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Agreed..and signed. Thanks for the link.
Novartis cancels PH3 Dovitinib vs. Sorafenib...
"...drug did not meet its primary endpoint of progression-free survival compared to sorafenib in patients with metastatic renal cell carcinoma (mRCC) after failure with prior therapies."
Supposedly a trial in VEGFR TKI resistant patients, but as you can see below Dovi should be competitive with Sora. This could still be the case and the trial was stopped due to safety concern that Novartis will never disclose.
Dovitinib inhibits FGFR, PDGFR, VEGF, cKIT, FLT3, CSFR1, Trk and RET similar to Pona's hit list, but at much higher IC50 values.
Compare IC50: FGFR1 /FGFR2 / FGFR3 / FGFR3 / VEGFR2
Ponatinib 2 / 2 / 18 / 8 / 1.5
Dovitinib 13 / 21 / 18 / 470 / 5.4
Sorafenib 64 / 825 / 1019 / - / 28
http://www.fiercebiotech.com/story/novartis-buries-phiii-kidney-cancer-failure-behind-q2-successes/2013-07-19
It says for "Interim analysis of PK and toxicity data".
But could be a bad sign since trial since update was from February. Likely a safety concern, Dovitinib seems to have a poor safety profile (see link) and if combined with a typical EGFR rash then that would just about kill it.
http://jco.ascopubs.org/content/29/12/e340.full
Note '113 reported no rash at ASCO, Pona reports 5% Grade 3/4 on the label.
This study makes EGFR/FGFR combo even more clear....
Missed this one from March 2013.
http://www.nature.com/oncsis/journal/v2/n3/full/oncsis20134a.html
"...we suggest that treatment with combinations of EGFR and FGFR inhibitors may be superior to sequential treatment with an FGFR inhibitor."
Keep an eye on this Phase 1 trial by Novartis/ Genentech(Roche)combining gefitinib and dovitinib, results by end of year.
http://clinicaltrials.gov/show/NCT01515969
More hope for Pona in NSCLC...
Like the sound of FGFR3 inhibitors being for used for "other" resistant pathways (mentions EGFR) in lung cancer.
"These results identify an FGF9-FGFR3 signal as a primary oncogenic pathway for lung adenocarcinoma and suggest that this pathway could be exploited for customized therapeutic applications for both primary tumors and those that have acquired resistance to inhibition of other signaling pathways."
http://cancerres.aacrjournals.org/content/early/2013/07/18/0008-5472.CAN-13-0495.abstract
Changes to '113 trial...added 5th Cohort for brain mets...
Trial size increased from 130 to 175.
Narrowed cohort #3 to EGFR with T790M.
Added new cohort #5: NSCLC patients whose tumors exhibit ALK rearrangements and who have active, measurable brain metastases:
-Either crizotinib naive or resistant;
-Have at least one measurable brain lesion
-Previously untreated brain metastases with radiologically documented new or progressing brain lesions.
Sounds like 1st line ALK with brain mets to me.
Saw that...expands Pona's activity against other targets...
Check out Table 12 for comparison of GI50 in all four FGFR types for 7 different cancer indications against the competition: Cediranib, Dovitinib, Nintedanib, and Brivanib.
FGFR chapter for Pona just beginning.
Footnote-
IC50 is the maximal concentration of drug to cause 50% inhibition of biological activity of cancer cells.
GI50 is the concentration of drug to cause 50% reduction in proliferation of cancer cells i.e. growth.
ED50 refers to the dose of the drug which causes 50% response in a biological system or which treats effectively 50% population.
The Case for Pona in Alzheimer's...
Now that we have stirred the pot on Parkinsons, let's not overlook the even bigger elephant in the neurogenerative room. This study was published online on 7.4.13 and makes a strong case for use of TKI's (Nilotinib & Bosutinib) in Alzheimer's Disease. Summary of study excerpted below.
http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302771/full
The paper explained
PROBLEM
Alzheimer's disease (AD) is an aging disorder that leads to memory loss. AD is characterized by intraneuronal tangles containing hyper-phosphorylated Tau (p-Tau) and extracellular ß-amyloid (Aß) plaques, derived from amyloid precursor protein (APP) cleavage and accumulation of Aß. Abl is found within neuritic plaques and neurofibrillary tangles (NFTs) and activated (via phosphorylation) in AD post-mortem brains. Src tyrosine kinase (TK) is also recognized in AD pathology via interaction with Tau. Abl inhibition prevents Aß1–42 fibrils and hydrogen peroxide (H2O2)-induced cell death, and hippocampal injection of Aß fibrils leads to an increase of Abl levels. These data led to the hypothesis that tyrosine kinase inhibitors (TKIs) will activate parkin and facilitate autophagic amyloid clearance, thus preventing cognitive decline in AD models. We used several TKIs, including Bosutinib and Nilotinib, which penetrate the brain and induce autophagy in AD models and evaluated the effects of TKIs on parkin-mediated autophagic amyloid clearance in AD models.
RESULTS
We identified two FDA-approved drugs, Bosutinib and Nilotinib, as potential therapies for AD. Our results indicate that decreased parkin solubility decreases functional interaction with a key autophagy molecule, Beclin-1, while TKIs reverse parkin-Beclin-1 interaction in AD models, leading to autophagic clearance of amyloid proteins. TKI-induced decrease of intraneuronal Aß1–42 led to plaque disappearance while lentiviral production of intraneuronal Aß1–42 resulted in plaque formation. Importantly, parkin is required for autophagosome maturation and autophagic clearance and TKIs enhance amyloid clearance and cognitive performance in a parkin-dependent manner.
IMPACT
Our studies show that TKI could be a therapeutic strategy, via degradation of amyloid proteins, in neurodegenerative diseases, including AD. We identified two FDA-approved drugs as potential therapies for AD. TKIs are well tolerated in human leukaemia patients and could be used with a smaller dose over a longer period of time to prevent progression from mild cognitive impairment (MCI) to AD.
True the new patent seems to narrow the broader neurogenerative patent from Oct. '12 to just Parkinsons Disease.
In my opinion Ariad is attempting to capitalize on recent studies validating use of ABL inhibitor in PD, which obviously plays into Pona's wheelhouse. If we have BIC ABL inhibitor, and cross the BBB,unassisted, at ratios multiples higher than other ABL TKI's, it follows that Pona would be a major player in PD.
From the patent-
"c-Abl is a major regulator of parkin function and phosphorylates parkin on tyrosine 143. This phosphorylation inhibits parkin's E3 ubiquitin ligase activity leading to accumulation of AIMP2 and FBP1 and loss of parkin's cytoprotective function and cell death. One Abl inhibitor, STI-571 , has been found to maintain parkin in a catalytically active and neuroprotective state by preventing phosphorylation of parkin. As such, it is believed that inhibition of c-Abl presents a viable approach for the treatment of PD."
With that said, I agree this has a long way to go, but based on the the priority date of April 2011, I assume mouse models are well underway and human trials are a year or so away. Abstracts for AACR 2014 are due November 15th and could be revealing on this topic.
Not likely. For some yet to be discovered reason occurrence of both neurodegenerative diseases and cancers in single patient are very rare. Not sure that it matters for Pona, best to be effective in blood, tissue, and brain.
From study-
"Alzheimer's patients were half as likely to develop cancer.
Cancer patients were 35% less likely to develop Alzheimer's."
http://www.medicalnewstoday.com/articles/263177.php
The Pona data for BBB is in the patent...
Look at World Patent, page 88 in the description section (near the end). There is a chart showing blood and brain concentrations and this is where the 30mg dose is suggested.
Regarding Bafetinib and the BBB...
The PLOS study states a significant "fraction" of INNO-406 crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. So to be fair the PLOS study might raise Bafetinib's effective crossing of the BBB from 10% to 35% (see figure 1).
Most of what the PLOS study has to say about Bafetinib crossing the BBB was shown in a 2007 study which concluded "the concentration of both INNO-406 and imatinib mesylate in the brain was approximately 10% of the corresponding plasma concentration."
http://bloodjournal.hematologylibrary.org/content/109/1/306.full.pdf
In any case I hope my main point was clear, all other ABL-TKI's cross the BBB in fractions of plasma concentrations, Pona crosses in multiples. Meaning we can dial back an oral dose, not increase, require a combo, or use IV.
By the way Bafetinib was designed as 2nd gen BCR/ABL for PH+CML to be more effective than imatinib and some of its mutations, but it has been in the clinic since 2005 still with no approval in leukemia. I think they missed their window for 2nd gen resistance in CML and now Pona has shut the door on the way out.
A brief history of ABL-TKI's attempts across BBB...
[Quoted from multiple sources]
Imatinib - "The cerebrospinal fluid (CSF) concentration of imatinib is less than 3% that of plasma in patients."
"Nilotinib concentration in liver is approximately 9–11 fold higher than plasma but CNS exposure is limited with brain and spinal cord concentrations being only 6 and 5% of plasma levels."
"Dasatinib brain concentrations were, on average, 12- to 31-fold lower than in plasma (ie, brain/plasma ratio or brain penetrance of 3.2%-8.6%."
Bosutinb - "No radioactivity was detected in the brain, indicating that bosutinib did not pass the blood-brain barrier."
"Bafetinib (INNO-406) does not sufficiently cross intact or disrupted blood-brain barrier, and therefore, systemic administration of bafetinib is not recommended when investigating this drug as a treatment for brain tumours."
Sorafenib - "Blood/brain penetration was low as indicated by brain uptake less than 10 % of blood or plasma exposure."
"Ponatinib was 2.79 times greater in brain relative to blood on an area under the curve (AUC) basis and 2.26 times greater on a the basis of maximum concentration observed (Cmax). The observed elimination half-life was also longer in brain than in blood."
Let's tally the score...0-10% for all other TKI's versus 279% for Ponatinib. I think we have clear winner, and with what will surely be an exceptional safety profile at something like 20-30mg dose per day.
Here's another promising excerpt from Parkinson's patent...
We have also found that the concentration of ponatinib in the brain tissue of the subjects receiving 30 mg of ponatinib can significantly exceed the concentration needed to increase the protective function of the gene product, parkin, in brain cells, in subjects having PD.
These results indicate that in these experiments, exposure to ponatinib was 2.79 times greater in brain relative to blood on an area under the curve (AUC) basis and 2.26 times greater on a the basis of maximum concentration observed (Cmax). The observed elimination half-life was also longer in brain than in blood.
Ariad awarded world patent for ABL-inhibitor in Parkinson's...
Maybe premature to add the 6.3 million people in the world suffering from Parkinson's Disease to Pona's hitlist, but getting World Patent #WO2013101281 on July 4th is a first big step.
http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013101281&recNum=1&maxRec=249&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28ariad%29&tab=PCT+Biblio
RET total market is about 12,800 patients worldwide...
RET in MTC occurs in 70% for total of 4,500 pts. WW per year
RET in NSCLC (adenocarcinoma) occurs in 1.3% for total of 8,300 pts. WW per year
Just to keep FGFR potential in perspective...
Although Pona is a best-in-class pan-FGFR inhibitor, soon to be validated in vivo in numerous trials and studies, Ariad is keeping its near-term potential focused on the largest markets via ISTs.
FGFR1 in NSCLC occurs in 2% of WW pts., roughly 20,000 patients each year, similar to populations for either RET and ROS1.
FGFR1 in SCC occurs in 21% WW pts., over 100,000 per year.
FGFR2 in endometrial occurs in 30% WW pts., or 160,000 patients per year.
FGFR3 in Bladder occurs in 50% WW pts., or 190,000 patients.
FGFR1/2 in Breast occurs in 14% WW pts., but this yields almost 200,000 per year.
(Note: assume US values at about 40% of WW total for all of the above)
Phase 2 IST trials in SCC and Endo are underway and I expect we will see a trial in Bladder by year end, given huge unmet need. Although Breast may have the largest FGFR population the market is very competitive, with many types of treatments and established early detection eligible for surgery. I think ASCO 2014 will be big for Pona, especially in FGFR cancers (no offense to its activity KIT, RET, & FLT3 driven cancers).
New test methods for identifying ALK...
Should help find that 1% more ALK current studies have reported above the 5% consensus. May also help identify other cancers with ALK translocations, I've seen mentions of breast and GBM.
http://iaslc.org/assets/News-Releases/JTO/August-JTO-Nitta-new-methods-for-ALK-status-diagnosis.pdf
By the way HB's $3M booked in France was at the already assumed reduced price for EU. For my purpose I'm assuming EU price at 3/4 US, so $86k per year, and with a 150% US market size, sales will be double current ramp by mid-2014.
Sprinkle a little early EPIC efficacy on that and you see how we can have positive EPS in 3rd quarter of 2014.
Rationale for TKI's in Neurogenerative Diseases...
No specific use of Pona here, but if Nilotinib and Bosutinib show activity against Alzheimer's Disease you can be sure Pona will too and likely be more potent. Anyone know of data for plasma concentrations of Pona in brain vs. blood?
http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302771/pdf
New Paradigm for Switching TKIs in CML...
CML KOL's set the table for switching TKI therapy in recent study from June 26, 2013.
"BCR-ABL1 transcript levels =10% at 3 months, <1% at 6 months, and =0.1% from 12 months onward, define optimal response, while >10% at 6 months and >1% from 12 months onward define failure, mandating a change of treatment."
Note EPIC trial has secondary outcome measure of rate of BCR-ABL1 transcript levels <10% at 3 months, which could be reached by ASH in December.
http://www.ncbi.nlm.nih.gov/pubmed/23803709
"Game Over" for Synribo in CML....
Not that anyone was worried about Synribo, but these results make you wonder why they (Teva via Cephalon via ChemGenex)kept pursuing trials, approval, and sales after Pona data in mid-2011 left absolutely no margin for success.
Results reported June 17th from a study of Synribo(omacetaxine) in CML with 2 or more prior TKI's compared to Pona (PACE):
MCyR of 20% vs. Pona 64%
Grade 3/4 AE's:
Thrombocytopenia 67% vs. Pona 34%
Neutropenia 47% vs. Pona 16%
Anemia 37% vs. Pona 8%
Weaker and more toxic? As HB would say...game over.
http://www.ncbi.nlm.nih.gov/pubmed/23787123
New IST trial for Pona in FGFR2 Endometrial...
Reported by Biomaven on SI board.
Not yet enrolling, very small trial of only 15 pts., but primary outcome is ORR (CR+PR) at 6 months, so should have results at ASCO 2014.
Let's hope the Exclusion Criteria for 'Women and Minorities' is a typo, otherwise this trail could be enrolling for quite some time.
http://clinicaltrials.gov/ct2/show/NCT01888562?term=ponatinib&recr=Open&rank=3
JMP Conference coming July 9-10...
Any chance we show a little love and share breaking news with Mike King?
Second patent update issued this month...
Two patent amendments issued in June. The latest one, 8,470,851, dated June 25th has been split off from 8,114,874 which was considered press-release worthy last February for protection of Ponatinib. The title of the new one distinguishes 'pyridine' from previous 'pyridazine'. Any chemists care to elaborate?
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=ariad.ASNM.&OS=AN/ariad&RS=AN/ariad
Of minor note, I was unaware Ariad sued USPTO for 400 day extension of '874 patent. These extensions are customary due to delays in patent office review. For example the '167 patent approved June 11th includes a 587 day extension (beyond the standard 14 year term).
http://news.priorsmart.com/ariad-pharmaceuticals-v-kappos-l6wK/
Interesting that HB only sold 11k this month...
I assume he will double up in one of the remaining two months of the 105b-1 plan. What does he know about July or August?
Never heard of a CAGR of 141%...
Comparison of select biotechs and projected CAGR thru 2017:
Biotech as a whole 8.7%
AMGN 4%
BIIB 17.8%
CELG 25.5%
GILD 30%
ARIA 141%
ONXX 38%
REGN 16.2%
UTHR 7.6%
One of these is not like the others.
By the way, assuming a PE of around 25-30, a CAGR of 141% would turn current pps into $300 by YE'17.
Decent video interview on 2nd gen ALK inhibitors...
http://cancergrace.org/lung/2013/06/24/second-generation-alk-inhibitors/
The Mother of All Combos...
I know its faint but methinks I hear a call for a '113+Pona+Rida combo for EGFR-resistance in glioblastoma.
"Here, we have identified a transcriptional repressive mechanism by which EGFRvIII regulates PDGFRß, shown that EGFR-inhibited GBMs become PDGFRß-dependent for survival through mTOR-dependent transcriptional de-repression, and showed that abrogation of EGFRvIII and PDGFRß stop tumor growth, providing a strong rationale for combination therapy. These results provide the first clinical and biologic evidence for the concept of RTK “switching” as an EGFR TKI resistance mechanism in GBM, and provide a molecular explanation for how tumors can become “addicted” to a nonamplified, nonmutated, physiologically regulated RTK to evade targeted treatment."
-David Akhavan et al, From May 2013 issue of Cancer Discovery
We will see 3-mos EPIC data at ASH...
To reach the all important 12-mos MMR data set in 50% of patients by mid-'14 means you achieved 3-mos data before ASH '13 (Dec 7-10). One of the secondary endpoints of EPIC is to compare 3-mos pts. achieving <10% BCR-ABL to ABL transcript levels versus imatinib. I think CCyR and MMR data at 3-mos will also be reported, but these are not endpoints.
Abstracts for ASH are due August 8th, noticed by mid-October, and published in Blood online by mid-November. Of course EPIC data would qualify as Late-Breaking but only six are accepted each year, submitted by Oct. 29th and also published mid.-Nov.
http://clinicaltrials.gov/ct2/show/NCT01650805?term=ariad+pharmaceuticals&rank=9
Time for Harvey to sell 100K, 4 of 6.
Lyn indispensable for EGFR? Reminds me of certain combo...
Pona IC50 for Lyn is 0.24.
http://www.mdanderson.org/newsroom/news-releases/2013/cancer-promoting-protein.html
"Conservative" was poor choice of words...
Meant something more like precise, by disclosing rational basis for target and mutations, with strong predictive pre-clinical data. Shouldn't single out Novartis either, as far as big pharmas go they have one of the better R&D outfits. Better example would be that Clovis poster for CO-1686, lacking in thoroughness, and too selective, emphasizing safety data for lower doses together with efficacy on higher doses.
jq appreciate your thoroughness, hard to RECIST data...
I get your point about Criz...the heavily pre-treated study A only yielded 50% ORR, so LDK's 60% ORR starting to look more impressive. Still think LDK's toxicity is a little too retro.
I wouldn't assume anything about '113 in Criz-naive with only 4 patients. I've grown to be more trusting of Ariad's conservative data presentations over Novartis-types, so I'm still optimistic that '113 will have 70%+ RECIST ORR in Criz-resistant at ESMO.
Did you know if Chugai has any RECIST confirmed data?
I agree it's unfair to compare...
But I still maintain a "next generation" drug needs to show a 10% or better improvement in either ORR, PFS, or OS. And certainly not LDK's worse safety profile with more grade 3/4 AE's than Criz. Doesn't LDK's near equal ORR in Criz-resist and naive populations suggest mutations are being missed? But of course if AP26113 inhibits most mutants why is ORR at 75% against Chugai's 93%. I've heard some predicting '113 ORR will be higher at ESMO.
Regarding Criz I was referring to these studies:
Profile 1005 PH2 (ORR 61%) At least one prior line of chemo, 72% had 2 or more.
Profile 1007 PH3 (ORR 65%) All patients had received one prior chemo.
If Chugai data holds up I would consider it a true 2nd gen, and same for '113 with superior brain met activity and reasonable safety, if it holds ORR above 70% and shows PFS 10-20% better than Criz.
I would ask about Pona for neurogenerative diseases...
Related of course to the pending patent application.
If too specific then I'll settle for "what's the next IND and when will it be filed"?
Paper from Dr.Shaw supporting why '113 is BIC...
Having proven at ASCO that '113 is the safest with equal or better response rates, and best activity in brain, it remains to be seen how durable the responses will be. Assuming pan-inhibition leads to durability, I think this article by Dr. Alice Shaw supports '113's potential as BIC, inhibiting the key mutations (L1196M, C1156Y, and L1152R) equal or better than Criz/LDK/Chugai, and a few novel ones (G1202R and T1151T) more effectively.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385512/
Interesting to me that Dr. Shaw is so silent on '113 when this study practically calls for a dual ALK/EFGR inhibitor, and possibly a KIT/ALK combo (did I just heard a call for Pona/'113 combo?). Don't you think a combo that targets ALK/ROS1/EGFR/RET/FGFR2/KIT might be effective in lung cancer?...just saying. If this were the old days it would be a miracle drug for lung cancer and every patient would start on it.
I think the battle for best 2nd gen ALK inhibitors will be decided on durability of response, PFS and OS. I know '113 and LDK also have activity in brain mets, but moving the needle on PFS past 9.7 mos (Criz) will be the true test for a next generation ALK inhibitor. This means waiting another 12-18 months for '113 and Chugai/Roche to have such data to compare against LDK.
True I didn't study the trial's inclusion/exclusion criteria but still surprising that with IC50 for parental ALK at 4-5 times lower than Criz, LDK yields similar RR. I assumed Medscape did some comparison before making this post-ASCO presentation.
http://img.medscape.com/images/805/623/805623_slides.ppt
I see LDK will go head to head with pemexetred both in Criz naive and Criz resistant in the PH3 trials. in PH3 Criz showed PFS of 7.7 mos. vs. 4.2 mos. PEM, and ORR was 66% vs. 29% PEM.
Just my opinion but I think LDK's PH3 results will be similar to Criz results, not show a 2nd gen improvement.
Why is LDK378 considered 2nd generation ALK?
ORR (Criz-naive) is marginally better than Criz - 62% vs. 60.8%
PFS is less than Criz - 8.6 mos. vs 9.7 mos.
Grade 3/4 AE's are worse than Criz - 37% vs. 18%
Shouldn't "2nd gen" be used for drugs that have significant benefit over first generation. I guess any activity in Criz-resistant population (ORR of 59%) qualifies as 2nd gen until true 2nd gen (like '113) comes online.
I really don't see market share for LDK in Criz-resistant versus '113, and if CH542802 data holds up in Phase 2 for Criz-naive then LDK may go the way of Bosutinib in CML, fighting for last place against a well established 1st generation drug.
By the way why does the Chugai data from ASCO include responses from the same 43 of 46 patients with data cut-off of July 31, 2012. Not that there's anything wrong with publishing year old data at ASCO, but if 93% OR is accurate why wait a year to start Phase 2 trial?
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70142-6/abstract
I see Roche has taken over the new Phase 2 trial in Criz-resistant population, the drug is now called RO542802. Maybe it took a year to negotiate the collaboration?
http://clinicaltrials.gov/ct2/show/NCT01871805?term=CH5424802&rank=2