VERA - Chinook's Atrasentan: A Promising Solution For IgA Nephropathy?

Summary

• Chinook is a clinical-stage biopharmaceutical firm that is developing precision medicines for kidney diseases, including treatments for rare, chronic, and severe kidney conditions.
• Its lead program, atrasentan, is a potent antagonist of the endothelin A receptor undergoing a phase 3 trial for IgA nephropathy.
• Current off-label treatments have limitations, such as ineffectiveness and adverse side effects with long-term use, and there are no effective therapies that can halt or reverse IgA nephropathy.
• In a phase 2 study, treatment with atrasentan was well-tolerated with no serious adverse events reported. Over 24 weeks of treatment, atrasentan showed a significant reduction in proteinuria levels, with a 58.5% decrease at 24 weeks.
• Endothelin A receptor antagonists may hold promise for IgAN (longer-term data is needed) and atrasentan may be their best bet. Chinook is a speculative "buy".

Introduction

Chinook Therapeutics ( KDNY ) is a clinical-stage biopharmaceutical firm focused on developing precision medicines for kidney diseases. Its pipeline includes treatments for rare, chronic, and severe kidney conditions, with a focus on well-defined clinical pathways. The company's lead program, atrasentan, is a potent antagonist of the endothelin A receptor undergoing phase 3 trials for IgA nephropathy and phase 2 trials for proteinuric glomerular diseases. Chinook has also developed BION-1301, a monoclonal antibody for IgA nephropathy, and established a joint venture in East Asia to accelerate its development and commercialization. The company is investigating CHK-336 for hyperoxaluria and collaborating with Evotec on various kidney diseases, including lupus nephritis and polycystic kidney disease.

The following article will focus on atrasentan for the treatment of IgA nephropathy.

Financials

Before we begin, let's take a look at Chinook's latest financial report . The company had a cash position of $397.7 million as of September 30, 2022, an increase from $355.1 million at the end of 2021. Chinook has $40 million in long-term debt. Research and development expenses increased to $42.0 million for Q3 2022 and $98.3 million for the nine months ended September 30, 2022, due to higher licensing and contract research costs, employee expenses and consulting fees. General and administrative expenses also increased to $10.0 million for Q3 2022 and $26.5 million for the nine months ended September 30, 2022, mainly due to higher employee expenses, consulting fees and higher support costs for operations. At writing (February 13, 2023), Chinook is valued at $1.54 billion (market capitalization).

IgA nephropathy - an overview

IgA nephropathy, also known as Berger's disease, is a kidney condition that happens when IgA deposits cause inflammation in the kidneys. This leads to scarring, causing the kidneys to lose function over time. The reason behind IgAN isn't known, but it may stem from a mix of genetic and environmental factors, possibly triggered by increased IgA levels during infections or other conditions. The deposit of IgA creates larger complexes with other proteins and get stuck in the kidneys, causing inflammation and leading to scarring and kidney damage. The activation of immune cells and release of proinflammatory cytokines add to the inflammation and tissue damage. In short, the pathophysiology of IgAN involves IgA deposits causing inflammation, scarring and progressive loss of kidney function.

Current treatments for IgA nephropathy

In December 2021, Tarpeyo (budesonide) received accelerated approval for reducing proteinuria in adults with IgA nephropathy. It became the first medication approved for this indication. The approval was based on a randomized, double-blind study that evaluated Tarpeyo's impact on proteinuria in patients with decreased kidney function who were taking RAAS inhibitor therapy (renin-angiotensin-aldosterone system). Participants took 16 mg Tarpeyo daily for nine months, followed by 8 mg for two weeks or a placebo. The primary endpoint, reduction in urine protein-to-creatinine ratio (UPCR) at nine months, showed an average 34% reduction with Tarpeyo compared to 5% with placebo. Further studies are needed to confirm Tarpeyo's effectiveness in slowing kidney decline.

Current treatments for IgA nephropathy include medications to manage symptoms such as high blood pressure, swelling, and excessive protein in the urine. These treatments include ACE inhibitors, ARBs, immunosuppressants, and steroids. When the disease progresses to end-stage kidney disease, dialysis or a kidney transplant may be necessary. However, current treatments have limitations, such as ineffectiveness and adverse side effects with long-term use. The slow progression of IgAN over many years also makes it difficult to manage. There are no effective therapies available that can halt or reverse IgAN progression, highlighting the need for better treatments for this disease.

Atrasentan & endothelin A receptor antagonism

Atrasentan, an endothelin A receptor antagonist, has the potential to lower proteinuria and safeguard kidney function. In 2019, the company obtained Atrasentan from AbbVie, and interim trial data showed consistent and significant reductions in proteinuria. The drug was effective in lowering proteinuria in diabetic nephropathy, but its potential benefits were offset by the occurrence of severe fluid retention , which is common among drugs in its class, in higher doses.

The endothelin A receptor holds significant importance in the context of IgA nephropathy (IgAN). Endothelin is a potent chemical that narrows blood vessels and triggers various signaling pathways in the kidneys. Activation of the ETA receptor is thought to contribute to the progression of IgAN as it has been linked to the production of proinflammatory cytokines, extracellular matrix proteins, and other elements that can lead to fibrosis and scarring of the kidneys.

Studies have shown that blocking the ETA receptor in animal models of IgAN can reduce proteinuria and improve kidney function, indicating that the ETA receptor could be a valuable target for treatments aimed at managing IgAN.

Proteinuria reduction in IgAN

Advantages

Reducing the levels of protein in the urine of individuals with IgAN offers several benefits, including:

• Slowing the progression of kidney disease: High levels of protein in the urine (proteinuria) can indicate significant damage to the kidneys and an increased risk of kidney failure. Lowering proteinuria can slow the advancement of IgAN.
• Preserving kidney function: Reducing proteinuria can help maintain kidney function and enhance overall kidney health.
• Improving quality of life: Decreasing proteinuria can lead to improvements in symptoms such as swelling and fatigue and overall enhance the quality of life for those with IgAN.
• Minimizing the risk of complications: Excessive protein in the urine can increase the chances of cardiovascular disease and other related issues. By reducing proteinuria, these risks can be diminished.

Lowering proteinuria is an essential goal in managing IgAN and has the potential to slow the progression of the disease and improve outcomes for patients.

Limitations

There are some drawbacks to using proteinuria as the primary endpoint for measuring the severity of IgA nephropathy:

• Limited specificity: Protein in urine is a general marker of kidney damage, and it can be elevated in various other health issues, making it difficult to interpret results.
• Difficulty predicting outcomes: Proteinuria levels can change quickly, and it's challenging to predict long-term outcomes based on one measurement.
• Inconsistent readings: The amount of protein in urine can vary greatly due to factors like hydration, diet, and exercise, making it tough to get reliable readings.
• Unclear correlation with disease: Although high levels of proteinuria suggest significant kidney damage, there is not always a clear link between proteinuria levels and the severity of the disease. Some people with severe IgA nephropathy may have lower proteinuria levels, while others with mild disease may have elevated levels.

Therefore, while proteinuria is an important marker in managing IgA nephropathy, it has its limitations in accurately reflecting the severity of the disease and predicting future outcomes.

The FDA has previously accepted proteinuria as a surrogate endpoint for kidney diseases. If Atrasentan proves to be both safe and effectively reduces proteinuria, Chinook may be eligible for accelerated approval, with full approval contingent upon the availability of more comprehensive and long-term data.

Atrasentan phase 2 data/phase 3 dosing in IgAN

The AFFINITY IgAN cohort study, which consisted of 20 fully enrolled patients with IgA nephropathy, was conducted to assess the effects of atrasentan treatment. 70% of the patients in the study had baseline proteinuria levels over one gram per day, even while on maximal RAAS inhibitor treatment, indicating they were a high-risk population for progression. The treatment with atrasentan was well-tolerated with no serious adverse events reported. Over 24 weeks of treatment, atrasentan showed a significant reduction in proteinuria levels, with a 58.5% decrease at 24 weeks . The reductions in proteinuria were not primarily due to changes in blood pressure or acute eGFR, and there was no evidence of fluid retention, as indicated by no changes in BNP or body weight.

In earlier trials, significant fluid retention was observed in patients taking higher doses of atrasentan, which restricted its therapeutic effectiveness.

Although it was expected that peripheral edema would constitute the majority of adverse events, it is reassuring that a clear dose–response relationship was seen, a low relative rate of edema occurred with the atrasentan dose that had the greatest effect on albuminuria reduction (0.75 mg), and most episodes were mild in severity. Although mild edema was most common, even with the highest dose studied, the frequency was significantly higher than observed with placebo, and therefore 1.75 mg of atrasentan may ultimately be a limiting therapeutic dose because greater efficacy was not established compared with the 0.75-mg group.

Source: JASN

Accordingly, Chinook is conducting clinical trials with lower doses of atrasentan, with a 0.75 mg dose being compared to a placebo in the phase 3 trial for IgA nephropathy. The goal is to address the negative history associated with the drug class while still retaining its benefits.

Other drug candidates for IgAN

• Alnylam Pharmaceuticals ( ALNY ) and Regeneron ( REGN ) announced top results, in June 2022, from their Phase 2 study of cemdisiran , an RNAi therapeutic for the treatment of IgA nephropathy. At Week 32, cemdisiran showed a 37% mean reduction from baseline in the 24-hour urine protein to creatinine ratio relative to placebo. Two of nine (22 percent) patients on placebo and 12 of 22 (55 percent) of patients on cemdisiran experienced treatment emergent AEs that were related to study drug.
• Novartis' ( NVS ) Phase 2 trial of iptacopan showed promise in stabilizing kidney function in patients with IgA nephropathy. The study met its primary endpoint of reducing proteinuria with a significant effect (p=0.038) at the highest dose of 200mg twice daily, resulting in a predicted 23% reduction compared to placebo after 90 days. Iptacopan is currently undergoing a phase 3 trial .
• Last month, Vera Therapeutics ( VERA ) reported Phase 2 data for atacicept , a dual inhibitor of BLyS and APRIL. The study showed a significant reduction in proteinuria, evaluated by UPCR at week 24, with the pooled 75/150 mg dose groups having a 31% mean reduction (p=0.037 vs placebo) and the individual 150 mg dose group showing a 33% mean reduction (p=0.047 vs placebo). Investors, however, were not impressed , as shares of Vera dropped 60%+.
• Travere Therapeutics ( TVTX ) is eagerly awaiting a decision from the FDA regarding the accelerated approval of their drug, sparsentan. Sparsentan, a dual endothelin angiotensin receptor antagonist, is seeking approval based on a surrogate endpoint of proteinuria reduction, as observed in the global clinical trial known as the PROTECT Study . The study enrolled 404 patients with IgAN and persistent proteinuria and found a 49.8% mean reduction in proteinuria after 36 weeks of sparsentan treatment, compared to a 15.1% reduction in patients treated with irbesartan (p<0.0001). The results of the study show that sparsentan was well-tolerated and preliminary data suggests a potential positive effect on eGFR after two years of treatment. The trial is fully enrolled and the top line results are expected in the second half of 2023. After the top line results are released, Travere anticipates receiving traditional approval. However, there is a concern regarding the potential long-term liver toxicity of sparsentan, which is a sulfonamide derivative and shares a similar risk with other approved ERAs like bosentan. To address this concern, the FDA has requested that Travere submit a REMS program. If approved, sparsentan is likely to feature boxed warnings on its label for the risks of embryo-fetal toxicity and liver toxicity. The safety profile of atrasentan, a potential follow-up drug, may provide therapeutic differentiation compared to sparsentan if approved.

Conclusion

In conclusion, Chinook Therapeutics' leading drug, atrasentan, is a highly effective endothelin A receptor antagonist that is currently undergoing phase 3 trials for IgA nephropathy and phase 2 trials for proteinuric glomerular diseases. There are limited options available for treating IgA nephropathy, which is a kidney disease caused by the build-up of IgA in the kidneys resulting in inflammation and scarring. Tarpeyo, which received Subpart H approval in 2021, is the first medication aimed at reducing proteinuria in patients with IgA nephropathy. Atrasentan holds the potential to not only decrease proteinuria but also protect kidney function by blocking the endothelin A receptor, which has been linked to the advancement of IgA nephropathy. With sparsentan expected to receive accelerated approval, endothelin receptor antagonists like atrasentan may play a crucial role in managing IgA nephropathy, although more data is needed to confirm their efficacy. Atrasentan has the potential to be the leading ERA for the treatment of IgA nephropathy. Chinook Biopharmaceuticals' shares are considered a speculative "buy," but investors are advised to consider the high degree of speculative risk before investing.

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