Abbvie to Galapagos: "It's not you, it's me"

Abbvie has decided to pass up the chance to co-develop filgotinib, preferring to advance their own internal candidate ABT-494 into phase 3 trials in rheumatoid arthritis. Admittedly, this came as an initial surprise given the strong efficacy results posted by filgotinib in the DARWIN1 and 2 trials. However, Abbvie has provided 12 week data for ABT-494, allowing a quick comparison of the 12 week data across oral JAK inhibitors in rheumatoid arthritis:

ACR70 Data Across Trials (12 week time point)

Tofacinitib data from 2x5 mg arm of Study IV, 2 mg arms of RA-BUILD and RA-BEACON, 2x100 mg arm of DARWIN1, 100 mg arm of DARWIN2 and 6 mg twice-daily arms of Balances -I and II. Data are a mix of LOCF and NRI reporting.

Given these data, Abbvie’s decision is not surprising. The spread in efficacy across the various JAK inhibitors suggests ABT-494 will be very competitive, and has the added benefit of being internally developed and wholly owned. Abbie also reports that they will be moving ABT-494 into phase 3 by the end of the year, serving their intent to rapidly capitalize on the phase 2 Balance data. This left Galapagos to announce that they’re already courting offers, but that phase 3 studies will begin no sooner than early 2016. Of these three investigational JAK inhibitors, this leaves baricitinib closest to an NDA, followed by ABT-494 and then filgotinib.

Since filgotinib’s future is the most speculative of the three, some general points bear consideration in predicting the type of deal Galapagos can expect to garner in a subsequent partnership. A data package including DARWIN1 and 2 would often be considered a de-risking proposition by potential suitors, allowing Galapagos to command more favourable deal terms. However, the following points may suggest that a future deal for filgotinib may not be as lucrative, or may result in Galapagos assuming more of the financial and regulatory risk than previously:

- Filgotinib will potentially be the 4th JAK inhibitor on the market after tofacitinib, baricitinib and ABT-494. With Abbvie rapidly moving into phase 3 trials, they seem to have done their best to ensure that Galapagos is a step behind. Any potential suitor will have to consider this as a major negative to the economics of the collaboration.

- Galapagos has claimed filgotinib is the most JAK1 selective (over JAK2) of the investigational inhibitors, potentially conferring a safety advantage over predecessors like tofacitinib and baricitinib. This was often underlined by a focus on the anemia side effect profile, a talking point that I suggested was largely overblown. Galapagos claims that filgotinib is 3x more JAK1 selective than ABT-494 and by their own internal data, they claim filgotinib is also 3x more JAK1 selective than tofacitinib. This would place ABT-494 around the same JAK1 selectivity range as tofacitinib. In effect, Abbvie does not appear to be daunted by the proposition that JAK1 selectivity is a de facto advantage. In that regard, this selling point may not resonate as well with potential suitors.

- The FDA and Galapagos agreed to exclude men from the 200 mg daily dose group, centered around a potential concern for side effects to the male fertility system. Even though the daily 100 mg dose groups look strong from an efficacy perspective, the potential suitor may deem that this issue merits consideration and, subsequently, a commitment of time and resources to address.

In sum, I remain of the opinion that filgotinib is an efficacious drug for rheumatoid arthritis and Galapagos will be able to find another collaborator. However, I suspect the new deal will not be as favourable as the previous.

Postscript / Erratum:

A previous version of this entry suggested Eli Lilly and Abbvie had comparable legacies in RA disease modifying agents. That can safely be considered as incorrect and has been edited. Hat tip.

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 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.