KPTI - Selinexor's Toxicity Makes It Unlikely For Karyopharm To Ever Be Profitable

2023-03-14 00:09:42 ET

Summary

• Karyopharm Therapeutics develops drugs for cancer and other diseases. Its main drug, Xpovio (selinexor), treats multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL).
• Despite gaining approval for the treatment of MM and DLBCL, Karyopharm is still unprofitable as the toxic effects of selinexor make it difficult for the drug to gain enough usage to generate significant revenue for the company.
• Karyopharm wishes to expand selinexor's label indications to include endometrial cancer and myelofibrosis.
• Karyopharm's net losses have exceeded $100 million in the past two years, and their high R&D expenses are expected to persist as they aim to expand selinexor's indications. Due to these factors, the company is expected to continue posting substantial net losses, making it an unappealing investment option.

Introduction

Karyopharm Therapeutics ( KPTI ) is a clinical-stage pharmaceutical company that focuses on developing drugs for the treatment of various forms of cancer and other diseases. The company's lead drug is Xpovio (selinexor) , a nuclear export inhibitor. Xpovio has been approved for the treatment of multiple myeloma and diffuse large B-cell lymphoma.

The upcoming article will provide information about the current and potential indications for Xpovio (selinexor).

Financials

The following data was compiled from Karyopharm's most recent financial report for the period ending December 31, 2022.

According to Karyopharm, Xpovio's net product revenue was $120.4 million for 2022. Last year, the company guided "Xpovio net product revenue to be in the range of $135 million to $145 million" for 2022.

Karyopharm's 2023 guide for Xpovio net product revenue is $125 million to $140 million. Karyopharm believes their cash runway is sufficient until "late 2025".

Current Indications

Xpovio is currently indicated for the following:

• "In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy."
• "In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti?CD38 monoclonal antibody."
• "For the treatment of adult patients with relapsed or refractory diffuse large B?cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial[s]."

Please note that, as the discussion below pertains to clinical trial data and potential indications, the drug Xpovio will be referred to as selinexor moving forward.

Treatment Landscape for R/R Multiple Myeloma

There are many approved treatment combinations for patients with relapsed and/or refractory multiple myeloma . Most patients experience serial relapses over time and will ultimately receive most, if not all, available agents at some point during their disease course. The choice of therapy for relapsed MM is influenced significantly by prior therapies received, response to those therapies, and likelihood of the disease being refractory to specific agents.

Due to their anti-inflammatory and anti-myeloma properties, steroids like dexamethasone are frequently administered alongside other agents to treat MM.

Use of Selinexor in Relapsed Refractory Multiple Myeloma: Efficacy & Toxicity Concerns

Selinexor is an oral nuclear export inhibitor used to treat relapsed refractory multiple myeloma [MM] in the US. The treatment is given alongside dexamethasone to adults who have undergone four or more prior therapies and have not responded well to other forms of treatment. Selinexor has been studied in single-arm studies on heavily treated populations, with results showing an overall response rate [ORR] of 21% in quad-refractory and penta-refractory patients in STORM Part 1 and 26% in triple-refractory patients in STORM Part 2. However, there are concerns regarding the drug's toxicity, which resulted in treatment interruption (80% of selinexor-treated STORM 2 patients) or discontinuation (18%).

According to the information on selinexor's label , there are several references to fatal adverse events that may result from infection (neutropenia) and bleeding (thrombocytopenia). The BOSTON study, which provided evidence for the approved combination use in multiple myeloma patients who have undergone at least one prior therapy, revealed that "fatal adverse reactions occurred in 6% of patients within 30 days of last treatment, including pneumonia (n=3) and sepsis (n=3)." Similarly, in the STORM study, "fatal adverse reactions occurred in 9% of selinexor treated patients," and "serious adverse reactions occurred in 58% of patients."

Selinexor-Dexamethasone Reduces QoL in Multiple Myeloma Patients with Implications for Clinical Use

In the STORM trial, investigators also evaluated the quality of life [QoL] of patients receiving the selinexor-dexamethasone combination therapy using the validated Functional Assessment of Cancer Therapy-MM [FACT-MM] questionnaire. The FACT-MM questionnaire assesses various domains of QoL, including physical, emotional, and social well-being, as well as functional status.

The trial's QoL outcomes indicated that patients experienced a decline in their QoL as treatment progressed, with most domains showing decreasing median scores. Notably, the physical and functional well-being domains demonstrated the most significant declines, indicating that the adverse effects of the treatment had a negative impact on patients' QoL.

According to the authors , these findings have several implications for the clinical use of selinexor. For one, physicians must inform patients about the potential negative impact of the treatment on QoL to help them understand what to expect during treatment and how to manage side effects.

Presumably due to the risk of toxicity and reduced quality of life, UpToDate recommends that patients with penta-refractory multiple myeloma consider enrolling in clinical trials instead of using selinexor-dexamethasone.

Managing Second or Later Relapses of Diffuse Large B Cell Lymphoma: Treatment Options and Goals

Diffuse large B cell lymphoma [DLBCL] is a type of cancer that can come back even after being treated. In cases where the cancer has returned for the second or more times, the main goals of treatment are to control the disease, relieve symptoms, and extend survival while minimizing the side effects of treatment. It's important to understand that curing the cancer is usually not possible in these situations, and the likelihood of a strong and long-lasting response to treatment decreases with each recurrence. Patients with DLBCL who have experienced relapses are encouraged to participate in clinical trials to help improve treatment options for this challenging disease.

When it comes to treatment options for second or later relapses of DLBCL, there is no one-size-fits-all approach. Different therapies can be effective in providing a significant response, but each option has its own set of potential side effects, and the duration of the response is not always clear. Factors such as the patient's overall health, previous treatment, and personal preferences should be taken into consideration when selecting a therapy. For some patients, supportive or palliative care may be the preferred option if the risks of treatment outweigh the potential benefits. Available treatments for DLBCL relapses include tafasitamab plus lenalidomide, polatuzumab vedotin/bendamustine/rituximab, loncastuximab tesirine, chemotherapy, and selinexor.

Efficacy & Safety of Selinexor Monotherapy in Relapsed or Refractory DLBCL

The SADAL study analyzed the effectiveness of selinexor monotherapy in relapsed or refractory DLBCL patients who could not undergo autologous hematopoietic stem cell transplantation. Selinexor was given orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity. The study included 134 patients, and the response rate was measured based on overall response rate [ORR] and duration of response. According to selinexor's label , the ORR was 29%, with a complete response of 13% and a partial response of 16%. However, selinexor caused significant toxicity, with fatal adverse reactions in 3.7% of patients within thirty days and 5% within sixty days of their last treatment, mainly due to infection. Serious adverse reactions were observed in 46% of patients, with infection being the most common. Adverse reactions led to the discontinuation of treatment in 17% of patients, with infection, fatigue, thrombocytopenia, and nausea being the most common reasons. The most common adverse reactions were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and fever in ?20% of patients.

Selinexor Fails FDA Approval for Endometrial Cancer, New Phase 3 Study Initiated for TP53 Wild-Type Patients

The Phase 3 SIENDO study examined the efficacy of selinexor as a front-line maintenance therapy for patients with advanced or recurrent endometrial cancer. The study revealed that patients who received selinexor had a median progression-free survival of 5.7 months, whereas those who received a placebo had a median PFS of 3.8 months (p=0.0486). Furthermore, an exploratory subgroup analysis showed a greater improvement in PFS for patients with TP53 wild-type cancer. However, the company did not disclose data on overall survival, which is a crucial clinical endpoint in cancer treatment. The absence of this information, amongst other details, raised questions among analysts. Despite initially hoping that the SIENDO study would support sNDA approval, the company's plans were foiled when the FDA disagreed.

During a productive meeting with the FDA, the Company received feedback that the current SIENDO study top-line results are unlikely to support an sNDA approval. Karyopharm and the FDA participants had differing views on the study significance and overall clinical benefit for the whole population and discussed that further exploration of patients with advanced or recurrent endometrial cancer with p53 wild-type is warranted.

Karyopharm

Subsequently, in the fourth quarter of 2022, a global Phase 3 study called the EC-042 Study was initiated to evaluate selinexor as a maintenance therapy for patients with TP53 wild-type advanced or recurrent endometrial cancer. The study will enroll up to 220 patients who will be randomly assigned to receive either selinexor or a placebo, and the primary endpoint of the study is PFS, with OS as the key secondary endpoint.

Subgroup analyses are known for their unreliability , and it remains uncertain whether TP53 wild-type advanced or recurrent endometrial cancer patients will derive any benefits from selinexor. It is worth considering that despite the trial meeting its primary endpoint, the FDA demonstrated reluctance to approve selinexor for endometrial cancer.

Updates on Karyopharm's Data for Selinexor-Ruxolitinib Therapy in Myelofibrosis Patients

Karyopharm is also trialing selinexor in myelofibrosis patients. Primary myelofibrosis [PFM] patients are classified as higher or lower risk, and management is based on risk, eligibility for hematopoietic cell transplantation [HCT], and symptom burden. For higher-risk patients eligible for HCT, transplantation is suggested. For those ineligible, clinical trials or symptom relief options are available. Lower-risk patients are given symptom-directed treatment, while asymptomatic patients are observed.

According to data presented by Karyopharm in December, selinexor-ruxolitinib combination therapy showed encouraging efficacy measures after 24 weeks, including SVR35 (92%), TSS50 (67%), and hemoglobin level stabilization (57%). However, the primary analysis population data displayed in smaller font on the same slide reveals lower rates of SVR35 (69%) and TSS50 (33%) at week 24.

Regarding safety, 10 out of 24 patients, including more than half of the high-dose selinexor group, discontinued the selinexor-ruxolitinib treatment for various reasons. Moreover, the higher selinexor dosage group had two cases of grade 4 thrombocytopenia (potentially life-threatening).

Karyopharm plans to discuss their Phase 3 plans with the FDA soon. Additionally, multiple other drugs for myelofibrosis are currently undergoing Phase 3 trials, making it more challenging to envision selinexor as a relevant treatment option for myelofibrosis, in my opinion.

Conclusion

Karyopharm has been operating since 2008, incurring an accumulated deficit of $1.3 billion . Its lead drug, selinexor, has undergone clinical testing across numerous indications , including wound healing, severe COVID-19 infection, advanced liposarcoma, refractory and/or relapsed Richter's transformation, hormone-insensitive prostate cancer, advanced relapsed/refractory squamous cell carcinomas, advanced gynecologic malignancies, relapsed acute myeloid leukemia, metastatic triple-negative breast cancer, poorly differentiated lung and gastroenteropancreatic tumors, relapsed small cell lung cancer, advanced thymic epithelial tumor progressing after primary chemotherapy, and advanced ovarian or endometrial cancers, in thousands of patients.

Despite receiving approval for treating multiple myeloma and diffuse large B-cell lymphoma, Karyopharm is still not profitable. In my view, the toxic effects of selinexor make it highly unlikely that Karyopharm will generate enough usage to become profitable. This article highlights the toxicity of selinexor, which has resulted in death and often required dosage reductions or discontinuations. Additionally, using selinexor with dexamethasone reduces patients' quality of life. Consequently, clinical trials are preferred over selinexor for patients with penta-refractory multiple myeloma due to its negative impact on quality of life and toxicity.

Karyopharm's decreasing valuation since early 2020 suggests that investors also have low expectations for selinexor. While Karyopharm's enterprise value of roughly $100 million doesn't necessarily indicate overvaluation, I recommend selling due to the company's net losses, which have surpassed $100 million in the past two years. Karyopharm's management is persistently striving to expand selinexor's indications, and as a result, research and development expenses are anticipated to remain high. Additionally, since selinexor is not a self-selling product, selling, general, and administrative expenses are also expected to remain high. Consequently, Karyopharm is expected, in my view, to continue posting net losses exceeding $100 million per year in the near term, adding to its already substantial deficit. Therefore, despite appearing inexpensive, Karyopharm does not seem like a promising investment opportunity, and investors may benefit from exploring other options.

Risks to Thesis

There are several potential risks that could challenge my bearish stance on Karyopharm and selinexor, including:

1. Positive clinical trial results: If Karyopharm's ongoing clinical trials for selinexor demonstrate significant efficacy in treating certain cancers, it could lead to increased adoption and usage, potentially driving revenue growth and investor interest.
2. FDA approval for additional indications: If the FDA approves selinexor for additional indications beyond multiple myeloma and diffuse large B-cell lymphoma, it could significantly increase the drug's market potential and revenue opportunities.
3. Improvements in toxicity profile: If Karyopharm can successfully mitigate the toxic effects of selinexor, it could lead to improved patient outcomes, potentially driving increased adoption and usage.
4. Strategic partnerships or acquisitions: Karyopharm could enter into strategic partnerships or be acquired by a larger pharmaceutical company, which could provide additional resources and expertise to drive selinexor's development and commercialization.
5. Macro factors: Finally, macroeconomic or market factors, such as changes in healthcare policy or shifts in investor sentiment, could also impact Karyopharm's prospects and valuation.

Overall, it is important to keep a close eye on new developments in clinical trials and potential partnerships or acquisitions that could impact the company's future prospects.

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