Discuss the future development of "Nobel Prize-blockbuster tumor drugs" from the perspective of clinical value

At the end of 2021, the Drug Evaluation Center of the State Food and Drug Administration issued the "Guiding Principles for Clinical Research and Development of Antitumor Drugs Oriented to Clinical Value"
.

Arguably, this is one of the guiding principles that has sparked the most heated discussion in the industry

However, what kind of clinical advantages can reflect the real clinical value? Here, the author takes the "Zomib" family, a key drug for multiple myeloma, as an example to discuss the real clinical value of tumor drugs with colleagues in the industry, and at the same time discuss the future development trend of proteasome inhibitors
.

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1

Nobel Prize Mechanism & Success Foundation

Nobel Prize Mechanism & Success Foundation

In 2004, the Nobel Prize in Chemistry was awarded to scientists who discovered the "ubiquitin-proteasome" pathway
.

From this, it is enough to see the clinical value of discovering this pathway and the significance of in-depth research

Figure 1.
1 2004 Nobel Prize in Chemistry - for the discovery of ubiquitin-mediated protein degradation

Let's talk about the classic pathway of "ubiquitin-proteasome"
.

The ubiquitin-proteasome, a key ATP-dependent degradation system related to protein quality control and maintenance of cellular homeostasis in eukaryotic cells, can specifically recognize and degrade a variety of protein substrates, especially unstable or denatured, Misfolded protein

This pathway is further elaborated: the target protein undergoes the action of ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2 and ubiquitin ligase E3 in turn, covalently modified polyubiquitin chains, and introduced into the proteasome system; The 26S proteasome formed by 20S binding recognizes and degrades it into short peptides
.

Figure 1.
2 Ubiquitin-proteasome pathway & 26S proteasome structure and function

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Efficacy characteristics are not only data enhancement

Efficacy characteristics are not only data enhancement

If the efficacy of the drug is not in place, it is impossible to talk about the clinical efficacy, let alone the clinical value in the true sense; but the improvement of drug efficacy is not only the smaller the value, the better, but also requires a comprehensive evaluation of the data and process
.

For proteasome inhibitors, there are currently three varieties on the market, namely the first marketed bortezomib, and two follow-up varieties, carfilzomib and ixazomib, and their efficacy is now described in detail.

.

➣ Bortezomib: First Drug/Injectable & Reversible

➣ Bortezomib: First Drug/Injectable & Reversible

Bortezomib can inhibit the trypsin-like activity of the 20S proteasome with a Ki value of 0.
6 nM; 1 hour after injection, the proteasome inhibition rate reaches 80%, and the recovery rate of proteasome function is 50% after 24 hours of injection, 72 hours after injection fully recovered
.

Studies on human MM cell lines showed IC50 values ​​of 3, 6 and 2 nM in U266, IM-9 and HsSultan cells, respectively; in chemo-resistant RPMI8226MM cells, doxorubicin-resistant (Dox/40 cells), mitoxantrone-resistant (MR20 cells), and melphalan-resistant (LR5 cells) had IC50 values ​​of 40, 20, and 20 nM, respectively; in dexamethasone-sensitive MM1S cells, dexamethasone/bortezomib Significantly inhibited the growth of MM1S cells in a dose-dependent manner
.

(PS: The preclinical efficacy showed a strong effect)

➣ Carfilzomib: 2nd injection / irreversible "zomib"

➣ Carfilzomib: 2nd injection / irreversible "zomib"

After the first administration, at a dose of 15 mg/m2, the whole blood proteasome chymotrypsin-like activity was inhibited by 80%, and the peripheral blood mononuclear cell proteasome chymotrypsin-like activity was inhibited by 70%; the administered dose was 27 mg/m2.
m2, PBMCs proteasome chymotrypsin-like activity was inhibited by 90%, and sustained chymotrypsin-like activity inhibition could be observed after repeated administration
.

(PS: also showed good non-clinical efficacy)

➣ Ixazomib: 3rd reversible/first oral "zomib"

➣ Ixazomib: 3rd reversible/first oral "zomib"

Ixazomib is more easily transported from plasma to tumor tissue than bortezomib, and has a shorter half-life of proteasome dissociation, thereby further improving pharmacokinetic and pharmacodynamic effects
.

(PS: It can be taken orally, which is an important breakthrough)

Table 2.
1 Marketed proteasome inhibitors (drug efficacy characteristics)

(Note: The table gives the inhibitory effect of the same reference)

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Pharmacokinetic characteristics should be focused on

Pharmacokinetic characteristics should be focused on

In the drug screening process, after obtaining the structure, the first consideration is usually drug efficacy screening
.

After initially obtaining acceptable pharmacodynamic data, whether it is from the perspective of drug development or the layout of compound patents, in general, the urgent need for pharmacokinetic work; and for proteasome inhibitors, pharmacokinetic work development is more urgent

➣ Bortezomib

➣ Bortezomib

In the early stage of development, after [14C]bortezomib was administered to rats, the drug could be rapidly distributed (about 10 minutes) to the adrenal gland, kidney, liver, prostate and spleen through imaging technology, and most of the metabolized drug was excreted in the form of bile
.

In clinical trials, after intravenous administration of bortezomib 1.
0mg/m2 and 1.
3mg/m2 to 11 MM patients, the mean maximum plasma concentrations of the first dose (day 1) were 57 and 112ng/mL, respectively
.

During subsequent administration, the mean maximum plasma concentrations of bortezomib ranged from 67 to 106 ng/mL (1.

➣ Carfilzomib

➣ Carfilzomib

Single dose clinical intravenous administration of carfilzomib 27mg/m2, Cmax and AUC were 4232 and 379ng/h·mL, respectively
.

Repeated dosing of carfilzomib at 15 and 27 mg/m2 resulted in similar AUC and half-lives on days 1, 15, and 16 of the first course of treatment, suggesting that carfilzomib had no cumulative effect

The steady-state volume of distribution of carfilzomib is large and varies widely at different doses, suggesting a broad tissue distribution
.

Given 20mg/m2 of this product, the average steady-state volume of distribution is 28L

➣ Ishazomi

➣ Ishazomi

Ixazomib is rapidly absorbed after oral administration, reaching the peak plasma concentration after about 1 hour, the absolute bioavailability is 58%, the binding rate to plasma proteins is as high as 99%, and it is distributed in red blood cells after binding
.

As the first orally administered Pls, the drug compliance is better; and compared with bortezomib, the dissociation half-life of the drug when combined with the subunit of the proteasome is shorter, about 1/6 of that of bortezomib

Table 3.
1 PK parameters of marketed proteasome inhibitors

(Note: This table gives the pharmacokinetic characteristics of the same reference)

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Clinical efficacy & clinical value

Clinical efficacy & clinical value

The basic attributes of medicines include safety, effectiveness, and quality control.
For patients, on the basis of safety, more attention is paid to the efficacy of medicines.
After all, people's traditional concept of medicines is to "treat disease and save lives"
.
Let's take a look at the clinical data of the three proteasome inhibitors to prove their clinical efficacy and value
.

➣ Bortezomib

➣ Bortezomib

Some key clinical information is as follows:

A study of 202 patients who had received at least two prior therapies and had recently been found to have progressive disease; this product was administered intravenously at a dose of 1.
3 mg/m2 twice a week for 2 weeks followed by a 10-day discontinuation (ie, 21 days) In the dose-response relationship study (M34100-24) of 54 patients with multiple myeloma, 1.
0 mg/m2 or 1.
3 mg/m2 of this product was injected each time, weekly 2 injections for 2 consecutive weeks, 1 week off
.
Complete responses were observed at both doses, with overall response rates (CR+PR) of 30% (8/27) and 38% (10/26), respectively
.
A randomized, open-label clinical study of untreated multiple myeloma (682 cases), compared with MP combined therapy, a statistically significant survival benefit was still observed in the combined MP group (HR=0.
695; p =0.
00043)
.
The estimated median survival time of the MP group was 43.
1 months, and the median survival time of the MP group combined with this product was estimated to be 56.
4 months
.

➣ Carfilzomib

➣ Carfilzomib

Some key clinical information is as follows:

288 patients with relapsed/refractory multiple myeloma (RRMM) who have received at least 2 previous treatments (including zolmi and duramide); PX-171-003-A0 trial, 28 days × 12 weeks, treatment dose of 20 mg PX-171-003-A1 , 28d is a course of treatment, continuous 2d administration per week for 3 weeks, and then discontinued for 12d, until the disease worsens, or unacceptable toxicity occurs, up to 12 courses of treatment, the total remission rate of the patients was 22.
9%, the average treatment period 3 months, the median remission period was 7.
8 months; the clinical benefit response rate was 37%, the median clinical benefit period was 8.
3 months, the progression-free survival was 3.
7 months, and the median overall survival was 15.
6 months
.
In Phase II PX-171-004, 35 patients with RRMM who had received bortezomib treatment; 28d is a course of treatment, a total of 12 courses of treatment, each course of 1, 2, 3, 8, 9, 15 and 16 days of intravenous 20 mg/m2 of this product was injected, and 4 mg of dexamethasone was used for prevention if necessary; the overall remission rate was 17.
1%, and the median remission period was greater than 10.
6 months
.
In the PX-171-006 study, carfilzomib combined with lenalidomide and a small amount of dexamethasone were used in patients with RRMM; the treatment cycle was 28 days, and the combined treatment did not reach the tolerated dose and showed good tolerance, The ORR at the highest dose was 78%
.

➣ Ishazomi

➣ Ishazomi

Some key clinical information is as follows:

60 patients with relapsed and/or refractory MM were treated with ixazomib monotherapy; a course of 4 weeks, the results showed that the maximum tolerated dose was 2.
97 mg m2 (9 patients, 18%) patients reached Partial remission or better; 60 patients with relapsed and/or refractory MM who had previously received bortezomib, lenalidomide, thalidomide, carfilzomib/marizomib, respectively, were given a single drug Ixazomib was treated with a dose of 0.
24-2.
23 mg m2, 1, 4, 8, and 11 days, with a cycle of 21 days.
In the end, 15% achieved partial remission and 76% achieved stable curative effect; 33 patients received at least For patients with relapsed and/or refractory MM with 2 treatment regimens, the dose is 5.
5 mg/week, each course of treatment is 4 weeks, and the oral administration is continued for the first 3 weeks of each course, and ends at the end of the second course of treatment Those who still did not get mild remission at the end of the 4th course of treatment, those who did not get partial remission at the end of the 4th course of treatment, or those with disease progression during the course of treatment, were treated with dexamethasone in combination.
The efficiency was 34%; 722 patients with relapsed, refractory, or relapsed + refractory MM had previously received 1-3 line therapy with lenalidomide and dexamethasone, but the effect was poor; Treatment with ixazomib in combination with lenalidomide and dexamethasone (ixazomib group) and placebo in combination with lenalidomide and dexamethasone (placebo group) showed that for recurrent and/or In refractory MM patients, ixazomib combined with lenalidomide and dexamethasone can achieve longer PFS and better clinical remission rate in patients who have received at least 1 previous treatment regimen.
Oral Pls Isha Zomib has high clinical application value
.
In 115 MM patients, the results showed that the PFS of the ixazomib group and the placebo group were 6.
7 months and 4.
0 months, respectively, and the overall survival was 25.
8 months and 15.
8 months, respectively, and the difference between the two groups was statistically significant.
On the one hand, it shows that the combination of ixazomib and lenalidomide and dexamethasone can effectively prolong the PFS of Chinese patients.
OS
.

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results and future

results and future

The above are the three proteasome inhibitors approved by the FDA, and "approved" is enough to prove the drug value of the three varieties
.
However, according to my country's current evaluation standards, does the approved data base meet my country's current market demand for new drugs? Whether it satisfies the recently issued "Guidelines for Clinical Research and Development of Antitumor Drugs Oriented by Clinical Value" is very much to be discussed
.

We first briefly summarize the main characteristics of the three drugs
.
Bortezomib, the first drug, is a clinical first-line drug, but the injection, the treatment window is slightly narrow, the medication cycle is too long, frequent dosing, and patient compliance is not good; Ixazomib, improves some of the shortcomings of bortezomib, The adverse reactions of the peripheral nervous system are reduced, and the resistance problem of bortezomib is optimized.
It is an irreversible inhibitor, but it is still injected; Ixazomib, the first oral administration, improves the curative effect and overcomes the resistance of bortezomib.
3 varieties are still very clinical value
.

So what kind of proteasome inhibitors need to be developed in the future?

First of all, judging from the existing high-stage clinical varieties, they are all oral drugs, and solving compliance and drug cycle is definitely a clinical direction that needs to be solved
.

Secondly, the adverse reactions of peripheral nervous system are a common problem of this kind of drugs, which is also the main content to be solved
.

Again, we still have to return to the point of clinical value.
The so-called clinical value, for proteasome inhibitors, is more for the clinical value of the indication of multiple myeloma.
Is the development direction of new drugs limited to similar drugs? Comparison of drugs to prove the advantages identified by developers? Or do you want more PK efficacy and value with clinical first-line drugs and treatment regimens? It is believed that more tendencies will be the latter
.

At present, there are countless clinical drugs for multiple myeloma, and more treatment options are emerging one after another.
As far as this indication field and proteasome inhibitors are concerned, it is not easy to develop drugs with real clinical value
.

References:

1.
Proteasome inhibitors: from research tools to drug candidates.
Chemistry & Biology 8 (2001) 739-758.

2.
Next-generation proteasome inhibitors for cancer therapy, Translational Research (2018), https://doi.
org/10.
1016/j.
trsl.
2018.
03.
002.

3.
Pharmacology differences among proteasome inhibitors: Implications for their use in clinical practice.
Pharmacological Research 167(2021)105537.
doi.
org/10.
1016/j.
phrs.
2021.
105537

4.
Proteasome inhibitors in cancer therapy.
NATUREREVIEWS|CLINICALONCOLOGY.
doi:10.
1038/nrclinonc.
2016.
206

5.
Bortezomib package insert

6.
Instructions for Ixazomib

7.
Carfilzomib Drug Instructions

8.
CNKI literature data

9.
Wanfang Literature Data