March 2021 | TOP10 failed clinical studies

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In March 2021, the "Monthly Clinical Research Report" screened out 10 studies worthy of attention that did not reach the primary clinical endpoints for your reference.

The following is the text:

1.

Neurocrine Biosciences company pipeline

Luvadaxistat is a potential First-in-class, oral, high-affinity d-amino acid oxidase (DAAO) selective inhibitor.

2.

Almost 80% of IBS patients are accompanied by recurrent or persistent abdominal pain.

The CAPTIVATE study is the first study to evaluate the treatment of IBS pain with CB2 full agonists.

Olorinab (APD371) is an oral, peripheral, and highly selective full agonist of CB2.

Arena Pharmaceuticals pipeline

3.

Apellis Pharmaceuticals company pipeline

APL-9 is an investigational drug designed to control the cascade of complement at C3, and may have the potential to treat a series of diseases caused by excessive or uncontrolled complement activation.

Source: Apellis Pharmaceuticals

Comment: Complement is a complex protein network consisting of more than 30 plasma proteins and membrane-bound proteins.

It is worth mentioning that Shutaishen C5a inhibitor BDB-001 and Shanghai Kangjing complement inhibitor CG001 have also carried out clinical studies on the treatment of COVID-19 in early 2020.

4.

AnaptysBio

Palmoplantar pustulosis is a rare chronic skin disease characterized by repeated episodes of palm and plantar pustules.
Common clinical symptoms include scales, erythema, itching, burning and pain, etc.
, and may last for many years.

Imsidolimab (ANB019) is an antibody that inhibits the function of interleukin 36 receptor (IL-36R).
AnaptysBio initially planned to develop it for generalized pustular psoriasis or pustular psoriasis, and EGFR-mediated skin toxicity fish scales Disease, hidradenitis suppurativa and acne.

Although the drug is not effective against palmoplantar pustulosis, another phase II trial (GALLOP) for moderate to severe pustular psoriasis has quite impressive results and has been awarded the FDA "orphan drug" designation.
Pustular psoriasis is also a life-threatening disease, and there is currently no approved treatment.
Imsidolimab is expected to start a phase III clinical trial for this indication in mid-2021.

5.
Phase III study of Canakinumab in the treatment of NSCLC

On March 9, Novartis announced that the IL-1β inhibitor Canakinumab (ACZ885) combined with docetaxel for the treatment of locally advanced or metastatic NSCLC Phase III (CANOPY-2) did not reach the primary endpoint of improving OS.
The study was conducted in 237 adult patients who had previously undergone platinum-based chemotherapy and PD-1/L1 inhibitor immunotherapy during or after progress.
Novartis will analyze the research data and announce detailed data at a subsequent medical conference.

Canakinumab is a human monoclonal antibody that selectively binds to human interleukin-1β (IL-1β) with high affinity and neutralizes the activity of IL-1β by blocking its interaction with the receptor.
Preliminary evidence shows that by neutralizing IL-1β, Canakinumab can turn pro-tumor inflammation into: 1) enhancing anti-tumor immune response; 2) reducing tumor cell proliferation, survival and invasiveness; 3) impairing angiogenesis.
Pro-tumor inflammation promotes tumor development by driving the carcinogenic process and inhibiting anti-tumor immune response.
Canakinumab is a First-in-class IL-1β inhibitor targeted to promote tumor inflammation in NSCLC.

The post-mortem analysis of the Phase III CANTOS trial for cardiovascular disease indicated that lung cancer mortality was significantly reduced as the dose of Canakinumab increased.
Based on this, Novartis launched the CANOPY series of studies.
Although the results announced this time are disappointing, Novartis still hopes that Canakinumab can play a role in lung cancer.
Currently, two other Phase III studies are still in progress, including validation of Canakinumab+Keytruda+ chemotherapy in newly diagnosed patients with advanced NSCLC (CANOPY-1), and CANOPY-A will determine whether it can prevent early NSCLC as an adjuvant treatment Recurrence after surgery.
Among them, CANOPY-1 should get results in 2021, while CANOPY-A will have to wait until 2023.

6.
Phase II study of Bintrafusp alfa in the treatment of biliary tract cancer

On March 16, Merck announced that Bintrafusp alfa (M7824) was used as a monotherapy in patients with locally advanced or metastatic biliary tract cancer (BTC).
The main data of the Phase II study (INTR @ PID BTC 047) was evaluated by the Independent Review Committee (IRC).
The ORR of BTC is 10.
1% (RECIST 1.
1), which has not reached the predetermined threshold for the research and cannot meet the requirements for submitting regulatory filings in the second-line BTC.

The NTR@PID BTC 047 study recruited 159 BTC patients to receive M7824 monotherapy and 1200 mg intravenously every two weeks until disease progression, death, unacceptable toxicity or withdrawal was confirmed.
After more than 9 months of follow-up, the ORR of this therapy was 10.
1% (95% CI: 5.
9%-15.
8%) as assessed by IRC.

Another placebo-controlled phase II/III trial is currently enrolling 512 patients to study the safety and effectiveness of M7824 combined with chemotherapy as the first-line treatment of BTC.
The primary endpoints include dose-limiting toxicity (DLT) and safety lead-in period Randomized OS (from the first dosing follow-up to the 4th year).

M7824 is a research bifunctional fusion protein that can simultaneously block TGF-β and PD-L1 in the tumor microenvironment.
The drug was discovered by Merck, Germany.
After GlaxoSmithKline paid up to US$4.
5 billion to Merck, the strategic alliance developed M7824.

Bintrafusp alfa (M7824) structure

Comment: Bintrafusp alfa (M7824) is a bifunctional fusion protein.
One end is an antibody structure (Y) that can recognize PD-L1, and the other end is a TGF-β receptor type II fusion protein that can bind to TGF-β (Trap ), which can block the two signal pathways of PD-L1 and TGF-β at the same time.
It belongs to the hot products in the field of specific double antibodies.
There are many clinical studies in NSCLC, cervical cancer, breast cancer, urothelial cancer, etc.
In progress.

Despite high hopes, M7824 has been frustrated frequently.
In January 2021, M7824 compared to Keytruda's first-line treatment of PD-L1 high-expressing advanced NSCLC head-to-head Phase III study (INTR@PID Lung 037) announced that it failed to reach the primary endpoint of PFS, which made it lose the ability to overtake in the field of lung cancer opportunity.

The desire for specific dual antibodies is very good.
Based on the combination of drugs or confirmed two targets, a new combination of innovations in drug forms can be made.
However, not every good wish can bring satisfactory results.
According to the current published clinical data, some bispecific antibodies have not even achieved the effect of drug combination, and the successive failure of M7824, perhaps, the specific bispecific antibodies are not as simple as "1+1>2" as we recognize , There are still problems waiting to be re-understood and resolved.

7.
Phase III study of Tilsotolimod in the treatment of melanoma

On March 18, Idera Pharmaceuticals announced that the TLR9 agonist Tilsotolimod (IMO-2125) combined with the CTLA4 antibody ipilimumab for the treatment of PD-1 refractory advanced melanoma is a key registered clinical phase III study (ILLUMINATE-301), The primary endpoint of ORR was not reached.
Affected by this news, Idera fell more than 60% after the market.

ILLUMINATE-301 is a randomized, global, multi-center, open-label Phase III clinical trial that compared Tilosotolimod combined with ipilimumab compared to ipilimumab in 481 patients with refractory advanced melanoma anti-PD-1 Efficacy of monoclonal antibody monotherapy.
The results of the study showed that the ORR of the combination drug group and the single drug group were 8.
8% and 8.
6%, respectively.
Although the primary endpoint of ORR has not been reached, Idera hopes to discuss potential development paths for this indication with regulatory agencies if the study continues and achieves a positive OS result.

Tilsotolimod is an investigational Toll-like receptor 9 agonist.
Intratumoral injection of Tilsotolimod has been shown to promote innate (type I IFN, antigen presentation) and adaptive (T cell) immune activation.
Tilsotolimod has obtained FDA’s fast track certification and orphan drug certification, and is being evaluated in multiple tumor types and in combination with multiple checkpoint inhibitors, including Tilsotolimod for patients with microsatellite stable colorectal cancer (MSS-CRC) Phase II study in combination with ipilimumab and nivolumab (ILLUMINATE-206).

8.
Phase III study of Rucotinib in the treatment of COVID-19-related ARDS

On March 18th, Incyte announced the results of the Phase III DEVENT study, which evaluated rucotinib (5 mg and 15 mg) plus standard of care (SoC) compared with SoC in COVID-19-related acute respiratory distress syndrome.
Efficacy and safety in ventilated patients (ARDS).
Although the results tended to be positive, there was no statistically significant difference in the mortality within 29 days of treatment in the overall study population.

However, in the majority (91%) of the American population (N=191) in the DEVENT study, the death rate in the treatment group showed a clinical and statistically significant improvement compared to the control group: 46.
7 in the 5 mg treatment group % Vs.
69.
1% (OR: 0.
39, P=0.
0189), and the 15 mg treatment group was 47.
1% vs.
66.
7% (OR: 0.
43, P= 0.
0215).
Incyte said it will discuss with the FDA to allow the use of rocotinib in patients with ARDS related to COVID-19 in the United States.

In addition, post-mortem analysis of the overall study population showed a statistically significant improvement in mortality (53.
6% vs 70.
7%).
Before or during the study, more than half of the patients (55%) received remdesivir treatment, and 90% of the patients received corticosteroid treatment.

As a first-in-class JAK1/JAK2 inhibitor, Rucotinib has been approved for the treatment of polycythemia vera (PV) in adults with insufficient response or intolerance to hydroxyurea; medium and high-risk myelofibrosis (MF), including primary MF, polycythemia vera MF and primary thrombocythemia MF; and used to treat steroid-refractory acute graft-versus-host disease in adults and children 12 years and older.

9.
Tesitetaxel in the treatment of breast cancer

On March 22, Odonate Therapeutics' stock price plummeted, closing down 79%, to $3.
96, because the company terminated the development of stastaxel and will also terminate the company's operations.

Based on the FDA's feedback at the pre-NDA meeting, Odonate Therapeutics believes that the clinical data of teseltaxel is unlikely to support the FDA's approval.
Therefore, it was planned to stop the development of testaside and shut down the company's operations.
The company will cooperate with clinical research institutions to transfer patients in ongoing clinical studies of tesitetaxel to appropriate alternative therapies.

Tesitetaxel is a microtubule stabilizer, which belongs to the taxane class of anticancer drugs.
As a new type of taxane compound, tesitetaxel has unique characteristics: (1) it will not be excreted by P-glycoprotein, (2) has high oral bioavailability, (3) has high Water solubility; (4) has a long half-life.

And, unlike paclitaxel and docetaxel, which cannot penetrate the blood-brain barrier in large amounts, the concentration of tesitetaxel in the brain is higher than the level required to kill tumor cells.
In August 2020, Odonate announced the positive top-line results of phase III (CONTESSA) of teselstat for the treatment of HR+/HER2-metastatic breast cancer.
Compared with the capecitabine single-agent group, teselstat significantly improved patients The median PFS (9.
8 vs 6.
9m) reduces the risk of disease development or death by 28.
4% [HR = 0.
716 (95% Cl: 0.
573-0.
895)].

However, the stock price plummeted 45.
35%.
Investors believe that the therapy has safety issues because the trial showed more neutropenia (71.
2% vs 8.
3%) and febrile neutropenia (12.
8% vs 1.
2).
%), leukopenia (10.
1% vs 0.
9%) and neuropathy (5.
9% vs 0.
9%) and other adverse events.
The proportion of discontinuation caused by adverse events was also significantly higher.
Among the patients treated with tesitetaxel plus capecitabine, 23.
1% of patients discontinued treatment due to any adverse events, while capecitabine monotherapy was 11.
9%.

10.
Phase III study of Tominersen in the treatment of Huntington's disease

On March 22, Roche announced that it had decided to discontinue Tominersen's Phase III clinical study (GENERATION HD1) for the treatment of Huntington's disease (HD).
The decision was based on the results of a pre-planned review, and an unblinded independent data monitoring committee (iDMC) made recommendations based on the subject’s potential benefit/risk profile.

In addition, another Tominersen open label extension study (GEN-EXTEND) will also be suspended.
After analyzing the data, the next step is decided.

Tominersen, previously known as IONIS-HTTRx or RG6042, is an antisense nucleic acid drug that degrades disease-causing mRNA through the RNA degradation system after binding to Huntingtin mRNA, and aims to reduce all forms of Huntingtin (HTT) (including its mutant mHTT) The production.
In December 2017, Roche obtained the development rights of tominersen from Ionis Pharmaceuticals with a license fee of US$45 million based on data from active phase I/II clinical studies.

In addition to Tominersen, on March 29, Wave Life Sciences also announced the clinical Ib/IIa (PRECISION-HD2 and PRECISION-HD1) research results of two antisense nucleic acid drugs for the treatment of HD.
The data shows that all the evaluated doses of WVE-120102 and WVE-120101 did not show statistically significant evidence of clinical efficacy, and Wave will terminate the relevant drug research.
Previously affected by the adverse effects of Tominersen's clinical results, Wave's stock price has fallen 21%, and this news once again aggravated the stock price falling to $5.
33, a 25% drop.

Huntington's disease (HD) is a rare inherited and progressive disease that can cause nerve cells in the brain to collapse, leading to problems with thinking, movement, and functional ability, resulting in disability.
HD has a devastating effect on people with the disease, and the genetic nature of HD means that it can have a profound impact on future generations or entire families.
The survival period after the onset of the disease is about 10-20 years.
Tetrabenazine and deuterated tetrabenazine are the first and first deuterated therapy approved by the FDA for the disease, respectively.