Vera Therapeutics Atacicept IgAN Phase 3 Trial

Executive Summary

Vera Therapeutics will announce interim 36-week Phase 3 results from their drug atacicept being tested in IgA nephropathy (IgAN) in Q2 2025. Atacicept is an investigational recombinant fusion protein designed to inhibit the activity of B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), both of which are crucial for B-cell maturation, function, and survival.

IgAN trials now use change in proteinuria as the primary endpoint to measure efficacy. The phase 2 data showed a 35% decrease in proteinuria at week 36, results that appear similar to those of the three other drugs already approved. The phase 3 (P3) trial design is essentially identical to that of the successful phase 2. Given the data's strength, the readout will likely be positive.

Vera’s stock is currently trading around $22/share. Based on past approvals in IgAN, I would expect the stock to rise about 50% on a positive readout. However, given the recent volatility in the market and the price of options, the entry will be key to maximizing the profits for this trial.

Background Information

Overview of IgAN

IgAN Nephropathy

IgAN, or IgA Nephropathy (also called Berger’s disease), is a chronic kidney disease caused by a buildup of immunoglobulin A (IgA) in the mesangium of the kidneys. This accumulation leads to inflammation in the glomeruli, which are the tiny filtering units of the kidney. Over time, this can impair the kidneys' ability to filter waste from the blood.

The current understanding of the disease is a “four hit” hypothesis – four events need to occur sequentially – for this disease to manifest. These four hits are:

• Hit 1 – Increased presence in the circulation of IgA1 molecules with reduced O-galactosylation of the IgA1 hinge region (Gd-IgA1).

• Hit 2 – The production of IgG and IgA autoantibodies that recognize Gd-IgA1.

• Hit 3 – Formation of circulating immune complexes containing IgG and IgA autoantibodies bound to Gd-IgA1.

• Hit 4 – Deposition of these circulating immune complexes in the glomerular mesangium, triggering kidney injury.

It is unclear why the immune complexes are deposited in the kidneys. They typically bind to active mesangial cells, which are upregulated in patients with IgAN. There is also evidence of a decreased clearance ability of these immune complexes in the liver and spleen.

This is a complicated, multifaceted disease etiology, and scientists are unsure of the mechanisms behind many of the steps.

The symptoms of IgAN include:

• Blood in the urine (visible or microscopic)

• Protein in the urine

• Swelling in the hands, feet, or face

• High blood pressure

• Loss of kidney function

Many patients do not recognize symptoms until the disease is advanced. The gold standard for diagnosis is a kidney biopsy.

Roughly 60,000-150,000 people have the disease in the US. The prevalence is estimated at 10-25 per 100k people.

Development History

There are now four approved drugs for the disease: Tarpeyo (TRF-budesonide), Filspari (sparsentan), Fabhalta (Iptacopan), and Vanrafia (atrasentan). Tarpeyo is a targeted release corticosteroid designed to release in the distal ileum. Corticosteroids suppress the production of IgA1 by B-cells, targeting the disease etiology at the source. However, not all IgA1 is produced in the distal ileum, so reductions in IgA1 should be modest. Clinical data suggests that GD-IGA1 levels dropped 20-30% after 9 months of treatment, while total IgA levels dropped 10-15%.

The P3 trial for Tarpeyo measured time-weighted eGFR levels over two years. The treatment group had a time-weighted average eGFR decline of -2.47mL/min/1.73m2. The placebo group had a decline of -7.52. There was also a significant reduction in urine protein-creatinine ratio with Tarpeyo compared to placebo. The patients continued supportive care in the form of ACE inhibitors and other molecules as necessary. For reference, a rapid decline in kidney function is considered 3-5 mL/min/1.73m2 per year. A reduction of only 2.5 in two years is a significant slowing of the disease.

Filspari inhibits angiotensin II and endothelin-1 receptors, decreasing blood pressure. Their P3 trial measured the change in proteinuria and eGFR over 110 weeks, compared against irbesartan. eGFR decreased by -2.5, compared to a -3.7 reduction in the ibesartan group. There was little change in proteinuria in the treatment group compared to a decline in the placebo group.

Fabhalta is a complement factor B inhibitor. It reduces the damage done to the kidneys by the deposition of the abnormal immune complexes in IgAN. Their P3 trial measured proteinuria change from baseline. An interim analysis showed a ~40% reduction in 24-hour UPCR from baseline at 9 months.

Atrasentan is a selective Endothelin A receptor antagonist. Their P3 study measured the proteinuria change from baseline. A 9-month interim analysis showed a 36.1% reduction in UPCR, compared to a 3% reduction for the placebo group.

There are seven molecules currently being tested in IgAN that have similar MOAs to atacicept and have shown promising results:

1. Telitacicept – Phase 2 and Phase 3 – RemeGen

   1. Telitacicept is a recombinant fusion protein designed to inhibit the B-lymphocyte stimulate (BlyS) and a proliferation-inducing ligand (APRIL). The molecule is currently undergoing phase 3 testing in China and phase 2 testing in the US.

   2. Phase 2 results from China:

      1. Phase 2 found a 49% reduction in mean proteinuria from baseline in the treated group.

2. BION-1301 (zigakibart) – Phase 3 – Chinook Therapeutics

   1. Zigakibart is a monoclonal antibody designed to target APRIL.

   2. Phase 2:

      1. After 52 weeks, the mean reduction in UPCR was about 50% in the treated group.

3. MOR202 (Felzartamab) – Phase 3 – Biogen

   1. Felzartamab is a monoclonal antibody targeting the CD38 glycoprotein.

   2. Phase 2:

      1. After nine doses over 6 months, the mean reduction in proteinuria was about 50%. This persisted over 24 months, suggesting that it could be dosed intermittently.

4. RO7434656 (Sefaxersen) – Phase 3 – Hoffman La Roche

   1. Sefaxersen is an antisense oligonucleotide (ASO) designed to reduce the production of complement factor B (CFB).

   2. Phase 2:

      1. It reduced proteinuria over the 29-week study length by 44%. The eGFR was stable.

5. Povetacicept – Vertex – Phase 3

   1. Povetacicept is a recombinant fusion protein designed to inhibit B cell-activating factor and APRIL.

   2. Phase 2:

      1. It reduced proteinuria by 64% at 36 weeks.

6. Sibeprenlimab – Otsuka – Phase 3

   1. Sibeprenlimab is a monoclonal antibody designed to inhibit APRIL.

   2. Phase 2:

      1. In the 8 mg/kg group, proteinuria decreased by 62% at 12 months. In the 2mg/kg group, proteinuria decreased by 47.2%. In the 4mg/kg group, proteinuria decreased by 58.8%.  eGFR was stable in the treated groups.

7. Ravulizumab – Alexion – Phase 3

   1. Ravulizumab is a monoclonal antibody designed to inhibit the complement system by targeting the C5 protein.

   2. Phase 2:

      1. Ravulizumab reduced proteinuria by ~40% by 26 weeks compared to a 16.8% reduction in the placebo group.

Atacicept and Vera

​Atacicept is an investigational recombinant fusion protein designed to inhibit the activity of B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), both of which are crucial for B-cell maturation, function, and survival. The rights to Atacicept are owned by Vera Therapeutics.

Mechanism of Action:

B cells go through an intricate maturation process, where they start in the bone marrow as pro-B cells and end in lymphoid tissue as mature naïve B cells. Central to this process are two signaling molecules. B-cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS), is a cytokine that binds to BAFF-R, Transmembrane Activator and Calcium-modulating cyclophilin ligand Interactor (TACI), and B-cell maturation antigen (BCMA). The second is known as A Proliferation-inducing ligand (APRIL). APRIL binds to TACI and BCMA to induce B-cell maturation and proliferation, with roles in survival and class switching as well (particularly to IgA).

Atacicept functions as a "decoy receptor" by combining the extracellular domain of the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) with the Fc portion of human immunoglobulin G (IgG). This structure allows atacicept to bind and neutralize BLyS and APRIL, thereby inhibiting their interaction with B-cell receptors. This inhibition leads to a decrease in B-cell activation and a reduction in the production of immunoglobulins, including the galactose-deficient IgA1 (Gd-IgA1) implicated in IgAN pathogenesis.

It has a history of failure prior to IgAN and has failed trials in MS, optic neuritis, RA, and Lupus. Both the MS and optic neuritis trials were terminated early as there were indications that atacicept made the diseases worse. In RA, there was no difference between placebo and actacicept. In the lupus trial, the 150mg was discontinued early due to two infection deaths. The 75mg treatment group failed to differentiate from placebo. However, the MS, optic neuritis, and RA trials occurred after the lupus trial, so safety is not a significant concern.

The studies of atacicept in IgAN are much more promising.

The phase two trial compared 150, 75, and 25mg atacicept once weekly dosages versus placebo over 36 weeks. They measured mean UPCR at 24 weeks and 36 weeks. A total of 116 people were enrolled. The mean reduction was 31% at week 25 and 35% at week 36, compared to a 2% increase at week 36 in the placebo group. Additionally, the treated group saw a slight increase in eGFR, whereas the placebo group saw a decline of 8%.

The phase 3 trial has an almost identical design to the successful phase 2. Vera Therapeutics enrolled 431 adults with biopsy confirmed IgAN, persistent proteinuria, and stable treatment on renin-angiotensin system inhibitors (RASi) for at least 12 weeks. The double-blind phase is 104 weeks with a 52-week open-label extension. The primary endpoint is the change in UPCR at 36 weeks, enabling Vera to submit a BLA in the second half of 2025.

Atacicept Discussion

This phase 3 trial is straightforward. The data appear similar to the other three drugs that have been already approved. The phase 3 study design is essentially a repeat of the phase 2 with a larger patient population. Considering the primary endpoint in phase 2 (proteinuria) was met with a high degree of statistical significance (p = 0.0042), it is highly likely the phase 3 readout is successful.

Conclusion

This phase 3 trial is straightforward. The data appear similar to the other three drugs that have been already approved. The phase 3 study design is essentially a repeat of the phase 2 with a larger patient population. Considering the primary endpoint in phase 2 (proteinuria) was met with a high degree of statistical significance (p = 0.0042), it is highly likely the phase 3 readout is successful.

However, the impact on the stock and the high price of options are the causes for consideration. When Tarpeyo was approved, Calliditas Theapeutics’ stock went up about 66%. Given the current price of around $22/share, I would expect a stock price in the low 30s after the readout. However, given the high volatility of the biotech market recently, entry timing here is important. The official readout is Q2 2025; the primary completion date given on clinicaltrials.gov is May 1st.