Roche ulcerative colitis drug flunks Phase I trial: regulatory roundup
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Regulatory roundup: Roche’s ulcerative colitis asset plunges after Phase I terminated

By Reynald Castaneda 01 Nov 2021 (Last Updated November 1st, 2021 14:08)

Eli Lilly’s lebrikizumab in eczema and AbbVie in blood cancers are among other assets reviewed by GlobalData’s Investigative News team.

Regulatory roundup: Roche’s ulcerative colitis asset plunges after Phase I terminated
Roche’s chances to advance RO7049665 in ulcerative colitis dropped by 33 points after its Phase I trial was terminated. Credit: Taljat David / Shutterstock.com

Need to know:

GlobalData’s Investigative News team reviews data generated by an in-house model that combines machine learning and its proprietary algorithm. Likelihood of Approval (LoA) provides the probability of a drug in securing market authorization; Phase Transition Success Rate (PTSR) indicates the probability of a drug advancing to the next stage of development. The model uses data points from individual drugs, clinical trials, regulatory milestones, company, and financial databases.

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Roche terminates Phase I UC trial

Roche’s chances to advance RO7049665 in ulcerative colitis dropped by 33 points after its Phase I trial was terminated. The therapy’s PTSR dropped to 34% after a trial termination update was posted on ClinicalTrials.gov. The trial termination also dropped RO7049665’s LoA to 5% after a four-point drop.

The reason cited for the trial’s (NCT03943550) termination was the “lack of robust clinical improvement in the underlying condition after eight weeks of treatment”, as per the study’s 20 October ClinicalTrials.gov update. The PTSR was appraised on 21 October.

The Phase I study was designed to evaluate the safety and pharmacokinetics of RO7049665 in 45 participants. RO7049665 is a conjugate of human interleukin-2 and immunoglobulin G. More specifically, the subcutaneously delivered therapy is expected to stimulate and expand T regulatory cells but not effector T cells.

Lilly bolsters approval shot in eczema

Eli Lilly’s lebrikizumab improved its approval likelihood, rising to 42%, in moderate-to-severe atopic dermatitis (eczema) after the status of one of its Phase III trials was updated to ‘completed’ on ClinicalTrials.gov. The 5-point increase in lebrikizumab’s LoA occurred on 21 October after the trial status was changed the day prior (20 October).

Results from the Phase III ADhere trial (NCT04250337), investigating lebrikizumab in combination with topical corticosteroids, will be available at YE, a 16 August announcement states. ADhere has two coprimary endpoints measured over a 16-week timeframe. The first endpoint is evaluating the proportion of patients who achieved a 0 or 1 score in the Investigator Global Assessment (IGA) scale, on top of a reduction of 2 or more points from baseline. The second endpoint is counting how many participants experience a 75% or higher reduction in the Eczema Area and Severity Index (EASI) from baseline.

In August, the company had announced positive results from two Phase III monotherapy lebrikizumab trials ADvocate1 (NCT04146363) and ADvocate1 (NCT04178967). Lilly gained lebrikizumab as part of its USD 1.1bn acquisition of Dermira in early 2020.

AbbVie likely to progress in blood cancers

AbbVie’s combination of Venclexta (venetoclax) and navitoclax saw the drugs’ respective PTSR in lymphoblastic lymphoma and acute lymphocytic leukemia (ALL) grow after a Phase I trial was completed and its results were posted. The PTSR rose by 16 points for Venclexta to 82% in lymphoblastic lymphoma and five points to 64% in ALL for navitoclax, respectively.

Results of the 69-subject open-label Phase I trial (NCT03181126) were posted on 14 October on ClinicalTrials.gov. GlobalData had its latest update on 20 October. The study sought to determine the safety, PK, and efficacy of Venclexta in combination with navitoclax in patients suffering from ALL or lymphoblastic lymphoma.

The study measured the number of participants with dose-limiting toxicities after the first dosing over a 28-day timeframe as one of the primary outcomes, and the complete response (CR) rate over a 9-month timeframe as one of the secondary outcomes. The study results involved 47 subjects who were in the dose escalation portion and 22 in a safety expansion cohort. The CR rate in all treated subjects was 56.5%, with an estimated median duration of complete response of 6.5 months.

In an earlier update with 47 patients from the dose escalation part, the CR rate was 59.6%. As per the latest update, over 97.1% had reported treatment-emergent adverse events (AE) while 10 subjects died due to fatal TEAEs. Two fatal TEAEs were determined to have been linked to Venclexta or navitoclax.

The study completion and results also spurred growth in the assets’ LoA. The LoA in ALL for navitoclax rose by one point to 8%, and by three points to 15% in lymphoblastic lymphoma for Venclexta.

Salarius completes Phase I CRC trial

Salarius Pharmaceuticals’ SP-2577 (seclidemstat) saw its PTSR climb by 10 points to 31% in colorectal cancer (CRC) upon completion of its Phase I trial. Seclidemstat is an oral, small molecule that inhibits LSD1, which is linked to several gene regulatory proteins in a variety of cancers.

The 23-patient Phase I (NCT03895684) was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of seclidemstat, and identify a recommended dose for the Phase II trial, according to a July 2019 media release that announced the enrolment of the first Phase I patient. The Phase I study recruited patients with advanced solid tumors such as breast, colorectal, and ovarian cancers barring those with Ewing sarcomas, as well those with as non-Ewing sarcomas and other cancers where there is single agent seclidemstat preclinical activity.

The Phase I status was updated on ClinicalTrials.gov on 18 October, with the asset’s PTSR revised on 20 October. Seclidemstat also saw a modest 2-point increase to 8% in its LoA following this news.

Entasis likely to progress in infectious disease

Entasis Therapeutics’ beta-lactamase inhibitor combination of durlobactam sodium and sulbactam (SUL-DUR) saw its PTSR rise across five infectious indications when positive Phase III results were announced. Among these, most significantly the PTSR for SUL-DUR in acinobacter infections grew by 16 points to 36% and nine points to 63% in hospital acquired pneumonia (HAP).

Topline results of the completed 207-subject Phase III (NCT03894046) were announced in a company press release dated 18 October. GlobalData had its latest update on 22 October.

The open-label study sought to determine the efficacy and safety of intravenously administered SUL-DUR in patients suffering from infections caused by Acinetobacter-baumannii calcoacetius complex bacteria. Both drugs in the combo inhibit beta-lactamase that is produced by bacteria, and reduce bacterial activity. Sulbactam is approved for use in treating infections caused by bacteria resistant to beta-lactam antibiotics.

The trial measured the all-cause mortality in participants with Acinetobacter-baumannii infections over a 28-day timeframe as the primary outcome. The mortality for SUL-DUR was 19%, while that with the comparator colistin was 32.2%. The combination met its primary safety objective in achieving a significant reduction in nephrotoxicity compared to colistin.

The study completion and results also spurred growth in the assets’ LoA. The LoA for SUL-DUR in Acinetobacter infections rose by 10 points to 23%, and by seven points to 48% in HAP.

Soliris biosimilar jumps in PNH

Samsung Bioepis’ biosimilar of AstraZeneca’s Soliris (eculizumab) saw its LoA in paroxysmal nocturnal haemoglobinuria (PNH) jump by 27 points to 50% after its Phase III trial listing was updated as completed. The biosimilar SB12’s ClinicalTrials.gov page was revised on 25 October, with the LoA appraised the next day (26 October).

Soliris was originally developed by Alexion Pharmaceuticals, which was acquired by AstraZeneca in July 2021. Soliris is one of the most expensive drugs in the world. It has a list price of about USD 470,000 annually, with a 2027 patent expiry, public information shows. With that in mind, many companies are developing Soliris biosimilars, potentially in time for launch once AstraZeneca’s patent ends.

In the 50-patient Phase III SB12 trial (NCT04058158), participants are randomized to receive either Soliris or the biosimilar. The trial has coprimary endpoints looking into hemolysis as measured by lactate dehydrogenase at week 26 and then week 52. Soliris was FDA approved in March 2007 for PNH and has since been approved in hemolytic uremic syndrome and myasthenia gravis. Samsung Bioepis is based in Incheon, South Korea.

Avrobio reports interim safety data

Avrobio’s two gene therapy candidates in rare diseases saw their PTSR jump five points each on the heels of positive interim safety data. The PTSR is now 60% for AVRRD-01 in Fabry disease, and 53% for AVRRD-02 in Gaucher’s disease.

For AVRRD-01, there were no reported drug-related AEs in the first eight patients dosed in the Phase II FAB-GT trial (NCT03454893). The same was reported in all five patients dosed in a Phase I study (NCT02800070), according to a 19 October company press release. The PTSR for both assets were updated on 21 October.

Additional efficacy data from both Fabry disease trials will be detailed in 1Q22. The 12-patient Phase II study is still enrolling and has a coprimary efficacy endpoint of change in the average number of Gb3 inclusions per kidney peritubular capillary (PTC) after 48 weeks. The Phase I trial has an estimated primary completion date of February 2024.

As for AVRRD-02 in Gaucher’s disease, there were also no reported treatment-related AEs for the first patient dosed in the Phase I/II Guard1 trial (NCT04145037). The 16-patient Gaucher’s disease has dosed its second patient, and its ClinicalTrials.gov page lists eight coprimary endpoints, including AEs and spleen and liver volume.

The interim safety data also resulted in modest bumps to each assets’ LoA. AVRRD-01’s LoA rose two points to 25%, while AVRRD-02’s LoA rose four points to 36%.

SIFI jumps in rare eye disease

SIFI’s polyhexanide monotherapy saw its LoA leap seven points to 15% in acanthamoeba keratitis (AK) after positive topline Phase III data was announced. AK is a rare, severe corneal infection associated with permanent visual impairment and blindness. Polyhexanide, administered as an eye drop, is an anti-infective polymer that acts on Acanthamoeba, a microscopic, free-living amoeba.

Catania, Italy-based SIFI reported topline Phase III (NCT03274895) results on 13 October, and the LoA change took effect on 21 October. The 130-patient trial divided patients into two groups: one receiving polyhexanide 0.08% monotherapy, and the other having polyhexanide 0.02% plus Sanofi’s Brolene (propamidine) 0.1%. The patients receiving polyhexanide 0.08% monotherapy met the primary endpoint of clinical resolution rate after 12 months.

SIFI said it eyes filing to the European Medicines Agency in 1H22. SIFI also plans to file in the US, where the company already has FDA orphan drug designation, though no specific timeframe has been given.

Ocular fails Phase II test

Ocular Therapeutix’s potential to advance OTX-CSI in dry eye disease dropped after a Phase II trial did not reach its primary endpoint. OTX-CSI’s PTSR lowered by 27 points to 17%. OTX-CSI is a long-acting cyclosporine intracanalicular insert.

The company announced topline Phase II OTX-CSI results on 22 October and the PTSR change occurred on 26 October. Following topline results, OTX-CSI’s LoA also dropped by six points to 3%.

The 140-subject Phase II study (NCT04362670) did not meet the efficacy primary endpoint of Schirmer’s Test that measures increased tear production at 12 weeks, as per the company’s press release. There was no difference between subjects who received two different formulations of OTX-CSI or participants in the vehicle arm.