Reducing Contraceptive Burden with Non-Hormonal Male Birth Control Using AI Drug Discovery

Proposal created by Simran Mayra, Liesl Anggijono, Anastasija Petrovic, Diba Dindoust

Problem:

In the United States, 98% of sexually active women have used birth control at some point in time, and 62% of those of reproductive age are currently using birth control. In fact, one of the most common forms of contraception is the birth control pill, with 151 million users.

Birth control options today aren’t good. Hormonal options that are available, most famously the pill, have unpleasant side effects (irregular bleeding, bloating, increased risk of depression and headaches + more serious side effects: high blood pressure, blood clots and stroke) and lowers the quality of life (a study shows a statistically significant reduction in general well-being by a first-choice OC in comparison with placebo in healthy women). The non-hormonal tools we have today such as condoms, diaphragms, etc. can often be unreliable or not used properly & copper IUDs hurt or cause excessive bleeding. Side effects are the reason around one-third of women stop their contraception in the first year of use. Moreover, the use of the contraceptive pill in the UK decreased from 45 percent in 2015 to 39 percent in 2019.

The presence of side effects depends on sensitivity to hormonal changes ( linked to genetic variants ). This is why finding a hormonal contraceptive method that works involves a lot of trial and error. Clinicians don’t have access to large-scale and detailed data which could help them predict which method will work best.

Male & Female Physiology In the Reproductive System

The development line of both male and female sex cells starts with stem cells. The difference is that women’s stem sex cells only exist before birth. Females are born with already differentiated sex cells called primary oocytes that mature into secondary oocytes which can be fertilized.

Men still have their stem sex cells after birth, which is why they can produce 1000 sperm per second. Given that our approach requires a morphological change of immature sex cells- for women, this would require deforming their primary oocytes which they cannot replenish (leading to sterilization).

For a pill to inhibit fertilization in a woman’s body, we would need to exhibit heavy hormonal changes (which, as we know, includes many life-disturbing side effects). Therefore, changing the morphology of primary oocytes is not an option for women. On the contrary, to inhibit sperm to fertilize, we do not need to exhibit heavy hormonal changes and cause men to deal with heavy burdens, neither will men be permanently sterilized.

Status Quo

With the exception of companies that produce mainstream hormonal birth control for women, male birth control remains to be one of reproductive biology and health’s biggest questions. Currently, the way we are approaching male birth control is through either 1) condoms or 2) a vasectomy. Both approaches are costly financially (costing thousands of dollars per operation) and personally. So, beyond incredible physical pain, it has been shown that the mental health of men was worsening post-op. Evidently, deducing to men with vasectomies reflecting a need for professional psychological counselling. In terms of previous attempts, there is no oral pill being commercially used, however, these are two recent clinical trials.

Trial 1, showed promise (2016): The injectable hormone drug was tested with a procedure called RISUG (reversible inhibition of sperm under guidance), which has been under development for decades in India. This treatment would be a one-time shot, where after the injection, sperm wouldn’t be able to leave the body. It would be reversible with another shot of the hormone, clearing the blockage and reversing the procedure.

Trial 2: Intrusive gel put in the scrotum to stop the movement of sperm coming out (non-hormonal but no pill). stopping production of sperm changes the shape of testes.

In 2012, a hormone-based gel that you rub over your upper arms once a day significantly lowered sperm counts with only minimal side effects. Studies on this option are still going on. Even with some side effects, 75% of the men interviewed after the study said they’d use it again.

TLDR: Hormonal birth control causes terrible side effects in women, and non-hormonal birth control as an oral contraceptive is not possible to create, without sterilizing women. Therefore, non-hormonal birth control for men seems to be an optimal approach to problem solve. Hormonal and non-hormonal birth control are both options for men. However, hormonal treatment would cause some side effects (very mild in relation to the adverse reactions in women). This is why non-hormonal birth control would be a more effective route, given the limited side effects- no hormonal imbalances are created.

Solution Overview

83% of men say they would take birth control.

Target protein

The solution we propose is non-hormonal birth control for men. Machine learning can be used to identify small molecule drugs that can inhibit a protein that gives sperms the shape that lets them fertilize an egg.

But why change the shape of sperms instead of just stopping their production?

Past studies have shown that if we stop sperm production it’ll change the testis shape.

A solution that does not change the physiology of men is to simply deform the sperm so that it temporarily loses its fertilization function. We can deform the sperm by inhibiting the protein that helps the maturation of spermatocytes into sperms during spermatogenesis. SPEM1 (spermatic maturation protein 1) is a protein that is very important when it comes to giving sperms their mature shape. SPEM1 plays a role in detaching cytoplasm from the spermatid nucleus and flagellum neck region, a step that results in the straightening of the sperm. In mice, without the SPEM1 gene, it was found by Zheng et al., 2007 that they were infertile. The mice sperms were severely deformed, with their heads completely bent backwards so that the tip of their head and their tail were touching. These sperms lacked motility due to their morphology.

In a study by Chang et al., 2021, triptonide, a natural compound purified from the Chinese herb Tripterygium Wilfordii Hook F was tested as a reversible contraceptive in male mice and monkeys. Triptonide targets the junction plakoglobin and disrupts its interaction with SPEM1 during spermiogenesis, the late stage of spermatogenesis. A single daily oral dose induced deformed sperms with minimal or no forward motility, close to 100% penetrance. Male fertility was regained after ~4–6 weeks of stopping the drug intake in both species. No discernable systematic toxic side effects were diagnosed after short and long-term use of the drug.

Solution:

Find an inexpensive small molecule SPEM1 inhibitor using a hit identification model (hit- SMC that could potentially be a drug).

Workflow:

We have created a prototype of the ML model that could identify inexpensive hits for SPEM1. In this workflow, we explain the steps involved in our hit identification model as well as steps that go beyond the scope of our next steps.

Simplified version above, explained in more detail below.

1. Create Dataset

Training data

• We would try out a bunch of small molecules on the SPEM1 target. This would be done by a high throughput screening (drug discovery process that allows automated testing of large numbers of chemical and/or biological compounds for a specific biological target.)
• Measure IC50 value (concentration of the small molecule drug needed to inhibit 50% of the protein target) which represents the activity of the small molecule on the SPEM1 target.
• Collect data on ADMET (absorption, distribution, metabolism, excretion, toxicology) and canonical smiles (how to represent molecules for machine learning).

→ this would be our first data set

Test data

• Put together the canonical smiles of as many inexpensive (maximum $0.03–0.05 per mg) small molecule compounds
• Find as many of the small molecule drugs and put their canonical smiles into a table

2) Hit Identification

→ Data Pre-Processing

Training data:

• Eliminate missing data, label compounds as being active (IC50 value less than 1000) , inactive (IC50 value is bigger than 10 000), or intermediate (IC50 value in between 1000–10 000)

The lower the IC50 value, the better- this means you will need less of the small molecule to inhibit 50% of the protein

• Converting IC50 values to pIC50 values
• Using canonical smiles calculate PubChem fingerprints

Test data:

• convert the canonical smiles into PubChem fingerprints

Combine test data and training data:

• Assign x and y values for regression model: x values will be PubChem fingerprints (represent the molecular structure of compounds), y values would be the PIC50 values
• remove low variance features by setting a variance threshold

Split test data and training data:

• use X and Y values of training data to train regressor models
• only use X value of test data in step 5

3) Test Machine Learning Regression Models

• compare regressors by using Lazy regressor (train data for various regressor models, calculating the adjusted r², r², RMSE, and time taken to determine the best regressor model.

4) Train data on Best Regressor Model from Step 3

• Train data and use scatterplot to compare how well the model was able to predict the pIC50 value in comparison to the Experimental PiC50 model.

We can’t calculate accuracy due to the high feature dimension hence we portray the data in a scatter plot.

5) predict Y value of test data

• the model predicts the test data
• determine if small molecules are active or not: active ( pIC50 >6), inactive (pIC50 <5)

Beyond our model:

These are the steps that would be in place to take SPEM1 inhibitor from point 0 to commercial use.

6) Calculate Lipinski Descriptors (Pharmacokinetics Test)

→ Lead optimization based on pharmacokinetic tests

Lipinski-Rule of thumb is used evaluate drug-likeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would make it a likely orally active drug in humans.

7) Predicting side effects

• Doing pharmacokinetic test (wet and dry lab) to figure out the interaction of drug with cells
• Show effectiveness of the drug on cell models, collect the data and use it to optimize hit identification ML model

8) Animal and human trials

• The purpose is to show the effectiveness of the drug (how active the compound is) and clarify the side effects

These steps are proven and all very feasible. They’re needed to take any small molecule drug to market, and this pre-clinical to the clinical pipeline has been in place for many years to gain FDA approval for any new drug.

Next steps:

What’s needed to pursue this idea?

1. Collect data on SPEM1 inhibitors:

• Wet lab work to try out a bunch of small molecules on the SPEM1 target by a high throughput screen. A collaboration with a biochemistry lab would be a wise choice.

1. Use collected data on the training of the prototype hit identification model: Github repository of the code to our hit identification model/prototype.

Financial Incentives:

The price of the SPEM1 inhibitor we hope to develop is $15 per 500 mg (minimum) — $25 per 500 mg (maximum)*. In comparison to the current price of birth control for women, our solution completely revolutionizes accessibility to essential drugs. Birth control pills for women in the United States can cost between $0–50, depending on the insurance plan. Over 180,700 women in the United States will have an unintended pregnancy, which has an associated cost of $320M to the health care system. 60% of women aged 15–29 in the United States don’t have access to contraception, due to cost-related reasons. All women deserve to have control over their fertility, and shouldn’t have to make grave sacrifices in order to achieve a state of healthy reproductive health.

The global contraceptive pills market is expected to grow from $16.51 billion in 2020 to $18.36 billion in 2021 at a compound annual growth rate (CAGR) of 11.19%. Therefore, looking at it from a bird’s eye view, the market is expected to reach $95.04 billion in 2025 at a CAGR of 7.63%. Additionally, in 2019, the pills segment led the market accounting for the largest revenue share of over 40% as pills were the most common and popular contraceptive method due to their convenience of use.

According to the United Nations’ Department of Economic and Social Affairs, by 2030, the world population will reach 8.6 billion and by 2050, it will be 9.8 billion. The prevalent anxiety is that such an explosion of numbers will create wide socio-economic imbalances, especially in poor countries. This desperate need to control population growth is expected to be one of the leading Contraceptive Pills Market trends in the immediate future. Furthermore, the increasing prevalence of teenage pregnancies, particularly in the U.S. is also driving the growth of this market.

*Calculated under the assumption that an inexpensive drug target of $0.03–0.05 per 1 mg can be found with our hit identification model.

Outcome

For 60 years, since the clinical trials for the birth control pill in the 1950s, women who rely on hormonal birth control for contraception and other uses have been suffering.

When looking into a case study of reproductive health and Ferran’s and Power’s Quality of Life Index (QLI) among metropolitan Portuguese communities, it is evident that an improvement in the contraception system is needed. Higher age groups, better economic status, higher age at first use, absence of long-term illness, reproductive illness and domestic violence were important determinants of reproductive health and quality of life among these women in our case study. Their reproductive health was in flux, and evidently so was their overall quality of life. If we are to apply the data of the Portuguese Quality of Life Indicator (Index) and the 25% effect reproductive health has on individual wellness, improving the birth control system and allowing for family planning and more prepared childhood environments, raises the life index by 1.25 on the scale out of 10.

Condoms have been the only contraceptive on the male’s part in a relationship. While condoms are great protection against STI’s, women are frequently burdened with the task of pregnancy protection by using birth control pills, even though the biology of their reproductive system is not the best suited to hormonal or non-hormonal birth control pills.

Ultimately, the untapped market of non-hormonal male birth control can surprisingly fix the problems present in current female contraception.

Without a doubt, the first step towards breaking into this market will be the creation of affordable and non-hormonal birth control for men, free from the burden of hormone-related side effects with the same if not higher efficacy.