Summary
- TG Therapeutics is a biopharmaceutical company focused on developing innovative treatments for B-cell malignancies and autoimmune diseases.
- Briumvi (ublituximab) is the company's lead product, an FDA-approved monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RRMS).
- Monoclonal antibody disease-modifying therapies are now a crucial treatment option for RRMS, with Tysabri, Lemtrada, Kesimpta, and Ocrevus among the monoclonal antibody DMTs that are currently approved and utilized.
- It is difficult to determine the place of Briumvi due to its perceived moderate effectiveness in comparison to other DMTs and its current price, which makes it less cost-effective than non-DMTs that are usually reserved for less severe patients.
- Therefore, investors can expect limited usage of Briumvi in later-line treatment of RRMS patients with low-risk tolerance, which will significantly reduce its market potential. TG Therapeutics is a "Strong Sell"
Introduction to TG Therapeutics and Ublituximab
TG Therapeutics ( TGTX ) is a biopharmaceutical company focused on the development and commercialization of innovative treatments for B-cell malignancies and autoimmune diseases. Ublituximab is the company's lead product, an FDA-approved monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis [MS], including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
This article will examine the current treatments for highly active relapsing-remitting MS and analyze the role of ublituximab, as well as its impact on TG Therapeutics.
Financials
Before we dive in, let's take a look at TG Therapeutic's most recent financials .
The financial results for the three and nine months ended September 30, 2022 show that the company had a net loss of $35.8 million and $145.3 million, respectively, compared to higher losses in the same periods in 2021. This decrease in net loss was due to cost-saving measures implemented and the withdrawal of UKONIQ from the market. Total research and development expenses also decreased, while selling, general, and administrative expenses decreased due to the withdrawal of UKONIQ. The company's cash position was $197.7 million as of September 30, 2022, and they expect it to be enough to fund their planned operations until 2024. They anticipate an increase in selling, general, and administrative expenses in the remaining months of 2022 as they prepare for the potential launch of ublituximab in RMS.
Understanding Multiple Sclerosis: Types, Symptoms, and Prevalence of Relapsing-Remitting MS
Multiple sclerosis [MS] is a chronic, progressive autoimmune disease that affects the central nervous system [CNS]. MS causes the immune system to attack the protective covering of nerve fibers in the CNS, leading to a range of symptoms that can include muscle weakness, numbness, and difficulty with coordination and balance. There are several forms of MS, including relapsing-remitting MS [RRMS], primary progressive MS, and secondary progressive MS.
RRMS is the most common form of MS, affecting approximately 85% of all MS patients. It is characterized by unpredictable episodes of new or worsening symptoms, known as relapses or flare-ups, followed by periods of partial or complete recovery, called remissions.
Highly active RRMS is a subtype of RRMS characterized by frequent relapses or high disease activity despite DMT treatment. It can be identified by criteria such as relapse frequency, severity, disability level, and MRI scan results. Treatment may involve more aggressive strategies such as switching to a stronger DMT or combining treatments. However, the term is not universally defined and may vary among healthcare providers.
Monoclonal Antibody Disease-Modifying Therapies for RRMS
Monoclonal antibody disease-modifying therapies (DMTs) have become an increasingly important treatment option for RRMS in recent years. These drugs work by targeting specific components of the immune system that are believed to contribute to the development and progression of the disease. They are designed to modify the underlying course of the disease by reducing the frequency and severity of relapses, delaying disability progression, and reducing the overall burden of RRMS.
There are currently several monoclonal antibody DMTs approved for the treatment of RRMS, including:
- Tysabri (natalizumab ) ( BIIB ), an integrin receptor antagonist, is indicated "as monotherapy for the treatment of patients with relapsing forms of MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations (...) is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy." Clinical trials have shown that it significantly reduces the risk of relapse and disability progression, and is also associated with a reduction in the number of new or enlarging hyperintense lesions on magnetic resonance imaging. However, it has been associated with an increased risk of progressive multifocal leukoencephalopathy, a rare and potentially fatal brain infection. As a result, some clinicians do not use Tysabri for patients who are anti-JCV antibody positive at baseline, which is estimated to be up to 45% of MS patients. Tysabri is given as a 300 mg IV infusion over one hour, every four weeks, and has an average wholesale price of around $128,000 per year. In the first six months of 2022, Tysabri generated approximately $1 billion in revenue. However, with key patents soon to expire, generics may soon enter the market.
- Lemtrada (alemtuzumab ) ( SNY ) targets CD52 and is indicated "for the treatment of patients with relapsing forms of MS. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS." It targets CD52 and is given as a 12 mg IV infusion for five consecutive days at the start of treatment, followed 12 months later by 12 mg daily for three consecutive days. Its average wholesale price is around $166,500 for the first year and $100,000 for the second year. Revenue peaked in 2017 at $528 million .
- Kesimpta (ofatumumab) ( NVS ) targets CD20 and is indicated "for the treatment of relapsing forms of MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults." It has been shown to reduce the annualized relapse rate and the number of patients with disability worsening confirmed at six months in clinical trials. The most common adverse effects observed are upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions. Kesimpta is given by subcutaneous injection of 20 mg administered at weeks zero, one, and two, followed by a monthly dose of 20 mg starting from week four. Its average wholesale price is around $147,000 per year, and despite being approved by the US FDA in August 2020, it is already generating an annual revenue run rate of over $1 billion .
- Ocrevus (ocrelizumab) ( RHHBY ) targets CD20 and is indicated for "relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, as well as primary progressive MS." Ocrevus has been shown to reduce the annualized relapse rate and the number of gadolinium-enhancing lesions detected by MRI scans. However, there are some rare but serious adverse effects of the drug, such as serious infections, immune-mediated colitis, hepatitis B reactivation, progressive multifocal leukoencephalopathy, and malignancy. The drug is administered via intravenous (IV) infusion, with a starting dose of 300 mg twice two weeks apart (over 2.5 hours), followed by 600 mg IV infusions every six months (either over 2.5 or 3.5 hours depending on tolerability). Ocrevus is the highest-selling drug for MS, generating over $5 billion in annual revenue , and it comes with a price tag of around $55,000 per year.
- Rituximab shares a similar mechanism of action with ocrelizumab, and while its effectiveness has not been extensively studied, it has been used off-label for years with perceived benefits. Research suggests that rituximab can reduce relapses and disease activity in MS patients and is associated with lower discontinuation rates compared to other disease-modifying therapies. Nonetheless, rituximab carries potential adverse effects such as infusion reactions, infection, and hepatitis B reactivation (boxed warnings). Close medical supervision is necessary during administration, and premedication is advised to minimize the frequency and severity of infusion reactions. The recommended dosing for rituximab is 1 g infusions administered two weeks apart, followed by 1 g infusions every six months. Since the expiration of its US patent in 2016, several biosimilars have emerged, providing a more cost-effective option for patients ( around $2,000/year ).
FDA Approves Ublituximab for Relapsing Forms of Multiple Sclerosis: A New Monoclonal Antibody Targeting CD20 Protein
Briumvi (ublituximab) ( TGTX ) is another monoclonal antibody that targets a protein called CD20, which is found on the surface of B cells. B cells are a type of white blood cell that play a key role in the immune system. CD20 is involved in the development and maturation of B cells and is also believed to play a role in the immune response that contributes to the development of MS.
Briumvi was approved by the FDA in December 2022 for the treatment of "relapsing forms of MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults." Clinical trials have shown that it is more effective than teriflunomide in reducing annualized relapse rates and the number of gadolinium-enhancing brain lesions. The most common adverse effects are infusion reactions and upper respiratory tract infections. Briumvi is administered intravenously, and patients should be monitored during and after infusions. The dosing for Briumvi is as follows: the first infusion is 150 mg (over four hours), the second infusion is 450 mg (over one hour), administered approximately two weeks after the first infusion, and subsequent infusions are also 450 mg, beginning 24 weeks after the first infusion and given every 24 weeks thereafter (over one hour). It costs $55,000/year .
Navigating the Decision-Making Process for Disease-Modifying Therapy in Highly Active RRMS: Considerations and Treatment Options
There is no standard regarding which disease-modifying therapy to utilize for RRMS. The decision is made between the clinician and patient. Key considerations include clinician preference, cost, safety, effectiveness, and convenience (e.g. subcutaneous versus intravenous, dosing frequency). Based on my research, clinical observations, and discussions with neurologists, this is, generally, how each DMT is utilized for highly active RRMS :
For initial treatment options, consider:
- Intravenous ocrelizumab (clinician preferred due to high effectiveness with tolerable safety profile and convenient, infrequent dosing)
- Intravenous natalizumab (if patient prioritizes effectiveness and are relatively risk-tolerant)
- Intravenous rituximab (cost effective, medium effectiveness)
- Subcutaneous ofatumumab (high effectiveness, tolerable safety profile, and convenient)
If there is an inadequate response to natalizumab, try ocrelizumab.
If there is an inadequate response to ofatumumab, try:
- Ocrelizumab
- Rituximab
- Natalizumab
If there is an inadequate response to either ocrelizumab or rituximab, try natalizumab.
After two inadequate responses, try intravenous alemtuzumab.
A Look at the Popularity of Different Intravenous Therapies for Multiple Sclerosis Treatment
Clinicians and patients seem to favor intravenous ocrelizumab due to its high effectiveness, tolerable safety profile, and infrequent dosing. As a result, it is expected to be prescribed frequently, which is reinforced by its status as the most prescribed MS drug.
For cases where cost is a significant factor, intravenous rituximab's medium effectiveness and cost-effectiveness make it a potential popular choice.
The high effectiveness, tolerable safety profile, and easy, at-home self-administration of subcutaneous ofatumumab could make it a popular treatment option for both patients and clinicians, as evidenced by its rapid market uptake.
Patients who prioritize effectiveness and have a higher risk tolerance may consider intravenous natalizumab as a secondary option. However, it may not be as commonly prescribed as ocrelizumab or ofatumumab.
Intravenous alemtuzumab is typically reserved as a later-line option after two inadequate responses to other drugs. As a result, it is not likely to be used as frequently as the other options.
ICER Report on Multiple Sclerosis Treatments Finds Inadequate Evidence for Ublituximab's Net Health Benefit Compared to Other Monoclonal Antibodies, Calls for Lower Prices for Cost-Effectiveness
The Institute for Clinical and Economic Review (ICER) has released a report evaluating the effectiveness and value of treatments for MS, including monoclonal antibodies and oral therapies. According to ICER's independent appraisal committee, there is currently insufficient evidence to distinguish the net health benefit of Briumvi (ublituximab) compared to other monoclonal antibodies, but the evidence supports its net health benefit compared to fingolimod and some fumarates, which are typically used for less active MS.
For ublituximab compared with natalizumab, ofatumumab, ocrelizumab, and rituximab, our NMA demonstrates that for ARR, ublituximab appears comparable. However, there is more uncertainty in the CDP outcome, with greater variability across drugs, although differences were not statistically significant. Additionally, rituximab was not included in the CDP NMA due to data limitations. Shortterm safety signals appear similar across the drugs, barring a black box warning of an elevated risk of PML with natalizumab and rituximab, but there is not long-term safety data for ublituximab yet. Thus, we judge that the evidence is insufficient to determine the comparative clinical effectiveness of ublituximab compared with other monoclonal antibodies.
ICER (emphasis added by author)
(Side note: ARR and CPD are important clinical outcomes used to measure the effectiveness of treatments for MS. ARR reflects disease activity and measures the frequency of relapses, while CPD reflects disease progression and measures a sustained increase in disability. Both outcomes provide valuable information for clinicians and researchers to evaluate treatment options and monitor disease activity in patients.)
ICER's analysis also revealed that the cost of monoclonal antibodies would need to be significantly reduced to meet traditional standards for cost-effectiveness. The report suggests that ublituximab and all currently available monoclonal antibodies for MS would achieve cost-effectiveness if priced between $16,500- $34,900 per year. Furthermore, ublituximab is deemed to have "low" long-term value for money compared to dimethyl fumarate, indicating that the latter may be a more cost-effective option for MS treatment.
Ublituximab: Limited Market Potential and Sparse Usage due to Insufficient Evidence and High Cost
The ICER statement, which questions ublituximab's ability to improve CPD, one of two core disease measures, in comparison to other monoclonal antibodies, is significant. This may limit its market potential, as clinicians could view it as less effective than other disease-modifying therapies (DMTs). One reason for the uncertainty surrounding ublituximab's effectiveness is that it is a new entrant in the market. As additional research becomes available, the perception of ublituximab's effectiveness may evolve. In the meantime, to mitigate this uncertainty, TG Therapeutics could have considered pricing ublituximab much lower than established DMTs such as ocrelizumab or natalizumab. However, they chose to price it near $55,000. Ublituximab, an intravenous therapy, is not likely to be the preferred treatment option for patients and clinicians due to the availability of less expensive oral treatments for less severe disease, as well as its cost and inconvenience. As a result, ublituximab is expected to have limited use at its current price and is more likely to be used as a later-line treatment (third or fourth) for highly active disease in patients with low risk-tolerance, particularly those who may experience challenges with other DMTs like alemtuzumab or natalizumab. The limited use of ublituximab is further compounded by the fact that risk-tolerance becomes less relevant after two or more inadequate responses to other treatments.
Conclusion
After considering the revenue generated by other DMTs, their strengths, limitations, and costs, I believe that TG Therapeutic's Briumvi will likely only achieve a maximum of $500 million in annual sales. Unlike other drugs that have high demand, Briumvi will require significant investments in marketing and sales since it is unlikely to sell itself. Additionally, the composition of matter patent for Briumvi will expire in 2029 and 2025 in the US and Europe, respectively. Although the company will defend its intellectual property, it is likely that the market exclusivity for Briumvi will only last for a few years. Given the apparent limited use of Briumvi in RRMS, increasing capital expenses, and a patent cliff, TG Therapeutics is unlikely to profit from it.
It is important to note that TG Therapeutics is currently valued at over $2 billion, and its pipeline , apart from ublituximab for RRMS, is still in the preclinical or stage 1 phase. Based on these factors, I believe that TG Therapeutics is overvalued, and my recommendation is "Strong Sell".
For further details see:
TG Therapeutics' Briumvi: A Tough Sell For Multiple Sclerosis Treatment Market