft spot for ugly ducklings with a lot of cash, low market caps and promising early data.
I'm not sure spleen size data would change the investment thesis as spleen response (as well as reduced allele burden) has shown very little prognostic value. For that matter, I'm not even sure JAK2 is even the right target given that in the Ph3 trial Jakafi also demonstrated quite good results in 11 patients without the mutation (RR=51%). While JAK2 mutation is critical for MPN appearance, there is some evidence that JAK2 actually arises as a secondary mutation.
Considering Jakafi's tox/safety issues (perhaps in part related to the drugs inhibition of wild-type JAK2 and JAK1) and lack of molecular response, doesn't that at least open the door for a 2nd drug?
So my "results are compelling" line gives you little comfort, hey.
What I'm hanging my hat on is that Behçet's isn't a different disease it's just the most severe form of non-infectious uveitis. The rational is that if it works in the worst case scenario then it "should" work in less severe forms of the same disease. That being said 7 pts isn't a lot to go on but the results are really unambiguous - either you can see or you can't.
Although the lack of direct PoC data has kept me from increasing my position, I'm comfortable with the risk/reward given that you are getting a Phase 3 asset, with an SPA in place, for a company with an EV of ~ $110M.
edit: just saw your follow-up post so I'll answer it here. My understanding is that the drug is approvable based on Eyeguard A and C, together, or either A or C but with B. So three possible "approvable" trial combinations AC, AB, CB.
yea, the initial pilot study consisted of only 7 patients in Turkey...so there's that, lol. The results were quite compelling though:
- Intraocular inflammation began to resolve in all 7 patients on Day 1, with a median time to first response of 4 days (range 1 to 14 days)
- Complete resolution of retinal findings was achieved in 4 to 21 days (median 14 days)
- Five out of 7 patients were in remission when they reached the Day 28 visit.
They have a strong balance sheet which should get them through all three Ph3 read-outs. The erosive osteoarthritis PoC data may offer an upside surprise in July/Aug time-frame plus any progress on the ultra-orphan indications could move the dial without having to risk the Eyeguard A binary.
XOMA ReadMeFirst
(Update: Notes from 02-26-2013 RBC Capital Markets Global Healthcare Conference )
Hopefully, this RMF will save folks some time and make it easier to research the company. It is meant to be a convenient jumping off point but, of course, it's not a substitute for your own dd.
Company Overview
#msg-83090011 Recent Company Presentations
#msg-83090054 Credit Suisse Investment Thesis
#msg-83090160 Servier Partnership Terms
#msg-83091150 Recent Financings and Baker Bros Investment
#msg-85039491 RBC Capital Markets Global Healthcare Conference Notes
XOMA 052 (Gevokizumab) Overview
#msg-83090144 XOMA/Servier to commercialize gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders
#msg-83091229 IL-1B has emerged as a therapeutic target for inflammatory disorders
#msg-83091258 Is Gevokizumab a “best-in-class” anti-IL-1ß therapeutic antibody?
#msg-83090127 Current Clinical Trials
Uveitis Program
#msg-83091071 Uveitis Market Forecast
#msg-83090431 Uveitis of Behçet’s Disease Pilot Trial Results
#msg-83090221 FDA Grants Orphan Drug Status to Gevokizumab
#msg-83090262 Servier Initiates Behçet's Phase 3 Clinical Trial (EYEGUARD-B)
#msg-83090953 Phase 3 clinical trial in patients with non-infectious uveitis intermediate, posterior, or pan-uveitis (NIU) (EYEGUARD-C)
Proof of Concept Program
#msg-83106427 Phase 2 Study of gevokizumab in moderate to severe acne vulgaris
#msg-83122761 Results of Phase 2 Study for Moderate to Severe Acne Vulgaris
#msg-83091380 Phase 2 study of gevokizumab in active inflammatory, erosive osteoarthritis of the hand
#msg-83091342 Non-Infectious Anterior Scleritis selected as next PoC candidate
Diabetes Program
#msg-83090114 Phase 2b trial of XOMA 052 in Type 2 diabetes patients did not achieve the primary endpoint
#msg-83091405 XOMA Discovers Two New Classes of Insulin Receptor-Regulating Antibodies
Cardiovascular Program
#msg-83091327 PoC Gevokizumab Study in Patients With a History of Acute Coronary Syndrome
Aceon Program (Perindopril/Amlodipine)
#msg-83091483 Aceon Phase 3 PATH Trial Meets Primary Endpoint
#msg-83091538 Credit Suisse' Take on the Aceon Opportunity
Competition
i#msg-83091092 Lux Biosciences declares intent to halt application efforts for uveitis treatment
#msg-83091763 Eyegate Pharma's pivotal Phase III study of EGP-437 in patients with anterior uveitis
#msg-83091599 XBiotech Announces Positive Phase II Results in Acne Vulgaris
XOMA Notes from RBC Capital Markets Global Healthcare Conference
Update on Ph3 Uveitis Trials
Eyeguard A (in active setting) data is expected at YE.
Eyeguard B (in behcets) data is expected mid-14.
Eyeguard C (maintenance setting) data is expected Q1 14.
Servier is reponsible for the first $50M in trial costs after which expenses are split 50/50. Based on discussions with the FDA, the company feels an NDA can be filed with results from any two of the three Ph3 trials. XOMA maintains rights in the US and Japan and fully intends to commercialize Gevokizumab in US. The 150,000 US pts are treated by approximately 170 specialists which lends itself to a very targeted salesforce. While the company did not discuss its pricing/commercialization plans, they intend to price Gevokizumab as a "biologic" (which I assume to mean $$$) and feel that uveitis could be a very large market for Gevokizumab .
The CEO touched on Servier's 21 patient follow-on trial that preceded the Eyeguard B Ph3 trial. While the data has not been published, the results from this trial precipitated Servier's decision to move quickly to Ph3.
As far as the Ph2 PoC trials go, the company was "encouraged" by the recently announced results (#msg-83122761) from the Ph2 acne vulgaris trial however feel that a higher dose/frequency will be needed in this indication. The company is currently assessing the commercial path forward.
Ph2 data from the Erosive Osteoarthritis of the Hand trial is anticipated mid-2013. This is a large (4 million) market with few treatments options. The company hopes that the PoC data will demontrate that this indication is driven by IL-1B (#msg-83091229) and, if so, feel it could represent the second significant opportunity for Gevokizumab.
In December, the company announced, in partnership with the National Eye Institute, a third (#msg-83091342) Ph2 PoC trial. The trial is in non-infectious anterior scleritis and data is expected by year end.
One interesting development is that the company is currently pursuing several ultra-orphan indications which, if successful, could potentially bring Gevokizumab to market even earlier than the 2015 time-frame in Uveitis.
Once again the company confirmed its desire to advance the XMET A and S program to the point where it can be partnered. The company re-iterated its interest in developing XMET D (the insulin receptor antagonist) on its own.
The company did not provide an update on the partnering status of the Servier licensed ACE inhibitor.
a couple of additional ARIA thoughts...
I was surprised to learn that out of 155 NRx only 50 were from the early access program. So 2:1 new scripts are from pts who weren't in the PACE clinical trial. Additionally 40% of NRx are already coming from community oncologists where I was initially concerned there would be slow uptake. Add in the fact that IMS is only capturing 45% of scripts and the my take is the launch is significantly ahead of consensus.
Vilcabamba aka the Valley of Longevity is an area with purportedly the oldest inhabitants in the world...just my (obviously obtuse) attempt at levity.
Based primarily on the ASH data, I started a position in GERN ($1.64). I thought it would fit in nicely with a few of my other beaten down bio's namely ARQL and XOMA. Here are some of the potential catalysts that could move the dial in 2013:
1) Expect preliminary data from a Mayo Clinic pilot study of imetelstat in patients with myelofibrosis
2) Based on the Mayo Clinic study, expect company to start a Phase 2 study in myelofibrosis.
3) Expand investigator-sponsored trials in 2013 to other hematologic myeloid indications, including AML.
4) Expect full clinical data from all patients enrolled in the multiple myeloma trial will be available in 2013 (Preliminary data from this study showed a rapid and significant decrease in myeloma progenitor cells that were detected in the blood over the course of imetelstat treatment in eight out of nine patients)
5) Expect the company to present data from a pre-specified sub-group analysis which suggested that imetelstat-treated NSCLC patients whose tumors had short telomeres at baseline experienced a clinically meaningful, statistically significant increase in PFS compared to patients in the control arm (n = 19; hazard ratio = 0.32; p = 0.042), which was not observed in imetelstat-treated patients whose tumors had medium-to-long telomeres (n = 38; hazard ratio = 0.83; p = 0.62).
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Open Issues/Risks/Questions:
When will they have a refined assay to prospectively measure telomere length in individual patient tumor samples? How will this impact their decision to run additional trials in solid tumors that have short telomeres?
What is the possibility of using imetelstat in earlier lines of therapy and/or in combination? (need to review AE profile in greater detail)
Why the lack of efficacy in solid tumors as compared to hematological indications?
Competitive Analysis - Review/Compare imetelstat results to reduction in JAK2 V617F allele burden in Jakavi myelofibrosis trial
I'm assuming peak sales in CML of $1.8B by 2020. To put $1.8B in perspective, that's about the revenue Tasigna and Sprycel generated in 2012.
At today's market cap, that's roughly a 2X multiple which I expect will expand as market uncertainty surrounding sales/gleevec going generic diminishes. Warning label or not, Iclusig is the best drug in a 5+ billion dollar market.
In my base case, I'm not currently assuming any revenue beyond CML.
I'm also invested in ARQL so, at this point, I'll take any sign of success :) I haven't seen the IC50 values on ARQ087, so, I'm not sure what they've got. I do think Ariad's pan-FGFR is the right approach in squamous cell carcinoma.
A couple of thoughts, first, i know i've been pounding the table on this for several years now but ponatinib is just a beast of a drug. It's far from just a Bcr-Abl inhibitor and potently inhibits FLT3, RET, KIT, and FGFR1 with IC50s of 15, 8, 7, and 21 nM, respectively. With regard to FGFR specifically, Ponatinib is a pan-FGFR inhibitor and is active across FGFR1-4. FGFR certainly appears active in a number of cancers:
"FGFR1 is amplified in 22% of squamous cell lung cancers and 10% of breast cancers. FGFR2 is amplified in 4% of breast cancers, 3-25% of gastric cancers and in colon cancer. In addition, activating mutations in FGFR2 and FGFR3 have been found in 10% of endometrial cancers and ~60% of non-muscle invasive bladder tumors, respectively. FGFR3 is aberrantly expressed in the 15% of multiple myelomas that carry the t(4;14)translocation and is mutated in approximately 5% of these cases. Finally, activating mutations in FGFR4 have been identified in 7.5% of primary rhabdomyosarcoma tumors and FGFR4 is overexpressed and has been shown to play a role in prostate, colon and liver cancers." (See Molecular Cancer Therapy Published January 11, 2012)
Being amplified in 22% of squamous cell carcinoma's, FGFR1 represents one of the first potential targets in squamous cell lung cancer - the second most common NSCLC subtype comprising 25% of NSCLC. Here's the link to Ariad's ASH 2010 poster of Ponatinib/FGFR http://bit.ly/V4UqKw Also, Sally's Pharma Strategy Blog has had an interesting series of posts on the importance of FGFR1 in squamous cell lung cancer.
A Phase II Study of Ponatinib in Advanced Squamous Cell Lung Cancers With FGFR Kinase Alterations is starting at Dana-Farber. The trial is genotyping for FGFR1 amplification as well as FGFR2/FGFR3 mutation. It will be interesting to see whether Ariad's pan-FGFR inhibitor approach will meet with greater success than one that targets FGFR2/3 specifically. However, pre-clinical data presented by Dana-Farber's Rachel Liao demonstrated that ponatinib is a potent FGFR2/3 inhibitor at IC50 10-50nM begins about 9 minutes in...also the Q&A session at the end)
Is there an opportunity for a FGFR2 specific inhibitor (eg ARQ087)? With additional trials perhaps specific FGFR inhibitors will prove to be targets for specific cancers, however, at this point, the Dana-Farber trial is taking the pan-inhibitor approach. Although, an interesting case study in head and neck squamous cell cancer is discussed beginning around the 12 minute mark.