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Introduction
Efzofitimod, developed by aTyr Pharma (NASDAQ:LIFE), is a drug aimed at treating pulmonary sarcoidosis or PS. A recent clinical study was conducted to evaluate the safety and efficacy of the drug. In this article, the results of the study will be analyzed and its potential as a treatment for PS will be evaluated.
Financials
Let’s first review aTyr Pharma’s latest quarterly report. As of September 30, 2022, the company’s cash, restricted cash, cash equivalents, and investments were reported at $79.6 million. The company also just earned an additional $10 million milestone payment. During the third quarter of 2022, research and development expenses were recorded at $9.9 million, which covered product development and manufacturing costs for the efzofitimod and ATYR2810 programs, as well as the initial expenses for the Phase 3 EFZO-FIT™ study. General and administrative expenses for the same quarter were reported at $3.6 million. The net loss for the quarter was $13.2 million. On September 30, 2022, the number of outstanding common shares was 29,009,382. As of writing (February 7, 2023), aTyr Pharma stock is valued at $71 million (market capitalization). Total debt is $8.65 million.
Pulmonary Sarcoidosis
Pulmonary sarcoidosis, PS, is a complex autoimmune disease that causes the formation of granulomas in the lungs, leading to fibrosis and reduced lung function. Despite the unmet need for effective treatments, current options are limited and come with side effects.
Current treatments
Corticosteroids, immunosuppressive, and cytotoxic agents (e.g. methotrexate) are the current treatment options for PS. Corticosteroids are a potent anti-inflammatory drug widely used to treat autoimmune diseases but have significant side effects with long-term use. Methotrexate is linked to toxicities.
Forced vital capacity
Forced Vital Capacity, FVC, is a commonly used endpoint in PS studies, as it measures lung function and provides insight into the extent of lung damage caused by the disease. FVC changes over time can reflect disease progression and response to treatment, making it a crucial indicator of the effectiveness of a therapy. Monitoring FVC is useful for tracking the disease and evaluating the efficacy of interventions.
The efficacy of reducing FVC decline has been the basis for the approval of nintedanib and pirfenidone for the treatment of Idiopathic Pulmonary Fibrosis by the FDA, highlighting the importance of FVC in evaluating the effectiveness of treatments for lung diseases.
Efzofitimod: An Analysis Of A Clinical Study
Efzofitimod, developed by aTyr Pharma, is a new drug composed of a splice variant of histidyl-tRNA synthetase. It is able to bind to the neuropilin 2 receptor protein, which is upregulated on the surface of immune cells that cause inflammation and granuloma formation in patients with pulmonary sarcoidosis.
Clinical study
An early-stage clinical study was conducted to evaluate the safety and efficacy of efzofitimod. The study was a randomized, double-blind, placebo-controlled trial that evaluated multiple doses of efzofitimod administered intravenously every 4 weeks for 24 weeks. Patients were randomized 2:1 to receive efzofitimod or placebo and underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16. The primary endpoint was the incidence of adverse events, and secondary endpoints included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales.
Results
The study evaluated three different doses of efzofitimod (1 mg/kg, 3 mg/kg, and 5 mg/kg) with 8 participants for each dose. The change in lung function was measured using Forced Vital Capacity (FVC%) at 4, 8, 12, 16, 20, and 24 weeks. The results showed no significant difference in the change in FVC% between the efzofitimod group and the placebo group for any of the doses or time points, as the p-values were all greater than 0.05.
My Analysis
The sample size of the study (8-9 patients in each group for each dose of efzofitimod) may have played a role in the drug’s inability to reach significance for key pulmonary function tests and steroid tapering, however, the lack of significance is likely due to factors other than sample size, such as the effectiveness of the drug, variability in the patient population, or limitations in the study design. Below, I review three, possibly interconnected, red flags that may have skewed efficacy data in efzofitimod’s favor.
1. Significant variability in key baseline characteristics between groups
The results of the efficacy data are uncertain due to significant variability in the baseline characteristics of the patient population. I conducted a two-sample t-test to compare the baseline characteristics (FEV1 and FVC) between the placebo and 5 mg/kg groups. Below is the calculation and its explanation:
This calculation is a hypothesis test comparing two groups of data – a placebo group with 12 participants (n=12) and a 5mg/kg group with 9 participants (n=9) – to see if there is a significant difference between their means. The mean (average) value of the placebo group is 77.3 and the mean value of the 5mg/kg group is 83.8.
The t-statistic is calculated by subtracting the mean of one group from the other, and dividing the result by the square root of the sum of the standard deviation of each group, divided by their respective sample size.
t-statistic = (mean1 – mean2) / sqrt(SD1^2 / n1 + SD2^2 / n2) = (77.3 – 83.8) / sqrt(11.5^2 / 12 + 16.6^2 / 9) = -2.06
The t-statistic of -2.06 is compared with a critical value of -1.833. If the t-statistic is less than the critical value, the null hypothesis (that there is no significant difference between the means) is rejected, meaning that there is evidence of a significant difference between the means of the two groups for FVC. In this case, the t-statistic of -2.06 is less than the critical value, so the null hypothesis is rejected and there is a significant difference between the means of the two groups for FVC.
The results (both t-statistics were less than the critical value of -1.833, which reject the null hypothesis that there were no significant difference in the means of the two groups for FEV1 & FVC) revealed that the 5 mg/kg group had significantly higher FEV1 & FVC values compared to the placebo group (the t-statistics convert to p-values of <0.05), indicating that the placebo group had more severe cases of PS. Despite this difference, efzofitimod still failed to produce significant results. It is noteworthy that the 1 mg/kg group had the lowest mean baseline FEV1 of all groups at 60.4% ± 10.2, and performed even worse than the placebo group in pulmonary function tests at the study’s conclusion. This may be linked to the lower mean baseline FEV1. According to UpToDate, a widely used resource among clinicians, a FEV1 value of 50-70% of the predicted value is considered moderate in terms of ventilatory impairment severity. The other group below 70% FEV1 was the placebo, whilst the 3 mg/kg and 5 mg/kg were 77.6% and 77.3%, respectively. Patients with moderate disease are more challenging to treat compared to those with mild disease. Additionally, the placebo group showed better results in terms of steroid burden and patient-reported outcomes [PRO] compared to the group receiving 1 mg/kg. It’s important to note that steroid burden and PRO are interconnected, as the use of corticosteroids decreases the quality of life measures.
2. Positive trends in steroid reduction likely a result of significant baseline variability
The study found that the average daily steroid doses for the 1-mg/kg, 3-mg/kg, and 5-mg/kg groups were 6.8 mg, 6.5 mg, and 5.6 mg respectively, compared to 7.2 mg for the placebo group. This resulted in a decrease of 5%, 9%, and 22% in steroid use when compared to the baseline. The comparison between the placebo and efzofitimod groups showed that the two higher dose groups of efzofitimod had a larger, although statistically insignificant, decrease in overall steroid use compared to the placebo group (a decrease of 2% for the 3 mg/kg group and a decrease of 12% for the 5 mg/kg group).
The authors of the CHEST article acknowledge that the variability in the approach to corticosteroid tapering may result in residual bias, but generally, it is expected to reduce the probability of positive outcomes. Nevertheless, they ignore the substantial difference in baseline FVC levels between the group receiving 5 mg/kg of the drug and the placebo group. Patients with elevated FVC levels are more likely to be able to tolerate steroid tapering, which could lead to implicit investigator bias favoring the treatment group due to differences in baseline characteristics.
Additionally, it is unknown whether any of the patients were able to completely discontinue steroid use. The study’s reductions in steroid use are therefore subject to interpretation. The authors state that reducing corticosteroid use was possible for all patient groups, which aligns with previous research that has shown that patients with sarcoidosis can gradually decrease their corticosteroid intake over several months. However, relapses are common, with rates ranging from 20% to 74%, and around 50% of these occur within 6 months of stopping therapy. If patients were stable on 5 mg of prednisone at week 16, the investigator had the option to eliminate steroids completely. The study lasted 24 weeks, which may not have allowed enough time for patients to experience a relapse after discontinuing steroids.
3. The improvement in patient-reported outcomes is likely due to the decrease in steroid burden, which may be attributed to implicit investigator bias as a result of substantial differences in baseline characteristics between the groups.
Efzofitimod in higher doses demonstrated significant improvements in specific patient-reported outcomes, such as quality of life scores, over different assessment weeks. However, these advancements may be due to the aggressive steroid-tapering regimen implemented by investigators in the drug groups, particularly in the 5 mg/kg group.
Conclusion
The trial of efzofitimod conducted by aTyr Pharma did not show a significant difference in the change of lung function (FVC%) compared to the placebo group. This result may be attributed to a variety of factors, including the efficacy of the drug, variability in the patient population, or limitations in the study design. Despite higher FVC values in the 5 mg/kg group of efzofitimod compared to the placebo group, there was no statistical significance in either corticosteroid tapering or the change in FVC%. The observed positive trends may be due to significant differences in baseline characteristics between groups, leading to implicit investigator bias. Perhaps the only conclusion that can be drawn from the data is that patients with mild disease had better outcomes than those with moderate disease, regardless of the group (placebo or drug). The poor performance of the 1 mg/kg group compared to the placebo group is substantial evidence to support this.
For the upcoming phase 3 trial, aTyr Pharma plans to focus on evaluating changes in daily prednisone dose, improvement in lung function, and health-related quality of life as its primary outcomes. However, given the lack of statistical significance in the previous trial, it is unlikely that efzofitimod will meet these goals. Based on this, aTyr Pharma is considered a “sell” in anticipation of phase 3 failure.
Although aTyr Pharma is valued near zero already (enterprise value), the company records losses exceeding $10 million every quarter and has accumulated a deficit of $410.1 million since inception. Therefore, so long as the company has lights on and its stock is traded on the market, there is always room down.
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