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, Ahmed Kotb, MD, discussed findings from a trial investigating navitoclax for the treatment of myelofibrosis. In safety findings from the trial, thrombocytopenia was the most common adverse effect, which was managed through dose reduction.

Q: What were the most common adverse effects and how severe were these?

I think it's important to look at the holistic data set. I think it's important to see the efficacy as well as the safety together. And let's look at the cohort 3. This is the cohort where navitoclax was added to ruxolitinib in the JAK-naive patient population. The primary endpoint, as I mentioned, was SVR35. And here, what we saw was about 63% of the patients achieved this endpoint at the 6-month landmark, as I mentioned, 24 weeks. This is quite unprecedented in this disease area.

What we also saw was that the longer you treated patients, more patients responded. So, we saw best overall response in about 78%. Again, this is very encouraging for us. We have a phase 3 trial that's ongoing, that is looking exactly at that, adding navitoclax-ruxolitinib versus ruxolitinib alone, so we're quite excited to see the outcomes of that study, because we believe this may be practice changing. At the same time, the other endpoints, like total symptom score reduction was about 40%. Again, very encouraging. We also saw that about a third of the patients showed a reduction in the bone marrow fibrosis. And what was very interesting was that irrespective of the amount of fibrosis the patient had at baseline, whether it was a lot of fibrosis or intermediate or a little amount of fibrosis, they had the chance to decrease this bone marrow fibrosis. So that was about 35%. So, that was also quite interesting and gives us the confidence that this agent may be having a disease modification potential.

From a side effect perspective, from an adverse event perspective, the most common adverse event was thrombocytopenia, it occurred in about 80% of the patients. It's an on-target side effect because BCL-XL, which is the target of navitoclax, is highly expressed on thrombocytopenia, thrombocytes, or platelets. So, we expected that it's a predictable and manageable adverse event. We didn't see any clinically meaningful bleeds happen in the study.

Q: How can these adverse effects be managed?

So, so far, we have not really seen that this adverse event has impacted the outcomes of therapy. It's kind of included within the outcomes that I've just mentioned. The way we manage it within the protocol is we do reduce the dose and when it gets to a certain level, we sometimes dose interrupt. We still keep baseline therapy, which is ruxolitinib. It's also important to know that thrombocytopenia is a side effect of both the agents, navitoclax and ruxolitinib, so there is an algorithm of how this is being managed.

Q: Is there anything you would like to add?

No, I think this is very exciting. I think that this is a new mechanism of action in a disease area that has not seen much advances over the last decades. I think we're quite hopeful that this molecule will add options to patients and to physicians. As I mentioned, we have a phase 3 trial, the TRANSFORM-1, which is running in the frontline setting. We also have a phase 3 trial that is running in the relapsed/refractory setting. We're hoping to see data from these studies by end of this year, early next year, and we will use this data to register navitoclax and hopefully bring it to patients in need. This also shows the investment that AbbVie is doing in oncology and the way we're trying to drive innovations across multiple blood cancers. We've obviously done a lot in CLL with venetoclax and IMBRUVICA. We're doing a lot also in AML with venetoclax, and we're expanding our portfolio to touch other blood cancers like lymphomas with epcoritamab, we have exciting data coming at EHA, and also you're going to see data here at ASCO from our solid tumor program. So, it really speaks to the breadth of our oncology portfolio and how we're evolving that.

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Thrombocytopenia was the most common adverse effect, which was managed through dose reduction.

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Manage Adverse Effects Associated With Navitoclax in Patients With Myelofibrosis

 interviewed Zahra Mahmoudjafari, PharmD, BCOP, DPLA; Alison Gulbis, PharmD, BCOP; and Kamakshi Rao, PharmD, BCOP, FASHP, on a 2022 ATOPP Summit session they will be co-presenting addressing research they conducted assessing the underlying causes of the hematology-oncology pharmacist great migration.

 Where are hematology-oncology pharmacists migrating to for the most part?

 Well, that is a great question. That's not something we could pull out from the survey, but speaking from what we know of people going, I'd say a lot of them went into pharmaceutical industry, especially with the increase in CAR-T products and other opportunities out there that were opening up for medical science liaison positions, etc. I think a lot of people have gone to that.

But in addition to that, there have been a lot of other nontraditional pharmacy roles that have opened up that people with clinical expertise really are being recruited for. That includes things like working for insurance companies, as a clinical pharmacist to help with decisions they may have to make with formularies or other access issues patients might have. There's health information technology, tons of people are looking for clinical pharmacists to help with the sector of the electronic health record [(EHR)] and how to build orderable, especially for chemotherapy, etc, and best practices and data mining, and looking at how do you pull data and extract it out of the EHR and bring it back to take care of the patient better.

So those are some nontraditional roles that I think are becoming more appealing to people also, because they're remote positions, for the most part. So I think those will be trends that continue. You may see a more equal shift across different types of positions that might be out there, not just industry.

 I would definitely echo that what we saw in our research, we have to absolutely acknowledge that our colleagues are well-trained and well-positioned to take on these roles, and that the title of clinical pharmacist is evolving.

There's also, to add to what Alison said, opportunities in continuing education, and some of our colleagues have moved onto support those types of roles. So there's no shortage of opportunities, and I have to acknowledge, that doesn't necessarily mean that clinical pharmacists are going to necessarily be in direct patient care roles like we were when we were training.

 Has there been any research conducted looking to assess this migration from the field?

 So there's a lot of research on burnout in health care professionals, and pharmacists get lumped into that in a lot of those surveys that have been done within the past 5 to 10 years. I think that what hasn't been addressed directly in terms of a study is how do you mitigate these migration issues, how do you keep and retain your employees, and how do you come up with ways to show that you appreciate them that you recognize their hard work their doing and that you're willing to give them time to do professional development activities.

There's commentary on that in some publications, but how do you make that go into play and how do you measure if that works to keep employees. That hasn't been research that's been done that I've been able to find.

 Yeah, I would say that was that was the motivation here is that we've had those anecdotal stories, we've heard the commentary, and we've read the opinion papers, but what we really thought was there's power that could be had if we could aggregate that data and start to show that it's not an institutional issue, it's not a regional issue; it's a nationwide professional issue. So that was really the goal when we started was to make sure that every oncology pharmacist in the country had a voice that we could aggregate together to show some power, and I think that's exactly what we saw in the study.

In that survey that we sent out we asked some directed questions around job satisfaction, around how that correlated with a desire to consider alternate careers or changing careers, but then we actually left an open commentary section, and that was the part that I think when we got results, I sent Zarah and Alison an email saying we have a couple of hours or days of reading ahead of us, because people just bared their souls, and it was so powerful to read those words.

As we started to really affinitize that data, it was so clear that it was common themes coming across consistently, so as 3 of us really sat and all 3 of us have read all the comments, we feel really confident that this is a really powerful way of looking at this data as a whole. So ours is just one piece that I would say warrants repetition throughout the pharmacy profession.

Is this migration occurring across the field among hematology-oncology professionals beyond pharmacy, or is it primarily occurring among pharmacists?

 I'd say yes, it is occurring across health care, not just hematology/oncology. I think even beyond health care, when you read articles about the “Great Resignation,” they don't focus just on health care professionals.

It's hard to pinpoint if, like we said earlier, is this because of the pandemic and all the things that occurred with it. Clearly, something has happening for people to notice it and talk about it, whether it be through a commentary in the 

 or other places where they're talking about this, but yeah, I think it's an issue across the board.

It might be that maybe we need to revisit all human professionals or all health care professionals, and are they doing what they should do at the top of their license? Do we need to make sure we're not giving administrative tasks to people who shouldn't be getting certain administrative tasks? Do we need to make sure we're giving protected time to all these people to develop professionally, because professional development is vital in health care in general, to make sure that you're on top of things, and you're in the know, with the new research and that you're networking with people. I think that was a big thing COVID-19 took away from us to networking with people. That's made an impact on how people rethink what they're doing across health care, and is this what they want doing and be in?

What is your outlook on the future for hematology-oncology pharmacy?

 That's a big question because there's a lot of weight behind that answer. But, quite honestly, I've been a hematology/oncology pharmacist for over 20 years now, and I remain optimistic about the impact and the value that hematology/oncology pharmacy professionals and pharmacists can have.

It is so clear the value that we have in helping optimize patient care and collaborating with our other health care providers and professionals to do strong research to teach and to advance care. Those opportunities all exist, and they will continue to grow over time. As all 3 of us are involved heavily in education as well, it's great to see the amount of interest there is in joining this profession and being part of that.

I would say there's a challenge to the profession as well. I think it is going to require local institutions and our profession as a whole to really embark on some very serious cultural change: It's about changing our value proposition and it's about trying to blend the business-minded pharmacy with the idea that we are a people-oriented profession, not just for our patients, but for the people that actually do the work. I think that the evolving focus and the evolving attention around building inclusive work environments is absolutely necessary to be leaned into.

So I think there is a challenge ahead for those that are trying to leave this profession to make it one that continues to be someplace that people choose to join, and maybe more importantly, a place that people choose to stay. I think a lot of people see clinical practice as that first entry point out of postgraduate training, our challenge is going to be how do we get them to see it as a place where they can continue to grow and evolve for a long swath of their career.

 Well, I feel like we've laid a lot out the issues and the problems, but I think there's also strategies to mitigate and make things better. So I don't think we want to leave this all doom and gloom. I think there's great promise for us.

I think from a mitigation and how do we move this in the right direction standpoint, I think it's a couple of things, and I invite my co-authors here to chime in. I think, on one hand, is just recognition that the landscape of opportunity has changed and supporting our people so that every individual has the opportunity to realize their best potential, whether that be within the patient care environment or outside is part of our job to move people into the roles that they best deserve.

I think a lot of times people migrating into roles outside of direct patient care, we've all heard the terms people say, 

‘Oh, they're moving to the dark side of admin or the dark side of industry.’

 Realistically, there are just so many sides, so I am more interested in people finding where they belong versus feeling like they are running from jobs that aren't satisfying and that don't have the right reward ratio.

I think individuals have a responsibility to communicate with their managers and managers have a responsibility to open, vulnerable, and thoughtful conversations with employees so you can understand what each individual is looking for. If we can really engage in getting to know the people who are helping us deliver care, then there's nothing that we can't do and there's nothing that we can't get past.

 Well, I agree, I would say we have an opportunity now. We understand the issue, we understand what it is our team members are asking for, so I think, as practice managers, we have to continue to advocate for, like Kamakshi said, our value, not only within our organizations but within ourselves, but also outside of our departments, with our providers, with our nursing colleagues, etc so they can give support to our pharmacists that are with us and are working day in and day out, trying to make their lives a little bit easier, giving them that time that they need to do the teaching, do the research, supporting them in whatever support means to them. And then recognizing that patient care is extra ordinary, it should not be ordinary, and making sure that they feel valued as well.

We also have an opportunity, as Kamakshi said, to figure out this value metric and apply it to clinical pharmacy in a way that's meaningful and not just institutionally specific, as that's something we definitely have yet to define from a clinical pharmacy standpoint. So I see opportunity to talk about this, and we've looked up the data and now we need to work on the next steps. So we're really looking forward to the discussion in San Diego and presenting the research. It's near and dear to us so it’s a exciting to present it because we've been sitting on it for a little bit and we're really excited to show it off and to really start the discussion with everyone.

Zahra Mahmoudjafari, PharmD, BCOP, DPLA; Alison Gulbis, PharmD, BCOP; and Kamakshi Rao, PharmD, BCOP, FASHP, discuss research conducted looking to assess the hematology-oncology pharmacist “great migration” from the field.

Hematology

® Hematology Resource Center is a comprehensive resource for clinical news and expert insights on the treatment of blood disorders, include blood and bone marrow cancers, anemia, hemophilia, blood-clotting disorders, and leukemia.

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® Pharmacy Technician Clinical Role section is a comprehensive resource for clinical news and expert insights on issues pertaining to hospital and health-system pharmacists.

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Expert: The Great Migration of Hematology, Oncology Pharmacists Brings a Call to Action for the Field

 (Absorica) is an FDA-approved oral dosage form of isotretinoin indicated to treat severe recalcitrant nodular acne. The FDA initially approved this retinoid in 1982 and pharmaceutical firms have marketed it in various dosage forms over the past 40 years.

Although very effective for nodular acne, pharmacists may be aware of oral isotretinoin’s disadvantages. Because isotretinoin is lipophilic, pharmacists have historically needed to counsel patients to take isotretinoin with a full, potentially higher fat meal. First approved in 2012, patients can take this specific lipid-encapsulated formulation without regard to meals.

A double-blind, randomized, parallel group trial confirmed the efficacy of this isotretinoin formulation. Researchers randomized 925 patients 12 years of age and older with severe recalcitrant nodular acne to either lipid-encapsulated isotretinoin or another oral isotretinoin capsule.

All study participants received 0.5 mg/kg/day in 2 divided doses for 4 weeks, followed by 1 mg/kg/day in 2 divided doses for 16 weeks. The researchers screened participants for total nodular lesion count every 4 weeks during the trial.

At week 20, more than 70% of isotretinoin in both groups (70% in the lipid-encapsulated isotretinoin group vs 75% in the comparator group) experienced a 90% reduction in total nodular lesion count from their baseline measurements.

The exact mechanism regarding the treatment of nodular acne is not fully understood. Like other retinoids, isotretinoin generally affects epithelial cells. It exerts dose-dependent inhibition of sebaceous gland function, thereby reducing sebum secretion, which is associated with improvement in nodular acne.

 Isotretinoin may also have additional beneficial effects, inhibiting keratinization and inflammation.

This formulation of isotretinoin is only approved for non-pregnant patients 12 years of age or older. Patients must also have failed to respond to other therapies, including systemic antimicrobials.

Isotretinoin is initially dosed at 0.5 to 1 mg/kg/day in 2 divided doses for most patients. Some patients with severe nodular acne causing scarring or manifesting on the trunk may require treatment with 2 mg/kg/day in 2 divided doses (

This particular form of isotretinoin can be given without regard to meals. Pharmacists should remember to dose based on actual body weight; however, the efficacy study cohort only included patients weighing up to 110 kg.

After a treatment duration of 15 to 20 weeks, prescribers can discontinue lipid-encapsulated isotretinoin if the total nodule count is reduced by at least 70%. A second course of therapy may be initiated but should not be started within 2 months of the previous course.

To avoid esophageal irritation, pharmacists should counsel patients to take their dose with a full glass of liquid. Patients forgetting a dose cannot take an extra dose and should be advised to skip the missed dose.

The most common adverse events (AE) include dry skin, headache, increased creatinine kinase, upper respiratory infection, and reduced visual acuity. These AEs have been reported in 5% or more of patients treated with isotretinoin.

As previously suggested, isotretinoin therapy is associated with significant side effects and toxicities. Isotretinoin includes a boxed warning due to an extremely high risk of embryo-fetal toxicity in pregnant patients and is, therefore, contraindicated in pregnancy.

It is only available through the iPLEDGE risk evaluation and mitigation strategy (REMS) to prevent use in pregnancy. Patients, prescribers, and pharmacies must be certified and registered with the REMS program before treating any patient with isotretinoin.

Providers need to be aware of the risk of psychiatric disturbances, including suicidal ideation, associated with isotretinoin therapy. Pharmacists should counsel patients and caregivers to report changes in the patient’s mood or behavior to their prescribers.

Isotretinoin is contraindicated in patients with a previous allergic reaction to isotretinoin and vitamin A. Due to post-marketing reports of life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), providers need to monitor patients for skin reactions.

Significant increases in triglycerides (>800 mg/dL) can occur in patients taking isotretinoin, and fatal cases of hemorrhagic pancreatitis have been reported. Lipid levels should be drawn at baseline and then periodically during treatment. Providers need to counsel patients to report any potential symptoms of pancreatitis at any time while receiving isotretinoin.

Pharmacists should counsel patients and caregivers to stop isotretinoin and contact the patient’s prescriber if any of these discussed symptoms occur. Due to an increased risk of intracranial hemorrhage with isotretinoin, concurrent tetracycline use should be avoided.

Pharmacists should also be aware of corticosteroids, phenytoin, and isotretinoin interactions. These agents can all potentially cause detrimental effects on musculoskeletal health and prescribers need to discuss concurrent therapy with patients.

Patients need to also avoid progesterone preparation, or “minipills,” as contraception due to inadequate contraceptive potential when given with isotretinoin. Pharmacists need to caution patients against the use of St. John’s Wort because of reports of pregnancies when combined with hormonal contraceptives.

Serious fetal harm, including congenital malformations and spontaneous abortion, can occur after isotretinoin use in pregnancy. Any patient capable of becoming pregnant must follow all iPLEDGE requirements, including 2 confirmed negative CLIA-certified laboratory conducted pregnancy tests. Pregnancy tests must be repeated each month, at the end of isotretinoin treatment, and one month after isotretinoin therapy discontinuation.

Patients who can become pregnant need to use 2 simultaneous forms of contraception for 1 month preceding, during, and 1 month after receiving isotretinoin. If unprotected sex occurs during this time, patients should stop taking isotretinoin and contact their prescriber for further instructions.

If a patient becomes pregnant, isotretinoin must be immediately discontinued. Further follow-up should occur with an OBGYN practitioner. Any fetal exposure to isotretinoin should be reported to FDA MedWatch and the iPLEDGE registry.

Due to potential infant risk, patients should be advised that breastfeeding is not recommended during treatment with isotretinoin and for at least 8 days after the last dose of isotretinoin.

Edmond M Nunes, PharmD, RPh, BCSCP is the pharmacy clinical coordinator at Sturdy Memorial Hospital in Attleboro, MA.

1. Absorica/Absorica LD is prescribing information. November 2019. Accessed May 14, 2022. 

https://www.absoricald.com/pdf/absoricald-prescribing-information.pdf

. 2021;20(5):s3-4. doi: 10.36849/JDD.s0721.

3. Jones M, Armstrong AW, Baldwin H, et al. Advances in oral isotretinoin therapy. 

. 2021;20(5):s5-s11. doi: 10.36849/JDD.s072A.

4. Zaenglein AI, Pathy AI, Sclosser BJ, et al. Guidelines of care for the management of acne vulgaris. 

5. Williams HC, Dellavalle RP, Garner S. Acne vulgaris. 

. 2021;379:361-72. doi: 10.1016/s0140-6736(11)60321-8.

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Isotretinoin exerts dose-dependent inhibition of sebaceous gland function, thereby reducing sebum secretion, which is associated with improvement in nodular acne.

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Clinical Overview: Isotretinoin (Absorica) for Severe Recalcitrant Nodular Acne

 interviewed Ken Thorpe, PhD, professor of public health at Emory University and chairman of Partnership to Fight Chronic Disease, on legislation that the US House of Representatives passed to put greater restrictions on the FDA’s accelerated approval pathway.

. Joining me is Ken Thorpe, a professor of public health at Emory University and a chairman of the Partnership to Fight Chronic Disease. Ken is here to discuss legislation that the US House of Representatives just passed to put greater restrictions on the FDA’s accelerated approval pathway.

So Ken, what is this legislation and what exactly does it restrict?

 Well, it's a piece of legislation that passed the House has yet to pass through the Senate. But in essence, what it’s saying is that it gives the Secretary broad authority to require, prior to approval in the program, that a drug go through a post-approval study. So at least have that setup.

Also it does give the Secretary the flexibility to not require one, and if it's not required, they would have to publish the reason why under the FDA website, given the rationale for it. So it's really just tightening up this process of really the post-approval confirmatory studies.

 You mentioned, just as a follow up, the Secretary—is the Secretary someone within the FDA or someone appointed by legislators?

 No, it would be over at the FDA. So it would be an FDA decision in terms of how this goes. The idea is to really, as the drug is getting approved, that there'd be a methodology laid out, enrollment targets, really the structure of the post-approval study process would have to be sitting there. Then the company, the manufacturer would have to provide some indication of progress within 180 days after the accelerated approval has been okayed.

So I think there was some concern that some of these medications that went through the accelerated approval process or not, on a timely basis, really going through the more formal confirmatory studies, although, again, most of them did, so approximately 80% of the drugs that are approved through the accelerated approval process, ultimately are approved through the traditional FDA evaluation method.

 Does the passing of this legislation in the House result in any immediate action or does that not take place until the Senate makes a decision?

 Yeah, no, there's no immediate action. We're going to have to wait on the Senate to pass their version. This is on the FDA user fee program, so there's some urgency to get it passed by next fiscal year on October 1. But the versions are somewhat different though, on the non-FDA user fee components. So they're going to have to come up with a reconciliation of sorts, to get both of the bills to match up on the language with this accelerated approval process. So no immediate action now.

 Why was the FDA’s accelerated approval pathway developed in the first place, and what have been the results of its development to date?

 Well, it was approved some time ago, really in response to the HIV/AIDS epidemic. At that time, obviously, that was a disease that we really had no treatment options for and the mortality rates, obviously, were very, very high. So the FDA put into place a process that they could get medications and treatments out to HIV/AIDS patients in a much faster time period, just given the seriousness of that illness. So, it has been incredibly successful, particularly for cancer patients and patients with rare diseases.

The process started in 1992, and there's been over 270 treatments that have been approved since then. So, I think the results have been impressive. There's been a reduction in cancer mortality deaths since 1992. Those types of medications, whether they be cancer or rare disease drugs, come to market a little over 3 years faster than they otherwise would. So it's really a critically important part of treating patients that have maybe limited, if no other, treatment options.

 What are the arguments being made by the critics of the FDA is accelerated approval pathway, and is there any validity to these arguments?

 Well, the argument that I hear most frequently is that the process is expensive, and that these medications are costing, particularly Medicaid programs, a lot of money. So we've spent a lot of time looking at that issue, just to see what role accelerated approval drugs play in the Medicaid budget and in the growth of Medicaid spending.

We've gone back to 2007 looking at this, and what we have found is that the growth of accelerated approval drug spending accounts for less than one half of 1% of the growth in Medicaid spending, and in any particular year, they account for less than one half of 1% of the total Medicaid budget. So I think that this criticism and concern of the program is really unfounded, they really don't consider they'll contribute to the growth and level of Medicaid spending.

We know that Medicaid expenditures are driving up because of increased enrollment, but also because they have to provide treatment to really expensive patients, disabled patients, that are eligible for both Medicare and Medicaid. That's where most of the spending is—roughly 40% of the Medicaid budget goes to treating those types of patients. So I think if we're really serious about slowing the growth in Medicaid spending, that we really need to look at what's driving it in the first place and the accelerated approval drugs or not.

 As a follow up question, do you believe or think that the impact of vaccine hesitancy that really emerged as a key problem during the pandemic in terms of vaccine uptake that that might have some role in this decision or this legislation that just passed the House?

 I don't think so. I really do think that a lot of this is coming from unfounded financial concerns, we've seen this from a couple of states that are asking for some flexibility in terms of how much they pay for these medications.

But again, as you look at the data on this, it really is not a driving concern for Medicaid budgets. So I think that, sure, I think it makes some sense to look at the timeline of some of the confirmatory trials post approval. Hopefully, just continue to give flexibility to the FDA to say, well, we really don't need to do this, and here's the reason why. But that's really the major thrust of what the House has passed.

 What are the arguments in support of the continuation of the FDA’s accelerated approval pathway, and do you think that these arguments might be paid a bit more attention in the Senate?

 I hope so. The main benefit is that it saves time and lives, instead of waiting years for an experimental drug to show a primary clinical endpoint, like prolonging the life of a cancer patient. In a clinical trial, this process allows the use of surrogate endpoints like shrinking a tumor, which are associated with extended life, and to get those new treatments to patients faster. Like I said, something on the order of 3 to 3 and a half years faster than otherwise would happen. So I think it's an incredibly important tool for treating patients that have cancer and rare diseases, and as we've seen it has been critically important in the HIV/AIDS world.

 How could this legislation impact the future of drug approvals?

 Again, I don't know that it's going to have a huge impact. Again, as I've mentioned, it's just providing some additional structure on the timing of when the manufacturers have to do the post-approval confirmatory, more traditional studies, and it gives give some guidance in terms of when the study layout has to be outlined. You'd have to provide reports back to the FDA within 180 days post approval just on the progress of what's going on. So I don't think the process will change, it's just more this timing and structure of these confirmatory studies that that have to happen.

 Yeah, I just want to say hopefully that when it's finally done, we don't want to create any uncertainty about drugs’ likely approval; this program has been incredibly successful in getting treatments to patients.

I understand the rationale for putting some more structure on the timing of confirmatory studies, and hopefully, the flexibility the FDA would retain and not requiring them, but we just certainly wouldn't want to raise concern or doubts about a drugs’ likely approval because it really has been such an important program for large number of patients that otherwise may not have other treatment options.

Ken Thorpe, PhD, professor of public health at Emory University and chairman of Partnership to Fight Chronic Disease, discusses legislation that the US House of Representatives recently passed to put greater restrictions on the FDA’s accelerated approval pathway.

Implications of Legislation Passed in the House That Places Restrictions on FDA Accelerated Approval Pathway for Cancer, Rare Disease Drug Pipeline

Novartis announced new data from the phase 3 ASCLEPIOS 1/2 and the ALITHIOS open-label extension showing continuous treatment with ofatumumab (Kesimpta) for relapsing forms of multiple sclerosis (RMS) significantly increased the odds of achieving no evidence of disease activity (NEDA-3) compared to switching from teriflunomide. The data were presented at the European Academy of Neurology Annual Meeting held in Vienna, Austria.

“Early initiation of high-efficacy therapies for the treatment of relapsing multiple sclerosis has been shown to improve long-term outcomes versus escalating from lower efficacy therapies,” Ludwig Kappos from University Hospital Basel, said in a statement. “NEDA-3 is an important endpoint for physicians to consider when deciding to initiate high efficacy therapy, with this latest data from ALITHIOS we can clearly see the benefit of starting [ofatumumab] early versus switching to it later from teriflunomide.”

The data show that after 4 years of treatment, 78.8% of those who continuously received ofatumumab achieved NEDA-3, which was defined as having no MS relapses, no disability worsening, and no MRI activity compared to 51.8% of those who switched from teriflunomide to ofatumumab in the extension phase.

The results build on previously presented efficacy data from both studies, showing sustained differences in cumulative responses, MRI lesion activity, and the risk of disability worsening between patients continuously treated with ofatumumab versus those who were switched at a later date.

Ofatumumab is a targeted treatment that is precisely dosed to deliver B-cell therapy and provides the flexibility of self-administration for adults with RMS. The drug is designed to be delivered subcutaneously via a once-a-month injection.

Ofatumumab is currently approved for treatment of RMS in the United States, European Union, United Kingdom, Canada, China, Switzerland, Singapore, Australia, Japan, Argentina, United Arab Emirates, Albania, and India.

According to the Mayo Clinic, MS is a disabling disease of the central nervous system, including the brain and the spinal cord. The cause of MS is unknown, and it is considered an autoimmune disease in which the body’s immune system attacks its own tissues. The immune system malfunction destroys the fatty substances that coats protective nerve fibers.

Individuals with MS can experience muscle stiffness, muscle spasms, paralysis, problems with bladder, bowel, or sexual functions, mental changes, depression, and epilepsy.

New Novartis extension phase data show nearly 80% of RMS patients treated with Kesimpta (ofatumumab) had no evidence of disease activity (NEDA-3). Novartis. News release. June 27, 2022. Accessed June 29, 2022. https://www.novartis.com/news/media-releases/new-novartis-extension-phase-data-show-nearly-80-rms-patients-treated-kesimpta-ofatumumab-had-no-evidence-disease-activity-neda-3

Mayo Clinic. Multiple sclerosis. Updated January 7, 2022. Accessed June 29, 2022. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269

After 4 years of treatment with ofatumumab, 78.8% of patients with relapsing forms of multiple sclerosis who continuously received ofatumumab achieved NEDA-3 compared to 51.8% of those who switched from teriflunomide to ofatumumab.

Neurology

Ofatumumab Shows Long-Term Improvements in Multiple Sclerosis Disease Activity 

The FDA has granted priority review to a Biologics License Application (BLA) for mosunetuzumab (Genentech) for the treatment of adults with relapsed or refractory (R/R) follicular lymphoma (FL) who were previously administered at least 2 systemic therapies.

The FDA is expected to make a decision on the potential first-in-class CD20xCD3 T-cell engaging, fully humanized immunoglobulin G1 bispecific antibody immunotherapy by December 29, 2022, according to Genentech. FL is the most common indolent form of non-Hodgkin lymphoma (NHL), which often recurs following initial therapy, with periods of remission and relapse. An estimated 13,000 new cases of FL will be diagnosed in the United States in 2022.

“New therapeutic options are needed for follicular lymphoma, which often relapses after initial therapy and becomes increasingly difficult to treat each time it returns. Clinical trial results have demonstrated durable responses with mosunetuzumab in advanced follicular lymphoma, representing a step toward shifting the treatment paradigm,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, in a press release. “Since mosunetuzumab does not require the collection or genetic modification of patient cells, it could become an effective, fixed-duration outpatient option without the barriers of travelling to a major academic center.”

The BLA submission followed positive results from the phase 1/2 GO29781 study, in which mosunetuzumab showed high complete response (CR) rates, as most responders (57% [95% CI: 49-70]) maintained their responses for at least 18 months, with manageable tolerability in patients with heavily pretreated FL.

At a median follow-up of 18.3 months, the CR rate was 60% (n=54/90), the objective response rate was 80% (n=72/90), and the median duration of response among patients who responded to treatment was 22.8 months (95% CI: 9.7-not estimable).

The most common adverse event was cytokine release syndrome (39%; n=86/218)—which was typically low grade (grade 1: 25.6%; grade 2: 14%; grade 3: 2.3%; grade 4: 0.5%), and all of which resolved—followed by (>20%) fatigue, headache, neutropenia, fever, and hypophosphatemia.

Mosunetuzumab was previously awarded FDA Breakthrough Therapy Designation in June 2020 for adults with R/R FL previously administered at least 2 systemic therapies, as well as Orphan Drug Designation in December 2018.

Mosunetuzumab is designed to target CD20 on the surface of B cells and CD3 on the surface of T cells, which activates and redirects T cells to engage and kill target B cells by releasing cytotoxic proteins into the B cells. Mosunetuzumab is being investigated as a monotherapy and in combination with other medicines, for the treatment of B-cell non-Hodgkin lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma, and other blood cancers.

FDA Grants Priority Review to Genentech’s Mosunetuzumab for People with Relapsed or Refractory Follicular Lymphoma. Genentech. News release. July 6, 2022. 

https://www.gene.com/media/press-releases/14958/2022-07-05/fda-grants-priority-review-to-genentechs

Clinical trial results show durable responses with mosunetuzumab in advanced follicular lymphoma.

Lymphoma

® Lymphoma Resource Center is a comprehensive resource for clinical news and expert insights on treatments for lymphoma, a cancer that begins in cells of the lymph system. Common treatments for lymphoma may involve chemotherapy, medication, radiation therapy, and stem cell transplant.

FDA Grants Priority Review to Mosunetuzumab for Relapsed or Refractory Follicular Lymphoma

Gilead Sciences announced the resubmission of a new drug application (NDA) to the FDA for lenacapavir for the treatment of HIV-1 infection in heavily treatment-experienced individuals with multi-drug resistant HIV-1 infection.

 is an investigational, long-acting HIV-1 capsid inhibitor that has yet to be approved by any regulatory authority for any use and its safety and efficacy are not established.

"There are [individuals] with HIV who have severely limited treatment options due to resistance to multiple antiretroviral therapy classes," Jared Baeten, MD, PhD, vice president of HIV Clinical Development at Gilead Sciences, said in a statement. "We are committed to addressing unmet needs and recognize the urgency for filling the critical treatment gap for people with multi-drug resistant HIV whose virus is no longer effectively responding to their current therapy."

Gilead resubmitted the NDA in response to the FDA 

 (CRL) issued in February 2022, which cited chemistry manufacturing and control (CMC) issues relating to the compatibility of lenacapavir in borosilicate vials as the reason for the FDA action.

In December 2021, the FDA placed a clinical hold on lenacapavir in borosilicate vials in all clinical studies because of emerging concerns about the compatibility of vials made of borosilicate glass with lenacapavir solution. This compatibility issue could potentially cause the formation of sub-visible glass particles in the solution of lenacapavir, according to the FDA.

In May, the FDA lifted a clinical hold placed on injectable 

 treatment and pre-exposure prophylaxis. However, oral formulation dosing of lenacapavir continued according to the relevant study protocol as the FDA evaluated corresponding data on the storage and compatibility of lenacapavir injection with an alternative vial made from aluminosilicate glass.

The NDA resubmission contains comprehensive CMC data to support the compatibility of the drug with an alternative vial type made from aluminosilicate glass.

Additionally, the NDA is supported by extensive pre-clinical and earlier clinical research data, as well as data from the phase 2/3 CAPELLA study. The CAPELLA study evaluated the antiviral activity of lenacapavir administered every 6 months as a subcutaneous injection, in combination with other antiretrovirals in individuals with multi resistant HIV-1 infection.

Once excepted by the FDA, a new PDUFA will be established for lenacapavir.

The original NDA was submitted to the FDA in June 2021 and selected for priority review due to the significant unmet need for this population. The submission was also supported by data from the CAPELLA trial.

The clinical data on lenacapavir were also presented at the 29th Conference on Retroviruses and Opportunistic Infections (Virtual CROI 2022).

The week 52 findings from the CAPELLA trial demonstrated that lenacapavir, which was administered subcutaneously every 6 months in combination with other antiretrovirals, achieved high rates of virologic suppression and clinically meaningful increases in CD4 counts in individuals living with HIV whose virus was no longer effectively responding to their current therapy.

The most common adverse events that were observed in the CAPELLA study were injection site reactions, nausea, diarrhea, and COVID-19.

Gilead resubmits new drug application to US Food and Drug Administration for lenacapavir, an investigational, long-acting HIV-1 capsid inhibitor. Gilead. News release. June 27, 2022. Accessed June 30, 2022. https://www.gilead.com/news-and-press/press-room/press-releases/2022/6/gilead-resubmits-new-drug-application-to-us-food-and-drug-administration-for-lenacapavir-an-investigational-longacting-hiv1-capsid-inhibitor

Gilead receives complete response letter from US FDA for investigational lenacapavir due to vial compatibility issues. Gilead. News release. March 1, 2022. Accessed June 30, 2022. https://www.gilead.com/news-and-press/press-room/press-releases/2022/3/gilead-receives-complete-response-letter-from-us-fda-for-investigational-lenacapavir-due-to-vial-compatibility-issues

Lenacapavir is an investigational, long-acting HIV-1 capsid inhibitor that is not yet approved by any regulatory authority.

® HIV Resource Center is a comprehensive resource for clinical news and expert insights on the treatment of HIV, a virus that attacks the body's immune system and, if left untreated, can lead to AIDS.

PrEP

Gilead Resubmits NDA for Lenacapavir, Updates Based on FDA Complete Response Letter

Jazz Pharmaceuticals has announced top-line results from the phase 3 RELEASE MSS1 trial, evaluating nabiximols oromucosal spray (JZP378, or Sativex) on clinical measures of spasticity in individuals with multiple sclerosis (MS).

The RELEASE MSS1 trial did not meet the primary endpoint of change in Lower Limb Muscle Tone-6 (LLMT-6) between baseline and day 21, measured by the Modified Ashworth Scale (MAS). The secondary endpoints of the RELEASE MSS1 trial were changes to the LLMT-4 defined by the MAS, safety, and tolerability of nabiximols oromucosal spray in individuals with MS spasticity.

"We remain committed to the nabiximols program and are actively assessing the RELEASE MSS1 trial results, which will be presented at a future medical meeting. We look forward to additional data from 2 other ongoing trials that have the potential to support a US FDA New Drug Application submission," Rob Iannone, MD, MSCE, executive vice president of global head of research and development at Jazz Pharmaceuticals, said in a statement.

Nabiximols oromucosal spray is a botanical mixture from extracts of cannabis sativa plants, cannabinoids delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as other cannabinoid and non-cannabinoid components. First approved in the United Kingdom in 2010, nabiximols oromucosal has been approved in 29 countries for the treatment of individuals with moderate to severe spasticity due to MS who have not responded adequately to other anti-spasticity medication based on previously completed clinical trials.

The study, the first and smallest of 3 clinical trials in the program, aimed to evaluate the safety and efficacy of nabiximols oromucosal spray in 68 individuals with MS spasticity.

Individuals in the RELEASE MSS1 trial were over 18 years of age with a confirmed diagnosis of any disease subtype of MS for at least 12 months prior to first visit, were expected to remain stable for the duration of the trial, and who experienced spasticity not relieved by their current anti-spasticity medications.

The individuals were randomized in a 1:1 ratio to 1 of 2 sequences comprised of treatment with nabiximols oromucosal spray and the placebo. The data from these trials will be evaluated as it become available and to support the overall registrational program in the United States.

The 2 additional phase 3 trials will complement and inform a comprehensive development plan. In RELEASE MSS3, investigators will evaluate the efficacy of the spray compared to the placebo when added to the standard of care for the improvement of muscle spasms associated with MS over a 12-week treatment period in an estimated 446 individuals.

In RELEASE MSS5, investigators plan to evaluate the effect of multiple doses of nabiximols oromucosal spray compared to the placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs in individuals with MS over a 3-week treatment period in an estimated 190 individuals.

The safety profile in RELEASE MSS1 was consistent with previously reported adverse events and there were no new safety signals in this population.

Jazz Pharmaceuticals announces top-line results from phase 3 trial evaluating nabiximols oromucosal spray in adult participants with multiple sclerosis spasticity. Jazz Pharmaceuticals. News release. June 28, 2022. Accessed June 30, 2022. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-top-line-results-phase-3-trial

Jazz Pharmaceuticals announced top-line results from the phase 3 RELEASE MSS1 trial, evaluating nabiximols oromucosal spray in individuals with multiple sclerosis.

Sativex Does Not Meet Primary Endpoint on Measures of Spasticity for Multiple Sclerosis

 Pravastatin sodium (Pravachol) is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to lower the risk of myocardial infarction, revascularization, and cardiovascular mortality in hypercholesterolemic patients without clinically evident congenital heart disease.

 For adults, the recommended starting dose is 40 mg once daily. Use 80 mg dose only for patients not reaching LDL-C goal with 40 mg. For significant renal impairment, the recommended starting dose is 10 mg once daily.

In short-term clinical trials, the most commonly reported adverse reactions (≥2% and > placebo) regardless of causality were musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache.

: Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C.

Pravastatin sodium (Pravachol) is indicated as an adjunctive therapy to diet to lower the risk of myocardial infarction, revascularization, and cardiovascular mortality in hypercholesterolemic patients without clinically evident congenital heart disease.

Heart Failure

® Heart Failure Resource Center is a comprehensive resource for clinical news and expert insights on treatments that address issues caused by the heart muscle not pumping blood as well as it should. 

Daily Medication Pearl: Pravastatin Sodium (Pravachol)

OTC/Lifestyle Pearl of the Day: Legatrin PM

: Legatrin PM is intended for relief of lower body pain.

 Acetaminophen (500 mg), diphenhydramine HCl (50 mg). Inactive ingredients: croscarmellose sodium, D&C red No. 27 lake, dicalcium phosphate, FD&C blue no. 1 lake, FD&C red no. 40 lake, FD&C yellow no. 6 lake, hydroxypropyl methylcellulose, magnesium silicate, magnesium stearate, microcrystalline cellulose, mineral oil, polyethylene glycol, stearic acid, titanium dioxide.

: Adults and children 12 years of age and older: 1 caplet at bedtime or as directed by a physician. Do not give to children under the age of 12 years unless directed by your physician. Do not exceed recommended dosage. Store at room temperature.

Consult a physician before use if you have glaucoma; breathing problems such as asthma, emphysema, chronic bronchitis or pulmonary disease; trouble urinating due to an enlarged prostate gland.

Legatrin PM is intended for relief of lower body pain.

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