Category Archives: $GILD

Gilead and the silly spat over Solvadi pricing

Dear readers and clients of sugarconebiotech.com,

Sunday’s NY Times did us the favor of moving the discussion about Sovaldi from treatment of HCV to HCV cure (nyti.ms/1tHcFIw). It’s about time…

We present a compelling report from Dr. Paul De Santis on the valuation and future of Gilead Sciences (GILD): Alpha BioPharma Evidence-Driven Rebuttal to Morgan and Goldman, Summary & Marketing Report.

On the heals of their impressive quarterly earnings and heading toward a transformative year, Gilead faces fundamental issues. Dr. De Santis uses comprehensive and relentless analysis, deeply vetted, to trace the paths Gilead may take, and argues that bearish analyses from Morgan Stanley, Goldman Sachs and others have led the Street to fundamentally undervalue this innovative, aggressive and ultimately triumphant company.

In the full report Dr. De Santis covers critical topics including

      M&A:  GILD will have the capacity to repurchase their entire market cap by 2020.

      HCV PRICING: Sovaldi pricing pressure will ease as the discussion shifts to cost per cure, not cost per treatment. Further, the emerging HCV competition (MRK, BMY, ABBV) has little incentive to discount price – consensus forecastsrely on premium pricing.

      HCV, EMERGING MARKETS: Sovaldi has first mover advantage in 26 Emerging Markets. The pricing model/methodology presented in this report was confirmed by GILD management – no sell-side firm has put together such a comprehensive model on E.M. 

      PIPELINE: Gilead will leverage $100B in FCF to accelerate their transformation into a premier Oncology franchise

      SUSTAINABILITY: As we’ve seen in other chronic diseases (MS, RA) the arrival of transformative therapies will drive market expansion over many years

If you maintain or trade positions in GILD, it’s competitors, partners or takeover targets I kindly suggest you acquire his detailed 145 page report. Pricing and download information are available directly from Dr. De Santis at drpauldesantis@alphabiopharmaadvisers.com. In addition to the report Dr. De Santis will send you real-time updates from the critical upcoming medical conferences (ASH, the AASLD Liver conference, CHEST, and ESMO) and important updates related to GILD and its’ competition through year-end.

We support this report based on the very high quality and content and our respect for the work of Dr. De Santis and his firm AlphaBioPharma.

To be fair, we are also long GILD.

Combination therapies for B cell lymphoma, part 2

Combination therapies for B cell lymphoma: CC-292 and idelalisib.

Lets begin by recapping where we were yesterday. We reviewed ibrutinib, the clear frontrunner in the race to bring new targeted oral therapies to B cell lymphoma physicians and patients. Ibrutinib is being developed by Pharmacyclics and Johnson & Johnson’s (JNJ) Janssen division, and was recently approved for the treatment of MCL. The drug is moving forward in many clinical trials spanning the B cell lymphoma space, and most of these trials are done in combination with other therapeutics, notably the antibody therapy rituximab (Rituxan). None of the trials are being run as collaborative efforts with other companies with one exception, a collaboration put in place with Onyx (now part of Amgen). None of the combinations are wholly owned by Pharmacyclics (PCYC) and JNJ. The interesting question of how best to tackle the cost of very expensive combo therapies in the oncology marketplace was raised.

Gilead (GILD) has developed the very exciting PI3Kdelta inhibitor, idelalisib (access to a recent review is here). Idelalisib data generated at lot of buzz at the American Society of Clinical Oncologists meeting (ASCO) and at ASH. While generally considered somewhat inferior to ibrutinib as a monotherapy, the phase 3 data in combination with rituximab was striking. The trial was run in rrCLL patients who had failed prior therapies (rituximab or chemo), so these are patients quickly running out of options. The ORR was 81%, but what was really impressive was the impact on PFS and OS. At 24 weeks twice as many patients were progression free in the idelalisib plus rituxumab arm (95%) versus the rituximab alone arm (46%). We’ll have to see how this therapy holds up, and we can expect interesting data at the 2014 conferences.

But back to our question for 2014 and beyond: how will combination therapies continue to develop for the treatment of lymphoma? Lets look at Gilead’s active clinical trials for idelalisib – note that some of these trials have already read out results.

Trial Number
Phase
date filed
Combination
Indication
NCT01732913311/14/2012rituximabrr iNHL
NCT0153951232/12/2012rituximabrrCLL
NCT0120393029/15/2010rituximabuntreated CLL, SCL
NCT01980875311/5/2013rituximabuntreated CLL
or chlorambucilÿ
NCT01732926311/14/2012bendamustine/rituximabrr iNHL
NCT01980888311/5/2013bendamustine/rituximabuntreated CLL
NCT0156929533/27/2012bendamustine/rituximabrrCLL
NCT0164479917/17/2012lenalidomide/rituximabrrFL
NCT018384341,24/19/2013nonerrMCL
lenalidomide/rituximab
NCT0165902138/3/2012ofatumumabrrCLL
NCT0179647022/19/2013GS-9973rrCLL,MCL,iNHL,DLBLC
NCT0108804811/12/2010RituximabrrCLL or rrMCL or rr iNHL
Bendamustine
Ofatumumab
Fludarabine
Everolimus
Bortezomib
Chlorambucil
ÿLenalidomide
Rituximab + Chlorambucil
Lenalidomide + Rituximab

At first glance this looks a lot like the list of trials listed for ibrutinib, and it is very similar. We see multiple combo trials with anti-CD20 mAbs (rituximab, ofatumumab), and several trials with Celgene’s lenalidomide (Revlimid), approved for MM. Again the choice of lenalidomide is interesting. The combination makes good sense biologically – lenalidomide should impact cells lodged in the bone marrow, where they would otherwise be resistant to anti-CD20 or idelalisib therapy. The question is how well is this combination therapy tolerated. The other interesting observation is that there are a fair number of trials in which the partner therapy is a chemotherapy (fludarabine, chlorambucil, bendamustine). Now these are all careful targeted to specific lymphomas in the last trial listed, NCT01088048, and you can look at the details here. I think this suggests that in addition to the high impact rituximab combinations, GILD is banking on seeing good efficacy in combination with standard chemotherapies. If so this will give the company an effective marketing and pricing edge.

Finally, and sensibly, we see a clinical trial in combination with Gilead’s own Syk inhibitor GS-9973. Gilead has advanced this inhibitor while also conducting a well publicized hunt for a BTK inhibitor to license, apparently without luck (and really, there just aren’t many good ones). The idea here is to knock out the Syk signaling to BTK, thus mimicking the effect of ibrutinib, in combination with eliminating PI3Kdelta signaling. If the combo is synergistic, and (importantly) well tolerated, GILD may be sitting on a unique therapeutic option. Again thinking of the marketplace, this could provide leverage with physicians and payers, although no one is suggesting that Gilead won’t price a combo as high as possible, as shown by the recent pricing of its HCV cocktail – and that drug at least can induce outright cures.

This brings us to Celgene, who is attempting to build combination therapies for lymphoma that it can control. Celgene is well behind ibrutinib in their development of CC-292, acquired with the Avila deal. Recently however they have adjusted the dosing schedule (to twice a day: bid) and are seeing reasonable ORRs between 55 – 67% depending on dose, as reported at ASH. The bid dosing regimens produced sustained responses through 7 months.

What is so interesting about the Celgene program is shown in the following table.

Drug
Trial Number
Phase
date filed
Combination
Indication
CC-292NCT017665831b10/29/2012lenalinomiderr NHL
CC-292NCT01732861111/14/2012lenalinomiderr CLL, SCL
CC-292NCT01744626112/5/2012rituximabrr CLL, SCL
AVL-292NCT0135193515/10/2011nonerr NHL, CLL, WG
lenalinomideNCT014006851,2April/May 2011bendamustine/rituximabCLL
and
NCT01558167
lenalinomideNCT0193800139/5/2013rituximabrrNHL, rrFL
lenalinomideNCT0119957528/31/2010rituximabrr CLL
lenalinomideNCT0155677633/14/2012nonehigh risk CLL

What we see here is a nice focused effort on bringing forward CC-292 with perhaps lenalinomide. I don’t know the regulatory hurdles imposed since the withdrawal of lenalidomide from a CLL trial earlier this year (but please comment if you do), and so the issue may be moot, but the idea is a good one – to rationally develop combinations that are wholly owned.

We can make some predictions.

JNJ will buy a clinical stage compound suitable for further development with ibrutinib. This could be an antibody targeting B cell lymphoma antigens (CD20, CD22, CD19, etc) or another small molecule asset.

Celgene will make similar moves but may take assets at a slightly earlier stage, maybe IND ready or Phase 1.

Gilead will continue development of its Syk inhibitor, but I suspect will also license clinical stage assets in order to diversify around idelalisib.

Assuming success in the early stage studies in relapsed/refractory patient populations, Gilead will aggressively position idelalisib for use with chemo in treatment naive patients.

If you have different ideas feel free to send those along. Next there will be just a short take on Abbvie, as they are on a slightly different course.

stay tuned.

LINKS TO THE #ASH13 ABSTRACT PREVIEW CHAPTERS @ SUGAR CONE BIO

ASH13 previews

Part 8.   ABT-199
Part 7.   CAR-T tech                        

Part 6b. new targets for Myelofibrosis           

Part 6a. Jak inhibitors in Myelofibrosis                       

Part 5.   Biologics for Non-Hodgkin Lymphomas              

Part 4.   New & noteworthy: CLL etc             

Part 3.   Btk and PI3K inhibitors for CLL      

Part 2.   Ibrutinib                              

Part 1.   Idelalisib

pre-ASH post on ADC technology:  here                         

ASH 2013 preview: Myeloproliferative Neoplasms, New Targets

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)
Part 6b. Myelofibrosis and related Myeloproliferative Neoplasms: Phase 1 and preclinical updates from ASH 2013.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
 
Back to it. In part 6a we looked at the phase 2/3 studies, and these are certainly focused on Jak inhibition, for reasons we discussed in part. Its worth noting that Jaks are a class of signaling proteins that hybridize shamelessly and because of this blocking any given Jak (Jak1, Jak2, Jak3, Tyk2) will necessarily block the activity of others in the context of signaling that requires hybridization. Conversely it has been demonstrated that blocking any given Jak may not be effective in settings where other family members can substitute. As always, it is complicated.
 
It has been mentioned that Jak inhibitors are not considered disease modifying or curative. They offer symptomatic relief, which relieve the pathological degradation of the bone marrow, and can do so for extended periods, as has been demonstrated with ruxolitinib. In this sense the treatment paradigm is not so different from some other targeted cancer therapies, where the name of the game is to keep the wolf from the door, at least for a time.
 
Regardless of the limited potential, Jak inhibitor development continues at a brisk pace, as demonstrated in the previous section. In earlier development we find yet more Jak inhibitors. Gilead will present data from the phase 1/2 trial (with extension) of the Jak1/2-selective inhibitor, momelotinib (Abstract #108). Confusingly, this trial used some new (to me) endpoints. One was a reduction in “palpable splenomegaly” which suggests the spleen was not imaged (?). Second (and useful I think) was “transfusion independence”. I like this because it clinically measures the impact of treatment on the most pathologically relevant endpoint, loss of RBCs and platelets in circulation. What is even more interesting about this trial is the extension data, showing a “median spleen response” of 324 days, with pretty huge variance. As noted with ruxolitinib, the variance cannot be traced to the presence or absence of Jak2 V617F mutation - I suspect Gilead will work to sort this out pretty quickly, so that bears watching unless of course the variance is due to the manner of measurement!
 
Early trial data will be reported for BMS911543, another Jak2-selective inhibitor (Abstract #664). Note that Jak3 and Tyk2 are hit with IC50s less than 100nM, so selectivity will depend on actual exposure, which is data not available yet. Anyway, the drug is given BID and the goal of the trial is to establish an MTD (not reached). Early efficacy data included analysis of responses of patients who had received a prior Jak inhibitor. Symptoms were well controlled and the spleen volume response (> 35% reduction in splenomegaly) was dose responsive – up to 70% of patients responded at the highest doses (note: small sample size). AEs were were the usual diarrhea, nausea and cytopenias. The investigators will update with data from 84 patients at the meeting.
 
Eli Lilly will present data from the LY2784544 phase 1 dose escalation trial (Abstract #665). Of note, this drug is described as being “selective” for the V617F mutant of Jak2. They are enrolling 38 patients (most MF, some PV) at 30 -300 mg per day, although at 200 mg and above they hit liver tox (grade 3 serum creatinine elevation) and the MTD is established at 120 mg/day. Other AEs are typical of the class and not severe. We are introduced to yet another way of measuring splenomegaly, this time as “spleen length”. There was a >50% improvement in 56% of the evaluable patients, furthermore, >50% of patients reported improved symptoms by TSS. An update is promised for the meeting.
 
Novel inhibitors are finally moving through preclincal and early clinical evaluation. Geron has a novel telomorase inhibitor, imetelstat, a lipid-conjugated oligonucleotide inhibitor of human telomerase (Abstract #662). Early data are impressive. AEs were modest, and responses (44%) included a fair number that appeared to be CRs or PRs. Here I quote: 
 
“The four (22%) CR patients experienced reversal of BM fibrosis and recovery of normal megakaryocyte morphology. Two CR patients were transfusion-dependent at baseline and became transfusion-independent … Among 13 patients with leukocytosis, 10 (77%) normalized their count or had >50% reduction. Eleven (61%) patients had complete or partial resolution of leukoerythroblastosis.”
 
Thats pretty impressive. The downside is that this was a small single center open label trial, so really, we just have to wait and see.
 
For an example of why such results can be so misleading, let look at a Phase 3 trial failure (Abstract #394). Here we have Celgene’s pomalidomide (approved under the name Pomalyst for the treatment of Multiple Myeloma). Phase 2 trials suggested that pomalidomide imporved severe anemia in MPN patients, including MF, PV and ET patients. The phase 3 trial enrolled 252 patients with MPN-associated MF who were dependent on RBC transfusions. There was no significant improvement in time to transfusion in drug-treated v placebo-treated cohorts.
 
So these early trials can be very misleading, but lets look even earlier, at some preclinical studies.
 
Novartis has some nice data showing elevation of Hedgehog signaling pathway targets in MF granulocytes (Abstract #666). Using in vitro and in vivo (mouse) models they demonstrate that Jak inhibition and Hedgehog inhibition have additive activity. The Jak inhibitor was INC424 and the Hedgehog inhibition was provided by Smoothened antagonism (sonidegib). Another novel approach is to target megakaryocytes, that contribute to MF pathogenesis. Using in vitro and in vivo models an academic collaboration (Abstract #109) shows that Aurora A kinase inhibition induces megakaryocyte arrest and this results in decreased bone marrow fibrosis, decreased infiltration of megakaryocytes and granulocytes into the liver and spleen, and decreased plasma TGFbeta, a potent pro-fibrotic growth factor.
Genetic analyses have demonstrated that certain signatures indicate risk for increased risk of leukemic conversion and decreased OS. These include ASXL1, EZH2, IDH1/2 and SRSF2 gene mutations (Abstract #104). EZH2 mutation accelerates the onset of primary MF (Abstract #110). However, patients carrying these mutations are not differentially impacted by ruxolitinib therapy, instead they have similar responses to patients without such mutations (Abstract #105). Novel pathways associated with MF include the arachidonate 5-lipoxygenase pathway (Abstract #111). An exciting new development is the identification of calreticulin mutations in patients that do not have Jak2 mutations, that is, the two appear to be mutually exclusive (Abtract #LBA1). This will spur investigation in novel drivers of MPN pathogenesis.
Obviously there is much more going on then can be covered here. The identification of the Jak2 mutation in MPN opened up a new era of drug development for these rare but nasty and lethal neoplasms. New findings will push us even further, and we can reasonably expect to see important advances over the next few years.
 
 

SnapShots from the American Society of Hematology Abstracts, Part 1

November 15, 2013
The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
Part 1. Small molecule PI3Kdelta inhibitor Idelalisib in the treatment of Chronic Lymphocytic Leukemia (CLL).
It is useful to remember that most CLL patients have indolent disease and are in a “watch and wait” mode with their physicians, who will not initiate treatment unless they see signs that the cancer is becoming active and/or the patient has one or more risk factors. Therefore in clinical trials the CLL patients are those at high risk. Typically “relapsed or refractory” CLL (rrCLL) patients have cytogenetic markers of poor prognosis (mutated p53, del(17p), del(11q), trisomy 12, mutated NOTCH1), or are patients who have failed multiple prior therapies (chemotherapy and/or antibody therapy such as Rituximab treatment), patients with “bulky” disease indicating lymph node and other lymphoid organ involvement, and patients with unmutated IGVH sequences. Often these high risk markers occur together. It is important to realize that at this time CLL is not considered a curable disease, and that the goal is therefore to increase median progression-free survival (PFS) and median overall survival (OS), the latter referring to time until death.
That said, we are witnessing a remarkable time. Terrific new therapies are being developed, and physicians look forward to offering their patients a chance at a cure.
Lets start with a drug class I think has great promise, inhibitors that act downstream of B cell receptor (BCR) signaling. CLL is a B cell lymphoma, and is dependent on chronic activation of these signaling pathways. Here is a model to get us oriented, from the Onclive website:
Note that Syk, Btk and PI3K are upstream (relative to the cell surface and BCR) and therefore are critical components of the pathway. Drugs targeting each of these signaling kinases have been developed. AKT, mTOR and others, generally more familiar to us from the solid tumor literature, are further downstream.
There are four isoforms of PI3K relevant to the drug class: alpha, beta, delta and gamma. Different drugs have selectivity for one or more of the isoforms.
For treatment of CLL, the lead therapeutic in the class Idelalisib is a PI3Kdelta(d) selective inhibitor from Gilead. PI3Kd signaling is known to be essential for the activation, proliferation, survival and tissue homing activity of lymphoma cells. On October 9th a phase 3 CLL clinical trial of this drug was stopped ahead of schedule based on a positive risk/benefit assessment. The drug is also under New Drug Application (NDA) review for indolent Non-Hodgkin’s Lymphoma iNHL) based on results from multiple phase 3 trials. Idelalisib is trailing just a step behind Ibrutinib, a BTK inhibitor, in the approval process – Ibrutinib was approved for Mantle Cell Lymphoma (MCL) on November 12th. Neither drug is approved for CLL, the most common lymphoma.
Both drugs have moved aggressively into combination therapy trials. Some of the early trials (phase 1 and 2) will report out interim data at ASH.
Abstract #4176 presents analyses of Idelalisib (IDELA) given in combination with Rituximab (Rtx) antibody therapy plus chemotherapy (B: bendamustine or C: chlorambucil) in high-risk rrCLL patients. Results are encouraging and shown in Table 1, where ORR = stable disease (SD) + partial response (PR) + complete response (CR). Its important to note that these are clinical trial terms and do not reflect outcomes, just observations at specific timepoints. Regardless we are looking for high % ORR, PR and CR. Importantly, the median duration of exposure was 18 months at the time of analysis, meaning that 18 months is the median amount of time patients have been exposed to drug without withdrawing due to toxicity, disease progression, or death. More importantly, the median duration of response (DOR) to therapy had not been reached within the 18 months (so that’s good, patients are still on drug and are still responding) nor had the median PFS been reached (so more patients have survived than have not survived). The IDELA-Rtx-C data are similar, just of shorter average duration with a median exposure = 7.7 months (I’m guessing here that this arm of the trial enrolled later). Also notable is the toxicity data from this trial, which tracked pretty consistently with the chemotherapy regimen. When the combination therapy included bendamustine, neutropenia was the defining toxicity, with > 60% of patients experiencing grade 3-4 neutropenia. When the combination therapy included chlorambucil, liver transaminase elevation was the defining toxicity, with > 21% of patients experiencing grade 3-4 liver toxicity. Its important to realize that these are severe, but manageable, toxicities for most patients.
Abstract 2878 presents a similar study, but in this case the combination therapy given with Idelalisib was limited to chemotherapy. Chemotherapy consisted of B: bendamustine, F: fludarabine or C: chlorambucil, given in standard doses. This trial was run in a heavily pre-treated patient population having a very poor prognosis. The data are very encouraging given the composition of the enrolled patient population (Table 1). The adverse events (AEs) were cytopenias and gastrointestinal tract (GI) disorders. This study demonstrates that Idelalisib has potent activity in combination with chemotherapy.
Abstract 4180 gives us data from an additional study, in which Idelalisib is paired with anti-CD20 antibody therapy (Table 1). As in the other studies the cohorts were comprised of a high risk patient population. This was a small phase 1 study with an extension arm, enrolling 40 patients. This study produced some sobering results that remind us how serious a disease aggressive CLL is, and how potent the drugs treating this disease have to be. Notably, 25% of patients did not enter the extension study due to disease progression, 6 patients died. A further 23% did not enter the extension study due to AEs. These data remind us that response rates readout at a specific pre-determined time during the trial, and do not reflect outcomes. Regardless the median PFS and DOR for all patients (N=40) and were 20 and 19 months, respectively. Median overall survival (OS) had not been reached.
The phase 3 study mentioned at the outset, which was stopped early due to significant evidence of clinical benefit, was very similar to, if much larger then, the Phase 1 study presented in abstract 4180. We don’t know much about the trial data yet, but Gilead’s press release states that the “Phase 3 study … evaluating idelalisib in previously-treated … CLL patients who are not fit for chemotherapy will be stopped early  … based on a predefined interim analysis showing highly statistically significant efficacy for the primary endpoint of progression-free survival in patients receiving idelalisib plus rituximab compared to those receiving rituximab alone. The safety profile of idelalisib was acceptable and consistent with prior experience in combination with rituximab in previously treated CLL.”
I think the general takeaway here is that a high proportion of those patients who respond did well over time. The fact that they did so without additional chemotherapy is very encouraging. PFS in either not being reached or is reached at 20 months or so. This suggests that impact on OS will be significant for all of the drug combinations presented. 
 
Additional analyses from Phase 1b and 2 studies were presented in abstract #1632. This abstract presents data comparing responses among CLL patients with high risk prognostic markers (del(17p) or TP53 mutation, del(11q), IGHV mutation and NOTCH1 mutation) to CLL patients without these markers. rrCLL patients given Idelalisib monotherapy or combination therapies responded equally well to treatment regardless of the presence or absence of these critical genetic markers of disease aggressiveness. That is a very important result that suggests great potential for CLL therapy with Idelalisib. The table is below.
 
Note that the response rates in the phase 2 Idelalisib + Rtx trial in previously untreated (i.e. newly diagnosed) patients are quite high, and this is exactly what you want to see as to drug moves to treat patients earlier in their disease course.
Next up is a review the Ibrutinib data in the same disease, and also a quick look at the other therapies in these drug classes.