Feature

Arthritis drug market rattles as upadacitinib wins race to FDA approval

In a landmark FDA approval, AbbVie’s upadacitinib has won the race to enter the drug market as the third JAK inhibitor approved for the treatment of moderate-to-severe rheumatoid arthritis, with the drug expected to be available in the United States within the month.

Although Gilead Sciences and its rival JAK inhibitor, filgotinib, will now only be able to procure fourth place in an increasingly crowded market, the company has set the stage for a potential 2020 drug launch — an expedited timeline that could drastically narrow updacitinib’s time in the market spotlight.

Similar to other patent holders for blockbuster biologic drugs, AbbVie has built a substantial market on the back of its flagship therapy, adalimumab, and has likewise defended its commercial exclusivity in the United States with more than 130 patents. However, newly available biosimilars in Europe — where the adalimumab patent expired in 2018 — have already begun to significantly erode international revenue for their bestseller product.

With U.S. biosimilar rivals set to launch in 2023, AbbVie has developed their own competing treatment for rheumatoid arthritis, upadacitinib, a JAK inhibitor alternative to injectable TNF inhibitor biologics such as adalimumab (Humira). Granted FDA priority review in February with subsequent approval in August, AbbVie expected to launch with only tofacitinib (Xeljanz, Pfizer) and baricitinib (Olumiant, Eli Lilly) as competing JAK inhibitors for RA; this confident projection could now be jeopardized by the accelerated move by filgotinib.

In July, Gilead petitioned the FDA to fast track the approval of filgotinib, a JAK inhibitor that has shown encouraging results in phase 3 trials for rheumatoid arthritis. The petition could bring filgotinib to the market in 2020, a year or two earlier than experts had been anticipating, a move that caught manufacturers and investors alike by surprise. Market analysts have noted that an expedited approval for filgotinib would significantly reduce the time that upadacitinib might have enjoyed on the market without a third competitor in this indication.

Jasvinder Singh

Although Wall Street investors are keen to see how this will impact the bottom line of these two pharmaceutical giants, and how this may rattle price points for other RA drugs, for rheumatologists like Jasvinder Singh, MD, MPH, professor of medicine at the University of Alabama at Birmingham, the bottom line for shareholders is less important than what happens in the clinic.

“The potential of having two new drugs, whenever they are available, is a wonderful development for my patients, and I see absolutely no drawbacks at all,” he said in an interview with Healio Rheumatology. “Any new options that are going to be available are going to help people with these diseases. I need new drugs for my patients. Additionally, the competition ultimately may bring the cost of these two drugs down. I don’t think there is a winner or loser in this situation.”

While filgotinib has set much of the rheumatology drug marketplace abuzz, Sonia Choi, a Gilead spokesperson, was cautious in discussing its current status in speaking with Healio Rheumatology. “At a recent meeting with the FDA, the company provided an update about the investigational, oral, selective JAK1 inhibitor filgotinib,” she said. “As a result of this discussion, a path forward has been established to submit the new drug application for filgotinib as a treatment for rheumatoid arthritis in 2019. It is not possible to confirm a potential approval date following the FDA review process. Its efficacy and safety have not been established.”

As for upadacitinib, beyond the RA market, it may prove a promising therapy for other rheumatic diseases. “Phase 3 trials of upadacitinib in psoriatic arthritis, Crohn’s disease, atopic dermatitis, ulcerative colitis and giant cell arteritis are ongoing and it is also being investigated for the treatment of ankylosing spondylitis,” an AbbVie spokesperson told Healio Rheumatology.

Potential pitfalls to approval

In the run-up to review, filgotinib is currently undergoing rigorous investigation in RA and other conditions. In the phase 3 FINCH 3 study, filgotinib plus methotrexate was associated with improvement in joint swelling and tenderness after 24 weeks of therapy, according to a statement from Gilead and Galapagos. Both the 100-mg and 200-mg formulations of the drug yielded positive results.

Like upadacitinib, filgotinib is also undergoing rigorous study in a cross-section of diseases. “Filgotinib is being investigated in the FINCH studies in rheumatoid arthritis, the EQUATOR phase 2 program in psoriatic arthritis, the TORTUGA study in ankylosing spondylitis, the DIVERSITY phase 3 trial in Crohn’s disease, along with small bowel and fistulizing Crohn’s disease phase 2 studies and the phase 3 SELECTION trial in ulcerative colitis,” Choi said.

If filgotinib has made headlines for any other reason, it is due to associations with testicular toxicity. “In routine animal studies of filgotinib, changes in semen parameters were observed in some animals receiving filgotinib at levels well above the highest intended clinical dose,” Choi said.

With this in mind, Gilead is conducting the MANTA study, a safety trial examining male reproductive safety of filgotinib in men with moderate to severe IBD, and the MANTA-RaY study, examining semen parameters of the drug in men with active RA, PsA, ankylosing spondylitis, and nonradiographic axial spondyloarthritis. “The MANTA study seeks to understand whether this finding [of changes in semen parameters] has any clinical relevance in men,” Choi said.

Regarding the possible testicular toxicity of filgotinib, Singh’s approach is to await further information. “These safety issues are always something to be seen once three or four trials are published,” he said. “As for whether this will impact the approval of filgotinib, the FDA is pretty sharp about making the right decisions with regard to patients. They are not beholden to the pharmaceutical industry when it comes to safety concerns.”

As for the competitor, a key study of upadacitinib was conducted by Klunder and colleagues, who looked at 6,399 plasma concentrations from 107 healthy individuals and 466 patients with RA gathered from other data sets.

Pharmacokinetic results showed that the drug follows a dose-proportional, bi-exponential disposition, according to the researchers. Patients with RA experienced a slightly lower upadacitinib clearance. Weight, gender, and mild or moderate renal impairment showed no associations with clinically relevant effects on upadacitinib exposure.

There has been much speculation about how filgotinib and upadacitinib will perform against one another in terms of efficacy, safety, and mechanism of action. For Singh, this is all just talk, at least for the moment, for one simple reason: “It is impossible to compare them because they have not been stacked up head-to-head in a clinical trial,” he said.

Compare and contrast

Angus Worthing

Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee, tried to view the potential rivalry between the two drugs in a positive light. “Approval of a third JAK inhibitor could improve overall patient access to treatments,” he said.

Much ado has been made about the differences between JAK1, JAK2 and JAK3 inhibitors, according to Singh. “It is all very interesting from the perspective of a basic science discussion,” he said. “However, it does not necessarily pan out with regard to side effect profile. These differences present mesmerizing and interesting hypotheses at best.”

For Singh, the true story of the drugs will be told in phase 4 post-marketing studies. “There are a lot of claims being made by the developers that one drug is better than the other, or about the safety profiles,” he said. “This one causes an increase in thromboembolisms, that one causes gastrointestinal perforations. Most of these are unsubstantiated claims. We will see how this pans out once the drugs are in use in the real world.”

Overall, Singh noted that both JAK inhibitors have demonstrated “generally good efficacy and safety” as they have moved through the clinical trial process. “I view them as being in the neighborhood of other JAK inhibitors and biologics that we have seen,” he said. “They both appear to be good drugs.”

To that point, Worthing addressed upadacitinib in the context of AbbVie’s other flagship rheumatology drug, adalimumab. “Although upadacitinib is a small molecule JAK inhibitor that preferentially inhibits JAK1 and [adalimumab] is a monoclonal antibody to TNF, both might actually work similarly, since TNF activates intracellular JAK pathways,” he said.

Choi declined to comment on how filgotinib might perform against upadacitinib or adalimumab. She also declined to comment on whether the recent petition to the FDA signifies more steps into the rheumatology arena for Gilead.

For its part, AbbVie intends to hold its position as a strong player in rheumatology. “Building off our nearly two decades of clinical expertise in the field of rheumatology, we remain committed to delivering better treatment options for patients with rheumatic diseases,” Aileen Pangan, executive medical director of Immunology Clinical Development at AbbVie, said in an interview. “We are continuing to advance our understanding of the science behind new pathways and targets.”

Looking at the big picture, Worthing encouraged rheumatologists to remain vigilant as these drugs make their way to market, for one important reason.

“Remember, pharmacy benefit managers control patient access in the U.S. market by writing step therapy formularies that are dictated by rebates from drug manufacturers,” he said. “FDA approval of upadacitinib — which is owned by the manufacturer of [adalimumab] — could allow PBMs to offer preferred access to two products in return for a single rebate from one drug maker.” “This could paradoxically reduce access to other therapies, and the possible cost savings might be hidden or thwarted by opaque PBM practices,” Worthing noted. “Rheumatologists who advocate for increased transparency in PBM dealings will be watching this closely.” – by Rob Volansky

References:

Klunder B, et al. Clin Pharmacokinet. 2018; doi: 10.1007/s40262-017-0605-6.

For more information:

  • Sonia Choi can be reached at 333 Lakeside Dr., San Mateo, California, 94404; email: Sonia.Choi@gilead.com.
  • Jasvinder Singh, MD, MPH, can be reached at 500 22nd St. South, Floor 2, Birmingham, AL 35233; email: jsingh@uabmc.edu.
  • Aileen Pangan can be reached at 1 North Waukegan Rd., North Chicago, IL, 60044; email: lindsay.cangemi@AbbVie.com.
  • Angus B. Worthing, MD, can be reached at 2730 University Blvd. West, Suite 310, Wheaton, MD 20902; email: JGivens@rheumatology.org.

Disclosure: Choi reports employment with Gilead. Pangan reports employment with AbbVie. Singh reports consulting fees — in amounts of less than $10,000 each — from Allergan Pharmaceuticals, Bioiberica, Crealta/Horizon, Fidia Pharmaceuticals, Iroko, Medscape, Merz, Regeneron, Savient, Takeda, UBM and WebMD, as well as research support from Savient Pharmaceuticals and Takeda. Worthing reports no relevant financial disclosures.

In a landmark FDA approval, AbbVie’s upadacitinib has won the race to enter the drug market as the third JAK inhibitor approved for the treatment of moderate-to-severe rheumatoid arthritis, with the drug expected to be available in the United States within the month.

Although Gilead Sciences and its rival JAK inhibitor, filgotinib, will now only be able to procure fourth place in an increasingly crowded market, the company has set the stage for a potential 2020 drug launch — an expedited timeline that could drastically narrow updacitinib’s time in the market spotlight.

Similar to other patent holders for blockbuster biologic drugs, AbbVie has built a substantial market on the back of its flagship therapy, adalimumab, and has likewise defended its commercial exclusivity in the United States with more than 130 patents. However, newly available biosimilars in Europe — where the adalimumab patent expired in 2018 — have already begun to significantly erode international revenue for their bestseller product.

With U.S. biosimilar rivals set to launch in 2023, AbbVie has developed their own competing treatment for rheumatoid arthritis, upadacitinib, a JAK inhibitor alternative to injectable TNF inhibitor biologics such as adalimumab (Humira). Granted FDA priority review in February with subsequent approval in August, AbbVie expected to launch with only tofacitinib (Xeljanz, Pfizer) and baricitinib (Olumiant, Eli Lilly) as competing JAK inhibitors for RA; this confident projection could now be jeopardized by the accelerated move by filgotinib.

In July, Gilead petitioned the FDA to fast track the approval of filgotinib, a JAK inhibitor that has shown encouraging results in phase 3 trials for rheumatoid arthritis. The petition could bring filgotinib to the market in 2020, a year or two earlier than experts had been anticipating, a move that caught manufacturers and investors alike by surprise. Market analysts have noted that an expedited approval for filgotinib would significantly reduce the time that upadacitinib might have enjoyed on the market without a third competitor in this indication.

Jasvinder Singh

Although Wall Street investors are keen to see how this will impact the bottom line of these two pharmaceutical giants, and how this may rattle price points for other RA drugs, for rheumatologists like Jasvinder Singh, MD, MPH, professor of medicine at the University of Alabama at Birmingham, the bottom line for shareholders is less important than what happens in the clinic.

“The potential of having two new drugs, whenever they are available, is a wonderful development for my patients, and I see absolutely no drawbacks at all,” he said in an interview with Healio Rheumatology. “Any new options that are going to be available are going to help people with these diseases. I need new drugs for my patients. Additionally, the competition ultimately may bring the cost of these two drugs down. I don’t think there is a winner or loser in this situation.”

While filgotinib has set much of the rheumatology drug marketplace abuzz, Sonia Choi, a Gilead spokesperson, was cautious in discussing its current status in speaking with Healio Rheumatology. “At a recent meeting with the FDA, the company provided an update about the investigational, oral, selective JAK1 inhibitor filgotinib,” she said. “As a result of this discussion, a path forward has been established to submit the new drug application for filgotinib as a treatment for rheumatoid arthritis in 2019. It is not possible to confirm a potential approval date following the FDA review process. Its efficacy and safety have not been established.”

PAGE BREAK

As for upadacitinib, beyond the RA market, it may prove a promising therapy for other rheumatic diseases. “Phase 3 trials of upadacitinib in psoriatic arthritis, Crohn’s disease, atopic dermatitis, ulcerative colitis and giant cell arteritis are ongoing and it is also being investigated for the treatment of ankylosing spondylitis,” an AbbVie spokesperson told Healio Rheumatology.

Potential pitfalls to approval

In the run-up to review, filgotinib is currently undergoing rigorous investigation in RA and other conditions. In the phase 3 FINCH 3 study, filgotinib plus methotrexate was associated with improvement in joint swelling and tenderness after 24 weeks of therapy, according to a statement from Gilead and Galapagos. Both the 100-mg and 200-mg formulations of the drug yielded positive results.

Like upadacitinib, filgotinib is also undergoing rigorous study in a cross-section of diseases. “Filgotinib is being investigated in the FINCH studies in rheumatoid arthritis, the EQUATOR phase 2 program in psoriatic arthritis, the TORTUGA study in ankylosing spondylitis, the DIVERSITY phase 3 trial in Crohn’s disease, along with small bowel and fistulizing Crohn’s disease phase 2 studies and the phase 3 SELECTION trial in ulcerative colitis,” Choi said.

If filgotinib has made headlines for any other reason, it is due to associations with testicular toxicity. “In routine animal studies of filgotinib, changes in semen parameters were observed in some animals receiving filgotinib at levels well above the highest intended clinical dose,” Choi said.

With this in mind, Gilead is conducting the MANTA study, a safety trial examining male reproductive safety of filgotinib in men with moderate to severe IBD, and the MANTA-RaY study, examining semen parameters of the drug in men with active RA, PsA, ankylosing spondylitis, and nonradiographic axial spondyloarthritis. “The MANTA study seeks to understand whether this finding [of changes in semen parameters] has any clinical relevance in men,” Choi said.

Regarding the possible testicular toxicity of filgotinib, Singh’s approach is to await further information. “These safety issues are always something to be seen once three or four trials are published,” he said. “As for whether this will impact the approval of filgotinib, the FDA is pretty sharp about making the right decisions with regard to patients. They are not beholden to the pharmaceutical industry when it comes to safety concerns.”

As for the competitor, a key study of upadacitinib was conducted by Klunder and colleagues, who looked at 6,399 plasma concentrations from 107 healthy individuals and 466 patients with RA gathered from other data sets.

PAGE BREAK

Pharmacokinetic results showed that the drug follows a dose-proportional, bi-exponential disposition, according to the researchers. Patients with RA experienced a slightly lower upadacitinib clearance. Weight, gender, and mild or moderate renal impairment showed no associations with clinically relevant effects on upadacitinib exposure.

There has been much speculation about how filgotinib and upadacitinib will perform against one another in terms of efficacy, safety, and mechanism of action. For Singh, this is all just talk, at least for the moment, for one simple reason: “It is impossible to compare them because they have not been stacked up head-to-head in a clinical trial,” he said.

Compare and contrast

Angus Worthing

Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee, tried to view the potential rivalry between the two drugs in a positive light. “Approval of a third JAK inhibitor could improve overall patient access to treatments,” he said.

Much ado has been made about the differences between JAK1, JAK2 and JAK3 inhibitors, according to Singh. “It is all very interesting from the perspective of a basic science discussion,” he said. “However, it does not necessarily pan out with regard to side effect profile. These differences present mesmerizing and interesting hypotheses at best.”

For Singh, the true story of the drugs will be told in phase 4 post-marketing studies. “There are a lot of claims being made by the developers that one drug is better than the other, or about the safety profiles,” he said. “This one causes an increase in thromboembolisms, that one causes gastrointestinal perforations. Most of these are unsubstantiated claims. We will see how this pans out once the drugs are in use in the real world.”

Overall, Singh noted that both JAK inhibitors have demonstrated “generally good efficacy and safety” as they have moved through the clinical trial process. “I view them as being in the neighborhood of other JAK inhibitors and biologics that we have seen,” he said. “They both appear to be good drugs.”

To that point, Worthing addressed upadacitinib in the context of AbbVie’s other flagship rheumatology drug, adalimumab. “Although upadacitinib is a small molecule JAK inhibitor that preferentially inhibits JAK1 and [adalimumab] is a monoclonal antibody to TNF, both might actually work similarly, since TNF activates intracellular JAK pathways,” he said.

Choi declined to comment on how filgotinib might perform against upadacitinib or adalimumab. She also declined to comment on whether the recent petition to the FDA signifies more steps into the rheumatology arena for Gilead.

PAGE BREAK

For its part, AbbVie intends to hold its position as a strong player in rheumatology. “Building off our nearly two decades of clinical expertise in the field of rheumatology, we remain committed to delivering better treatment options for patients with rheumatic diseases,” Aileen Pangan, executive medical director of Immunology Clinical Development at AbbVie, said in an interview. “We are continuing to advance our understanding of the science behind new pathways and targets.”

Looking at the big picture, Worthing encouraged rheumatologists to remain vigilant as these drugs make their way to market, for one important reason.

“Remember, pharmacy benefit managers control patient access in the U.S. market by writing step therapy formularies that are dictated by rebates from drug manufacturers,” he said. “FDA approval of upadacitinib — which is owned by the manufacturer of [adalimumab] — could allow PBMs to offer preferred access to two products in return for a single rebate from one drug maker.” “This could paradoxically reduce access to other therapies, and the possible cost savings might be hidden or thwarted by opaque PBM practices,” Worthing noted. “Rheumatologists who advocate for increased transparency in PBM dealings will be watching this closely.” – by Rob Volansky

References:

Klunder B, et al. Clin Pharmacokinet. 2018; doi: 10.1007/s40262-017-0605-6.

For more information:

  • Sonia Choi can be reached at 333 Lakeside Dr., San Mateo, California, 94404; email: Sonia.Choi@gilead.com.
  • Jasvinder Singh, MD, MPH, can be reached at 500 22nd St. South, Floor 2, Birmingham, AL 35233; email: jsingh@uabmc.edu.
  • Aileen Pangan can be reached at 1 North Waukegan Rd., North Chicago, IL, 60044; email: lindsay.cangemi@AbbVie.com.
  • Angus B. Worthing, MD, can be reached at 2730 University Blvd. West, Suite 310, Wheaton, MD 20902; email: JGivens@rheumatology.org.

Disclosure: Choi reports employment with Gilead. Pangan reports employment with AbbVie. Singh reports consulting fees — in amounts of less than $10,000 each — from Allergan Pharmaceuticals, Bioiberica, Crealta/Horizon, Fidia Pharmaceuticals, Iroko, Medscape, Merz, Regeneron, Savient, Takeda, UBM and WebMD, as well as research support from Savient Pharmaceuticals and Takeda. Worthing reports no relevant financial disclosures.