Tag: cystic fibrosis

Vertex reports great results for its latest trials targeting double DF508 and single DF508 combos

Hopefully by now you’ve all seen the fantastic results that Vertex reported last week regarding their latest trials with precision therapy for those with both double DF508 and a single DF508 mutation combo. Vertex shares are up 21% and the reported results are pretty exciting. Although the trials were for patients 18 and older, it sounds like they’re fast tracking the next late stage trials (earmarked for early 2018) so let’s hope pediatric trials follow swiftly. Continue reading “Vertex reports great results for its latest trials targeting double DF508 and single DF508 combos”

PharmaNAC gets the thumbs up from Standford trial

Oxidative stress is defined as an excessive load of reactive oxygen species (ROS), which cause ongoing or reversible damage in the body. This can occur in individual cells, and in specific body organs, and can affect the health of patients at the whole body level.
Antioxidants can chemically react with ROS to quench and thus inactivate these reactive, damaging molecules. Cystic fibrosis is characterized by oxidative stress throughout the body and chronic inflammation in the lungs. Patients with CF are deficient in the body’s major anti-oxidant, glutathione (GSH). This is thought to be due to many reasons, including dietary insufficiency, but being the major anti-oxidant of the body, GSH is highly utilized in areas of oxidative stress and inflammation. GSH serves multiple functions and is utilized by cells to regulate physiological functions such as DNA transcription, RNA translation, and subsequent protein synthesis. It is utilized to regulate protein functions and is vital in regulating dietary absorption of nutrients, storage and availability of essential proteins and fatty acids.
Oxidation reactions are essential to fight infection and are generated when neutrophils ingest bacteria to rid the body of pathogens. For reasons still unclear, in CF, the environment in the airways is strongly pro-inflammatory. After neutrophils have been recruited, neutrophil-derived oxidants are released into the airways, and contribute to ongoing tissue destruction. Oxidants, which include hydrogen peroxide, hypochlorous acid, and other damaging particles called free radicals are released and create a vicious perpetual cycle of tissue destruction.

Continue reading “PharmaNAC gets the thumbs up from Standford trial”

FDA approves Orkambi

Orkambi, a New Cystic Fibrosis Drug, Wins F.D.A. Approval

JULY 2, 2015

A new drug for people with the most common genetic type of cystic fibrosis won approval from the Food and Drug Administration on Thursday.

The drug, Orkambi, is the second cystic fibrosis treatment brought to market by Vertex Pharmaceuticals, a biotechnology company based in Boston. It is expected to make the company consistently profitable; it has lost several billion dollars since it was founded 26 years ago.

Both Vertex drugs are the first to try to counteract the underlying genetic defect that causes the disease, as opposed to treating symptoms.

Vertex’s first cystic fibrosis drug, Kalydeco, which was approved in 2012, is applicable to a small percentage of those with cystic fibrosis, those with particular genetic muations. Sales of Kalydeco reacched $464 million in 2014, accounting for the bulk of Vertex’s revenue.

Orkambi, by contrast, could be useful for nearly half of cystic fibrosis patients, those who have two copies of the most common mutation, known as F508del. The initial approval, however, is only for patients 12 and older.

Analysts expect annual sales of Orkambi to eventually exceed $3 billion. Orkambi is a combination of ivacaftor, the active ingredient in Kalydeco, and a second drug called lumacaftor.

Approval was expected because a committee of outside advisers to the F.D.A. endorsed the drug in May by a 12-1 vote. The agency’s own staff, however, had given the product a lukewarm review, saying its effectiveness in improving lung function was small.

Vertex did not immediately announce the price of Orkambi. Kalydeco costs more than $300,000 a year for each patient, a price that has drawn criticism from some doctors who treat cystic fibrosis.

Wall Street analysts have been expecting Vertex to charge less for Orkambi, perhaps $200,000 to $250,000 a year.

That is because Orkambi would be used by more patients, meaning Vertex would not have to charage as much per patient to recoup its investment. Also, Orkambi is less effective than Kalydeco in improving lung function, meaning it will have less value in the eyes of insurance companies and government agencies that pay for these drugs.

Keeping CF lungs infection free

A must watch for any CF paediatric parent.

Different doctors give different advice. So do different clinics. There’s no getting around it. We do not have an agreement on modes and models of care from one country to the next or even one clinic to the next.

As parents we can’t avoid the responsibility of making the most informed decisions possible, which is why we all need to seek out information and experiences beyond our own as much as we can. The real reason is not just hearing other doctors speak but also listening to other parents and children with CF. These are the people on the battlegrounds at the forefront of day-to-day care of this disease, just as we are. The CFRI is a terrific organisation that offers loads of resources and they recently had a paediatric conference on “Tools to help your CF child thrive” – this is the first presentation from that series. I’m going to post them one by one with a short summary over the next few weeks.

So here’s a summary of the first session :

What are the things we need to do to keep CF lungs healthy: Tips from a CF researcher who is also the parent of a CF child  Continue reading “Keeping CF lungs infection free”

QLD Orkambi trial shows really positive results

Screen Shot 2015-05-18 at 8.22.50 pmQueensland researchers may have discovered a game-changing treatment for children suffering from cystic fibrosis.

The Queensland Children’s Medical Research Institute has released results from world-first clinical trials of a new treatment that combined two existing drugs, lumacaftor and ivacaftor.

Neither had shown significant clinical outcomes when used alone, but QCMRI interim director Claire Wainwright said the combination treatment had resulted in up to 39 per cent fewer lung infections.

“Cystic fibrosis is the most common life-threatening genetic condition affecting children in Australia, so these results are incredibly exciting,” Professor Wainwright said.

“As well as the 30-39 per cent reduction in lung infections, our trial participants reported a decrease in events requiring hospitalisation or use of IV antibiotics.

“Results like this mean our novel treatment is a potential game changer for the way we treat CF and other genetic disorders in the future.”

Cystic fibrosis sufferers have abnormally thick mucus linings in the lungs, which clog air passages and result in repeated infections and blockages.

It affects the respiratory, digestive and reproductive systems and usually leads to a shortened life expectancy, around 37 years on average.

“Research into novel treatments like the one we trialled is essential to improve the quality of life for CF patients,” Professor Wainwright said.
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“There is still no cure for CF but with treatments like this proving successful, our research could have positive outcomes for CF patients not just here in Australia but internationally for years to come.”

More than 1100 children under the age of 12 participated in the six-month study, which involved two randomised, double-blind, phase 3 clinical trials.

Senior researcher Scott Bell said 187 hospitals in Australia, Europe and the United States collaborated in the trials.

“Nine CF centres in Australia have been involved in the study and patients have been eagerly awaiting the results,” Professor Bell said.

“More than 1000 patients in Australia have the potential to benefit from the treatment in the future.”

The Food and Drug Administration will make a decision on the treatment in July, after which it will be assessed by the Therapeutic Goods Administration to determine market availability and costs.

Source: Beaudeserttimes.com.au


Lumacaftor/Ivacaftor Combo Helps Common CF Mutation

Phase III trial finds drug combo boosts forced expiratory volume in homozygous DF508del cystic fibrosis patients

  • This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Note that this pair of randomized trials of lumacaftor and ivacaftor in combination improved lung function in patients with cystic fibrosis.
  • These results have led to a recommendation for approval by the FDA.

DENVER — Combination of approved cystic fibrosis drug, ivacaftor (Kalydeco), and experimental drug, lumacaftor, improved forced expiratory volume in patients with common gene mutation, researchers reported.

In two, phase III randomized, controlled, multi-center trials including over 1,000 cystic fibrosis patients with the Phe508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, found the drug delivered in two different dose combinations improved predicted forced expiratory volume by 2.6% to 4.0% compared to a placebo without drastic increases in serious adverse events (4.2% versus 1.6%), Claire E. Wainwright, MBBS, MD, of Lady Cilento Children’s Hospital in Queensland, Australia, and colleagues, presented at the American Thoracic Society annual meeting.

These findings were also reported in the New England Journal of Medicine.

The drug, which is being developed by Vertex and will be marketed under the brand name Orkambi, was recommended for approval by an FDA advisory committee last week.

Phe508del mutation in CFTR is the big target for CF patients, Pamela B. Davis, MD, PhD, Dean of the School of Medicine at Case Western Reserve University, wrote in the New England Journal of Medicine.

Roughly half of cystic fibrosis patients in the U.S. are homozygous for this mutation, and more than 90% have at least one allele, she wrote.

Ivacaftor is generally used for patients with the Gly551Asp mutation. It works on the fraction of time that the CFTR channel is open, the “open probability,” of the mutant protein, but it doesn’t work on patients who are homozygous for the Phe508del mutation, Davis added. Lumacaftor improves the processing of the mutant CFTR by prolonging its residence at the cell surface, but it doesn’t improve the open probability.

“The combination of lumacaftor and ivacaftor produced significant improvements in lung function and weight gain, as well as significant amelioration of respiratory symptoms and pulmonary exacerbations,” Davis wrote. “However, the extent of improvement was not as great as that produced by ivacaftor alone in the treatment of patients with the Gly551Asp mutation.”

Davis compared the forced expiratory volume improvements seen in the trials to those seen with inhaled DNase, and even slightly less than those seen with inhaled tobramycin. Davis does note that neither inhalants address the basic defect in the protein the way ivacaftor does.

Davis proposed that the combination of ivacaftor and lumacaftor create a need for higher doses of ivacaftor, as lumacaftor is a strong CYP3A inducer and ivacaftor is a sensitive CYP3A substrate and weak inhibitor, as the combination can cause problems with other cystic fibrosis drugs that the patient might need to take.

In light of these complexities, Davis suggested a tailored dose would probably work better than the fixed doses used in the trials. She also mentioned two laboratory studies demonstrating prolonged exposure to the combination eventually interfered with lumacaftor’s mechanisms by reducing the protein release from the endoplasmic reticulum, thereby reducing the chloride transport activity originally seen in the combination.


Wainwright’s team conducted two phase III, randomized, controlled trials to test the effects of combining lumacaftor, a CFTR corrector, and ivacaftor, a CFTR potentiator. The trials were know as TRAFFIC and TRANSPORT. All patients were at least 12 years old, and were homozygous for the Phe508del CFTR mutation.

Both trials were double-blinded, and dose-identical. For 24 weeks, 1,108 patients, across 187 centers, either received either 600 mg of lumacaftor once a day with 250 mg of ivacaftor every 12 hours, 400 mg of lumacaftor every 12 hours with 250 mg of ivacaftor every 12 hours, or a placebo.

Patients were assigned to each group on a 1:1:1 ratio, and allowed to remain on their pre-study medications. Controls were matched for age, gender, and pulmonary function.

Changes in forced expiratory volume were measured at baseline. The mean of which was 61% of the predicted value.

At 24 weeks, the mean absolute improvement in the predicted forced expiratory volume ranged from 2.6% to 4.0% (P<0.001). The improvements in mean relative treatment difference ranged from 4.3% to 6.7% (P<0.001).

Compared to the placebo group, pulmonary exacerbations were 30% lower in the 600mg/day of lumacaftor group (P=0.001) and 39% lower in the 400mg/12-hours of lumacaftor group (P<0.001).

Improvements in forced expiratory volume were seen as early as day 15 on the therapy across treatment arms.

Relative improvements in percentage of predicted forced expiratory volume of 5% or higher were reported by 39% to 46% in the treatment arms versus 22% in the placebo group (odds ratio 2.9 for 600 mg/day and 2.2 for 400 mg/12-hours). That of 10% or higher were found among 24% to 27% of those in the treatment arms compared to 13% in the placebo group.

The researchers also reported clinically meaningful reductions in the rates of protocol-defined pulmonary exacerbations in both treatment arms compared to placebo: rate ratio 0.57 to 0.72 (P<0.001 to P=0.05). However, these rate ratios didn’t reach significance in the testing hierarchy.

After 24 weeks on the therapy, slight weight gains were noted in the treatment groups, 1.23 kg and 1.57 kg, on average. The researchers estimated that either better caloric absorption, possibly due to normalized intestinal pH, or lower energy expenditure from improvements in symptoms explained this result.

CFQ-R scores, though improved in the 600 mg/day of lumacaftor group, did not meet the criteria for clinical difference of 4 points.

Serious Adverse Events

Serious adverse events were reported among 28.6% of those in the placebo arm, and 17.3% to 22.8% of patients in the pooled treatment arms. The most common event was infective pulmonary exacerbations, which comprised 24.1% of SAEs in the placebo group, and 13% in the combined treatment arms.

Drop out rates were 4.2% for those in the combined treatment groups, and 1.6% in the placebo group. Elevated creatine kinase levels occurred in 4 patients, hemoptysis in 3, bronchospasm in 2, dyspnea in 2, pulmonary exacerbations in 2, and rash in 2 patients. No deaths were reported.

Seven patients in the treatment arms, and none in the placebo group, experienced abnormal liver function.

ORKAMBI given the green light for FDA Review

May 12, 2015

Food and Drug Administration Advisory Panel Voted 12 to 1 to Recommend Approval of ORKAMBI™ (lumacaftor/ivacaftor) to Treat People with Cystic Fibrosis Ages 12 and Older Who Have Two Copies of the F508del Mutation

FDA decision expected by July 5, 2015

Approximately 8,500 people with cystic fibrosis in the U.S. have two copies of the F508del mutation and are ages 12 and older

Pills In JarsBOSTON–(BUSINESS WIRE)– Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the U.S. Food and Drug Administration’s (FDA) Pulmonary-Allergy Drugs Advisory Committee (PADAC) voted 12 to 1 to recommend that the FDA approve ORKAMBITM (lumacaftor/ivacaftor) for use in people with cystic fibrosis (CF) ages 12 and older who have two copies of the F508del mutation in the CFTR gene. Advisory committees provide the FDA with independent scientific and medical advice on safety, effectiveness and appropriate use of potential new medicines. The FDA is expected to make a decision on the approval of ORKAMBI by July 5, 2015 under the Prescription Drug User Fee Act (PDUFA). The FDA is not bound by the committee’s recommendation but often follows its advice. If approved, ORKAMBI will be the first and only medicine to treat the underlying cause of CF for eligible people with CF ages 12 and older with two copies of the F508del mutation in the CFTR gene. People with two copies of the F508del mutation represent the largest group of people with CF. There are approximately 8,500 people ages 12 and older with two copies of the F508del mutation in the U.S.

“Today’s positive recommendation brings the cystic fibrosis community one step closer to potential approval of the first medicine to treat the underlying cause of this disease for many more people,” said Jeffrey Chodakewitz, M.D., Executive Vice President and Chief Medical Officer at Vertex. “We look forward to continuing to work with the FDA and other regulatory agencies throughout the world to make ORKAMBI available to eligible patients as soon as possible.”

Cystic fibrosis is a rare genetic disease that is caused by defective or missing CFTR proteins resulting from mutations in the CFTR gene. The defective or missing proteins result in poor flow of salt and water into and out of the cell in a number of organs, including the lungs. In people with two copies of the F508del mutation, the CFTR protein is not processed and trafficked normally within the cell, resulting in little to no CFTR protein at the cell surface.

ORKAMBI is a combination of lumacaftor, which is designed to increase the amount of functional protein at the cell surface by addressing the processing and trafficking defect of the protein, and ivacaftor, which is designed to enhance the function of the CFTR protein once it reaches the cell surface. ORKAMBI is an oral medicine that, if approved, would be taken as fully co-formulated tablets that contain both lumacaftor and ivacaftor.

Vertex (VRTX) Soars After Hours as FDA Panel Backs Cystic Fibrosis Drug Orkambi

Vertex Soars After Hours as FDA Panel Backs Cystic Fibrosis Drug Orkambi
May 12, 2015
By Riley McDermid, BioSpace.com Breaking News Sr. EditorA delegation of executives of Vertex Pharmaceuticals (VRTX) successfully argued today before the U.S. Food and Drug Administration (FDA) Pulmonary-Allergy Drugs Advisory Committee that its cystic fibrosis drug Orkambi has merit, causing the panel to vote 12-1 to approve the drug. For a complete breakdown of the questions asked and how the panelist voted, please click here.

There had been some concern the treatment may not be approved after notes form the panel leaked last week showing the FDA had significant concerns about the efficacy or Orkambi. But investors who had been waiting all day for the news and applauded the decision, pushing Vertex up almost 9 percent in aftermarket trading.

“Today’s positive recommendation brings the cystic fibrosis community one step closer to potential approval of the first medicine to treat the underlying cause of this disease for many more people,” said Jeffrey Chodakewitz, executive vice President and chief medical officer at Vertex. “We look forward to continuing to work with the FDA and other regulatory agencies throughout the world to make ORKAMBI available to eligible patients as soon as possible.”

One of the ingredients of Orkambi is ivacaftor, which Vertex markets under the name Kalydeco. Kalydeco is used to treat patients with one specific mutation in the CFTR gene, not including F508del, the most common cystic fibrosis mutation. Orkambi combines ivacaftor with lumacaftor.

Neither lumacaftor nor ivacaftor, by themselves, help cystic fibrosis patients with the F508del mutation. But a combination of the two has shown positive results in clinical trials and the FDA agreed that the benefits were large enough to allow approval.

“Despite the questions raised by the FDA and the panelists’ willingness to consider the FDA’s arguments this morning (after multiple speakers during the open public hearing), the panelists this afternoon came out in general support of Orkambi,” wrote biotech analyst Mark Schoenebaum in a note Tuesday.

“The panelists generally agree that a comparative efficacy study of Orkambi vs Kalydeco in homozygous F508del patient could be done post-approval if necessary,” he said.

Kalydeco generated $464 million in revenue last year. In the U.S., there are about 30,000 CF patients, but only 7 percent have the specific gene mutation that Kalydeco treats. If Orkambi is effective and gets approved, it could potentially be used to treat about 15,000 of those patients in the U.S. alone, although more likely be applicable about 8,500 patients 12 years and older. However, potential revenue if approved, is projected at $5 billion within a couple years.

The Vertex portion of the presentation was concluded by Bonnie Ramsey, director of the Center for Clinical and Translational Research at Seattle Children’s Hospital and the Washington School of Medicine, saying Orkambi “will have a major impact” on her CF patients.

News last Friday that the FDA’s Pulmonary-Allergy Drugs Advisory Committee has released its briefing notes ahead of the meeting initially spooked the market, but the company has roared back as Wall Street agreed the document is an overall positive.

When parsed thoroughly the documents appeared to show the FDA believes that there is a statistically significant benefit over placebo in FEV1 but has questions about the small treatment effect and the lack of ivacaftor monotherapy and lumacaftor monotherapy controls in the Phase III trials, said analysts.

The lead biotech analyst at Citigroup, Yaron Werber, said a closer look at the FDA’s notes show the regulator is generally open to the idea of approving Orkambi.

“Given that Orkambi has Breakthrough designation, which provides for enhanced interaction, FDA notes that they and EMA agreed with the study designs and continuously provided constructive guidance,” wrote Werber.

“As such we believe that FDA needs to raise this question for discussion but is supportive of the trial design. The key question is whether the benefit is clinically meaningful. We believe that the AdCom will vote positively for approval of Orkambi given the lack of alternative treatment options for cystic fibrosis patients homozygous for the F508del mutation in the CFTR gene.”

Big news for DF508 carriers

two-pills-500-466x298On May 12, 2015, the Pulmonary-Allergy Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) will hold a hearing to discuss Vertex Pharmaceuticals’ new drug application for approval of the lumacaftor/ivacaftor combination therapy for the treatment of cystic fibrosis in patients age 12 years and older who are homozygous for the F508del mutation.

The results of a phase 3 clinical trial with lumacaftor and ivacaftor showed statistically significant improvements in lung function and other markers. Sue Landgraf, CFRI’s executive director, will address the committee during oral presentations from the public, advocating for FDA approval of the combination therapy.

To read the FDA’s announcement of the hearing, click here.


What were the results of the ivacaftor and lumacaftor Phase 3 clinical trials?

Participants in the Phase 3 trials who received the combination treatment showed significant improvements in lung function and other important health measures, compared with those on placebo, and these gains were sustained throughout the 24-week trials.

Both trials tested the same two doses of lumacaftor in combination with ivacaftor. All groups of participants receiving the treatment achieved the trials’ primary endpoint goal of a mean absolute improvement in lung function (measured by FEV1), with a range of 2.6  4 percentage point improvement across the groups.

Those taking the combination treatment also had significant improvements in multiple secondary endpoints, including a mean relative improvement in FEV1 between 4.3 and 6.7 percent; improved weight gain; and significant reductions in the rate of pulmonary exacerbations and associated hospitalizations and IV antibiotic use.

How were the Phase 3 clinical trials conducted?

The two six-month Phase 3 clinical trials studied the combination treatment in people with two copies of the F508del mutation ages 12 and older. In total, more than 1,100 study volunteers participated at nearly 200 clinical trial sites in North America, Europe and Australia.

Both trials tested the same two doses of lumacaftor in combination with ivacaftor. Participants were monitored and given laboratory tests and surveys to measure lung function, body weight and body mass index, hospitalization rates and overall health and quality of life.

The trials were “double-blinded:” neither the participants nor the trial researchers knew which groups received the drug combination and which group received placebo.

Most Phase 3 trials are about one year long. However, the combination trials were completed in about half the time typically required for a Phase 3 trial, following the FDA’s awarding the potential combination treatment “Breakthrough Therapy Designation,” intended to speed the development of select potential therapies that treat life-threatening diseases or conditions.

Will the combination treatment be available to people with CF who are younger than 12 years of age?

The drug combination must be tested in people under age 12 to determine its safety and efficacy in this patient group. Vertex plans to conduct a clinical trial of the combination treatment in people with CF with two copies of the F508del mutation ages 6 to 11 in the first half of 2015.

Why weren’t the results from the Phase 3 combination trials as good as the results from studies of ivacaftor alone in people with G551D?

The potential combination treatment targets a more complex problem in CF than Ivacaftor targets.

Ivacaftor has been approved for people ages 6 and older with the G551D mutation and several closely related mutations. In people with these mutations, the CFTR protein is at its proper place at the cell surface but does not function normally. Instead, it acts like a locked gate. Only one drug is needed to help increase CFTR activity and unlock that gate, allowing the normal flow of salt and fluids that helps thin the thick mucus that builds up in the lungs of people with CF.

In people with the most common CF mutation, F508del, a series of problems prevents the CFTR protein from taking its correct shape and reaching its proper place on the cell surface. Addressing these problems requires a multi-pronged approach that takes place in different parts of the cell. Lumacaftor is designed to help move the defective CFTR protein to the cell surface, while ivacaftor improves its function once it is there.

Is this drug combination a cure for CF?

The combination treatment is not a cure for CF. However, based on the results from the Phase 3 trials in people with two copies of the F508del mutation ages 12 and older, the two drugs in combination have been shown to significantly improve lung function and other important measures of the disease.

The Phase 3 results further validate findings from other late-stage studies that have demonstrated it is possible for an oral drug to improve key symptoms of CF by addressing the defective CFTR protein caused by mutations in the CF gene.

What is the current status of Vertex’s FDA approval application as it stands now?

On Nov. 5, 2014, Vertex Pharmaceuticals Inc. submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of the combination of ivacaftor (Kalydeco™) and the potential therapy lumacaftor (VX-809). The potential combination drug is designed for people with cystic fibrosis ages 12 and older who have two copies of the most common mutation of cystic fibrosis, F508del.

Results from Phase 3 trials of the combination drug showed that people with two copies of the F508del mutation ages 12 and older who received the treatment had significant improvements in lung function and other key measures of the disease.

Both ivacaftor and lumacaftor are designed to treat the underlying cause of CF — a defective protein, called CFTR, caused by mutations in the CF gene.

Vertex has requested a priority review of the combination drug, which, if granted, could shorten the FDA review timeframe from approximately 12 months to 8 months.

Mushrooms cooked in butter, rosemary & lemon

IMG_3911  This is a great one if you can get your child to eat mushrooms. They’re jam packed full of goodness.

In the absence of sunlight or supplements, eating mushrooms is a good way to up your vitamin D levels, and the only vegetarian food source of vitamin D. They are also a good source of B vitamins, which help provide energy by breaking down proteins, fats and carbohydrates, and play a key role in the nervous system.

Simply cook in LOADS of butter and sprinkle a little rosemary on top, saute until soft and delicious.

A good squeeze of lemon is not only a nice flavour addition, it also breaks through the fatty taste which can sometimes be too much on a little palette.

(One thing we’ve noticed is that when we put too much butter or oil in a dish, kids get almost a ‘fatty taste fatigue’ from the taste of fat so we often try to break up the taste with something fresh).