# US 12,014,835 B2 · Methods for evaluating therapeutic benefit of combination therapies

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- Number: US 12,014,835 B2
- Document ID: US12014835B2
- Status: Granted
- Kind: B2
- Application number: 17/180,280
- Filed: 2021-02-19
- Published: 2021-11-18
- Granted: 2024-06-18
- Earliest claimed: 2020-02-19
- Assignees: Vanderbilt University; Duet BioSystems Inc.
- Applicants: Vanderbilt University; DUET Biosystems, Inc.
- Inventors: Christian T. Meyer; Vito Quaranta; Leonard A. Harris; Buddhi Bishal Paudel; David J. Wooten; Laurent Audoly
- Web page: https://patentgrep.com/patent/US12014835B2

## CPC

- G16H 50/20: for computer-aided diagnosis, e.g. based on medical expert systems
- G16H 70/20: relating to practices or guidelines
- G16C 20/30: Prediction of properties of chemical compounds, compositions or mixtures
- G16H 20/10: relating to drugs or medications, e.g. for ensuring correct administration to patients
- G06N 3/042: Knowledge-based neural networks; Logical representations of neural networks
- G06N 3/048: Activation functions
- G06N 5/045: Explanation of inference; Explainable artificial intelligence [XAI]; Interpretable artificial intelligence
- G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G06N: COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS

## Abstract

The invention provides methods for evaluating the therapeutic benefit of a combination therapy useful for treating a medical disorder, such as cancer.

## Claims

### Claim 1

A method for evaluating the therapeutic benefit of a combination therapy comprising a first therapeutic agent and a second therapeutic agent to be used in combination to treat a medical disorder, the method comprising the steps of:
(a) determining, with an electronic processor, a difference in efficacy towards the medical disorder between (i) the combination and (ii) the most efficacious single therapeutic agent in the combination;
(b) determining, with the electronic processor, a difference in potency towards the medical disorder for the first therapeutic agent between when (i) the first therapeutic agent is used alone and (ii) the first therapeutic agent is used in combination with the second therapeutic agent;
(c) determining, with the electronic processor, a difference in potency towards the medical disorder for the second therapeutic agent between when (i) the second therapeutic agent is used alone and (ii) the second therapeutic agent is used in combination with the first therapeutic agent;
(d) selecting the combination, the first therapeutic agent, or the second therapeutic agent, to prescribe for a patient, based on the determining steps of (a), (b), and (c); and
optionally, administering the selected one of the combination, the first therapeutic agent, or the second therapeutic agent to the patient.

### Claim 2 (depends on 1)

The method of claim 1, wherein step (a) comprises determining, with the electronic processor, for a plurality of different doses for each therapeutic agent in the combination, the difference in efficacy towards the medical disorder between (i) the combination and (ii) the most efficacious single therapeutic agent in the combination.

### Claim 3 (depends on 1)

The method of claim 1, wherein step (a) comprises determining, with the electronic processor, across a dosage range for each therapeutic agent in the combination, the difference in efficacy towards the medical disorder between (i) the combination and (ii) the most efficacious single therapeutic agent in the combination.

### Claim 4 (depends on 1)

The method of claim 1, wherein step (b) comprises determining, with the electronic processor, for a plurality of different doses of the first therapeutic agent, the difference in potency towards the medical disorder for the first therapeutic agent between when (i) the first therapeutic agent is used alone and (ii) the first therapeutic agent is used in combination with the second therapeutic agent.

### Claim 5 (depends on 1)

The method of claim 1, wherein step (c) comprises determining, with the electronic processor, for a plurality of different doses of the second therapeutic agent, the difference in potency towards the medical disorder for the second therapeutic agent between when (i) the second therapeutic agent is used alone and (ii) the second therapeutic agent is used in combination with the first therapeutic agent.

### Claim 6 (depends on 1)

The method of claim 1, wherein results from determining, with the electronic processor, the difference in efficacy towards the medical disorder from step (a) are cross-referenced with results from one or both of:
(i) results from determining the difference in potency towards the medical disorder for the first therapeutic agent from step (b), and
(ii) results from determining the difference in potency for the second therapeutic agent from step (c);
to generate a graphical display of therapeutic effect according to the dose of first therapeutic agent and dose of second therapeutic agent.

### Claim 7 (depends on 1)

The method of claim 1, wherein the method comprises determining, with the electronic processor, a therapeutic effect (Ed) towards the medical disorder for the combination therapy, at a given concentration of first therapeutic agent and second therapeutic agent, using Equation 1:
E
d
=
C
1
h
1
⁢
C
2
h
2
⁢
E
0
+
d
1
h
1
⁢
C
2
h
2
⁢
E
1
+
C
1
h
1
⁢
d
2
h
2
⁢
E
2
+
(
α
2
⁢
d
1
)
h
1
⁢
d
2
h
2
⁢
E
3
C
1
h
1
⁢
C
2
h
2
+
d
1
h
1
⁢
C
2
h
2
+
C
1
h
1
⁢
d
2
h
2
+
(
α
2
⁢
d
1
)
h
1
⁢
d
2
h
2
(
Equation
⁢
⁢
1
)
wherein:
C1 is the concentration of the first therapeutic agent required to achieve 50% of the maximum efficacy of the combination therapy towards the medical disorder;
C2 is the concentration of the second therapeutic agent required to achieve 50% of the maximum efficacy of the combination therapy towards the medical disorder;
h1 is the Hill coefficient for the dose-response curve of the first therapeutic agent when the first therapeutic agent is used alone;
h2 is the Hill coefficient for the dose-response curve of the second therapeutic agent when the second therapeutic agent is used alone;
d1 is concentration of the first therapeutic agent;
d2 is concentration of the second therapeutic agent;
E0 is the basal effect (i.e. the efficacy when neither the first nor second therapeutic agent is used to treat the medical disorder);
E1 is the maximum efficacy towards the medical disorder of the first therapeutic agent when the first therapeutic agent is used alone;
E2 is the maximum efficacy towards the medical disorder of the second therapeutic agent when the second therapeutic agent is used alone;
E3 is the maximum efficacy towards the medical disorder of the combination therapy; and
α2 is the fold-change in the concentration of the first therapeutic agent required to achieve 50% of the maximum efficacy towards the medical disorder of the combination therapy compared to when the first therapeutic agent is used alone.

### Claim 8 (depends on 7)

The method of claim 7, wherein the therapeutic effect (Ed) is determined, with the electronic processor, at a plurality of different doses for the first therapeutic agent and at a plurality of different doses for the second therapeutic agent.

### Claim 9 (depends on 7)

The method of claim 7, wherein determining, with the electronic processor, the therapeutic effect (Ed) includes using a Bayesian curve fitting algorithm with a particle swarm optimizer to seed priors for a Markov chain Monte Carlo Optimization.

### Claim 10 (depends on 7)

The method of claim 7, wherein the therapeutic effect (Ed) is displayed graphically, with the electronic processor, according to the determined therapeutic effect (Ed) across different doses for the first therapeutic agent and across different doses for the second therapeutic agent.

### Claim 11 (depends on 1)

The method of claim 1, wherein the method comprises determining, with the electronic processor, a therapeutic effect (Ed) towards the medical disorder for the combination therapy, at a given concentration of first therapeutic agent and second therapeutic agent, using Equation 2:
E
d
=
[
E
0
⁢
⁢
E
1
⁢
⁢
E
2
⁢
⁢
E
3
]
⁢
·
⁢
[
⁢
-
(
r
1
⁢
d
1
h
1
+
r
2
⁢
d
2
h
2
)
r
-
1
r
-
2
0
r
1
⁢
d
1
h
1
-
(
r
-
1
+
r
2
⁡
(
α
1
⁢
d
2
)
h
2
)
0
r
-
2
r
2
⁢
d
2
h
2
0
-
(
r
1
⁡
(
α
2
⁢
d
1
)
h
1
+
r
-
2
)
r
-
1
1
1
1
1
⁢
]
-
1
·
[
0
0
0
1
]
(
Equation
⁢
⁢
2
)
wherein:
C1 is the concentration of the first therapeutic agent required to achieve 50% of the maximum efficacy of the combination therapy towards the medical disorder;
C2 is the concentration of the second therapeutic agent required to achieve 50% of the maximum efficacy of the combination therapy towards the medical disorder;
h1 is the Hill coefficient for the dose-response curve of the first therapeutic agent when the first therapeutic agent is used alone;
h2 is the Hill coefficient for the dose-response curve of the second therapeutic agent when the second therapeutic agent is used alone;
d1 is concentration of the first therapeutic agent;
d2 is concentration of the second therapeutic agent;
E0 is the basal effect (i.e. the efficacy when neither the first nor second therapeutic agent is used to treat the medical disorder);
E1 is the maximum efficacy towards the medical disorder of the first therapeutic agent when the first therapeutic agent is used alone;
E2 is the maximum efficacy towards the medical disorder of the second therapeutic agent when the second therapeutic agent is used alone;
E3 is the maximum efficacy towards the medical disorder of the combination therapy;
α1 is the fold-change in the concentration of the second therapeutic agent required to achieve 50% of the maximum efficacy towards the medical disorder of the combination therapy compared to when the second therapeutic agent is used alone;
α2 is the fold-change in the concentration of the first therapeutic agent required to achieve 50% of the maximum efficacy towards the medical disorder of the combination therapy compared to when the first therapeutic agent is used alone;
r1 is the rate of transition for the first therapeutic agent from the unaffected state to the affected state;
r−1 is r1*C1h1;
r2 is the rate of transition for the second therapeutic agent from the unaffected state to the affected state; and
r−2 is r2*C2h2.

### Claim 12 (depends on 11)

The method of claim 11, wherein the therapeutic effect (Ed) is determined, with the electronic processor, at a plurality of different doses for the first therapeutic agent and at a plurality of different doses for the second therapeutic agent.

### Claim 13 (depends on 11)

The method of claim 11, wherein determining, with the electronic processor, the therapeutic effect (Ed) includes using a Bayesian curve fitting algorithm with a particle swarm optimizer to seed priors for a Markov chain Monte Carlo Optimization.

### Claim 14 (depends on 11)

The method of claim 11, wherein the therapeutic effect (Ed) is displayed graphically, with the electronic processor, according to the determined therapeutic effect (Ed) across different doses for the first therapeutic agent and different doses for the second therapeutic agent.

### Claim 15 (depends on 1)

The method of claim 1, further comprising evaluating, with the electronic processor, the pharmacokinetic properties of all therapeutic agents in the combination therapy; and selecting, with the electronic processor, at least one selected from a group consisting of a dosage amount and an identity of at least one therapeutic agent in the combination therapy to improve the therapeutic benefit of the combination in view of the pharmacokinetic properties.

### Claim 16 (depends on 1)

The method of claim 1, further comprising evaluating, with the electronic processor, the safety profile of all therapeutic agents in the combination therapy; and selecting, with the electronic processor, at least one selected from a group consisting of a dosage amount and an identity for at least one therapeutic agent in the combination therapy that improves the safety profile of the combination therapy.

### Claim 17 (depends on 1)

The method of claim 1, further comprising evaluating, with the electronic processor, a toxicity profile of all therapeutic agents in the combination therapy, and selecting, with the electronic processor, at least one selected from a group consisting of a dosage amount and an identity for at least one therapeutic agent in the combination therapy that improves the toxicity profile of the combination therapy.

### Claim 18 (depends on 1)

The method of claim 1, further comprising evaluating, with the electronic processor, patient biological pathways of all therapeutic agents in the combination therapy; and selecting, with the electronic processor, the identity of at least one therapeutic agent in the combination therapy so that the combination therapy impacts at least two different biological pathways in the patient in order to improve the therapeutic benefit of the combination.

### Claim 19 (depends on 1)

The method of claim 1, further comprising evaluating, with the electronic processor, the therapeutic index of all therapeutic agents in the combination therapy; and selecting, with the electronic processor, at least one selected from a group consisting of a dosage amount and an identity of at least one therapeutic agent in the combination therapy that improves the therapeutic index of the combination therapy.

### Claim 20 (depends on 1)

The method of claim 1, further comprising (i) selecting, with the electronic processor, a dosage amount for at least one therapeutic agent in the combination that improves the therapeutic benefit towards the medical disorder or (ii) altering, with the electronic processor, the identity of at least one therapeutic agent in the combination therapy to improve the therapeutic benefit towards the medical disorder.