A Phase IIa, Non-Randomized, Open-Label Dose Expansion Trial of Isunakinra in Combination With Pembrolizumab in Patients With Metastatic or Unresectable, Locally Advanced Colorectal Cancer

This study will enroll patients with colorectal cancer that is locally advanced or metastatic. The tumor must be microsatellite stable (MSS), have a tumor mutational burden that is high (TMB-H) and be kras mutated. Patients must have been treated with available approved treatments already. In this study the investigators are testing a new type of immunotherapy, the potent IL-1 inhibitor isunakinra to be added to already approved immunotherapy (PD-1/PD-L1 inhibitor) in an attempt to get this treatment to work in this treatment resistant type of tumor.

Start Date30 Jan 2025

Sponsor / Collaborator

Buzzard Pharmaceuticals AB

NCT04121442

/ CompletedPhase 1/2

Phase I/IIa, Non-Randomised, Open-Label Dose Escalation and Expansion Trial With Isunakinra Alone and in Combination With a PD-1/PD-L1 Inhibitor in Patients With Metastatic or Unresectable, Locally Advanced Malignant Solid Tumors

Isunakinra - a potent Interleukin-1 receptor inhibitor - will be given to patients with solid tumors to determine safety and tolerability of three different doses. Isunakinra will then be combined with a PD-(L)1 inhibitor. Pharmacokinetics and Pharmacodynamic effects of monotherapy treatment as well as the combination will be evaluated.

Start Date01 Sep 2020

Sponsor / Collaborator

Buzzard Pharmaceuticals AB

[+1]

JPRN-jRCT2080223361

/ CompletedPhase 3

Confirmatory study of EN-P05 in patients with tube feeding.

Start Date02 Dec 2016

Sponsor / Collaborator

EN Otsuka Pharmaceutical Co., Ltd.

100 Clinical Results associated with Isunakinra

100 Translational Medicine associated with Isunakinra

100 Patents (Medical) associated with Isunakinra

Literatures (Medical) associated with Isunakinra

01 Jul 2022·European journal of medicinal chemistryQ1 · MEDICINE

Pep5-based antitumor peptides containing multifunctional fragments with enhanced activity and synergistic effect

Q1 · MEDICINE

Article

Author: Liu, Yang ; Feng, Siliang ; Zheng, Zhibing ; Cheng, Maosheng ; Zhang, Han ; Cheng, Qin ; Tian, Long ; Meng, Qingbin ; Wang, Taoran ; Meng, Zhao

In this study, we designed a series of hybrid peptides based on pep5-TAT (P-05), comprising antitumor segment (pep5), endosomal escape segment ((LLHH)₃) and cell penetrating/membrane disrupting segment (TAT, R₉, sC18₂). These peptides exhibited remarkable antitumor activity towards tumor cells (HepG2, A549). Among them, the IC₅₀ values of peptide P-09 were 4.0 and 4.8 times lower than those of P-05 in HepG2 and A549 cells, respectively. It was proved that P-09 could enter tumor cells through endocytosis and direct penetration and induce the apoptosis and necrosis. The antitumor effects were attributed to the synergistic effect of membrane disruption and proteasome inhibition, which occurred during and after the cellular entry, respectively. The whole process was accompanied by excessive ROS production. In vivo, P-09 exhibited enhanced ability to inhibit the growth of HepG2 subcutaneous tumor xenografts than P-05 in nude mice. In brief, this work provided valuable insights into the design of peptide-based antitumor agents with synergistic antitumor effects.

01 May 2019·Applied opticsQ3 · ENGINEERING & TECHNOLOGY

Effects of forward models on the semi-analytical retrieval of inherent optical properties from remote sensing reflectance

Q3 · ENGINEERING & TECHNOLOGY

Article

Author: Zhou, Wen ; Ma, Ronghua ; Lin, Junfang

Inherent optical properties (IOPs) play a key role in modulating an aquatic light field; they are the core link for remotely sensing water constituents based on ocean color remote sensing. Many semi-analytical algorithms (SAAs) have been developed to obtain IOPs from remote sensing reflectance (R_rs) data; these algorithms require a forward model (FM) to link the IOPs to R_rs. Most currently available SAAs use the FM presented by Gordon et al.[J. Geophys. Res.93, 10909 (1988)JGREA20148-022710.1029/JD093iD09p10909] (G88 hereafter) without knowledge of how other models would impact the retrieval of IOPs from R_rs. This study evaluates the effects of two popular SAAs, namely, the quasi-analytical algorithm (QAA) and the generalized IOP algorithm (GIOP), combined with six different FMs on the retrieval of IOPs from a synthetic data set generated with Hydrolight software. The results indicated that different FMs can have quite different effects on the computed R_rs(λ), and the effects were not uniform across the R_rs spectrum. Of the six FMs tested, G88 and P05 [Appl. Opt.44, 1236 (2005)APOPAI0003-693510.1364/AO.44.001236] produced the best estimates of R_rs(λ) at 350, 440, and 550 nm in both oceanic and coastal sub-datasets; they also were less impacted by changes in the particle phase function. M02 also produced a good estimation of R_rs but only at 440 nm, and L04 performed well only in the oceanic condition. When the two SAAs were combined with the six FMs, in the oceanic condition, QAA and GIOP combined with M02 (QM02 and GM02) provided better quality for the absorption coefficient [a(λ)] at 350, 440, and 550 nm when compared with the SAAs combined with the other models. However, for the retrieval of the particle backscattering coefficient [b_bp(λ)] in the oceanic condition, QAA and GIOP combined with L04 (QL04 and GL04) performed better than the others, and GL04 always provided a better estimation of b_bp(λ) than QL04. In the coastal condition, QAA and GIOP combined with G88 or P05 produced slightly better quality of IOPs compared with the other four FMs. Compared with GIOP in the coastal condition, QAA combined with G88 or P05 always showed better quality of retrieval of a(λ) but weaker quality of retrieval of b_bp(λ).

01 May 2018·Eye & contact lensQ4 · MEDICINE

Preclinical Development of EBI-005: An IL-1 Receptor-1 Inhibitor for the Topical Ocular Treatment of Ocular Surface Inflammatory Diseases

Q4 · MEDICINE

Article

Author: Bracken King ; Elizabeth Hopkins ; Allyson Masci ; Eric S. Furfine ; Kelly Tenneson ; Kathy Collins ; Jay Hou ; Jeremy Fry ; Christian Li ; Steve Weber ; Gary Wolfe ; Joseph Kovalchin

Objective::

Topical interleukin (IL)-1 receptor (R)1 blockade is therapeutically active in reducing signs and symptoms of dry eye disease. Herein, we describe in vitro and in vivo nonclinical Investigational New Drug (IND)-enabling studies of EBI-005, a novel protein chimera of IL-1β and IL-1 receptor antagonist (IL-1Ra or anakinra) that potently binds IL-1R1 and blocks signaling. These studies provide an assessment of receptor affinity, drug bioavailability, immunogenic response, safety, and tolerability in mice and rabbits.

Methods::

In vitro and in silico along with Good Laboratory Practices (GLP) and non-GLP in vivo studies in mice and rabbits assessed the topical ocular and systemic immunogenicity and toxicology of EBI-005. Animals were treated with EBI-005 once daily subcutaneously or four times daily by topical ocular administration for up to 6 weeks (with 2-week recovery phase).

Results::

EBI-005 has 500 times higher affinity than anakinra to IL-1R1. Predictive immunogenicity testing suggested that EBI-005 is not more immunogenic. Systemic bioavailability of EBI-005 is low (1.4% in mice and 0.2% in rabbits) after topical ocular administration. EBI-005 penetrated into the anterior ocular tissues within 15 min of topical ocular administration. However, it is low or undetectable after 4 hr and does not form a depot after repeated topical ocular administration. EBI-005 was safe and well tolerated, and exposure to drug was maintained despite an antidrug antibody response after systemic administration, based on IND-enabling toxicology and safety pharmacology studies.

Conclusions::

Ocular doses of EBI-005 at 50 mg/mL in mice and rabbits totaling 0.15 mg/eye in mice and 1.5 mg/eye in rabbits, administered 4 times daily, did not produce adverse effects, and demonstrated excellent bioavailability in target tissues with low systemic exposure. In addition, immunogenic response to the drug did not cause adverse effects or diminish the drug's activity in most cases. The results support drug administration of the highest anticipated human clinical study dose of a 20 mg/mL solution (40 μL 3 times daily in each eye).

News (Medical) associated with Isunakinra

16 Aug 2021

·medcitynews.com

Sesen Bio says rejected bladder cancer drug may need new clinical trial

Sesen Bio reached agreement with the FDA a week ago on the product label for its new bladder cancer drug, one of the final steps for bringing a new drug to the market. Wrapping up product labeling is usually a sure sign regulatory approval is forthcoming. But on Monday, Sesen CEO Tom Cannell said the biotech may need to run a new clinical trial. From Cannell’s telling, until receiving the FDA letter rejecting the drug Vicineum on Friday, there were no indications that the submission was in trouble. During a July 13 meeting, the agency did not flag any deficiencies in the clinical trial data, nor did it ask for a confirmatory clinical trial or require input from an advisory committee comprised of independent experts. The rejection of the drug, which the company had projected could become a blockbuster seller globally, was a “surprising turn of events,” Cannell said during a Monday conference call. According to Sesen, the FDA’s letter provided recommendations about additional clinical and statistical data analyses. Providing this information may require another clinical trial. The company added that the regulator raised chemistry, manufacturing, and controls issues. Sesen develops targeted protein fusion therapies. These drugs are made by genetically fusing a targeting antibody with another protein that’s toxic to tumors, yielding a single molecule that is rapidly taken up by the targeted cancer cell. These therapies are intended to be an alternative to antibody drug conjugates (ADC), in which a cytotoxic payload is chemically linked to a targeting antibody. While ADCs have secured regulatory approvals, Sesen has said its fusion proteins could offer efficacy and safety advantages. Vicineum, Sesen’s lead drug candidate, was developed to treat non-muscle invasive bladder cancer that has not responded to earlier treatment with Bacillus Calmette-Guerin (BCG), an immunotherapy commonly used to treat early-stage bladder cancer. The company tested Vicineum, which is injected directly into the tumor, in an open-label study enrolling 133 patients. The main goal of the Phase 3 clinical trial was to measure the complete response rate to the therapy. As of the May 2019 cutoff date, 82 patients in the study could be evaluated. At the three-month mark, the complete response rate was 39%; at six months, 26%; at nine months, 20%; and after one year, 17%. Though FDA agreed to the complete response endpoint, Cannell said that the agency’s guidance ahead of the clinical trial left the door open for another study. “In the February 2018 guidance, the FDA states that a single arm trial clinical trial with a complete response rate and duration of response as the primary endpoint, can provide primary evidence of effectiveness to support a marketing application,” Cannell told financial analysts. “However, in that guidance the FDA also makes it clear that an additional trial may be necessary.” Cannell said Sesen needs to clarify what the FDA needs to see from this clinical trial, such as whether the main goal should be measuring complete response and duration of response to the therapy. The company needs to know whether 90 to 100 patients is enough, or whether the agency wants a larger sample size. Also unclear is whether the FDA wants a study running longer than 12 months. Sesen is seeking clarity about the FDA’s manufacturing concerns. Cannell said that Vicineum made for clinical trials came from the company’s Winnipeg facility, which does not have the capacity for commercial-scale production. Sesen has agreements with Fujifilm Diosynth Biotechnologies, Baxter Oncology, and Qilu Pharmaceutical for manufacturing of Vicineum. Cannell said that Sesen must be able to show that the drug made by the company’s commercial partners is almost identical to the drug that was tested in clinical trials. Sesen was previously known as Eleven Biotherapeutics, a biotech that focused on developing protein drugs to treat eye diseases. The company shifted its focus to cancer with the 2016 acquisition of Canada-based Viventia Bio. That deal happened after Eleven reported its drug isunakinra failed a pair of Phase 3 studies, first in dry eye disease and then later in conjunctivitis. Eleven changed its name to Sesen in 2018. The FDA’s Vicineum rejection could amount to at least a two-year delay for the drug. If Sesen needs another 12-month trial, enrolling patients and conducting the study means a new biologics license application could be ready in 2023, Cannell said. After resubmission, the FDA timetable for a response is six months. As of the end of the second quarter of this year, Sesen reported a cash position of $151.1 million. Cannell said that the company believes the capital is sufficient to support the resubmission of the Vicineum application. Image by Getty Images

CollaborateAntibodyImmunotherapyAcquisitionLicense out/in

12 Aug 2016

·www.biospace.com

Struggling Eleven Bio Explores Sale of the Company

August 12, 2016 By Alex Keown , BioSpace.com Breaking News Staff CAMBRIDGE, Mass. – Shares of Eleven Biotherapeutics have jumped nearly 12 percent this morning after the company released its quarterly reports which includes a note that executives may look to sell the company or some of its assets as an answer to recent financial issues stemming from two failed drug trials. In its quarterly report, which included a note about strategic alternatives, was an item about a possible company sale, as well as entering into strategic partnerships or the sale of some assets not involved in a recent deal with Roche. Another option the company could consider is a distribution of all or a portion of payments Roche will make to the company under the license agreement struck in June. Eleven and Roche entered into a $270 million deal to develop Eleven’s experimental EBI-031 treatment for eye-related diseases, such as diabetic macular edema and uveitis. EBI-031 is a humanized monoclonal antibody that binds Interleukin-6 (IL-6) and inhibits all known forms of IL-6 cytokine signaling. EBI-031 was designed for intravitreal delivery using Eleven Biotherapeutics’ AMP-Rx platform. The drug blocks both free IL-6 and IL-6 complexed to the soluble IL-6 receptor. Under the agreement Eleven will be entitled to an upfront payment of $7.5 million, along with potential future milestone payments of up to $262.5 million. The first potential future milestone payment of $22.5 million, is subject to the effectiveness of an investigational new drug application for EBI-031, which was filed with and accepted by the U.S. Food and Drug Administration. For the past year, Eleven Biotherapeutics has struggled with the failure of two experimental therapies. On Jan. 10, the company announced that its Phase III clinical trial of EBI-005 (isunakinra) for severe allergic conjunctivitis did not meet its primary endpoint. That was the second time EBI-005 failed to live up to expectations. In May 2015, the company reported that EBI-005, this time being studied for the treatment of moderate to severe dry eye disease, failed to prevent damage to the cornea or reduce eye pain in comparison to the control group. With its failed drug trials, Eleven Biotherapeutics’ stock has struggled, to say the least. Since the January failure of EBI-005, shares of Eleven have struggled to rise above $1 per share, earning the threat of delisting from Nasdaq on March 3. However, over the past couple of months, shares of Eleven have steadily risen following the agreement with Roche and a round of layoffs to a high this morning of $4.83 per share. In its report, Eleven showed revenue of $300,000 for the three months ended June 30, compared to $100,000 for the same period in 2015. The company said a net loss to shareholders was $6.5 million during the same time period. Eleven said it has approximately $8.5 million in cash and cash equivalents, which it believes combined with the first payment from Roche, will be sufficient to fund operations through 2017.

Phase 3License out/inFinancial StatementPhase 2Clinical Result

13 Jun 2016

·www.biospace.com

Struggling Eleven Bio Forges Deal Worth $270 Million with Pharma Giant Roche

June 13, 2016 By Alex Keown , BioSpace.com Breaking News Staff CAMBRIDGE, Mass. – Struggling Eleven Biotherapeutics may have finally caught a break. The company struck a $270 million deal with pharma giant Roche to develop Eleven’s experimental EBI-031 treatment for eye-related diseases, such as diabetic macular edema and uveitis. As a result, have soared this morning, hitting a high of $3.90 per share as of 9:35 a.m. Currently the stock is up more than 51 percent this morning, trading at $2.79 per share. EBI-031 is a humanized monoclonal antibody that binds Interleukin-6 (IL-6) and inhibits all known forms of IL-6 cytokine signaling. EBI-031 was designed for intravitreal delivery using Eleven Biotherapeutics’ AMP-Rx platform. The drug blocks both free IL-6 and IL-6 complexed to the soluble IL-6 receptor. Under the agreement, Eleven will be entitled to an upfront payment of $7.5 million, along with potential future milestone payments of up to $262.5 million. The first potential future milestone payment of $22.5 million, is subject to the effectiveness of an investigational new drug application for EBI-031, according to a statement issued by Eleven Biotherapeutics. The payment is time-related. If the IND becomes effective before Sept. 15, the company will receive the $22 million, but Eleven will lose $2 million if the IND becomes effective after Sept. 15, the company said. Eleven Biotherapeutics submitted the IND this morning to the U.S. Food and Drug Administration, Abbie Celniker , Eleven’s president and chief executive officer said in a statement. “We are pleased to see Roche poised to further develop this potent IL-6 blocker for the potential benefit of patients. As previously announced, we also continue to evaluate additional strategic alternatives with a goal to maximize shareholder value,” Celniker said. For the past year, Eleven Biotherapeutics has struggled with the failure of two experimental therapies. On Jan. 10, the company announced that its Phase III clinical trial of EBI-005 (isunakinra) for severe allergic conjunctivitis did not meet its primary endpoint. That was the second time EBI-005 failed to live up to expectations. In May 2015, the company reported that EBI-005, this time being studied for the treatment of moderate to severe dry eye disease, failed to prevent damage to the cornea or reduce eye pain in comparison to the control group. With its failed drug trials, Eleven Biotherapeutics’ stock has struggled, to say the least. Since the January failure of EBI-005, shares of Eleven have struggled to rise above $1 per share, earning the threat of delisting from Nasdaq on March 3. The notice was issued after the stock fell below $1 per share and did not meet the $5,000,000 minimum stockholders’ equity requirement.

Phase 3License out/inPhase 2Financial Statement

100 Deals associated with Isunakinra

External Link

KEGG	Wiki	ATC	Drug Bank
D11759	-	-	DB12373

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Conjunctivitis, Allergic	Phase 3	United States	Sesen Bio, Inc.	01 Jul 2015
Dry Eye Syndromes	Phase 3	United States	Sesen Bio, Inc.	01 Jan 2014
Metastatic Colorectal Carcinoma	Phase 2	United States	Buzzard Pharmaceuticals AB	30 Jan 2025
Solid tumor	Phase 2	Sweden	Buzzard Pharmaceuticals AB	15 Jul 2022
Locally Advanced Malignant Solid Neoplasm	Phase 2	United States	Buzzard Pharmaceuticals AB	01 Sep 2020

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ESMO_IO2023	Not Applicable	Advanced Malignant Solid Neoplasm	15	Isunakinra	jkiiqravck(ezckfrvtrk) = zccjnzqekc ljqufowizg (exabpsxtlk )	-	07 Dec 2023
				Isunakinra + Nivolumab	jkiiqravck(ezckfrvtrk) = hjvcvwtpon ljqufowizg (exabpsxtlk )
NCT04121442 (ASCO 12023 \| ASCO 22023) Manual	Phase 1	Solid tumor	15	Isunakinra	bteoqwtibn(vsphypnhvq) = suyrhxwctj mibemwxukp (qvwqyxsbjo ) View more	Positive	26 May 2023
NCT01745887 (EBI, Pubmed) Manual	Phase 1	Dry Eye Syndromes	-	EBI-005	lvdarnqdvs(trmatjsuvw) = aagzlhdnnw cbbbufmala (gqqeiyjugw ) View more	Positive	01 Sep 2017
				Placebo	-
NCT01998802 \| NCT02405039 (EBI-005, ARVO2015)	Phase 3	Inflammation	-	EBI-005 5 mg/mL	abuqhzxfec(uyxasutgwm) = dmonshdnok tnxdobbeci (dklikszvem ) View more	Positive	01 Jun 2015
				EBI-005 20 mg/mL	abuqhzxfec(uyxasutgwm) = gdkvyoasdw tnxdobbeci (dklikszvem ) View more
NCT01998802 (BusinessWire) Manual	Phase 3	Dry Eye Syndromes	669	EBI-005	ogzfkgzwwq(fkhgdtzusb) = xitzekrznv yxkzpxyjqj (rdoaearwln ) View more	Negative	18 May 2015
				Placebo	-
ARVO2014	Not Applicable	Xerophthalmia	74	EBI-005 5 mg/mL	eacwujfxhl(ridcfrwlsw) = iamnjlfkcb kurrwqbbbh (qpbwnisjxu )	-	01 Apr 2014
				EBI-005 20 mg/mL	eacwujfxhl(ridcfrwlsw) = htecdhnvmu kurrwqbbbh (qpbwnisjxu )

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