JAK Inhibitors for Rheumatoid Arthritis (Follow-Up)

Galapagos followed up strong 12 week data with equally impressive 24 week data for their two trials, DARWIN 1 and 2, testing the use of their selective JAK1 inhibitor filgotinib in rheumatoid arthritis (RA). In an earlier comparison, 12 week data from the DARWIN 1 trial compared well against the marketed incumbent JAK inhibitor tofacitinib, as well as the late stage competitor baricitinib. The following graph compares the 24 week data by focusing in on the best dose results for DARWIN 1 and 2 compared toIncyte’s newly released RA-BUILD and RA-BEACON data, along with tofacitinib data as a comparator (Study IV in the prescribing information). First is a comparison of the relative change in disease activity through the American College of Rheumatology (ACR) scale, and subsequently the absolute disease activity score (DAS28) index below 2.6, which is considered a sign of remission:

ACR70 and DAS28(CRP) < 2.6 (Placebo Adjusted)

Note: tofacitinib DAS28 data are DAS28-ESR, not DAS28(CRP); for DARWIN 2, the 12 week placebo responses were carried over to 24 weeks for the purpose of comparison.

As always, these comparisons between investigational drugs are inexact. Particularly, the exclusion criteria for the four referenced trials are not identical. Whereas Incyte accepted patients treated with prior anti-TNF drugs in the RA-BEACON study, RA-BUILD and DARWIN 1 and 2 all excluded prior anti-TNF therapy. And unlike the other 3 trials, DARWIN 1 did not require enrollees to have demonstrated an inadequate response to a prior conventional disease modifying agent (cDMARD). In effect, these trials likely have patient populations that, in order of RA severity, are DARWIN 1 < RA-BUILD < DARWIN 2 < RA-BEACON. This ranking, although not definitive, can be generally observed in the placebo response trend across these trials.

The general efficacy trend for these drugs, along with tofacitinib’s concern over gastrointestinal perforations, suggests that the investigational drugs baricitinib and filgotinib will have a chance to compete for market share. For prospective investors, the comparative outlook for baricitinib versus filgotinib is likely more interesting.

In terms of efficacy, the trend for filgotinib’s numbers appears superior. Galapagos has done a good job of identifying and focusing in on the doses that provide maximal response. However, the company has noted there was no significant difference in the efficacy between 100 and 200 mg total dose results, and in DARWIN 2, 100 mg filgotinib often had numerically larger ACR values than 200 mg. In effect, final data from prospective phase 3 trials with filgotinib are more likely to fluctuate within the range of efficacy presented by the 100 and 200 mg total doses rather than specifically replicating the highest values. In that regard, and given the differences in enrollment between the baricitinib and filgotinib trials, a final efficacy comparison between these two drugs will likely be a push. Neither drug is likely to prove superior efficacy over the other.

In regards to safety, some analysts are suggesting an advantage for filgotinib, primarily due to the hemoglobin level comparison for patients on filgotinib versus baricitinib. I suspect this factor is being overrated, particularly for drugs within the same class. Long time followers of the oncology space will know that carboplatin is perceived (and possibly even proven) to be more tolerable than cisplatin. Further in oncology, convenience due to a lack of concomitant steroid administration has been touted as an advantage for enzalutamide in its competition against abiraterone in prostate cancer. Although such conveniences and advantages can provide an upper hand in the long run, they’re not rapidly converted into market share absent a clear efficacy benefit. Carboplatin never squeezed out cisplatin from use despite comparable efficacy and improved adverse event profile (generally summarized here). Arguably, enzalutamide is now slowly taking over abiraterone due primarily to the mounting evidence for improved efficacy that has emerged since its approval; its advantage in dosing convenience did not create immediate and large dividends in the market. In effect, unless the adverse event profile significantly impacts management and practice, small changes in percentage one way or another are unlikely to be market-defining. In this regard, I don’t expect the hemoglobin effect of baricitinib versus filgotinib to be meaningful in the marketplace. Hemoglobin levels with baricitinib are primarily between 10 g/dL and the lower limit of normal, and do not fall under 8 g/dL. Many individuals with RA already present with anemia of chronic disease and have hemoglobin below the lower limit of normal. Nonetheless, the anemia in these patients is not targeted as a primary focus of care; rather, the underlying disease is the target. In that regard, mild changes in hemoglobin level with baricitinib versus filgotinib are unlikely to be a strong raison d’etre to prescribe one over the other, especially when these changes in hemoglobin levels do not require any intervention. Had either drug demonstrated a meaningful edge for infection risk, one could have made a meaningful case for an advantage to play out in the marketplace.


As an overall efficacy and safety proposition, there does appear to be a gap between baricitinib / filgotinib versus tofacinitib. If baricitinib is approved, it has the first shot at exploiting this gap but with no assurances that it will rapidly or meaningfully change prescriber preferences. If filgotinib is moved into registrational trials for the US market, I expect it to gain approval with a compelling efficacy package. However, the efficacy and safety proposition between baricitinib and filgotinib does not appear to be large. Looking forward, I expect first-to-market will be a larger factor in the competition between baricitinib and filgotinib.

Uniqure and the Celladon Legacy

Virus-based gene therapies are demonstrating strong proof-of-concept primarily for hematological diseases. To date, however, the data targeting solid organs has been weak. This was best exemplified by the recent results for Celladon’s Mydicar therapy providing AAV-mediated SERCA protein expression for heart failure (HF) patients. As readers might recall, prior posts outlined that Celladon’s preclinical data were exceptionally weak and failed to show increased target protein expression. Without this, there was little reason to expect success in their randomized CUPID-2 trial regardless of the results in the dose-finding CUPID-1 trial. CUPID-2 ended with a hazard ratio of 0.93 in a modified intent-to-treat population, confirming that the “therapy” was effectively a placebo. This outcome strongly encourages future investors in HF-targeted gene therapies to ensure that the preclinical data achieves one fundamental observation: verifiable change in expression of the targeted protein.

In addition to their hematological programs, European outfit Uniqure is also directing their AAV efforts to address heart failure. Based on their preclinical publications, Uniqure have seemingly come out ahead where Celladon clearly failed. Uniqure’s proof-of-concept studies in pigs receiving their AAV9-based construct to increase S100A1 protein expression seems both reliable and conclusive. At multiple points throughout this publication, the authors are able to show convincing evidence of S100A1 protein at levels above and beyond baseline. Why have Uniqure succeeded in providing convincing proof-of-concept where Celladon have failed? Although Uniqure is using an AAV2/9 construct whereas Celladon opted for AAV2/1, I do not think this makes a material impact. Preclinical data testing the tropism of these vectors have shown that both can target the heart efficiently in rodents, suggesting that the choice of capsid type is not the discriminator. Rather, Uniqure’s retroinfusion with accompanying left anterior descending (LAD) coronary occlusion is likely the key factor. Celladon’s preclinical and clinical data have conclusively shown that intracoronary infusion of AAV is not sufficient to transduce the myocardium, and Uniqure’s modification of working in a retrograde fashion is a novel and effective means of addressing delivery. Although not as simple and convenient as a daily pill, the infusion / temporary LAD occlusion method used by Uniqure is achievable and, given the state of the technology, necessary to achieve transduction of the myocardium and target protein expression.


Although Uniqure and their team are to be commended for their technical achievement and thorough preclinical work, I remain skeptical of the S100A1 program and, by extension, their collaboration with Bristol-Myers Squibb. Although this blog attempts to be as quantitative and data-driven as possible, the reservations surrounding these programs are, admittedly, qualitative and a “gut” feeling.

To add context to the gut feeling, we can set the stage for what these programs are attempting to achieve. Simply put, both programs from Uniqure and Celladon were attempting to restore what was once abundant. In the case of Celladon, they were attempting to capitalize on literature observations that the expression of SERCA2a declines in the context of the failing heart. Similarly, Uniqure is pointing to a decrease in S100A1 in the failing heart as a point of intervention. Simply put, this approach relies on an underlying belief that restoring something to the levels found in the “normal” heart will allow the failing heart to recover some or all of its lost function. In effect, the strategy treats heart failure as if it was analogous to the pathophysiological settings wherein enzyme replacement therapies succeed. Missing glucocerebrosidase because you have Gaucher’s disease? We can provide the enzyme to attempt to restore it to physiological levels. Is your failing heart low on S100A1? We have an AAV for you. Unfortunately, I think this strategy is very flawed when applied to heart failure.


It is very well established that heart failure impacts the heart in a myriad of ways. At the molecular level, we can observe changes in protein signaling and protein abundance. But at a more macro level, there are clear structural changes that occur. The figure from Wikipedia does a good job of showing representative structural changes and remodeling that are evident in various pathophysiological states. 

Simply put, this figure is the backbone for my skepticism. If we take the example of S100A1, the preclinical data suggest that ischemia-induced HF (which often takes a first step through hypertrophy) induces a state of the heart wherein S100A1 expression level is less than it was under normal conditions. Therefore, the presumption is that increasing S100A1 in the hypertrophic or failing / remodeled heart will allow the heart to return to normal. This, in my view, is a logical flaw. In effect, I believe this reflects a cognitive dissonance that treats the remodeled heart as simply a normal heart with reduced S100A1 (or reduced SERCA2a, or reduced protein X) expression. However, this simply isn’t true. The remodeled heart has altered structure including myocyte disarray, aberrant signaling, and changes in the expression level of a myriad number of proteins. In effect, the context has changed. As a simple analogy, consider the case of the smoker who develops emphysema. At the point of emphysema diagnosis, quitting smoking will not simply reverse the course of disease. The damage is done, alveoli and capillary beds have expired. In effect, cessation of smoking by an emphysematic patient does not have the same effect as cessation of smoking for someone who has not yet developed emphysema. The contexts have changed, and therefore the treatment and care strategies are not simply interchangeable. Similarly, my contention is attempting to “restore” a singular protein level to that found in the normal heart provides no guarantee of recovery for a remodeled heart. In support of this argument for S100A1 specifically, human heart tissue from nonfailing, failing and left ventricular assist device (LVAD) supported hearts show that although there is a decrease in inotropic response and S100A1 protein in failing hearts, LVAD supported hearts demonstrated restored inotropic response yet no restoration of S100A1. In that respect, these human tissue data suggest a peripheral rather than pivotal role for S100A1.


The counterpoint to this is, obviously, the hundreds of mouse and porcine studies showing that restoration of intracellular protein X to the failing heart restores function and rescues the model. But the level of success of each and every one of these studies is reason to be highly skeptical and, to a certain extent, dismissive of the “restoration of protein X rescues the heart” narrative. Additionally, consider the drugs used in the clinic for patients with / developing heart failure. By and large, they impact whole intracellular signaling cascades through modulation of surface receptors rather than focus on restoration of a single intracellular protein. Even in that context, the HR benefit is around 20%. Therefore, if manipulation of a whole signaling pathway in the heart yields a 20% benefit, what can reasonably be expected from focusing on an individual intracellular protein?

Tinib versus Tinib

Competition between approved and investigational drugs is undoubtedly good for patients. In myelofibrosis (MF), Incyte’s drug ruxolitinib has been the sole JAK inhibitor approved to date, primarily on the basis of the registrational trials COMFORT-I and II. Cell Therapeutics and their partner Baxter have also set sights on the MF space, having initiated PERSIST-1 and 2 to further the cause for pacritinib, their JAK inhibitor.

Incyte’s registration trials, COMFORT-I and II, enrolled patients with baseline platelet counts >100,000/uL, and had dose reduction strategies in their protocols for emergent exacerbation of thrombocytopenia. Subsequent to these trials, Incyte has initiated additional studies that have accrued results from ruxolitinib dosing strategies to accommodate patients with platelet counts below 100,000/uL. To wit, the prescribing information for ruxolitinib includes dosing strategies for patients with platelet counts between 50,000 - 100,000/uL. Nonetheless, ruxolitinib was approved on the strength of its treatment effect in patients with >100,000/uL platelet count. The development strategy for pacritinib is focused on this point, and pays special attention to MF patients with baseline platelet counts below 100,000/uL. The first large study for pacritinib is PERSIST-1, with topline data released in March and more details released at ASCO.

Table 1 provides a comparison of spleen responses for the various pacritinib and ruxolitinib trials to date. When possible, the data have been split up into platelet subgroups to facilitate comparisons. No such comparison is perfect, but absent head-to-head data, it’s a reasonable exercise.

Based on the results to date, some trends are visible. First and foremost, for patients with platelets >100,000/uL, ruxolitinib provides better spleen response. This population is, arguably, two thirds of the MF population. Conversely, for patients with platelet counts below 50,000/uL, ruxolitinib yields to pacritinib. The package insert directs caregivers to hold ruxolitinib administration if platelets fall below 50,000/uL, providing pacritinib with an open opportunity. As for the remaining patients with starting platelet counts between 50,000 and 100,000/uL, it is difficult to suggest superiority of one drug over the other. Cumulatively, 38 of 134 patients (~28%) treated with ruxolitinib have had responses as compared to ~11% for pacritinib. Nonetheless, these ruxolitinib data are from open label or expanded access trials, and would likely see a step down in a controlled, randomized setting.

Next up for pacritinib is PERSIST-2, a trial that is enrolling ~300 MF patients with platelet counts less than 100,000/uL. These patients are split into 3 arms: pacritinib 400 mg QD, pacritinib 200 mg BID, and a best available therapy arm that, unlike PERSIST-1, may include ruxolitinib. If the best available therapy arm primarily features ruxolitinib use, and the spleen responses remain similar to those outlined in Table 1, there is little chance of the pooled pacritinib arms besting ruxolitinib. To be more precise, the primary endpoint of PERSIST-2 takes into count both spleen responses and patient reported Total Symptoms Scores (TSS). In COMFORT-I and PERSIST-1, approximately 50% and 25% of ruxolitinib and pacritinib treated patients, respectively, noted a 50% or greater reduction in TSS. In effect, a head-to-head trial favors ruxolitinib for the majority of the MF population. Unless PERSIST-2 enrolls a large percentage of patients with starting platelets <50,000/uL, pacritinib is unlikely compare favourably if the best available therapy arm has extensive ruxolitinib use.


The following consideration for this setting is safety. Ruxolitinib has demonstrable impacts on both red blood cell and platelet counts, requiring dose reductions or transfusions. Pacritinib’s ability to be dosed for patients with platelets <50,000/uL likely confirms its advantage in eliciting less thrombocytopenia. At this time, it is difficult to compare anemia data across the trials, in part because the transfusion dependence criteria were divergent:

  • COMFORT-I: IWG criteria wherein “Baseline transfusion dependence was defined as the receipt of ≥2 units of RBC products in the 4 weeks prior to randomization, and on-study transfusion independence was defined as the absence of transfusions for any period of ≥8 weeks.”

  • PERSIST-1: As per the press release, defined as “patients treated with pacritinib who were severely anemic and transfusion dependent – requiring at least six units of blood in the 90 days prior to study entry.”


By the above criteria, 41.2% vs 46.9% in the active and comparator arms in COMFORT-1 and 25% vs 0% in the active and comparator arms in PERSIST-1 became transfusion independent. 


In all, the results from PERSIST-1 suggest that pacritinib is a less potent member of the JAK inhibitor class, signaled not only by its modest efficacy, but also by its more lenient adverse event profile. Going forward, pacritinib’s dataset in PERSIST-2 will be pivotal in determining its competitiveness in the MF space. If the best available therapy arm in PERSIST-2 is able to accommodate a high percentage of patients receiving ruxolitinib, the primary efficacy endpoint is unlikely to be met.

JAK Inhibitors for Rheumatoid Arthritis

With Pfizer's Xeljanz (tofacitinib) already on the market for rheumatoid arthritis (RA), two investigational JAK inhibitors, baricitinib (JAK1/2 inhibitor) and filgotinib (selective JAK1 inhibitor), are in late stage development. With larger datasets slowly emerging, this post will be a placeholder to provide updated data and, within reason, head-to-head comparisons.


RA-Build versus DARWIN 1

These two trials are in moderate to severe RA patients who continue on their background conventional disease modifying anti-rheumatic drug (cDMARD) in addition to the investigational drug. Both exclude prior use of biologic DMARDs (bDMARD), namely anti-TNF drugs such as adalimumab. Provided below are some relevant trial inclusion and exclusion criteria to better understand the comparison:


RA-Build (Baricitinib sponsored by Incyte / Eli Lilly)

Inclusion Criteria

  • Have a diagnosis of adult-onset RA as defined by the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) 2010 Criteria for the Classification of RA
  • Have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints
  • Have a C-reactive protein (CRP) or high-sensitivity C-reactive protein (hsCRP) measurement ≥1.2 times the upper limit of normal (ULN)
  • Have had an insufficient response or are intolerant to cDMARDs and either:
    • Have had regular use of a cDMARD for at least the 12 weeks prior to study entry with a continuous, nonchanging dose for at least 8 weeks prior to study entry
    • For participants not receiving a cDMARD at the time of entry, the investigator will document in the participant's history that the participant had failed, was unable to tolerate, or had a contraindication to treatment with a cDMARD


Exclusion Criteria

  • Are currently receiving corticosteroids at doses >10 mg per day of prednisone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids within 2 weeks of study entry or within 6 weeks of planned randomization
  • Have started treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or have been receiving an unstable dosing regimen of NSAIDs within 2 weeks of study entry or within 6 weeks of planned randomization
  • Are currently receiving concomitant treatment with methotrexate (MTX), hydroxychloroquine, and sulfasalazine or combination of any 3 cDMARDs
  • Have ever received any biologic DMARD

See full trial details here.


DARWIN 1 (Filgotinib sponsored by Galapagos)

Inclusion Criteria

  •  have a diagnosis of RA since at least 6 months and meeting the 2010 ACR/EULAR criteria of RA and ACR functional class I-III
  • have ≥6 swollen joints (from a 66 joint count) and ≥8 tender joints (from a 68 joint count) at Screening and at Baseline
  • Screening serum CRP ≥0.7 time ULN
  • have received MTX for ≥6 months and have been on a stable dose (15 to 25 mg/week) of MTX for at least 4 weeks prior to Screening and willing to continue on their current regimen for the duration of the study. Stable doses of MTX as low as 10 mg/week are allowed when there is documented evidence of intolerance or safety issues at higher doses.


Exclusion Criteria

  • current therapy with any DMARD other than MTX
  • current or previous RA treatment with a biologic DMARD, with the exception of biologic DMARDs administered in a single clinical study setting more than 6 months prior to Screening (12 months for rituximab or other B cell depleting agents), where the biologic DMARD was effective, and if discontinued, this should not be due to lack of efficacy
  • previous treatment at any time with a cytotoxic agent, other than MTX, before Screening.

See full trial details here.


Below are summarized the 12 week data from RA-Build and DARWIN1, focusing only on the percentage of patients meeting the ACR20, 50 and 70 endpoints. The first two bar graphs include the placebo arm in the respective trials, whereas the third graph compares both datasets with their placebo groups subtracted. The method is an inexact comparison, but is provided as a best approximation for head-to-head comparison. Although once daily and twice daily doses of filgotinib were tested, the two best twice daily doses are plotted. This is in part to simplify the presentation, while being mindful that the twice daily dosing appeared to provide qualitatively improved results for filgotinib. Included in this plot is a best comparison to the percentages achieved by the recommended dose of tofacitinib in Study IV of the tofacitinib registration package. 

RA-Build (12 Weeks Baricitinib)

N = 228, 229, and 227 for placebo, 2mg and 4mg QD respectively.

Data Source at this link. Roll over for the underlying values. 

DARWIN 1 (12 Weeks Filgotinib)

N = 86, 86, 85, and 84 for placebo, 25mg, 50mg and 100mg BID respectively.

Data source at this link (pdf file).

Placebo Adjusted

Note: Baricitinib doses are 2mg and 4mg QD; Filgotinib doses are 50 and 100mg BID; Tofacitinib dose is 5mg BID

Incyte's AACR Synopsis

Incyte used the basic research-focused American Association of Cancer Research meeting to articulate its drug development strategy going forward. In essence, the lessons learned from the development of ruxolitinib appear to have transitioned the company firmly into an oncology drug developer. To wit, compare a pipeline presentation from June 2008 (left) to now:

Click to enlarge

One can’t be blamed for drawing a blank at the various candidates that existed 7 years ago. Attrition of clinical candidates is inevitable, leaving the more salient observation that the therapeutic areas of focus have narrowed. The large depth of field view that once kept diseases such as multiple sclerosis and HIV in focus has changed to a shallow depth of field firmly focused on the in-house oncology programs.

Going forward, the company plans to treat its IDO1 inhibitor INCB24360 as a clinical area of focus and expansion, much the same as it has done for ruxolitinib. Unlike the monotherapy approach for ruxolitinib, Incyte has initiated multiple clinical trials examining INCB24360 in combination with PD-1 and PD-L1 targeting approaches offered by the likes of Merck and Bristol Myers. Arguably this is an attempt to use INCB24360 as the spearhead of their advance into immuno-oncology. Within this space, Reid Huber introduced a two-pronged approach:

  1. IDO1, JAK and PI3Kδ as intracellular (read: small molecule) targets that can modify the mix of suppressor and effector lymphoid and myeloid cells within the tumour environment.
  2. Antibody-based approaches to activating (GITR / OX40) or antagonizing (TIM-3 / LAG-3) cell surface targets to manipulate T cell function.

This framing was followed by a brief presentation from Gregory Beatty to introduce some principles behind immune escape mechanisms, the role of various T cell populations, and how IDO1, JAK and PI3Kδ signaling can be written into the immuno-oncology narrative. This blended nicely into Peggy Scherle’s presentation of in-house efforts to demonstrate the parts that JAK, IDO1 and PI3Kδ inhibition can play, alone or in combination, in modulating the balance of suppressor versus effector lymphocyte populations that infiltrate the tumour. The talk focused solely on their preclinical work, comprised of a standard biotech menu of flow cytometry data accompanied by tumour growth inhibition in mouse models. Nonetheless, the preclinical PAN02 model outlining the divergence of JAK inhibition efficacy in immunocompetent versus immunocompromised mice was interesting. In addition, the continued emphasis on the populations of tumor infiltrating lymphocytes suggests that the company is very interested in context-specific changes in these cells populations following JAK1, PI3Kδ and IDO1 inhibition. At the least, these data provided a strong preclinical rationale for their view that exploiting JAK and its near-neighbour pathways may help build on top of the immuno-oncology edifice.

As for those related pathways, two subsequent speakers introduced and expanded on the rationale behind the PIM kinase and BET bromodomain inhibitor programs. Candidate INCB53914 is an inhibitor of all three PIM kinase isoforms and based on preclinical data appears poised for use in acute myeloid leukemia (AML) and multiple myeloma (MM), two settings proposed to have PIM1/3 and PIM2 dependency, respectively. The mechanism of action of this inhibitor appears to involve reducing BAD phosphorylation, thereby supporting a pro-apoptotic context, as well as reducing the activation state of AKT and mTORC. The PIM kinase inhibitor may additionally help to reduce the stability of Myc, a canonic proto-oncogene that is also targeted by their new BRD inhibitor INCB54329. This new candidate is Incyte’s first entry into the epigenetics area, and was demonstrated to reduce c-Myc expression in tumours and to combine agreeably with JAK1 inhibition in MM models.

During the discussion of these preclinical data, this signaling figure got plenty of screen time. With JAK1/2 and PI3Kδ inhibitors already in the clinic, they will soon be joined by PIM kinase and BRD inhibitors. In effect, Incyte appears focused on exploiting its internal strength in targeting the JAK / STAT pathway. One perspective on this strategy is to accept that the company is branching out targets in a thorough and organic manner. However, is there a risk of expending resources in a redundant fashion? Is there a significant advantage to be had by reducing c-Myc expression via a BRD inhibitor and a PIM kinase inhibitor versus just the one? Is the concomitant reduction in downstream mTORC1 signaling mediated by a PI3Kδ inhibitor usefully augmented by PIM kinase inhibition?

The implicit message in the Incyte approach is that there can be significant gains by made by employing both, not simply because of their shared targets, but also because of their differentiated, contextual effects. For example, in the PAN02 model, JAK1 inhibition and PI3Kδ inhibition had distinct effects on the population and balance of effector versus suppressor lymphoid and myeloid cells. Although either drug alone may reduce tumor burden through slightly overlapping pathways, their unique effects on the balance of effectors and suppressors may be the nuance that rationalizes their use in combination.

My impression behind this iterative and overlapping pursuit of pathways is that there is an internal belief they will benefit from some gains in overall response rate, but that the larger gains will be from patients who go into deeper remission. In other words, significant gains in response duration are being valued rather than a rote focus on response rates. This may be prudent, as more and more presentations from prominent immuno-oncology approaches (CTLA4, PD-1, PD-L1) are showing the value of deep remissions and a flattening of the Kaplan-Meier curve. Perhaps the value of this type of combination therapy was revealed by their enthusiasm for the upcoming data testing JAK1 + PI3Kδ inhibition in advanced and refractory Hodgkins Lymphoma. They specifically noted having observed an “interesting signal” and that discussions with the FDA on a registration strategy were to be initiated. Since the combo is just now emerging from a dose finding trial, a meaningful signal in the clinic may have galvanized their internal thinking about the feasibility of their overall strategy.


Odds and Ends

- One point of discussion was the clinical trial examining the combination of the JAK1 inhibitor INCB39110 with gemcitabine and nab-paclitaxel. Focusing on first line pancreatic cancer patients, it was noted that discontinuations within the first 2-4 months were greater than they had expected. In that regard, they will explore a lower dose of INCB39110 that will maintain JAK1 inhibition at the level observed with ruxolitinib treatment in the RECAP trial. The hope is to reduce discontinuations while maintaining adequate target inhibition. I suspect that this continued dosing will continue and push back the phase 3 initiation until some JANUS data are revealed. The JANUS data will provide a strong readout on the ability of JAK1/2 inhibition to make an impact, if at all, on the target subsets of pancreatic cancer patients. If JANUS-1/2 do not show efficacy, it would be difficult to get excited about another phase 3 with a selective JAK1 inhibitor. I’m skeptical about the prospects for this indication.

- For long time Incyte followers, they’ll remember that the announcement of the Jakafi (INCB18424) collaboration with Novartis included a seemingly out of place piece: worldwide development and commercialization rights to INCB28060, a c-Met inhibitor. At the time it was hard to see how the two assets were related, and beyond that, it was surprising that they licensed a compound even before it had dosed a patient in a phase I study. With the strategy articulated at AACR, it may be that this molecule was an early victim of their future focus, and the licensing agreement was a practical divestiture of a tangential asset. c-MET dependent signaling relies on multiple adaptor proteins (SHC / Grb / Gab) and can activate a downstream MAP kinase pathway. Incyte may have decided at the time that this was divergent to their focus on JAK / STAT related signaling, prompting them to license the asset to Novartis.

- The counterpoint to the above is that the company is also exploring an FGFR inhibitor, INCB54828, that can impact MAP kinase signaling. However, this receptor can also activate PI3K signaling, suggesting they may have arrived at this program organically through their JAK/PI3Kδ work.

- INCB54828 is billed as a selective FGFR inhibitor. The IC50 values for FGFR1, 2 and 3 are ~1 nM, but for FGFR4 and VEGFR2 they are 30 an 70 nM, respectively. Although clearly potent against FGFR1-3, the single dose PK data presented with the poster suggests that FGFR4 and VEGFR2 inhibition can also be expected.

Cardio3, Celyad and Basketball Analogies

On top of news that Cardio3 is preparing to IPO on a US exchange and recent news that they’ve received USPTO allowance for a patent covering their CAR-T approach, we’ll soon have to bid farewell to the company that brought us all this progress. The reason is seemingly innocuous: they’re changing their name to Celyad.

In an earlier post, I had opined/speculated/guessed:

Therefore, it does come as a surprise to see a company called Cardio3 slowly morph into an equal part oncology company. Again, perhaps this is prudent by management. However, long term followers of biotechnology companies will recognize this as the possible first move in a classic Biotech Pivot (Tm). The rules of the Biotech Pivot state that as the day of judgment nears on your lead product, mentions of other pipeline efforts shall increase.

So is Cardio3 executing the Biotech Pivot? Or is this simply prudent management by an experienced team? A prediction is that the March 2015 analysis is benign and that the company continues Chart-1 as is and that Chart-2 enrollment is extremely slow for the first half of 2015. And, luckily for investors, there will be plenty of talk on the CAR-T side to keep them busy… or distracted.

Today’s news suggests that, perhaps, the pivot is well underway. It should not be too surprising, especially considering that the company’s foray into the US exchanges is looking to capitalize on investor sentiment towards immunotherapy approaches in oncology. The field is hot and patient responses can be rapid and remarkable, and a "cardio" label may not have been the best way to ride the wave. That said, it will be interesting to observe their approach to the legacy cardiovascular program. It was recently announced that Chart-1 passed an interim futility analysis. This isn’t too surprising, as my understanding is that these analyses provide a large breadth for the interim results to drive through. Going forward, outsiders are unlikely to have any further updates on Cardio3/Celyad’s Chart-1 trial until its 2016 data release. However, savvy observers can track the pace of Chart-2 advancement as a surrogate of Chart-1 progress.

Perhaps it is too early to suggest that Cardio3 is in full pivot, but it sure looks like the company is about to pick up its dribble.

ITT Treasure Hunt

Celladon management engaged in a brief, ~23 minute conference call to review the company’s 4th quarter achievements. It appears only 2 or 3 investment analysts are interested in the story, as the questions posed were few. Admittedly, it can be hard to attract attention in a crowded biotechnology sector, and we wish them luck in drumming up more interest.


As mentioned previously here and here, Celladon is investigating the use of Mydicar, an AAV1 encoding SERCA2a, as a therapeutic for heart failure patients. The company is currently running the CUPID 2 trial, and it is due to provide top line data by the end of April / early May. Their aim is to demonstrate a 45% risk reduction (HR = 0.55) in time to recurrent heart failure rehospitalizations. As noted previously, I’m skeptical that this barrier can be met simply because the company has not provided convincing evidence of SERCA2a protein upregulation in large animal models receiving Mydicar.

During the conference call, the company articulated further their view towards the CUPID 2 data release. Disappointingly, they have steered investors away from expecting data to be presented on an intent-to-treat (ITT) basis. As a teaser, investors were told that the company approached the FDA with a plan to undertake a modified ITT (mITT) analysis wherein they could omit data from patients who did not receive placebo / Mydicar or who had events prior to dosing. As previously discussed, ITT analyses are the gold standard, and companies that attempt to mine trial results for subgroups are often putting on a brave face. In that regard, the red flag raised by this pre-emptive mITT declaration is deep crimson in color.

To be fair, it was noted that if a significant difference exists between the ITT and the reported mITT results (a >5% range was mentioned), investors may be notified of the ITT results. However, if mITT and ITT were close, then investors should not expect the ITT disclosure. But given the a priori declaration of an mITT data presentation, and the flexibility that the company may have in deciding what this modified group is, it brings up two linked considerations for the data release:


- The exclusion of patients who did not receive placebo / Mydicar or who had events prior to dosing may not necessarily be the modification that they use. The company noted that this modification would include less than 5% of the patients in the trial. The corollary here is that the company appears to have access to the blinded data. Otherwise, how else would they be aware of the percentage of patients that fell into this group? Therefore, interested observers have to be accepting of the fact that Celladon may have a lot of leeway in creating the specifics behind this mITT subgroup. Popular subgroups in these types of HF trials often include patients with ejection fraction (EF) less than X% or patients with NYHA HF Class X and Y. Time will tell if Celladon gets creative. In Biotechland, subgroup creativity is inversely proportional to efficacy of the drug.

- Will the mITT description completely obscure the ITT dataset? The company noted that if the ITT and mITT results are close, investors won’t be informed of the ITT at this time. But what will they consider ITT? For example, if they find a baseline EF subgroup that showed p = 0.07 for Mydicar versus placebo, but can then fall to p < 0.05 if they remove patients who did not receive Mydicar / placebo as well as removing events prior to dosing, then the EF/dosing-adjusted mITT “reaches” statistical significance. In this case, if your mITT patient base is EF/dosing-adjusted, what is your “ITT” comparator? Only EF-adjusted? That, by itself, is not true ITT either. Again, in Biotechland, your difficulty in finding the ITT outcome in a data release is inversely proportional to the efficacy of the drug.


I suspect the above two points already feature prominently in the canon of skeptical biotech observers. Time will tell how Celladon negotiates this, but all indications are that the data release may well be more “complicated” than first imagined.

Tokai and Galeterone

To challenge the incumbents enzalutamide (Xtandi) and abiraterone (Zytiga), Tokai is investing in galeterone as a challenger in the prostate cancer space. Tokai designed galeterone as a CYP17 inhibitor but has found that the drug also has anti-androgen effects, and more interestingly, that it exhibits a second-order effect of inducing androgen receptor (AR) degradation via a proteasome-mediated pathway. The importance of this multi-prong inhibition is underlined by the utility of abiraterone (a CYP17 inhibitor) and enzalutamide, an AR antagonist. If only for its CYP17 and AR antagonism, the development of galeterone is worth following.


However, the differentiating wildcard for galeterone is its additional ability, in vitro, to promote degradation of the AR. This is particularly relevant in the case of one splice site variant of the AR, termed AR-V7, that truncates the protein after the stretch encoded by exon 3, effectively producing a receptor without the ligand binding domain. This variant is particularly problematic for patients being treated for enzalutamide, as it removes the drug’s target binding domain. The result: presence of the AR-V7 splice variant correlates with lack of response to enzalutamide (and abiraterone) therapy in an AR-V7 expressing patient population. In effect, being able to reduce full length and AR splice variant expression via protein degradation would circumvent the problems caused by mutants and variants of the AR receptor that no longer offer regulation via ligand binding. Therefore, it is worth vetting the data to date to determine if galeterone induces degradation of the AR and if this effect may translate to the clinic.


The preclinical data demonstrating the impact of galeterone on AR degradation has been published in a few studies. The proteasome-dependent degradation of the AR appears valid for both full length as well as the AR-V7 splice variant. What is also consistent from these studies is that the degradation induced by galeterone treatment is not readily evident until concentrations of 10 uM and above, with 15 uM being the typical concentration used*. At concentrations below 5 uM galeterone, degradation is not readily observed. This is worrisome when attempting to translate this in vitro feature to the in vivo setting, as Tokai’s clinical data with the new tablet formulation demonstrates a drug Cmax of ~1 ug/mL, which, for a structure with an Mr of ~400, results in a concentration of 2.5 uM. In effect, Tokai’s preclinical data demonstrate that this concentration of galeterone is not sufficient to induce degradation of the AR in vitro.


These data should be kept in mind when vetting the ARMOR2 data provided by the company. To forward the differentiating claim regarding AR degradation, the company notes that 6 of 7 treatment naive patients with AR splice variants responded to galeterone treatment. The assumption to be made by investors is that these patients are responding to treatment due to the differentiating MOA of galeterone. However, the burden of proof remains on the company, and remains unmet.

First of all, the aforementioned preclinical data regarding the concentration of galeterone required to achieve AR degradation is well above the Cmax of the drug observed in the phase I trial. Therefore, the scientific case for this activity manifesting in vivo is weak. A possible caveat is that there could be significant accumulation of the drug in the tissue in order to reach 3-4x serum levels and therefore support AR degradation. However, that needs to be shown rather than assumed.

The second caveat is that the company did not test specifically for the AR-V7 splice variant. Their assay is a qualitative two-step immunoassay wherein they survey for presence of the AR with an NH2-terminal directed antibody, and then overlay these results with an antibody directed against a COOH-terminal epitope. The presumption here is that the presence of AR variants missing the COOH-terminal region will show differential staining with this two-step assay. It is important to note here that the simple absence of the COOH-terminal does not directly show presence of the AR-V7 splice variant. There are multiple splice variants of the AR, and some may act as dominant negatives rather than ligand-independent constitutively active forms as in the case of AR-V7. Therefore, Tokai’s presentation of this 7 patient cohort does not provide evidence of in vivo activity against the AR-V7 variant.

Questions and comments welcome.


* It should be noted that in the ARMOR2 slide deck, in slide 7 it is shown that 20 uM is not sufficient for ~100% degradation yet in slide 20, it appears that 5 uM is sufficient for ~100% degradation. Therefore, there is significant variability in the numbers shown in this slide deck. As these are not peer reviewed, more weight to the company’s own peer reviewed data is merited. Below, I’ve pasted a few of the relevant figures demonstrating the various effective concentrations demonstrated in Tokai’s own data.

Note: Compound 5 is galeterone

Note: Compound 5 is galeterone

Incyte 4Q 2014 Notes

Just a few notes from the latest quarterly conference call. For the company, it seems 2015 will be a year to set up an eventful 2016 rather than being an exciting year in and of itself.


And so, in no particular order:


  1. On the PV front, their estimates for the addressable population appears to be roughly equal to the myelofibrosis population of around 25000. Nonetheless, the expectation is that take-up will be slow as this patient population is ripe for a watchful-waiting approach rather than a quick-get-them-on-this-drug approach. Therefore, strong sales in PV would be an upside to their 525-565 million 2015 net product revenue. I don’t expect strong sales in that indication to materialize.
  2. The FGFr inhibitor, INCB54828, is an FGFr1, 2 and 3 inhibitor.
  3. Of the two PI3Kd inhibitors, they’re calling INCB40093 highly selective whereas INCB50465 is being termed a Delta inhibitor. They note that in the preclinical models, the profile of INCB50465 is clean enough to dose at high levels, but the biological relevance of dosing to 99%+++ inhibition of the target remains unclear to me.
  4. It was noted that there will be no milestone payments received from Eli Lilly during 2015. With the remaining phase 3 trials of baricitinib in RA due to read out this year, the comment suggests that there will be no NDA filing in 2015 (provided results merit one). Perhaps not too surprising, but nonetheless suggests no baricitinib related revenue until late 2016, if at all.
  5. They will initiate an INCB39110 + Gemzar + Abraxane trial in first line pancreatic cancer later this year. The only reason this was interesting is for the lack of mention of any CRP related enrollment or stratification. Others will note that there are currently two Janus trials testing ruxolitinib in pancreatic cancer using CRP levels as part of the enrollment criteria. Perhaps CRP wasn’t mentioned for this INCB39110 trial because it is still at an exploratory stage. Nonetheless, it merits attention.

Mailbag (February 14, 2015)

An inaugural edition of the mailbag. Questions are block formatted. Allons-y…


"I read with interest your article. Everybody has the right to his opinion, but coming from someone with your background, who worked for the mayo clinic for years in the field of myocardial remodeling, your opinion carries particular weight for me."

The findings from your own research should carry the most weight. The articles on this website are personal opinion sprinkled with a few weak jokes.

1) You have worked at mayo till august 2014. You must be aware that mayo clinic is a shareholder of cardio3. Did you meet doctors … during your period when you were at mayo clinic to discuss your skepticism? What intrigues me is your tweet, published on june 4th 2013 where you say, i quote “I read the recently published paper. My advice would be to stay far away”. You were at Mayo Clinic at that time, is your opinion based only on the lecture of the paper or other knowledge you have from working at Mayo Clinic?

I have not collaborated with any investigators in any research relating to bone marrow derived regenerative cell therapies. I gather my information from Pubmed and The Google and render my own opinion. My skepticism or optimism is irrelevant to the efforts of this or any company. Collaborations and licensing deals that companies may have with each other are their own responsibility; I only know what is publicly disseminated.


"2) Have you also written this message (broken link) I ask the question because your twitter account points to the username poorgradstudent . Are you suggesting that the trial is a giant bust?"

The Twitter handle is linked on this site. Apologies, but your other link did not work for me.

3) Concerning the results of the C-Cure trial, if the trial demonstrated a 7% increase in the LVEF for the 21 treated patients, what made me invest in cardio3 is the fact that ALL of the treated patients have seen an increase in the LVEF as is shown in the table in the published results. This seems to be statistically significant. Does your analysis take into account the fact that the Chart-1 trial uses C-Cathez (this was not the case during the phase 2 trial) with a much higher cell retention rate? Or the fact that that Chart-1 trial has an inclusion criteria of LVEF ≤ 30% while the phase 2 had an inclusion criteria of LVEF ≤ 40%, knowing that the best results are obtained when the LVEF is the lowest? My conclusion is that the results of Chart-1 may be superior to the results of the phase 2 trial.

I only considered what was described in the C-Cure trial. I can not make extrapolations based on how different those results would be when repeated with another catheter. Similarly, I can not make extrapolations based on LVEF groupings.

4) You say, i quote “only 21 of the 32 ITT patients were included in the efficacy analysis on a per-protocol basis ends up on weaker footing than if the efficacy analysis was completed on an ITT basis (...) Cardio3 will face similar challenges in their registrational phase III trials. However, they are unlikely to convince regulators if they deviate away from an ITT trial analysis. All told, there is reason to be highly cautious of extrapolating the C-Cure results into expectations for Chart-1 and -2”.

That is true, 2 patients were excluded because they did not meet clinical inclusion criteria and no bone marrow was harvested, 2 were excluded because they did not meet bone marrow inclusion criteria and declined repeat bone marrow harvest, and 7 were excluded as quality control inclusion criteria were not met and declined repeat bone marrow harvest. But Christian Homsy said, if i recall well, at the Investor Day on January 30, 2015, that the percentage of patients that can’t have their bone marrow harvested adequately was driven down from 25% in the phase 2 trial to 13% and even 8% after repeat harvesting. Don’t you think a 92% success rate is sufficient?

I do not know what harvesting percentage is sufficient. My comment was simply based on the considerations one must make when reading an intent-to-treat analysis versus a per-protocol analysis.

5) You say, I quote “The claim is that the interactions with the FDA are the cause, specifically a change in the primary endpoint of the trial. Curious. Perhaps this timing gives outsiders a view into the confidence expressed by the company”.

It is true that Cardio3 is pushing back patient enrollment for Chart-2. But there may be another reason: Cardio3 wants to obtain FDA approval to use C-Cathez in order to obtain a higher cell retention rate and better results. And to obtain this approval they need the futility results from Europe? This is a mere conjecture that I make, I might be mistaken, but what do you think of this alternative?

Comments relating to this point can be heard on the webcast of the Investor’s Day presentation. They mention a delay due to interactions with the FDA, primarily relating to the trial endpoints. I accept this to be accurate. I do not have any conjecture to make about the choice of catheter in use, and do not know if or how that impacts their FDA interactions.

6) You must know that Chart-3 will soon start in china and a trial in japan. If the investors in Cardio3 didn’t believe in it why would they be constructing a 10,000 square feet stem cell GMP production facility in Hong Kong alongside a 10,000 square feet medical center with state-of-the-art equipment? I invite you to visit their web site: http://www.medisun.hk/

Since they require facilities to generate their cell-based therapy, I don’t consider the construction / establishment of these facilities to have any bearing on the prospects of their trials. I consider these facilities simply to be a necessity for their work.


Note: The excerpts from the email were edited for clarity, and names of individuals not employed by Cardio3 were removed. Also, a few spelling corrections were presumptively made.


Comments and questions welcome.