Science

China Biotech Goes International, Series Report (2) - On the Importance of Clinical Trial Design

Introduction

In the current process of domestic innovative drug development to catch up with the international leading level, clinical trials have become the key to determine success or failure. Recently Conrad Biomedicals Ltd. announced the 12-week top-line results of the Phase 2 clinical trial of CBP-307 for the treatment of moderate-to-severe ulcerative colitis, which achieved statistical significance in terms of clinical remission rate (a drug approval index recognized by both FDA and CDE) and other secondary endpoints, and showed pharmacological activity that effectively downregulated lymphocyte count, and CBP-307 generally showed good tolerability. However, the improvement in the primary efficacy endpoint, the Modified Mayo Score, did not reach statistical significance compared to baseline in the trial group. The results were interpreted in more depth and objectively with reference to the progress of similar drug development and reviews by leading foreign investment banks.

1

Preface

Ulcerative colitis (UC) is a continuous, inverted, non-specific chronic inflammatory disease of the intestine involving the mucosa and submucosa of the colon, with clinical manifestations of persistent or recurrent diarrhea, mucopurulent stools with abdominal pain and varying degrees of systemic symptoms, with a disease duration of more than 4-6 weeks, which can greatly reduce the quality of life of individuals. Patients need to be hospitalized. The global market for UC drugs is estimated to have exceeded $7.5 billion, accounting for 10% of the total immune market, and the market for UC drugs is expected to reach $11-12 billion by 2026.

In recent years, the number of reported cases of UC in China has increased significantly, and it is gradually becoming a common intestinal disease and the main cause of chronic diarrhea, and it is expected that the prevalence of UC in China will gradually approach that of western countries (>40/100,000 people). the cause of UC is still unclear, and it is not curable for the time being. domestic treatment with aminosalicylic acid and steroid hormones is the main treatment, and immunosuppressive drugs are less commonly used.

Given the significant unmet clinical need, multiple targeted therapies are being actively explored both domestically and internationally, with major targets and mechanisms including: selective S1P receptor modulators, Janus kinase (JAK) 3 inhibitors, human interleukin (IL)-12, IL-22, IL-23 and IL-36 inhibitors and dihydroorotic acid dehydrogenase (DHODH) inhibitors. Among them, BMS' (formerly Receptors) selective S1P receptor modulator Ozanimod was approved for marketing by the FDA and EMA in 2020, and Pfizer's (formerly Arena Pharmaceuticals) Etrasimod just recently completed a clinical phase 3 study, with both related acquisition deals valued at over $6 billion. confirming the enormous potential of this class of drugs.

In clinical studies of drugs for the treatment of UC, clinical remission rates based on the modified Mayo score (assessing stool frequency, rectal bleeding and endoscopy scores) and the full Mayo score (adding the physician's overall assessment to the modified Mayo score) are the primary efficacy endpoints recognized by the FDA and CDE for registration approval, as well as in clinical trials supporting earlier approved drugs for the treatment of UC.

2

Interpretation of CBP-307 clinical results

CBP-307 is a small molecule oral sphingosine 1-phosphate receptor 1 (S1P1) modulator discovered by Conrad based on its own proprietary immunomodulatory technology, with the following mechanism of action.

China Biotech Goes International, Series Report (2) - On the Importance of Clinical Trial Design

*S1P1 mediates the migration of T cells from lymph nodes into the peripheral circulation so that activated T cells can migrate into tissues to release inflammatory mediators. CBP-307 induces internalization of S1P1 on the surface of T cells, trapping T cells in lymph nodes and preventing them from migrating to sites of inflammation, thereby reducing inflammation.

CBP-307CN002 is an ongoing phase 2 study designed to evaluate the efficacy and safety of CBP-307 as an induction and maintenance treatment for adult patients with moderately severe UC. This randomized, double-blind, placebo-controlled, multicenter study enrolled 145 subjects in two dose active drug groups (CBP-307 0.1 mg [n=39]; CBP-307 0.2 mg [n=53]) and one placebo group (n=53), with subjects from more than 60 study centers in 4 countries. The Phase 2 UC trial maintenance treatment and safety follow-up is continuing, and this release is the Phase 1 12-week top-line results, as interpreted by Pharmadoo as follows.

Positive clinical results for CBP-307, with clinical remission rates (a key indicator for FDA and CDE marketing approval) already meeting expectations

China Biotech Goes International, Series Report (2) - On the Importance of Clinical Trial Design

As seen in the above graph, the 0.2 mg CBP-307 group achieved a higher and statistically significant clinical remission rate compared to the placebo group in both the modified and complete Mayo-based scores. A continuation of this trend in the Phase 3 study would be sufficient to meet the requirements for marketing approval.

As for the least squares (LS) mean change from baseline in the modified Mayo score, the primary efficacy endpoint that is prone to controversy, it did not reach statistical significance, as detailed in the figure below (left), but is statistically significantly different when based on the full Mayo score (right).

China Biotech Goes International, Series Report (2) - On the Importance of Clinical Trial Design

We note that the magnitude of change in scores in the placebo group of the study was greater (-2.01 and -2.74) than the values of the main competitor in the same category, Etrasimod, in the relevant clinical study (-1.5 and -2.08), which had an impact on the outcome statistics.

According to incomplete statistics, the proportion of moderate UC patients in China is more than 40%, and about 20% of severe patients. For innovative oral S1P1 modulators, for prudential reasons, the execution of domestic clinical trials often tends to include patients with moderate rather than severe, which may have a certain selection bias, resulting in large baseline variation; more significant efficacy differences may be obtained in subsequent studies if the number of enrolled patients can be increased, or the proportion of severe patients can be increased.

In addition, patients enrolled in the relevant clinical trials of Ozanimod and Etrasimod had longer mean years of disease (>6 years) and may have had higher Mayo scores and thus baseline differences, and thus may have had more of a decline in scores in the clinical trials compared to CBP-307.

The current trial population has a higher proportion of Asians (48/53 in the 0.2 mg CBP-307 group, 90.6%), and with reference to previous studies conducted by other competing products, there are differences in clinical data between European, American and Asian UC patients: in the phase 3 study of vedolizumab, the clinical remission and response in the placebo group of Japanese patients was significantly higher than that of global patients, resulting in data performance in the dosing group of Japanese subjects In the phase 3 study of infliximab, the disease duration was 1-2 years shorter in Chinese patients compared to global patients, and the response rate in the placebo group was higher in Chinese subjects compared to global patients. Therefore, we speculate that better statistical data can be obtained if more European and American patients are included in the future.

Foreign professional organizations such as Fierce Biotech, Bioworld, Jefferies and SVB Leerink have acknowledged that the disclosed clinical results demonstrate a good clinical benefit for CBP-307, with Jefferies also noting that the remission rate obtained in this trial may be better than other competing products in the same target if corrected for placebo. In addition, the efficacy and safety of CBP-307 has been generally accepted by the PI of the well-known IBD clinical studies at home and abroad. Although the choice of the primary endpoint in Phase 2 has had some impact on the interpretation of the results, it should not be required to re-run the clinical trial, and it is expected that there will be no problem to continue the Phase 3 clinical study in the future (there is no shortage of examples in the industry where the phase 2 clinical results did not match the expected primary endpoint, but were eventually approved successfully by optimizing the design of subsequent pivotal clinical trials, such as gefitinib (Gefitinib, Navulizumab, etc.).

Piper Sandler had a dedicated post last month reviewing the preclinical and clinical phase I data for CBP-307, which showed the strongest activity (EC50) against S1P1 (compared to major competitors), significantly lower potency against S1P4 and S1P5, and essentially no activity against S1P3 (a receptor subtype with known safety concerns). Stronger lymphocyte count suppression is achieved at lower doses and faster lymphocyte recovery after discontinuation (<7d), significantly reducing the time to immune recovery after treatment discontinuation with CBP-307 compared to published data from similar products, thereby reducing the risk of infection in patients.

China Biotech Goes International, Series Report (2) - On the Importance of Clinical Trial Design

These advantages give the developers sufficient confidence, and we have reason to believe that by optimizing the clinical trial design and further improving the quality of patient enrollment, CBP-307 is expected to achieve even better clinical results in the future.

3

China Biotech must challenge the first line of international

The overall level of China's innovative drug R&D has not yet entered the international second tier, and many projects have been seen in the past in a state of two "10s": according to incomplete statistics, according to the median data, China's new class 1 drugs listed in 2019-2020 are 10 years behind the global First-in-class products listed; the same target The overall lag in R&D progress means that there is more information and experience to refer to when entering the clinical research phase. For the current enterprises following the international frontline, information resources and reference experience are often very limited, and they will undoubtedly face a lot of difficulties to make the most suitable clinical trial design for specific projects, and there will be more elements of exploration, so naturally they cannot guarantee that the choice they make is always appropriate. Therefore, the internationalization of new drug innovation is also a road of "rainbow after the storm". Challengers must be brave enough to innovate in the real world, continue to learn and adjust and improve in time to obtain breakthroughs and ultimately succeed.

We therefore believe that there are at least three areas that need to be strengthened.

1. Strengthen the access to information resources and reference for decision making.

2. Substantially increase the investment of talents and resources related to clinical research, and make advance plans for various situations that may arise.

3. Make good use of the convenient conditions for conducting clinical research in China (cost control, expert resources, policy support, etc.), and the joint efforts of many parties to protect the project.

Relying on its own R&D big data, rich experience in consulting projects and external expert resources, Pharmado Group is willing to help China Biotech.

4

Concluding remarks

Leading biotech, represented by Conrad, has made active efforts to catch up with the international leading level in drug innovation for self-exempt diseases. In the future, Conrad will actively seek partners to expand clinical research at home and abroad to benefit patients in more countries, and become an active pathfinder to enter the international market alongside with companies such as Baekje Shenzhou, Cinda, Junshi and Tianjing. Under the background of complex and changing international situation, the understanding and support from domestic R&D, investment and review parties are needed. Involving innovative targets and complex diseases, continuous refinement and optimization during clinical development will become the norm. The "missed primary endpoint" in the ongoing phase 2 study does not obscure the positive results of other indicators, but suggests the direction of subsequent optimization of clinical trial design. The advantages of CBP-307 suggest that it may have the potential to be the best in class, or at least comparable to international first-line new drugs, and has the potential to add to the second tier of Chinese innovative drug development.

Reference.

https://www.nature.com/articles/d41573-021-00194-5

https://investors.connectbiopharm.com/presentations-events/events

https://www.fiercebiotech.com/biotech/chasing-bristol-myers-and-pfizer-connect-fails-phase-2-ulcerative-colitis-trial-spies-path

https://www.bioworld.com/articles/518497-connect-seeks-to-partner-s1p-drug-after-phase-ii-falls-short?v=preview

CNTB Leerink 5.4.22

CNTB Jefferies 5.3.22

CNTB Piper 4.8.22