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Introduction
Skipta, the leading social network of specialized online medical communities for verified healthcare professionals, recently hosted a virtual advisory board session, through its proprietary Skipta Gather technology, asking physicians what they saw as the current unmet needs in the treatment of rheumatoid arthritis (RA). Rheumatologists surveyed wanted oral medications with higher efficacy and more favorable safety profiles [1].  They also noted that the products, once on the market, should be inexpensive with adequate coverage. Expressing frustration with the current treatment paradigm for RA, rheumatologists want more flexibility in prescribing therapies targeting different pathways to be available earlier on in the treatment algorithm. Several doctors mentioned that they are eager to employ a “treat to target” strategy, which requires access to various kinds of medication early on as physicians are meant to be more aggressive about switching individual patients from medications that don’t work. In the forum, the need for additional novel classes of RA medications was also supported by physicians’ concern for patients who have failed all lines of therapy. These insights underscore the need for therapies targeting additional pathways for RA treatment options.

Initially approved in B-cell malignancies, Bruton’s tyrosine kinase (BTK) inhibitors have emerged as a novel class of RA treatments [2]. Unfortunately, it seems these drugs have idled in mid-stage clinical trials for RA [3]. This review dives into the sea of Informa Pharma Intelligence data to provide an understanding of BTK inhibitors for the treatment of RA and what may be anchoring these drugs to early phase development for this indication. Pharmaprojects is used to navigate the landscape of RA-targeting BTK inhibitors, Trialtrove provides a picture of each drugs ability to sink or swim in individual trials, while Pharmapremia offers details on speed of development for these drugs.

Navigating Rough Waters: Initial RA Trials for BTK Inhibitors
Earlier in the year, the RAjuvenate study, evaluating Eli Lilly’s BTK inhibitor poseltinib in RA patients, failed to stay afloat after an interim analysis indicated that the trial would not likely meet the targeted efficacy, measured by ACR20 at week 12 for Part B of the study [4]. The first trial evaluating BTK inhibition in RA had suffered a similar fate as Celgene’s spebrutinib besylate did not meet its primary endpoint of improvement of ACR20 at 4 weeks in 2016.

Although not shipwrecked by lack of efficacy, AstraZeneca’s (AZ) acalabrutinib may be cut adrift for the treatment of RA. Trialtrove data shows that in early 2015, Acerta commenced ACE-RA-001, assessing the BTK inhibitor with a primary endpoint of DAS28 at week 4. Closing a year after initiation, and shortly after AZ acquired a majority equity stake in Acerta, the trial enrolled less than half of the target 70-patient accrual. The concurrent acquisition and trial shut-down is hardly surprising given AZ’s minor presence in the RA space [5]. Although no results are currently available for this trial, AZ does continue to list the study in their quarterly clinical trials appendix, indicating that potential for a label expansion outside of oncology is still an option for this drug [6].

Donning a Life Vest: Considering Dual Target Inhibition
Amidst the tempest of failed trials, a shift in strategy has emerged to buoy the effects of targeting BTK by inhibiting additional kinases. Both AbbVie and Gilead are considering dual BTK/Janus kinase (JAK) inhibition for clinical trials. AbbVie’s dual JAK1/BTK inhibitor, ABBV-599, is currently listed as being in early pipeline development while in 2017 Gilead mentioned exploring the JAK1 selective inhibitor, filgotinib, in combination with BTK inhibitor, tirabrutinib, for the treatment of RA [7].

Tacking into the Wind: Reversible BTK Inhibition
Many efforts to identify BTK inhibitors have produced compounds that bind irreversibly to cysteine-481 in the ATP binding site of BTK [8]. The adverse events emerging from first-to-market BTK targeting drug, ibrutinib, indicate that covalently bound BTK inhibitors may pose safety concerns resulting from off-target binding to equivalent cysteine residues in other kinases. Such risk may be acceptable for the treatment of a terminal illness, but for chronic diseases, a substandard safety profile can cause drugs to run aground in clinical development. Therefore, alternate methods of targeting BTK are also being explored for the treatment of RA.

In early 2016, Roche and Bristol-Myers Squibb’s (BMS) noncovalent BTK inhibitors, fenebrutinib and BMS-986142, initiated studies in RA patients [4]. Rather than targeting the cysteine residue, these drugs were designed to fill the H3 specificity pocket. In a study published in 2018, Genentech (a Roche company) makes the case that fenebrutinib is the best-in-class BTK inhibitor comparing the potency and selectivity of this compound to major competitors [8].


Table 1. Phase II randomized, controlled, BTK inhibitor trials conducted in RA patients

BTK - inhibitors

Source: Trialtrove®, August 2018


To highlight the superiority of these products, both Roche and BMS are employing advanced clinical trial design to give a wide berth to the competition. As shown in Table 1, these companies are trying to make headway by demonstrating exceptional disease activity reduction with primary outcomes of ACR50 and ACR70. Rheumatologists are interested in top notch for new treatment options since RA is a saturated market with long term safety data available for many drug options [1]. Both reversible BTK inhibitor trials also span a range of patient sub-sets by including those with resistance to conventional synthetic DMARDs as well as biologic DMARDs. Roche may additionally convince physicians and payers early on with the inclusion of comparator adalimumab, a TNF inhibitor many rheumatologists wish to see in direct comparison with novel kinase inhibitors.

Although evobrutinib was the first BTK inhibitor to initiate a second study in RA patients, Roche and BMS’ reversible inhibitors may take the wind out of Merck KGaA’s sails with their superior trial design. Merck KGaA’s Phase IIb study includes a more limited patient set, requiring study participants to be naïve to biologic DMARDs and resistant only to methotrexate [4]. Additionally, a primary outcome of ACR20 may scuttle evobrutinib’s trial when compared to potential positive results from more stringent fenebrutinib’s ACR50 or BMS’s ACR70. Merck KGaA will need to muster primary endpoints with higher efficacy and include additional treatment-resistant patient populations to win the confidence of physicians and payers.

Trailing in the Wake of Oncology: the Speed of BTK Development
With no mention of Phase III activity, this class of drugs is slowly paddling along in RA clinical trials while these products have sailed through development in oncology [3]. As shown in Figure 1, products being developed for hematologic cancers take 8.6 years on average to go from Phase I to approval. First-to-market BTK inhibitor, ibrutinib, initially entered clinical development in 2009 and was approved for mantle cell lymphoma in 2013, almost two years faster than the average speed of drug development for this indication (6.3 years) [9]. Pharmapremia data, depicted in Figure 1, shows that BTK inhibitor development in RA is indeed slower than the RA average of 3.6 years. Going on half a decade in Phase II, BTK inhibitors do appear to be marooned in the middle of RA clinical development.

Figure 1. Pharmapremia phase success rates and timelines

BKT Inhibitors_blog_figure1


Abbreviations used in figure: MCL=mantle cell lymphoma; RA=rheumatoid arthritis; BTK=Bruton’s tyrosine kinase; PoS=probability of success; LoA=likelihood of approval; Dur=duration; adv=advanced to next phase; NDA=New Drug Application; BLA=Biologics License Application

Source: Pharmapremia, August 2018

Conclusion
Although the smooth sailing to approval in oncology has not been the case for RA, sponsors designing BTK inhibitors have yet to abandon ship in the choppy waters of RA drug development. Companies are looking beyond irreversible, non-selective, single-target inhibition to shore up safety and improve efficacy. Besides developing reversible BTK inhibitors, sponsors are also optimizing molecules to reduce off-target effects and evaluating multi-kinase inhibition. This may help to address the concerns expressed by physicians about the safety of kinase inhibitors and their lack of efficacy compared to other classes of RA treatments [1].

Identifying new strategies to improve efficacy and safety profiles could produce novel oral drugs that may move up the treatment algorithm. Multiple rheumatologists expressed an interest in employing the aggressive “treat to target” paradigm requiring access to different therapies earlier in the treatment algorithm. With a likelihood of approval of less than 12% for Phase II drugs in development for RA, companies with early stage candidates are certainly fighting against the current [3]. Only time will tell if it will be anchors aweigh allowing BTK inhibitors to cruise into the market.

References

[1].Skipta, August 2018.

[2]. Norman P (2016) Investigational Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs, 25(8):891-9. Available from: https://www.tandfonline.com/doi/full/10.1080/13543784.2016.1182499 [Accessed on August 3, 2018].

[3]. Pharmapremia, August 2018.

[4]. Trialtrove®, August 2018.

[5]. Datamonitor Healthcare, August 2018.

[6]. AstraZeneca (2018) Clinical Trials Appendix Q1 2018 Results Update. Available from: https://www.astrazeneca.com/content/dam/az/PDF/2018/Q1-2018/Q1 2018 Clinical trials appendix.pdf [Accessed on August 3, 2018].

[7]. Pharmaprojects®, August 2018.

[8]. Crawford J, Johnson A, Misner D, Belmont L, et al. (2018) Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development. J Med Chem, 61(6):2227-2245. Available from: https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01712 [Accessed on August 3, 2018].

[9]. Biomedtracker, August 2018.

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