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Item 1. Business

2024-03-21 compared with 2023-03-15 · 293 added, 306 removed, 689 unchanged (47% of the section changed)

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Our pipeline is comprised of three product candidates.

Our lead product candidate, CTX-009, is a bispecific antibody targeting Delta-like ligand 4 (“DLL4”), a ligand of Notch-1, and vascular endothelial growth factor A (“VEGF-A”).

Simultaneous blockade of the VEGF-A and the Notch pathways is known to turn productive angiogenesis into non-productive angiogenesis, which leads to tumor shrinkage and apoptosis.

Our second program CTX-471, is an agonistic antibody targeting a member of the tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD-137, a co-stimulatory receptor which is mostly expressed on activated, but not on resting T-cells and NK cells.

Our third program, CTX-8371, is a bispecific antibody targeting the programmed cell death protein-1 (“PD-1”), an inhibitory immune checkpoint receptor and its ligand PD-L1, two validated immune-oncology targets.

CTX-009 is currently undergoing clinical studies as a monotherapy and in combination with chemotherapy in the United States, South Korea and China. 

We currently have two open clinical trials with CTX-009 in the United States:

A Phase 2 trial of CTX-009 as monotherapy in patients with metastatic colorectal cancer (“CRC”) who received two or three prior treatment regimens and a Phase 2/3 trial of CTX-009 in combination with paclitaxel in patients with biliary tract cancer (“BTC”) who received one prior treatment regimen.

In addition, a Phase 2 trial of CTX-009 in combination with paclitaxel in patients with BTC who received one or two prior lines of treatment is ongoing in South Korea.

The first stage of the Phase 2 South Korean trial is substantially complete and the data  was reported at the 2023 American Society of Clinical Oncology Gastrointestinal (“ASCO GI”) Symposium in January 2023 and is summarized below. 

CTX-009, our bispecific antibody targeting DLL4 and VEGF-A, is currently undergoing clinical studies as a monotherapy and in combination with chemotherapy in the United States.

We currently have two open U.S.

clinical trials with CTX-009:

a Phase 2 trial of CTX-009 as monotherapy in patients with metastatic colorectal cancer (“CRC”) who received two or three prior treatment regimens and a randomized Phase 2/3 trial of CTX-009 in combination with paclitaxel in patients with biliary tract cancer (“BTC”) who received one prior treatment regimen.

The two initial indications of BTC and CRC for CTX-009 were selected based on the results of the Phase 1,1b and 2 clinical trials and the significant unmet need for effective therapeutic regimens in these patient populations.

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each year and over 200,000 patients worldwide.

BTC patients have a poor prognosis despite first line treatment with chemotherapy and immunotherapy, and no accepted standard of care in later treatment lines.

Patients with BTC have a poor prognosis despite first line treatment with chemotherapy and immunotherapy, and no accepted standard of care in later treatment lines.

For CRC, there are approximately 153,000 new patients diagnosed each year in the United States and more than 1.9 million patients worldwide.

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We intend to expand the development of CTX-009 to additional tumor types with significant unmet need such as ovarian cancer and gastric cancer, among others.

Following the generation of positive clinical data in later lines of therapy, we plan on studying CTX-009 in earlier settings in all of the indications where the data supports it.

CTX-471 is undergoing a two-part clinical trial.

Following the generation of positive clinical data in later lines of therapy, we plan on studying CTX-009 in earlier settings in all indications where the data support it.

CTX-471, our CD137 agonistic antibody, is undergoing a two-part clinical trial.

A Phase 1a trial of CTX-471 as monotherapy in patients with solid tumors who were previously treated with at least one checkpoint blocker and showed benefit for 3 months or more but ultimately progressed is fully enrolled and nearing completion.

As of January 31, 2023, there are three patients remaining on treatment.

In addition, a Phase 1b trial of CTX-471 in combination with the PD-1 inhibitor KEYTRUDA®

in patients with selected solid tumors has begun in November 2022.This Phase 1b trial is currently enrolling and dosing patients in the dose-escalation portion of the study.

As of January 31, 2024, there is one patient remaining on treatment.

In addition, a Phase 1b trial of CTX-471 in combination with the PD-1 inhibitor KEYTRUDA® in patients with selected solid tumors began in November 2022.

The dose-escalation part of the study has been fully enrolled and enrollment in the dose expansion cohorts has begun.

In the expansion cohort part of the study, we plan to enroll 60 patients with melanoma, non-small cell lung cancer (“NSCLC”) and small cell lung cancer (“SCLC”), who will randomly receive one of two doses.

CTX-471 targets a key node of the immune system with the goal of identifying a next generation immune-oncology treatment for the majority of patients who do not have a sustained response to current therapies across a variety of cancers.

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melanoma, small cell lung cancer and mesothelioma.

In the ongoing Phase 1b combination trial of CTX-471 with KEYTRUDA®

we are looking to restore responses in patients who were previously treated with a checkpoint inhibitor, initially responded but then progressed.

The hypothesis we are testing is whether the addition of CTX-471 to KEYTRUDA®

will restore responses in those patients.

In the ongoing Phase 1b combination trial of CTX-471 with KEYTRUDA® we are looking to restore responses in patients who were previously treated with a checkpoint inhibitor, initially responded, but then progressed.

The hypothesis we are testing is whether the addition of CTX-471 to KEYTRUDA® will restore responses in those patients.

This trial is being conducted in patients with one of the following solid tumors:

non-small cell lung cancer, small cell lung cancer, melanoma, mesothelioma, and head and neck cancer.

melanoma, non-small cell lung cancer and small cell lung cancer.

Restoration of meaningful responses in one or more of those indications can help shape the regulatory path for CTX-471.

Our third program, CTX-8371, is at a pre-clinical stage.

We have recently completed GLP toxicology studies and we plan to submit an investigational new drug (IND) application to the FDA in the first half of 2023.

Once the IND is cleared, we will advance CTX-8371 to a first-in-human Phase 1 clinical trial.

Our third program, CTX-8371, a bispecific antibody targeting PD-1 and PD-L1, is currently in a first-in-human Phase 1 clinical trial.

We filed an investigational new drug application (“IND”) for CTX-8371 in the third quarter of 2023 and the IND was cleared by the FDA in the fourth quarter of 2023.

The study is now open in the U.S.

with the first patient expected to be dosed in the clinical trial by early second quarter 2024.

CTX-8371 emerged from an unbiased screen conducted with our StitchMabs TM platform.

We have subsequently tested CTX-8371 in several in vitro and in vivo models where it demonstrated enhanced activation of immune responses when compared with commercially available checkpoint blockers.

We believe that CTX-8371 has a potential to become a next generation checkpoint inhibitor with improved activity across various solid tumors relative to commercially available checkpoint blockers.

Additionally, we are in the process of preclinically evaluating proprietary combination regimens of CTX-8371 with our other product candidates, CTX-009 and CTX-471.

We believe that CTX-8371 has a potential to become a next generation checkpoint inhibitor with improved activity across various solid tumors relative to approved checkpoint blockers.

Additionally, we are in the process of preclinically evaluating proprietary combination regimens of CTX-8371 with our other product candidates, CTX-009 and CTX-471.

In the fourth quarter of 2023 we announced a CEO succession plan;

Vered Bisker-Leib, who was previously Compass President and COO, transitioned to Compass Chief Executive Officer and joined Compass board of directors and Thomas Schuetz, MD, PhD, Compass’ Scientific Founder and previously Chief Executive Officer, transitioned to President of Research and Development and appointed Vice Chair of the Compass board of directors.

The transition took place on January 9, 2024.

Our management team has a successful track record of building and growing biotechnology companies.

Our Chief Executive Officer and co-founder, Thomas J.

Schuetz, M.D., Ph.D.

has over 30 years of experience in oncology, biopharmaceutical drug development and life science venture investing.

Prior to co-founding Compass Therapeutics, Dr.

Schuetz was a venture partner with OrbiMed Advisors LLC where he participated in OrbiMed’s investments in Enobia Pharma (sold to Alexion), Relypsa (sold to Galenica), Arteaus Therapeutics (sold to Eli Lilly), and Audentes (sold to Astellas) and served on the board of each of these companies.

Schuetz was also the chief medical officer of Therion Biologic Corporation and was vice president of clinical affairs at Transkaryotic Therapies, a company acquired by Shire.

Our President and Chief Operating Officer, Vered Bisker-Leib, Ph.D., M.B.A., has over 19 years of experience in strategy, finance, business development, and operations of biotechnology and pharmaceutical companies.

Under her financial leadership, Compass completed public and private financing transactions that generated $275 million in total proceeds since 2020.

Bisker-Leib identified and led the acquisition of TRIGR Therapeutics in a stock-for-stock transaction, which resulted in the addition of CTX-009 to the Compass’

Our Chief Executive Officer, Vered Bisker-Leib, Ph.D., M.B.A., has over 20 years of experience in strategy, finance, business development, and operations of biotechnology and pharmaceutical companies.

Under her financial leadership, Compass completed public and private financing transactions that generated more than $290 million in total proceeds since 2020.

Bisker-Leib identified and led the acquisition of TRIGR Therapeutics in a stock-for-stock transaction, which resulted in the addition of CTX-009 to the Compass’ pipeline.

Bisker-Leib is also a board member of Ayala Pharmaceuticals.

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Bisker-Leib was chief business officer of Cydan (a biotech accelerator) and served as an executive director and global head of business development for the cardiovascular and metabolic franchises of Bristol-Myers Squibb.

Our President of Research and Development and Co-Founder, Thomas J.

Schuetz, M.D., Ph.D.

has over 30 years of experience in oncology, biopharmaceutical drug development and life science venture investing.

Prior to co-founding Compass Therapeutics, Dr.

Schuetz was also the chief medical officer of Therion Biologics Corporation and was vice president of clinical affairs at Transkaryotic Therapies, a company acquired by Shire.

The figure below details our pipeline of product candidates:

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Our strategy to achieve this goal includes:

Advance our product candidate, CTX-009 (DLL4 x VEGF-A bispecific), through clinical development to drug approval in multiple indications, either as a monotherapy or in combination with other therapies .

CTX-009 is an investigational bispecific antibody that simultaneously blocks DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.

We chose BTC and CRC as our first indications based on a number of factors, including CTX-009 activity observed in the Phase 1, 1b and 2 clinical trials and lack of effective therapies for these patient populations in the targeted lines of therapy.

We have initiated a Phase 2 trial of CTX-009 in patients with advanced colorectal cancer and a Phase 2/3 trial of CTX-009 in combination with paclitaxel in patients with BTC.

Additionally, we intend to explore the potential of CTX-009 in other indications where the data supports its potential therapeutic benefit such as ovarian cancer, gastric cancer, pancreatic cancer, renal cell cancer, liver cancer, neuroendocrine cancer and more.

Advance our product candidate, CTX-009 (DLL4 x VEGF-A bispecific antibody), through clinical development to drug approval in multiple indications, either as a monotherapy or in combination with other therapies .

CTX-009 is an investigational bispecific antibody that simultaneously blocks the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.

We have initiated a Phase 2 trial of CTX-009 in patients with advanced colorectal cancer and a randomized Phase 2/3 trial of CTX-009 in combination with paclitaxel in patients with BTC.

Additionally, we intend to explore the potential of CTX-009 in other indications where the data support its potential therapeutic benefit such as ovarian cancer, gastric cancer, pancreatic cancer, renal cell cancer, liver cancer, neuroendocrine cancer and more.

We are also developing a plan to study the combination of CTX-009 with our other product candidates, CTX-8371 and CTX-471.

Advance our product candidate, CTX-471 (CD137 agonist), through clinical development to evaluate its therapeutic potential alone and in combination with other therapies, and define a regulatory pathway for approval.

 We seek to translate the antitumor activity of CTX-471 observed in preclinical testing and in our Phase 1 trial into meaningful clinical results in patients with solid tumors, such as small cell lung cancer ("SCLC"), mesothelioma and melanoma.

Advance our product candidate, CTX-471 (CD137 agonist antibody), through clinical development to evaluate its therapeutic potential alone and in combination with other therapies, and define a regulatory pathway for approval.

Our first Phase 1a clinical trial was conducted in patients who relapsed or progressed after at least three months of stable disease on prior checkpoint therapies.

This trial is nearing completion and as of January 31, 2023 has three patients remaining on trial.

Additionally, in November 2022, we dosed the first patient in a Phase 1b trial of CTX-471 in combination with KEYTRUDA®.

This trial is enrolling patients with metastatic or locally advanced non-small cell lung cancer, melanoma, small cell lung cancer, mesothelioma, and head and neck cancer that have progressed after treatment with a checkpoint inhibitor.

Patients enrolled in the trial will be treated with CTX-471 in combination with KEYTRUDA® with the goal of restoring response.

Advance CTX-8371 (PD-1 x PD-L1 bispecific) into clinical development as a next generation checkpoint inhibitor.

CTX-8371 , our bispecific inhibitor that targets PD-1 and PD-L1, has demonstrated higher antitumor activity in preclinical experiments than a single PD-1, a single PD-L1, or combinations of PD-1 and PD-L1 inhibitors.

IND-enabling studies, including GLP toxicology studies have been completed.

Our goal is to submit an IND application in the first half of 2023 and advance CTX-8371 into first-in-human study in the second half of 2023.

If successful, we could deliver early safety and top-line data in the first half of 2024.

As of January 31, 2024, one patient remains on trial.

Additionally, in November 2022, we dosed the first patient in a Phase 1b trial of CTX-471 in combination with KEYTRUDA®.

Patients enrolled in the trial will be treated with CTX-471 in combination with KEYTRUDA® with the goal of restoring response.

The dose-escalation portion of the study has been fully enrolled and enrollment in the dose expansion cohorts has begun.

In the dose expansion cohorts, we plan on enrolling 60 patients with melanoma, NSCLC and SCLC, who will randomly receive one of two doses.

This trial is enrolling patients with metastatic or locally advanced NSCLC, melanoma, and SCLC who have progressed after treatment with a checkpoint inhibitor.

Advance CTX-8371 (PD-1 x PD-L1 bispecific antibody) through clinical development as a next generation checkpoint inhibitor.

CTX-8371 , our bispecific inhibitor that targets PD-1 and PD-L1, has demonstrated better antitumor activity in preclinical experiments than a single PD-1, a single PD-L1, or combinations of PD-1 and PD-L1 inhibitors.

We submitted an IND to the FDA in the third quarter of 2023 and the FDA cleared the IND for CTX-8371 in the fourth quarter of 2023 allowing us to initiate a first-in-human Phase 1 clinical trial.

The study is now open in the U.S.

and we expect to dose the first patient in this study by early second quarter 2024.

Seek strategic partnerships for select product candidates.

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Product Candidates

We currently have two product candidates in the clinical stage of development:

CTX-009 and CTX-471.

In addition, our third program, CTX-8371, is expected to be in the clinic in the second half of 2023.

We currently have three product candidates in the clinical stage of development:

CTX-009, CTX-471 and CTX-8371.

CTX-009 (DLL4 X VEGF-A bispecific antibody)

CTX-009 (a.k.a.

ABL001) is an investigational bispecific antibody that is designed to simultaneously block DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.

Preclinical and early clinical data of CTX-009 as a monotherapy and in combination with chemotherapy suggest that blockade of both pathways provides robust anti-tumor activity across several solid tumors, including colorectal, gastric, cholangiocarcinoma, pancreatic and non-small cell lung cancer.

CTX-009 is undergoing clinical development in patients with advanced solid tumors in the United States, South Korea and China.

A Phase 1 dose escalation and dose expansion monotherapy trial in patients with solid tumors and a Phase 1b trial of CTX-009 in combination with chemotherapy were completed in South Korea.

In addition, a Phase 2 trial of CTX-009 in combination with chemotherapy in patients with advanced biliary tract cancer is ongoing in South Korea.

The first part of the Phase 2 trial has recently been completed and data from that study were presented at ASCO GI in January 2023.

ABL001) is an investigational bispecific antibody that is designed to simultaneously block the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.

Preclinical and early clinical data of CTX-009 as a monotherapy and in combination with chemotherapy suggest that blockade of both pathways provides robust anti-tumor activity across several solid tumor indications, including colorectal, gastric, cholangiocarcinoma, pancreatic and non-small cell lung cancer.

CTX-009 is undergoing clinical development in patients with advanced solid tumors in the United States.

A Phase 1 dose escalation and dose expansion monotherapy trial in patients with solid tumors, a Phase 1b trial of CTX-009 in combination with chemotherapy and a Phase 2 trial of CTX-009 in combination with chemotherapy in patients with advanced biliary tract cancer were completed in South Korea.

Data from the Phase 2 trial were presented at ASCO GI in January 2023.

We currently have two open clinical trials in the United States:

a Phase 2 trial of CTX-009 in patients with advanced colorectal cancer and a Phase 2/3 trial of CTX-009 in combination with paclitaxel in patients with advanced biliary tract cancer.

a Phase 2 trial of CTX-009 in patients with advanced colorectal cancer and a randomized Phase 2/3 trial of CTX-009 in combination with paclitaxel in patients with advanced biliary tract cancer.

We have licensed exclusive global rights to CTX-009, outside of South Korea, from ABL Bio, Inc.

(“ABL Bio”), a South Korea-based clinical-stage company focused on developing antibody therapeutics.

South Korean rights are held by Handok Pharmaceuticals, Inc.

(“Handok”) and China rights were out-licensed from the Company to Elpiscience Biopharmaceuticals Co., Limited (“Elpiscience”).

Monotherapy Clinical Trial of CTX-009

An open-label, Phase 1 dose escalation and expansion trial designed to identify the optimal dose and to evaluate the safety, tolerability, pharmacokinetics (“PK”), pharmacodynamics and the anti-tumor activity of CTX-009 in patients with advanced solid tumors after failure of standard of care treatment was conducted by ABL Bio in South Korea.

This trial consisted of a Phase 1a monotherapy dose escalation arm and a Phase 1b dose expansion arm.

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The dose escalation portion of the trial took place without interruption, and the highest dose arm was 17.5 mg/kg.

Importantly, the maximal tolerated dose has not been determined in this trial.

Importantly, the maximal tolerated dose was not determined in this trial.

CTX-009 was observed to be generally well-tolerated.

There were 44 Treatment Related Adverse Events (“TRAEs”) observed in more than 5% of the 45 patients enrolled.

The most prominent TRAE was hypertension, which was observed in 37.8% of the patients.

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Sixteen of the 40 evaluable patients were dosed at the 10 or 12.5 mg/kg dose levels, which represent what we project to be the efficacious dose levels.

Among those 16 patients, there were three partial responses ("PRs") confirmed by RECIST 1.1 with an overall response rate ("ORR") of 18.8% and eight patients with stable disease (“SD”), with a clinical benefit rate ("CBR") of 68.8%.

Two of the three PRs were in advanced colorectal patients and one of the three PRs was in an advanced gastric cancer patient.

Two of the three PRs were in patients with advanced colorectal cancer and one of the three PRs was in a patient with advanced gastric cancer.

In addition, one of the patients with gastric cancer had a 35% decline in tumor mass relative to baseline.

However, that regression was not confirmed upon a second CT scan, and hence not included in the ORR, and the best response of this patient included in the data set is stable disease.

The average time to progression (“TTP”) of the advanced colorectal cancer patients treated at the 10 or 12.5 mg/kg was 6.7 months, and the average TTP of the advanced gastric cancer patients treated at the 10 or 12.5 mg/kg was 3.9 months.

Phase 1 monotherapy trial:

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Prior VEGF target therapy

Median time to

progression (“TTP”)

Median time to progression (“TTP”)

Colorectal cancer

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Combination Clinical Trial of CTX-009

An open-label, combination Phase 1b clinical trial to evaluate the safety, PK, anti-tumor activity and the recommended Phase 2 dose (“RP2D”) of CTX-009 in combination with paclitaxel or irinotecan chemotherapy was conducted by ABL Bio and Handok in South Korea.

This trial was initiated in June 2020, enrollment was completed in December 2020, and the trial was completed in November 2021 (clinicaltrials.gov identifier NCT04492033).

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In general, CTX-009 was observed to be well-tolerated.

Adverse Events (“AEs”) that were determined to be probably or possibly related to CTX-009 treatment included Grade 3 hypertension observed in four patients (24%).

Other AEs observed were Grade 3 neutropenia (12%), Grade 3 anemia (18%) and Grade 3 thrombocytopenia (12%), which were all attributed to the concomitant chemotherapy agent (paclitaxel or irinotecan).

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Drug-related adverse events

observed in > 1 patient   

Thrombocytopenia*

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Of the four patients with advanced cholangiocarcinoma enrolled in the trial, there were two PRs confirmed by RECIST 1.1 with 41% and 62% declines in tumor burden, respectively, representing an ORR in cholangiocarcinoma of 50%.

A third patient with cholangiocarcinoma had stable disease with 28% decline in the patient’s tumor burden, and therefore the CBR observed in cholangiocarcinoma is three out of four, or 75%.

The responses in cholangiocarcinoma were particularly durable with a median duration of response, or DOR, of 9.7 months.

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The significant findings presented were as follows:

CTX-009 was generally well-tolerated and demonstrated single agent activity in heavily pre-treated patients with solid tumors that are resistant to anti-VEGF therapies, mostly of colorectal and gastric origins

The maximum tolerated dose (“MTD”) was not reached, and the RP2D of CTX-009 were determined to be 10.0 and 12.5 mg/kg biweekly

ORR of CTX-009 as a monotherapy across all doses tested (0.3 – 17.5 mg/kg) was 8% and the CBR was 62% in patients treated at the 3rd and 4th line settings

CTX-009 was generally well-tolerated and demonstrated single agent activity in heavily pre-treated patients with solid tumors who were resistant to anti-VEGF therapies, mostly of colorectal and gastric origins

The maximum tolerated dose (“MTD”) was not reached, and the RP2D of CTX-009 were determined to be 10.0 and 12.5 mg/kg biweekly

ORR of CTX-009 as a monotherapy across all doses tested (0.3 – 17.5 mg/kg) was 8% and the CBR was 62% in patients treated at the 3rd and 4th line settings

Treatment with CTX-009 as a monotherapy at the RP2D (10.0 mg/kg and 12.5 mg/kg) led to 18.8% (n=3/16) ORR, not including an additional unconfirmed PR, and a 68.5% CBR (n=11/16)

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A Phase 2 trial of CTX-009 in combination with paclitaxel was initiated by Handok in the first quarter of 2021 in patients with BTCs.

The study is being conducted at four leading medical centers in Seoul, South Korea, and is nearing completion.

The study has been completed and final data analysis has begun.

The trial enrolled patients with unresectable advanced, metastatic, or relapsed BTCs who had received one or two prior systemic therapies.

This Phase 2 trial utilizes a Simon Two-Stage adaptive design where the criteria to advance to the second stage of the trial was three PRs observed in 21 evaluable patients.

As of November 9, 2022, in the preliminary analysis of all 24 patients participating in the study, CTX-009 with paclitaxel demonstrated a 37.5% ORR based on 9 patients with Partial Responses (“PRs”) that were confirmed by RECIST 1.1.

The trial has met the criteria to advance to Part 2 and Part 1 of the study is mostly complete.

As of November 9, 2022, there was one patient remaining on treatment. 

The results of Part 1 of the Phase 2 trial were presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (“ASCO GI”) in January 2023.

As of November 9, 2022, in the preliminary analysis of all 24 patients participating in the study, CTX-009 with paclitaxel demonstrated a 37.5% ORR based on 9 patients with PRs that were confirmed by RECIST 1.1.

The trial has met the criteria to advance to Part 2 and Part 1 of the study is now complete.

The results of Part 1 of the Phase 2 trial were presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (“ASCO GI”) in January 2023.

Safety Data Summary

As of November 9, 2022, safety data has been analyzed and CTX-009 was observed to be generally well-tolerated.

The Phase 2 safety data are generally consistent with the safety data of the Phase 1 trials.

Of the 24 patients enrolled in the first stage of the trial, all patients had at least one treatment emergent adverse event (“TEAE”).

CTX-009 safety data has been analyzed and was observed to be generally well-tolerated.

The Phase 2 safety data are generally consistent with the safety data of the Phase 1 trials.

Of the 24 patients enrolled in the first stage of the trial, all patients had at least one treatment emergent adverse event (“TEAE”).

Grade 3 or greater TEAEs were reported in 95.8% of patients regardless of the relationship to CTX-009 or paclitaxel, including decreased neutrophil count (83.3%), hypertension (16.7%), anemia (20.8%), and decreased platelet count (12.5%).

Grade 3 or greater adverse events that were designated to be of special interest (“AESIs”) by the trial investigators were hemoptysis or hemorrhage (12.5%) and GI or tumor perforation (8.3%), with 0% for pulmonary hypertension, wound healing complication and cardiac failure.

The table below depicts a summary of the TEAEs in 24 patients as of November 9, 2022.

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Activity Data Summary

The first stage of the trial has enrolled 24 patients and 22 of those patients are considered evaluable.

Nine PRs confirmed by RECIST 1.1 have been observed leading to an ORR of 37.5%, and 22 of the 24 patients evaluated have had stable disease or better with a decline in tumor burden leading to a CBR of 92%.

The first stage of the trial enrolled 24 patients and 22 of those patients are considered evaluable.

Nine PRs confirmed by RECIST 1.1 were observed leading to an ORR of 37.5%, and 22 of the 24 patients evaluated have had stable disease or better with a decline in tumor burden leading to a CBR of 92%.

PRs were observed in all four tumor sub-types types (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma).

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In the third line, 13 patients were treated with 2 PRs observed, leading to an ORR of 15.4% in the second sub-group.

After a median follow up of approximately 12 months, the median progression free survival (“PFS”) was 9.4 months, median duration of response (“DOR”) was 6.9 months and median overall survival (“OS”) was 12.5 months. 

For reference, one regimen that has been studied in patients with advanced BTC is FOLFOX, the regimen recommended in the guidelines of the National Comprehensive Cancer Network (NCCN) for patients with BTC treated in the second-line setting.

FOLFOX demonstrated a median PFS of 4.0 months and a median OS of 6.2 months in a randomized study against best supportive care.

FOLFOX demonstrated an ORR of 5%, a median PFS of 4.0 months, and a median OS of 6.2 months in a randomized study against best supportive care.

The waterfall plot below depicts the best response for the 22 patients evaluated in the trial as of November 9, 2022.

Phase 2 Data as of November 9, 2022

CTX-009 + paclitaxel in BTC

Best Response by Patient

As of November 9, 2022, one patient remains on study.

This patient has been on the study with a durable partial response for more than 580 days.

The swimmer plot below depicts the duration that each patient has been on treatment as of November 9, 2022 (N=24):

Phase 2 Data as of November 9, 2022

CTX-009 + paclitaxel in BTC

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Patients treated in the second line setting had a median PFS of 10.0 months and patients treated in the third line setting had a median PFS of 5.5 months.

Phase 2 Data as of November 9, 2022

CTX-009 + paclitaxel in BTC

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Patients treated in the second line setting had a median OS of 11.7 months and patients treated in the third line setting has a median OS of 12.9 months.

Phase 2 Data as of November 9, 2022

CTX-009 + paclitaxel in BTC

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Status of CTX-009 Development

Our strategy is to develop CTX-009 in all of the indications in which patients have a need for effective and novel therapeutic agents and data supports the potential therapeutic benefit of CTX-009.

We chose BTC and CRC as our lead indications based on a number of factors, including CTX-009 activity observed in the Phase 1, 1b and 2 clinical trials, lack of effective therapies for these patient populations in the targeted lines of therapy and the potential for a straight-forward regulatory route to approval.

We submitted an Investigational New Drug (“IND”) application to the U.S.

Food and Drug Administration (the “FDA”) in December 2021 for CTX-009 and the FDA cleared our IND application in January 2022.

Our strategy is to develop CTX-009 in all of the indications in which patients have a need for effective and novel therapeutic agents and data support the potential therapeutic benefit of CTX-009.

We chose BTC and CRC as our lead indications based on a number of factors, including CTX-009 activity observed in the Phase 1, 1b and 2 clinical trials, lack of effective therapies for these patient populations and the potential for a straight-forward regulatory route to approval.

We submitted an IND to the FDA in December 2021 for CTX-009 and the FDA cleared our IND application in January 2022.

The following trials are being conducted in the United States under this IND.

Biliary Tract Cancers –

Biliary Tract Cancers – BTC

Following conversations with the FDA, we submitted a protocol for a randomized Phase 2/3 trial for CTX-009 in combination with paclitaxel in adult patients with unresectable, advanced, metastatic or recurrent biliary tract cancers who have received one prior systemic chemotherapy regimen.

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The primary endpoint of the trial is ORR and the secondary endpoints include PFS, DCR, DOR and OS among other.

The trial can be found on www.clinicaltrials.gov (Identifier NCT 05506943).

We have opened several clinical sites and are currently recruiting patients for this trial.

Dependingon the trial results, this trial could serve as a registrational trial to support a biologics license application ("BLA") submission for CTX-009 in combination with paclitaxel as a treatment of BTC patients in the second line setting. 

Patients who were randomized to receive paclitaxel and have progressed on their regimen may cross over to the CTX-009 plus paclitaxel arm after progression on paclitaxel if they still meet the enrollment criteria for the study.

A detailed description of the trial can be found on www.clinicaltrials.gov (Identifier NCT 05506943).

We are currently enrolling patients for this trial.

Depending on the trial results, this trial could serve as a registrational trial to support a biologics license application ("BLA") submission for CTX-009 in combination with paclitaxel as a treatment of BTC patients in the second line setting.

Enrollment is expected to be completed by mid-year 2024, with top line data expected in the second half of 2024.

Based on the trial results, a BLA could be filed as early as the second half of 2025.

Colorectal Cancer –

We submitted a protocol to the FDA for a Phase 2 monotherapy clinical trial to assess the safety and efficacy of CTX-009 in patients with metastatic colorectal cancer who have received two or three prior systemic therapies.

Colorectal Cancer – CRC

We are also conducting a Phase 2 monotherapy clinical trial of CTX-009 in patients with metastatic colorectal cancer who have received two or three prior systemic therapies.

This trial is designed to assess the safety and efficacy of CTX-009 as a monotherapy in patients with advanced colorectal cancer.

A schema of the trial design is provided below:

The trial utilizes a Simon Two-Stage adaptive design where the criteria to advance to the second stage of the trial is three PRs observed in 37 patients enrolled in Part A of the trial.

Based on the Simon Two-Stage design, when the criteria for the first stage is met, the trial progresses to the second stage, at which time 47 additional patients will be enrolled.

The trial can be found on www.clinicaltrials.gov (identifier NCT 05513742).   

In January 2023, the first patient was dosed in this trial.

Initial results from this trial may be available in the second half of 2023.

The trial utilizes a Simon Two-Stage adaptive design where the criteria to advance to the second stage of the trial is three PRs observed in 37 patients enrolled in Stage 1 of the trial.

Based on the Simon Two-Stage design, when the criteria for the first stage is met, the trial may progress to the second stage, at which time 47 additional patients could be enrolled.

The trial can be found on www.clinicaltrials.gov (identifier NCT 05513742).

In January 2023, the first patient was dosed in this trial and enrollment in Stage 1 of the trial was complete in the first quarter of 2024.

Initial results from Stage 1 of this trial are expected by mid-year 2024.

Additional Plans for CTX-009

We intend to explore the potential of CTX-009 in additional indications, based on data from pre-clinical models, potential biomarkers such as DLL4, and clinical data from CTX-009 trials providing signs of potential activity of CTX-009 in additional indications such as ovarian cancer, gastric cancer, pancreatic cancer, renal cell cancer, liver cancer, neuroendocrine cancer and others.

In addition, we are developing a plan to study the combination of CTX-009 with our novel bispecific checkpoint blocker, CTX-8371, and with other checkpoint blockers, such as pembrolizumab and atezolizumab.

Additionally, we are considering the combination of CTX-009 with our novel CD137 agonistic antibody, CTX-471, which is currently in a Phase 1b clinical trial in patients with advanced solid tumors.

CTX-471 (CD137agonist antibody)

CTX-471, our monoclonal antibody product candidate, is a fully human, IgG4 monoclonal antibody that is an agonist of CD137, a key co-stimulatory receptor on immune cells.

Binding of CTX-471 to CD137 has been observed to lead to ligand-stimulated activation of T-cells and NK cells.

In treated mice, dosing with CTX-471 led to extensive reprogramming of the tumor microenvironment, including increased recruitment of immune cells, reversion of exhausted cytotoxic CD8+ T-cells, reductions in immunosuppressive regulatory T-cells and reductions in immunosuppressive tumor-associated macrophages.

Long after the completion of the treatment with CTX-471, a period described as eight half-lives of the antibody, treated mice exhibited immune memory that prevented reestablishment of the same tumor.

In treated mice, dosing with CTX-471 led to extensive reprogramming of the tumor microenvironment, including increased recruitment of immune cells, reversal of exhausted cytotoxic CD8+ T-cells, reductions in immunosuppressive regulatory T-cells and reductions in immunosuppressive tumor-associated macrophages.

Long after the completion of the treatment with CTX-471, a period equal to eight half-lives of the antibody, treated mice exhibited immune memory that prevented reestablishment of the same tumor.

The CD137 antigenic site recognized by CTX-471 does not block the binding of CD137 ligand and is differentiated from the site recognized by CD137 antibodies from competitors.

We designed the antibody using different backbones and chose to use a human IgG4 backbone for CTX-471 to enable engagement of Fc receptors Fc g RI and Fc g RIIb to facilitate CD137 cross-linking while avoiding binding to Fc g RIIIa and depletion of immune effector cells through ADCC.

We designed the antibody using different backbones and chose to use a human IgG4 backbone for CTX-471 to enable engagement of Fc receptors FcɣRI and FcɣRIIb to facilitate CD137 cross-linking while avoiding binding to FcɣRIIIa and depletion of immune effector cells through ADCC.

Immune cell depletion experiments showed that the activity of CTX-471 required the presence of CD4+ T-cells, CD8+ T-cells, and NK cells, indicating a coordinated involvement of both innate and adaptive immune cells.

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In addition, we have observed potent activity in other syngeneic tumor models including tumor eradication in the A20 model of lymphoma, the MC38 model of colon carcinoma and in the EMT6 model of breast cancer.

We believe that the ability of CTX-471 to transform the tumor microenvironment through the combined action of immune cell recruitment, alleviation of T-cell exhaustion, suppression of Tregs, and reduction of tumor suppressing macrophages leads to CTX-471’s antitumor activity in mouse models.

Phase 1 Clinical Trial of CTX-471

We are conducting a Phase 1, open-label, first-in-human trial of CTX-471 administered as a monotherapy or in combination with pembrolizumab (KEYTRUDA®) in patients with metastatic or locally advanced malignancies that have progressed while receiving an approved PD-1 or PD-L1 inhibitor.

We selected this population of patients for this trial because multiple clinical trials and meta-analyses have shown that not all patients respond to checkpoint inhibitor therapy due to many possible factors.

By focusing on those that did previously respond to checkpoint inhibitor therapy, we believe that this trial design enriches for patients who have tumors that are capable of being recognized and killed by their immune systems.

We believe that disease progression after the initial checkpoint inhibitor response is likely due to an increase in immunosuppressive activity that CTX-471 has the potential to overcome.

The trial is being conducted with two treatment arms, the Monotherapy Arm and the Combination Arm.

Each arm will have two parts:

a dose escalation cohort and a dose expansion cohort.

The Monotherapy Arm is nearing completion and enrollment began in the Combination Arm in the fourth quarter of 2022.

This Phase 1 trial is an open-label multiple ascending dose, dose escalation trial.

After a period of 28 days to allow checkpoint inhibitors and other drugs to be eliminated from the body, each patient receives CTX-471 by intravenous infusion every two weeks either alone or in combination with pembrolizumab (IV) infusion 400 mg every six weeks.

Disease progression is measured by CT scans every eight weeks.

We collect blood samples to assess standard safety biomarkers as well as cytokines and potential pharmacodynamic biomarkers. Baseline tumor biopsies are also collected for retrospective analyses.

The primary objective of the dose escalation stage of the trial is to assess the safety and tolerability of CTX-471 monotherapy at various doses alone and in combination with pembrolizumab.

The goal of the dose expansion stage is to determine an optimized dose for future clinical trials.

Secondary endpoints include measures of overall response rate and progression-free survival, among others.

Dosing Strategy

In contrast to dosing strategies for other immuno-oncology antibodies, such as checkpoint inhibitors where the goal is often to deliver a dose that is capable of fully inhibiting the receptor at all times, our dose selection for this trial is aimed at binding to only a fraction of the available CD137 receptors.

In contrast to dosing strategies for other immuno-oncology antibodies, such as checkpoint inhibitors where the goal is often to deliver a dose that is capable of fully inhibiting the receptor at all times, our dose selection for CTX-471 studies was aimed at binding to only a fraction of the available CD137 receptors.

Dosing of an agonist antibody, such as CTX-471, at levels capable of binding to the majority of receptors can lead to inappropriate cell activation and downregulation of the receptor and overall weaker activity.

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Thus, for many agonist antibodies, it is likely that both intermediate affinities and intermediate doses will deliver optimal activity.

Phase 1 Clinical Trial of CTX-471

The trial is being conducted with two treatment arms, the Monotherapy Arm and the Combination Arm.

Each arm will have two parts:

a dose escalation cohort and a dose expansion cohort.

The Monotherapy Arm is nearing completion and enrollment began in the Combination Arm in the fourth quarter of 2022.

Phase 1 Clinical Trial Data

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The dose expansion stage of the monotherapy trial (Phase 1b monotherapy) is currently ongoing and nearing completion.

Dose Escalation –

Monotherapy Arm

Dose Escalation – Monotherapy Arm

In the Phase 1a dose escalation stage, 19 patients received CTX-471 in the four dosing cohorts set forth in Figure 8 below.

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CTX-471 was observed to be generally well-tolerated in the Phase 1a stage of the trial.

There were two serious adverse events (“SAEs”) determined to be treatment-related, which included one hypoxia event that resolved with approximately one day of supplemental oxygen therapy and one immune thrombocytic purpura event that also resolved.

The dose-limiting toxicities were two events of thrombocytopenia in Cohort 4, which was expanded from three to six patients to collect additional safety data.

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The Phase 1a stage of the trial is now complete.

None of the patients enrolled in the Phase 1a stage of the trial had a complete response or a partial response by RECIST.

None of the patients enrolled in the Phase 1a stage of the trial had a complete response (“CR”) or a PR by RECIST.

The best overall response has been stable disease.

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We estimate that a dose of 0.3 mg/kg would lead to a peak receptor occupancy of approximately 50% and a dose of 0.6 mg/kg would lead to a peak receptor occupancy of approximately 70%.

Dose Expansion –

Monotherapy Arm

The dose expansion stage of the trial is nearing completion, and as of January 31, 2023, there are three ongoing patients in the trial.

60 patients with 18 different cancers have been enrolled in the trial and all of those patients are evaluable.

Four patients had a PR;

three of the four have been confirmed by RECIST 1.1 and the fourth PR is unconfirmed and will remain unconfirmed.

Dose Expansion – Monotherapy Arm

The dose expansion stage of the trial is fully enrolled, and as of January 31, 2024, there is one ongoing patient in the trial and the study is nearing completion.

60 patients with 17 different cancers have been enrolled in the trial.

One patient (noted below) had a CR and four additional patients had a PR.

Of the four partial responses observed in this dose expansion cohort, three PRs have been confirmed by RECIST 1.1 and the fourth PR is unconfirmed and will remain unconfirmed.

There have been nine SAEs related to CTX-471 in the dose expansion stage of the trial.

All nine events resolved .

The first PR observed in the trial was in a patient with advanced small cell lung cancer who was previously treated with carboplatin/etoposide and atezolizumab (a PD-L1 blocker) regimen at the first line followed by a treatment with nivolumab (a PD-1 blocker) in the second line.

After progression on prior regimens this patient joined CTX-471 trial and had a PR at week 17 which was confirmed at week 25.

This patient has now been dosed with CTX-471 for more than two years with a sustained and durable PR.

Below is a series of CT scan images from this patient of the largest mass (RUL Lung) which was ~4 cm at baseline.

In October 2021, a second PR was observed in a patient with metastatic melanoma who was previously treated with nivolumab and progressed on nivolumab.

The responses observed as described below:

A PR was observed in a patient with metastatic melanoma who was previously treated with nivolumab and progressed on nivolumab.

Below is a series of CT scan images from this patient.

The patient had multiple metastases at baseline and has reached PR based on a 38% decline in linear tumor burden at week nine.

The patient had multiple metastases at baseline and reached a PR based on a 38% decline in linear tumor burden at week nine.

This PR was confirmed at week 17.

In December 2021, a third PR was observed in a patient with metastatic melanoma of mucosal origin who was previously treated with first-line regimen of ipilimumab plus nivolumab followed by second-line nivolumab as a monotherapy.

After progressing on the prior regimens, the patient had joined CTX-471 trial with multiple metastases at baseline.

A PR was observed in a patient with metastatic melanoma of mucosal origin who was previously treated with first-line regimen of ipilimumab plus nivolumab followed by second-line nivolumab as a monotherapy.

After progressing on the prior regimens, the patient had joined the trial with multiple metastases at baseline.

This patient reached a PR based on a 58% decline in linear tumor burden at week 17.

This PR was not confirmed.

In July 2022, we observed a fourth PR in the ongoing Phase 1b monotherapy trial of CTX-471 in a patient with mesothelioma.

This response has also been confirmed.

A PR was observed in a patient with mesothelioma.

This response was confirmed by RECIST 1.1.

A PR was observed in a patient with melanoma treated in the third line setting.

This response was confirmed by RECIST 1.1.

This patient has been on the study for more than 2 years and is still ongoing.

The CR was observed in a patient with advanced small cell lung cancer who was previously treated with the carboplatin/etoposide and atezolizumab (a PD-L1 blocker) regimen in the first line followed by a treatment with nivolumab (a PD-1 blocker) in the second line.

After progression on prior regimens this patient joined the trial and had a PR at week 17 which was confirmed at week 25.

This patient was dosed with CTX-471 for more than three years with a durable PR, and in Q4 2023, following tumor regression observed by CT-Scan, the patient was tested by PET scan and a CR was determined.

Below is a series of CT scan images from this patient of the largest mass (RUL Lung) which was ~4 cm at baseline.

Of note, out of the five responses observed in this trial, three responses were in patients with melanoma, leading to a response rate of 27% in this subgroup of melanoma patients (3 out of 11).

The other responses were in mesothelioma (1 out of 4) and SCLC (1 out of 3).

Dosing - Combination Arm

In October 2022, we announced a clinical collaboration with Merck (known as MSD outside the United States and Canada) to evaluate CTX-471 in combination with KEYTRUDA®

(pembrolizumab).

Compass is the study sponsor and Merck provides the clinical supply of KEYTRUDA®.

In October 2022, we announced a clinical collaboration with Merck (known as MSD outside the United States and Canada) to evaluate CTX-471 in combination with KEYTRUDA® (pembrolizumab).

Compass is the study sponsor and Merck provides the clinical supply of KEYTRUDA®.

Additionally, we formed a joint development committee (JDC) with Merck to review the results of this clinical trial.

In November 2022, we announced the first patient was dosed in the combination arm of the Phase 1 trial.

This Combination Arm is enrolling patients with metastatic or locally advanced non-small cell lung cancer, melanoma, small cell lung cancer, mesothelioma and head and neck cancer that have progressed after treatment with a PD-1 or PD-L1 checkpoint inhibitor.

Patients enrolled in the trial will be treated with CTX-471 in combination with pembrolizumab with the goal of restoring response. 

We expect the first interim data readout from the trial in the second half of 2023.

Patients enrolled in the combination arm will be treated with CTX-471 by intravenous infusion every two weeks in combination with a fixed dose of pembrolizumab (400 mg) by intravenous infusion every six weeks with the goal of restoring response.

The dose-escalation portion of the study enrolled patients with metastatic or locally advanced non-small cell lung cancer, melanoma, small cell lung cancer, mesothelioma and head and neck cancer that have progressed after treatment with a PD-1 or PD-L1 checkpoint inhibitor.

At the end of 2023, the dose-escalation portion of the study was fully enrolled and this portion of the study is near completion.

No dose-limiting toxicities were observed.

As of January 30, 2024, there have been no responses observed in the dose escalation portion of the Phase 1 combination study.

In the expansion cohort, we plan on enrolling 60 patients with melanoma, NSCLC and SCLC, who will be randomly receive one of two doses of CTX-471:

0.3 (mg/Kg) every two weeks or 0.6 (mg/Kg) every two weeks in combination with a fixed dose of pembrolizumab (400 mg) every six weeks.

Enrollment in the dose expansion cohorts began in Q4 2023.

Development Plans for CTX-471

The results of the monotherapy and combination arms of the Phase 1 trial will inform us on the next development steps.

CTX-8371 (PD-1 x PDL-1 Bispecific Antibody)

CTX-8371 is a bispecific antibody that binds to both PD-1 and PD-L1, the targets of well-known and widely used checkpoint inhibitor antibodies.

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In mouse xenografts, treatment with CTX-8371 led to significantly greater tumor growth control and longer survival than treatment with a PD-1 inhibitor alone, a PD-L1 inhibitor alone or the combination of PD-1 and PD-L1 inhibitors.

IND-enabling studies on CTX-8371, including GLP toxicology studies in non-human primates (“NHPs”) were completed in the first quarter of 2023.

The FDA cleared the IND for CTX-8371 in the fourth quarter of 2023 and the first patient in the Phase 1 clinical trial is expected to be dosed by early second quarter 2024.

CTX-8371 is a PD-1 x PD-L1 bispecific antibody

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Binding of PD-L1 to its receptor, PD-1, on immune T-cells leads to suppression of cytotoxic CD8+ T-cells preventing immune attack of the tumor.

gastric cancer, cervical cancer;

and other cancers with microsatellite instability or mismatch repair deficiency.

Multiple inhibitors of PD-1 and PD-L1 have been approved as therapies for a broad range of tumors including melanoma, NSCLC, small cell lung cancer, head and neck squamous cell cancer, renal cell carcinoma, bladder cancer, gastric cancer, cervical cancer and other cancers with microsatellite instability or mismatch repair deficiency.

While PD-1/PD-L1 checkpoint therapies have resulted in remarkable clinical efficacy across multiple cancer types, their efficacy, even in tumors with high immunogenicity, is limited to approximately 20% of patients.

Nevertheless, sales of checkpoint therapies in 2021 were estimated to be $31 billion and expected to reach $148 billion by 2030 with a compounded average growth rate of 18.8% between 2020 and 2030.

Nevertheless, sales of checkpoint therapies in 2022 were estimated to be $34 billion, and grew to $39.8 billion in 2023 at a compounded annual growth rate (CAGR) of 16.4%.

The PD-1 and PD-L1 inhibitors market is expected to reach $70 billion in 2027 at a CAGR of 15.1%.

There is no approved therapy that combines inhibition of both PD-1 and PD-L1 in the same molecule.

Discovery and Preclinical Activity for CTX-8371

The desire to improve the efficacy of PD-1/PD-L1 inhibitors has sparked multiple attempts to create bispecific antibodies in which one antigen binding site targets PD-1 or PD-L1 and the other targets immuno-oncology receptors such as CTLA-4 or LAG-3.

In contrast to those bispecific efforts described by others that have focused on a single pair of antigen-binding domains at a time, we have applied our StitchMabs TM technology to broadly screen for pairs of bispecific antigen-binding domains with the highest potential to generate antitumor activity.

Our efforts were enabled not only by the StitchMabs TM technology, but also by our investment in generating a broad portfolio of selective antibodies to 40 potential immune targets across the innate and adaptive immune system.

Our efforts were enabled not only by the StitchMabs TM technology, but also by our investment in generating a broad portfolio of selective antibodies to approximately 40 potential immune targets across the innate and adaptive immune system.

We designed our combinatorial screen such that one antigen-binding domain was directed against PD-1, and the other selected from our library of candidate antibodies.

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Our unbiased screening led us to an antibody that pairs a PD-1 binding domain and a PD-L1 binding domain.

This novel bispecific antibody contributed to T-cell activation that outperformed the activation observed in response to treatment with PD-1-only antibodies.

We designated CTX-8371 as the bispecific antibody we constructed using our common light chain antibodies having a PD-1 and PD-L1 antigen binding domains.

This novel bispecific antibody contributed to T-cell activation that outperformed the activation observed in response to treatment with only PD-1 antibodies.

We designated CTX-8371 as the bispecific antibody we constructed using our common light chain antibodies having a PD-1 and PD-L1 antigen binding domain.

A PD-1 x PD-L1 bispecific antibody outperformed single PD-1 antibodies in a T-cell activation assay

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Indirect CD28 agonist:

 increasing the pool of free CD80 on tumor cells making it available to bind and activate the CD28 T-cell co-stimulatory receptor, thereby, sending a positive signal to the T-cell, which enhances its activation.

Differentiated mechanism of action of CTX-8371 drives enhanced T-cell activation

We also found that the greater activity of CTX-8371 in our T-cell activation assay compared to PD-1 inhibition also extended to PD-L1 inhibition.

Furthermore, CTX-8371 was associated with significantly more antitumor activity in a murine B16F10 melanoma model than was monotherapy with either a PD-1 inhibitor or a PD-L1 inhibitor or combination of both.

Tumor growth in monotherapy-treated mice and in the combination PD-1 and PD-L1-treated mice was slowed to approximately half that observed with tumors in untreated mice.

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Dosing with CTX-8371 led to tumor growth inhibition in the syngeneic EMT-6 breast cancer model and in the syngeneic MB49 bladder cancer model

In April 2022, we presented preclinical data on CTX-8371’s potential unique mechanism of action ("MOA") that involves cleavage of cell surface PD-1, at the 2022 American Association for Cancer Research ("AACR") annual meeting.

A summary of the results are as follows:

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Treatment with CTX-8371 in the aggressive MC38-hPD-L1 colorectal mouse model led to a dose-proportional reduction in tumor volume and a complete eradication of tumors at the highest dose

Taken together, the murine and cynomolgus monkey PK data, receptor occupancy data, and in vivo efficacy data in murine models will be used to calculate the predicted human efficacious dose range for CTX-8371

Taken together, the murine and cynomolgus monkey PK data, receptor occupancy data, and in vivo efficacy data in murine models was used to calculate the predicted human efficacious dose range for CTX-8371

Development Plans for CTX-8371

We completed our first GMP manufacturing campaign for CTX-8371 in the second quarter of 2022.

IND-enabling studies, including GLP toxicology studies in NHPs, were completed in the first quarter of 2023.

We are currently targeting an IND submission to the FDA for CTX-8371 in the first half of 2023.

An IND was submitted to the FDA in the third quarter of 2023.

This IND was cleared by the FDA in October 2023.

In the first quarter of 2024 we initiated a first-in-human Phase 1 study of CTX-8371 in patients with metastatic or locally advanced malignancies.

This Phase 1 trial is a multiple ascending, dose escalation and there are five doses planned in this study:

0.1, 0.3, 1.0, 3.0 and 10 mg/Kg.

Patients eligible to participate in the trial are patients who progressed while receiving an approved PD-1 or PD-L1 inhibitor.

Other eligibility criteria include patients with metastatic of locally advanced melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin’s Lymphoma and triple negative breast cancer.

The first patient in this Phase 1 clinical trial is expected to be dosed by early second quarter 2024.

Early-Stage Discovery

Our approach has been based on the observation that traditional methods of antibody discovery are slow, inefficient, and are limited by lack of diversity of antigenic sites, or epitopes, that are recognized using these methods.

We believe these limitations impair drug developers’

ability to identify the best product candidates.

Traditionally, our approach to early-stage discovery has been based on the observation that traditional methods of antibody discovery are slow, inefficient, and are limited by lack of diversity of antigenic sites, or epitopes, that are recognized using these methods.

We believe these limitations impair drug developers’ ability to identify the best product candidates.

We have created several technological solutions that are designed to address the key challenges in antibody development with the goal of incorporating our solutions into bispecific product candidates.

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Each heavy and light chain pair forms a binding site where the antibody specifically binds its target, which is also known as an antigen.

The immune system is capable of not only fighting foreign invaders, but also of recognizing and eliminating a human body’s own cells that have become pathogenic after transformation, such as in cancer.

There are two broad classes of antibodies used in cancer therapy.

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and possess excellent physical and biochemical properties.

We describe these antibodies as having good ‘drug-like’

We describe these antibodies as having good ‘drug-like’ properties.

To generate additional antibody candidates, we can also immunize a proprietary line of humanized transgenic mice with antigens of interest to isolate a diverse set of fully human antibodies that share a common human light chain, but distinct native mouse heavy chains.

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We further simplified the manufacturing of our bispecific antibodies by assembling a single heavy chain construct that encodes both antigen-binding domains.

As a result, the manufacturing of our bispecifics closely resembles that of standard monoclonal antibodies, which include—one heavy chain and one light chain.

As a result, the manufacturing of our bispecifics closely resembles that of standard monoclonal antibodies, which include one heavy chain and one light chain.

Our focus on common light chain antibodies simplifies the process of converting our StitchMabs TM screening candidates into bispecific antibody product candidates.

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License Agreements

CTX-009 (DLL4 X VEGF-A bispecific antibody)

Our wholly owned subsidiary Trigr Therapeutics, Inc.

(“TRIGR”) and ABL Bio, a South Korean biotechnology company, entered into an exclusive global (excluding South Korea) license agreement (the “TRIGR License Agreement”) which granted TRIGR a license to ABL001, ABL Bio’s bispecific antibody targeting DLL4 and VEGF-A (renamed CTX-009).

Under the terms of the agreement, ABL Bio and TRIGR would jointly develop CTX-009, with ABL Bio responsible for development of CTX-009 throughout the end of Phase 1 clinical trials and TRIGR responsible for the development of CTX-009 from Phase 2 and onward.

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As a result of the TRIGR acquisition, we have assumed all the rights and obligations of the TRIGR License Agreement.

CTX-471 (CD137 agonist antibody)

We entered into an amended and restated collaboration agreement with Adimab, LLC ("Adimab"), dated February 11, 2015, as amended.

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With respect to company-owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be useful in protecting our commercial products and methods of manufacturing the same.

For more information, please see “Risk Factors—Risks Related to Our Intellectual Property.”

We seek to protect our proprietary position by, among other things, filing patent applications in the United States and internationally in certain jurisdictions where it is available.

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Our patent estate includes patent applications with claims relating to our product candidates, methods of use and manufacturing processes, and claims for potential future products and developments.

As of January 31, 2023, we have greater than 80 patent applications pending in the United States and foreign jurisdictions relating to CTX-009, CTX-471, CTX-8371 and other discovery and research programs.

We have 6 patents issued in the United States related to our CTX-471 program, and 1 patent issued in the United States related to our CTX-8371 program.

We also have access to patents issued in Australia, Europe and the United States related to our antibody and display programs as well as patents issued in Australia, Canada, China, Europe, Japan, Korea, Russia and United States related to our CTX-009 program.

More specifically, we have licensed 2 pending patent families with approximately 29 issued patents in U.S.

and foreign jurisdictions related to our DLL4/VEGF antibody program including, but not limited to, our CTX-009 therapeutic candidate.

As of January 31, 2024, we have greater than 80 issued patents and patent applications pending in the United States and foreign jurisdictions relating to CTX-009, CTX-471, CTX-8371 and other discovery and research programs.

We have 7 patents issued in the United States and 1 patent issued in Taiwan related to our CTX-471 program, and 1 patent issued in the United States related to our CTX-8371 program.

We also have access to patents issued in Australia, Europe and the United States related to our antibody and display programs, as well as 27 patents issued in Australia, Canada, China, Europe, Japan, Korea, Russia and 2 in United States related to our CTX-009 program.

More specifically, we have licensed 2 patent families with 2 issued patents in U.S.

and 27 issued patents in foreign jurisdictions, related to our DLL4/VEGF antibody program including, but not limited to, our CTX-009 therapeutic candidate.

Patents in these patent families are generally expected to start to expire in 2033, subject to possible extension.

We own 4 pending patent families with 7 issued U.S.

patents, 4 U.S.

Utility or provisional patent applications, and 40 patent applications in foreign jurisdictions, related to our CD137 agonist antibody therapeutic platform including, but not limited to, our CTX-471 therapeutic candidate.

patents and 1 issued patent in Taiwan, 3 U.S.

patent applications, and 43 patent applications in foreign jurisdictions, related to our CD137 agonist antibody therapeutic platform including, but not limited to, our CTX-471 therapeutic candidate.

Patents that grant from these patent families are generally expected to start to expire in 2038, subject to possible patent term extension.

We own 2 pending patent families with 1 issued U.S.

We own 1 pending patent family with 1 issued U.S.

patent, 1 U.S.

Utility or provisional patent applications, and 18 patent applications in foreign jurisdictions, related to our PD-1/PD-L1 bispecific antibody therapeutic platform including, but not limited to, our CTX-8371 therapeutic candidate.

patent application, and 18 patent applications in foreign jurisdictions, related to our PD-1/PD-L1 bispecific antibody therapeutic platform including, but not limited to, our CTX-8371 therapeutic candidate.

Patents that grant from these patent families are generally expected to start to expire in 2039, subject to possible patent term extension.

We own, or have an ownership interest in, 2 pending patent families with 2 U.S.

Utility or provisional patent applications and 3 patent applications in foreign jurisdictions related to our discovery and research programs.

Patents that grant from these patent families are generally expected to start to expire in 2039, subject to possible patent term extension.

We own 3 pending patent families with 3 U.S.

Utility or provisional patent applications and 1 patent application in foreign jurisdictions related to our antibody and display programs including, but not limited to, common light chains and mammalian display platforms.

pending patent applications and 3 patent applications in foreign jurisdictions, related to our CD277 discovery and research programs.

Patents that grant from these patent families are generally expected to start to expire in 2039, subject to possible patent term extension.

We own 1 pending patent family with 1 U.S.

pending patent application and 1 patent application in foreign jurisdictions related to our antibody and display programs including, but not limited to, common light chains and mammalian display platforms.

Patents that grant from this patent family are generally expected to start to expire in 2039, subject to possible patent term extension.

Trademark Protection

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To the extent that our consultants, contractors or collaborators use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

For further information, please see “

Risk Factors —

Risks Related to Our Intellectual Property .”

For further information, please see “ Risk Factors — Risks Related to Our Intellectual Property .”

The biotechnology and pharmaceutical industries, and the immuno-oncology subsector, are characterized by rapid evolution of technologies, fierce competition and strong defense of intellectual property.

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Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy, safety and convenience of our products.

Currently marketed oncology drugs and therapeutics range from traditional cancer therapies, including chemotherapy, to antibody-drug conjugates, such as Genentech Inc.’s Kadcyla, to immune checkpoint inhibitors targeting CTLA-4, such as BMS’s Yervoy, to PD-1/PD-L1, such as BMS’s Opdivo, Merck & Co.’s Keytruda and Genentech’s Tecentriq, to T cell-engager immunotherapies, such as Amgen’s Blincyto and VEGF targets, such as Genentech Inc.’s Avastin.

In addition to these marketed therapies, numerous compounds are in clinical development for the potential treatment of cancer.

Biliary tract cancers are aggressive and rare gastrointestinal cancers that have a very poor prognosis. 

First line treatment of locally advanced or metastatic BTC includes the chemotherapy combination of gemcitabine and cisplatin, often with the addition of the PD-1 inhibitor Imfinzi®

(durvalumab).

In September of 2022, AstraZeneca received FDA approval of durvalumab in combination with gemcitabine/cisplatin for the first line treatment of BTC. 

Biliary tract cancers are aggressive and rare gastrointestinal cancers that have a very poor prognosis.

First line treatment of locally advanced or metastatic BTC includes the chemotherapy combination of gemcitabine and cisplatin, often with the addition of the PD-1 inhibitor Imfinzi® (durvalumab).

In September of 2022, AstraZeneca received FDA approval of durvalumab in combination with gemcitabine/cisplatin for the first line treatment of BTC.

The only FDA approved therapies for second line treatment of BTC are targeted therapies that address specific tumor mutations or solid tumors that are microsatellite instability high.

There is also recently emerging clinical data that blockade of the human epidermal growth factor receptor 2 (“Her-2”) may be beneficial to the small subset of patients in whom HER-2 is amplified.

We believe that these targeted therapies are appropriate for 10-15% of BTC patients.

Colorectal cancer is the second most common cause of cancer deaths in the United States and constitutes approximately 10% of all annually diagnosed cancer and cancer related deaths globally.

Treatment of metastatic disease in the first line typically includes either the VEGF inhibitor Avastin®

(bevacizumab) or an EGFR inhibitor such as Erbitux®

(cetuximab), combined with chemotherapy.

Treatment of metastatic disease in the first line typically includes either the VEGF inhibitor Avastin® (bevacizumab) or an EGFR inhibitor such as Erbitux® (cetuximab), combined with chemotherapy.

Treatment in the second line includes re-treatment with either a VEGR or EGFR inhibitor and a different chemotherapy regimen that is either oxaliplatin or irinotecan based.

Approved therapies for advanced patients with metastatic disease are limited, with approved agents such as Lonsurf®

(trifluridine and tipiracil) and Stivarga®

(regorafenib) offering only 1-2% response rates and improvement in survival of 1-2 months. 

Approved therapies for advanced patients with metastatic disease are limited, with approved agents such as Lonsurf® (trifluridine and tipiracil) and Stivarga® (regorafenib) offering only 1-2% response rates and improvement in survival of 1-2 months.

If we are successful in advancing one or more of our product candidates toward registrational trials and filing a BLA or BLAs, and if we are successful at obtaining approvals from the FDA or any other regulatory agency to market one or more of our product candidates, then the availability of reimbursement from government and other third-party payors will also significantly affect the pricing and competitiveness of our products.

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If we fail to comply with applicable FDA or other requirements at any time during the product development process, clinical testing, the approval process or after approval, we may become subject to administrative or judicial sanctions.

These sanctions could include the FDA’s refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, untitled or warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties or criminal prosecution.

Any FDA enforcement action could have a material adverse effect on us.

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completion of extensive nonclinical laboratory tests and nonclinical animal studies, all performed in accordance with the Good Laboratory Practices ("GLP"), regulations;

submission to the FDA of an investigational new drug application ("IND"), which must become effective before human clinical trials may begin and must be updated annually;

submission to the FDA of an IND, which must become effective before human clinical trials may begin and must be updated annually;

approval by an independent institutional review board ("IRB"), or ethics committee representing each clinical site before each clinical trial may be initiated;

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A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.

Additionally, approval must also be obtained from each clinical trial site’s IRB, before the trials may be initiated and the IRB must monitor the trial until completed.

There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.

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The investigational product is administered to an expanded patient population, generally at geographically dispersed clinical trial sites to generate enough data to statistically evaluate safety, purity and potency, to evaluate the overall benefit-risk profile of the investigational product, and to provide an adequate basis for physician labeling.

In some cases, the FDA may condition approval of a BLA for a product candidate on the sponsor’s agreement to conduct additional clinical trials after approval.

In other cases, a sponsor may voluntarily conduct additional clinical trials after approval to gain more information about the biological product.

Such post-approval trials are typically referred to as Phase 4 clinical trials.

In March 2022, the FDA released a final guidance entitled “Expansion Cohorts:

Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,”

which outlines how drug developers can utilize an adaptive trial design commonly referred to as a seamless trial design in early stages of oncology drug development (i.e., the first-in-human clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial.

In March 2022, the FDA released a final guidance entitled “Expansion Cohorts:

Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” which outlines how drug developers can utilize an adaptive trial design commonly referred to as a seamless trial design in early stages of oncology drug development (i.e., the first-in-human clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial.

Information to support the design of individual expansion cohorts is included in IND applications and assessed by FDA.

Expansion cohort trials can potentially bring efficiency to drug development and reduce development costs and time.

Sponsors must also report to the FDA, within certain timeframes, serious and unexpected adverse reactions, any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator’s brochure, or any findings from other studies or animal or in vitro testing that suggest a significant risk in humans exposed to the product candidate.

The FDA, the IRB, or the clinical trial sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

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Applications for orphan drug products are exempted from the BLA application fee and may be exempted from program fees, unless the application includes an indication for other than a rare disease or condition.

A BLA must include all relevant data available from pertinent nonclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.

Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including trials initiated by investigators.

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The FDA may request additional information rather than accept an application for filing.

Once a BLA has been submitted, the FDA’s goal for novel biological products generally is to review the application within ten months after it accepts the application for filing, or, if the application relates to an unmet medical need in a serious or life-threatening indication, six months after the FDA accepts the application for filing.

The review process is often significantly extended by the FDA’s requests for additional information or clarification.

Before approving a BLA, the FDA typically will inspect the facility or facilities where the product is manufactured.

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The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA ’

s Decision on a BLA

The FDA ’ s Decision on a BLA

After the FDA evaluates the BLA and conducts relevant inspections, it may issue an approval letter or a Complete Response Letter.

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The FDA also may condition approval on, among other things, changes to proposed labeling, development of adequate controls and specifications, or a commitment to conduct one or more post-market studies or clinical trials.

Such post-market testing may include Phase 4 clinical trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

New government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

Such post-market testing may include Phase 4 clinical trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

Expedited Review and Accelerated Approval Programs

A sponsor may seek approval of its product candidate under programs designed to accelerate FDA’s review and approval of BLAs.

For example, fast track designation may be granted to a biological product intended for treatment of a serious or life-threatening disease or condition that has potential to address unmet medical needs.

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Under the accelerated approval program, the FDA may approve a BLA for a product that is intended to treat a serious or life-threatening disease or condition upon the determination that the product generally provides meaningful therapeutic benefit to patients over available treatments and demonstrates an effect on either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Accelerated approval is usually contingent on a sponsor’s agreement to conduct post-approval confirmatory trials or complete ongoing trials in a diligent manner to verify the product’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.

Under the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), the FDA is now permitted to require, as appropriate, that post-approval confirmatory trials be underway prior to approval or within a specific time period after accelerated approval is granted and the FDA has increased authority for expedited procedures to withdraw approval of a product or an indication approved under accelerated approval if, for example, the confirmatory trial is not conducted with due diligence or fails to verify the predicted clinical benefit of the product.

Additionally, the FDA generally requires, unless otherwise informed by the agency, that all advertising and promotional materials intended for dissemination or publication within 120 days of marketing approval be submitted to the agency for preapproval and pre-use review.

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The benefits of breakthrough therapy designation include the same benefits as a fast-track designation, in addition to intensive guidance from FDA to ensure an efficient development program.

Finally, with respect to oncology products, the FDA may review applications under Real-Time Oncology Review (“RTOR”) established by the FDA’s Oncology Center of Excellence.

RTOR allows an applicant to pre-submit components of the application to allow the FDA to review clinical data before the complete filing is submitted in order to create more efficient review process to ensure that safe and effective treatments are available to patients as early as possible, while maintaining and improving review quality.

Drugs considered for review under RTOR must, among other things, be likely to demonstrate substantial improvements on a clinically relevant endpoint(s) over available therapy and must have easily interpreted endpoints.

In addition, no aspect of the application should be likely to require a longer review time (for example, a Risk Evaluation and Mitigation Strategy).

To determine eligibility for RTOR, the FDA requires top-line efficacy and safety results from an applicant.

Post-Approval Requirements

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FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon us and any third-party manufacturers that we may decide to use.

Manufacturers and manufacturers’

facilities are also required to comply with applicable product tracking and tracing requirements.

Manufacturers and manufacturers’ facilities are also required to comply with applicable product tracking and tracing requirements and notify the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

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A sponsor can submit amendments to an agreed upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from nonclinical studies, early phase clinical trials, and/or other clinical development programs.

Pediatric exclusivity is another type of non-patent exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the five-year and three-year non-patent and orphan exclusivity.

This six-month exclusivity may be granted if a BLA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.

Pediatric exclusivity is another type of non-patent exclusivity in the United States and, if granted for a biologic, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity for all formulations, dosage forms, and indications of the biologic, including the five-year and three-year non-patent and orphan exclusivity.

This six-month exclusivity may be granted if a BLA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.

The data do not need to show the product to be effective in the pediatric population studied;

rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted.

If reports of FDA-requested pediatric trials are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection covering the product are extended by six months.

This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot accept or approve another application relying on the BLA sponsor’s data.

Patent Term Restoration

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The Hatch- Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process.

However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of a BLA, plus the time between the submission date and the approval of that application.

Only one patent applicable to an approved product is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent and within 60 days of the product’s approval.

Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

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In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.

During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity, and potency of its product.

In addition, The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products.

The first biologic submitted under the abbreviated approval pathway that is determined to be interchangeable with the reference product is eligible for a period of exclusivity against other biologics submitted under the abbreviated approval pathway during which time the FDA may not determine that another product is interchangeable with the same reference product for any condition of use.

The FDA may approve multiple “first”

interchangeable products so long as they are all approved on the same first day of marketing.

This exclusivity period, which may be shared amongst multiple first interchangeable products, lasts for the lesser of (i) one year after the first commercial marketing, (ii) 18 months after approval if there is no legal challenge, (iii) 18 months after the resolution in the applicant’s favor of a lawsuit challenging the biologic’s patents if an application has been submitted, or (iv) 42 months after the application has been approved if a lawsuit is ongoing within the 42-month period.

Products deemed “interchangeable”

by the FDA may be readily substituted by pharmacies and such substitution is which are governed by state pharmacy law.

The FDA may approve multiple “first” interchangeable products so long as they are all approved on the same first day of marketing.

Products deemed “interchangeable” by the FDA may be readily substituted by pharmacies and such substitution is which are governed by state pharmacy law.

European Union/Rest of World Government Regulation

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Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.

In the European Union, for example, a clinical trial authorization application ("CTA"), must be submitted for each clinical protocol to each country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively.

Once the CTA is accepted in accordance with a country’s requirements, the clinical trial may proceed.

The requirements and process governing the conduct of clinical trials vary from country to country.

In all cases, the clinical trials are conducted in accordance with GCP, the applicable regulatory requirements, and the ethical principles that have their origin in the Declaration of Helsinki.

To obtain regulatory approval of an investigational medicinal product under European Union regulatory systems, we must submit a marketing authorization application.

To obtain regulatory approval of a medicinal product under European Union regulatory systems, we must submit a marketing authorization application.

The content of the BLA filed in the United States is similar to that required in the European Union, with the exception of, among other things, country-specific document requirements.

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If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Authorization Procedures in the European Union

Clinical Trial Approval in the European Union

In April 2014, the European Union adopted the Clinical Trials Regulation (EU) No 536/2014, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022.

The Clinical Trials Regulation is directly applicable in all European Union Member States meaning no national implementing legislation in each European Union Member State is required.

The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the European Union.

Under the new coordinated procedure for the approval of clinical trials, the sponsor of a clinical trial is required to submit a single application for approval of a clinical trial to a reporting European Union Member State through a European Union Portal.

The submission procedure is the same irrespective of whether the clinical trial is to be conducted in a single European Union Member State or in more than one European Union Member State.

Marketing Authorization Procedures in the European Union

Medicines can be authorized in the European Union by using either the centralized authorization procedure or national authorization procedures.

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The centralized procedure is compulsory for human medicines that are:

derived from biotechnology processes, such as genetic engineering, contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders or autoimmune diseases and other immune dysfunctions, and officially designated orphan medicines.

For medicines that do not fall within these categories, an applicant has the option of submitting an application for a centralized marketing authorization to the European Commission following a favorable opinion by the EMA, as long as the medicine concerned is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health.

derived from biotechnology processes, such as genetic engineering, contain a new active substance indicated for the treatment of certain diseases, such as HIV, AIDS, cancer, diabetes, neurodegenerative disorders or autoimmune diseases and other immune dysfunctions, advanced therapy medicines (gene-therapy, somatic cell-therapy or tissue-engineered medicines) and officially designated orphan medicines.

Under the centralized procedure, the EMA’s Committee for Medicinal Products for Human Use ("CHMP") is responsible for conducting the initial assessment of a product and for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.

Under the centralized procedure in the European Union, the maximum timeframe for the evaluation of a marketing authorization application is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP).

Clock stops may extend the timeframe of evaluation of a marketing authorization application considerably beyond 210 days.

Where the CHMP gives a positive opinion, it provides the opinion together with supporting documentation to the European Commission, who makes the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.

Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation.

In this circumstance, the EMA ensures that the opinion of the CHMP is given within 150 days, excluding clock stops, but it is possible that the CHMP can revert to the standard time limit for the centralized procedure if it considers that it is no longer appropriate to conduct an accelerated assessment.

National authorization procedures .

There are also two other possible routes to authorize medicinal products in several European Union countries, which are available for investigational medicinal products that fall outside the scope of the centralized procedure:

There are also two other possible routes to authorize medicinal products in several European Union countries, which are available for medicinal products that fall outside the scope of the centralized procedure:

Decentralized procedure .

Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one European Union country of medicinal products that have not yet been authorized in any European Union country and that do not fall within the mandatory scope of the centralized procedure.

Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one European Union Member State of medicinal products that have not yet been authorized in any European Union Member State and that do not fall within the mandatory scope of the centralized procedure.

Mutual recognition procedure .

In the mutual recognition procedure, a medicine is first authorized in one European Union Member State, in accordance with the national procedures of that country.

Following this, further marketing authorizations can be sought from other European Union countries in a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization.

In the mutual recognition procedure, a medicine is first authorized in one European Union Member State, in accordance with the national procedures of that Member State.

Following this, further marketing authorizations can be sought from other European Union Member States in a procedure whereby the Member State concerned agree to recognize the validity of the original, national marketing authorization.

In some cases, a Pediatric Investigation Plan ("PIP"), or a request for waiver or deferral, is required for submission prior to submitting a marketing authorization application.

A PIP describes, among other things, proposed pediatric trials and their timing relative to clinical trials in adults.

New Chemical Entity Exclusivity

In the European Union, new chemical entities, sometimes referred to as new active substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

This data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic (abbreviated) application for eight years, after which generic marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years.

Data and Market Exclusivity in the European Union

In the European Union, innovative medicinal products approved on the basis of a complete and independent data package qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

This data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the innovator’s pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the European Union, during a period of eight years from the date on which the reference product was first authorized in the European Union.

During an additional two-year period of market exclusivity, a generic or biosimilar MAA can be submitted and authorized, and the innovator’s data may be referenced, but no generic or biosimilar medicinal product can be placed on the European Union market until the expiration of the market exclusivity.

The overall ten-year period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Accelerated Review

In this circumstance, EMA ensures that the opinion of the CHMP is given within 150 days, excluding clock stops.

There is no guarantee that a product will be considered by the EMA to be an innovative medicinal product, and products may not qualify for data exclusivity.

Even if a product is considered to be an innovative medicinal product so that the innovator gains the prescribed period of data exclusivity, another company nevertheless could also market another version of the product if such company obtained a marketing authorization based on a marketing authorization application with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.

The aforementioned European Union rules are generally applicable in the EEA.

Reform of the Regulatory Framework in the European Union

The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the European Union for all medicines (including those for rare diseases and for children).

The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval.

In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals, which will be debated by the European Parliament.

Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into European Union law.

Pharmaceutical Coverage, Pricing and Reimbursement

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Our ability to successfully commercialize our product candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from third-party payors, including government healthcare programs (e.g., Medicare, Medicaid), managed care providers, private health insurers, health maintenance organizations, and other organizations.

Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.

No uniform policy of coverage and reimbursement for drug products exists among third-party payors.

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The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the reimbursement rate that the payor will pay for the product.

One payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage and reimbursement for the product, and the level of coverage and reimbursement can differ significantly from payor to payor.

Third-party payors may also limit coverage to specific products on an approved list, or formulary, which might not include all of the FDA-approved products for a particular indication.

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The requirements governing drug pricing vary widely from country to country.

For example, in the European Union Member States can restrict the range of medicinal products for which their national health insurance systems provide reimbursement and they can control the prices of medicinal products for human use.

For example, the European Union Member States can restrict the range of medicinal products for which their national health insurance systems provide reimbursement and they can control the prices of medicinal products for human use.

To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently available therapies.

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In the United States and in some foreign jurisdictions, there have been, and likely will continue to be, a number of legislative and regulatory changes and proposed changes regarding the healthcare system directed at broadening the availability of healthcare, improving the quality of healthcare, and containing or lowering the cost of healthcare.

For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, collectively, the Affordable Care Act ("ACA"), among other things, subjects biological products to potential competition by lower-cost biosimilars, expands the types of entities eligible for the 340B drug discount program, addresses a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increases rebates for drugs sold to Medicaid programs owed by manufacturers under the Medicaid Drug Rebate Program and extends the rebate program to individuals enrolled in Medicaid managed care organizations, establishes annual fees and taxes on manufacturers of certain branded prescription drugs, and created a mandatory discount program for certain Medicare Part D beneficiaries in which manufacturers must agree to offer 50% (increased to 70% pursuant to the Bipartisan Budget Act of 2018 ("BBA"), effective as of January 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

Since its enactment, there have been numerous judicial, administrative, executive, and legislative efforts to expand, repeal, replace or modify the ACA, some of which have been successful, in part, in modifying the law, as well as court challenges to the constitutionality of the law.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

It is unclear how other healthcare reform measures of the Biden administration or other efforts, if any, to challenge, repeal or replace the ACA will impact our business.

For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, collectively, the Affordable Care Act ("ACA"), among other things, subjects biological products to potential competition by lower-cost biosimilars, expands the types of entities eligible for the 340B drug discount program, increases rebates for drugs sold to Medicaid programs owed by manufacturers under the Medicaid Drug Rebate Program and extends the rebate program to individuals enrolled in Medicaid managed care organizations, establishes annual fees and taxes on manufacturers of certain branded prescription drugs, and created a mandatory discount program for certain Medicare Part D beneficiaries in which manufacturers must agree 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

In addition, other legislative and regulatory changes have been proposed and adopted in the United States since the ACA was enacted:

On August 2, 2011, the U.S.

Budget Control Act of 2011, among other things, included aggregate reductions of Medicare payments to providers of 2% per fiscal year.

These reductions went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2030, with the exception of a temporary suspension that lasted from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.

Following the suspension, a 1% payment reduction began April 1, 2022, and remained through June 30, 2022.

The 2% payment reduction resumed on July 1, 2022.

Budget Control Act of 2011, among other things, included aggregate reductions of Medicare payments to providers of 2% per fiscal year, which will remain in effect through 2031.

On January 2, 2013, the U.S.

American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers.

American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

On April 13, 2017, CMS published a final rule that gives states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces.

On May 30, 2018, the Right to Try Act, was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.

On May 23, 2019, CMS published a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.

On December 20, 2019, former President Trump signed into law the Further Consolidated Appropriations Act (H.R.

1865), which repealed the Cadillac tax, the health insurance provider tax, and the medical device excise tax.

It is impossible to determine whether similar taxes could be instated in the future.

On May 23, 2019, CMS published a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.

On March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.

Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives.

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Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the cost of drugs under Medicare and reform government program reimbursement methodologies for drug products.

For example, at the federal level, President Biden signed an Executive Order on July 9, 2021 affirming the administration’s policy to (i) support legislative reforms that would lower the prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and biosimilars;

and (ii) support the enactment of a public health insurance option.

Among other things, the Executive Order also directs HHS to provide a report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the price that the Federal government pays for drugs, and address price gouging in the industry;

and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.

FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

On September 25, 2020, CMS stated drugs imported by states under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report these drugs for “best price”

or Average Manufacturer Price purposes.

Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these drugs.

If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.

Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation ("MFN"), Model under which Medicare Part B reimbursement rates would have been be calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita.

However, on December 29, 2021 CMS rescinded the Most Favored Nations rule.

Additionally, on November 30, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026.

The Inflation Reduction Act of 2022 (the “IRA”) further delayed implementation of this rule to January 1, 2032.

For example, at the federal level, President Biden has issued multiple executive orders that have sought to reduce prescription drug costs.

In February 2023, HHS also issued a proposal in response to an October 2022 executive order from President Biden that includes a proposed prescription drug pricing model that will test whether targeted Medicare payment adjustments will sufficiently incentivize manufacturers to complete confirmatory trials for drugs approved through FDA’s accelerated approval pathway.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

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government to negotiate Medicare Part B and Part D pricing for certain high-cost drugs and biologics without generic or biosimilar competition, require companies to pay rebates to Medicare for drug prices that increase faster than inflation, and delay the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one orphan designation and for which the only approved indication is for that disease or condition.

If a product receives multiple orphan designations or has multiple approved indications, it may not qualify for the orphan drug exemption.

The implementation of the IRA is currently subject to ongoing litigation challenging the constitutionality of the IRA’s Medicare drug price negotiation program.

The effect of IRA on our business and the healthcare industry in general is not yet known.

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or knowingly concealing or knowingly and improperly avoiding or decreasing an obligation to pay money to the federal government.

Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

The FCA also permits a private individual acting as a “whistleblower” to bring qui tam actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery.

Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

The FCA also permits a private individual acting as a “whistleblower” to bring qui tam actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery.

When an entity is determined to have violated the FCA, the government may impose civil fines and penalties for each false claim, plus treble damages, and exclude the entity from participation in Medicare, Medicaid and other federal healthcare programs;

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Similar to the federal Anti-Kickback Statute, a person or entity can be found guilty of violating HIPAA without actual knowledge of the statute or specific intent to violate it;

the federal Physician Payment Sunshine Act, created under the ACA and its implementing regulations, which requires drug, device, medical supply, and biologics manufacturers to disclose payments under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to HHS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners;

the federal Physician Payment Sunshine Act, created under the ACA and its implementing regulations, which requires drug, device, medical supply, and biologics manufacturers to disclose payments under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to HHS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other licensed healthcare practitioners and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

HIPAA, as amended by the Health Information Technology and Clinical Health Act of 2009 ("HITECH"), and its implementing regulations, which imposes, among other things, certain requirements relating to the privacy, security and transmission of individually identifiable health information.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” those independent contractors or agents of covered entities that create, receive, maintain, transmit or obtain protected health information in connection with providing a service on behalf of a covered entity.

HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions;

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” those independent contractors or agents of covered entities that create, receive, maintain, transmit or obtain protected health information in connection with providing a service on behalf of a covered entity.

federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs;

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state and local laws that require the licensure of sales representatives;

state laws that require biopharmaceutical companies to comply with the biopharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government;

state and local laws that require the registration of pharmaceutical sales representatives;

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If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to similar actions, penalties and sanctions.

Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert a company’s attention from its business.

We are also subject to the U.S.

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Corporate Information

We were incorporated as Olivia Ventures, Inc.

in the State of Delaware on March 20, 2018.

We were incorporated in the State of Delaware on March 20, 2018.

On June 17, 2020, a wholly-owned subsidiary of ours merged with and into Compass Therapeutics, a private limited liability company formed in 2014.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business