Abbvie Inc. put competitors on notice by reporting that three phase III trials of its IL-23 antagonist, risankizumab (formerly BI-655066 and ABBV-066), that collectively enrolled more than 1,600 patients met the co-primary and ranked secondary endpoints, achieving greater efficacy than Stelara (ustekinumab, Johnson & Johnson) and its legacy drug, Humira (adalimumab), in patients with moderate to severe plaque psoriasis.

After 16 weeks of treatment, risankizumab, dosed at 150 mg, met the co-primary endpoints of at least a 90 percent improvement in the Psoriasis Area and Severity Index (PASI 90) and a static Physician Global Assessment (sPGA) score of clear or almost clear (sPGA 0/1) across all three studies compared to placebo or adalimumab.

At week 16, data from the IMMvent study showed that 72 percent of patients who received risankizumab, dosed at 150 mg, achieved PASI 90 compared to 47 percent of patients treated with adalimumab (80 mg initially followed by 40 mg every two weeks starting one week after the initial dose). SPGA 0/1 was achieved by 84 percent of risankizumab patients compared to 60 percent of adalimumab patients at week 16. Additionally, complete skin clearance, or PASI 100, was achieved at week 16 by 40 percent of patients who received risankizumab compared to 23 percent of patients treated with adalimumab.

During the second phase (week 16 to week 44) of IMMvent, patients with a response of PASI 50 to less than PASI 90 to adalimumab at week 16 were re-randomized to switch to risankizumab (n=53) or continue adalimumab (n=56). Of these patients, 66 percent achieved PASI 90 at week 44 when switched to risankizumab compared to 21 percent of those who continued on adalimumab. Additionally, 40 percent of patients who switched to risankizumab achieved PASI 100 at week 44 compared to 7 percent of those who continued with adalimumab. All primary and ranked secondary endpoints in the study achieved statistical significance with "p" values of <0.001.

In ultIMMa-1 and ultIMMa-2 – replicate trials evaluating the safety and efficacy of risankizumab (150 mg) compared to placebo or ustekinumab (45 or 90 mg based on patient weight) – 75 percent of patients in the treatment arms achieved PASI 90 after 16 weeks of treatment compared to 5 percent of patients who received placebo in ultIMMa-1 and 2 percent who received placebo in ultIMMa-2. Response rates also blew away comparator ustekinumab, which achieved PASI 90 response rates of 42 percent in ultIMMa-1 and 48 percent in ultIMMa-2.

Similarly, sPGA 0/1 was achieved by 88 percent and 84 percent of risankizumab patients in ultIMMa-1 and -2 at week 16, respectively, compared to 8 percent and 5 percent of placebo patients, respectively, and 63 percent and 62 percent, respectively, for participants who received ustekinumab.

At week 16 and at one year, twice as many patients treated with risankizumab achieved PASI 100 compared to ustekinumab. At week 16, 36 percent and 51 percent of risankizumab patients achieved PASI 100 in ultIMMa-1 and -2, respectively, compared to 12 percent and 24 percent of ustekinumab patients. At one year, 56 percent and 60 percent of risankizumab patients achieved PASI 100 in ultIMMa-1 and -2, respectively, compared to 21 percent and 30 percent of ustekinumab patients.

PASI 90 was achieved by 82 percent and 81 percent of risankizumab patients in ultIMMa-1 and -2 at one year, respectively, compared to 44 percent and 51 percent of ustekinumab patients.

Like IMMvent, primary and ranked secondary endpoints achieved statistical significance across both ultIMMa trials, with "p" values of <0.001 compared to placebo and ustekinumab.

Top-line data 'hit on every metric'

The safety profile of risankizumab was consistent with that observed in phase II trials, with no new signals detected across the three studies. In ultIMMa-1 and -2, serious adverse events (SAEs) through week 16 occurred in 2 percent of patients on risankizumab compared to 3 percent and 1 percent of patients on placebo and 8 percent and 3 percent of patients on ustekinumab, respectively. Through one year, SAEs in ultIMMa-1 and -2 occurred in 8 percent and 7 percent of patients in the continuous risankizumab group, respectively, compared to 11 percent and 7 percent of patients treated continuously with ustekinumab.

In ultIMMa-2, one patient who received risankizumab died from a sudden cardiac arrest 101 days after the last study dose. A second patient on the study drug died 161 days following the last dose, with the cause of death unknown. No deaths occurred in ultIMMa-1.

In IMMvent, SAEs occurred by week 16 in 3 percent of patients in both the risankizumab and adalimumab groups. From week 16 through week 44, SAEs occurred in 6 percent of patients re-randomized to the risankizumab group and 4 percent who continued on adalimumab. One adalimumab patient was diagnosed with stage IV gallbladder cancer and died three weeks after diagnosis during the study. A second adalimumab patient was diagnosed with gallstones and underwent gall bladder surgery, resulting in death after the patient's condition deteriorated during the procedure. One patient treated with risankizumab died of an acute myocardial infarction on study day 73.

The three risankizumab patients who died had histories of cardiovascular risk factors, and their deaths were deemed by investigators as unrelated to the study drug.

Abbvie, which is scheduled to report its third-quarter earnings Friday morning, declined additional comment on the phase III data or filing plans. But analysts weren't shy. Jefferies Group LLC's Jeffrey Holford deemed findings from the first phase III studies of risankizumab so striking that he predicted "another pipeline smash hit" for Abbvie that could potentially rival the Humira franchise, which represented $16.1 billion, or 63 percent, of the North Chicago-based company's sales last year but faces upcoming competition in the U.S. and EU from Amgen Inc.'s adalimumab biosimilar.

A settlement and nonexclusive licensing agreement between the companies reached last month settled 10 Humira-related patents with expiration dates ranging from 2022 to 2033, enabling Amgen to launch its biosimilar, Amgevita, in Europe on Oct. 16, 2018, and Amjevita in the U.S. on Jan. 31, 2023. (See BioWorld, Sept. 29. 2017.)

"Whilst investor hopes were already high on risankizumab, we believe the top-line data reported today hit on every metric, with clear head to head superiority vs. Stelara and Humira, as well as strong cross trial comps vs. Cosentyx [secukinumab, Novartis AG], Taltz [ixekizumab, Eli Lilly and Co.] and Tremfya [guselkumab, Johnson & Johnson]," Holford wrote in a flash note, predicting peak sales of $1.5 billion in psoriasis alone.

Holford based his comparison with the other approved agents – citing the usual cross-trial comparison caveats – by noting that the phase III VOYAGE 1 and 2 studies of Tremfya, the only approved IL-23, showed week 16 PASI 90 response rates of 64 percent to 73 percent for the Tremfya arm. Further, he pointed out, risankizumab has a less frequent dosing regimen than Tremfya. Additionally, risankizumab's efficacy looks favorable relative to the IL-17 Taltz, he concluded, which demonstrated PASI 90 of 68 percent to 71 percent and sPGA score of clear or almost clear skin in 81 percent to 83 percent of psoriasis patients in three phase III studies.

Evercore ISI analyst Josh Schimmer concurred, writing in an email that the phase III data on risankizumab were "similarly robust" to Tremfya and "solid" vs. Taltz. Risankizumab's phase III performance also was "clearly better than Humira and Stelara" and "probably better than Cosentyx," he added.

Piper Jaffray's Richard Purkiss noted that, in the two replicate phase III studies, risankizumab demonstrated "the highest rate of complete skin clearance among all products that are currently marketed for this immune disorder."

Bigger bucks potentially could accrue to Abbvie from sales in additional indications. Abbvie has trials of risankizumab underway in psoriatic arthritis and Crohn's disease and has disclosed ulcerative colitis as another target indication. The company and collaborator Boehringer Ingelheim GmbH also have a phase IIa study underway in asthma, and Boehringer previously completed a phase II proof-of-concept study in ankylosing spondylitis, according to Cortellis Clinical Trials Intelligence.

In short, risankizumab eventually could take up Humira's mantle.

Abbvie last year agreed to pay Boehringer Ingelheim, of Ingelheim, Germany, $595 million up front to lead future development and commercialization of risankizumab. (See BioWorld Today, March 8, 2016.)

Despite the rosy reviews, Abbvie's shares (NASDAQ:ABBV) fell 2.4 percent on Thursday, closing at $89.56 for a loss of $2.21. Schimmer laid the blame at the feet of bumpy third-quarter earnings in big biotech, writing, "Thanks CELG/AMGN for offsetting what should have been a great day for ABBV." (See related story in this issue.)