The FLOW Trial

Assessing the fallout of Novo’s early termination and anticipating positive results

FLOW Trial Impact Assessment

Novo Nordisk’s FLOW trial investigated the effects of Semaglutide on kidney outcomes in individuals with type 2 diabetes and chronic kidney disease, but was halted on October 10, 2023 due to early efficacy based on an interim analysis . The trial was designed as a randomized, double-blind, parallel-group, multinational, phase 3b study to explore the impact of Semaglutide, a once-weekly GLP-1RA, on the progression of renal impairment. The FLOW trial was initiated in 2019, and over 3,500 people were enrolled. They concluded that the results from an interim analysis met certain pre-specified criteria for stopping the trial early for efficacy.

Novo Nordisk remains blinded to the results until trial completion. Novo Nordisk expects data readout during the first half year of 2024.This decision reflects a positive indication concerning Semaglutide’s efficacy in the given context.

Background

Obesity is not just a matter of weight, but typically comes hand in hand with a variety of other diseases (We call these “Co-morbidities” in fancy-speak), such as diabetes (High blood sugar) and hypertension (High blood pressure). Unfortunately, both high blood sugar and high blood pressure, tends to lead to kidney problems. The kidney acts as a filtration system for the body, removing waste products, such as toxins, through urination and retaining substances, such as salts and water. The ability to do this depends on a network of very tiny blood vessels inside the kidney, called glomeruli. Blood pumped into glomeruli creates hydrostatic pressures with the plasma surrounding the glomeruli, inside a structure called Bowman’s capsule, which surrounds the glomeruli; thus removing unwanted substances.

High blood pressure has the potential to damage these tiny blood vessels through physical stress, whereas high blood sugar can lead to chemical change-induced damage.

Kidney function is measured primarily through estimated Glomerular Filtration Rate (eGFR), which is an estimate (There are more precise ways of measuring Glomerular Filtration Rate, such as introducing a foreign substance such as inulin, but these tend to be more labour-intensive) of the rate at which the kidney is disposing unwanted substances from the body (Specifically creatinine); and measured through Urinary Albumin to Creatinine Ratio (UACR), which is a ratio of the amount of albumin and creatinine in urine (In patients with functional kidneys, Albumin normally does not get into the urine, whereas creatinine does. The presence of albumin in urine, suggests it is leaking into the urine, due to a damaged glomerulus. Imagine a filter that has become damaged and is allowing substances to get through).

Chronic Kidney Disease (CKD) is estimated to affect around 50% of T2DM patients globally (Thomas et al, 2016). According to the CDC, in 2023 around 14% of adults in the US have CKD, 1/3 adults with diabetes and 1/5 adults with blood pressure, have CKD.

Thus a natural question that rose through the development of Novo’s Semaglutide, was what effect it may have on diabetic patients with CKD.

Past studies of Semaglutide on kidney function in diabetic patients (Medical Stuff, skip to Investment Implications if it makes you glaze over)

A Spanish study (Not funded by Novo, although the authors have received speaking fees from Novo), found that weekly subcutaneous Semaglutide (0.25mg) injections after 12 months, as expected, led to an average decrease in HbA1c (A measurement of blood glucose) of 0.73%, average decrease in systolic blood pressure by 9.85 mmHg and average decrease in diastolic blood pressure of 5.92mmHg, compared to baseline.
These effects indeed translated to UACR being reduced by an average of -162.21 mg/g. eGFR increased only by 2.2 mL/min/1.73 m² , but did not achieve statistical significance (A statistical threshold where we deem that the results are unlikely due to statistical noise/chance).
(Aviles Bueno et al, 2022).

SUSTAIN 1 – 7 were clinical trials with Semaglutide, originally intended to investigate its effect on other conditions. A post hoc study (Think of this as additional analysis after the study is completed, for the purpose of exploratory research (Mann et al, 2020). It is a type of data-mining, which comes in hand with all the advantages and disadvantages that data-mining typically has) of the SUSTAIN clinical trials was aimed at measuring kidney function, specifically eGFR and UACR. This type of analyses has to be treated carefully, since data from the SUSTAIN clinical trials are being pooled together, which introduces some caveats since the trials are not necessarily directly comparable

Data is a little nuanced so bear with us.
SUSTAIN 1-5 and 7 showed that across all patients receiving Semaglutide (1 mg), an Estimated Treatment Difference (ETD, think of this as an adjusted difference, taking account of other statistical factors) of -2.02 mL/min/1.73 m² for eGFR was measured, after 30 weeks of treatment. This is an undesirable (Higher eGFR indicates better kidney function), albeit small, effect.
However, looking closer at the data, the ETD comparing from baseline to week 12 is -3 mL/min/1.73 m², whereas comparing week 12 to week 30, the ETD for Semaglutide (1 mg) vs placebo is an increase of 0.56 mL/min/1.73 m² . This suggests that Semaglutide causes a (dare I say it) transitory decrease in eGFR, up to week 12, but does not get more worse over time.
Further evidence comes from SUSTAIN 6, which lasted 104 weeks, where the ETD for Semaglutide (1 mg) treated patients on eGFR was an increase of 0.97 mL/min/1.73 m² .

Taken together, along with previous results of the Spanish study, these results suggest that Semaglutide may produce transitory dips in eGFR, but that this tapers off and effectively has no change on eGFR, compared to placebo.

However, UACR metrics is where things get interesting.

For SUSTAIN 1-5, patients on Semaglutide (1 mg) after 30 weeks had a 16.4% decrease in their UACR (Lower UACR indicates better kidney function).
The results were echoed in SUSTAIN 6, where after 104 weeks, a decrease of 14.2% in UACR was seen in patients on Semaglutide (1 mg), whereas placebo controls showed an increase of 30.2%.

The tl;dr is that across two measures of kidney function, one showed virtually no difference (eGFR) whereas the other showed an improvement (UACR). One way to simplify this is to imagine that the the flow of substances through the filter is unchanged, but the filter itself has been fixed, leading to better filtration results. Ideally, you would have increased flow and filter, (Which allows you to filter things faster), but a better filter and unchanged flow is still beneficial

(This analogy is not strictly correct, eGFR is not influenced solely by the rate of blood flow and it also influenced by the integrity of the filter, but it will do for now).

Although somewhat tricky to reconcile, these results need to be taken in the context of the side- effects of Semaglutide, which can include vomiting and diarrhea, both of which can cause hypovolemia (Less blood volume), which in turn can slow the rate at which blood passes through the kidneys (flow), and thus lowering eGFR, and may also help explain the transitory nature of the decrease in eGFR. Furthermore, the decrease in blood pressure seen from Semaglutide treatment may also help to lower eGFR on the margin, although the effect (If existent) would be quite small)

This formed the basis of Novo’s clinical trial, FLOW, which was supposed to be a randomised, double-blinded, placebo-controlled phase 3b trial, across 28 countries and with 3534 people enrolled, testing the effects of once weekly Semaglutide (1mg) on delaying CKD progression in T2DM patients.

As primary endpoints it would aim to delay:

- Onset of >50% reduction in eGFR, compared to baseline
- Onset of eGFR being persistently below 15 mL/min/1.73 m²
- Initiation of kidney replacement therapy (Dialysis or transplantation)
- Death from kidney disease

On 10 October 2023, after market hours, Novo announced that they would stop the trial based on meeting pre-specified criteria for stopping the trial early for efficacy.

It is important to note, that Novo themselves do not decide whether the pre-specified criteria have been met, but rather an independent Data Monitoring Committee (DMC) did.

Although the data has not been shared yet, which is expected to occur in the first half of 2024, one can speculate to what kind of results might have led to such a decision being made.

The study started 2019-06-17, and was originally meant to be a 5 year study, until 2024-8-19. One might speculate that within 4 years, most people in the placebo-controlled group may have succumbed to the primary endpoints, whereas a reasonable proportion on Semaglutide had yet to.

Whether this is just a delay in the onset of CKD (treating the symptoms) or something more fundamental, remains to be seen. However, given that the underlying causes of CKD in diabetic patients is caused by both higher blood glucose and higher blood pressure, and that GLP1R agonists such as Semaglutide have already shown to reduce blood glucose (as was their original intention) and reduce blood pressure; they are mechanistically direct in addressing the underlying cause of CKD in diabetic patient and thus we find it more likely that the effect is addressing the fundamental cause.

Investment Implications

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