Blog | 8/21/2024

Is There an Optimal Development Pathway for New MDD Therapeutics?

By Noah Rudisill and Michael Davitian

Introduction

Major depressive disorder (MDD), with its large and growing patient population with significant unmet need, is increasingly becoming a focus of therapeutic development. An estimated 29MM patients currently suffer from MDD in the US, and prevalence is expected to continue to grow with increased mental health awareness and new therapeutic options. Despite widespread use of generic antidepressants, the MDD market is forecast to reach upwards of $13B by 2030, driven by new therapies offering improved efficacy to address the significant unmet need in MDD. [1] As pharmaceutical companies have invested in developing novel treatments for MDD, the pipeline has grown to include a robust array of potential therapies. Interestingly, clinical development approaches show a mix of approaches, with some therapies in development as a monotherapy, others as an adjunct treatment, and some being studied as both in separate trials. Each approach provides opportunities and poses challenges with respect to trial feasibility, the ability to demonstrate efficacy, and the translatability to real-world therapeutic use, ultimately impacting physician use and adoption in MDD.

Current MDD Treatment

Pharmacologically treated MDD patients typically start on low-cost generic SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin-norepinephrine reuptake inhibitors), and/or bupropion following diagnosis. However, many patients don’t achieve full symptom relief or may not be able to continue treatment due to side effects including insomnia and sexual dysfunction. Additionally, patients may experience flu-like symptoms or nausea following discontinuation of SSRIs, SNRIs, or tricyclic antidepressants. Up to 30% of all MDD patients require management with additional adjunct therapies and may have treatment-resistant depression, which is defined by the FDA as failing to respond to at least two adequate courses of antidepressant treatment.*[3-7]

This unmet need has created a large market opportunity and driven significant investment in developing new treatments for MDD. Drug developers have created a pipeline with diverse targets and mechanisms of action, such as NMDA receptors, 5HT receptors, and kappa opioid receptors (KOR).

However, therapies that are currently in development will likely be prescribed to MDD patients only after they have failed to respond adequately to one or more lines of generic first-line antidepressants. Payers are unlikely to allow patients to receive higher cost novel medicines before they have tried more cost-effective alternatives. Drug developers, then, must consider how to study and commercialize their drug in these later line populations.

Development Approaches

A key question facing developers is whether they should study their drug as an adjunct to supplement first-line antidepressants or as a monotherapy. Most MDD therapeutics currently in Phase III (75% or 6 of 8 trials) use an adjunct design, while about half (18 of 37 trials) of Phase II programs use a monotherapy approach with the other half pursuing either an adjunct trial (12 of 37 trials) or combination of both adjunct and monotherapy trials (4 of 37 trials).**[2] Companies can consider running a Phase II monotherapy followed by a Phase III adjunct trial, but that approach introduces risk since the Phase II tells you less about how the drug will perform in the Phase III. Also, this approach may complicate regulatory submissions if the sponsor wants to use their Phase II data for their submissions since regulators may object if they perceive the trial populations as different (background antidepressants vs. none).

While some therapeutic mechanisms may lend themselves to an adjunct design, such as atypical antipsychotics, many mechanisms are amenable to either design. And we see that companies frequently vary in their approach. There are several examples where two companies leveraging similar mechanisms have taken different development approaches:

Neumora’s navacaprant and Janssen’s aticaprant are both kappa opioid receptor (KOR) antagonists in Phase III of development, but Neumora is pursuing a monotherapy trial for navacaprant while Janssen is pursuing an adjunct trial for aticaprant. Equity analysts covering the companies speculate that Neumora's monotherapy approach could offer a more distinct data profile compared to Janssen's adjunct approach.[1]
Atai Life Science and Douglas Pharmaceuticals are developing ketamine analogs. Atai is pursuing an adjunct approach for arketamine while Douglas is using a monotherapy approach for R-107. Atai ultimately pursued an adjunct approach for arketamine after it showed similar efficacy in two separate monotherapy and adjunct Phase II trials.[1, 8-9]

The mix of design choices reflects the complex development, regulatory and commercial tradeoffs associated with each design. With respect to development, data generated from a monotherapy trial is more straightforward to interpret and can show efficacy more easily since there are no confounding effects from concomitant use of other antidepressants. In contrast, adjunct trials often enroll patients with partial responses to their current antidepressant treatment, which may result in more modest differences between experimental and comparator trial arms since the background antidepressant is likely providing some efficacy. A monotherapy design may also shorten trial duration, especially for rapid-acting agents. This is because adjunct trials need to wait for patients to fully respond to first-line SSRIs and SNRIs – which may take 6-8 weeks – to observe the additive effect of the study drug. Finally, sponsors of adjunct studies must carefully design and execute their trials to limit the noise created by the variable use of background treatments: firstly, by determining what background therapies are allowed; and secondly, by ensuring patients are on a steady dose of their background medication and remain adherent in the lead-in to the study and throughout the study’s duration.

However, adjunct trials have advantages. Patients may be more willing to enroll in an adjunct trial where they will be guaranteed to receive some form of active treatment (in the form of the background therapy with first-line antidepressants) for their depressive episode, which is undoubtedly clinically significant since they are considering enrolling in a trial. Also, some patients may be reluctant to stop treatment with first-line antidepressants if they are getting a partial effect and/or where they may experience the withdrawal effects described above (e.g., flu-like symptoms or nausea). Finally, adjunct trials are also more representative of real-world use in clinical practice, and efficacy data may be more appealing to physicians.

Label Implications

The decision to pursue an adjunct or monotherapy trial design affects the resulting label for treatment. Therapies trialed as a monotherapy are likely to receive a general and non-specific label for the treatment of MDD. Both Fabre-Kramer’s Exxua, approved September 2023, and Axsome Therapeutics’ Auvelity, approved August 2022, were trialed as monotherapies and received a label for the treatment of MDD without requirements that they be used as monotherapies. In contrast, Johnson and Johnson’s Spravato, approved March 2019, was trialed as an adjunct therapy for TRD and received a label explicitly stating it was indicated for use in combination with another oral antidepressant. Similarly, AbbVie’s Vraylar was trialed as an adjunct therapy for MDD and approved in September 2015 for the adjunctive treatment of MDD. At least from a (US FDA) regulatory perspective, monotherapy trial designs would seem to be more attractive than adjunct trial designs because they provide a broader label. [1, 10-14]

Obviously, drug developers can expand their labels post approval, and this may be an attractive lifecycle management strategy. After establishing a foothold with Spravato as an adjunct, Johnson and Johnson conducted a Phase IV trial evaluating its efficacy as a monotherapy for TRD patients and announced submission to the FDA for approval as a TRD monotherapy in July 2024. Needless to say, for companies that are able to do so, generating data in both monotherapy and adjunctive use cases strengthens the evidence package and improves physician confidence, likely leading to broader use and use earlier in the treatment paradigm. [15]

Commercial Implications

Given the non-specific label, a large share of patients treated with drugs trialed as monotherapies may be treated concomitantly with other antidepressants. In fact, most patients treated with Auvelity use it as an adjunct: a real-world data study of that drug showed 83.7% of patients were prescribed Auvelity in the adjunct setting.[16]

While drugs trialed as monotherapies may be used in combination with other treatments and often are, the data generated from their clinical studies may provide less clarity to physicians on how to use the drug. In cases where the drug is prescribed as an adjunct (which may be most of the time), the clinical data is less relevant and provides less guidance to physicians about more/less effective combinations, how to manage dosing, safety and tolerability issues, etc. As highlighted above, many patients get partial relief from first line generic antidepressants and in these circumstances, physicians may seek to complement their treatment with an adjunct rather than replacing the current medication entirely. In these cases, physicians may prefer treatments where there is greater clarity about their role as adjuncts. This is likely to become increasingly true as the range of treatment options grows with the approval of novel therapies.

A potential implication of this is that drugs trialed as monotherapies may need more robust medical affairs strategies and functions to ensure the company invests in thoughtful post-marketing studies that further elucidate the role of the drug in the treatment paradigm and to provide a large MSL team to support physicians as they make prescribing decisions.

Therapeutics trialed in the adjunct setting may have an additional advantage in future indication expansion and other lifecycle management strategies. Inclusion criteria for adjunct trials in MDD may allow for enrollment of patients on atypical antipsychotics, such as olanzapine, or even lithium, allowing developers to gather preliminary safety and efficacy data in combination with these agents. This may provide a head-start when thinking about combination studies in those indications.

Interestingly, the choice of study design has little impact on payer coverage and management decisions. The main factor influencing formulary placement and utilization management in MDD is the drug price and budget impact. For any high-cost novel MDD therapeutic, payers will likely require failure of two or more antidepressants prior to approving use of the novel treatment. After a novel treatment is permitted, the budget impact of pairing it with a generic is marginal and payers typically don’t manage this aggressively or at all.

Experience from recently launched MDD drugs suggests either development approach can result in commercial success if executed appropriately. Auvelity, trialed as a monotherapy, has shown early signs of commercial success: it is on track to reach ~$300MM in 2024, its second full year following launch. Spravato, trialed as an adjunct for TRD, achieved global sales of $271MM, and is on track to eclipse $1B in annual sales by end of year.[17-18]

Conclusion

Companies seeking to develop and commercialize new MDD therapeutics must consider whether to study their drug as a monotherapy or an adjunct. Since generics are entrenched in the MDD treatment landscape, high-cost, novel medications will be reserved for later-line patients who don’t respond adequately to frontline generics. How these novel treatments are studied among these patients has important development, regulatory and commercial implications, as summarized in the table above. This is not to say that one approach is necessarily better than the other, but rather that this choice results in different opportunities that companies can exploit and risks or disadvantages they should mitigate against. A drug’s launch strategy and competitive positioning, its post-marketing studies and lifecycle management plans, and the commercial and R&D investments needed to enable success will be affected by this development choice. As such, we recommend companies consider this development decision carefully, considering and planning for all its downstream implications.

*The criteria for defining treatment-resistant depression are not uniform and may diverge from the FDA's definition, varying among physicians and clinical trials.

**The trial design of the other Phase II therapies in development is unspecified and not publicly available.

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Noah Rudisill is a Senior Analyst and member of the Biopharma practice at Health Advances.

Michael Davitian is a Partner in our Biopharma practice, where he focuses on building the firm’s expertise in neuroscience and ophthalmology.