Reader TTS

_Not all SERDs are created equal_ Our evolving understanding of the underlying biology of breast cancer, both early in the disease and as resistance develops with current treatments,

continues to advance and enables the development of further improvements in new therapies. The history of the development of new therapies targeting the estrogen receptor (ER) for metastatic

breast cancer has not been one of disruptive innovation that drastically changes the standard of care, but rather progress over time that has made a significant difference in extending

progression-free survival and overall outcomes for patients. After the initial discovery of the ER in 1958, it took nearly 20 years for the first endocrine, or hormonal, therapy called

tamoxifen to come to market. Tamoxifen, which is still widely used today nearly 50 years later, modulates the effects of hormones on estrogen receptors in breast cancer cells. Approximately

75% of all breast cancers are ER-positive, and so targeting ER signaling with endocrine therapy has been and continues to be the backbone for the treatment of ER+ breast cancer. The ER is a

ligand-regulated transcription factor. When its activating ligand, estrogen, binds to the ER, it becomes activated and leads to estrogen-receptor signaling for cellular growth and

proliferation. In the normal course in a pubescent female, this natural mechanism influences breast tissue growth and development. However, in the case of breast cancer, the tumor cells

hijack this mechanism for their own benefit to drive uncontrolled tumor growth. Early in the disease, ER signaling is the primary growth mechanism for ER+/HER2- breast cancer, but over time

as patients receive treatments and the cancer subsequently progresses, resistance mechanisms can develop to treatment regimens enabling the tumor to escape the therapy and hence create the

need for a combination of more advanced treatments. CLASSES OF ENDOCRINE THERAPIES After tamoxifen, a new class of endocrine therapies, AROMATASE INHIBITORS (AIS), came to market in the

1990s. AIs starve the body of estrogen production and leave little-to-no estrogen available to turn on the un-activated ER. AIs have been an effective endocrine therapy and are often used in

a first line metastatic setting. However, eventually resistance mechanisms develop to treatment with an AI, the most common form of which is an activating mutation in the estrogen receptor

where the ER is constitutively active. In this setting, AIs are no longer effective because the mutant ER is already activated regardless of the presence of estrogen. Another class of

endocrine therapies is ER ANTAGONISTS, which are drugs that bind directly to the ER and compete with estrogen to ensure that the ER will not be activated. Tamoxifen, mentioned above, can

best be classified as a _SERM_, or a selective ER modulator, as it binds and inactivates the ER, but only partially. In fact, tamoxifen is a mixed agonist/antagonist – in some cases it works

very well and shuts down the estrogen receptor, and in other cases, it actually turns the ER on. In the early 2000s an improvement on tamoxifen, fulvestrant, was approved by the FDA, and it

was a breakthrough for the treatment of ER+/HER2- metastatic breast cancer. Fulvestrant is a complete estrogen receptor antagonist_,_ or_ CERAN_, as it completely shuts-off the ER. As a

result of binding to the ER, fulvestrant also has the effect of increasing ER turnover, or degrading the ER, and has hence been considered a _SERD_, or selective estrogen receptor degrader.

It is important to note that degradation is not the primary mechanism of action, and in fact even in the best scenarios SERDs leave about 20% of receptor present in the cell with many cancer

cells remaining ER+. This means that ER signaling can still occur to enable growth and proliferation if that remaining ER is not shut off. Unfortunately, fulvestrant has a major limitation

in that it is not orally bioavailable. It is delivered via once-monthly, intramuscular injections that results in limited overall drug exposure and also limits clinical utility. The

potential of fulvestrant has therefore never been fully realized, making it suboptimal against wild type receptors and even less effective against receptors carrying activating mutations.

THE IDEAL ER ANTAGONIST With an evolving understanding of the ER signaling pathway and the resistance mechanisms that develop, scientists and clinicians have been searching for ways to

discover and develop a better fulvestrant. A next generation _CERAN_ would achieve the following: * COMPLETE ER ANTAGONISM so that both wild type and mutant ERs are turned off for a deep and

durable response to treatment * ORALLY BIOAVAILABLE to improve ease of administration, treatment adherence, and promote a better quality of life * GOOD DRUG EXPOSURE with a steady, high

level of drug available in the body to ensure the ER remains turned off at all times * ROBUST ACTIVITY EVEN IN THE PRESENCE OF MUTATIONS of the ER or acquired drug resistance * COMBINABLE

WITH OTHER MEDICINES like cyclin-dependent kinase (CDK) 4/6 inhibitors with favorable tolerability and without metabolizing or diminishing the effectiveness of those drugs Today, there are a

number of next generation ER antagonists in development that are attempting to achieve the above ideal, but important nuances in the pharmacokinetics and drug-drug interactions of each

molecule have led to different results in terms of efficacy and tolerability in the clinic. Furthermore, the proper design and execution of a clinical trial to confirm a potential new

therapy’s benefit over standard-of-care is crucial. With the above in mind, we designed Olema Oncology’s lead CERAN candidate, OP-1250, to embody all the above properties and apply learnings

from predecessors regarding study design and patient selection for evaluation in a pivotal study. OP-1250 has demonstrated encouraging Phase 1/2 clinical results with evidence of activity

in a monotherapy setting and favorable tolerability in early clinical studies in combination with a CDK 4/6 inhibitor. It is now in Phase 2 clinical development for patients living with

recurrent, locally advanced or metastatic ER+/HER2- breast cancer. We have observed early and encouraging signs of favorable tolerability, attractive pharmacokinetic properties supporting

once-daily oral dosing, high and stable drug exposure, and anti-tumor activity as a monotherapy or in combination with current treatments. We plan to initiate a pivotal monotherapy study

targeted to begin in mid-2023. We have recently been granted FDA Fast Track designation for OP-1250 for ER+/HER2- metastatic breast cancer that has progressed following one or more lines of

endocrine therapy with at least one line given in combination with a CDK 4/6 inhibitor, which will help facilitate the development and expedite the review of the drug. We are hopeful that we

can show OP-1250 to be a differentiated ER antagonist and potential endocrine therapy of choice for ER+ breast cancer. A HOPEFUL FUTURE  This year in the U.S. alone, an estimated 290,560

people (287,850 women and 2,710 men) will be diagnosed with invasive breast cancer. During Breast Cancer Awareness Month, it is especially important to understand the exciting progress made

in treating ER+/HER2- metastatic breast cancer – while there have been recent setbacks in some development programs, not all ER antagonists are created equal. Some programs show great

potential to not only improve on progression-free survival but could also advance both the treatment experience and improve outcomes for millions of women around the world. We are inspired

by the potential Olema Oncology has to transform the breast cancer treatment landscape, and we are hopeful for what the future may hold for women’s cancer care. To learn more about Olema’s

science and approach to targeting endocrine-dependent cancers, visit www.olema.com/science, and for risks related to forward-looking statements referenced in the article, please read our

corporate deck.